Rapid diagnosis of influenza A and B by 24-h fluorescent focus assays.
Murine monoclonal antibodies directed against type-specific antigens of influenza A and B viruses have been shown to be useful diagnostic reagents for the detection of influenza viruses by immunofluorescence testing of nasopharyngeal cells. We have developed fluorescent focus assays utilizing these antibodies in cell culture chamber slides and shell vials for the rapid diagnosis of influenza A and B. Chamber slide assays were compared with virus isolation in 160 specimens from 135 patients with symptoms of influenza. Virus isolation was compared with immunofluorescence testing in 38 of the 160 specimens. Compared with virus isolation, 24-h cell culture chamber slide assays had a sensitivity of 75% and a specificity of 96%. Immunofluorescence testing of nasopharyngeal cells was only 38% sensitive and 91% specific. Shell vial assays were compared with virus isolation for 89 specimens. At 16 to 18 h postinoculation, the shell vial assay was 84% sensitive and 100% specific. We conclude that both chamber slide and shell vial assays are rapid, sensitive, and specific techniques for the diagnosis of influenza.


The management of reduced fetal movements in an uncomplicated pregnancy at term: results from an anonymous national online survey in the Republic of Ireland.
There is currently inconsistent evidence and clinical guidance on how to best manage a pregnancy complicated by reduced fetal movements. This novel, web-based, anonymous questionnaire evaluated 96 assessment and management approaches from doctors working in obstetrics in the Republic of Ireland who were presented with a clinical scenario of a primigravida concerned about reduced fetal movements at 39+3 weeks' gestation. This study identified a lack of clinical practice guidelines available in maternity hospitals in the Republic of Ireland. We demonstrated that almost all clinicians applied more than one assessment method and that most incorporated a cardiotocograph into their assessment. There was a low uptake of simple symphysio-fundal height measurement and high usage of kickcharts. The minority of clinicians admitted or induced their patients. This survey identified the need for national and international guidelines to ensure safe antepartum care and delivery.


Airway mast cells in a rhesus model of childhood allergic airways disease.
Asthma is a leading cause of morbidity in children. Risk factors include chronic exposure to allergens and air pollution. While chronically activated mast cells contribute to the pathophysiology of asthma in part through their proteases such as chymase and tryptase, previous studies of airway mast cell abundance and distribution in asthmatics have been inconsistent. To determine whether repeated episodic exposures to environmental pollutants during postnatal lung development alter airway mast cell abundance and distribution, we exposed infant rhesus monkeys to a known human allergen, house dust mite antigen (HDMA), and/or a known environmental pollutant, ozone (O(3)), and quantitatively compared the abundance of tryptase- or chymase-positive mast cells in three airway levels. Mast cells are resident in multiple compartments of the airway wall in infant rhesus monkeys raised from birth in filtered air. Tryptase- and chymase-positive cells were most abundant in trachea and least in terminal bronchioles. The majority of tryptase-positive and almost all chymase-positive cells were in extracellular matrix and smooth muscle bundles. Chronic exposure to HDMA elevated the abundance of both tryptase- and chymase-positive cells in the trachea and intrapulmonary bronchi. Neither exposure to O(3) nor HDMA + O(3) increased mast cell accumulations in the airway wall. We conclude that during postnatal airway development (1) mast cells are a resident airway cell population even in the absence of toxic air contaminants; (2) aeroallergen exposure alters large airway mast cell distribution and abundance, increasing chymase-positive mast cells; and (3) this response is attenuated by exposure to oxidant air pollutants.


Early changes in the hypothalamic region in prodromal Huntington disease revealed by MRI analysis.
Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat. Its length can be used to estimate the time of clinical diagnosis, which is defined by overt motor symptoms. Non-motor symptoms begin before motor onset, and involve changes in hypothalamus-regulated functions such as sleep, emotion and metabolism. Therefore we hypothesized that hypothalamic changes occur already prior to the clinical diagnosis. We performed voxel-based morphometry and logistic regression analyses of cross-sectional MR images from 220 HD gene carriers and 75 controls in the Predict-HD study. We show that changes in the hypothalamic region are detectable before clinical diagnosis and that its grey matter contents alone are sufficient to distinguish HD gene carriers from control cases. In conclusion, our study shows, for the first time, that alterations in grey matter contents in the hypothalamic region occur at least a decade before clinical diagnosis in HD using MRI.


Targets of octopamine action in the lobster: cyclic nucleotide changes and physiological effects in hemolymph, heart and exoskeletal muscle.
We have examined three potential targets of octopamine action of the lobster--hemolymph, heart and exoskeletal muscle--and found that each tissue responds to the amine with increases in cyclic adenosine 3': 5'-monophosphate (cAMP) and changes in measurable physiological phenomena. A highly specific octopamine-stimulated increase in cAMP is observed in hemolymph, and this effect is probably due to the presence of a unique octopamine receptor on hematocytes. Pharmacological studies show that synephrine is a potent agonist of the hemolymph receptor for octopamine and that the alpha adrenergic receptor blockers phentolamine and dibenamine and the dopamine receptor blocker, chlorpromazine, are antagonists. Addition of octopamine to lobster hemolymph increases the rate of changes the nature of the clotting reaction. AMP levels in lobster heart are elevated by both octopamine and serotonin. Both amines also increase the rate and the amplitude of the heart beat. Octopamine, serotonin and dopamine all increase cAMP levels in lobster exoskeletal muscle preparations, and each amine causes changes in muscle tension and the strength of nerve evoked contractions. In none of the tissues studied have we been able to establish a direct relationship between amine-stimulated increases in cAMP levels and the physiological responses.


Assessing Renal Microvascular Reactivity by Laser Speckle-Contrast Imaging in Angiotensin-II-Treated Mice.
The kidney is one of the main organs affected by microvascular damage wrought by hypertension. We developed an approach to investigate renal microcirculatory disturbance in live mice by measuring post-occlusive reactive hyperemia (PORH), a reactivity test exploring endothelial and neuro-microvascular functioning. Laser speckle-contrast analysis (LASCA) assesses microvascular blood flow; it provides real-time images of spatial and temporal blood flow dynamics. We compared basal blood flow and PORH test between control and angiotensin-II-treated mice (Ang-II) to validate the model. The study objective was to develop an approach to investigate renal microcirculation, and then to compare microvascular reactivity assessed on LASCA in control versus Ang-II mice. Thirty 7-week-old wild-type C57BL/6J mice were allocated into two groups. One received angiotensin-II via osmotic minipumps (Ang-II; n=15); the other served as control (n=15). Basal blood flow was measured on LASCA. The PORH test was then performed in the two groups. Control mice had significantly lower basal renal microcirculatory flow, expressed in perfusion units (PU), than Ang-II-treated mice (1448 ± 96 vs 1703 ± 185 PU, respectively; P < 0.05). Peak flow was lower in controls than in Ang-II mice (1617±104 vs.1724 ± 205 PU, respectively; P=0.21). Control mice had significantly higher kidney PORH than Ang-II mice (8±3 vs 1±4%, respectively; P < 0.05). We developed an innovative technique to study renal microcirculation in mice. Ang-II-treated mice showed significantly higher basal blood flow than controls, while PORH was significantly higher in controls than in Ang-II mice.


An evaluation of validity, reliability, and readability of the Critical Care Family Needs Inventory.
The benefits of caring for the family as well as the patient are well supported in the literature. The Critical Care Family Needs Inventory (CCFNI) has been used by several researchers to identify the needs of family members when a relative is admitted to a critical care setting. However, no research to date has comprehensively evaluated the instrument's content validity, test--retest reliability, or readability. The CCFNI, after review by a panel of 16 experts, was given on two separate occasions to a random sample of 51 family members of adult patients in both medical and surgical intensive care units. Overall content validity was established, but the panel found numerous redundancies among the need statements, suggesting that several items might need to be eliminated or combined. Among family members, a percentage of exact agreement of 70% or greater was calculated for 86.7% of the need statements demonstrating acceptable test--retest reliability. The Gunning Fog Index, used to evaluate readability, was calculated at 9.0, indicating that the CCFNI could be read and understood by those with a ninth grade reading level. Suggestions are made for additional studies to establish the reliability and validity of this widely used instrument.


MicroRNA-424 regulates the expression of CX3CL1 (fractalkine) in human microvascular endothelial cells during Rickettsia rickettsii infection.
Cytokines and chemokines trigger complex intracellular signaling through specific receptors to mediate immune cell recruitment and activation at the sites of infection. CX3CL1 (Fractalkine), a membrane-bound chemokine also capable of facilitating intercellular interactions as an adhesion molecule, contributes to host immune responses by virtue of its chemoattractant functions. Published studies have documented increased CX3CL1 expression in target tissues in a murine model of spotted fever rickettsiosis temporally corresponding to infiltration of macrophages and recovery from infection. Because pathogenic rickettsiae primarily target vascular endothelium in the mammalian hosts, we have now determined CX3CL1 mRNA and protein expression in cultured human microvascular endothelial cells (HMECs) infected in vitro with Rickettsia rickettsii. Our findings reveal 15.5 ± 4.0-fold and 12.3 ± 2.3-fold increase in Cx3cl1 mRNA expression at 3 h and 24 h post-infection, coinciding with higher steady-state levels of the corresponding protein in comparison to uninfected HMECs. Since CX3CL1 is a validated target of microRNA (miR)-424-5p (miR-424) and our earlier findings demonstrated robust down-regulation of miR-424 in R. rickettsii-infected HMECs, we further explored the possibility of regulation of CX3CL1 expression during rickettsial infection by miR-424. As expected, R. rickettsii infection resulted in 87 ± 5% reduction in miR-424 expression in host HMECs. Interestingly, a miR-424 mimic downregulated R. rickettsii-induced expression of CX3CL1, whereas an inhibitor of miR-424 yielded a converse up-regulatory effect, suggesting miR-424-mediated regulation of CX3CL1 during infection. Together, these findings provide the first evidence for the roles of a host microRNA in the regulation of an important bifunctional chemokine governing innate immune responses to pathogenic rickettsiae.


Does dynamic hyperinflation contribute to dyspnoea during exercise in patients with COPD?
Dynamic hyperinflation (DH) during exercise occurs in most but not all patients with advanced chronic obstructive pulmonary disease (COPD). It is not known whether the presence or absence of DH has implications for dyspnoea and exercise tolerance. Therefore, we compared detailed ventilatory and sensory responses to exercise in hyperinflators and nonhyperinflators with moderate-to-severe COPD. Nonhyperinflators (n=65) were retrospectively identified from a sample of 427 patients and case-matched to a group of hyperinflators (n=65) based on sex, age, body mass index and % predicted forced expiratory volume in 1 s. Resting pulmonary function and constant work rate cycle exercise responses were compared. Hyperinflators decreased inspiratory capacity (IC) from rest to peak exercise by 0.46±0.24 L whereas the nonhyperinflators increased IC by 0.10±0.15 L (p<0.0001). There were no significant group differences in endurance time (9.11±5.98 versus 8.87±5.24 min) or dyspnoea intensity for any given time or ventilation. An inflection in tidal volume versus ventilation occurred in the majority of nonhyperinflators (n=61) and hyperinflators (n=62) at a similar time and ventilation. Mechanical constraints on tidal volume expansion and the attendant rise in dyspnoea intensity were similar in both groups. Dyspnoea intensity during exercise was associated with progressive mechanical constraints on tidal volume expansion regardless of the presence of DH.


Variation transmission model for setting acceptance criteria in a multi-staged pharmaceutical manufacturing process.
Pharmaceutical manufacturing processes consist of a series of stages (e.g., reaction, workup, isolation) to generate the active pharmaceutical ingredient (API). Outputs at intermediate stages (in-process control) and API need to be controlled within acceptance criteria to assure final drug product quality. In this paper, two methods based on tolerance interval to derive such acceptance criteria will be evaluated. The first method is serial worst case (SWC), an industry risk minimization strategy, wherein input materials and process parameters of a stage are fixed at their worst-case settings to calculate the maximum level expected from the stage. This maximum output then becomes input to the next stage wherein process parameters are again fixed at worst-case setting. The procedure is serially repeated throughout the process until the final stage. The calculated limits using SWC can be artificially high and may not reflect the actual process performance. The second method is the variation transmission (VT) using autoregressive model, wherein variation transmitted up to a stage is estimated by accounting for the recursive structure of the errors at each stage. Computer simulations at varying extent of variation transmission and process stage variability are performed. For the scenarios tested, VT method is demonstrated to better maintain the simulated confidence level and more precisely estimate the true proportion parameter than SWC. Real data examples are also presented that corroborate the findings from the simulation. Overall, VT is recommended for setting acceptance criteria in a multi-staged pharmaceutical manufacturing process.


Scanning electron microscopy of ciliae and saccharine test for ciliary function in septal deviations.
To investigate the difference in mucociliary clearance and surface mucosal structure of the nasal septum and lateral nasal wall in patients with and without septal deviation. The saccharine-dye test was used to measure the mucociliary clearance time in both nasal cavities of 20 patients with nasal septal deviation (study group) and was compared with that of 30 patients without septal deviation (control group). Bilateral septal and lateral nasal wall mucosal biopsies were taken from the study group during septoplasty, and unilateral biopsies were taken from 10 of the control group. These biopsies were studied under the scanning electron microscope. In the study group, mucociliary clearance on the side opposite the septal deviation was significantly slower than on the other side. Mucociliary clearance on both sides of the deviated septum of the study group was significantly slower than clearance in the control group. There was no statistically significant difference in the distribution of mucosal cilia of the cavities on either side of the deviated septum in the study group, nor between the distribution in the study group and controls. Patients with septal deviation display no change in mucosal surface anatomy but have decreased mucociliary activity on both sides of the deviation, the least activity being on the side opposite the deviation.


[Non-specific adaptation reactions in burns and their correction].
The burn disease influence on the adaptational reactions of the organism was studied up in 192 injured persons. The stress-reaction was suggested the most unfavorable for the prognosis. The severity of pathological reactions is lowering, correlating with the complications occurrence frequency, while simultaneous application of conventional methods of treatment with combined detoxication and nonmedicinal immunomodulation.


Quantitative analysis of the diffusion-weighted steady-state free precession signal in vertebral bone marrow lesions.
: Diffusion-weighted steady-state free precession (DW-SSFP) sequences have shown great potential for the differential diagnosis of benign osteoporotic and malignant neoplastic vertebral compression fractures, which appear hypo- to isointense or hyperintense in DW-SSFP magnetic resonance imaging, respectively. In contrast to other diffusion weighting sequences, the DW-SSFP signal depends not only on the apparent diffusion coefficient (ADC), but also on the tissue relaxation times and sequence parameters. The purpose of the present study was to provide a detailed analysis of the DW-SSFP signal in benign and malignant vertebral lesions (VLs) and in vertebral bone marrow (VBM) to understand the observed signal alterations and their dependence on tissue and sequence parameters. : Magnetic resonance imaging was performed in 40 patients with benign (n = 20) or malignant (n = 20) VLs to determine the fat fraction and tissue parameters (ADC, T1, T2, T2*) for both the water and fat signal. With these values, the DW-SSFP signal was simulated and compared with the measured signals for different diffusion gradients by determining the signal intensity ratio between the SSFP signals of the lesions and of normal-appearing VBM for both malignant and benign VLs. : The simulated DW-SSFP contrast agreed well with the measured contrast and provided a very good differentiation between benign osteoporotic and malignant VLs. ADCs were significantly different in both lesion types (malignant 1.36 vs. osteoporotic 1.77 × 10 mm/s); however, the observed contrast differences were caused predominantly by an opposed-phase readout in combination with significantly different T2* values (malignant 22 vs. osteoporotic 14 ms) and fat fractions (malignant 3.9% vs. osteoporotic 12%) in the lesions as well as significantly different fat fractions in normal-appearing VBM (malignant 42% vs. osteoporotic 52%) of both patient groups. : Although the ADCs of the evaluated malignant and benign VLs showed highly significant differences, the influence of diffusion on the DW-SSFP signal contrast is relatively low compared with other tissue parameters due to the very complex signal mechanism of the SSFP sequence. Thus, the observed DW-SSFP signal contrast of different VLs (hypo-/isointense vs. hyperintense signal) is rather fat- and T2*-weighted than diffusion-weighted. The intermediate diffusion weighting of the applied SSFP sequence, however, helps to shift the different contrasts into a signal range that is easily visually accessible.


USB Storage Device Forensics for Windows 10.
Significantly increased use of USB devices due to their user-friendliness and large storage capacities poses various threats for many users/companies in terms of data theft that becomes easier due to their efficient mobility. Investigations for such data theft activities would require gathering critical digital information capable of recovering digital forensics artifacts like date, time, and device information. This research gathers three sets of registry and logs data: first, before insertion; second, during insertion; and the third, after removal of a USB device. These sets are analyzed to gather evidentiary information from Registry and Windows Event log that helps in tracking a USB device. This research furthers the prior research on earlier versions of Microsoft Windows and compares it with latest Windows 10 system. Comparison of Windows 8 and Windows 10 does not show much difference except for new subkey under USB Key in registry. However, comparison of Windows 7 with latest version indicates significant variances.


Protective effect of N-(E)-p-coumaroyltyrosine on LPS-induced acute inflammatory injury and signaling pathway analysis.
N-trans-p-coumaroyltyrosine (N-(E)-p-coumaroyltyrosine, NPCT), extracted and purified from Abri Mollis Herba, is an amino acid amide. The defense mechanism of NPCT against inflammatory response is still unknown. In this study, lipopolysaccharide (LPS)-induced zebrafish acute inflammatory injury model was established to observe the inhibitory effect of NPCT on the aggregation of inflammatory cells in the yolk sac of zebrafish, as well as the inhibitory effect of NPCT on inflammatory and gas signaling factors. Results show that NPCT could inhibit inflammatory cell infiltration in zebrafish yolk sac, the migration and aggregation of macrophages and neutrophils to the site of inflammation, and the release of Nitric Oxide (NO) and Reactive Oxygen Species (ROS) in zebrafish, indicating that NPCT could substantially significantly prevent the development of LPS-induced acute systemic inflammation. In addition, the analysis results of RNA-seq showed that in the model group versus the administered group, the differentially expressed genes were mainly enriched to inflammatory signaling pathways, such as the NOD-like receptor signaling pathway and Toll-like receptor signaling pathway, which were down-regulated in the administered group. The TLR4, MyD88, IRAK4, NF-κB, IκB, NLRP3, Caspase-1, ASC, IL-1β, and IL-6 genes were significantly different in the transcripts, and the overall trend of the qPCR results was consistent with the transcriptome sequencing results. Therefore, NPCT had a significant inhibitory effect on LPS-induced acute inflammatory injury in zebrafish, and its anti-inflammatory mechanism may be through the regulation of key genes on the NOD-like receptor signaling pathway and Toll-like receptor signaling pathway, thereby affecting the release of relevant inflammatory cytokines.


Anticoagulants in atrial fibrillation patients with chronic kidney disease.
Atrial fibrillation is an important cause of preventable, disabling stroke and is particularly frequent in patients with chronic kidney disease (CKD). Stage 3 CKD is an independent risk factor for stroke in patients with atrial fibrillation. Warfarin anticoagulation is efficacious for stroke prevention in atrial fibrillation patients with stage 3 CKD, but recent observational studies have challenged its value for patients with end-stage renal disease and atrial fibrillation. Novel oral anticoagulants such as dabigatran, apixaban and rivaroxaban are at least as efficacious as warfarin with reduced risks of intracranial haemorrhage. However, all these agents undergo renal clearance to varying degrees, and hence dosing, efficacy, and safety require special consideration in patients with CKD. Overall, the novel oral anticoagulants have performed well in randomized trials of patients with stage 3 CKD, with similar efficacy and safety profiles as for patients without CKD, albeit requiring dosing modifications. The required period of discontinuation of novel oral anticoagulants before elective surgery is longer for patients with CKD owing to their reduced renal clearance. Although much remains to be learned about the optimal use of these new agents in patients with CKD, they are attractive anticoagulation options that are likely to replace warfarin in coming years.


How developmental coordination disorder affects daily life: The adolescent perspective.
Few studies have focused on the implications of developmental coordination disorder (DCD) in the teen years. Understanding the unique needs of adolescents with DCD and the challenges they face are imperative to inform clinical care. To understand how DCD affects daily life from adolescents living with the disorder. Participants were recruited from a database of adolescents who were formally diagnosed with DCD in childhood. Nineteen semi-structured interviews of adolescents with DCD (13-18 years) were conducted and analyzed using an interpretive description approach. Data analysis revealed four overarching themes: (1) Through the years; (2) Standing out, left out, opting out; (3) Rising into Resilience; and (4) Help me to be me. Adolescents with DCD face challenges in physical, cognitive, social, emotional, and mental health domains, but their success can be optimized through provision of support, fostering social connections, the use of strategies, and increasing public understanding. Few services currently exist for adolescents with DCD, as treatment is not standard of care. Insights gained from this study provide client-centred evidence to advocate for intervention for adolescents with DCD, and guide recommendations for clinical care and community support to meet the needs of this under-served population. WHAT THIS PAPER ADDS?: This paper qualitatively explores the lived experience of adolescents with DCD, adding to the limited research within this population. Expanding beyond the typical focus of motor challenges, this paper highlights the widespread influence of DCD on daily life, including in cognitive, mental health, and social-emotional domains. Common environmental contexts that exacerbate challenges during adolescent years are explored, including high school PE class and electives, learning to drive, beginning employment, and preparing for post-secondary education. Through an interpretive description methodology, this paper delves into clinical and practical solutions to support adolescents with DCD, from an individualized and client-centered perspective.


Variation in brain organization and cerebellar foliation in chondrichthyans: sharks and holocephalans.
The widespread variation in brain size and complexity that is evident in sharks and holocephalans is related to both phylogeny and ecology. Relative brain size (expressed as encephalization quotients) and the relative development of the five major brain areas (the telencephalon, diencephalon, mesencephalon, cerebellum, and medulla) was assessed for over 40 species from 20 families that represent a range of different lifestyles and occupy a number of habitats. In addition, an index (1-5) quantifying structural complexity of the cerebellum was created based on length, number, and depth of folds. Although the variation in brain size, morphology, and complexity is due in part to phylogeny, as basal groups have smaller brains, less structural hypertrophy, and lower foliation indices, there is also substantial variation within and across clades that does not reflect phylogenetic relationships. Ecological correlations, with the relative development of different brain areas as well as the complexity of the cerebellar corpus, are supported by cluster analysis and are suggestive of a range of 'cerebrotypes'. These correlations suggest that relative brain development reflects the dimensionality of the environment and/or agile prey capture in addition to phylogeny.


Fas/Fas ligand expression and characteristics of primed CD45RO+ T cells in the inflamed mucosa of ulcerative colitis.
Chronic immune activation in the colon is characteristic of ulcerative colitis (UC). Fas/Fas ligand (FasL) system is a mechanism responsible for activation-induced cell death (AICD), which maintains homeostasis within the immune system. Thus, Fas/FasL expression on activated colonic T cells of UC patients, as well as the susceptibility of such T cells to AICD was investigated in order to determine the role of activated colonic T cells in the long lasting inflammation in UC. Fas, FasL, and CD45RO expression on peripheral blood and colonic T cells of UC patients were assayed by flow cytometry. Apoptosis of colonic T cells induced by anti Fas antibody was assessed using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assay. The majority of colonic T cells expressed both CD45RO and Fas in the colonic mucosa, a situation that was quite different from that in the peripheral blood. The number of CD45RO+CD8+ and Fas+CD8+ T cells was significantly lower in UC patients than the controls, unlike the number of Fas+CD4+ T cells. In contrast, the number of both CD45RO+CD4+ and CD45RO+CD8+ T cells in UC mucosa expressing FasL was significantly higher than in the controls. While Fas mediated apoptosis of CD45RO+CD8+ T cells was higher in UC patients than the controls, the number of apoptotic CD45RO+CD4+ T cells from UC mucosa was not. In UC patients, CD45RO+CD4+ T cells are less sensitive to apoptotic signals mediated by Fas. These phenomena may contribute to the pathogenesis of UC.


Stable Rates of Obstructive Hypertrophic Cardiomyopathy in a Contemporary Era.
Hypertrophic cardiomyopathy is the most common genetic heart disease in the US, with an estimated prevalence of 1 in 500. However, the extent to which obstructive hypertrophic cardiomyopathy is clinically recognized is not well-established. Therefore, the objective of this study was to estimate the annual prevalence of clinically diagnosed oHCM in the US from 2016 to 2018. Data from the MarketScan® database were queried from years 2016 to 2018 to identify patients with ≥1 claim of oHCM (International Statistical Classification of Disease and Related Health Problems diagnosis code: I42.1). Prevalence rates for oHCM were calculated and stratified by sex and age. In 2016, 4,612 unique patients had clinical diagnosis of oHCM, resulting in an estimated oHCM prevalence of 1.65 per 10,000. The prevalence of oHCM in males and females was 2.07 and 1.26, respectively. Prevalence of oHCM was highest in patients 55-64 years of age (4.82). Prevalence of oHCM generally increased with age, from 0.36 per 10,000 in those under 18 to 4.82 per 10,000 in those 55-65. Trends in prevalence of oHCM over time, including by sex and age group, remained similar and consistent in 2017 and 2018. The prevalence of oHCM was stable over the 3-year time period, including higher rates of oHCM in males and patients aged 55-64 years. These results suggest that the majority of privately insured patients with oHCM are undiagnosed in the US and reinforce the need for policies and research to improve the clinical identification of oHCM patients in the US.


Detection of Barrett's oesophagus through exhaled breath using an electronic nose device.
Timely detection of oesophageal adenocarcinoma (OAC) and even more so its precursor Barrett's oesophagus (BO) could contribute to decrease OAC incidence and mortality. An accurate, minimally-invasive screening method for BO for widespread use is currently not available. In a proof-of-principle study in 402 patients, we developed and cross-validated a BO prediction model using volatile organic compounds (VOCs) analysis with an electronic nose device. This electronic nose was able to distinguish between patients with and without BO with good diagnostic accuracy (sensitivity 91% specificity 74%) and seemed to be independent of proton pump inhibitor use, the presence of hiatal hernia, and reflux. This technique may enable an efficient, well-tolerated, and sensitive and specific screening method to select high-risk individuals to undergo upper endoscopy.


Effect of age on left ventricular systolic function in humans: a study of systolic isovolumic acceleration rate.
The aim of this study was to examine the effect of age on left ventricular (LV) systolic function in normal healthy adults. Eighty consecutive subjects without cardiovascular disease underwent standard and tissue Doppler (TD) echocardiographic imaging. LV systolic function was assessed by load-dependent indices as ejection fraction (EF) and myocardial systolic velocities by TD as well as by the load-independent index, systolic isovolumic acceleration rate (IVA). None of the echocardiographic measurements of systolic function declined with age (mean IVA for the group, 286 +/- 123 cm s(-2); IVA vs. age, r = 0.21, P = 0.1). Likewise, LV end diastolic dimension, wall thickness, mass and left atrial maximum volume were not significantly related to age. On the other hand, as previously reported, echocardiographic indices of diastolic function showed a significant decline with age (P < 0.05). When the group was stratified by gender, isovolumic velocity and acceleration were higher in men than women, but the differences were not significant (P = 0.12 and 0.37, respectively). No significant relation was observed between age and measurements of LV systolic function by regression analysis in women (P > 0.1). However, in men, a positive correlation was noted between average IVA and age (r = 0.63, P = 0.007). In conclusion, age is not associated with a change in cardiac structure and LV systolic function, but is accompanied by a decline in echocardiographic indices of diastolic function. With respect to gender, age does not appear to influence LV systolic function in women, but is associated with an increase in IVA and septal systolic ejection in men.


Blood biomonitoring of metals in subjects living near abandoned mining and active industrial areas.
A human blood biomonitoring campaign to detect the environmental exposure to metals (Cd, Cu, Cr, Mn, Pb and Zn) in 265 subjects was performed in the South-Western part of Sardinia (an Italian island) that is a particular area with a great history of coal and metal mining (Pb/Zn mainly) activities and large industrial structures (as metallurgy). Subjects living near the industrial plant area had geometric means (GM) of blood Cd (0.79 μg/l), Cu (971 μg/l), Mn (12.2 μg/l), and Pb (55.7 μg/l) significantly higher than controls (Cd, 0.47 μg/l; Cu, 900 μg/l; Mn 9.98 μg/l; Pb, 26.5 μg/l) and than people living nearby the past mining sites. Subjects living next to one dismissed mine were statistically higher in blood Cu (GM, 1,022 μg/l) and Pb (GM, 41.4 μg/l) concentrations than controls. No differences were observed in people living in the different mining sites, and this might be related to the decennial disclosure of mines and the adoption of environmental remediation programmes. Some interindividual variables influenced blood biomonitoring data, as smoke and age for Cd, gender for Cu, age, sex and alcohol for Pb, and age for Zn. Moreover, blood metal levels of the whole population were similar to reference values representative of the Sardinian population and acceptably safe according to currently available health guidelines.


[Causative factor of Ca2+ transport reduction by sarcoplasmic reticulum fragments under the action of acetylcholine].
The uncoupling of Ca2+ uptake and ATP hydrolysis by acetylcholine (ACh) and choline has been demonstrated on fragmented sarcoplasmic reticulum (FSR) isolated from femoral muscles of Rana ridibunda. The uncoupling depends on the content of oxalate in the incubation medium. An increase in the Ca/ATP ratio caused by serum albumin observed at low oxalate concentrations is indicative of participation of free fatty acids in the uncoupling effect of ACh and choline. The effects of ACh and choline are especially well-pronounced in the case of FSR preparations pretreated with a fatty acid. ACh and choline have no effect on FSR from femoral muscles of Rana temporaria at all oxalate concentrations studied, which may be due to the absence of free fatty acids in these preparations. A pronounced uncoupling effect of ACh is observed after FSR incubation with a fatty acid; the activity of choline is pronounced in a much lesser degree. It is concluded that a decrease in the Ca/ATP ratio in the presence of ACh is due to the enhancement of the uncoupling effects of endogenous free fatty acids.


Model systems for studying trophoblast differentiation from human pluripotent stem cells.
This review focuses on a now well-established model for generating cells of the trophoblast (TB) lineage by treating human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) with the growth factor BMP4. We first discuss the opposing roles of FGF2 and BMP4 in directing TB formation and the need to exclude the former from the growth medium to minimize the co-induction of mesoderm and endoderm. Under these conditions, there is up-regulation of several transcription factors implicated in TB lineage emergence within 3 h of BMP4 exposure and, over a period of days and especially under a high O(2) gas atmosphere, gradual appearance of cell types carrying markers for more differentiated TB cell types, including extravillous TB and syncytioTB. We describe the potential value of including low molecular weight pharmaceutical agents that block activin A (INHBA) and FGF2 signaling to support BMP4-directed differentiation. We contend that the weight of available evidence supports the contention that BMP4 converts human ESC and iPSC of the so-called epiblast type unidirectionally to TB. We also consider the argument that BMP4 treatment of human ESC in the absence of exogenous FGF2 leads only to the emergence of mesoderm derivatives to be seriously flawed. Instead, we propose that, when signaling networks supporting pluripotency ESC or iPSC become unsustainable and when specification towards extra-embryonic mesoderm and endoderm are rendered inoperative, TB emerges as a major default state to pluripotency.


Spatial-Temporal Parameters of Gait Associated With Alzheimer Disease: A Longitudinal Analysis.
Alzheimer's disease (AD) is one of the biggest social and medical concerns in the aging world. A dual task of walking and talking is a particularly practical means to assess AD considering the cognitive and behavioral changes that characterize the disease. The purpose of the study was to assess the effect of the dual task of walking and talking on people with early stage AD under differing cognitive load levels of talking. Participants (9 women and 5 men, mean age (years) = 78.03, standard deviation [SD] = 12.06) with mild or moderate AD (mean Dementia Rating Scale 2 score = 88.14, SD = 7.07) completed 12 monthly walking sessions under no, low, or high cognitive load. They also completed the low and high cognitive load tasks while seated. Linear mixed-effects modeling revealed that values in the Functional Ambulation Profile, stride length, and velocity decreased as tasks became more complex and double support time increased at the same rate. The walking and seated conditions comparison indicated that participants' performance on both low and high cognitive tasks was poor when they were walking rather than seated. The results show that people with early stage AD exhibited gait impairments that increased over time and when completing tasks with greater cognitive load.


The familial aggregation of atopic diseases and depression or anxiety in children.
Children with asthma and atopic diseases have an increased risk of depression or anxiety. Each of these diseases has strong genetic and environmental components; therefore, it seems likely that there is a shared liability rather than causative risk. To investigate the existence and nature of familial aggregation for the comorbidity of atopic diseases and depression or anxiety. Participants came from the Childhood and Adolescent Twin Study in Sweden (CATSS), n = 14 197. Current and ever asthma, eczema, hay fever and food allergy were reported by parents. Internalizing disorders were identified using validated questionnaires. Familial co-aggregation analysis compared monozygotic (MZ) twins and same-sex dizygotic (DZ) twins for atopic disease in 1 twin with internalizing disorder in the other to test for genetic liability. Several familial liability candidates were also tested including parental education, recent maternal psychological stress, childhood family trauma and parental country of birth. Familial co-aggregation analysis found that if 1 twin had at least 1 current atopic disease the partner twin was at risk of having an internalizing disorder regardless of their own atopic status (adjusted OR 1.22 (95% CI 1.08, 1.37). Similar results were found for each atopic disease ever and current. MZ associations were not higher than DZ associations, suggesting that the liability is not genetic in nature. Including other familial candidates to the models made little difference to effect estimates. Atopic diseases and depression or anxiety tend to occur together in families; therefore, when treating for 1 disease, the physician should consider comorbidity in both the individual and the individual's siblings. We did not find evidence to support a genetic explanation for comorbidity, and further exploration is needed to disentangle the environmental and epigenetic reasons for familial aggregation.


Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers.
This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg, and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual-absorption rate model (fast zero-order and slow first-order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high K(m) value was obtained indicating that clearance was mildly nonlinear. Absorption was slow (t(max) approximately 24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%-100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (S(max)), sensitivity (SC(50)), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC(50) of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex-dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmacokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained.


Pharmacokinetics of 14C-isotretinoin in healthy volunteers and volunteers with biliary T-tube drainage.
The pharmacokinetics of isotretinoin and 4-oxoisotretinoin in blood, as well as the blood concentrations and urinary, biliary, and fecal excretion of carbon-14 were studied using liquid scintillation counting techniques and reverse phase HPLC methods following a single 80-mg oral suspension dose of 14C-isotretinoin to four healthy male subjects and two patients with biliary T-tube drainage. Approximately 80% of the dose was recovered as 14C in excreta during the course of the study of which about equal fractions were in the urine and feces. Secondary peaks in blood concentrations of 14C were observed in the healthy subjects whereas they were not seen in the patients with T-tubes. The harmonic mean apparent half-life for isotretinoin in the blood of the healthy subjects was 13.6 hr, whereas the corresponding value for the 14C was 90 hr. Although a rigorous comparison of pharmacokinetic parameters between healthy subjects and T-tube patients was not feasible due to the limited number of subjects studied, comparisons of certain trends in the pharmacokinetic profiles gave some possible insights into the role of biliary excretion and enterohepatic cycling on the disposition of isotretinoin. The data for isotretinoin and 4-oxoisotretinoin coupled with the total carbon-14 data suggest that the oral dose of 14C-isotretinoin is absorbed to a similar extent by the healthy subjects and T-tube patients, whereas T-tube patients clear the drug more rapidly. The biliary excretion and possible enterohepatic circulation of isotretinoin and its metabolites may have significant impact on the pharmacokinetic profile of isotretinoin in man.


A Media Biopsy: Examining the Quality of Cancer Reporting in Australia, 1997 and 2017.
This article investigates the quality of cancer reporting from a time of prosperity to a time of austerity for the press. Australia is a useful case study because of its concentrated press media market that has experienced a decline in the number of newsroom reporters from the 20th to the 21st century. We undertake a content analysis of news stories published in 1997 and 2017 about cancer treatments and cancer medical research. Using keyword searching techniques of the news database Factiva, 633 news reports about cancer were detected. Of these, 120 stories met the research criteria. Each story was assessed across eight variables using a coding tool, the Media Quality Index (MQI). The study finds 2017 stories had lower scores (equating to less quality) across all eight variables compared to the 1997 cohort. Of statistical significance, 2017 stories were less likely to quantify the benefits of a proposed intervention, while stories discussing medical research were less comprehensive about research findings. The 2017 stories were less likely to discuss side effects or the potential for harm, and were more sensational, with incongruent headlines compared to content. The empirical evidence pointing to a deterioration in mainstream media reporting about cancer has implications for broader health literacy. It may foster unrealistic patient expectations about clinical practice and treatment options, with public policy implications such as overutilization of health services. The study serves as a reminder to medical practitioners that health communication directly with patients is vital as media reporting alone cannot reliably inform patients about their cancer diagnosis and treatment.


Effects of state anxiety on performance using a task-switching paradigm: an investigation of attentional control theory.
Low- and high-anxious participants performed arithmetical tasks under task-switching or nontask-switching conditions. These tasks were low or high in complexity. The task on each trial was either explicitly cued or not cued. We assumed that demands on attentional control would be greater in the task-switching condition than in the nontask-switching condition, and would be greater with high-complexity tasks than with low-complexity ones. We also assumed that demands on attentional control would be greater when cues were absent rather than present. According to attentional control theory (Eysenck, Derakshan, Santos, & Calvo, 2007), anxiety impairs attentional control processes required to shift attention optimally within and between tasks. We predicted that there would be greater negative effects of high state anxiety in the task-switching condition than in the nontask-switching condition. Our theoretical predictions were supported, suggesting that state anxiety reduces attentional control.


[Follow-up of children less than five years of age suffering from respiratory diseases: literature review].
Study of a descriptive nature, aiming at identifying publications related to respiratory diseases in children aged less than five years, in national and international periodicals and in some textbooks, from 1990 through 2002, and identifying the ones which describe respiratory diseases over the course of children's growth and development. Twenty-seven works were analyzed. Some features are presented referring to quantity of authors published, language of publication, and methodological as well as thematic aspects: respiratory diseases in children, their determiners and risk factors; use of health services for children suffering from respiratory problems; follow-up and respiratory diseases in childhood.


Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis.
Right heart catheterisation is the gold standard for the diagnosis of pulmonary hypertension. However, echocardiography is frequently used to screen for this disease and monitor progression over time because it is non-invasive, widely available and relatively inexpensive. To perform a systematic review and quantitative meta-analysis to determine the correlation of pulmonary pressures obtained by echocardiography versus right heart catheterisation and to determine the diagnostic accuracy of echocardiography for pulmonary hypertension. MEDLINE, EMBASE, Papers First, the Cochrane collaboration and the Cochrane Register of controlled trials were searched and were inclusive as of February 2010. Studies were only included if a correlation coefficient or the absolute number of true-positive, false-negative, true-negative and false-positive observations was available, and the 'reference standards' were described clearly. Two reviewers independently extracted the data from each study. Quality was assessed with the quality assessment for diagnostic accuracy studies. A random effects model was used to obtain a summary correlation coefficient and the bivariate model for diagnostic meta-analysis was used to obtain summary sensitivity and specificity values. Results 29 studies were included in the meta-analysis.The summary correlation coefficient between systolic pulmonary arterial pressure estimated from echocardiography versus measured by right heart catheterisation was 0.70 (95% CI 0.67 to 0.73; n=27).The summary sensitivity and specificity for echocardiography for diagnosing pulmonary hypertension was 83% (95% CI 73 to 90) and 72% (95% CI 53 to 85;n=12), respectively. The summary diagnostic OR was 13(95% CI 5 to 31).Conclusions Echocardiography is a useful and noninvasive modality for initial measurement of pulmonary pressures but due to limitations, right heart catheterisation should be used for diagnosing and monitoring pulmonary hypertension.


Determination of CYP2D6 *3, *4, and *10 frequency in women with breast cancer in São Luís, Brazil, and its association with prognostic factors and disease-free survival.
The CYP2D6 enzyme is crucial for the metabolism of tamoxifen. The CYP2D6 gene is highly polymorphic, and individuals can be extensive, intermediate, or poor tamoxifen metabolizers. The aim of this study was to determine the frequencies of the CYP2D6 *3, *4, and *10 alleles in women with breast cancer who were treated with tamoxifen and analyze the association of enzyme activity with prognostic factors and disease-free survival. We observed a high frequency of CYP2D6 *10, with an allelic frequency of 0.14 (14.4%). The *3 allele was not present in the studied population, and *4 had an allelic frequency of 0.13 (13.8%). We conclude that patients with reduced CYP2D6 activity did not present worse tumor characteristics or decreased disease-free survival than women with normal enzyme activity, as the difference was not statistically significant. We also observed a high frequency of CYP2D6 *10, which had not been previously described in this specific population. This study is the first in north-northeastern Brazil that aimed to contribute to the knowledge of the Brazilian regional profile for CYP2D6 polymorphisms and their phenotypes. These findings add to the knowledge of the distribution of different polymorphic CYP2D6 alleles and the potential role of CYP2D6 genotyping in clinical practice prior to choosing therapeutic protocols.


Non-additive effects of pollen limitation and self-incompatibility reduce plant reproductive success and population viability.
Mating system is a primary determinant of the ecological and evolutionary dynamics of wild plant populations. Pollen limitation and loss of self-incompatibility genotypes can both act independently to reduce seed set and these effects are commonly observed in fragmented landscapes. This study used a simulation modelling approach to assess the interacting effects of these two processes on plant reproductive performance and population viability for a range of pollination likelihood, self-incompatibility systems and S-allele richness conditions. A spatially explicit, individual-based, genetic and demographic simulation model parameterized to represent a generic self-incompatible, short-lived perennial herb was used to conduct simulation experiments in which pollination probability, self-incompatibility type (gametophytic and sporophytic) and S-allele richness were systematically varied in combination to assess their independent and interacting effects on the demographic response variables of mate availability, seed set, population size and population persistence. Joint effects of reduced pollination probability and low S-allele richness were greater than independent effects for all demographic response variables except population persistence under high pollinator service (>50 %). At intermediate values of 15-25 % pollination probability, non-linear interactions with S-allele richness generated significant reductions in population performance beyond those expected by the simple additive effect of each independently. This was due to the impacts of reduced effective population size on the ability of populations to retain S alleles and maintain mate availability. Across a limited set of pollination and S-allele conditions (P = 0·15 and S = 20) populations with gametophytic SI showed reduced S-allele erosion relative to those with sporophytic SI, but this had limited effects on individual fecundity and translated into only modest increases in population persistence. Interactions between pollen limitation and loss of S alleles have the potential to significantly reduce the viability of populations of a few hundred plants. Population decline may occur more rapidly than expected when pollination probabilities drop below 25 % and S alleles are fewer than 20 due to non-additive interactions. These are likely to be common conditions experienced by plants in small populations in fragmented landscapes and are also those under which differences in response between gameptophytic and sporophtyic systems are observed.


Hormonal regulation of the metabolism of carcinogens in renal tissue of BALB/c mice.
The role of androgens in the regulation of carcinogen metabolism in the renal tissue of BALB/c mice was investigated. Kidney microsomal enzyme preparations from mature and immature animals were used in mutagenic studies using the Ames test. Androgen receptors (cytosolic and nuclear) were also evaluated. The results show that the microsomal enzymes from mature males had greater potential to biotransform dimethylnitrosamine than did the microsomal enzymes from mature females or immature animals. Testosterone treatment of mature females or immature animals resulted in a significant increase in the mutagenic ability of their renal microsomal enzymes. Androgen receptors were detected in kidney cytosols of mature and immature animals (both males and females); however, nuclear androgen receptors were detected only in the mature males. Testosterone treatment resulted in a significant accumulation of nuclear androgen receptors in the kidneys of mature females and immature animals. The relationships among mutagenic activity, androgen receptors, the levels of N-demethylase (an enzyme responsible for conversion of dimethylnitrosamine to its active metabolite), dietary fat, and the carcinogen metabolism are discussed.


Target and non-target impact of systemic insecticides on a polyphagous aphid pest and its parasitoid.
Systemic insecticides are used to control agricultural pests globally and their non-target impact at non-lethal doses on beneficial arthropods has been recognized. We assessed the baseline toxicity of imidacloprid, thiamethoxam and sulfoxaflor-based insecticides on the polyphagous aphid pest, Aphis gossypii (Hemiptera: Aphididae), and their non-target effects on its main parasitoid, Aphidius colemani (Hymenoptera: Braconidae), evaluated by residual contact exposure to the median lethal (LC50), the low lethal (LC20) and the sublethal (LC1) concentrations of the three tested insecticides, earlier estimated for the target pest. The results showed that the LC50s for the aphid were 6.4 × 10-3, 5 × 10-3, 2.9 × 10-2 times lower compared to the label concentrations of imidacloprid, thiamethoxam and sulfoxaflor, respectively. LC50 of thiamethoxam caused the highest mortality rate on the parasitoid followed by sulfoxaflor, while imidacloprid had the lowest impact. No significant sublethal effects on reprodution were observed for A. colemani survived to the insecticide exposure. Our findings highlight the importance of case-specific evaluation to optimize pesticide applications in Integrated Pest Management packages taking into account the ecological services provided by biological control agents.


Induction and activity of NO synthase in bone-marrow-derived macrophages are independent of Ca2+.
The aim of the present study was to analyse whether an increase in the intracellular free Ca2+ concentration ([Ca2+]i) plays a role as a signal mediating synthesis of nitric oxide (NO) in bone-marrow-derived macrophages, either by stimulating induction of NO synthase or by regulating the activity of the enzyme. Therefore we compared the effects of various synthetic analogues of bacterial lipopeptide and of lipopolysaccharide (LPS) on NO production (assessed as nitrite formation during an incubation for 24 h) and on [Ca2+]i [measured with the fluorescent probe indo-1 (1-[2-amino-5-(6-carboxyindol-2-yl)phenoxy]-2- 2-(2'-amino-5'-methylphenoxy)ethane-NNN'N'-tetra-acetic acid)]. Strongly dissociating effects were evoked on nitrite formation and on [Ca2+]i by the stimuli. LPS was preferentially effective on nitrite formation, whereas the Ca2+ ionophore ionomycin and AlF3 induced increases only in [Ca2+]i. The lipopeptides N-palmitoyl-(S)-[2,3-bis(palmitoyloxy)-(2RS)- propyl]-(R)-cysteinylalanylglycine, N-palmitoyl-(S)-[2,3-bis(palmitoyloxy)- (2RS)-propyl]-(R)-cysteinylseryl-lysyl-lysyl-lysine and (S)-(1,2- dicarboxyhexadecyl)ethyl-N-palmitoylcysteinylseryl-lysyl-lys yl-lysine stimulated both parameters, but the maximal effects on nitrite formation and the shape of the dose-response curves did not parallel the effects on [Ca2+]i. Reduction of extracellular Ca2+ with EGTA significantly inhibited increases in [Ca2+]i, but did not change nitrite formation. Furthermore, NO synthesis in the cytosolic fraction of stimulated macrophages was not affected by Ca2+ over the concentration range 10 nM-2 microM. We conclude that increases in [Ca2+]i are not required for NO production in bone-marrow-derived macrophages. Thus the cellular regulation of NO production strikingly differs from that in the vascular endothelium, brain and adrenal gland.


The effects of multiple anaesthetic episodes on equine recovery quality.
Although rare, 70% of equine fatalities during recovery from general anaesthesia (GA) are due to catastrophic fractures from poor recovery quality. To determine the effect of repeated GA recovery on GA recovery quality. Experimental blinded trial. Eight adult horses underwent six GA events on sevoflurane for distal limb MRI examination over a 14-week period. Prior to GA recovery, xylazine was administered. Randomly ordered video-recorded GA recoveries were scored by three blinded board certified veterinary anaesthesiologists, unaware of patient identity or GA event number, for nine parameters using a 100 mm visual analogue scale (VAS) where 0 = worst and 100 = best. The number of attempts to stand, duration of lateral and sternal recumbency, total recovery duration and physiologic parameters during each GA event were recorded. Repeated measures ANOVA were used to detect differences. Agreement between observer VAS scores was determined via inter-rater reliability using an intraclass correlation. With GA recovery experience, VAS scores for balance and coordination, knuckling, and overall quality of recovery were improved and the duration of lateral recumbency was increased. There were no differences in total recovery duration, number of attempts to stand, physiologic parameters other than heart rate during GA, or VAS scores for activity in lateral recumbency, move to sternal, move to stand, or strength. Each GA event was relatively short and there was no surgical stimulation. The same results may not occur if there was surgical stimulation and pain during each GA event. Recovery from GA improves with multiple anaesthetic episodes in horses. Clinicians can advise clients that horses are likely to have better GA recovery on repeated GA recovery due to improved balance and coordination and reduced knuckling. Additionally, there is no change in anaesthetic morbidity with six repeated GA events over a 14-week period.


Prevention of viral transmission in HD units: the value of isolation.
We have investigated the influence of isolation of patients with different viral serology status on the transmission of viral hepatitis among patients on hemodialysis (HD). Our kidney center was designed to facilitate isolation of infected patients and implement infection control pre-cautions. These included separate rooms, separate entrances and exit sites, and designated HD machines for patients with hepatitis B, hepatitis C, and sero-negative patients. In addition, universal infection control polices and procedures were implemented. These included proper chemical and heat disinfection of all HD machines following each HD session. These measures were complemented with education and training of the nursing staff detailing strict adherence to all infection control policies and procedures. All of our patients and staff were vaccinated against hepatitis B. Our results showed that after four years of follow-up, there was a decrease in the annual incidence of hepatitis C seroconversion from an average of 2.4% to 0.2%. The current prevalence of hepatitis C is 29% compared to 57% at the start of the study. In addition, there have been no reported sero-conversion cases of hepatitis B. Furthermore, our data also confirmed that the prevalence of hepatitis C (as well as hepatitis B) is more frequent in HD (29%) than peritoneal dialysis (5%) units. Surgical procedures, blood transfusion, and frequent visits to different dialysis units remain the major risk factors for contracting viral hepatitis. In conclusion, these results clearly show that isolation of patients and machines, together with strict adherence to infection control policies and procedures, result in a significant decline in the incidence and prevalence and better control of viral hepatitis transmission among HD patients.


Increased odds of bladder and bowel symptoms in early Parkinson's disease.
To compare the prevalence of urinary and bowel symptoms in a sample of adults with early Parkinson's disease (PD) and healthy controls (HC). Data were obtained from the Michael J. Fox Parkinson's Progression Markers Initiative (PPMI). Prevalent bladder (urinary incontinence (UI) and nighttime voiding) and bowel (constipation and fecal incontinence (FI)) symptoms were defined as occurring at least sometimes when queried using the Scale for Outcomes in PD for Autonomic Symptoms. The proportion of men (65% vs 64%) and the mean age (61.0 ± 9.7 vs 60.2 ± 11.2 years) was similar between early PD (n = 423) and HC (n = 195). UI and constipation were more prevalent among early PD versus HC (UI: 26.7% vs 8.2%, constipation: 32.4% vs 11.8%; P's < 0.0001). Prevalent nighttime voiding was high among both groups, but not significantly different (82.5% vs 84.1%, P = 0.62). FI was infrequent in both. The odds of UI and constipation were significantly higher in early PD even after adjustment for age, sex, cognition, and overactive bladder (UI model only), constipation (UI and constipation models only), depression, and anxiety medication usage (UI: OR: 4.39 [95% CI: 2.92, 5.87]; constipation: 3.34 [2.20, 4.42]; P's < 0.0001). While constipation is known to precede PD diagnosis, these data suggest that the occurrence of UI is elevated in early PD compared to a well-matched HC population.


Pediatric Surgery Firearm Injury Collaborative Symposium.
Injury from a firearm is now the leading cause of death of children and youth under age 19 in the United States (U.S.) [1] and the incidence of these deaths continues to increase each year [2]. For every death from firearm violence, there are several young people who have been injured by a bullet but not killed. As pediatric surgeons, we are on the front lines of treating these young patients. We have the unforgettable memories of delivering the horrible news to parents in "quiet rooms." [3]. As these injuries fall within our scope of practice, it is incumbent on us as professionals to work to prevent these injuries, apply best practices and work for the best pathways to recovery for our patients who do survive. There is a diverse community of pediatric surgeons tackling this public health problem in a variety of ways [4]. In a pre-meeting symposium at the APSA 2023 Annual meeting, we brought together a community of pediatric surgeons working on this critical area. The following summarizes the presentations of the symposium, with topics including Risk Factors, Injury Prevention, Treatment, Public Initiatives, and National Collaborative Efforts. TYPE OF STUDY: Review Article, Proceedings of a Symposium. LEVEL OF EVIDENCE: 1 through 4 all presented.


The vascularity of the rotator cuff.
The major arterial supply to the rotator cuff is derived from the ascending branch of the anterior humeral circumflex artery, the acromial branch of the thoracoacromial artery, as well as the suprascapular and posterior humeral circumflex arteries. The pathogenesis of rotator cuff tears has been considered to be influenced by the microvascular supply of the rotator cuff tendons. Most cadaver studies have demonstrated a hypovascular area within the critical zone of the supraspinatus tendon. It has been suggested that this area of hypovascularity has a significant role in the attritional degeneration of the aging tendon. More recent studies of the microvascular supply to the supraspinatus tendon in symptomatic patients with impingement syndrome suggest that in the area of greatest impingement, i.e., the critical zone, there is actually hypervascularity. In contrast to the cadaver investigations, these studies seem to imply that hypervascularity or neovascularization is associated with symptomatic rotator cuff disease secondary to mechanical impingement.


First-in-Man Noninvasive Initial Diagnostic Approach of Primary CNS Lymphoma Versus Glioblastoma Using PET With 18 F-Fludarabine and l -[methyl- 11 C]Methionine.
This study sought to assess 18 F-fludarabine ( 18 F-FLUDA) PET/CT's ability in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastoma multiformes (GBMs). Patients harboring either PCNSL (n = 8) before any treatment, PCNSL treated using corticosteroids (PCNSLh; n = 10), or GBM (n = 13) were investigated with conventional MRI and PET/CT, using 11 C-MET and 18 F-FLUDA. The main parameters measured with each tracer were SUV T and T/N ratios for the first 30 minutes of 11 C-MET acquisition, as well as at 3 different times after 18 F-FLUDA injection. The early 18 F-FLUDA uptake within the first minute of injection was equally considered, whereas this parameter was combined with the later uptakes to obtain R FLUDA 2 and R FLUDA 3 ratios. No significant differences in 11 C-MET uptakes were observed among PCNSL, PCNSLh, and GBM. With 18 F-FLUDA, a clear difference in dynamic GBM uptake was observed, which decreased over time after an early maximum, as compared with that of PCNSL, which steadily increased over time, PCNSLh exhibiting intermediate values. The most discriminative parameters consisting of R FLUDA 2 and R FLUDA 3 integrated the early tracer uptake (first 60 seconds), thereby provided 100% specificity and sensitivity. 18 F-FLUDA was shown to likely be a promising radiopharmaceutical for differentiating PCNSL from other malignancies, although a pretreatment with corticosteroids might compromise this differential diagnostic ability. The diagnostic role of 18 F-FLUDA should be further investigating, along with its potential of defining therapeutic strategies in patients with PCNSL, while assessing the treatments' effectiveness.


Description of pharmacists' reported interventions to prevent prescribing errors among in hospital inpatients: a cross sectional retrospective study.
Prescribing errors (PEs) are a common cause of morbidity and mortality, both in community practice and in hospitals. Pharmacists have an essential role in minimizing and preventing PEs, thus, there is a need to document the nature of pharmacists' interventions to prevent PEs. The purpose of this study was to describe reported interventions conducted by pharmacists to prevent or minimize PEs in a tertiary care hospital. A retrospective analysis of the electronic medical records data was conducted to identify pharmacists' interventions related to reported PEs. The PE-related data was extracted for a period of six-month (April to September 2017) and comprised of patient demographics, medication-related information, and the different interventions conducted by the pharmacists. The study was carried in a tertiary care hospital in Riyadh region. The study was ethically reviewed and approved by the hospital IRB committee. Descriptive analyses were appropriately conducted using the IBM SPSS Statistics. A total of 2,564 pharmacists' interventions related to PEs were recorded. These interventions were reported in 1,565 patients. Wrong dose (54.3 %) and unauthorized prescription (21.9 %) were the most commonly encountered PEs. Anti-infectives for systemic use (49.2 %) and alimentary tract and metabolism medications (18.2 %) were the most common classes involved with PEs. The most commonly reported pharmacists' interventions were dose adjustments (44.0 %), restricted medication approvals (21.9 %), and therapeutic duplications (11 %). In this study, PEs occurred commonly and pharmacists' interventions were critical in preventing possible medication related harm to patients. Care coordination and prioritizing patient safety through quality improvement initiatives at all levels of the health care system can play a key role in this quality improvement drive. Future studies should evaluate the impact of pharmacists' interventions on patient outcomes.


Wild Mediterranean plants as traditional food: a valuable source of antioxidants.
Some wild Mediterranean plants used as traditional food are an extraordinary source of antioxidants. We tested some properties of 10 of these herbaceous plants, used in Liguria (Northwest Italy) to prepare a traditional dish known as "prebuggiun." A total of 9 of them were found to have a polyphenol content and antioxidant properties similar or better than those of red chicory and blueberry, which are, in the case of vegetables and fruits, among the richest of antioxidants. Practical Application: In this article, we reported a study on wild plants growing in the Mediterranean area. These herbs have been neglected and this study aimed to revalue these plants because they are an extraordinary source of antioxidants. The increasing demand for natural antioxidants (additives in the food industry too) justifies the search for new sources of natural antioxidants. The revaluation of these plants will be interesting for: (1) consumer health, rediscovering a vegetable source of high antioxidant power; (2) possibility of producing new commercial products, such as food supplements of high quality and low cost; (3) pharmacological applications.


Supraventricular tachyarrhythmias in Ebstein anomaly: management and outcome.
This study was undertaken to review the role of electrophysiology testing and to determine the early and late results of medical and surgical management of supraventricular tachyarrhythmias in Ebstein anomaly. We reviewed 130 patients between 1990 and 2001 with Ebstein anomaly and history of tachyarrhythmia with a median age of 25 years (mean age 27.5 years); 106 underwent electrophysiologic testing and 24 had documented atrial flutter or fibrillation. We excluded 21 patients: negative results of testing (n = 18), ventricular tachycardia (n = 2), and junctional tachycardia (n = 1). The remaining 109 patients had more than one mechanism: accessory pathway-mediated tachycardia (n = 49), atrioventricular nodal reentrant tachycardia (n = 10), and atrial flutter/fibrillation (n = 70). Eighty-three patients underwent at least one arrhythmia procedure combined with surgery for Ebstein anomaly. Early mortality was 4.8%. Forty-one patients underwent surgical ablation of an accessory pathway without recurrent accessory pathway-mediated tachycardia at a mean follow-up of 48 months. Seven patients underwent surgical perinodal cryoablation for atrioventricular nodal reentrant tachycardia without recurrence at a mean follow-up of 57 months. Forty-eight patients underwent surgical intervention for atrial flutter or fibrillation (right-sided maze procedure, n = 38, and cryoablation of the atrial isthmus, n = 10). Freedom from recurrent atrial flutter or fibrillation was 75% at a mean follow-up of 34 months. Concomitant arrhythmia procedures can be performed without increase in early mortality and should be added to Ebstein repairs for all patients who have supraventricular tachyarrhythmias. Surgical procedures for accessory pathway-mediated tachycardia and atrioventricular nodal reentrant tachycardia give excellent (100%) freedom from recurrence of those arrhythmias. Surgical intervention for atrial flutter/fibrillation yields freedom from late recurrence in 75% of cases.


Muscle fatigue during cross country sprint assessed by activation patterns and electromyographic signals time-frequency analysis.
The aims of this study were as follows: (i) analysis of activation patterns during the spurt of two heats of a cross country skiing sprint with the double poling technique and (ii) quantification of muscle fatigue of the investigated muscles. Eight elite skiers were tested and surface electromyographic signals (EMG) were recorded from seven muscles of the upper and lower limbs. For each subject and each muscle, the activation intervals were calculated for relying on a double-threshold statistical detector and the average rectified value was calculated on each activation interval. The detected activations were processed by a time-frequency algorithm in order to assess the progression of muscle fatigue. The EMG activation patterns and EMG amplitude highlighted no significant difference between the two spurts, despite a generally lower speed in the second spurt. The frequency analysis showed that upper body muscles are the first to be affected by fatigue and that clear signs of muscle fatigue appear right from the first spurt of the sprint simulation (i.e., biceps and triceps brachii) with a decrease in the instantaneous mean frequency. Biceps brachii activations and fatigue demonstrated the involvement of this muscle in propulsion.


Intramolecular regulation of phosphorylation status of the circadian clock protein KaiC.
KaiC, a central clock protein in cyanobacteria, undergoes circadian oscillations between hypophosphorylated and hyperphosphorylated forms in vivo and in vitro. Structural analyses of KaiC crystals have identified threonine and serine residues in KaiC at three residues (T426, S431, and T432) as potential sites at which KaiC is phosphorylated; mutation of any of these three sites to alanine abolishes rhythmicity, revealing an essential clock role for each residue separately and for KaiC phosphorylation in general. Mass spectrometry studies confirmed that the S431 and T432 residues are key phosphorylation sites, however, the role of the threonine residue at position 426 was not clear from the mass spectrometry measurements. Mutational approaches and biochemical analyses of KaiC support a key role for T426 in control of the KaiC phosphorylation status in vivo and in vitro and demonstrates that alternative amino acids at residue 426 dramatically affect KaiC's properties in vivo and in vitro, especially genetic dominance/recessive relationships, KaiC dephosphorylation, and the formation of complexes of KaiC with KaiA and KaiB. These mutations alter key circadian properties, including period, amplitude, robustness, and temperature compensation. Crystallographic analyses indicate that the T426 site is phosphorylatible under some conditions, and in vitro phosphorylation assays of KaiC demonstrate labile phosphorylation of KaiC when the primary S431 and T432 sites are blocked. T426 is a crucial site that regulates KaiC phosphorylation status in vivo and in vitro and these studies underscore the importance of KaiC phosphorylation status in the essential cyanobacterial circadian functions. The regulatory roles of these phosphorylation sites--including T426--within KaiC enhance our understanding of the molecular mechanism underlying circadian rhythm generation in cyanobacteria.


[Fixed-bearing versus mobile-bearing total knee arthroplasty: a prospective randomized clinical and radiological study].
Mobile-bearing total knee arthroplasty has become increasingly popular over the last few years since this option presents several theoretical advantages compared with the fixed-bearing models. The clinical advantage remains to be demonstrated. We therefore conducted a prospective randomized trial to ascertain the potential benefits. This study included patients treated by three senior orthopedic surgeons. Each group included 52 prostheses in 52 patients in the fixed-bearing group and 50 patients in the mobile-bearing group. The per- and postoperative protocols were the same for both groups. Implants were cemented in all cases and patellae were resurfaced. The SF-12, the Knee Society Score (KSS), the Hospital of Special Surgery score (HSS) and pain and joint motion were noted before and after surgery. Among the 104 prostheses implanted, 100 were reviewed at mean follow-up of 36 months (range 24-41). One patient in the fixed-bearing group died six months after surgery from an unrelated cause. Three patients were lost to follow-up: one in the fixed-bearing group and two in the mobile-bearing group. There was no difference between groups for the SF-12, KSS, HSS, pain and joint motion measured postoperatively. Postoperative femorotibial alignment was one degree varus on average in the fixed-bearing group and zero degree in the mobile-bearing group. At last follow-up, there were no radiological signs of prosthesis loosening. One patient in the fixed-bearing group developed a deep venous thrombosis, complicated by pulmonary embolism. Two of the mobile-bearing prostheses were revised, one for patellar fracture caused by a bicycle accident and one for prosthesis infection in a patient with endocarditis 1.5 years after implantation. The clinical results were similar for the two groups in terms of function, pain, general status and complications. The outcome at 36 months was considered excellent or good in 90% of the fixed-bearing group and 88% in the mobile-bearing group. This study did not reveal any difference between the two groups regarding maximal flexion and anterior knee pain, two parameters which would theoretically show short-term improvement with the mobile bearing. Mid- and long-term follow will be required to confirm these findings and to determine the survival of these two types of implants.


"A huge part of my life": Exploring links between music, medical education, and students' developing identities as doctors.
This article was migrated. The article was marked as recommended. This paper explores the place of music in the development of future doctors, through the lens of a mixed method, longitudinal evaluation of a two-week music and medicine special studies project for second and third year medical students. Methods of evaluation included a cohort-wide survey (n=147) and individual interviews with students who had undertaken the music and medicine project (n = 4). Analysis of survey responses indicated that music is important to medical students and that many students recognise links between music and medicine. Medical students who undertook the music and medicine project reported benefits for their ongoing development, including changes in the way they understand and use music in their own lives and exposure to career options they had not considered previously. These benefits are discussed in relation to Dennhardt et al.'s (2016) framework of epistemic functions of arts-based teaching in medical education and to wider debates about whether medical humanities teaching should be compulsory or optional. We then propose that there is room for music in medical education within integrated medical humanities teaching, to promote critical thinking and openness to new perspectives. Optional music and medicine study should also be available for medical students who identify as musicians, to support them in the process of developing their identities as doctors.


Further studies on carry-over effects of dietary crude protein and triiodothyronine (T3) in broiler chickens.
Indian River male broiler chickens growing from 7 to 28 d of age were fed on diets containing either 120 or 210 g crude protein and 0 or 1 mg triiodothyronine (T3)/kg diet to study in vitro lipogenesis (IVL). In addition, a carry-over period (180 g crude protein/kg diet from 28 to 40 d of age) was used to test the persistence of prior treatment effects. The higher protein level increased, but T3 decreased (P < 0.01) growth and feed consumption at 28 d of age. The lower protein level increased (P < 0.05) and T3 decreased IVL in 28-d-old chickens. These effects were only sustained for 6 d following the switch to a common diet at 28 d. IVL at 40 d of age was not affected by either crude protein or T3 fed during the 7-28 d period. The higher protein level increased plasma insulin-like growth factor-1 during the period from 7 to 28 d; however, this effect lasted for only 6 d following the switch to a common diet. Plasma growth hormone (GH) at 28 d of age was inversely related to dietary protein level. Changing to a common level of crude protein did not change plasma GH values at 12 d, indicating that the nutritional state of the young chicken may affect GH at a later period of life. Metabolic changes noted in this study were rapid and maintained for a short period of time following the feeding of a common diet.


Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder.
The prevalence of autism spectrum disorders (ASD) is increasing, but its etiology remains elusive and hence an effective treatment is not available. Previous research conducted on animal models suggests that microbiota-gut-brain axis may contribute to ASD pathology and more human research is needed. This study was divided into two stages,.At the discovery stage, we compared the differences in gut microbiota profiles (using 16S rRNA sequencing), fecal SCFAs (using GC-MS) and plasma neurotransmitters (using UHPLC-MS/MS) of 26 children with ASD and 24 normal children. All 26 children with ASD participated in the intervention stage, and we measured the gut microbiota profiles, SCFAs and neurotransmitters before and after probiotics + FOS (n = 16) or placebo supplementation (n = 10). We found that gut microbiota was in a state of dysbiosis and significantly lower levels of Bifidobacteriales and Bifidobacterium longum were observed at the discovery stage in children with ASD. An increase in beneficial bacteria (Bifidobacteriales and B. longum) and suppression of suspected pathogenic bacteria (Clostridium) emerged after probiotics + FOS intervention, with significant reduction in the severity of autism and gastrointestinal symptoms. Compared to children in the control group, significantly lower levels of acetic acid, propionic acid and butyric acid were found, and a hyperserotonergic state (increased serotonin) and dopamine metabolism disorder (decreased homovanillic acid) were observed in children with ASD. Interestingly, the above SCFAs in children with autism significantly elevated after probiotics + FOS intervention and approached those in the control group. In addition, our data demonstrated that decreased serotonin and increased homovanillic acid emerged after probiotics + FOS intervention. However, the above-mentioned changes did not appear in the placebo group for ASD children. Probiotics + FOS intervention can modulate gut microbiota, SCFAs and serotonin in association with improved ASD symptoms, including a hyper-serotonergic state and dopamine metabolism disorder.


Distinct pharmacological properties of ET-1 and ET-3 on astroglial gap junctions and Ca(2+) signaling.
Astrocytes represent a major target for endothelins (ETs), a family of peptides that have potent and multiple effects on signal transduction pathways and can be released by several cell types in the brain. In the present study we have investigated the involvement of different ET receptor subtypes on intercellular dye diffusion, intracellular Ca(2+) homeostasis, and intercellular Ca(2+) signaling in cultured rat astrocytes from hippocampus and striatum. Depending on the ET concentration and the receptor involved, ET-1- and ET-3-induced intracellular Ca(2+) increases with different response patterns. Both ET-1 and ET-3 are powerful inhibitors of gap junctional permeability and intercellular Ca(2+) signaling. The nonselective ET receptor agonist sarafotoxin S6b and the ET(B) receptor-selective agonist IRL 1620 mimicked these inhibitions. The ET-3 effects were only marginally affected by an ET(A) receptor antagonist but completely blocked by an ET(B) receptor antagonist. However, the ET-1-induced inhibition of gap junctional dye transfer and intercellular Ca(2+) signaling was only marginally blocked by ET(A) or ET(B) receptor-selective antagonists but fully prevented when these antagonists were applied together. The ET-induced inhibition of gap junction permeability and intercellular Ca(2+) signaling indicates that important changes in the function of astroglial communication might occur when the level of ETs in the brain is increased.


The multisite violence prevention project: impact of a universal school-based violence prevention program on social-cognitive outcomes.
This study evaluated the impact of a universal school-based violence prevention program on social-cognitive factors associated with aggression and nonviolent behavior in early adolescence. The effects of the universal intervention were evaluated within the context of a design in which two cohorts of students at 37 schools from four sites (N = 5,581) were randomized to four conditions: (a) a universal intervention that involved implementing a student curriculum and teacher training with sixth grade students and teachers; (b) a selective intervention in which a family intervention was implemented with a subset of sixth grade students exhibiting high levels of aggression and social influence; (c) a combined intervention condition; and (d) a no-intervention control condition. Short-term and long-term (i.e., 2-year post-intervention) universal intervention effects on social-cognitive factors targeted by the intervention varied as a function of students' pre-intervention level of risk. High-risk students benefited from the intervention in terms of decreases in beliefs and attitudes supporting aggression, and increases in self-efficacy, beliefs and attitudes supporting nonviolent behavior. Effects on low-risk students were in the opposite direction. The differential pattern of intervention effects for low- and high-risk students may account for the absence of main effects in many previous evaluations of universal interventions for middle school youth. These findings have important research and policy implications for efforts to develop effective violence prevention programs.


Disposition of disodium cromoglycate administered in three particle sizes.
1 Disodium cromoglycate (DSCG) was administered in three particle sizes to five human subjects. 2 Urinary excretion of DSCG, as a proportion of the dose, was highest following small particles; the lower values recorded following intermediate-sized and large particles were similar. 3 DSCG deposited in the mouth was highest following large particles; the lower values recorded following intermediate-sized and small particles were similar. 4 The data were examined in relation to the recent observation that the protective effect of small particles of DSCG is dramatically superior to that of large particles.


Membrane-perturbing domains of HIV type 1 glycoprotein 41.
Structural and functional studies were performed to assess the membrane actions of peptides based on HIV-1 glycoprotein 41,000 (gp41). Previous site-directed mutagenesis of gp41 has shown that amino acid changes in either the N-terminal fusion or N-leucine zipper region depressed viral infection and syncytium formation, while modifications in the C-leucine zipper domain both increased and decreased HIV fusion. Here, synthetic peptides were prepared corresponding to the N-terminal fusion region (FP-I; gp41 residues 519-541), the nearby N-leucine zipper domain (DP-107; gp41 residues 560-597), and the C-leucine zipper domain (DP-178; gp41 residues 645-680). With erythrocytes, FP-I or DP-107 induced dose-dependent hemolysis and promoted cell aggregation; FP-I was more hemolytic than DP-107, but each was equally effective in aggregating cells. DP-178 produced neither hemolysis nor aggregation, but blocked either FP-I- or DP-107-induced hemolysis and aggregation. Combined with previous nuclear magnetic resonance and Fourier transform infrared spectroscopic results, circular dichroism (CD) spectroscopy showed that the alpha-helicity for these peptides in solution decreased in the order: DP-107 >> DP-178 > FP-I. CD analysis also indicated binding of DP-178 to either DP-107 or FP-I. Consequently, DP-178 may inhibit the membrane actions mediated by either FP-I or DP-107 through direct peptide interactions in solution. These peptide results suggest that the corresponding N-terminal fusion and N-leucine zipper regions participate in HIV infection, by promoting membrane perturbations underlying the merging of the viral envelope with the cell surface. Further, the C-leucine zipper domain in "prefusion" HIV may inhibit these membrane activities by interacting with the N-terminal fusion and N-leucine zipper domains in unactivated gp41. Last, exogenous DP-178 may bind to the N-terminal and N-leucine zipper domains of gp41 that become exposed on HIV stimulation, thereby preventing the fusogenic actions of these gp41 regions leading to infection.


Executive functions form a single construct and are associated with schooling: Evidence from three low- and middle- income countries.
Measuring executive function (EF) among adults is important, as the cognitive processes involved in EF are critical to academic achievement, job success and mental health. Current evidence on measurement and structure of EF largely come from Western, Educated, Industrialized, Rich and Democratic (WEIRD) countries. However, measuring EF in low-and-middle-income countries (LMICs) is challenging, because of the dearth of EF measures validated across LMICs, particularly measures that do not require extensive training, expensive equipment, or professional administration. This paper uses data from three LMIC cohorts to test the feasibility, validity and reliability of EF assessment in adults using three sub-tests (representing key components of EF) of the NIH Toolbox Cognitive battery. For each cohort, all three EF measures (inhibition, flexibility and working memory) loaded well onto a unidimensional latent factor of EF. Factor scores related well to measures of fluid intelligence, processing speed and schooling. All measures showed good test-retest reliability across countries. This study provides evidence for a set of sound measures of EF that could be used across different cultural, language and socio-economic backgrounds in future LMIC research. Furthermore, our findings extend conclusions on the structure of EF beyond those drawn from WEIRD countries.


Animal use in the chemical and product manufacturing sectors - can the downtrend continue?
During the 1990s and early 2000s, a number of manufacturing companies in the cosmetic, personal care and household product industries were able to substantially reduce their use of animals for testing (or to not use animals in the first place). These reductions were almost always the result of significant financial contributions to either direct, in-house alternatives research, or to support personnel whose duties were to understand and apply the current state-of-the-art for in vitro testing. They occurred almost exclusively in non-regulatory areas, and primarily involved acute topical toxicities. Over the last few years, the reduction in animal use has been much less dramatic, because some companies are still reluctant to change from the traditional animal studies, because systemic, repeat-dose toxicity is more difficult to model in vitro, and because many products still require animal testing for regulatory approval. Encouragingly, we are now observing an increased acceptance of non-animal methods by regulatory agencies. This is due to mounting scientific evidence from larger databases, agreement by companies to share data and testing strategies with regulatory agencies, and a focus on smaller domains of applicability. These changes, along with new emphasis and financial support for addressing systemic toxicities, promise to provide additional possibilities for industry to replace animals with in vitro methods, alone or in combination with in silico methods. However, the largest advance will not occur until more companies commit to using the non-animal test strategies that are currently available.


Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines.
Sulforaphane, an isothiocyanate found in cruciferous vegetables, has been shown to induce phase 2 detoxication enzymes and inhibit the growth of chemically induced mammary tumors in rats, although the exact mechanisms of action of sulforaphane are not understood. In this study, we evaluated the effects of sulforaphane on cell growth and death in several human breast cancer cell lines and examined the hypothesis that sulforaphane acts as a histone deacetylase (HDAC) inhibitor in these cell lines. Sulforaphane treatment inhibited cell growth, induced a G(2)-M cell cycle block, increased expression of cyclin B1, and induced oligonucleosomal DNA fragmentation in the four human breast cancer cell lines examined, MDA-MB-231, MDA-MB-468, MCF-7, and T47D cells. Activation of apoptosis by sulforaphane in MDA-MB-231 cells seemed to be initiated through induction of Fas ligand, which resulted in activation of caspase-8, caspase-3, and poly(ADP-ribose) polymerase, whereas apoptosis in the other breast cancer cell lines was initiated by decreased Bcl-2 expression, release of cytochrome c into the cytosol, activation of caspase-9 and caspase-3, but not caspase-8, and poly(ADP-ribose) polymerase cleavage. Sulforaphane inhibited HDAC activity and decreased the expression of estrogen receptor-alpha, epidermal growth factor receptor, and human epidermal growth factor receptor-2 in each cell line, although no change in the acetylation of H3 or H4 was seen. These data suggest that sulforaphane inhibits cell growth, activates apoptosis, inhibits HDAC activity, and decreases the expression of key proteins involved in breast cancer proliferation in human breast cancer cells. These results support testing sulforaphane in vivo and warrant future studies examining the clinical potential of sulforaphane in human breast cancer.


Evaluation of physiological parameters before and after respiratory physiotherapy in newborns with acute viral bronchiolitis.
Acute viral bronchiolitis is a respiratory disease with high morbidity that affects newborn in the first two years of life. Its treatment with physiotherapy has been highlighted as an important tool, however, there is no consensus regarding its effects on patients improvement. We aimed to evaluate the physiological parameters before and after the procedure respiratory therapy in newborn with acute viral bronchiolitis. This was a cross sectional observational study in 30 newborns with acute viral bronchiolitis and indicated for physiotherapy care in a hospitalized Urgency and Emergency Unit. It was collected the clinical data of newborn through evaluation form, and we measured heart rate (HR), oxygen saturation (SpO2) and respiratory rate (RR). We measured the variables before physiotherapy treatment, 3, 6 and 9 minutes after the physiotherapy treatment. There has been no change in HR, however, we observed a decrease in RR at 6 and 9 min compared to 3 min and increase in SpO2 at 3, 6 and 9 min compared to before physiotherapy. Respiratory physiotherapy may be an effective therapy for the treatment of newborn with Acute Viral Bronchitis.