A lipodystrophy-causing lamin A mutant alters conformation and epigenetic regulation of the anti-adipogenic MIR335 locus.
Mutations in the Lamin A/C (LMNA) gene-encoding nuclear LMNA cause laminopathies, which include partial lipodystrophies associated with metabolic syndromes. The lipodystrophy-associated LMNA p.R482W mutation is known to impair adipogenic differentiation, but the mechanisms involved are unclear. We show in this study that the lamin A p.R482W hot spot mutation prevents adipogenic gene expression by epigenetically deregulating long-range enhancers of the anti-adipogenic MIR335 microRNA gene in human adipocyte progenitor cells. The R482W mutation results in a loss of function of differentiation-dependent lamin A binding to the MIR335 locus. This impairs H3K27 methylation and instead favors H3K27 acetylation on MIR335 enhancers. The lamin A mutation further promotes spatial clustering of MIR335 enhancer and promoter elements along with overexpression of the MIR355 gene after adipogenic induction. Our results link a laminopathy-causing lamin A mutation to an unsuspected deregulation of chromatin states and spatial conformation of an miRNA locus critical for adipose progenitor cell fate.


The nexus of nursing leadership and a culture of safer patient care.
To explore the connection between +6 nursing leadership and enhanced patient safety. Critical reports from the Institute of Medicine in 1999 and Francis QC report of 2013 indicate that healthcare organisations, inclusive of nursing leadership, were remiss or inconsistent in fostering a culture of safety. The factors required to foster organisational safety culture include supportive leadership, effective communication, an orientation programme and ongoing training, appropriate staffing, open communication regarding errors, compliance to policy and procedure, and environmental safety and security. As nurses have the highest patient interaction, and leadership is discernible at all levels of nursing, nurse leaders are the nexus to influencing organisational culture towards safer practices. The position of this article was to explore the need to form a nexus between safety culture and leadership for the provision of safe care. Safety is crucial in health care for patient safety and patient outcomes. A culture of safety has been exposed as a major influence on patient safety practices, heavily influenced by leadership behaviours. The relationship between leadership and safety plays a pivotal role in creating positive safety outcomes for patient care. A safe culture is one nurtured by effective leadership. Patient safety is the responsibility of all healthcare workers, from the highest executive to the bedside nurse, thus effective leadership throughout all levels is essential in engaging staff to provide high quality care for the best possible patient outcomes.


Transient perceptual neglect: visual working memory load affects conscious object processing.
Visual working memory (VWM) is a capacity-limited cognitive resource that plays an important role in complex cognitive behaviors. Recent studies indicate that regions subserving VWM may play a role in the perception and recognition of visual objects, suggesting that conscious object perception may depend on the same cognitive and neural architecture that supports the maintenance of visual object information. In the present study, we examined this question by testing object processing under a concurrent VWM load. Under a high VWM load, recognition was impaired for objects presented in the left visual field, in particular when two objects were presented simultaneously. Multivariate fMRI revealed that two independent but partially overlapping networks of brain regions contribute to object recognition. The first network consisted of regions involved in VWM encoding and maintenance. Importantly, these regions were also sensitive to object load. The second network comprised regions of the ventral temporal lobes traditionally associated with object recognition. Importantly, activation in both networks predicted object recognition performance. These results indicate that information processing in regions that mediate VWM may be critical to conscious visual perception. Moreover, the observation of a hemifield asymmetry in object recognition performance has important theoretical and clinical significance for the study of visual neglect.


Matrix metalloproteinase-1 and -9 activation by plasmin regulates a novel endothelial cell-mediated mechanism of collagen gel contraction and capillary tube regression in three-dimensional collagen matrices.
Here, we describe a new function for plasmin and matrix metalloproteinases (MMPs), which is to regulate the regression of capillary tubes in three-dimensional extracellular matrix environments. Using a well-described capillary morphogenesis system in three-dimensional collagen matrices, a new model of capillary regression has been established by adding plasminogen to the culture medium. Plasminogen is converted to plasmin by endothelial cell plasminogen activators which then induces matrix metalloproteinase-dependent collagen gel contraction and capillary regression. Plasminogen addition results in activation of MMP-1 and MMP-9, which then results in collagen proteolysis followed by capillary regression. The endothelial cells undergo apoptosis following gel contraction as detected by flow cytometric analysis as well as by detectable caspase-3 cleavage and caspase-dependent cleavage of the actin cytoskeletal regulatory protein, gelsolin. In addition, directly correlating with the contraction response, tyrosine phosphorylation of p130cas, an adapter protein in the focal adhesion complex, is observed followed by disappearance of the protein. Proteinase inhibitors that block MMPs (TIMP-1 or TIMP-2), plasminogen activators (PAI-1) or plasmin (aprotinin) completely block the gel contraction and regression process. In addition, chemical inhibitors of MMPs that block capillary regression also block MMP-1 and MMP-9 activation suggesting that a key element in this regression response is the molecular control of MMP activation by endothelial cells. Blocking antibodies directed to MMP-1 or MMP-9 interfere with capillary regression while blocking antibodies directed to PAI-1 accelerate capillary regression suggesting that endogenous synthesis of PAI-1 negatively regulates this process. These data present a novel system to study a new mechanism that may regulate regression of capillary tubes, namely, plasmin and MMP-mediated degradation of extracellular matrix.


Molecular phylogeny of Macaranga, Mallotus, and related genera (Euphorbiaceae s.s.): insights from plastid and nuclear DNA sequence data.
Macaranga and Mallotus (Euphorbiaceae s.s.) are two closely related, large paleo(sub)tropical genera. To investigate the phylogenetic relationships between and within them and to determine the position of related genera belonging to the subtribe Rottlerinae, we sequenced one plastid (trnL-F) and three nuclear (ITS, ncpGS, phyC) markers for species representative of these genera. The analyses demonstrated the monophyly of Macaranga and the paraphyly of Mallotus and revealed three highly supported main clades. The genera Cordemoya and Deuteromallotus and the Mallotus sections Hancea and Oliganthae form a basal Cordemoya s.l. clade. The two other clades, the Macaranga clade and the Mallotus s.s. clade (the latter with Coccoceras, Neotrewia, Octospermum, and Trewia), are sister groups. In the Macaranga clade, two basal lineages (comprising mostly sect. Pseudorottlera) and a crown group with three geographically homogenous main clades were identified. The phylogeny of the Mallotus s.s. clade is less clear because of internal conflict in all four data sets. Many of the sections and informal infrageneric groups of Macaranga and Mallotus do not appear to be monophyletic. In both the Macaranga and Mallotus s.s. clades, the African and/or Madagascan taxa are nested in Asian clades, suggesting migrations or dispersals from Asia to Africa and Madagascar.


Physiological and biochemical effect of 24-epibrassinoslide on cold tolerance in maize seedlings.
Germination and early seedling growth are important for establishment of maize because maize is chilling sensitive crop and low temperature during early period of growth can be detrimental to subsequent crop growth and productivity. Therefore, it is important to protect maize seedling from cold stress. A study was conducted on induced cold tolerance by 24-epibrassinoslide (EBR) at the Indian Agricultural Research Institute, New Delhi, India. Maize seedlings were raised in green house condition (25/18 °C day-night temperatures). Ten days old seedlings were treated with EBR (0.0, 0.01, 0.1, 1.0 and 10 μM) and then divided into two sets, one set was kept in greenhouse (25/18 °C day-night temperatures) and another was transferred to net house (cold stress). Data on various morpho-physiological traits was recorded after 7, 14 and 21 days of treatment. Exogenous application of 1.0 μM EBR had significant effect on growth and morpho-physiological traits under both conditions. The maize seedlings treated with EBR were more tolerant to cold stress than the untreated one. Significant increase in plant height, dry matter accumulation, chlorophyll content, total soluble proteins and starch contents was observed under both conditions, however, the results were more pronounced under cold stress. 1.0 μ M concentration being the most effective under both conditions. Maintenance of high tissue water content, reduced membrane injury index, increased total chlorophyll, soluble sugar and protein content were taken as the possible indicators of EBR induced chilling tolerance.


Kir6.1-dependent KATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain-of-function.
Spontaneous contractions are essential for normal lymph transport and these contractions are exquisitely sensitive to the KATP channel activator pinacidil. KATP channel Kir6.1 and SUR2B subunits are expressed in mouse lymphatic smooth muscle (LSM) and form functional KATP channels as verified by electrophysiological techniques. Global deletion of Kir6.1 or SUR2 subunits results in severely impaired lymphatic contractile responses to pinacidil. Smooth muscle-specific expression of Kir6.1 gain-of-function mutant (GoF) subunits results in profound lymphatic contractile dysfunction and LSM hyperpolarization that is partially rescued by the KATP inhibitor glibenclamide. In contrast, lymphatic endothelial-specific expression of Kir6.1 GoF has essentially no effect on lymphatic contractile function. The high sensitivity of LSM to KATP channel GoF offers an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1 or SUR2, and suggests that glibenclamide may be an appropriate therapeutic agent. This study aimed to understand the functional expression of KATP channel subunits in distinct lymphatic cell types, and assess the consequences of altered KATP channel activity on lymphatic pump function. KATP channel subunits Kir6.1 and SUR2B were expressed in mouse lymphatic muscle by PCR, but only Kir6.1 was expressed in lymphatic endothelium. Spontaneous contractions of popliteal lymphatics from wild-type (WT) (C57BL/6J) mice, assessed by pressure myography, were very sensitive to inhibition by the SUR2-specific KATP channel activator pinacidil, which hyperpolarized both mouse and human lymphatic smooth muscle (LSM). In vessels from mice with deletion of Kir6.1 (Kir6.1-/- ) or SUR2 (SUR2[STOP]) subunits, contractile parameters were not significantly different from those of WT vessels, suggesting that basal KATP channel activity in LSM is not an essential component of the lymphatic pacemaker, and does not exert a strong influence over contractile strength. However, these vessels were >100-fold less sensitive than WT vessels to pinacidil. Smooth muscle-specific expression of a Kir6.1 gain-of-function (GoF) subunit resulted in severely impaired lymphatic contractions and hyperpolarized LSM. Membrane potential and contractile activity was partially restored by the KATP channel inhibitor glibenclamide. In contrast, lymphatic endothelium-specific expression of Kir6.1 GoF subunits had negligible effects on lymphatic contraction frequency or amplitude. Our results demonstrate a high sensitivity of lymphatic contractility to KATP channel activators through activation of Kir6.1/SUR2-dependent channels in LSM. In addition, they offer an explanation for the lymphoedema observed in patients with Cantú syndrome, a disorder caused by gain-of-function mutations in genes encoding Kir6.1/SUR2.


Availability, accessibility, and affordability of neurodiagnostic tests in 37 countries.
To determine the availability, accessibility, and affordability of EEG, EMG, CSF analysis, head CT, and brain MRI for neurologic disorders across countries. An online, 60-question survey was distributed to neurology practitioners in 2014 to assess the presence, wait time, and cost of each test in private and public health sectors. Data were stratified by World Bank country income group. Affordability was calculated with reference to the World Health Organization's definition of catastrophic health expenditure as health-related out-of-pocket expenditure of >40% of disposable household income, and assessment of providers' perceptions of affordability to the patient. Availability of EEG and EMG is correlated with higher World Bank income group (correlation coefficient 0.38, test for trend p = 0.046; 0.376, p = 0.043); CSF, CT, and MRI did not show statistically significant associations with income groups. Patients in public systems wait longer for neurodiagnostic tests, especially MRI, EEG, and urgent CT (p < 0.0001). The mean cost per test, across all tests, was lower in the public vs private sector (US $55.25 vs $214.62, p < 0.001). Each drop in World Bank income group is associated with a 29% decrease in the estimated share of the population who can afford a given test (95% confidence interval -33.4, 25.2; p < 0.001). In most low-income countries surveyed, only the top 10% or 20% of the population was able to afford tests below catastrophic levels. In surveyed lower-middle-income countries, >40% of the population, on average, could not afford neurodiagnostic tests. Neurodiagnostic tests are least affordable in the lowest income settings. Closing this "diagnostic gap" for countries with the lowest incomes is essential.


Health wearable devices for weight and BMI reduction in individuals with overweight/obesity and chronic comorbidities: systematic review and network meta-analysis.
To analyse the comparative effectiveness of different health wearable-based physical activity (PA) promotion intervention strategies against each other and control for reducing body weight and body mass index (BMI) in individuals with overweight/obesity and chronic comorbidities. Systematic review and network meta-analysis (PROSPERO identifier: CRD42020158191). We performed two independent searches from December 2019 to September 2020 in PubMed, MEDLINE, Scopus, Web of Science, Central Register of Controlled Trials, EMBASE and PsycINFO databases for articles published in English between 2007 and 2020. Inclusion criteria were based on the PICOS framework. We included randomised controlled trials of health wearable-based interventions using two or more PA intervention arms/strategies and compared their effects on participants' body weight (kg) and BMI (kg/m2) with a control group. Data were analysed using a Bayesian network meta-analysis to directly and indirectly compare the effects of the six different intervention strategies (comparators). The six comparators were: (1) control group (ie, usual care, waitlist); (2) comparison group (ie, traditional, non-health wearable PA interventions); (3) commercial health wearable-only intervention (eg, Fitbit, Polar M400); (4) research grade health wearable-only intervention (ie, accelerometers or pedometers); (5) multicomponent commercial health wearable intervention (eg, Fitbit + nutrition counselling); and (6) multicomponent research grade health wearable intervention. The results were reported as standardised mean differences (SMDs) with associated 95% credible intervals (CrIs). From 641 screened records, 31 studies were included. For body weight reduction in individuals with overweight/obesity and chronic comorbidities, accelerometer/pedometer-only (SMD -4.44, 95% CrI -8.94 to 0.07) and commercial health wearable-only (SMD -2.76, 95% CrI -4.80 to -0.81) intervention strategies were the most effective compared with the three other treatments and control. For BMI reduction, multicomponent accelerometer/pedometer (SMD -3.43, 95% CrI -4.94 to -2.09) and commercial health wearable-only (SMD -1.99, 95% CrI -4.95 to 0.96) intervention strategies were the most effective compared with the other four conditions. Health wearable devices are effective intervention tools/strategies for reducing body weight and BMI in individuals with overweight/obesity and chronic comorbidities.


Medical student engagement and leadership within a new learning community.
Many medical schools are establishing learning communities to foster cohesion among students and to strengthen relationships between students and faculty members. Emerging learning communities require nurturing and attention; this represents an opportunity wherein medical students can become involved as leaders. This study sought to understand issues related to active involvement among students who chose to become highly engaged in a newly developed learning community. Between April and June 2008, 36 students who assumed leadership roles within the Colleges Program were queried electronically with open-ended questions about their engagement. Qualitative analysis of the written responses was independently performed by two investigators; coding was compared for agreement. Content analysis identified major themes. 35 students (97%) completed the questionnaire. Motives that emerged as reasons for getting involved included: endorsing the need for the program; excitement with the start-up; wanting to give back; commitment to institutional excellence; and collaboration with talented peers and faculty. Perceived benefits were grouped under the following domains: connecting with others; mentoring; learning new skills; and recognition. The most frequently identified drawbacks were the time commitment and the opportunity costs. Ideas for drawing medical students into new endeavors included: creating defined roles; offering a breadth of opportunities; empowering students with responsibility; and making them feel valued. Medical students were drawn to and took on leadership roles in a medical school curricular innovation. This example may prove helpful to others hoping to engage students as leaders in learning communities at their schools or those wishing to augment student involvement in other programs.


Pseudotumors due to IgG4 immune-complex tubulointerstitial nephritis associated with autoimmune pancreatocentric disease.
Autoimmune pancreatitis (AIP) is a mass-forming chronic fibroinflammatory condition centered on the pancreatobiliary system and characterized by predominant immunoglobulin G4 (IgG4)-positive plasma cells. Recent reports have brought to light the multiorgan involvement of this disease. We describe a series of 5 cases of tubulointerstitial nephritis (TIN) associated with AIP and characterize the clinical, pathologic, ultrastructural, and immunopathologic features of TIN. The specimens consisted of 4 biopsies and 1 nephrectomy. The average patient age was 64 years (range 45 to 78) and the male to female ratio was 4:1. All had histologic and/or clinical and radiographic evidence of AIP, mass-forming sclerosing cholangitis, or both. The clinical impression in 4 patients was a renal mass or vasculitis. Two patients had renal insufficiency. Histologic preparations revealed a dense tubulointerstitial lymphoplasmacytic infiltrate. Eosinophils were often numerous. Tubulitis and tubular injury were present, along with tubular atrophy with focally thickened tubular basement membranes (TBMs). The histologic appearance ranged from a cellular, inflammatory pattern without tubular atrophy to a striking expansive interstitial fibrosis with tubular destruction. The nephrectomy specimen demonstrated a masslike nodular pattern of inflammation with normal renal tissue elsewhere. Glomeruli were uninvolved. By immunohistochemistry or immunofluorescence, numerous plasma cells in the infiltrate were positive for IgG4. TBM granular IgG deposits, predominantly of the IgG4 subclass, were detected in 4 of 5 cases by either immunofluorescence or immunohistochemistry. By electron microscopy, corresponding amorphous electron-dense deposits were present in the TBM in these cases. This type of TIN, typically characterized by a masslike lesion consisting of a lymphoplasmacytic infiltrate with eosinophils and prominent IgG4-positive plasma cells and immune-complex deposits in the TBM, may be part of a systemic IgG4-related disease, which we term "IgG4-associated immune complex Multiorgan Autoimmune Disease" (IMAD).


Effects of (-)-tertatolol, (-)-penbutolol and (+/-)-pindolol in combination with paroxetine on presynaptic 5-HT function: an in vivo microdialysis and electrophysiological study.
The antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) might be enhanced by co-administration of 5-HT1A receptor antagonists. Thus, we have recently shown that the selective 5-HT1A receptor antagonist, WAY 100635, blocks the inhibitory effect of an SSRI on 5-HT cell firing, and enhances its ability to elevate extracellular 5-HT in the forebrain. Here we determined whether the beta-adrenoceptor/5-HT1A receptor ligands (+/-)-pindolol, (-)-tertatolol and (-)-penbutolol, interact with paroxetine in a similar manner. Both (-)-tertatolol (2.4 mg kg(-1) i.v.) and (-)-penbutolol (2.4 mg kg(-1) i.v.) enhanced the effect of paroxetine (0.8 mg kg(-1) i.v.) on extracellular 5-HT in the frontal cortex, whilst (+/-)-pindolol (4 mg kg(-1) i.v.) did not. (-)-Tertatolol (2.4 mg kg(-1) i.v.) alone caused a slight increase in 5-HT however, (-)-penbutolol (2.4 mg kg(-1) i.v.) alone had no effect. In electrophysiological studies (-)-tertatolol (2.4 mg kg(-1) i.v.) alone had no effect on 5-HT cell firing but blocked the inhibitory effect of paroxetine. In contrast, (-)-penbutolol (0.1-0.8 mg kg(-1) i.v.) itself inhibited 5-HT cell firing, and this effect was reversed by WAY 100635 (0.1 mg kg(-1) i.v.). We have recently shown that (+/-)-pindolol inhibits 5-HT cell firing via a WAY 100635-sensitive mechanism. Our data suggest that (-)-tertatolol enhances the effect of paroxetine on forebrain 5-HT via blockade of 5-HT1A autoreceptors which mediate paroxetine-induced inhibition of 5-HT cell firing. In comparison, the mechanisms by which (-)-penbutolol enhances the effect of paroxetine on extracellular 5-HT is unclear, since (-)-penbutolol itself appears to have agonist properties at the 5-HT1A autoreceptor. Indeed, the agonist action of (+/-)-pindolol at 5-HT1A autoreceptors probably explains its inability to enhance the effect of paroxetine on 5-HT in the frontal cortex. Overall, our data suggest that both (-)-tertatolol and (-)-penbutolol are superior to (+/-)-pindolol in terms of enhancing the effect of an SSRI on extracellular 5-HT. Both (-)-tertatolol and (-)-penbutolol are worthy of investigation for use as adjuncts to SSRIs in the treatment of major depression.


Synthesis and antiviral evaluation of base-modified deoxythreosyl nucleoside phosphonates.
l-α-2'-Deoxythreosyl nucleoside phosphonates and their phosphonodiamidate prodrugs with a hypoxanthine, 2,6-diaminopurine, 2-amino-6-cyclopropylaminopurine, 7-deazaadenine, 5-fluorouracil and 5-methylcytosine heterocycle as a nucleobase were synthesized and evaluated for their inhibitory activity against HIV and HBV. The 2,6-diaminopurine modified analogue 23a displayed the most potent activity against HIV, with an EC50 value of 11.17 μM against HIV-1 (IIIB) and an EC50 value of 8.15 μM against HIV-2 (ROD). The application of the prodrug strategy on nucleoside phosphonate 23a led to a 200-fold boost in anti-HIV potency. None of the compounds showed any activity against HBV at the highest concentration tested.


Comparison of five point-of-use drinking water technologies using a specialized comparison framework.
Three novel and two commercially available low-cost point-of-use (PoU) water treatment technologies were comparatively evaluated using a specialized comparison framework targeted at them. The comparison results and specialized framework have been discussed. The PoU systems were evaluated principally in terms of performance, flow rate and cost per volume of water treated (quantitatively), ease of use, potential acceptability and material availability (qualitatively) with main focus on rural and suburban settings. The three novel systems assessed were developed in an ongoing research project aimed at developing a multibarrier low-cost PoU water treatment system. The comparative evaluation and analysis revealed that the commercially available systems may often produce water free of pathogens (with an apparent 100% removal for Escherichia coli and fecal coliforms) but may not be affordable for application to the poorest groups in much of the developing world. The novel systems, which were principally constructed from local materials, were more affordable, can supply relatively safe water and can be constructed by users with minimal training. Overall, bacterial removal effectiveness, ease of use, flow rate, material availability, cost and acceptability aspects of water were identified as key to potential adoption and sustainability of the evaluated low-cost PoU systems.


Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies.
Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and long-term subjective effects of psilocybin in healthy humans by pooling raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1-4 oral doses of psilocybin (45-315 µg/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk.


Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/- murine hearts modelling the Brugada syndrome.
Brugada syndrome (BrS) is associated with a loss of Na+ channel function and an increased incidence of rapid polymorphic ventricular tachycardia (VT) and sudden cardiac death. A programmed electrical stimulation (PES) technique assessed arrhythmic tendency in Langendorff-perfused wild-type (WT) and genetically modified (Scn5a+/-) 'loss-of-function' murine hearts in the presence and absence of flecainide and quinidine, and the extent to which Scn5a+/- hearts model the human BrS. Extra-stimuli (S2), applied to the right ventricular epicardium, followed trains of pacing stimuli (S1) at progressively reduced S1-S2 intervals. These triggered VT in 16 out of 29 untreated Scn5a+/- and zero out of 31 WT hearts. VT occurred in 11 out of 16 (10 microM) flecainide-treated WT and nine out of the 13 initially non-arrhythmogenic Scn5a+/- hearts treated with (1.0 microM) flecainide. Quinidine (10 microM) prevented VT in six out of six flecainide-treated WT and 13 out of the 16 arrhythmogenic Scn5a+/- hearts in parallel with its clinical effects. Paced electrogram fractionation analysis demonstrated increased electrogram durations, expressed as electrogram duration (EGD) ratios, with shortening S1-S2 intervals in arrhythmogenic Scn5a+/- hearts, and prolonged ventricular effective refractory periods (VERPs) in non-arrhythmogenic Scn5a+/- hearts. Flecainide increased EGD ratios in WT (at 10 microM) and non-arrhythmogenic Scn5a+/- hearts (at 1.0 microM), whereas quinidine (10 microM) reduced EGD ratios and prolonged VERPs in WT and arrhythmogenic Scn5a+/- hearts. However, epicardial and endocardial monophasic action potential recordings consistently demonstrated positive gradients of repolarization in WT, arrhythmogenic and non-arrhythmogenic Scn5a+/- hearts under all pharmacological conditions. Together, these findings demonstrate proarrhythmic effects of flecainide in WT and Scn5a+/- murine hearts that recapitulate its clinical effects. They further attribute the arrhythmogenic phenomena observed here to re-entrant substrates resulting from delayed epicardial activation despite an absence of transmural heterogeneities of repolarization, in sharp contrast to recent characterizations in 'gain-of-function' Scn5a+/Delta murine hearts modelling the long-QT(3) syndrome.


Scaling of BMP gradients in Xenopus embryos.
Metazoan organisms can 'scale', that is, maintain similar proportions regardless of size. Ben-Zvi et al. use experiments in Xenopus to support a quantitative model that explains morphological scaling as the result of scaling of a gradient of bone morphogenetic protein (BMP) signals. We believe that the evidence for scaling in Xenopus is misinterpreted, and that their model for embryonic patterning disagrees with prior data. The experiments they present supporting their model admit alternative interpretations.


Fertility intentions and recent births among US abortion patients.
To examine fertility intentions among abortion patients and the potential of abortion for avoiding short birth intervals. We used national data from a sample of more than 8000 individuals obtaining abortions in the United States in 2014. We created a measure of fertility intentions based on prior births and responses to an item asking about future childbearing expectations. We identify respondents who reported having a birth in the last 12 months as at risk of a short birth interval. We used simple logistic regression to assess for differences in these measures according to key demographic variables. Most commonly, 39% of patients intended to have (more) children, with similar proportions wanting to delay a first birth (20%) or postpone a second or higher order birth (19%). Some 31% of abortion patients had completed childbearing; they had one or more prior births and did not want to have any more children. Similar proportions of respondents were not sure if they wanted to have children (16%) or did not want to have any children (15%). Among abortion patients who had children, 14% had had a birth in the prior year. We estimate that as many as 77,800 short birth intervals were averted in 2014 because individuals had access to abortion. These findings support the view that abortion allows individuals to plan and space their births according to their reproductive life plans and intentions. Access to abortion may help thousands of individuals in the United States avoid short birth intervals, potentially leading to improvements in maternal and child health.


Abnormal podocyte TRPML1 channel activity and exosome release in mice with podocyte-specific Asah1 gene deletion.
Podocytopathy and associated nephrotic syndrome (NS) have been reported in a knockout mouse strain (Asah1fl/fl/PodoCre) with a podocyte-specific deletion of α subunit (the main catalytic subunit) of acid ceramidase (Ac). However, the pathogenesis of podocytopathy of these mice remains unknown. The present study tested whether exosome release from podocytes is enhanced due to Asah1 gene knockout, which may serve as a pathogenic mechanism switching on podocytopathy and associated NS in Asah1fl/fl/PodoCre mice. We first demonstrated the remarkable elevation of urinary exosome excretion in Asah1fl/fl/PodoCre mice compared with WT/WT mice, which was accompanied by significant Annexin-II (an exosome marker) accumulation in glomeruli of Asah1fl/fl/PodoCre mice, as detected by immunohistochemistry. In cell studies, we also confirmed that Asah1 gene knockout enhanced exosome release in the primary cultures of podocyte isolated from Asah1fl/fl/PodoCre mice compared to WT/WT mice. In the podocytes from Asah1fl/fl/PodoCre mice, the interactions of lysosome and multivesicular body (MVB) were demonstrated to be decreased in comparison with those from their control littermates, suggesting reduced MVB degradation that may lead to increase in exosome release. Given the critical role of transient receptor potential mucolipin 1 (TRPML1) channel in Ca2+-dependent lysosome trafficking and consequent lysosome-MVB interaction, we tested whether lysosomal Ca2+ release through TRPML1 channels is inhibited in the podocytes of Asah1fl/fl/PodoCre mice. By GCaMP3 Ca2+ imaging, it was found that lysosomal Ca2+ release through TRPML1 channels was substantially suppressed in podocytes with Asah1 gene deletion. As an Ac product, sphingosine was found to rescue TRPML1 channel activity and thereby recover lysosome-MVB interaction and reduce exosome release of podocytes from Asah1fl/fl/PodoCre mice. Combination of N, N-dimethylsphingosine (DMS), a potent sphingosine kinase inhibitor, and sphingosine significantly inhibited urinary exosome excretion of Asah1fl/fl/PodoCre mice. Moreover, rescue of Aash1 gene expression in podocytes of Asah1fl/fl/PodoCre mice showed normal ceramide metabolism and exosome secretion. Based on these results, we conclude that the normal expression of Ac importantly contributes to the control of TRPML1 channel activity, lysosome-MVB interaction, and consequent exosome release from podocytes. Asah1 gene defect inhibits TRPML1 channel activity and thereby enhances exosome release, which may contribute to the development of podocytopathy and associated NS.


Immunoadjuvant Properties of the Rho Activating Factor CNF1 in Prophylactic and Curative Vaccination against Leishmania infantum.
There is a need to develop new effective immunoadjuvants for prophylactic or therapeutic vaccines against intracellular pathogens. The activation of Rho GTPases by bacterial cytotoxic necrotizing factor 1 (CNF1) elicits humoral protective responses against protein antigens. Here, we set out to investigate whether CNF1 activity initiates humoral immunity against co-administered parasite antigens and anti-microbial immune signaling. We report that co-administration of wild-type (WT) CNF1 with Leishmania (L.) promastigote antigens at the nasal mucosa triggered prophylactic and curative vaccine responses against this parasite. Vaccination of the mucosa with promastigote lysate antigens combined with WT CNF1 conferred protection against high inoculum L. infantum infection, which reached 82% in the spleen. Immune parameter analysis by antigen recall indicated robust T-helper (Th)1 polarization of immune memory cells, with high IL-2 and IFN-γ production combined with decreased IL-4 production. Additionally, we explored the curative effect of WT CNF1 on previously infected animals. We observed that PL combined with WT CNF1, but not the inactive C866S mutant CNF1 (mCNF1), induced a 58% decrease in the parasite burden in the spleen.


A network's gender composition and communication pattern predict women's leadership success.
Many leaders today do not rise through the ranks but are recruited directly out of graduate programs into leadership positions. We use a quasi-experiment and instrumental-variable regression to understand the link between students' graduate school social networks and placement into leadership positions of varying levels of authority. Our data measure students' personal characteristics and academic performance, as well as their social network information drawn from 4.5 million email correspondences among hundreds of students who were placed directly into leadership positions. After controlling for students' personal characteristics, work experience, and academic performance, we find that students' social networks strongly predict placement into leadership positions. For males, the higher a male student's centrality in the school-wide network, the higher his leadership-job placement will be. Men with network centrality in the top quartile have an expected job placement level that is 1.5 times greater than men in the bottom quartile of centrality. While centrality also predicts women's placement, high-placing women students have one thing more: an inner circle of predominantly female contacts who are connected to many nonoverlapping third-party contacts. Women with a network centrality in the top quartile and a female-dominated inner circle have an expected job placement level that is 2.5 times greater than women with low centrality and a male-dominated inner circle. Women who have networks that resemble those of high-placing men are low-placing, despite having leadership qualifications comparable to high-placing women.


Non-cognate enzyme-DNA complex: structural and kinetic analysis of EcoRV endonuclease bound to the EcoRI recognition site GAATTC.
The crystal structure of EcoRV endonuclease bound to non-cognate DNA at 2.0 angstroms resolution shows that very small structural adaptations are sufficient to ensure the extreme sequence specificity characteristic of restriction enzymes. EcoRV bends its specific GATATC site sharply by 50 degrees into the major groove at the center TA step, generating unusual base-base interactions along each individual DNA strand. In the symmetric non-cognate complex bound to GAATTC, the center step bend is relaxed to avoid steric hindrance caused by the different placement of the exocyclic thymine methyl groups. The decreased base-pair unstacking in turn leads to small conformational rearrangements in the sugar-phosphate backbone, sufficient to destabilize binding of crucial divalent metal ions in the active site. A second crystal structure of EcoRV bound to the base-analog GAAUTC site shows that the 50 degrees center-step bend of the DNA is restored. However, while divalent metals bind at high occupancy in this structure, one metal ion shifts away from binding at the scissile DNA phosphate to a position near the 3'-adjacent phosphate group. This may explain why the 10(4)-fold attenuated cleavage efficiency toward GAATTC is reconstituted by less than tenfold toward GAAUTC. Examination of DNA binding and bending by equilibrium and stopped-flow florescence quenching and fluorescence resonance energy transfer (FRET) methods demonstrates that the capacity of EcoRV to bend the GAATTC non-cognate site is severely limited, but that full bending of GAAUTC is achieved at only a threefold reduced rate compared with the cognate complex. Together, the structural and biochemical data demonstrate the existence of distinct mechanisms for ensuring specificity at the bending and catalytic steps, respectively. The limited conformational rearrangements observed in the EcoRV non-cognate complex provide a sharp contrast to the extensive structural changes found in a non-cognate BamHI-DNA crystal structure, thus demonstrating a diversity of mechanisms by which restriction enzymes are able to achieve specificity.


Selective deletion of the Hnf1beta (MODY5) gene in beta-cells leads to altered gene expression and defective insulin release.
Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF1beta (or vHNF1) are closely related transcription factors expressed in liver, kidney, gut, and pancreatic beta-cells. Many HNF1 target genes are involved in carbohydrate metabolism. Human mutations in HNF1alpha or HNF1beta lead to maturity-onset diabetes of the young (MODY3 and MODY5, respectively), and patients present with impaired glucose-stimulated insulin secretion. The underlying defect in MODY5 is not known. Analysis of HNF1beta deficiency in mice has not been possible because HNF1beta null mice die in utero. To examine the role of HNF1beta in glucose homeostasis, viable mice deleted for HNF1beta selectively in beta-cells (beta/H1beta-KO mice) were generated using a Cre-LoxP strategy. beta/H1beta-KO mice had normal growth, fertility, fed or fasted plasma glucose and insulin levels, pancreatic insulin content, and insulin sensitivity. However, beta/H1beta-KO mice exhibited impaired glucose tolerance with reduced insulin secretion compared with wild-type mice but preserved a normal insulin secretory response to arginine. Moreover, beta/H1beta-KO islets had increased HNF1alpha and Pdx-1, decreased HNF4 mRNA levels, and reduced glucose-stimulated insulin release. These results indicate that HNF1beta is involved in regulating the beta-cell transcription factor network and is necessary for glucose sensing or glycolytic signaling.


Reactive oxygen species scavengers improve voltage-gated K(+) channel function in pulmonary arteries of newborn pigs with progressive hypoxia-induced pulmonary hypertension.
Abstract Changes in voltage-gated K(+) (Kv) channel function contribute to the pathogenesis of pulmonary hypertension. Yet the mechanisms underlying Kv channel impairments in the pulmonary circulation remain unclear. We tested the hypothesis that reactive oxygen species (ROSs) contribute to the Kv channel dysfunction that develops in resistance-level pulmonary arteries (PRAs) of piglets exposed to chronic in vivo hypoxia. Piglets were raised in either room air (control) or hypoxia for 3 or 10 days. To evaluate Kv channel function, responses to the Kv channel antagonist 4-aminopyridine (4-AP) were measured in cannulated PRAs. To assess the influence of ROSs, PRAs were treated with the ROS-removing agent M40403 (which dismutates superoxide to hydrogen peroxide), plus polyethylene glycol catalase (which converts hydrogen peroxide to water). Responses to 4-AP were diminished in PRAs from both groups of hypoxic piglets. ROS-removing agents had no impact on 4-AP responses in PRAs from piglets exposed to 3 days of hypoxia but significantly increased the response to 4-AP in PRAs from piglets exposed to 10 days of hypoxia. Kv channel function is impaired in PRAs of piglets exposed to 3 or 10 days of in vivo hypoxia. ROSs contribute to Kv channel dysfunction in PRAs from piglets exposed to hypoxia for 10 days but are not involved with the Kv channel dysfunction that develops within 3 days of exposure to hypoxia. Therapies to remove ROSs might improve Kv channel function and thereby ameliorate the progression, but not the onset, of pulmonary hypertension in chronically hypoxic newborn piglets.


Natural Hazard Susceptibility Assessment for Road Planning Using Spatial Multi-Criteria Analysis.
Inadequate infrastructural networks can be detrimental to society if transport between locations becomes hindered or delayed, especially due to natural hazards which are difficult to control. Thus determining natural hazard susceptible areas and incorporating them in the initial planning process, may reduce infrastructural damages in the long run. The objective of this study was to evaluate the usefulness of expert judgments for assessing natural hazard susceptibility through a spatial multi-criteria analysis approach using hydrological, geological, and land use factors. To utilize spatial multi-criteria analysis for decision support, an analytic hierarchy process was adopted where expert judgments were evaluated individually and in an aggregated manner. The estimates of susceptible areas were then compared with the methods weighted linear combination using equal weights and factor interaction method. Results showed that inundation received the highest susceptibility. Using expert judgment showed to perform almost the same as equal weighting where the difference in susceptibility between the two for inundation was around 4%. The results also showed that downscaling could negatively affect the susceptibility assessment and be highly misleading. Susceptibility assessment through spatial multi-criteria analysis is useful for decision support in early road planning despite its limitation to the selection and use of decision rules and criteria. A natural hazard spatial multi-criteria analysis could be used to indicate areas where more investigations need to be undertaken from a natural hazard point of view, and to identify areas thought to have higher susceptibility along existing roads where mitigation measures could be targeted after in-situ investigations.


Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement.
Sentinel node biopsy (SNB) has been at the forefront of the surgical staging of melanoma patients for the past 15 years. The high accuracy of this prognostic staging procedure is now recognised in all international guidelines for melanoma. However during this period there have been a number of important changes in the management of melanoma, many occurring within the past five years. The outcomes of five recent randomised Phase 3 trials have established the role of adjuvant targeted therapy and immunotherapy in resected Stage 3 and Stage 4 disease and have potentially changed the role of SNB. Two landmark international prospective studies have examined the benefit of performing a completion lymph node dissection (CLND) following the detection of microscopicallyinvolved sentinel nodes. Finally, the marked increase in the incidence of melanoma and the role of SNB in potentially guiding therapy has resulted in a significant increase in the pathological workload of the dermatopathology services. To address these issues a multi-disciplinary consensus meeting involving many melanoma experts from the UK was convened in May 2018. Three main areas were considered: oncology, surgery and pathology. This report is a summary of the conclusions reached, which were agreed by the clinicians attending the meeting and then externally peer reviewed. The recommendations summarised in this Consensus Statement.


Lactobacillus reuteri attenuated allergic inflammation induced by HDM in the mouse and modulated gut microbes.
Gut microbiome plays an essential role in asthma development, and probiotic-based manipulation of the gut microbiome has been proposed to prevent asthma. Although the preventive effect of Lactobacillus supplementation against allergies has been reported, the precise Lactobacillus species beneficial for effective prevention of asthma remain unidentified and the underlying mechanisms remain unclear. Therefore, we aimed to investigate the efficacy of oral administration of six Lactobacillus species and the mechanism underlying asthma prevention via gut microbiome modulation. We investigated the effects of oral administration of L. rhamnosus, L. fermentum, L. casei, L. gasseri, L. salivarius, and L. reuteri (five strains of each species) on asthma and gut microbiome of house dust mite (HDM)-treated murine models of asthma. Of these, L. reuteri administration was the most effective: it alleviated airway inflammation, decreased total IgE and HDM-IgG1, and reduced Th2-associated pro-inflammatory cytokines. Moreover, modulation of specific microbial genera by L. reuteri was more effective in asthma prevention than the modulation of the overall microbiota composition. Lactobacillus and Enterococcus were enriched after L. reuteri supplementation and were closely associated with total IgE and IL-13 production. Furthermore, L. reuteri specifically altered the gut microbial function toward butyrate generation. Thus, L. reuteri may reduce the risk of asthma development by modulating specific gut microbiota to improve the lung immune environment. Our study suggests a novel option for gut microbiome manipulation via L. reuteri supplementation for suppression of asthma and other allergic diseases.


Psychiatric disorders in rapid-onset dystonia-parkinsonism.
Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals. Twenty-nine ATP1A3 mutation-positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinson's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV, Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive-Compulsive Scale. NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%). ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation.


State policy, popular discourse, and the silence on homosexual acts in early modern Sweden.
In Sweden, homosexual acts between men were mentioned in secular law for the first time in 1608. Despite the explicit criminalization, very few trials are known from the seventeenth and eighteenth centuries, and the new National Law Code of 1734 contained no sanction at all. The central issue of this essay is how the insignificant number of court cases and the seemingly very limited judicial interest in the issue of sodomy in Early Modern Sweden should be interpreted. The silence of the new law is explained by a shift in the official policy from deterrence to a policy of silence, but the low number of court cases was foremost dependent on a lacking actualization and problematization of homosexual acts in the Swedish popular discourse on sexuality, gender, and prestige. Finally, it is argued that this undeveloped popular discourse probably also corresponded to a meagre and rather restricted sexual practice.


Investigating chemoresistance to improve sensitivity of childhood T-cell acute lymphoblastic leukemia to parthenolide.
Current therapies for childhood T-cell acute lymphoblastic leukemia have increased survival rates to above 85% in developed countries. Unfortunately, some patients fail to respond to therapy and many suffer from serious side effects, highlighting the need to investigate other agents to treat this disease. Parthenolide, a nuclear factor kappa (κ)B inhibitor and reactive oxygen species inducer, has been shown to have excellent anti-cancer activity in pediatric leukemia xenografts, with minimal effects on normal hemopoietic cells. However, some leukemia initiating cell populations remain resistant to parthenolide. This study examined mechanisms for this resistance, including protective effects conferred by bone marrow stromal components. T-cell acute leukemia cells co-cultured with mesenchymal stem cells demonstrated significantly enhanced survival against parthenolide (73±11%) compared to cells treated without mesenchymal stem cell support (11±9%). Direct cell contact between mesenchymal cells and leukemia cells was not required to afford protection from parthenolide. Mesenchymal stem cells released thiols and protected leukemia cells from reactive oxygen species stress, which is associated with parthenolide cytotoxicity. Blocking cystine uptake by mesenchymal stem cells, using a small molecule inhibitor, prevented thiol release and significantly reduced leukemia cell resistance to parthenolide. These data indicate it may be possible to achieve greater toxicity to childhood T-cell acute lymphoblastic leukemia by combining parthenolide with inhibitors of cystine uptake.


The Presence of Human Immunodeficiency Virus-Associated Neurocognitive Disorders Is Associated With a Lower Adherence to Combined Antiretroviral Treatment.
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are defined according to their diagnostic degrees as follows: asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia. Because high adherence to combined antiretroviral therapy (cART) is required to maintain viral suppression among HIV-infected patients, it is important to investigate the impact of HAND on medication adherence. Our study hypothesis was that patients with HAND had a lower medication adherence than patients who did not have HAND. This was an observational, exploratory, 2-center pilot study of patients who had a state-of-the-art neurocognitive assessment performed between January 2011 and June 2015 while also being followed at their respective adherence clinics. Adherence was measured with electronic monitors. Patients' sociodemographic characteristics, HIV viral load, and CD4 counts were retrieved from the Swiss HIV Cohort Study database. At each time t, adherence was computed as the proportion of patients taking medication as prescribed at that time. We included 59 patients, with a median (Q1, Q3) age of 53 years (47-58) and 39 (66%) were male participants. Twenty-two patients (35%) had no neurocognitive deficits, 16 (27%) patients had HAND, and 21 (35%) patients had non-HAND (mostly depression). Implementation over 3 years showed a significant decline (50%) in medication adherence among patients diagnosed with HAND in comparison with patients who had a normal neuropsychological status or a non-HIV-related cognitive deficit (implementation stayed 90% during follow-up). Our findings support the hypothesis that HAND is associated with reduced cART adherence.


Design, Synthesis and Anti-inflammatory Activity of Derivatives 10-R-3-Aryl-6,7-dihydro-2H-[1,2,4] triazino[2,3-c]quinazolin-2-ones of Spiro-fused Cyclic Frameworks.
Present work is devoted to the purposeful search of novel promising anti-inflammatory agents among the insufficiently known 3'-R-10'-R1-spiro[hetaryl-3(4),6'-[1,2,4]triazino[2,3-c]quinazolin]-2'(7'H)-ones. The virtual combinatorial library of previously unknown spiro-condensed derivatives of [1,2,4]triazino[2,3-c]quinazolines was formed and promising COX-2 inhibitors were identified by molecular docking method. Potential anti-inflammatory agents were synthesized by [5+1]-cyclocondensation of substituted 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with heterocyclic ketones. The structures of synthsized compounds were verified by complex of physicochemical methods and spectral characteristics features were discussed. Obtained compounds were studied for anti-inflammatory activity using formalin induced paw edema model and highly active compounds were identified. Conducted SAR-analysis showed that combination of triazino[2,3-c] quinazoline moiety with spiro-condensed fragments is a reasonable approach for creating novel anti-inflammatory agents.


Cancer and other causes of death among a cohort of dry cleaners.
Mortality among 5365 members of a dry cleaning union in St. Louis, Missouri, was less than expected for all causes combined (SMR = 0.9) but slightly raised for cancer (SMR = 1.2). Among the cancers, statistically significant excesses occurred for oesophagus (SMR = 2.1) and cervix (SMR = 1.7) and non-significant excesses for larynx (SMR = 1.6), lung (SMR = 1.3), bladder (SMR = 1.7), thyroid (SMR = 3.3), lymphosarcoma and reticulosarcoma (SMR = 1.7), and Hodgkin's disease (SMR = 2.1). Mortality from emphysema was also significantly raised (SMR = 2.0). Eleven of the 13 deaths from oesophageal cancer occurred among black men. The risk of this cancer showed a significant association with estimated cumulative exposure to dry cleaning solvents (rising to 2.8-fold in the highest category) but not with level or duration of exposure. Mortality from kidney cancer was not excessive as reported in other studies. Excesses for emphysema and cancers of the larynx, lung, oesophagus, bladder, and cervix may be related to socioeconomic status, tobacco, or alcohol use. Although the number of deaths was small, the greatest risk for cancers of the lymphatic and haematopoietic system (fourfold) occurred among workers likely to have held jobs where exposures were the heaviest. Small numbers and limited information on exposure to specific substances complicates interpretation of this association but is unlikely to be due to confounding by tobacco use. It was not possible to identify workers exposed to specific dry cleaning solvents but mortality among those entering the union after 1960, when use of perchloroethylene was predominant, was similar to those entering before 1960.


Perioperative respiratory complications in patients with asthma.
Patients with asthma are thought to be at high risk for pulmonary complications to develop during the perioperative period, and these complications may lead to serious morbidity. Existing medical records were reviewed to determine the frequency of and risk factors for perioperative pulmonary complications in a cohort of residents of Rochester, Minnesota, who had asthma and who underwent anesthesia and surgery at the Mayo Clinic in Rochester. Medical records were reviewed for all residents of Rochester, Minnesota, who were initially diagnosed as having definite asthma according to strict criteria from 1 January 1964 through 31 December 1983 who subsequently had at least one surgical procedure involving a general anesthetic or central neuroaxis block at the Mayo Clinic (n = 706). Bronchospasm was documented in the perioperative records of 12 patients (1.7% [exact 95% confidence interval, 0.9 to 3%]). Postoperative respiratory failure developed in one of these patients. Laryngospasm developed in two additional patients during operation. All episodes of bronchospasm and laryngospasm in the immediate perioperative period were treated successfully. No episodes of pneumothorax, pneumonia, or death in the hospital were noted. For univariate analysis, characteristics associated with complications included the recent use of antiasthmatic drugs, recent asthma symptoms, and recent therapy in a medical facility for asthma. Patients in whom complications developed were significantly older at diagnosis and at surgery. The frequency of perioperative bronchospasm and laryngospasm was surprisingly low in this cohort of persons with asthma. These complications did not lead to severe respiratory outcomes in most patients. The frequency of complications was increased in older patients and in those with active asthma.


Spectrum of lateral medullary syndrome. Correlation between clinical findings and magnetic resonance imaging in 33 subjects.
Computed tomography is insufficient in evaluation of medullary lesions. Although lateral medullary infarction is a relatively common type of cerebrovascular disease, detailed correlation between clinical findings and magnetic resonance imaging (MRI) has not yet been reported. We studied 33 consecutive patients with lateral medullary infarction who showed appropriate MRI lesions and correlated their clinical findings with the MRI results. Gait ataxia (88%), vertigo/dizziness (91%), nausea/vomiting (73%), dysphagia (61%), hoarseness (55%), Horner sign (73%), and facial (85%) and hemibody (94%) sensory changes were frequent clinical findings. MRI results showed that the lesions located in the rostral part of the medulla were usually diagonal band-shaped and were associated with more severe dysphagia, hoarseness, and the presence of facial paresis, whereas the caudal lesions, situated usually in the lateral surface of the medulla, appeared to correlate with more marked vertigo, nystagmus, and gait ataxia. Nausea/vomiting and Horner sign were common regardless of the lesion location, and lesions extending ventromedially correlated with facial sensory change on the contralateral side of the lesion. Analysis of MRI findings in rostrocaudal and dorsoventral aspects allows us, although not unequivocally, to make anatomicoclinical correlations in the evaluation of patients with lateral medullary stroke syndrome.


Patient satisfaction with virtual clinic during Coronavirus disease (COVID-19) pandemic in primary healthcare, Riyadh, Saudi Arabia.
The novel coronavirus, officially known as COVID-19, was first reported in Wuhan, China in December of 2019. Since that time, medical services in Saudi Arabia have adapted to the situation by delivering medical care via virtual clinics. Therefore, the present study aimed to assess patients' level of satisfaction with virtual clinics during the COVID-19 pandemic in Saudi Arabia. This cross-sectional study was conducted among patients who had experienced virtual clinics in primary healthcare centers in Riyadh, Saudi Arabia. An online validated questionnaire was sent to all participants who had at least one virtual visit between March 2020 to July 2020. The data sought included demographics, level of satisfaction and questions related to their experience with virtual clinics. Computed frequencies and percentages for categorical variables, and median, mean, and standard deviation for continuous variables. Satisfaction scores were compared between groups using Mann-Whitney U test and Kruskal Wallis test. A total of 439 patients completed the questionnaire (response rate 97.5%); 54% were male. The participants were divided into three age groups: 18-39, 40-59, and ≥60 years. Overall level of patients' satisfaction with virtual clinic was 68.1%. Factors statistically significantly associated with satisfaction included gender, age group and level of education (post-graduate and middle school) and being well-informed on the use of telemedicine. Specific age groups that were significant were 18-39 and 40-59 years; 50.2% of the males found telemedicine very convenient, compared to only 36.1% females. Family medicine clinics were the most commonly visited virtual clinics, whereas obstetrics and gynecology clinics were the least attended virtual clinics. The inability to meet the health-care professional face-to-face was reported by 53.8% as the most important disadvantage. This study shows a high level of satisfaction with virtual clinics in Saudi Arabia during the COVID-19 pandemic despite the service being relatively new in healthcare service in the country. Our study demonstrated that satisfaction was linked to age, gender, education and the type of clinic used.


Flexible Bayesian additive joint models with an application to type 1 diabetes research.
The joint modeling of longitudinal and time-to-event data is an important tool of growing popularity to gain insights into the association between a biomarker and an event process. We develop a general framework of flexible additive joint models that allows the specification of a variety of effects, such as smooth nonlinear, time-varying and random effects, in the longitudinal and survival parts of the models. Our extensions are motivated by the investigation of the relationship between fluctuating disease-specific markers, in this case autoantibodies, and the progression to the autoimmune disease type 1 diabetes. Using Bayesian P-splines, we are in particular able to capture highly nonlinear subject-specific marker trajectories as well as a time-varying association between the marker and event process allowing new insights into disease progression. The model is estimated within a Bayesian framework and implemented in the R-package bamlss.


Characteristics of fibromyalgia in Muslim Bedouin women in a primary care clinic.
Fibromyalgia (FM) has been described and studied in various sociocultural settings in both developed and developing countries. To study the clinical manifestations of FM and to describe its effect on quality of life in the unique setting of Muslim Bedouin women in the southern Israel Negev desert area. One hundred two Bedouin women were recruited from a primary health care clinic in the Negev area. All patients fulfilled American College of Rheumatology criteria for the diagnosis of FM. Tenderness was assessed by manual dolorimetry and the fibromyalgia impact questionnaire was utilized to estimate the severity of FM symptoms. Anxiety and depression were assessed by the Arthritis Impact Measurement Scales subscales and quality of life was evaluated by the SF-36 questionnaire. The study population was characterized by a low educational level, a high rate of consanguinity, a high number of children per mother, and a high rate of polygamy. There was a high frequency of classic FM symptoms such as pain and fatigue, as well as anxiety and depression. The overall impact of FM on quality of life was exceedingly high (8.9 on a scale of 0 to 10). FM is relatively common in the unique setting of Muslim Bedouin women and has a very significant impact on their quality of life as well as on their dependents. Physicians involved in the primary care of this population should be attentive to the manifestations of FM and related disorders.


Quantitative proteomics reveals specific metabolic features of acute myeloid leukemia stem cells.
Acute myeloid leukemia is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Because this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus information about posttranscriptionally regulated genes and associated networks is lacking. Here, we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provide strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA-processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts, and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.


Responses of anterior lateral line afferent neurones to water flow.
The mechanoreceptive lateral line system detects hydrodynamic stimuli and plays an important role in a number of types of fish behaviour, including orientation to water currents. The lateral line is composed of hair cell receptor organs called neuromasts that occur as superficial neuromasts on the surface of the skin or canal neuromasts located in subepidermal canals. Both are innervated by primary afferents of the lateral line nerves. Although there have been extensive studies of the response properties of lateral line afferents to vibrating sources, their response to water flow has not been reported. In this study, we recorded extracellularly from anterior lateral line afferents in the New Zealand long-fin eel Anguilla dieffenbachii while stimulating the eel with unidirectional water flows at 0.5-4 cm s(-)(1). Of the afferents, 80 % were flow-sensitive to varying degrees, the response magnitude increasing with flow rate. Flow-sensitive fibres gave non-adapting tonic responses, indicating that these fibres detect absolute flow velocity. Further studies are needed to confirm whether flow-sensitive and flow-insensitive fibres correlate with superficial and canal neuromasts, respectively.


Genetic control of plant organ growth.
Summary 319 I. Introduction 320 II. The cell biology and biophysics of growth 320 III. Timing is everything: what determines when proliferation gives way to expansion? 323 IV. Anisotropic growth and the importance of polarity 325 V. How does organ identity and developmental patterning modulate growth behaviour? 326 VI. Coordination of growth at different scales 327 VII. Conclusions 329 Acknowledgements 329 References 330 The growth of plant organs is under genetic control. Work in model species has identified a considerable number of genes that regulate different aspects of organ growth. This has led to an increasingly detailed knowledge about how the basic cellular processes underlying organ growth are controlled, and which factors determine when proliferation gives way to expansion, with this transition emerging as a critical decision point during primordium growth. Progress has been made in elucidating the genetic basis of allometric growth and the role of tissue polarity in shaping organs. We are also beginning to understand how the mechanisms that determine organ identity influence local growth behaviour to generate organs with characteristic sizes and shapes. Lastly, growth needs to be coordinated at several levels, for example between different cell layers and different regions within one organ, and the genetic basis for such coordination is being elucidated. However, despite these impressive advances, a number of basic questions are still not fully answered, for example, whether and how a growing primordium keeps track of its size. Answering these questions will likely depend on including additional approaches that are gaining in power and popularity, such as combined live imaging and modelling.


Coping strategies of families in HIV/AIDS care: some exploratory data from two developmental contexts.
Caring for a family member with HIV/AIDS presents multiple challenges that strain a family's physical, economic and emotional resources. Family carers provide physical care and financial support and deal with changes in family relationships and roles, often with little support from outside of the family. Carers in developing countries face even greater challenges, due to lack of medical and support services, poverty and widespread discrimination against those with HIV/AIDS. Little is known about how family carers cope with these challenges or about the ways that development impacts on the process of coping. The current study explored coping strategies used by family carers in two contexts, Kerala, India and Scotland, UK. As part of a larger study, 28 family carers of persons living with HIV/AIDS were interviewed -23 in Kerala and 5 in Scotland. A modified version of the Ways of Coping scale was used to assess coping strategies. Responses were compared on the total number of coping responses used as well as on selected subscales of the WOC. Differences were assessed using the Mann-Whitney U-test. The two cohorts differed significantly in terms of the coping strategies used. The carers from Scotland used a larger number of different coping strategies and scored higher on measures of problem focused coping, positive reappraisal, seeking social support, self-controlling and distancing/detachment. Respondents from Kerala scored higher on a measure of self-blame. Results are discussed in terms of the impact of community resources on coping strategies.


Coastal livelihood transitions under globalization with implications for trans-ecosystem interactions.
Anthropogenic threats to natural systems can be exacerbated due to connectivity between marine, freshwater, and terrestrial ecosystems, complicating the already daunting task of governance across the land-sea interface. Globalization, including new access to markets, can change social-ecological, land-sea linkages via livelihood responses and adaptations by local people. As a first step in understanding these trans-ecosystem effects, we examined exit and entry decisions of artisanal fishers and smallholder farmers on the rapidly globalizing Caribbean coast of Nicaragua. We found that exit and entry decisions demonstrated clear temporal and spatial patterns and that these decisions differed by livelihood. In addition to household characteristics, livelihood exit and entry decisions were strongly affected by new access to regional and global markets. The natural resource implications of these livelihood decisions are potentially profound as they provide novel linkages and spatially-explicit feedbacks between terrestrial and marine ecosystems. Our findings support the need for more scientific inquiry in understanding trans-ecosystem tradeoffs due to linked-livelihood transitions as well as the need for a trans-ecosystem approach to natural resource management and development policy in rapidly changing coastal regions.


Reappraisal Modulates Attentional Bias to Angry Faces.
Heightened attentional bias to emotional information is one of the main characteristics of disorders related to emotion dysregulation such as anxiety, depression, and substance abuse. Although reappraisal, an emotion regulation strategy, is known to effectively modulate subjective experience of emotions, it remains unknown whether reappraisal can alter attentional biases to emotional information. In the current research, we investigated the influence of instruction-induced state reappraisal (Study 1) and trait reappraisal (Study 2) on attentional biases to happy and angry faces. In Study 1, healthy young women were recruited and randomly assigned to one of the three groups: up-, down-, and no-regulation. Participants were instructed to reappraise their emotions to increase and decrease emotional experience while viewing an emotionally negative film clip. Attentional bias was assessed with a dot-probe task with pictures of angry and happy facial expressions. In Study 2, a separate group of healthy young men and women participated. Participants' trait reappraisal and suppression as well as state and trait anxiety were assessed. A dot-probe task was completed by all participants. Statistical tests in Study 1 revealed that participants who reappraised to decrease negative emotions while viewing an emotionally negative film clip had reduced attentional bias to subsequently presented angry faces compared to participants who reappraised to increase negative emotions. Multiple regression analyses in Study 2 revealed that trait reappraisal predicted slower orienting toward angry faces, whereas state anxiety predicted slower disengagement from angry faces. Interestingly, trait suppression predicted slower disengagement from happy faces. Taken together, these results suggest that both instruction-induced state reappraisal and trait reappraisal are linked to reduced attentional bias to negative information and contribute to better understanding of how everyday emotion regulation styles contribute to attentional processing of emotional information.


Current status of in silico, preclinical and clinical study registries across the globe: A systematic review and meta-analysis.
Registration of study protocols brings about transparency and traceability and the amount of publication bias can be estimated. In this study, we have collected and presented data regarding clinical study registries, preclinical, in vitro and in silico study registries across the globe. We searched via Google Search Engine with appropriate keywords e.g. name of country (n = 198), name of continent (n = 7), registry, study registry, animal, in silico, virtual, simulation, preclinical, animal, clinical trial. The overall pooled prevalence of clinical study registries and WHO primary registries in per continent was calculated using Medcalc software. The overall pooled prevalence of clinical study registries were 13% in each continent. The prevalence of WHO primary study registries were 8.9% of the countries per continent. Overall, there are 17 primary registries associated with WHO ICTRP as primary registries, 2 partner registries and 6 registries are affiliated to ICMJE. However, the amount of preclinical animal study registry was quite less (n = 4). Regarding in vitro studies, only country specific in vitro fertilization registries were available, however, in other research domains, registries were absent. Only one simulation study registry was available. At priori study registration is essential to deal with selective reporting. Comparison between study protocol and final report allows us to know the protocol deviations and allows us to evaluate risk of bias and internal validity of the research findings. Although trialists are responsible for the completeness of records, yet the registries must have some measures for their periodic update and quality control of the data.


Disturbances of prostacyclin metabolism in children with hemolytic-uremic syndrome and in first degree relatives.
Plasma from 24 children with hemolytic uremic syndrome (HUS) (10 in acute, 14 in remission phase), 42 first degree relatives and 24 controls were studied for PGI2 supporting activity (PSA) from human umbilical arterial rings and the concentration of PGI2 metabolite (PGI2m). HUS patients in acute phase showed very low or absent level of plasma PSA, which remained depressed 3 months following presentation. Plasma from 2 out of 5 acute HUS patients showed inhibition against PGI2-like activity, and depressed preservation of PGI2 effect. The mean value of PGI2m in acute phase of HUS patients was elevated initially, but fell below control range by the day 14 and remained decreased at the end of 3rd month. Patients on long term remission showed a significantly lower concentration of plasma PGI2m. Eight of 14 HUS patients in remission and 18 of 42 family members had lower PSA levels than the controls. These studies confirmed a decreased PSA in HUS and suggest that persistently low PSA levels may reflect an inherited predisposition.


Measuring facial grimacing for quantifying patient agitation in critical care.
The effective delivery of sedation in critical care relies primarily on an accurate and consistent measure of a patient's agitation level. However, current methods for assessing agitation are subjective and prone to error, often leading to over sedation or cycles between agitation and oversedation. This paper builds on previous work developing agitation sensors based on heart rate and blood pressure variability, and overall whole body motion. In this research, the focus is on real-time measurement of high-resolution facial changes that are observed to occur in agitation. An algorithm is developed that measures the degree of facial grimacing from a single digital camera. The method is demonstrated on simulated patient facial motion to prove the concept. A consistent measure is obtained that is robust to significant random head movement and compares well against visual observation of different levels of grimacing. The method provides a basis for clinical validation.


What is the role of timing in the surgical and rehabilitative care of community-dwelling older persons with acute hip fracture?
To determine the relationship of surgical repair of acute hip fracture within 2 days of hospital admission, followed by more than 5 sessions per week of physical and occupational therapy (PT/OT), to outcomes after acute hip fracture. Comparison of hip fracture outcomes via secondary analysis of data obtained by retrospective medical record review according to timing of surgical repair and frequency of PT/OT, adjusted for patient, medical care, and hospital characteristics. The study included the medical records of 1880 elderly Medicare recipients admitted from the community to 284 acute care hospitals in 5 states during 1981 and 1982 or 1985 and 1986 with a primary diagnosis of acute hip fracture who underwent surgical repair and received PT/OT. None. The postoperative day when ambulation first occurred, the length of hospital stay, and return to the community. Earlier surgical repair was associated with a shorter length of hospital stay (5 fewer days, P < .001) without a statistically significant increase in medical complications. High frequency PT/OT was associated with earlier ambulation (odds ratio [OR], 1.76; 95% confidence limits [CL], 1.50, 2.07). Patients who ambulated earlier [corrected] had shorter lengths of stay (6.5 fewer days, P < .001), were more likely to return to the community (OR, 1.45; 95% CL, 1.16, 1.81), and had better 6-month survival (OR, 2.8; 95% CL, 2.06, 3.88), and patients younger than 85 years had fewer in-hospital complications (11% vs 4%, P < .001). Surgical repair within the first 2 days of hospitalization and more than 5 PT/OT sessions per week were associated with better health outcomes in a nationally representative sample of elderly patients with hip fracture.


Effects of hypoperfusion in Alzheimer's disease.
The role of hypoperfusion in Alzheimer's disease (AD) is a vital component to understanding the pathogenesis of this disease. Disrupted perfusion is not only evident throughout disease manifestation, it is also demonstrated during the pre-clinical phase of AD (i.e., mild cognitive impairment) as well as in cognitively healthy persons at high-risk for developing AD due to family history or genetic factors. Studies have used a variety of imaging modalities (e.g., SPECT, MRI, PET) to investigate AD, but with its recent technological advancements and non-invasive use of blood water as an endogenous tracer, arterial spin labeling (ASL) MRI has become an imaging technique of growing popularity. Through numerous ASL studies, it is now known that AD is associated with both global and regional cerebral hypoperfusion and that there is considerable overlap between the regions implicated in the disease state (consistently reported in precuneus/posterior cingulate and lateral parietal cortex) and those implicated in disease risk. Debate exists as to whether decreased blood flow in AD is a cause or consequence of the disease. Nonetheless, hypoperfusion in AD is associated with both structural and functional changes in the brain and offers a promising putative biomarker that could potentially identify AD in its pre-clinical state and be used to explore treatments to prevent, or at least slow, the progression of the disease. Finally, given that perfusion is a vascular phenomenon, we provide insights from a vascular lesion model (i.e., stroke) and illustrate the influence of disrupted perfusion on brain structure and function and, ultimately, cognition in AD.


Unique levels of expression of N-methyl-D-aspartate receptor subunits and neuronal nitric oxide synthase in the rostral ventrolateral medulla of the spontaneously hypertensive rat.
The rostral ventrolateral medulla (RVLM) is the major brainstem region contributing to sympathetic control of blood pressure. We have compared the expression of N-methyl-d-aspartate (NMDA) receptor subunits (NR1, NR2A-D), NR1 splice variants (NR1-1a/1b, -2a/2b, -3a/3b, -4a/4b), and the neuronal and inducible isoforms of NO synthase (nNOS and iNOS) in the RVLM of Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), based on the hypothesis that altered NMDA receptor make-up or altered expression of endogenous NO may be associated with the increase in sympathetic output described from this site in hypertension. Total RNA was extracted and reverse transcribed from the RVLM of mature male WKY and SHR (16-23 weeks). Conventional polymerase chain reaction (PCR) indicated that only the NR1 splice variants NR1-2a, NR1-2b, NR1-4a and NR1-4b were expressed in the RVLM of either species. Quantitative real-time PCR indicated that for both strains of rat, mRNA for the NR1 subunit (all splice variants) was the most abundant (16.5-fold greater, P< or =0.05, relative to the NR2A subunit). Amongst the NR2A-D subunits, NR2C was the most abundant (7- and 1.7-fold greater relative to the NR2A subunit, P< or =0.05, WKY and SHR, respectively). Relative to WKY, mRNA levels for the NR2C and NR2D subunits in the SHR RVLM were significantly lower (0.3- and 0.25-fold less, P< or =0.05), while nNOS was significantly higher (1.76-fold greater, P< or =0.05). This was confirmed immunohistochemically for nNOS expression. These results demonstrate differential expression levels of NMDA receptor subunits and NOS isoforms in the RVLM region of SHR when compared to WKY rats.


Water palatability, a matter of taste.
The aim of this trial was to test whether the temperature or additives of the drinking water affected water uptake by nursery pigs. We designed a repeated 4 × 4 Latin Square to control for confounding factors such as; carry-over effects, learning of a preferential taste, daily variation within groups and regular increase of uptake over a day due to diurnal drinking patterns. Water types tested were control water (A); warm water (33 °C); (B); organic acid additive 1 (C), and organic acid additive 2 (D). The piglets drank more of water C than of control water (A). The uptake of water D was marginally higher than control water (A). There was no difference in uptake of water B and A. However, a learning effect was observed resulting in increasing amounts of water type C and D taken up over the four consecutive days. A carry-over was not fully prevented as pigs always consumed less during the second hour and water D was consumed less during the fourth and final hourly observation period each day. The experimental design can be used in future trials for evaluation of the water uptake and preference of water additives for pigs. The tested commercial organic acid additives did not adversely affect water uptake of drinking water, water uptake increased instead.


Reliable and efficient a posteriori error estimation for adaptive IGA boundary element methods for weakly-singular integral equations.
We consider the Galerkin boundary element method (BEM) for weakly-singular integral equations of the first-kind in 2D. We analyze some residual-type a posteriori error estimator which provides a lower as well as an upper bound for the unknown Galerkin BEM error. The required assumptions are weak and allow for piecewise smooth parametrizations of the boundary, local mesh-refinement, and related standard piecewise polynomials as well as NURBS. In particular, our analysis gives a first contribution to adaptive BEM in the frame of isogeometric analysis (IGABEM), for which we formulate an adaptive algorithm which steers the local mesh-refinement and the multiplicity of the knots. Numerical experiments underline the theoretical findings and show that the proposed adaptive strategy leads to optimal convergence.


Rotavirus vaccination coverage and adherence to recommended age among infants in Flanders (Belgium) in 2012.
In Belgium, rotavirus vaccination has been recommended and partially reimbursed since October 2006. Through a retrospective survey in 2012, we estimated the coverage rate of the rotavirus vaccination in Flanders among infants born in 2010. Using a standardised questionnaire, 874 families were interviewed at home, collecting information on demographic characteristics, socio-economic background and documented vaccination history (updated from medical files and vaccination database, if needed). Adherence to the recommended age for vaccination (8, 12 and 16 weeks) was also assessed. The coverage rate for two doses of rotavirus vaccination was 92.2% (95% confidence interval: 90.2-93.8). Respectively 31.7% and 10.1% of the children received their first and second dose at the recommended age. Incomplete vaccination was often a deliberate choice of the parents. Only eight children (1%) were vaccinated after the maximum age of 26 weeks. Factors identified by multiple logistic regression as related to incomplete vaccination were: living in the province of Antwerp, unemployed mother, and three or more older siblings in the household. Four years after introduction, the coverage rates were surprisingly high for a vaccine that is not fully reimbursed and not readily available in the vaccinator's fridge, which is the case for the other recommended infant vaccines.


Concave and convex phases in ambiguous figures showing colour shifts. Mach's figure and the AMBEGUJAS phenomenon.
Two ambiguous figures (Mach's book-figure and the AMBEGUJAS phenomenon) have been studied. They show colour shifts synchronised with the shifts of their alternative phases. The perceived concave phase appeared to have chromatic surface colour, but the perceived convex phase can appear to be in coloured illumination and shadow (film colour). The two perceived reversible shapes of the Mach figure (the book and the tent) and the three perceived alternative shapes of the Mondrians used in the AMBEGUJAS phenomenon (a roof, a ceiling, and a tile) all can appear to have chromatic surface colours in their concave phases but appear to have coloured illumination and shadow in their convex phases.


Modulation of inflammation and cytokine production by dietary (n-3) fatty acids.
The production of pro-inflammatory cytokines, such as interleukin-1 and tumor necrosis factor, is pivotal in the response to infection. However, overproduction of these cytokines might be detrimental. It has been suggested that (n-3) fatty acids suppress inflammation and ameliorate the course of infection by decreasing the production of pro-inflammatory cytokines. We here, review these effects. Use of (n-3) fatty acids induced moderate clinical improvements in rheumatoid arthritis, psoriasis and colitis, but not in systemic lupus erythematosus. Data on critically ill burn or postoperative cancer patients are still inconclusive. The (n-3) fatty acids markedly inhibited sterile inflammation in animal studies and improved survival in some experimental infections. T cell responses decreased in healthy volunteers but remained unchanged or increased in certain patient groups. The production of pro-inflammatory cytokines decreased in most human studies. The (n-3) fatty acids increased cytokine production capacity in mice. Differences in cytokine-producing cell types studied may account for these paradoxical responses in humans and mice. Although the increased cytokine production in mice is partly mediated by effects on prostaglandins, mechanisms of action in other species remain to be elucidated. The (n-3) fatty acids may be of moderate benefit in some chronic inflammatory diseases. Their therapeutic value and possible hazards in critically ill patients remain to be established.


Hyperuniformity and its generalizations.
Disordered many-particle hyperuniform systems are exotic amorphous states of matter that lie between crystal and liquid: They are like perfect crystals in the way they suppress large-scale density fluctuations and yet are like liquids or glasses in that they are statistically isotropic with no Bragg peaks. These exotic states of matter play a vital role in a number of problems across the physical, mathematical as well as biological sciences and, because they are endowed with novel physical properties, have technological importance. Given the fundamental as well as practical importance of disordered hyperuniform systems elucidated thus far, it is natural to explore the generalizations of the hyperuniformity notion and its consequences. In this paper, we substantially broaden the hyperuniformity concept along four different directions. This includes generalizations to treat fluctuations in the interfacial area (one of the Minkowski functionals) in heterogeneous media and surface-area driven evolving microstructures, random scalar fields, divergence-free random vector fields, and statistically anisotropic many-particle systems and two-phase media. In all cases, the relevant mathematical underpinnings are formulated and illustrative calculations are provided. Interfacial-area fluctuations play a major role in characterizing the microstructure of two-phase systems (e.g., fluid-saturated porous media), physical properties that intimately depend on the geometry of the interface, and evolving two-phase microstructures that depend on interfacial energies (e.g., spinodal decomposition). In the instances of random vector fields and statistically anisotropic structures, we show that the standard definition of hyperuniformity must be generalized such that it accounts for the dependence of the relevant spectral functions on the direction in which the origin in Fourier space is approached (nonanalyticities at the origin). Using this analysis, we place some well-known energy spectra from the theory of isotropic turbulence in the context of this generalization of hyperuniformity. Among other results, we show that there exist many-particle ground-state configurations in which directional hyperuniformity imparts exotic anisotropic physical properties (e.g., elastic, optical, and acoustic characteristics) to these states of matter. Such tunability could have technological relevance for manipulating light and sound waves in ways heretofore not thought possible. We show that disordered many-particle systems that respond to external fields (e.g., magnetic and electric fields) are a natural class of materials to look for directional hyperuniformity. The generalizations of hyperuniformity introduced here provide theoreticians and experimentalists new avenues to understand a very broad range of phenomena across a variety of fields through the hyperuniformity "lens."


Characteristics of Physicians Who Dismiss Families for Refusing Vaccines.
Physicians dismissing families who refuse vaccines from their practices is controversial. We assessed the following among pediatricians (Peds) and family physicians (FPs): (1) reported prevalence of parental refusal of 1 or more vaccines in the infant series; (2) physician response to refusal; and (3) the association between often/always dismissing families and provider/practice characteristics and state exemption laws. Nationally representative survey conducted June to October 2012. A multivariable analysis assessed association of often/always dismissing families with physician/practice characteristics, state philosophical exemption policy, and degree of difficulty obtaining nonmedical exemptions. The response rate was 66% (534/815). Overall, 83% of physicians reported that in a typical month, ≥1% of parents refused 1 or more infant vaccines, and 20% reported that >5% of parents refused. Fifty-one percent reported always/often requiring parents to sign a form if they refused (Peds 64%, FP 29%, P < .0001); 21% of Peds and 4% of FPs reported always/often dismissing families if they refused ≥1 vaccine. Peds only were further analyzed because few FPs dismissed families. Peds who dismissed families were more likely to be in private practice (adjusted odds ratio [aOR] 4.90, 95% confidence interval [CI] 1.40-17.19), from the South (aOR 4.07, 95% CI 1.08-15.31), and reside in a state without a philosophical exemption law (aOR 3.70, 95% CI 1.74-7.85). Almost all physicians encounter parents who refuse infant vaccines. One-fifth of Peds report dismissing families who refuse, but there is substantial variation in this practice. Given the frequency of dismissal, the impact of this practice on vaccine refusers and on pediatric practices should be studied.


Microvascular blood viscosity in vivo and the endothelial surface layer.
The apparent viscosity of blood in glass tubes declines with decreasing diameter (Fåhraeus-Lindqvist effect) and exhibits a distinctive minimum at 6-7 microm. However, flow resistance in vivo in small vessels is substantially higher than predicted by in vitro viscosity data. The presence of a thick endothelial surface layer (ESL) has been proposed as the primary cause for this discrepancy. Here, a physical model is proposed for microvascular flow resistance as a function of vessel diameter and hematocrit in vivo; it combines in vitro blood viscosity with effects of a diameter-dependent ESL. The model was developed on the basis of flow distributions observed in three microvascular networks in the rat mesentery with 392, 546, and 383 vessel segments, for which vessel diameters, network architecture, flow velocity, and hematocrit were determined by intravital microscopy. A previously described hemodynamic simulation was used to predict the distributions of flow and hematocrit from the assumed model for effective blood viscosity. The dependence of ESL thickness on vessel diameter was estimated by minimizing deviations of predicted values for velocities, flow directions, and hematocrits from measured data. Optimal results were obtained with a layer thickness of approximately 0.8-1 microm for 10- to 40-microm-diameter vessels and declined strongly for smaller diameters, with an additional hematocrit-dependent impact on flow resistance exhibiting a maximum for approximately 10-microm-diameter vessels. These results show that flow resistance in vivo can be explained by in vitro blood viscosity and the presence of an ESL and indicate the rheologically effective thickness of the ESL in microvessels.