Do social inequalities exist in terms of the prevention, diagnosis, treatment, control and monitoring of diabetes? A systematic review.
The major increase in the prevalence of diabetes mellitus (DM) has led to the study of social inequalities in health-care. The aim of this study is to establish the possible existence of social inequalities in the prevention, diagnosis, treatment, control and monitoring of diabetes in Organisation for Economic Co-operation and Development (OECD) countries which have universal healthcare systems. We searched MEDLINE, EMBASE and the Cochrane Database of Systematic Reviews for all relevant articles published up to 15 December 2007. We included observational studies carried out in OECD countries with universal healthcare systems in place that investigate social inequalities in the provision of health-care to diabetes patients. Two independent reviewers carried out the critical assessment using the STROBE tool items considered most adequate for the evaluation of the methodological quality. We selected 41 articles from which we critically assessed 25 (18 cross-sectional, 6 cohorts, 1 case-control). Consistency among the article results was found regarding the existence of ethnic inequalities in treatment, metabolic control and use of healthcare services. Socioeconomic inequalities were also found in the diagnosis and control of the disease, but no evidence of any gender inequalities was found. In general, the methodological quality of the articles was moderate with insufficient information in the majority of cases to rule out bias. This review shows that even in countries with a significant level of economic development and which have universal healthcare systems in place which endeavour to provide medical care to the entire population, socioeconomic and ethnic inequalities can be identified in the provision of health-care to DM sufferers. However, higher quality and follow-up articles are needed to confirm these results.


Application of management tools to integrate ecological principles with the design of marine infrastructure.
Globally the coastal zone is suffering the collateral damage from continuing urban development and construction, expanding resource sectors, increasing population, regulation to river flow, and on-going land change and degradation. While protection of natural coastal habitat is recommended, balancing conservation with human services is now the challenge for managers. Marine infrastructure such as seawalls, marinas and offshore platforms is increasingly used to support and provide services, but has primarily been designed for engineering purposes without consideration of the ecological consequences. Increasingly developments are seeking alternatives to hard engineering and a range of ecological solutions has begun to replace or be incorporated into marine and coastal infrastructure. But too often, hard engineering remains the primary strategy because the tools for managers to implement ecological solutions are either lacking or not supported by policy and stakeholders. Here we outline critical research needs for marine urban development and emerging strategies that seek to mitigate the impacts of marine infrastructure. We present case studies to highlight the strategic direction necessary to support management decisions internationally.


The ligninolytic system of the white rot fungus Pycnoporus cinnabarinus: purification and characterization of the laccase.
The white rot fungus Pycnoporus cinnabarinus was characterized with respect to its set of extracellular phenoloxidases. Laccase was produced as the predominant extracellular phenoloxidase in conjunction with low amounts of an unusual peroxidase. Neither lignin peroxidase nor manganese peroxidase was detected. Laccase was produced constitutively during primary metabolism. Addition of the most effective inducer, 2,5-xylidine, enhanced laccase production ninefold without altering the isoenzyme pattern of the enzyme. Laccase purified to apparent homogeneity was a single polypeptide having a molecular mass of approximately 81,000 Da, as determined by calibrated gel filtration chromatography, and a carbohydrate content of 9%. The enzyme displayed an unusual behavior on isoelectric focusing gels; the activity was split into one major band (pI, 3.7) and several minor bands of decreasing intensity which appeared at regular, closely spaced intervals toward the alkaline end of the gel. Repeated electrophoresis of the major band under identical conditions produced the same pattern, suggesting that the laccase was secreted as a single acidic isoform with a pI of about 3.7 and that the multiband pattern was an artifact produced by electrophoresis. This appeared to be confirmed by N-terminal amino acid sequencing of the purified enzyme, which yielded a single sequence for the first 21 residues. Spectroscopic analysis indicated a typical laccase active site in the P. cinnabarinus enzyme since all three typical Cu(II)-type centers were identified. Substrate specificity and inhibitor studies also indicated the enzyme to be a typical fungal laccase. The N-terminal amino acid sequence of the P. cinnabarinus laccase showed close homology to the N-terminal sequences determined for laccases from Trametes versicolor, Coriolus hirsutus, and an unidentified basidiomycete, PM1. The principal features of the P. cinnabarinus enzyme system, a single predominant laccase and a lack of lignin- or manganese-type peroxidase, make this organism an interesting model for further studies of possible alternative pathways of lignin degradation by white rot fungi.


Sensorimotor function and axonal integrity in adrenomyeloneuropathy.
Gait abnormalities and sensorimotor disturbances are principal defects in adrenomyeloneuropathy (AMN). However, to our knowledge, their association with overall impairment and neuroanatomical changes has not been defined. To understand how sensorimotor impairments create mobility deficits and to analyze how these impairments are related to specific metrics of axonal integrity. Cross-sectional study assessing impairments, including vibration sensation, strength, spasticity, and global measures of walking and balance. Fractional anisotropy was measured to evaluate the integrity of the corresponding brainstem tracts. Men with AMN and healthy control subjects. Individuals with sensory loss only showed minimal walking deficits. Concomitant strength and sensory loss resulted in slower walking, with abnormal knee control; increased spasticity led to an exaggerated trunk motion and a knee-flexed (crouched) posture. Hip strength was an independent predictor of walking velocity in subjects with AMN. Subjects with sensory loss only had greater sway amplitudes during standing balance testing, which did not worsen with additional impairments. There were significant associations among sway amplitude, great toe vibration sense, and dorsal column fractional anisotropy. Brainstem fractional anisotropy in AMN was significantly negatively correlated with impairment, indicating that overall tract integrity is associated with sensorimotor abnormalities in AMN. Impairment measures capture specific abnormalities in walking and balance that can be used to direct rehabilitation therapy in AMN. Tract-specific magnetic resonance imaging metrics, such as fractional anisotropy (used herein to evaluate structure-function relationships), significantly reflect disease severity in AMN.


Maternal DHA and the development of attention in infancy and toddlerhood.
Infants were followed longitudinally to document the relationship between docosahexaenoic acid (DHA) levels and the development of attention. Erythrocyte (red-blood cell; RBC) phospholipid DHA (percentage of total fatty acids) was measured from infants and mothers at delivery. Infants were assessed in infant-control habituation at 4, 6, and 8 months augmented with psychophysiological measures, and on free-play attention and distractibility paradigms at 12 and 18 months. Infants whose mothers had high DHA at birth showed an accelerated decline in looking over the 1st year and increases in examining during single-object exploration and less distractibility in the 2nd year. These findings are consistent with evidence suggesting a link between DHA and cognitive development in infancy.


Methods for correcting tilt anisoplanatism in laser-guide-star-based multiconjugate adaptive optics.
Multiconjugate adaptive optics (MCAO) is a technique for correcting turbulence-induced phase distortions in three dimensions instead of two, thereby greatly expanding the corrected field of view of an adaptive optics system. This is accomplished with use of multiple deformable mirrors conjugate to distinct ranges in the atmosphere, with actuator commands computed from wave-front sensor (WFS) measurements from multiple guide stars. Laser guide stars (LGSs) must be used (at least for the forseeable future) to achieve a useful degree of sky coverage in an astronomical MCAO system. Much as a single LGS cannot be used to measure overall wave-front tilt, a constellation of multiple LGSs at a common range cannot detect tilt anisoplanatism. This error alone will significantly degrade the performance of a MCAO system based on a single tilt-only natural guide star (NGS) and multiple tilt-removed LGSs at a common altitude. We present a heuristic, low-order model for the principal source of tilt anisoplanatism that suggests four possible approaches to eliminating this defect in LGS MCAO: (i) tip/tilt measurements from multiple NGS, (ii) a solution to the LGS tilt uncertainty problem, (iii) additional higher-order WFS measurements from a single NGS, or (iv) higher-order WFS measurements from both sodium and Rayleigh LGSs at different ranges. Sample numerical results for one particular MCAO system configuration indicate that approach (ii), if feasible, would provide the highest degree of tilt anisoplanatism compensation. Approaches (i) and (iv) also provide very useful levels of performance and do not require unrealistically low levels of WFS measurement noise. For a representative set of parameters for an 8-m telescope, the additional laser power required for approach (iv) is on the order of 2 W per Rayleigh LGS.


Molecular identification of an IgE-dependent histamine-releasing factor.
An immunoglobulin E (IgE)-dependent histamine-releasing factor (HRF) produced by lymphocytes of atopic children and present in biological fluids of allergic patients has been identified and purified. Amino-terminal sequencing revealed extensive homology to a mouse protein, p21, and its human homolog, p23. Both recombinant proteins caused histamine release from the human basophils of a subpopulation of donors, and this release was dependent on IgE. Polyclonal antibodies recognized and removed the biological activity of recombinant and native HRF. HRF identifies a heterogeneity of IgE and is believed to play a prominent role in chronic allergic disease processes.


Perspectives of people with Parkinson's disease and family carers about disease management in community settings: A cross-country qualitative study.
To explore perceptions of people with Parkinson's disease and family carers about the use and impact of health and social care services, community and voluntary sector resources for the management of Parkinson's disease. Resources from outside the formal health care system and collaborations between different levels and sectors could address the unmet needs of people with Parkinson's disease and their family carers and improve the management of Parkinson's disease in the community setting. A qualitative exploratory study was carried out in Denmark, Norway, Spain and the United Kingdom and was reported using the COREQ. Individual semi-structured interviews were conducted with people with Parkinson's disease and family carers between May and August 2020. Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis. A meta-ethnographic approach was used to analyse and synthesise cross-national findings. Forty-seven people with Parkinson's disease and 39 family carers participated in the four countries. Four themes and eight sub-themes emerged: (1) Personalised care for needs throughout the Parkinson's disease journey; (2) Accessibility of different types of support systems (including initiatives to support emotional well-being, physical rehabilitation, information on the healthcare services, voluntary associations and community groups); (3) Multiagency collaborations, a more comprehensive approach; (4) Acknowledgment of people with Parkinson's and family carers own role in Parkinson's disease management. An integrated and person-and-community-centred approach, which includes the participation of the health, social, voluntary and community sectors, is desired by people with Parkinson's disease and their family carers to improve the management of Parkinson's in the community setting. These findings could contribute to the creation of more sustainable care systems at the European level that would better respond to individual and changing needs in people with Parkinson's disease and their family carers, and in other long-term conditions. The Patient and Public Involvement groups contributed to the design of the study, the interview guides and validation of findings. This study will inform the management of Parkinson's disease at the community level and the use of resources not only directly linked to the health system. Taking into account all the actors that provide care and support to people with Parkinson' disease and family carers facilitates the creation of strategies that better respond to individual needs. Nurses and other health and social care professionals in the community and specialist levels of care should collaborate to develop multisectoral strategies that promote personalised and integrated care throughout the Parkinson's journey.


Amplitude dependency of regional chest wall resistance and elastance at normal breathing frequencies.
Current methods for measurement of chest wall properties assume that resistance (R) and elastance (E) are independent of the volume breathed. In six healthy subjects relaxed at functional residual capacity, we measured total and regional R and E of the chest wall within the range of normal breathing frequencies (0.2 to 0.6 Hz) and tidal volumes (250 to 750 ml), using volume forcing at the mouth as previously described. With these methods, esophageal and gastric pressures are compared with surface displacements measured with inductance plethysmographic belts to calculate R and E of rib cage and diaphragm-abdomen "pathways." Rib cage R and E were 25 to 30% higher than that of the total chest wall at each frequency and volume, whereas diaphragm-abdomen R and E were at least five times higher. R of the chest wall and each of the pathways decreased by about 70% with increasing frequency and by about 30% with increasing tidal volume. E of the chest wall and each of the pathways also decreased by about 30% with increasing tidal volume but was independent of frequency in this range. These results are consistent with nonlinear, viscoplastic models presented elsewhere. We conclude that: (1) despite the great structural differences between the rib cage and diaphragm-abdomen, each exhibits nonlinear behavior similar to that of the total chest wall; (2) chest wall R and E depend importantly on frequency and tidal volume.


Increases in Na/K pump numbers in isolated human lymphocytes exposed to lithium in vitro. Reversal by myo-inositol and by inhibitors of protein kinase C and the Na/H antiport.
Lithium (1-8 mM) caused a dose-dependent increase in the number of [3H]ouabain binding sites and in sodium/potassium (Na/K) pump activity in normal lymphocytes after incubation for 72 h. The increase in Na/K pump activity was due to an increase in the Vmax of the pump, with no change in the apparent affinity (Km) for potassium (rubidium). There was no change in the turnover number of the pump and the intracellular sodium concentration fell. The increase in [3H]ouabain binding sites was prevented by the addition of myo-inositol (10 mM), by inhibition of the protein kinase C with staurosporine (100 nM) and by inhibition of the Na/H antiport with dimethylamiloride (50 microM). These results suggest that the increase in Na/K pump activity caused by lithium is due to an increase in pump numbers and not due to increased activity of individual pumps or to an alteration in the affinity of the pumps for potassium. The increase in Na/K pump numbers and activity in lymphocytes exposed to lithium for 72 h may be related to altered Na/H antiport activity secondary to inhibition of phosphoinositol breakdown by lithium.


Intracellular NAD+ levels are associated with LPS-induced TNF-α release in pro-inflammatory macrophages.
Metabolism and immune responses have been shown to be closely linked and as our understanding increases, so do the intricacies of the level of linkage. NAD(+) has previously been shown to regulate tumour necrosis factor-α (TNF-α) synthesis and TNF-α has been shown to regulate NAD(+) homoeostasis providing a link between a pro-inflammatory response and redox status. In the present study, we have used THP-1 differentiation into pro- (M1-like) and anti- (M2-like) inflammatory macrophage subset models to investigate this link further. Pro- and anti-inflammatory macrophages showed different resting NAD(+) levels and expression levels of NAD(+) homoeostasis enzymes. Challenge with bacterial lipopolysaccharide, a pro-inflammatory stimulus for macrophages, caused a large, biphasic and transient increase in NAD(+) levels in pro- but not anti-inflammatory macrophages that were correlated with TNF-α release and inhibition of certain NAD(+) synthesis pathways blocked TNF-α release. Lipopolysaccharide stimulation also caused changes in mRNA levels of some NAD(+) homoeostasis enzymes in M1-like cells. Surprisingly, despite M2-like cells not releasing TNF-α or changing NAD(+) levels in response to lipopolysaccharide, they showed similar mRNA changes compared with M1-like cells. These data further strengthen the link between pro-inflammatory responses in macrophages and NAD(+). The agonist-induced rise in NAD(+) shows striking parallels to well-known second messengers and raises the possibility that NAD(+) is acting in a similar manner in this model.


Balanced, gated-mode photon detector for quantum-bit discrimination at 1550 nm.
A photon detector that combines two avalanche photodiodes (APDs) has been demonstrated for quantum-bit discrimination at 1550 nm. Spikes accompanied by signals in a gated mode were canceled by balanced output from the two APDs. The spike cancellation enabled one to reduce the threshold in the discriminators and thus the gate pulse voltage. The dark count probability and afterpulse probability were reduced to 7x10(-7) and 7x10(-4) , respectively, without affecting the detection efficiency (11%) at 178 K.


Streptococcus gwangjuense sp. nov., Isolated from Human Pericoronitis.
A novel facultative anaerobic, Gram-stain-negative coccus, designated strain ChDC B345T, was isolated from human pericoronitis lesion and was characterized by polyphasic taxonomic analysis. The 16S ribosomal RNA gene (16S rDNA) sequence revealed that the strain belonged to the genus Streptococcus. The 16S rDNA sequence of strain ChDC B345T was most closely related to those of Streptococcus mitis NCTC 12261T (99.5%) and Streptococcus pseudopneumoniae ATCC BAA-960T (99.5%). Complete genome of strain ChDC B345T was 1,972,471 bp in length and the G + C content was 40.2 mol%. Average nucleotide identity values between strain ChDC B345T and S. pseudopneumoniae ATCC BAA-960T or S. mitis NCTC 12261T were 92.17% and 93.63%, respectively. Genome-to-genome distance values between strain ChDC B345T and S. pseudopneumoniae ATCC BAA-960T or S. mitis NCTC 12261T were 47.8% (45.2-50.4%) and 53.0% (51.0-56.4%), respectively. Based on these results, strain ChDC B345T (= KCOM 1679T = JCM 33299T) should be classified as a novel species of genus Streptococcus, for which we propose the name Streptococcus gwangjuense sp. nov.


Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up.
Substantial evidence associates persistent organic pollutants (POP) with metabolic disturbances related to diabetes, but longitudinal studies with repeated measures are scarce. We aimed to characterize the association between background exposures to POPs with repeated measures of glucose homeostasis over 23-years. Within the Coronary Artery Risk Development in Young Adults study (year 0 ages: 18-30 years), we measured POPs in serum obtained in 1987-88 (follow-up year 2) in 90 non-diabetic controls and 90 cases diabetes-free at year 2 who became diabetic by year 20. We analyzed 32 POPs detectable in ≥75% of participants and created summary scores for 32 POPs, 23 polychlorinated biphenyls (PCB), and 8 organochlorine pesticides (OCP). Dependent variables were measures of glucose homeostasis at years 0-25 (up to 8 examinations). We explored associations using repeated measures regression adjusted for race, sex, concurrent body mass index (BMI), examination center and period, separately for cases and controls. The associations between the three summary scores and measures of glucose homeostasis were present for observations at ages 40-55 years, and particularly between 48-55 years: the 23 PCB summary was associated with HbA1c (never-diabetics: slope [value per unit of summary score], β=0.008, p=0.02; diabetics: β=0.03, p=0.07), fasting glucose (never-diabetics: β=0.24, p=0.003; diabetics: β=1.10, p=0.03), and insulin sensitivity% (never-diabetics: β=-2.82, p<0.001, diabetics: β=-0.31, p=0.30). No associations were observed at younger ages. Glucose homeostasis may worsen after decades of exposure to PCBs and OCPs at background environmental levels, independent of BMI and after participants reached the 5th decade of life.


Anti-glial nuclear antibody: marker of lung cancer-related paraneoplastic neurological syndromes.
We describe a new antibody, called anti-glial nuclear antibody (AGNA), in patients with paraneoplastic neurological syndromes (PNS) and small-cell lung carcinoma (SCLC). AGNA was initially identified in 24 sera of our archives by immunohistochemistry on rat cerebellum. AGNA positive sera showed a characteristic nuclear staining of the Bergmann glia in the Purkinje cell layer. Immunoblots and probing a cerebellar expression library with AGNA sera did not identify the antigen. Twenty of the 24 patients with AGNA had PNS and all but two had lung cancer. AGNA was identified in 13/113 (11.5%) patients with SCLC compared with 0/122 with other types of cancer (p<0.0001). The frequency of AGNA was not higher than expected for the presence of SCLC in the different PNS subtypes except in LEMS (p=0.0002). AGNA was present in 13/30 (43%) of LEMS patients with SCLC, compared with 0/19 of LEMS patients without cancer (p=0.0006). We conclude that the recognition of AGNA is helpful since this antibody is found in PNS associated with SCLC, particularly LEMS, in which other onconeural antibodies are absent.


[Sonographic appearances of subcutaneous and cutaneous oedema -- correlation with histopathology].
To correlate the sonographic findings of tissue oedema with histopathological changes in order to find an explanation for the different sonographic appearances of oedema. Subcutaneous and cutaneous tissue of the chest wall, the abdominal wall, and the thigh of 4 human cadavers with clinically evident oedema were examined sonographically. A specimen was then taken from each region for histological examination. Twelve cutis-subcutis-regions underwent sonographic-histological correlation. 9 out of 12 subcutaneous regions exhibited a diffusely increased echogenicity. 5 of the 9 regions with increased echogenicity also showed hypoechoic bands (up to 3 mm) within the subcutaneous tissue. Histologically, all of the 9 sonographically altered subcutaneous regions displayed lentiform or band-like optically empty spaces within the connective tissue between lobules of fatty tissue as well as between groups of fat cells within lobules of fatty tissue corresponding to fluid. Hypoechoic stripes at sonography represented very broad bands of fluid. The cutis appeared hyperechoic in all cases. At histology, 9 of 12 cases exhibited uniformly distributed optically empty spaces between connective tissue fibres of the dermis. Dermal thickness corresponded to the degree of oedema. Subcutaneous oedema results in diffusely increased echogenicity, which is caused by the difference in acoustic impedance occurring at the edges of numerous bands of fluid. In addition, hypoechoic bands are observed if broad spaces of fluid are present in severe cases. Encased fluid in the dermis is uniformly distributed between connective tissue fibres. Sonographically, the homogenous hyperechoic appearance of normal dermis remains unaltered in cases of oedema, but dermal thickness increases.


Processing of pro-B-type natriuretic peptide: furin and corin as candidate convertases.
B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) are the products of the enzyme-mediated cleavage of their precursor molecule, proBNP. The clinical significance of proBNP-derived peptides as biomarkers of heart failure has been explored thoroughly, whereas little is known about the mechanisms of proBNP processing. We investigated the role of 2 candidate convertases, furin and corin, in human proBNP processing. We measured proBNP expression in HEK 293 and furin-deficient LoVo cells. We used a furin inhibitor and a furin-specific small interfering RNA (siRNA) to explore the implication of furin in proBNP processing. Recombinant proBNPs were incubated with HEK 293 cells transfected with the corin-expressing plasmid. We applied mass spectrometry to analyze the products of furin- and corin-mediated cleavage. Reduction of furin activity significantly impaired proBNP processing in HEK 293 cells. Furin-deficient LoVo cells were unable to process proBNP, whereas coexpression with furin resulted in effective proBNP processing. Mass spectrometric analysis revealed that the furin-mediated cleavage of proBNP resulted in BNP 1-32, whereas corin-mediated cleavage led to the production of BNP 4-32. Some portion of proBNP in the plasma of heart failure patients was not glycosylated in the cleavage site region and was susceptible to furin-mediated cleavage. Both furin and corin are involved in the proBNP processing pathway, giving rise to distinct BNP forms. The significance of the presence of unprocessed proBNP in circulation that could be cleaved by the endogenous convertases should be further investigated for better understanding BNP physiology.


The Caenorhabditis elegans gene T23G5.5 encodes an antidepressant- and cocaine-sensitive dopamine transporter.
A small subset of neurons in the nematode Caenorhabditis elegans utilizes the catecholamine dopamine (DA) as a neurotransmitter to control or modulate movement and egg-laying. Disruption of DA-mediated behaviors represents a potentially powerful strategy to identify genes that are likely to participate in dopaminergic systems in man. In vertebrates, extracellular DA is inactivated by presynaptic DA transport proteins (DATs) that are also major targets of addictive agents, including amphetamines and cocaine. We used oligonucleotides derived from the C. elegans genomic locus T23G5.5 to isolate and characterize T23G5.5 cDNAs. Our studies predict that mRNAs from this locus encode a 615-amino-acid polypeptide with twelve stretches of hydrophobicity suitable for transmembrane domains, similar to that found in vertebrate catecholamine transporters. The inferred translation product bears highest identity (43-47%) to catecholamine (DA, norepinephrine, epinephrine) transporters within the GAT1/NET gene family and possesses conserved residues implicated in amine substrate recognition. Consistent with these findings, HeLa cells transfected with the C. elegans cDNA exhibit saturable and high affinity DA transport (Km = 1.2 microM) that is dependent on extracellular Na+ and Cl- and blocked by inhibitors of mammalian catecholamine transporters, including norepinephrine transporter- and DAT-selective antagonists, tricyclic antidepressants, and the nonselective amine transporter antagonists cocaine and D-amphetamine. These studies validate the T23G5.5 locus as encoding a functional catecholamine transporter, providing important comparative sequence information for catecholamine transporter structure/function studies and a path to identify regulators of dopaminergic signaling via genetic or pharmacologic manipulation of C. elegans cDNA in vivo.


Access to diagnostic facilities in children with cancer in Colombia: Spotting opportunity and distance from a sample.
Delivering health care timely and geographically accessible are determining factors for the prognosis of children with cancer. This study analyzed geographic access and timeliness to diagnostic services in Colombia. In this Colombian national childhood cancer database-based study, patients and their diagnostic facilities were individually and separately space positioned. Distances between the household to the diagnostic facility, and between the clinical date of suspicion and diagnosis were determined. Using exploratory data analysis, we obtained a probability density function (lambda), which expressed a correlation percentage between the residential location of the patient and either travel time or timeliness of treatment. 27 % of the sample of 731 patients had access to diagnostic centres in less than 30 min. The travel-distance to diagnostic centres was lowest in the Caribe and Andina Regions (43 % and 32 % distances up to 30 km respectively). However, in Amazonía and Orinoquía Regions, 87 % and 81 % had to travel more than 90 km - representing very long travel times. For more than 23 % of patients, time to diagnosis was more than 90 days, in Orinoquía, this was above 90 days for 1/3 of patients. Despite relatively short travel distances in the Caribe-Region, for 61 % time to diagnosis exceeded 30 days. This study identified clear shortcomings in the Colombian Health System related to the quality of childhood cancer-related health care in terms of timeliness, cancer networks, and geographic access. These inequities not only depend on sociodemographic-characteristics and should be intervened upon.


Rehospitalization and emergency department use rates before and after vagus nerve stimulation for epilepsy: use of state databases to provide longitudinal data across multiple clinical settings.
Data regarding rehospitalization and emergency department (ED) visits following vagus nerve stimulation (VNS) present data analysis challenges. We present a method that uses California's multiple databases to more completely assay VNS efficacy. The Healthcare Cost and Utilization Project's California Inpatient and Ambulatory Surgery databases were assayed for all VNS surgeries from 2005 to 2009. Patients were selected by epilepsy diagnosis codes and VNS procedure codes. Patients (total N = 629) were tracked across multiple databases using unique identifiers. Thirty-day and one-year post-implantation rates of VNS complication and healthcare visits were abstracted, along with one-year preoperative hospital and ED use. Statistics included correction for multiple comparisons. The one-year reoperation rate for adult patients (N = 536) was 3.9%; during the second year, an additional 3.2% of patients had reoperations. Within the first 30 days, <2% of patients experienced a complication. Four percent of patients were readmitted to a hospital, and 11.6% of patients visited an ED. The most common reason for rehospitalization or ED visit was seizure. In the first year after VNS, total seizure-related visits (hospitalization and ED) were 17% lower (2.12 visits per year to 1.71; p = 0.03). In the second year following VNS, seizure-related visits were 42% lower (2.21 visits per year to 1.27, p = 0.01). Pediatric patients (N = 93) had comparable results. VNS surgery has low rates of complications and reoperations and is associated with reduced incidence of seizure-related ED visits and hospital admissions in the first and second postoperative years.


Discharge from physiotherapy following stroke: the management of disappointment.
Stroke tends to result in a range of disabilities which have been shown to benefit from rehabilitation, in particular physiotherapy. Patients tend to have high expectations of the extent of recovery they can achieve through physiotherapy, and subsequently view discharge from physiotherapy before they have achieved that degree of recovery as disappointing and distressing. Current literature suggest that explicit discussion between physiotherapists and patients of the anticipated extent of recovery tends to be avoided during the programme of physiotherapy treatment, making discharge from physiotherapy the point at which potentially differing expectations might be expected to be confronted. This paper explores how the process of discharge is managed and experienced by patients and physiotherapists. It draws on Craib's (1994) ideas about how disappointment is managed in modern society. A qualitative longitudinal study was conducted with 16 stroke patients and their physiotherapists. These data comprise interview and observational material. The study found that the discharge of stroke patients from physiotherapy is not a point when patients' expectations and optimism about recovery are confronted. The notion of natural recovery that was raised with patients by physiotherapists at discharge and the information physiotherapists gave about exercise post-discharge had the effect of maintaining patients' high expectations and hopes about recovery. This has implications for the process of adaptation and adjustment that the patient eventually goes through in order to accommodate their altered abilities and identity. We argue that a number of factors contribute to the denial of disappointment within this interaction and that services need to be developed in ways that enable physiotherapists to engage with the possibility of disappointment about stroke outcome with patients, thereby making a positive contribution to the process of adaptation and adjustment that stroke survivors experience following discharge.


Recurrence of infection and hernia following partial versus complete removal of infected hernia mesh: a systematic review and cohort meta-analysis.
The aim of this systematic review and meta-analysis was to determine whether complete removal of infected hernia mesh (CMR) provides better results as compared to partial removal (PMR). PubMed, EMBASE, Cochrane Library, and MEDLINE via Ovid were systematically searched for records published from 1980 to 2018 by three independent researchers (GM, GS, and GG). Quality assessment, data extraction and analysis were performed according to the Cochrane Handbook for Systematic Reviews of Interventions. Mantel-Haenszel method with odds ratio and 95% confidence interval (OR (95% CI)) as the measure of effect size of dichotomous primary and secondary endpoints was utilized. Random-effects model was used for meta-analysis. Five observational studies totaling 421 patients were included in the meta-analysis. Rates of infection recurrence were 58.5% (62/106) in PMR and 25.5% (62/315) in CMR. The difference was statistically significant [OR (95% CI) 4.15 (2.30, 7.47); p < 0.001]. Rates of hernia recurrence were 9.7% (8/82) in PMR vs. 40.2% (41/102) in CMR. This difference was not statistically significant [OR (95% CI) 0.25 (0.04, 1.62); p = 0.15]. Low risk of publication bias was found using funnel plots and Egger's test. This meta-analysis found significantly increased rates of infection recurrence in patients undergoing partial removal of infected hernia mesh as compared to complete removal. Complete removal of infected hernia mesh may be associated with increased rates of hernia recurrence. Further longitudinal observational studies are needed to confirm these findings.


Subdiffraction-limited radius measurements of microcylinders using conventional bright-field optical microscopy.
A technique for measuring the radius of dielectric microcylinders with subdiffraction-limited precision is presented. Diffraction fringes arising from the dielectric cylinder are measured using conventional bright-field optical microscopy and compared with theory to deduce the radii. The technique has been demonstrated measuring the radii of the major-ampullate silks from Plebs eburnus spiders. Precision better than 50 nm is demonstrated, using a standard optical microscope with a numerical aperture of 0.6 for the objective. Accuracy was verified using scanning electron microscopy. This technique will facilitate rapid, precise measurement of dielectric microcylinder radii, enabling a new optical-microscopy-based measurement approach for these challenging micro-optics.


Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model.
Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model. CD133+CD44+ cells from HCT116, a human colon cancer cell line, were sorted by Fluorescence-activated cell sorting (FACS) and treated with WPE at the concentrations of 0, 10, 20, and 40 µg/mL for 6 days. Telomere lengths were assessed by quantitative real-time PCR (qRT-PCR) using telomere specific primers and DNA extracted from the cells, which was further adjusted with single-copy gene and reference DNA (ddCt ). Telomerase activity was also measured by qRT-PCR after incubating the PCR mixture with cell protein extracts, which was adjusted with reference DNA (dCt ). Transcriptions of hTERT and c-MYC were determined using conventional RT-PCR. Telomere length of WPE-treated cells was significantly decreased in a dose-dependent manner (5.16 ± 0.13 at 0 µg/mL, 4.79 ± 0.12 at 10 µg/mL, 3.24 ± 0.08 at 20 µg/mL and 3.99 ± 0.09 at 40 µg/mL; P = 0.0276). Telomerase activities concurrently decreased with telomere length (1.47 ± 0.04, 1.09 ± 0.01, 0.76 ± 0.08, and 0.88 ± 0.06; P = 0.0067). There was a positive correlation between telomere length and telomerase activity (r = 0.9090; P < 0.0001). Transcriptions of both hTERT and c-MYC were also significantly decreased in the same manner. In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.


Specialization of CDK1 and cyclin B paralog functions in a coenocystic mode of oogenic meiosis.
Oogenesis in the urochordate, Oikopleura dioica, occurs in a large coenocyst in which vitellogenesis precedes oocyte selection in order to adapt oocyte production to nutrient conditions. The animal has expanded Cyclin-Dependant Kinase 1 (CDK1) and Cyclin B paralog complements, with several expressed during oogenesis. Here, we addressed functional redundancy and specialization of CDK1 and cyclin B paralogs during oogenesis and early embryogenesis through spatiotemporal analyses and knockdown assays. CDK1a translocated from organizing centres (OCs) to selected meiotic nuclei at the beginning of the P4 phase of oogenesis, and its knockdown impaired vitellogenesis, nurse nuclear dumping, and entry of nurse nuclei into apoptosis. CDK1d-Cyclin Ba translocated from OCs to selected meiotic nuclei in P4, drove meiosis resumption and promoted nuclear envelope breakdown (NEBD). CDK1d-Cyclin Ba was also involved in histone H3S28 phosphorylation on centromeres and meiotic spindle assembly through regulating Aurora B localization to centromeres during prometaphase I. In other studied species, Cyclin B3 commonly promotes anaphase entry, but we found O. dioica Cyclin B3a to be non-essential for anaphase entry during oogenic meiosis. Instead, Cyclin B3a contributed to meiotic spindle assembly though its loss could be compensated by Cyclin Ba.


Scope and quality of Cochrane reviews of nutrition interventions: a cross-sectional study.
All countries face significant challenges from complex manifestations of malnutrition, which affects one in three people globally. Systematic reviews provide ready-to-use syntheses of quality-appraised evidence to inform decision-making for actions. To enhance the utility and quality of future Cochrane nutrition evidence, we described the scope and quality of all nutrition systematic reviews in the Cochrane Database of Systematic Reviews (CDSR). We screened all active CDSR records (31 July 2015) to identify reviews and protocols using pre-specified eligibility criteria and definitions. Duplicate, independent data extraction included criteria for inclusion of studies in completed reviews (PICOS). We assessed methodological quality (AMSTAR), use of GRADE, mapped reviews against 2013 Global Burden of Disease data, and categorised the paradigm (medical, lifestyle and socio-ecological) of the review question. We analysed our results using descriptive statistics. We screened 8484 records, and included 470 (8%) completed reviews (in 45 Cochrane Review Groups (CRGs)) and 169 (7%) protocols (in 41 CRGs) published by 47 of 53 CRGs with reviews. Most completed reviews were produced by the Pregnancy and Childbirth (n = 73), Neonatal (n = 64), Metabolic and Endocrine Disorders (n = 33), Developmental, Psychosocial and Learning Problems (n = 26), Kidney and Transplant (n = 18) and Heart (n = 18) CRGs. Only 27% (n = 129) of reviews had searches for new studies in 2013 or thereafter. Supplementation/supplement interventions were most common (50%; n = 235; majority with micronutrients; 73%, n = 173), followed by food interventions (20%; n = 95). All reviews included randomised controlled trials; about 5% included other designs; 25% used GRADE; the median AMSTAR score was 9 (interquartile range: 7 to 10), 51% were high (AMSTAR 9-11) and 49% moderate (AMSTAR 5-8) quality. More than 80% framed questions using a medical paradigm. For top causes of years-of-life-lost, most reviews addressed preterm birth, diabetes and ischaemic heart disease; for leading risk factors for disability-adjusted-life-years, most targeted childhood undernutrition and high body mass index. Nutrition reviews comprised 8% of active CDSR records, were widely distributed across nearly all CRGs and reflected the double nutrition burden. This analysis presents a comprehensive description of the scope and quality of Cochrane nutrition reviews, and identifies gaps for future activities to support actions to address the nutrition burden, in line with the current nutrition agenda and impetus.


Ontogenetic variation in the auditory sensitivity of black sea bass (Centropristis striata) and the implications of anthropogenic sound on behavior and communication.
Black sea bass (Centropristis striata) is an important fish species in both commercial and recreational fisheries of southern New England and the mid-Atlantic Bight. Due to the intense urbanization of these waters, this species is subject to a wide range of anthropogenic noise pollution. Concerns that C. striata are negatively affected by pile driving and construction noise predominate in areas earmarked for energy development. However, as yet, the hearing range of C. striata is unknown, making it hard to evaluate potential risks. This study is a first step in understanding the effects of anthropogenic noise on C. striata by determining the auditory detection bandwidth and thresholds of this species using auditory evoked potentials, creating pressure and acceleration audiograms. These physiological tests were conducted on wild-caught C. striata in three size/age categories. Results showed that juvenile C. striata had the significantly lowest thresholds, with auditory sensitivity decreasing in the larger size classes. Furthermore, C.striata has fairly sensitive sound detection relative to other related species. Preliminary investigations into the mechanisms of their sound detection ability were undertaken with gross dissections and an opportunistic micro-computed tomography image to address the auditory structures including otoliths and swim bladder morphology. Crucially, the auditory detection bandwidth of C. striata, and their most sensitive frequencies, directly overlap with high-amplitude anthropogenic noise pollution such as shipping and underwater construction.


Prioritizing candidate disease miRNAs by topological features in the miRNA target-dysregulated network: case study of prostate cancer.
Recently, microRNAs (miRNA), small noncoding RNAs, have taken center stage in the field of human molecular oncology. However, their roles in tumor biology remain largely unknown. According to the assumption that miRNAs implicated in a specific tumor phenotype will show aberrant regulation of their target genes, we introduce an approach based on the miRNA target-dysregulated network (MTDN) to prioritize novel disease miRNAs. Target genes have predicted binding sites for any miRNA. The MTDN is constructed by combining computational target prediction with miRNA and mRNA expression profiles in tumor and nontumor tissues. Application of the proposed method to prostate cancer reveals that known prostate cancer miRNAs are characterized by a greater number of dysregulations and coregulators and the tendency to coregulate with each other and that they share a higher proportion of targets with other prostate cancer miRNAs. Support vector machine classifier, based on these features and changes in miRNA expression, is constructed and gives an average overall prediction accuracy of 0.8872 in cross-validation tests. The classifier is then applied to miRNAs in the MTDN. Functions enriched by dysregulated targets of novel predicted miRNAs are closely associated with oncogenesis. In addition, predicted cancer miRNAs within families or from different families show combinatorial dysregulation of target genes, as revealed by analysis of the MTDN modular organization. Finally, 3 miRNA target regulations are verified to hold in prostate cancer cells by transfection assays. These results show that the network-centric method could prioritize novel disease miRNAs and model how oncogenic lesions are mediated by miRNAs, providing important insights into tumorigenesis.


Benthic foraminiferal response to trace element pollution-the case study of the Gulf of Milazzo, NE Sicily (Central Mediterranean Sea).
The response of benthic foraminiferal assemblages to trace element pollution in the marine sediments of the Gulf of Milazzo (north-eastern Sicily) was investigated. Since the 1960s, this coastal area has been a preferred site for the development of two small marinas and a commercial harbour as well as for heavy industry. Forty samples collected in the uppermost 3-4 cm of an undisturbed layer of sediment in the littoral environment were used for this benthic foraminiferal analysis. The enrichment factors (EFs) of selected trace elements (As, Co, Cr, Cu, Mn, Ni, Pb and Zn) were also calculated. Changes both in benthic foraminiferal assemblages and in some trace elements concentrations have provided evidence that the gulf's littoral zone can be subdivided into three sectors characterised by environmental changes in the marine ecosystem. In the sector unpolluted, close to the Milazzo Cape, foraminiferal assemblages exhibit high values of species richness and foraminiferal density while trace element concentrations and their EFs are very low. Here, the highest densities of Miliolids and epiphytic species are present. On the contrary, in the sector polluted, from the marinas to the crude oil refinery, foraminiferal density and species diversity are low, and assemblages are dominated, albeit with very low densities, by species that tolerate stressed environmental conditions, such as LOFAs, agglutinants and Ammonia spp. Here, the highest trace elements concentrations of Pb, Zn and Cu and related EFs were detected. Eastwards, in the sector moderately polluted, foraminiferal populations are quite poor. They are characterised by low values of species richness and foraminiferal densities, nevertheless trace element concentrations become lower than in the other sectors and their EFs are often below 1. Deformed foraminifera, with percentages up to 7.14 %, were found in all three of the sectors. Differences in benthic foraminiferal assemblages, coupled with results from statistical analysis, indicate that anthropogenic trace element pollution could be considered as one of the most important causes of the modifications of foraminiferal assemblages in the study area.


An autopsied case of V180I Creutzfeldt-Jakob disease presenting with panencephalopathic-type pathology and a characteristic prion protein type.
A 73-year-old Japanese woman showed slowly progressive aphasia, apraxia and dementia. She had no family history of prion disease or dementia. One year later she showed parkinsonism and corticobasal degeneration was initially suspected. On MRI, the left temporal neocortex seemed swollen on T2-weighted images in the initial stage, and a later high-signal intensity region was observed in the cerebral cortex in diffusion-weighted images. The patient developed myoclonus and an akinetic mutism state 15 months and 22 months after onset, respectively. Consecutive electroencephalography revealed no periodic sharp-wave complexes. Prion protein (PrP) gene analysis revealed a valine to isoleucine point mutation at codon 180, and methionine homozygosity at codon 129. This patient's clinical symptoms and disease course were atypical for Creutzfeldt-Jakob disease (CJD), and a stable state with nasal tube-feeding lasted several years. She died of respiratory failure at the age of 81, 102 months after the onset. Autopsy revealed widespread spongiform degeneration with weak synaptic-type PrP deposition, confirming the diagnosis of genetic CJD. Neurons in the cerebral cortex were relatively preserved in number and hypertrophic astrocytosis was generally moderate for such long-term disease, but cerebral white matter showed diffuse severe myelin pallor with tissue rarefaction suggestive of panencephalopatic-type pathology. The cerebellar cortex was relatively well preserved with observation of mild spongiform change in the molecular layer, moderate neuron loss in the Purkinje neuron layer, and scattered small plaque-like PrP deposition. Western blot analysis of protease-resistant PrP showed a characteristic pattern without a diglycoform band. V180I CJD is an interesting form of genetic CJD with regards to the clinicopathologic, molecular and genetic findings.


Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells.
In mice, a subpopulation of gut dendritic cells (DCs) expressing CD103 drives the development of regulatory T (T(reg)) cells. Further, it was recently described that the cross-talk between human intestinal epithelial cells (IECs) and DCs helps in maintaining gut immune homeostasis via the induction of non-inflammatory DCs. In this study, an analysis was carried out to determine whether IECs could promote the differentiation of CD103+ tolerogenic DCs, and the function of primary CD103+ DCs isolated from human mesenteric lymph nodes (MLNs) was evaluated. Monocyte-derived DCs (MoDCs) and circulating CD1c+ DCs were conditioned or not with supernatants from Caco-2 cells or IECs isolated from healthy donors or donors with Crohn's disease and analysed for their ability to induce T(reg) cell differentiation. In some cases, transforming growth factor beta (TGFbeta), retinoic acid (RA) or thymic stromal lymphopoietin (TSLP) were neutralised before conditioning. CD103+ and CD103- DCs were sorted by fluorescence-activated cell sorting (FACS) from MLNs and used in T(reg) cell differentiation experiments. It was found that human IECs promoted the differentiation of tolerogenic DCs able to drive the development of adaptive Foxp3+ T(reg) cells. This control was lost in patients with Crohn's disease and paralleled a reduced expression of tolerogenic factors by primary IECs. MoDCs differentiated with RA or IEC supernatant upregulated the expression of CD103. Consistently, human primary CD103+ DCs isolated from MLNs were endowed with the ability to drive T(reg) cell differentiation. This subset of DCs expressed CCR7 and probably represents a lamina propria-derived migratory population. A population of tolerogenic CD103+ DCs was identified in the human gut that probably differentiate in response to IEC-derived factors and drive T(reg) cell development.


Risk Factors in Adolescent Hypertension.
Hypertension is a complex and multifaceted disease, with many contributing factors. While diet and nutrition are important influences, the confounding effects of overweight and obesity, metabolic and genetic factors, racial and ethnic predispositions, socioeconomic status, cultural influences, growth rate, and pubertal stage have even more influence and make diagnosis quite challenging. The prevalence of hypertension in adolescents far exceeds the numbers who have been diagnosed; studies have found that 75% or more go undiagnosed. This literature review summarizes the challenges of blood pressure classification in adolescents, discusses the impact of these confounding influences, and identifies actions that will improve diagnosis and treatment outcomes.


'It's Not Easy': School Nurse Pain Assessment Practices for Students with Special Needs.
Assessing pain in children with special needs presents unique challenges for school nurses, as no evidence-based or clinical standards to guide practices have been established for use in the school setting. Additionally, school nurse staffing has not kept pace with the growth in the population of children with special needs, which has increased by 60% since 2002. The aim of this study was to explore school nurses' pain assessment practices for students with special needs. A cross-sectional study was conducted via the web. Participants/Subjects: Of 3,071 special needs school nurses invited, 27% participated (n = 825). STATA13 was used to analyze descriptive statistics, while content analysis was performed in NVIVO 10. The majority of participants assessed pain in students with special needs using objective assessments (97.34%) and consultations with teachers (91.09%) and parents (88.64%). School nurses utilize pain assessment methods used previously in other practice areas, and rated pain assessment practices at the low benchmark of adequate. Overall, school nurses assess pain by selecting approaches that are best matched to the abilities of the student with special needs. When assessing students with special needs, nurses should utilize objective clinical assessments, teacher consultations, and parent input scales. In addition to continuing education, policies facilitating lower nurse-to-student ratios are needed to improve pain assessment practices in the school setting. Research to understand the perspectives of nurses, teachers, parents, and students is needed to support the creation of evidence-based policies and procedures.


RPL23 Links Oncogenic RAS Signaling to p53-Mediated Tumor Suppression.
The ribosomal protein (RP)-MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC-induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad antioncogenic mechanism, we crossed mice bearing an MDM2(C305F) mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic Hras(G12V) transgene. Interestingly, the MDM2(C305F)-mutant mice, which are hypersensitive to c-MYC-induced tumorigenesis, are not hypersensitive to oncogenic Hras(G12V)-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein whereas RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2(C305F) mutant, correlates with increased p53 expression in MDM2(C305F) cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by downregulation of RPL23. Thus, although the RPL11-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic c-MYC-induced tumorigenesis, the RPL23-MDM2-p53 pathway coordinates with the p19ARF-MDM2-p53 pathway against oncogenic RAS-induced tumorigenesis. Cancer Res; 76(17); 5030-9. ©2016 AACR.


A 50-kDa membrane protein mediates sialic acid-independent binding and infection of conjunctival cells by adenovirus type 37.
The ocular tropism of adenovirus type 37 (Ad37) does not correlate with the wide distribution of the 46-kDa coxsackievirus and adenovirus receptor (CAR), the major receptor for most adenovirus serotypes. We previously found that Ad37 infects and binds well to conjunctival cells (Chang C), but poorly to lung epithelial (A549) cells that express CAR and hypothesized that this serotype uses a distinct receptor that is selectively expressed on conjunctival cells. To test this, we produced particles of a fiber-deleted Ad5 vector containing the Ad37 fiber protein. The "pseudotyped" vector infected Chang C cells better than A549 cells using a CAR-independent pathway. Ad37 binding was calcium-dependent and was abolished by protease digestion of cell surface proteins. Using a virus overlay protein blot assay (VOPBA), we detected calcium-dependent Ad37 binding to 50- and 60-kDa membrane proteins on permissive Chang C cells. In contrast, calcium-dependent binding was detected with only the 60-kDa protein on nonpermissive A549 cells. Ad19p, a closely related serotype that failed to bind to conjunctival cells, recognized the 60-kDa, but not the 50-kDa, protein. Ad37 has been reported to use sialic acid instead of CAR as a cell receptor on A549 cells. Pretreatment of Chang C cells with neuraminidase abolished Ad37 binding to only the 60-kDa protein, suggesting that sialic acid mediates Ad37 binding to the 60-kDa protein. The pseudotyped Ad37 vector was also able to infect neuraminidase-treated Chang C cells. Thus, subgroup D adenoviral binding to the 50-kDa protein is calcium-dependent and cell type- and serotype-specific, whereas binding to the 60-kDa protein is not necessary for infection of conjunctival cells. Together, these data suggest that the 50-kDa protein is the major receptor for Ad37 on conjunctival cells.


Shifting abortion care from a hospital to a community sexual and reproductive health care setting.
Community sexual and reproductive health (SRH) services are well placed to deliver abortion assessment services and early medical abortion (EMA), but comparative data on safety and acceptability from both settings are important for future service planning. Retrospective review of computerised records of 1342 women undergoing outpatient EMA (≤9 weeks) in a community SRH or hospital department of gynaecology in the same city, and a self-completed, anonymous survey of 303 women requesting abortion at both sites. Primary outcome was safety in terms of re-attendance rates for a complication related to EMA. Secondary outcomes were telephone contact with each site for an EMA-related concern and satisfaction with information about abortion (defined as score out of 10) received at each site. There was no difference in re-attendance rates to either service for a complication following outpatient EMA (2.7%). A higher proportion of women undergoing EMA at the SRH site made telephone contact compared to women at the hospital site (18.8% vs 10.8%; p=0.033). Women rated both settings highly in terms of information received before abortion (9.2 and 9.6 out of 10) at the hospital and SRH sites, respectively. This study suggests that provision of outpatient EMA in a community SRH setting is as safe as that delivered from a hospital setting, and that women are similarly satisfied with the information they receive about abortion from each setting. More abortion assessment and outpatient EMA services in Great Britain could shift from hospital to community SRH settings.


Novel antibody markers of unstable atherosclerotic lesions.
Detection of autoantibodies in human serum assists in the diagnosis of patients with autoimmune diseases. Diagnostic antibody signatures have also been proposed for colon, pancreatic, and breast cancers. In this issue of the JCI, Cleutjens et al. describe the application of a peptide array technique toward the development of antibody biomarkers of ruptured atherosclerotic lesions (see the related article beginning on page 2979). A phage-display library was prepared from mRNA derived from ruptured peripheral human atherosclerotic plaques, and the phages containing immunoreactive peptides were screened with serum from patients with ruptured atherosclerotic lesions. Antibodies reacting with 2 peptides, E1 and E12, were particularly sensitive for the early diagnosis of acute myocardial infarction. Further studies that include an adequate number of patients presenting very early after the onset of symptoms and additional control patient populations are warranted to compare the utility of these biomarkers to those in clinical use.


Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
gamma-Aminobutyric acid type A receptors (GABARs) have long been implicated in mediating ethanol (EtOH) actions, but so far most of the reported recombinant GABAR combinations have shown EtOH responses only at fairly high concentrations (> or = 60 mM). We show that GABARs containing the delta-subunit, which are highly sensitive to gamma-aminobutyric acid, slowly inactivating, and thought to be located outside of synapses, are enhanced by EtOH at concentrations that are reached with moderate, social EtOH consumption. Reproducible ethanol enhancements occur at 3 mM, a concentration six times lower than the legal blood-alcohol intoxication (driving) limit in most states (0.08% wt/vol or 17.4 mM). GABARs responsive to these low EtOH concentrations require the GABAR delta-subunit, which is thought to be associated exclusively with alpha 4- and alpha 6-subunits in vivo, and the beta 3-subunit, which has recently been shown to be essential for the in vivo anesthetic actions of etomidate and propofol. GABARs containing beta 2-instead of beta 3-subunits in alpha 4 beta delta- and alpha 6 beta delta-receptor combinations are almost 10 times less sensitive to EtOH, with threshold enhancement at 30 mM. GABARs containing gamma 2-instead of delta-subunits with alpha 4 beta and alpha 6 beta are three times less sensitive to EtOH, with threshold responses at 100 mM, a concentration not usually reached with social EtOH consumption. These combined findings suggest that "extrasynaptic" delta-subunit-containing GABARs, but not their "synaptic" gamma-subunit-containing counterparts, are primary targets for EtOH.


Design and application of two oligonucleotide probes for the identification of Geodermatophilaceae strains using fluorescence in situ hybridization (FISH).
Bacteria of the family of Geodermatophilaceae are actively involved in the decay processes [Urzì, C. and Realini, M. (1998) Int Biodeterior Biodegrad 42: 45-54; Urzì, C., Salamone, P., Schumann, P., and Stackebrandt, E. (2000) Int J Syst Evol Microbiol 50: 529-536] of stone monuments. Characterization of isolates includes phenotypic, chemotaxonomic and genetic analysis often requiring long-term procedures. The use of specific probes for members of Geodermatophilaceae family could be useful for the easy detection of those strains colonizing rock surfaces and involved in the biodeterioration. Two 16S rRNA-targeted oligonucleotide probes were designed for the specific detection of members of the family Geodermatophilaceae using fluorescence in situ hybridization (FISH); one probe specific for members of the two genera Geodermatophilus/Blastococcus and the second for members of the genus Modestobacter.


Apgar score after induction of anesthesia for canine cesarean section with alfaxalone versus propofol.
The effects of alfaxalone and propofol on neonatal vitality were studied in 22 bitches and 81 puppies after their use as anesthetic induction agents for emergency cesarean section. After assessment that surgery was indicated, bitches were randomly allocated to receive alfaxalone 1 to 2 mg/kg body weight or propofol 2 to 6 mg/kg body weight for anesthetic induction. Both drugs were administered intravenously to effect to allow endotracheal intubation, and anesthesia was maintained with isoflurane in oxygen. Neonatal vitality was assessed using a modified Apgar score that took into account heart rate, respiratory effort, reflex irritability, motility, and mucous membrane color (maximum score = 10); scores were assigned at 5, 15, and 60 minutes after delivery. Neither the number of puppies delivered nor the proportion of surviving puppies up to 3 months after delivery differed between groups. Anesthetic induction drug and time of scoring were associated with the Apgar score, but delivery time was not. Apgar scores in the alfaxalone group were greater than those in the propofol group at 5, 15, and 60 minutes after delivery; the overall estimated score difference between the groups was 3.3 (confidence interval 95%: 1.6-4.9; P < 0.001). In conclusion, both alfaxalone and propofol can be safely used for induction of anesthesia in bitches undergoing emergency cesarean section. Although puppy survival was similar after the use of these drugs, alfaxalone was associated with better neonatal vitality during the first 60 minutes after delivery.


The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus.
Mutations at the steel locus (Sl) of the mouse affect the same cellular targets as mutations at the white spotting locus (W), which is allelic with the c-kit proto-oncogene. We show that KL, a hematopoietic growth factor obtained from conditioned medium of BALB/c 3T3 fibroblasts that stimulates the proliferation of mast cells and early erythroid progenitors, specifically binds to the c-kit receptor. The predicted amino acid sequence of isolated KL-specific cDNA clones suggests that KL is synthesized as an integral transmembrane protein. Linkage analysis maps the KL gene to the Sl locus on mouse chromosome 10, and KL sequences are deleted in the genome of the Sl mouse. These results indicate that the Sl locus encodes the ligand of the c-kit receptor, KL.


Harnessing attosecond science in the quest for coherent X-rays.
Modern laser technology has revolutionized the sensitivity and precision of spectroscopy by providing coherent light in a spectrum spanning the infrared, visible, and ultraviolet wavelength regimes. However, the generation of shorter-wavelength coherent pulses in the x-ray region has proven much more challenging. The recent emergence of high harmonic generation techniques opens the door to this possibility. Here we review the new science that is enabled by an ability to manipulate and control electrons on attosecond time scales, ranging from new tabletop sources of coherent x-rays to an ability to follow complex electron dynamics in molecules and materials. We also explore the implications of these advances for the future of molecular structural characterization schemes that currently rely so heavily on scattering from incoherent x-ray sources.


Vaccines in development against West Nile virus.
West Nile encephalitis emerged in 1999 in the United States, then rapidly spread through the North American continent causing severe disease in human and horses. Since then, outbreaks appeared in Europe, and in 2012, the United States experienced a new severe outbreak reporting a total of 5,387 cases of West Nile virus (WNV) disease in humans, including 243 deaths. So far, no human vaccine is available to control new WNV outbreaks and to avoid worldwide spreading. In this review, we discuss the state-of-the-art of West Nile vaccine development and the potential of a novel safe and effective approach based on recombinant live attenuated measles virus (MV) vaccine. MV vaccine is a live attenuated negative-stranded RNA virus proven as one of the safest, most stable and effective human vaccines. We previously described a vector derived from the Schwarz MV vaccine strain that stably expresses antigens from emerging arboviruses, such as dengue, West Nile or chikungunya viruses, and is strongly immunogenic in animal models, even in the presence of MV pre-existing immunity. A single administration of a recombinant MV vaccine expressing the secreted form of WNV envelope glycoprotein elicited protective immunity in mice and non-human primates as early as two weeks after immunization, indicating its potential as a human vaccine.


Both ongoing alpha and visually induced gamma oscillations show reliable diversity in their across-site phase-relations.
Neural oscillations have emerged as one of the major electrophysiological phenomena investigated in cognitive and systems neuroscience. These oscillations are typically studied with regard to their amplitude, phase, and/or phase coupling. Here we demonstrate the existence of another property that is intrinsic to neural oscillations but has hitherto remained largely unexplored in cognitive and systems neuroscience. This pertains to the notion that these oscillations show reliable diversity in their phase-relations between neighboring recording sites (phase-relation diversity). In contrast to most previous work, we demonstrate that this diversity is restricted neither to low-frequency oscillations nor to periods outside of sensory stimulation. On the basis of magnetoencephalographic (MEG) recordings in humans, we show that this diversity is prominent not only for ongoing alpha oscillations (8-12 Hz) but also for gamma oscillations (50-70 Hz) that are induced by sustained visual stimulation. We further show that this diversity provides a dimension within electrophysiological data that, provided a sufficiently high signal-to-noise ratio, does not covary with changes in amplitude. These observations place phase-relation diversity on the map as a prominent and general property of neural oscillations that, moreover, can be studied with noninvasive methods in healthy human volunteers. This opens important new avenues for investigating how neural oscillations contribute to the neural implementation of cognition and behavior.


A Damage-Independent Role for 53BP1 that Impacts Break Order and Igh Architecture during Class Switch Recombination.
During class switch recombination (CSR), B cells replace the Igh Cμ or δ exons with another downstream constant region exon (CH), altering the antibody isotype. CSR occurs through the introduction of AID-mediated double-strand breaks (DSBs) in switch regions and subsequent ligation of broken ends. Here, we developed an assay to investigate the dynamics of DSB formation in individual cells. We demonstrate that the upstream switch region Sμ is first targeted during recombination and that the mechanism underlying this control relies on 53BP1. Surprisingly, regulation of break order occurs through residual binding of 53BP1 to chromatin before the introduction of damage and independent of its established role in DNA repair. Using chromosome conformation capture, we show that 53BP1 mediates changes in chromatin architecture that affect break order. Finally, our results explain how changes in Igh architecture in the absence of 53BP1 could promote inversional rearrangements that compromise CSR.


Antibodies as crypts of antiinfective and antitumor peptides.
Antibodies (Abs), often associated with antimicrobial and antitumor agents, have emerged as an important class of novel drugs for antigen-driven therapeutic purposes in diverse clinical settings, including oncology and infectious diseases. Abs commonly give rise in the treated host to anti-Ab responses, which may induce adverse reactions and limit their therapeutic efficacy. Their modular domain architecture has been exploited to generate alternative reduced formats (Fabs, scFvs, dAbs, minibodies, multibodies), essentially devoid of the Fc region. The presence of complementarity determining regions (CDRs) ensures the maintenance of selective binding to antigens and supports their use for biotechnological and therapeutic applications. Paradigmatic Abs mimicking the wide-spectrum antimicrobial activity of a yeast killer toxin (killer Abs) have revealed the existence of a family of Abs exerting a direct in vitro and/or in vivo microbicidal activity. Based on the variable sequence of an antiidiotypic recombinant killer Ab, CDR-related peptides have been synthesized, engineered by alanine-scanning and selected according to antimicrobial, antiviral and immunomodulatory properties. Irrespective of the native Ab specificity, synthetic CDRs from unrelated murine and human monoclonal Abs, have shown to display differential in vitro, in vivo and/or ex vivo antifungal (Candida albicans), antiviral (HIV-1) and antitumor (melanoma cells) activities. Alanine substitution of single residues of synthetic CDR peptides resulted in further differential increased/unaltered/decreased biological activity. The intriguing potential of Abs as source of antiinfective and antitumor therapeutics will be discussed, in light of recent advances in peptide design, stability and delivery.


Treatment of subglottic stenosis, due to Wegener's granulomatosis, with intralesional corticosteroids and dilation.
To determine the longterm efficacy of intralesional long-acting corticosteroid injection plus dilatation (ILCD) for subglottic stenosis (SGS) in Wegener's granulomatosis (WG). Since November 1994, all patients with WG who presented with SGS of more than 50% or symptoms of airway compromise were treated with intralesional injection of methylprednisolone acetate, injected directly into the stenotic segment, followed by microsurgical lysis of the stenotic ring and serial dilatation with Maloney bougies or Fogarty catheter balloon. The procedure was repeated at a later date if re-stenosis occurred. Patient outcome was evaluated over a period of 7 years. Twenty-one patients underwent 64 procedures. Mean followup was 40.6 months. Patients who did not have scarring from prior procedures required a mean of 2.4 procedures at mean intervals of 11.6 months to maintain subglottic patency. Patients with established laryngotracheal scarring required a mean of 4.1 procedures at mean intervals of 6.8 months to maintain patency. None of the 21 patients required a new tracheostomy. Only 2 significant complications occurred, both pneumothoraces. There were no adverse longterm sequelae. ILCD is effective therapy for SGS due to WG. Best results are obtained when these endoscopic techniques are performed prior to other forms of surgery, which may produce extensive scar formation. Based on this experience, the authors recommend ILCD as the preferred therapy in WG-SGS.


A longitudinal study of environmental tobacco smoke exposure in children: parental self reports versus age dependent biomarkers.
Awareness of the negative effects of smoking on children's health prompted a decrease in the self-reporting of parental tobacco use in periodic surveys from most industrialized countries. Our aim is to assess changes between ETS exposure at the end of pregnancy and at 4 years of age determined by the parents' self-report and measurement of cotinine in age related biological matrices. The prospective birth cohort included 487 infants from Barcelona city (Spain). Mothers were asked about maternal and household smoking habit. Cord serum and children's urinary cotinine were analyzed in duplicate using a double antibody radioimmunoassay. At 4 years of age, the median urinary cotinine level in children increased 1.4 or 3.5 times when father or mother smoked, respectively. Cotinine levels in children's urine statistically differentiated children from smoking mothers (Geometric Mean (GM) 19.7 ng/ml; 95% CI 16.83-23.01) and exposed homes (GM 7.1 ng/ml; 95% CI 5.61-8.99) compared with non-exposed homes (GM 4.5 ng/ml; 95% CI 3.71-5.48). Maternal self-reported ETS exposure in homes declined in the four year span between the two time periods from 42.2% to 31.0% (p < 0.01). Nevertheless, most of the children considered non-exposed by their mothers had detectable levels of cotinine above 1 ng/mL in their urine. We concluded that cotinine levels determined in cord blood and urine, respectively, were useful for categorizing the children exposed to smoking and showed that a certain increase in ETS exposure during the 4-year follow-up period occurred.


Association of the steroid synthesis gene CYP11a with polycystic ovary syndrome and hyperandrogenism.
Biochemical data implicate an underlying disorder of androgen biosynthesis and/or metabolism in the aetiology of polycystic ovary syndrome (PCOS). We have examined the segregation of the genes coding for two key enzymes in the synthesis and metabolism of androgens, cholesterol side chain cleavage (CYP11a) and aromatase (CYP19), with PCOS in 20 multiply-affected families. All analyses excluded CYP19 cosegregation with PCOS, demonstrating that this locus is not a major determinant of risk for the syndrome. However, our results provide evidence for linkage to the CYP11a locus (NPL score = 3.03, p = 0.003). Parametric analysis using a dominant model suggests genetic heterogeneity, generating a maximum HLOD score of 2.7 (alpha = 0.63). An association study of 97 consecutively identified Europids with PCOS and matched controls demonstrates significant allelic association of a CYP11a 5' UTR pentanucleotide repeat polymorphism with hirsute PCOS subjects (p = 0.03). A strong association was also found between alleles of this polymorphism and total serum testosterone levels in both affected and unaffected individuals (p = 0.002). Our data demonstrate that variation in CYP11a may play an important role in the aetiology of hyperandrogenaemia which is a common characteristic of polycystic ovary syndrome.


Two-step induction of primitive erythrocytes in Xenopus laevis embryos: signals from the vegetal endoderm and the overlying ectoderm.
Primitive blood cells differentiate from the ventral mesoderm blood islands in Xenopus embryos. In order to determine the tissue interactions that propagate blood formation in early embryogenesis, we used embryos that had the ventral cytoplasm removed. These embryos gastrulated normally, formed a mesodermal layer and lacked axial structures, but displayed a marked enhancement of alpha-globin expression. Early ventral markers, such as msx-1, vent-1 and vent-2 were highly expressed at the gastrula stage, while a dorsal marker, goosecoid, was diminished. Several lines of experimental evidence demonstrate the critical role of animal pole-derived ectoderm in blood cell formation: 1) Mesoderm derived from dorsal blastomeres injected with beta-galactosidase mRNA (as a lineage tracer) expressed alpha-globin when interfaced with an animal pole-derived ectodermal layer; 2) Embryos in which the animal pole tissue had been removed by dissection at the blastula stage failed to express alpha-globin; 3) Exogastrulated embryos that lacked an interaction between the mesodermal and ectodermal layers failed to form blood cells, while muscle cells were observed in these embryos. Using dominant-negative forms of the BMP-4 and ALK-4 receptors, we showed that activin and BMP-4 signaling is necessary for blood cell differentiation in ventral marginal zone explants, while FGF signaling is not essential. In ventralized embryos, inactivation of the BMP-4 signal within a localized area of the ectoderm led to suppression of globin expression in the adjacent mesoderm layer, but inactivation of the activin signal did not have this effect. These observations suggest that mesodermal cells, derived from a default pathway that is induced by the activin signal, need an additional BMP-4-dependent factor from the overlying ectoderm for further differentiation into a blood cell lineage.


Histone deacetylase inhibitors: Isoform selectivity improves survival in a hemorrhagic shock model.
Hemorrhage is a leading preventable cause of death. Nonselective histone deacetylase inhibitors (HDACIs), such as valproic acid (VPA), have been shown to improve outcomes in hemorrhagic shock (HS). The HDACs can be divided into four functional classes (I, IIa/IIb, III, and IV). Classes I, IIa/IIb, and III have previously been implicated in the pathophysiology of HS. This study aimed to determine which HDAC class, or classes, are responsible for the survival benefit observed with nonselective HDACIs. Survival study: Sprague-Dawley rats were subjected to lethal HS (50% hemorrhage) and randomized to the following groups (n = 8): (1) no treatment, (2) normal saline vehicle, (3) cyclodextrin vehicle, (4) MS275 (class I HDACI), (5) VPA (class I/IIa HDACI), (6) MC1568 (class IIa HDACI), (7) ACY1083 (class IIb HDACI), and (8) EX527 (class III HDACI). Survival was monitored for 24 hours. Mechanistic study: Sprague-Dawley rats were subjected to sublethal HS (40% hemorrhage) and randomized to the same groups (n = 3), excluding EX527, based on results of the survival study. Tissues were harvested at 3 hours posttreatment, and expression of phosphorylated-AKT, β-catenin, acetylated histones H3 and H4, and acetylated α-tubulin were analyzed in myocardial tissue. Survival rate was 12.5% in the untreated group, and did not improve with vehicle or MS275 treatment. EX527 improved survival to 50%, although this did not achieve statistical significance (p = 0.082). However, treatment with VPA, MC1568, and ACY1083 improved survival rates to 87.5%, 75%, and 75%, respectively (p < 0.05). The VPA-induced acetylation of both histones H3 and H4, while MC1568 and ACY1083 increased acetylation of histone H4. ACY1083 also induced acetylation of α-tubulin. All treatment groups, except MS275, increased phosphorylated-AKT, and β-catenin. Inhibition of HDAC classes IIa or IIb, but not class I, activates prosurvival pathways, which may be responsible for the improved outcomes in rodent models of HS.


A new class of cell surface antigens. Quantitative absorption studies defining cell-lineage-specific antigens on hemopoietic cells.
A new class of cell surface antigens are described which are expressed on cells within a particular differentiation pathway. These antigens, termed cell-lineage-specific antigens, are shown to be distinct from differentiation antigens and from histocompatibility antigens. The presence of these antigens was demonstrated by raising antisera against terminally differentiated hemopoietic cells such as platelets, thymocytes, and macrophages and showing cross-reaction with the pluripotent stem cells from which these cells were derived. Quantitative absorption studies of each antiserum showed the antigens to be largely cell-lineage-specific. For example, the anti-stem cell activity in anti-platelet serum was not absorbed out with thymocytes or macrophages from the same mouse strain but was removed by absorption with platelets. Absorption of each antiserum with nonhemopoietic mouse tissues such as brain, kidney, liver, and testis did not reduce anti-stem cell activity. Thus, each antiserum was shown to be tissue specific and species specific. Hemopoietic cells from mouse strains other than CBA absorbed out most of the anti-stem cell activity indicating cell-lineage-specific antigens to be common to the mouse strains tested.


Vastus Lateralis Architecture Changes During Pregnancy - A Longitudinal Study.
While the incidence of falls has been described to increase with pregnancy, the mechanism behind this is unclear. Pregnancy associated changes in lower extremity muscle strength could be a possible factor influencing injury risk. Thus, the aim of this longitudinal study was to investigate muscle strength and architectural properties of the lower limbs in different stages of pregnancy and postpartum. In nineteen pregnant women (30 ± 4 years) and fifteen non-pregnant controls (28 ± 4 years) muscle strength and architectural properties of the vastus lateralis muscle were assessed combining dynamometry, ultrasound, kinematic, and electromyographic measurements. Body mass and body composition were determined using bioimpedance analysis. In the pregnant women, the measurements were conducted in the 16 ± 4th (EP) and 29 ± 4th week of pregnancy (LP) as well as in the 32 ± 9th week postpartum (PP). Muscle thickness and pennation angle of the fascicles significantly increased at LP, while muscle strength remained constant during and after pregnancy. Body mass, skeletal muscle mass, fat mass, intracellular and extracellular water also peaked at LP. Postpartum values did not differ from the controls. Changes in the muscle properties were not related to changes in body mass and body composition. Conditions during pregnancy promote changes in the vastus lateralis architecture indicating muscle hypertrophy. However, pregnancy did not increase muscle strength while body mass progressively increases. Therefore, in the event of balance perturbations pregnant women may not be able to meet the requirements for the increased physical demand.


Concurrent validity and reliability of the Community Balance and Mobility scale in young-older adults.
With the growing number of young-older adults (baby-boomers), there is an increasing demand for assessment tools specific for this population, which are able to detect subtle balance and mobility deficits. Various balance and mobility tests already exist, but suffer from ceiling effects in higher functioning older adults. A reliable and valid challenging balance and mobility test is critical to determine a young-older adult's balance and mobility performance and to timely initiate preventive interventions. The aim was to evaluate the concurrent validity, inter- and intrarater reliability, internal consistency, and ceiling effects of a challenging balance and mobility scale, the Community Balance and Mobility Scale (CBM), in young-older adults aged 60 to 70 years. Fifty-one participants aged 66.4 ± 2.7 years (range, 60-70 years) were assessed with the CBM. The Fullerton Advanced Balance scale (FAB), 3-Meter Tandem Walk (3MTW), 8-level balance scale, Timed-Up-and-Go (TUG), and 7-m habitual gait speed were used to estimate concurrent validity, examined by Spearman correlation coefficient (ρ). Inter- and intrarater reliability were calculated as Intra-class-correlations (ICC), and internal consistency by Cronbach alpha and item-total correlations (ρ). Ceiling effects were determined by obtaining the percentage of participants reaching the highest possible score. The CBM significantly correlated with the FAB (ρ = 0.75; p < .001), 3MTW errors (ρ = - 0.61; p < .001), 3MTW time (ρ = - 0.35; p = .05), the 8-level balance scale (ρ = 0.35; p < .05), the TUG (ρ = - 0.42; p < .01), and 7-m habitual gait speed (ρ = 0.46, p < .001). Inter- (ICC2,k = 0.97), intrarater reliability (ICC3,k = 1.00) were excellent, and internal consistency (α = 0.88; ρ = 0.28-0.81) was good to satisfactory. The CBM did not show ceiling effects in contrast to other scales. Concurrent validity of the CBM was good when compared to the FAB and moderate to good when compared to other measures of balance and mobility. Based on this study, the CBM can be recommended to measure balance and mobility performance in the specific population of young-older adults. Trial number: ISRCTN37750605 . (Registered on 21/04/2016).


Neutrophils: Beneficial and Harmful Cells in Septic Arthritis.
Septic arthritis is an inflammatory joint disease that is induced by pathogens such as Staphylococcus aureus. Infection of the joint triggers an acute inflammatory response directed by inflammatory mediators including microbial danger signals and cytokines and is accompanied by an influx of leukocytes. The recruitment of these inflammatory cells depends on gradients of chemoattractants including formylated peptides from the infectious agent or dying cells, host-derived leukotrienes, complement proteins and chemokines. Neutrophils are of major importance and play a dual role in the pathogenesis of septic arthritis. On the one hand, these leukocytes are indispensable in the first-line defense to kill invading pathogens in the early stage of disease. However, on the other hand, neutrophils act as mediators of tissue destruction. Since the elimination of inflammatory neutrophils from the site of inflammation is a prerequisite for resolution of the acute inflammatory response, the prolonged stay of these leukocytes at the inflammatory site can lead to irreversible damage to the infected joint, which is known as an important complication in septic arthritis patients. Thus, timely reduction of the recruitment of inflammatory neutrophils to infected joints may be an efficient therapy to reduce tissue damage in septic arthritis.


Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth.
Lung disease causes most of the morbidity and mortality in cystic fibrosis (CF). Understanding the pathogenesis of this disease has been hindered, however, by the lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with mutated CFTR genes. We now report that, within months of birth, CF pigs spontaneously developed hallmark features of CF lung disease, including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting that the lungs of CF pigs have a host defense defect against a wide spectrum of bacteria. In humans, the temporal and causal relations between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation but were less often sterile than controls. Moreover, after introduction of bacteria into their lungs, pigs with CF failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Our finding that pigs with CF have a host defense defect against bacteria within hours of birth provides an opportunity to further investigate CF pathogenesis and to test therapeutic and preventive strategies that could be deployed before secondary consequences develop.


Ligand-induced changes in the conformational dynamics of a bacterial cytotoxic endonuclease.
Knowledge about the conformational dynamics of a protein is key to understanding its biochemical and biophysical properties. In the present work we investigated the dynamic properties of the enzymatic domain of DNase colicins via time-resolved fluorescence and anisotropy decay analysis in combination with steady-state acrylamide quenching experiments. The dynamic properties of the apoenzyme were compared to those of the E9 DNase ligated to the transition metal ion Zn(2+) and the natural inhibitor Im9. We further investigated the contributions of each of the two tryptophans within the E9 DNase (Trp22 and Trp58) using two single-tryptophan mutants (E9 W22F and E9 W58F). Wild-type E9 DNase, E9 W22F, and E9 W58F, as well as Im9, showed multiple lifetime decays. The time-resolved and steady-state fluorescence results indicated that complexation of E9 DNase with Zn(2+) induces compaction of the E9 DNase structure, accompanied by immobilization of Trp22 along with a reduced solvent accessibility for both tryptophans. Im9 binding resulted in immobilization of Trp22 along with a decrease in the longest lifetime component. In contrast, Trp58 experienced less restriction on complexation of E9 DNase with Im9 and showed an increase in the longest lifetime component. Furthermore, the results point out that the Im9-induced changes in the conformational dynamics of E9 DNase are predominant and occur independently of the Zn(2+)-induced conformational effects.


Vimentin, carcinoembryonic antigen and keratin in the diagnosis of mesothelioma, adenocarcinoma and reactive pleural lesions.
An immunohistochemical study of reactive pleural lesions, adenocarcinomas and mesotheliomas using carcinoembryonic antigen (CEA), cytokeratin and vimentin was carried out. All the specimens were obtained at surgery except for 11 mesotheliomas found at necropsy. Vimentin was positive in 23 of 27 mesotheliomas and negative in all the adenocarcinomas and 4 of 17 reactive mesothelial lesions. Conversely, CEA was positive in all the adenocarcinomas but negative in all mesotheliomas. Immunoreactivity for vimentin was seen in only 3 of 11 post-mortem mesotheliomas. Vimentin is a useful adjunct to the tissue diagnosis of mesothelioma especially when CEA is negative and cytokeratin positive. Its use appears largely confirmed to well fixed surgically derived tissues.


Usability and feasibility of PreventS-MD web app for stroke prevention.
Most strokes and cardiovascular diseases (CVDs) are potentially preventable if their risk factors are identified and well controlled. Digital platforms, such as the PreventS-MD web app (PreventS-MD) may aid health care professionals (HCPs) in assessing and managing risk factors and promoting lifestyle changes for their patients. This is a mixed-methods cross-sectional two-phase survey using a largely positivist (quantitative and qualitative) framework. During Phase 1, a prototype of PreventS-MD was tested internationally by 59 of 69 consenting HCPs of different backgrounds, age, sex, working experience, and specialties using hypothetical data. Collected comments/suggestions from the study HCPs in Phase 1 were reviewed and implemented. In Phase 2, a near-final version of PreventS-MD was developed and tested by 58 of 72 consenting HCPs using both hypothetical and real patient (n = 10) data. Qualitative semi-structured interviews with real patients (n = 10) were conducted, and 1 month adherence to the preventive recommendations was assessed by self-reporting. The four System Usability Scale (SUS) groups of scores (0-50 unacceptable; 51-68 poor; 68-80.3 good; >80.3 excellent) were used to determine usability of PreventS-MD. Ninety-nine HCPs from 27 countries (45% from low- to middle-income countries) participated in the study, and out of them, 10 HCPs were involved in the development of PreventS before the study, and therefore were not involved in the survey. Of the remaining 89 HCPs, 69 consented to the first phase of the survey, and 59 of them completed the first phase of the survey (response rate 86%), and 58 completed the second phase of the survey (response rate 84%). The SUS scores supported good usability of the prototype (mean score = 80.2; 95% CI [77.0-84.0]) and excellent usability of the final version of PreventS-MD (mean score = 81.7; 95% CI [79.1-84.3]) in the field. Scores were not affected by the age, sex, working experience, or specialty of the HCPs. One-month follow-up of the patients confirmed the high level of satisfaction/acceptability of PreventS-MD and (100%) adherence to the recommendations. The PreventS-MD web app has a high level of usability, feasibility, and satisfaction by HCPs and individuals at risk of stroke/CVD. Individuals at risk of stroke/CVD demonstrated a high level of confidence and motivation in following and adhering to preventive recommendations generated by PreventS-MD.


Tube bundle system: for monitoring of coal mine atmosphere.
A tube bundle system (TBS) is a mechanical system for continuously drawing gas samples through tubes from multiple monitoring points located in an underground coal mine. The gas samples are drawn via vacuum pump to the surface and are typically analyzed for oxygen, methane, carbon dioxide and carbon monoxide. Results of the gas analyses are displayed and recorded for further analysis. Trends in the composition of the mine atmosphere, such as increasing methane or carbon monoxide concentration, can be detected early, permitting rapid intervention that prevents problems, such as a potentially explosive atmosphere behind seals, fire or spontaneous combustion. TBS is a well-developed technology and has been used in coal mines around the world for more than 50 years. Most longwall coal mines in Australia deploy a TBS, usually with 30 to 40 monitoring points as part of their atmospheric monitoring. The primary uses of a TBS are detecting spontaneous combustion and maintaining sealed areas inert. The TBS might also provide mine atmosphere gas composition data after a catastrophe occurs in an underground mine, if the sampling tubes are not damaged. TBSs are not an alternative to statutory gas and ventilation airflow monitoring by electronic sensors or people; rather, they are an option to consider in an overall mine atmosphere monitoring strategy. This paper describes the hardware, software and operation of a TBS and presents one example of typical data from a longwall coal mine.


Timing is everything: priority effects alter community invasibility after disturbance.
Theory suggests that communities should be more open to the establishment of regional species following disturbance because disturbance may make more resources available to dispersers. However, after an initial period of high invasibility, growth of the resident community may lead to the monopolization of local resources and decreased probability of successful colonist establishment. During press disturbances (i.e., directional environmental change), it remains unclear what effect regional dispersal will have on local community structure if the establishment of later arriving species is affected by early arriving species (i.e., if priority effects are important). To determine the relationship between time-since-disturbance and invasibility, we conducted a fully factorial field mesocosm experiment that exposed tundra zooplankton communities to two emerging stressors - nutrient and salt addition, and manipulated the arrival timing of regional dispersers. Our results demonstrate that invasibility decreases with increasing time-since-disturbance as abundance (nutrient treatments) or species richness (salt treatments) increases in the resident community. Results suggest that the relative timing of dispersal and environmental change will modify the importance of priority effects in determining species composition after a press disturbance.