The von Hippel-Lindau Chuvash mutation in mice alters cardiac substrate and high-energy phosphate metabolism.
Hypoxia-inducible factor (HIF) appears to function as a global master regulator of cellular and systemic responses to hypoxia. HIF pathway manipulation is of therapeutic interest; however, global systemic upregulation of HIF may have as yet unknown effects on multiple processes. We used a mouse model of Chuvash polycythemia (CP), a rare genetic disorder that modestly increases expression of HIF target genes in normoxia, to understand what these effects might be within the heart. An integrated in and ex vivo approach was employed. Compared with wild-type controls, CP mice had evidence (using in vivo magnetic resonance imaging) of pulmonary hypertension, right ventricular hypertrophy, and increased left ventricular ejection fraction. Glycolytic flux (measured using [(3)H]glucose) in the isolated contracting perfused CP heart was 1.8-fold higher. Net lactate efflux was 1.5-fold higher. Furthermore, in vivo (13)C-magnetic resonance spectroscopy (MRS) of hyperpolarized [(13)C1]pyruvate revealed a twofold increase in real-time flux through lactate dehydrogenase in the CP hearts and a 1.6-fold increase through pyruvate dehydrogenase. (31)P-MRS of perfused CP hearts under increased workload (isoproterenol infusion) demonstrated increased depletion of phosphocreatine relative to ATP. Intriguingly, no changes in cardiac gene expression were detected. In summary, a modest systemic dysregulation of the HIF pathway resulted in clear alterations in cardiac metabolism and energetics. However, in contrast to studies generating high HIF levels within the heart, the CP mice showed neither the predicted changes in gene expression nor any degree of LV impairment. We conclude that the effects of manipulating HIF on the heart are dose dependent.


[Prevalence of indirect sharing of drug-injecting paraphernalia in Galicia, Madrid, Seville and Valencia [Spain]].
To study drug-injecting practices, particularly indirect sharing of injecting paraphernalia (ISIP), and sexual risk behavior. We performed a cross-sectional study of 1638 users of needle exchange programs (NEPs). Different types of ISIP were studied: taking diluted drugs in a syringe used by others, placing the needle in a recipient with other used needles, and reusing cleaning liquid previously used by others. The prevalence of injecting with syringes already used by others was 16% in Galicia, 4.7% in Madrid, 17.6% in Seville and 13.2% in Valencia (p < 0.001). With geographical variations, other types of ISIP (Galicia: 32.4%; Madrid: 28.5%; Seville: 42.6%; Valencia: 27.4% -p < 0.001-) were more frequent than injecting with syringes already used by others (Galicia: 32.4%; Madrid: 28.5%; Seville: 42.6%; Valencia: 27.4% -p < 0.001-). The percentage not injecting with syringes used by others but performing ISIP was 21.7%, 25.3%, 28.2% and 18.1% (p < 0.01) respectively. In all geographical areas, sexual risk practices were more prevalent with steady sex partners (68.6%, 72.0%, 77.8%, 72.8% [NS]) than with casual partners (36.6%, 40.9%, 37.9%, 23.9% [NS]). Among injectors with a stable partner, 81.3% in Galicia, 75.9% in Madrid, 86.1% in Seville and 79.7% in Valencia reported that his/her serological status was negative for HIV or was unknown (p < 0.001). ISIP is more prevalent than injection with syringes already used by others. For a substantial percentage of injectors, ISIP is the only risk practice. ISIP and the low use of condoms, particularly with steady partners, could be a contributory factor to the spread of HIV, hepatitis C virus, and hepatitis B virus infection.


Basement membrane-dependent survival of retinal ganglion cells.
The present study investigates the role of the inner limiting membrane (ILM) in the survival of ganglion cells (GCs) in embryonic chick and mouse retina. In chick embryos, the ILM was enzymatically removed at embryonic day (E)5 and E7 in ovo, and GCs were counted over the following 7 days of incubation. In mice, the ILM ruptured early in development due to a targeted mutation of laminin-gamma1. The number of surviving GCs in late embryonic homozygous mutant mice was compared to GC counts in heterozygotic and nonmutant siblings. The survival of GCs was also assayed in vitro, using the ILM as a substrate. When the ILM was removed in E5 chick embryos, almost all GCs underwent apoptosis by E10. GC apoptosis was prevented by reconstituting the ILM shortly after its disruption. Apoptosis of retinal GCs also occurred in mouse embryos with a fragmented ILM. ILM disruption in both chick and mice not only affected GC survival but also led to the retraction of the end-feet processes of radial cells from the GC layer. In vitro, GCs thrived better on substrates of radial cell end feet than on plain ILM, indicating that the contact with the end feet is more important than the presence of the ILM for GC survival. The radial cell end feet are the natural substrate for GCs and are essential for their survival. The importance of the ILM lies in its function to anchor the radial end feet to the vitreal surface of the retina.


Development of a particle-trap preconcentration-soft ionization mass spectrometric technique for the quantification of mercury halides in air.
Measurement of oxidized mercury, Hg(II), in the atmosphere poses a significant analytical challenge as Hg(II) is present at ultra-trace concentrations (picograms per cubic meter air). Current technologies are sufficiently sensitive to measure the total Hg present as Hg(II) but cannot determine the chemical speciation of Hg(II). We detail here the development of a soft ionization mass spectrometric technique coupled with preconcentration onto nano- or microparticle-based traps prior to analysis for the measurement of mercury halides in air. The current methodology has comparable detection limits (4-11 pg m(-3)) to previously developed techniques for the measurement of total inorganic mercury in air while allowing for the identification of HgX2 in collected samples. Both mercury chloride and mercury bromide have been sporadically detected in Montreal urban and indoor air using atmospheric pressure chemical ionization-mass spectrometry (APCI-MS). We discuss limitations and advantages of the current technique and discuss potential avenues for future research including quantitative trace measurements of a larger range of mercury compounds.


Common 4977 bp deletion and novel alterations in mitochondrial DNA in Vietnamese patients with breast cancer.
Mitochondrial DNA (mtDNA) has been proposed to be involved in carcinogenesis and ageing. The mtDNA 4977 bp deletion is one of the most frequently observed mtDNA mutations in human tissues and may play a role in breast cancer (BC). The aim of this study was to investigate the frequency of mtDNA 4977 bp deletion in BC tissue and its association with clinical factors. We determined the presence of the 4977 bp common deletion in cancer and normal paired tissue samples from 106 Vietnamese patients with BC by sequencing PCR products. The mtDNA 4977 bp deletion was significantly more frequent in normal tissue in comparison with paired cancer tissue. Moreover, the incidence of the 4977 bp deletion in BC tissue was significantly higher in patients with estrogen receptor (ER) positive as compared with ER negative BC tissue. Preliminary results showed, in cancerous tissue, a significantly higher incidence of novel deletions in the group of patients with lymph node metastasis in comparison with the patients with no lymph node metastasis. We have found 4977 bp deletion in mtDNA to be a common event in BC and with special reference to ER positive BC. In addition, the novel deletions were shown to be related to lymph node metastasis. Our finding may provide complementary information in prediction of clinical outcome including metastasis, recurrence and survival of patients with BC.


Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer.
Cancer was recently annexed to diabetic complications. Furthermore, recent studies suggest that cancer can increase the risk of diabetes. Consequently, diabetes and cancer share many risk factors, but the cellular and molecular pathways correlating diabetes and colon and rectal cancer (CRC) remain far from understood. In this study, we assess the effect of hyperglycemia on cancer cell aggressiveness in human colon epithelial adenocarcinoma cells in vitro and in an experimental animal model of CRC. Our results show that Nox (NADPH oxidase enzyme) 4-induced reactive oxygen species (ROS) production is deregulated in both diabetes and CRC. This is paralleled by inactivation of the AMPK and activation of the mammalian target of rapamycin (mTOR) C1 signaling pathways, resulting in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) accumulation, induction of DNA damage, and exacerbation of cancer cell aggressiveness, thus contributing to the genomic instability and predisposition to increased tumorigenesis in the diabetic milieu. Pharmacologic activation of AMPK, inhibition of mTORC1, or blockade of Nox4 reduce ROS production, restore the homeostatic signaling of 8-oxoguanine DNA glycosylase/8-oxodG, and lessen the progression of CRC malignancy in a diabetic milieu. Taken together, our results identify the AMPK/mTORC1/Nox4 signaling axis as a molecular switch correlating diabetes and CRC. Modulating this pathway may be a strategic target of therapeutic potential aimed at reversing or slowing the progression of CRC in patients with or without diabetes.-Mroueh, F. M., Noureldein, M., Zeidan, Y. H., Boutary, S., Irani, S. A. M., Eid, S., Haddad, M., Barakat, R., Harb, F., Costantine, J., Kanj, R., Sauleau, E.-A., Ouhtit, A., Azar, S. T., Eid, A. H., Eid, A. A. Unmasking the interplay between mTOR and Nox4: novel insights into the mechanism connecting diabetes and cancer.


Distribution of bacterial populations in a stratified fjord (Mariager Fjord, Denmark) quantified by in situ hybridization and related to chemical gradients in the water column.
The vertical distribution of major and intermediate electron acceptors and donors was measured in a shallow stratified fjord. Peaks of zero valence sulfur, Mn(IV), and Fe(III) were observed in the chemocline separating oxic surface waters from sulfidic and anoxic bottom waters. The vertical fluxes of electron acceptors and donors (principally O2 and H2S) balanced within 5%; however, the zones of oxygen reduction and sulfide oxidation were clearly separated. The pathway of electron transfer between O2 and H2S was not apparent from the distribution of sulfur, nitrogen, or metal compounds investigated. The chemical zonation was related to bacterial populations as detected by ethidium bromide (EtBr) staining and by in situ hybridization with fluorescent oligonucleotide probes of increasing specificity. About half of all EtBr-stained cells were detectable with a general oligonucleotide probe for all eubacteria when digital image analysis algorithms were used to improve sensitivity. Both EtBr staining and hybridization indicated a surprisingly uniform distribution of bacteria throughout the water column. However, the average cell size and staining intensity as well as the abundance of different morphotypes changed markedly within the chemocline. The constant overall cell counts thus concealed pronounced population shifts within the water column. Cells stained with a delta 385 probe (presumably sulfate-reducing bacteria) were detected at the chemocline at about 5 x 10(4) cells per ml, and this concentration increased to 2 x 10(5) cells per ml beneath the chemocline. A long slim rod-shaped bacterium was found in large numbers in the oxic part of the chemocline, whereas large ellipsoid cells dominated at greater depth. Application of selective probes for known genera of sulfate-reducing bacteria gave only low cell counts, and thus it was not possible to identify the dominant morphotypes of the sulfate-reducing community.


How Social Welfare and Health Professionals Understand "Race," Racism, and Whiteness: A Social Justice Approach to Grounded Theory.
Social welfare and health professionals continually practice within communities, either directly as practitioners or indirectly by supervising students and co-workers. The current study investigated how social welfare and health professionals conceptualized race, racism, and whiteness in health disparities discourse. Employing constructivist grounded theory, through a social justice lens, the researchers developed a theoretical model based upon the collective experiences of social workers, nurses, and physicians. The analysis revealed four theoretical categories that characterized facets of how social welfare and health professionals' understand race, racism, and whiteness: (1) self-defined skin color; (2) (pre)judgments and discrimination; (3) privilege and power; and (4) conceptual conflation and unfamiliarity. The findings suggest more emphasis during training and in workplace settings on concepts such as power, inequities, and structural racism may significantly improve the efficacy and scope of REHD interventions by expanding social welfare and health professionals' understanding of race, racism, and whiteness beyond interpersonal level interactions.


Assessing recent warming using instrumentally homogeneous sea surface temperature records.
Sea surface temperature (SST) records are subject to potential biases due to changing instrumentation and measurement practices. Significant differences exist between commonly used composite SST reconstructions from the National Oceanic and Atmospheric Administration's Extended Reconstruction Sea Surface Temperature (ERSST), the Hadley Centre SST data set (HadSST3), and the Japanese Meteorological Agency's Centennial Observation-Based Estimates of SSTs (COBE-SST) from 2003 to the present. The update from ERSST version 3b to version 4 resulted in an increase in the operational SST trend estimate during the last 19 years from 0.07° to 0.12°C per decade, indicating a higher rate of warming in recent years. We show that ERSST version 4 trends generally agree with largely independent, near-global, and instrumentally homogeneous SST measurements from floating buoys, Argo floats, and radiometer-based satellite measurements that have been developed and deployed during the past two decades. We find a large cooling bias in ERSST version 3b and smaller but significant cooling biases in HadSST3 and COBE-SST from 2003 to the present, with respect to most series examined. These results suggest that reported rates of SST warming in recent years have been underestimated in these three data sets.


Ganoderma lucidum polysaccharide enhances radiosensitivity of hepatocellular carcinoma cell line HepG2 through Akt signaling pathway.
Ganoderma lucidum polysaccharide (GLP) is a well-known traditional Chinese medicine, known for its anti-cancer and immunomodulatory properties. The present study aims to investigate whether GLP has a therapeutic effect on hepatocellular carcinoma (HCC) cells exposed to radiation. Immunofluorescence was used to detect the nuclei, the protein expression was measured by western blot analysis and flow cytometry was used to detect the rate of cell apoptosis. GLP treatment was demonstrated to enhance radiation-induced growth inhibition and apoptotic death of HCC cells. At a molecular level, GLP suppressed the activities of DNA repair-associated proteins including ataxia-telangiectasia mutated (ATM) and DNA dependent-protein kinase (DNA-PK) in liver cancer cells under radiation conditions. Furthermore, the addition of an Akt inhibitor elevated the activities of DNA-PK and ATM and attenuated the GLP-induced HepG2 cell injury under the radiation condition. In conclusion, the present study demonstrates that GLP enhances the radiosensitivity of HCC cells via the regulation of Akt signaling pathways, implying a potential therapeutic effect of GLP as a radiation sensitizer in HCC treatment.


Estimating thumb-index finger precision grip and manipulation potential in extant and fossil primates.
Primates, and particularly humans, are characterized by superior manual dexterity compared with other mammals. However, drawing the biomechanical link between hand morphology/behaviour and functional capabilities in non-human primates and fossil taxa has been challenging. We present a kinematic model of thumb-index precision grip and manipulative movement based on bony hand morphology in a broad sample of extant primates and fossil hominins. The model reveals that both joint mobility and digit proportions (scaled to hand size) are critical for determining precision grip and manipulation potential, but that having either a long thumb or great joint mobility alone does not necessarily yield high precision manipulation. The results suggest even the oldest available fossil hominins may have shared comparable precision grip manipulation with modern humans. In particular, the predicted human-like precision manipulation of Australopithecus afarensis, approximately one million years before the first stone tools, supports controversial archaeological evidence of tool-use in this taxon.


Torque magnetometry study of the spin reorientation transition and temperature-dependent magnetocrystalline anisotropy in NdCo5.
We present the results of torque magnetometry and magnetic susceptibility measurements to study in detail the spin reorientation transition (SRT) and magnetic anisotropy in the permanent magnet NdCo5. We further show simulations of the measurements using first-principles calculations based on density-functional theory and the disordered local moment picture of magnetism at finite temperatures. The good agreement between theory and experimental data leads to a detailed description of the physics underpinning the SRT. In particular we are able to resolve the magnetization of, and to reveal a canting between, the Nd and Co sublattices. The torque measurements carried out in the ac and ab planes near the easy direction allow us to estimate the anisotropy constants, K 1, K 2 and K 4 and their temperature dependences. Torque curves, τ(γ) recorded by varying the direction of a constant magnetic field in the crystallographic ac plane show a reversal in the polarity as the temperature is changed across the SRT (240 < T < 285 K). Within this domain, τ(γ) exhibits unusual features different to those observed above and below the transition. The single crystals of NdCo5 were grown using the optical floating zone technique.


Association between dietary inflammatory index and serum C-reactive protein concentrations in the Japan Collaborative Cohort Study.
Diet plays an important role in the regulation of chronic inflammation, which is linked to cardiovascular disease (CVD) and several cancers. The dietary inflammatory index (DII®) was developed to estimate the inflammatory potential of an individual's diet. We examined the association between DII scores and serum high-sensitivity C-reactive protein (hs-CRP) concentrations using the baseline data from the Japan Collaborative Cohort Study (JACC Study). Data were from 1176 control subjects (650 men and 526 women) in a nested case-control study of several cancers and CVD in the JACC Study who were free of cancer and CVD at baseline. DII scores were calculated from 26 food parameters that were derived from a validated food frequency questionnaire administered at the baseline. Energy-adjusted DII scores were calculated using the residual method. Serum hs-CRP concentrations were measured by latex-enhanced nephelometry or enzyme-immunoassay. In multivariable logistic regression analysis adjusting for potential confounders including sex, age, smoking habits, drinking habits, body mass index, and history of hypertension, the odds ratio (OR) and 95% confidence intervals (CI) for high serum hs-CRP concentrations (>1.0 mg/L) was significantly higher in the highest versus the lowest DII quartile (ORQuartile4vs1 = 1.32, 95% CI = 1.01 to 2.52). Likewise, a 1-point increase in DII score was associated with a 14% increased risk of high serum hs-CRP concentrations (ORContinuous = 1.09, 95%CI = 1.01 to 1.19). A pro-inflammatory diet, as represented by high DII scores, was associated with high serum hs-CRP concentrations in this Japanese population.


Childhood asthma: exhaled nitric oxide in relation to clinical symptoms.
Bronchial asthma is associated with increased levels of exhaled nitric oxide which are suppressible by glucocorticosteroid inhalation. Children with bronchial asthma were studied to elucidate the relation between endogenous NO release and recent symptoms of bronchial obstruction. Twenty-five children with atopic asthma and 11 healthy control subjects were enrolled and exhaled NO was studied using chemiluminescence analysis. The subjects breathed purified air (<0.5 parts per billion (ppb) NO) exclusively through their mouths. Orally expired NO was measured during continuous nasal aspiration (1.3 L x min(-1)) to remove nasally produced NO. Nasal NO concentration was determined within the aspirated gas. Orally expired NO concentration was 2.5+/-0.3 ppb (mean +/-SEM) in healthy control subjects, 3.19+/-0.88 ppb (NS) in symptom-free children, and 8.28+/-0.81 ppb (p< or =0.01) in children with bronchial asthma who had had recent symptoms of bronchial obstruction. Similarly, in the subgroup of children treated regularly with inhaled glucocorticosteroids those with recent symptoms had significantly higher orally exhaled NO concentrations than healthy control subjects (9.5+/-1.5 ppb, p<0.05). The nasal NO concentration was 152.8+/-12.7 ppb in healthy control subjects and not significantly different in asthmatic children. In this group of asthmatic children, recent symptoms of bronchial obstruction were linked to significantly higher concentrations of NO in orally exhaled gas and to increased oral NO excretion rates. If substantiated by further studies, measurement of orally exhaled NO during nasal aspiration may become useful to monitor disease control in asthmatic children.


Molecular characterization of a heterothallic mating system in Pseudogymnoascus destructans, the Fungus causing white-nose syndrome of bats.
White-nose syndrome (WNS) of bats has devastated bat populations in eastern North America since its discovery in 2006. WNS, caused by the fungus Pseudogymnoascus destructans, has spread quickly in North America and has become one of the most severe wildlife epidemics of our time. While P. destructans is spreading rapidly in North America, nothing is known about the sexual capacity of this fungus. To gain insight into the genes involved in sexual reproduction, we characterized the mating-type locus (MAT) of two Pseudogymnoascus spp. that are closely related to P. destructans and homothallic (self-fertile). As with other homothallic Ascomycota, the MAT locus of these two species encodes a conserved α-box protein (MAT1-1-1) as well as two high-mobility group (HMG) box proteins (MAT1-1-3 and MAT1-2-1). Comparisons with the MAT locus of the North American isolate of P. destructans (the ex-type isolate) revealed that this isolate of P. destructans was missing a clear homolog of the conserved HMG box protein (MAT1-2-1). These data prompted the discovery and molecular characterization of a heterothallic mating system in isolates of P. destructans from the Czech Republic. Both mating types of P. destructans were found to coexist within hibernacula, suggesting the presence of mating populations in Europe. Although populations of P. destructans in North America are thought to be clonal and of one mating type, the potential for sexual recombination indicates that continued vigilance is needed regarding introductions of additional isolates of this pathogen.


Maternal smoking and the risk for clubfoot in infants.
Clubfoot is one of the most common major birth defects, with a prevalence of approximately 1 per 1,000 live births. The etiology of clubfoot is complex and not well understood, and yet, few epidemiologic studies of risk factors have been conducted. Maternal smoking has been suggested as a possible risk factor. The purpose of this population-based, case-control study was to examine the association between maternal smoking and clubfoot. Data from the North Carolina Birth Defects Monitoring Program matched to North Carolina birth certificates and health services data were used in the analysis of 443 cases of clubfoot and 4,492 randomly sampled controls for the years 1999-2003. Smoking data were ascertained from the birth certificates, and the reliability of the data was assessed by comparing them with reported smoking from the North Carolina Pregnancy Risk Assessment Monitoring System. Multiple logistic regression was used to calculate crude and adjusted ORs and 95% CIs for smoking and clubfoot. The crude OR for maternal smoking during pregnancy and clubfoot was 1.49 (95% CI: 1.15, 1.92). Controlling for maternal age, race/ethnicity, infant's sex, and timing of prenatal care initiation did not appreciably change the results (adjusted OR 1.40; 95% CI: 1.07, 1.83). This study is consistent with the hypothesis that smoking during pregnancy is associated with a slightly increased risk of an infant being born with clubfoot. Further research is needed to confirm this association, and to identify potential genetic factors that may modify the magnitude of the risk.


RhoA of the Rho family small GTPases is essential for B lymphocyte development.
RhoA is a member of the Rho family small GTPases that are implicated in various cell functions including proliferation and survival. However, the physiological role of RhoA in vivo remains largely unknown. Here, we deleted RhoA in the B cell and hematopoietic stem cell (HSC) populations in RhoA(flox/flox) mice with CD19 and Mx promoter-driven Cre expression, respectively. Deletion of RhoA by CD19(Cre/+) significantly blocked B cell development in spleen, leading to a marked reduction in the number of transitional, marginal zone, and follicular B cells. Surprisingly, neither B cell proliferation in response to either LPS or B cell receptor (BCR) engagement nor B cell survival rate in vivo was affected by RhoA deletion. Furthermore, RhoA(-/-) B cells, like control cells, were rescued from apoptosis by BCR crosslinking in vitro. In contrast, RhoA deficiency led to a defect in B cell activating factor (BAFF)-mediated B cell survival that was associated with a dampened expression of BAFF receptor and a loss of BAFF-mediated Akt activation. Finally, HSC deletion of RhoA by Mx-Cre severely reduced proB/preB and immature B cell populations in bone marrow while common lymphoid progenitors were increased, indicating that RhoA is also required for B cell progenitor/precursor differentiation. Taken together, our results uncover an important role for RhoA at multiple stages of B cell development.


Hydroxychloroquine prescription trends and predictors for excess dosing per recent ophthalmology guidelines.
Hydroxychloroquine (HCQ) retinopathy may be more common than previously recognized; recent ophthalmology guidelines have revised recommendations from ideal body weight (IBW)-based dosing to actual body weight (ABW)-based dosing. However, contemporary HCQ prescribing trends in the UK remain unknown. We examined a UK general population database to investigate HCQ dosing between 2007 and 2016. We studied trends of excess HCQ dosing per ophthalmology guidelines (defined by exceeding 6.5 mg/kg of IBW and 5.0 mg/kg of ABW) and determined their independent predictors using multivariable logistic regression analyses. Among 20,933 new HCQ users (78% female), the proportions of initial HCQ excess dosing declined from 40% to 36% using IBW and 38% to 30% using ABW, between 2007 and 2016. Among these, 47% of women were excess-dosed (multivariable OR 12.52; 95% CI 10.99-14.26) using IBW and 38% (multivariable OR 1.98; 95% CI,1.81-2.15) using ABW. Applying IBW, 37% of normal and 44% of obese patients were excess-dosed; however, applying ABW, 53% of normal and 10% of obese patients were excess-dosed (multivariable ORs = 1.61 and 0.1 (reference = normal); both p < 0.01). Long-term HCQ users showed similar excess dosing. A substantial proportion of HCQ users in the UK, particularly women, may have excess HCQ dosing per the previous or recent weight-based guidelines despite a modest decline in recent years. Over half of normal-BMI individuals were excess-dosed per the latest guidelines. This implies the potential need to reduce dosing for many patients but also calls for further research to establish unifying evidence-based safe and effective dosing strategies.


Protein kinase inhibitors and blood pressure control in spontaneously hypertensive rats.
Considerable evidence suggests that protein kinase C activation participates in the regulation of vascular smooth muscle tone. The objective of the current study was to examine the relations between inhibition of protein kinase C (PKC) and myosin light-chain kinase (MLCK) and vasorelaxation and blood pressure regulation in spontaneously hypertensive rats (SHR). Putative PKC inhibitors from two chemical classes, staurosporinelike (staurosporine and K252A) and isoquinolinesulfonamides (H7 and HA1004), were tested for their ability to 1) inhibit PKC and MLCK from SHR aorta, 2) relax isolated SHR aorta, and 3) lower blood pressure in conscious SHR. A rank order of potency for the inhibition of PKC and MLCK was established, with the staurosporinelike compounds (staurosporine PKC IC50 = 54 nM) clearly more potent than the isoquinolinesulfonamides (H7 PKC IC50 = 128 microM). The rank order of potency for inhibition of PKC was retained for inhibition of MLCK for all compounds. Staurosporine (EC50 = 75 nM) and H7 (EC50 = 2 microM) caused concentration-dependent relaxation of SHR aorta, but only staurosporine produced vasorelaxation at concentrations consistent with the inhibition of PKC or MLCK. Dose-dependent reductions in arterial pressure of SHR were demonstrated after intravenous injection of staurosporine and HA1004. A single intravenous injection of staurosporine (0.3 mg/kg) lowered blood pressure for more than 10 hours. Staurosporine also lowered blood pressure after oral administration. The depressor response to staurosporine was unaffected by sympathetic beta-adrenergic blockade. In conclusion, the vasorelaxant and antihypertensive actions of staurosporine in SHR are consistent with the inhibition of PKC but could also be equally related to inhibition of MLCK. Not all PKC inhibitors produce vasorelaxation and lower blood pressure. Moreover, the lack of correlation between in vitro vasodilation and PKC or MLCK inhibition for the isoquinolinesulfonamide protein kinase inhibitors H7 and HA1004 suggests that these agents do not cause vasorelaxation in SHR by inhibition of these enzymes.


Nonlinear analysis of electroencephalogram in frontotemporal lobar degeneration.
Frontotemporal lobar degeneration (FTLD) is a form of dementia characterized by a profound alteration in personality and social behavior and is associated with atrophy in the frontal and temporal brain regions. Despite recent advances, diagnosis of FTLD remains challenging. In the last decade, different studies have combined EEG analysis with mathematical models and theories that consider EEG signals as the result of nonlinear chaotic activity. The aim of the present study was to determine whether new nonlinear dynamic analysis can provide useful information on brain activity in FTLD patients. 19-lead EEG was recorded in patients with clinical diagnosis of FTLD and in healthy controls under two different conditions: closed eyes and open eyes. A nonlinear measure of complexity, correlation dimension (D2), was calculated. Our results show an increase in D2 in healthy individuals when the eyes are open, in keeping with an increase in information processing. Conversely, in FTLD patients, no increase in D2 occurred in the open eyes condition, and D2 was significantly lower than that observed in controls. Our results suggest that the dynamic processes underlying the EEG are less chaotic and complex in FTLD patients compared with normal individuals, thus providing important information on both brain functioning and possible clinical diagnostic applications.


Functional analysis of HSF4 mutations found in patients with autosomal recessive congenital cataracts.
The goal of this study was to functionally evaluate three previously uncharacterized heat shock factor protein 4 (HSF4) mutations (c.595_599delGGGCC, c.1213C>T, c.1327+4A>G) encoding mutant HSF4 proteins (G199EfsX15, R405X, and M419GfsX29) with missing C-terminal ends. These HSF4 mutations were previously identified in families with congenital autosomal recessive cataracts. FLAG-tagged recombinant wild type (WT) and mutant HSF4 proteins were analyzed using the protein stability assay, cellular immunofluorescence, Western blotting, electrophoretic mobility shift assay (EMSA), and reporter activation. HSF4 mutant proteins did not differ in the protein turnover rate when compared with WT HSF4. Immunofluorescence revealed that WT and mutant HSF4 proteins were properly trafficked to the nucleus. EMSA analysis revealed that the G199EfsX15 and M419GfsX29 proteins exhibited decreased heat shock element (HSE)-mediated DNA binding, whereas the R405X mutant exhibited increased HSE-mediated DNA binding when compared with WT HSF4. All three HSF4 mutant proteins exhibited abolished HSE-mediated luciferase reporter activation. Detailed evaluation of the C-terminal region identified three novel domains: two activation domains and one repression domain. The three HSF4 autosomal recessive mutations evaluated here result in a loss of HSF4 function due to a loss of regulatory domains present at the C-terminal end. These findings collectively indicate that the transcriptional activation of HSF4 is mediated by interactions between activator and repressor domains within the C-terminal end.


Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation.
Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease.


Co-circulation of two extremely divergent serotype SAT 2 lineages in Kenya highlights challenges to foot-and-mouth disease control.
Amongst the SAT serotypes of foot-and-mouth disease virus (FMDV), the SAT 2 serotype is the most widely distributed throughout sub-Saharan Africa. Kenyan serotype SAT 2 viruses have been reported to display the highest genetic diversity for the serotype globally. This complicates diagnosis and control, and it is essential that patterns of virus circulation are known in order to overcome these difficulties. This study was undertaken to establish patterns of evolution of FMDV serotype SAT 2 in Kenya using complete VP1 coding sequences in a dataset of 65 sequences from Africa, collected over a period of 50 years. Two highly divergent lineages were observed to co-circulate, and occasional trans-boundary spread was inferred, emphasizing the value of constant monitoring and characterization of field strains for improved diagnosis and appropriate vaccine application as well as the need for regional approaches to control.


Organization of intracellular reactions with rationally designed RNA assemblies.
The rules of nucleic acid base-pairing have been used to construct nanoscale architectures and organize biomolecules, but little has been done to apply this technology in vivo. We designed and assembled multidimensional RNA structures and used them as scaffolds for the spatial organization of bacterial metabolism. Engineered RNA modules were assembled into discrete, one-dimensional, and two-dimensional scaffolds with distinct protein-docking sites and used to control the spatial organization of a hydrogen-producing pathway. We increased hydrogen output as a function of scaffold architecture. Rationally designed RNA assemblies can thus be used to construct functional architectures in vivo.


A protein allergen microarray detects specific IgE to pollen surface, cytoplasmic, and commercial allergen extracts.
Current diagnostics for allergies, such as skin prick and radioallergosorbent tests, do not allow for inexpensive, high-throughput screening of patients. Additionally, extracts used in these methods are made from washed pollen that lacks pollen surface materials that may contain allergens. We sought to develop a high-throughput assay to rapidly measure allergen-specific IgE in sera and to explore the relative allergenicity of different pollen fractions (i.e. surface, cytoplasmic, commercial extracts). To do this, we generated a protein microarray containing surface, cytoplasmic, and commercial extracts from 22 pollen species, commercial extracts from nine non-pollen allergens, and five recombinant allergenic proteins. Pollen surface and cytoplasmic fractions were prepared by extraction into organic solvents and aqueous buffers, respectively. Arrays were incubated with <25 uL of serum from 176 individuals and bound IgE was detected by indirect immunofluorescence, providing a high-throughput measurement of IgE. We demonstrated that the allergen microarray is a reproducible method to measure allergen-specific IgE in small amounts of sera. Using this tool, we demonstrated that specific IgE clusters according to the phylogeny of the allergen source. We also showed that the pollen surface, which has been largely overlooked in the past, contained potent allergens. Although, as a class, cytoplasmic fractions obtained by our pulverization/precipitation method were comparable to commercial extracts, many individual allergens showed significant differences. These results support the hypothesis that protein microarray technology is a useful tool for both research and in the clinic. It could provide a more efficient and less painful alternative to traditionally used skin prick tests, making it economically feasible to compare allergen sensitivity of different populations, monitor individual responses over time, and facilitate genetic studies on pollen allergy.


Cost-effectiveness in the diagnosis and treatment of carcinoma of unknown primary origin.
Between 2% and 9% of patients with cancer present with metastatic nonsquamous cell carcinoma of unknown primary origin. Traditionally, a series of investigations is undertaken to locate the primary origin of the tumour, although many of these tests are often painful or distressing to patients, unsuccessful in locating the primary site and costly to the health care system. Moreover, even if a tumour is found it usually cannot be treated surgically. However, a small number of cancers of unknown primary origin can be cured, arrested or effectively palliated with systemic treatment. This study compares the costs and outcomes of the current practice of comprehensively searching for the primary tumour with those of an alternative, limited approach that identifies only the primary tumours for which relatively effective systemic therapy exists. Decision trees were constructed for the two diagnostic approaches and their associated therapeutic options. Costs and probabilities were integrated with published data on the survival of patients with each type of cancer. The results indicate that the comprehensive diagnostic strategy may increase 1-year survival rates from 11.0% to 11.5%. On the basis of Ontario cost data it is calculated that the additional costs of a comprehensive search for 1000 patients will range from approximately $2 million to $8 million, depending on the subsequent treatment strategy.


European guidelines for empirical antibacterial therapy for febrile neutropenic patients in the era of growing resistance: summary of the 2011 4th European Conference on Infections in Leukemia.
Owing to increasing resistance and the limited arsenal of new antibiotics, especially against Gram-negative pathogens, carefully designed antibiotic regimens are obligatory for febrile neutropenic patients, along with effective infection control. The Expert Group of the 4(th) European Conference on Infections in Leukemia has developed guidelines for initial empirical therapy in febrile neutropenic patients, based on: i) the local resistance epidemiology; and ii) the patient's risk factors for resistant bacteria and for a complicated clinical course. An 'escalation' approach, avoiding empirical carbapenems and combinations, should be employed in patients without particular risk factors. A 'de-escalation' approach, with initial broad-spectrum antibiotics or combinations, should be used only in those patients with: i) known prior colonization or infection with resistant pathogens; or ii) complicated presentation; or iii) in centers where resistant pathogens are prevalent at the onset of febrile neutropenia. In the latter case, infection control and antibiotic stewardship also need urgent review. Modification of the initial regimen at 72-96 h should be based on the patient's clinical course and the microbiological results. Discontinuation of antibiotics after 72 h or later should be considered in neutropenic patients with fever of unknown origin who are hemodynamically stable since presentation and afebrile for at least 48 h, irrespective of neutrophil count and expected duration of neutropenia. This strategy aims to minimize the collateral damage associated with antibiotic overuse, and the further selection of resistance.


Haptic object perception: spatial dimensionality and relation to vision.
Enabled by the remarkable dexterity of the human hand, specialized haptic exploration is a hallmark of object perception by touch. Haptic exploration normally takes place in a spatial world that is three-dimensional; nevertheless, stimuli of reduced spatial dimensionality are also used to display spatial information. This paper examines the consequences of full (three-dimensional) versus reduced (two-dimensional) spatial dimensionality for object processing by touch, particularly in comparison with vision. We begin with perceptual recognition of common human-made artefacts, then extend our discussion of spatial dimensionality in touch and vision to include faces, drawing from research on haptic recognition of facial identity and emotional expressions. Faces have often been characterized as constituting a specialized input for human perception. We find that contrary to vision, haptic processing of common objects is impaired by reduced spatial dimensionality, whereas haptic face processing is not. We interpret these results in terms of fundamental differences in object perception across the modalities, particularly the special role of manual exploration in extracting a three-dimensional structure.


FUGUE: sequence-structure homology recognition using environment-specific substitution tables and structure-dependent gap penalties.
FUGUE, a program for recognizing distant homologues by sequence-structure comparison (http://www-cryst.bioc.cam.ac.uk/fugue/), has three key features. (1) Improved environment-specific substitution tables. Substitutions of an amino acid in a protein structure are constrained by its local structural environment, which can be defined in terms of secondary structure, solvent accessibility, and hydrogen bonding status. The environment-specific substitution tables have been derived from structural alignments in the HOMSTRAD database (http://www-cryst.bioc. cam.ac.uk/homstrad/). (2) Automatic selection of alignment algorithm with detailed structure-dependent gap penalties. FUGUE uses the global-local algorithm to align a sequence-structure pair when they greatly differ in length and uses the global algorithm in other cases. The gap penalty at each position of the structure is determined according to its solvent accessibility, its position relative to the secondary structure elements (SSEs) and the conservation of the SSEs. (3) Combined information from both multiple sequences and multiple structures. FUGUE is designed to align multiple sequences against multiple structures to enrich the conservation/variation information. We demonstrate that the combination of these three key features implemented in FUGUE improves both homology recognition performance and alignment accuracy.


Secondary metabolites from Eurotium species, Aspergillus calidoustus and A. insuetus common in Canadian homes with a review of their chemistry and biological activities.
As part of studies of metabolites from fungi common in the built environment in Canadian homes, we investigated metabolites from strains of three Eurotium species, namely E. herbariorum, E. amstelodami, and E. rubrum as well as a number of isolates provisionally identified as Aspergillus ustus. The latter have been recently assigned as the new species A. insuetus and A. calidoustus. E. amstelodami produced neoechinulin A and neoechinulin B, epiheveadride, flavoglaucin, auroglaucin, and isotetrahydroauroglaucin as major metabolites. Minor metabolites included echinulin, preechinulin and neoechinulin E. E. rubrum produced all of these metabolites, but epiheveadride was detected as a minor metabolite. E. herbariorum produced cladosporin as a major metabolite, in addition to those found in E. amstelodami. This species also produced questin and neoechinulin E as minor metabolites. This is the first report of epiheveadride occurring as a natural product, and the first nonadride isolated from Eurotium species. Unlike strains from mainly infection-related samples, largely from Europe, neither ophiobolins G and H nor austins were detected in the Canadian strains of A. insuetus and A. calidoustus tested, all of which had been reported from the latter species. TMC-120 A, B, C and a sesquiterpene drimane are reported with certainty for the first time from indoor isolates, as well as two novel related methyl isoquinoline alkaloids.


Impetigo: incidence and treatment in Dutch general practice in 1987 and 2001--results from two national surveys.
Impetigo is a common skin infection in children. The epidemiology is relatively unknown, and the choice of treatment is subject to debate. The objective of our study was to determine the incidence and treatment of impetigo in Dutch general practice, and to assess trends between 1987 and 2001. We used data from the first (1987) and second (2001) Dutch national surveys of general practice. All diagnoses, prescriptions and referrals were registered by the participating general practitioners (GPs), 161 and 195, respectively. The incidence rate of impetigo increased from 16.5 (1987) to 20.6 (2001) per 1000 person years under 18 years old (P < 0.01). In both years, the incidence was significantly higher in summer, in rural areas and in the southern region of the Netherlands, compared with winter, urban areas and northern region, respectively. Socioeconomic status was not associated with the incidence rate. From 1987 to 2001, there was a trend towards treatment with a topical antibiotic (from 43% to 64%), especially fusidic acid cream and mupirocin cream. Treatment with oral antibiotics (from 31% to 14%) and antiseptics (from 11% to 3%) was prescribed less often. We have shown an increased incidence of impetigo in the past decade, which may be the result of an increased tendency to seek help, or increased antibiotic resistance and virulence of Staphylococcus aureus. Further microbiological research on the marked regional difference in incidence may contribute to understanding the factors that determine the spread of impetigo. Trends in prescribing for impetigo generally follow evidence-based knowledge on the effectiveness of different therapies, rather than the national practice guideline.


National Eye Survey of Trinidad and Tobago (NESTT): prevalence, causes and risk factors for presenting vision impairment in adults over 40 years.
To estimate the prevalence, causes and risk factors for presenting distance and near vision impairment (VI) in Trinidad and Tobago. This is a national, population-based survey using multistage, cluster random sampling in 120 clusters with probability-proportionate-to-size methods. Stage 1 included standardised, community-based measurement of visual acuity. Stage 2 invited all 4263 people aged ≥40 years for comprehensive clinic-based assessment. The Moorfields Eye Hospital Reading Centre graded fundus photographs and optical coherence tomography images independently. The response rates were 84.2% (n=3589) (stage 1) and 65.4% (n=2790) (stage 2), including 97.1% with VI. The mean age was 57.2 (SD 11.9) years, 54.5% were female, 42.6% were of African descent and 39.0% were of South Asian descent. 11.88% (95% CI 10.88 to 12.97, n=468) had distance VI (logarithm of the minimum angle of resolution [logMAR] >0.30), including blindness (logMAR >1.30) in 0.73% (95% CI 0.48 to 0.97, n=31), after adjustment for study design, non-response, age, sex and municipality. The leading causes of blindness included glaucoma (31.7%, 95% CI 18.7 to 44.8), cataract (28.8%, 95% CI 12.6 to 45.1) and diabetic retinopathy (19.1%, 95% CI 4.2 to 34.0). The leading cause of distance VI was uncorrected refractive error (47.4%, 95% CI 43.4 to 51.3). Potentially avoidable VI accounted for 86.1% (95% CI 82.88 to 88.81), an estimated 176 323 cases in the national population aged ≥40 years. 22.3% (95% CI 20.7 to 23.8, n=695) had uncorrected near VI (logMAR >0.30 at 40 cm with distance acuity <0.30). Significant independent associations with distance VI included increasing age, diagnosed diabetes and unemployment. Significant independent associations with near VI included male sex, no health insurance and unemployment. Trinidad and Tobago's burden of avoidable VI exceeds that of other high-income countries. Population and health system priorities are identified to help close the gap.


Clinical value of right hemicolectomy for appendiceal carcinoids using pathologic criteria.
Appendiceal carcinoids (AC) are usually adequately treated by appendectomy. The European Neuroendocrine Tumours Society (ENETS) has recently reconsidered the previous pathologic criteria to identify patients at high risk of extra-appendiceal disease, who are thought to require right hemicolectomy (RHC). The aim of this retrospective, observational study was to evaluate previous and currently introduced criteria, in identifying patients with AC in whom RHC is justified. Twelve patients who underwent RHC for AC were retrospectively identified. Demographic and follow-up data were collected and appendectomy specimens were reviewed for the presence of indications leading to RHC defined as: tumor diameter ≥2 cm, tumor location at the base, mesoappendiceal extension, mitotic index Ki-67≥2%. RHC specimens were examined to identify evidence of extra-appendiceal disease, remaining and/or metastatic disease. Four patients fulfilled two criteria and 8 one criterion for RHC. Two patients had tumors ≥2.0 cm, 5 located at the base, 8 invading the mesoappendix and periappendiceal fat; Ki-67 PI was 1% in all cases measured except one, in which it was 3%. Post-RHC, 3 patients (25%) had extra-appendiceal disease (no residual disease was identified in surgical margins); 1 had tumor at the colon specimen and 2 had lymph node metastasis. All 3 patients fulfilled only one pathologic criterion; 1 had tumor mesoappendiceal extension and 2 tumor location at the base of the appendix. Applying previous and currently introduced pathologic criteria, 25% of high-risk patients with AC had identifiable extra-appendiceal disease following RHC that might be not detected following the recently introduced ENETS criteria.


Ethical dilemmas in family caregiving for the elderly: implications for occupational therapy.
An analysis of 60 ethnographic interviews with family caregivers for frail community-based elderly persons has suggested that ethical dilemmas are an important organizing framework for family caregiving. The present paper explores this conjecture as it relates to the practice of occupational therapy with older clients and their families. Major themes of ethical dilemmas in family caregiving, as derived from the ethnographic data, are described. Verbatim interview data are presented to illustrate the close ties between caregiving activity and the caregiver's ethical convictions. Occupational therapists are encouraged to seek understanding of their clients' ethical beliefs in order to maximize the potential for a therapeutic relationship built on mutual understanding and partnership.


MUCO-DIS: a New AFM-Based Nanoscale Dissolution Technique.
Mucoadhesion-based drug delivery systems have recently gained interest because of their bio-adhesion capability, which results in enhanced residence time leading to prolonged duration of action with the mucosal surface, potentially improving compliance and convenience. Mucoadhesion testing of these formulations is widely reported; however, this is technically challenging due to the absence of any standard methods and difficulty in conducting mucoadhesion, formulation-mucosal surface interaction, mucosal surface topography and drug release in a single experiment. As these measurements are currently conducted separately, on replicate formulations, results can often be subjective and difficult to correlate. Hence, the aim of the present study was to develop a new AFM-based single-entity ex vivo muco-dissolution (MUCO-DIS) technique to simultaneously evaluate mucoadhesion force, 3D surface topography, polymer dissolution and drug release characteristics. To demonstrate the potential of the current technique, the interactions between model pectin microparticles containing metformin HCl and a range of gastrointestinal mucosal surfaces (gastric, small intestine, large intestine and buccal) were studied. This novel system has not only successfully determined the mucoadhesion force, polymer dissolution and drug release information but has also highlighted the difference in microparticle performance with different mucosal targets. The current work has highlighted the potential of this newly developed MUCO-DIS system and we believe this will be a valuable tool for characterising these popular pharmaceutical formulations. This technique could also provide an opportunity to other scientific fields to evaluate materials, substrate behaviour and their interactions in their hydrated state at nanoscale with real-time chemical and surface mapping.


Analysis and simulation of the phenomenon of secondary spots of the TDI CCD camera irradiated by CW laser.
The phenomenon of secondary spots is observed in the experiment of TDI CCD camera irradiated by CW He-Ne laser. It is considered to be related to the scattering of the slit in front of the sensor and the reflection of the window of the TDI CCD chip. Additional experiments and ray tracing simulation are performed to study the mechanism of the secondary spots. The experimental and simulated results demonstrated that the scattering of the side walls of the slit is the main source of the secondary spots. Furthermore, the operation mode of rotary scanning provides the chance of scattering incident beam to the side wall of the slit. This paper will provide a preliminary hint to the optimum design of slit in camera to reduce the effects of the secondary spots to the image quality.


Reproductive toxicity of ethylene glycol monoethyl ether in Aldh2 knockout mice.
Ethylene glycol monoethyl ether (EGEE) can cause damage to testes and sperm, and its metabolites are believed to play an important role in its toxicity. Aldehyde dehydrogenase 2 (ALDH2) is involved in the metabolism of this chemical. To investigate whether and how the enzyme affects the toxicity of EGEE, we conducted experiments comparing Aldh2 knockout mice with wild-type mice. Administration of EGEE at 100 and 600 mg/kg/day for one week did not induce any significant change in the weight and body weight ratios of testes, prostate and epididymides in either Aldh2 knockout or wild-type mice. However, motion of sperm from the spermaduct, as analyzed with a Hamilton-Thorne Sperm analyzer, was slightly decreased in the low dose group, and significantly lower in the high dose group; and the percentage of progressive sperm was also reduced in the two EGEE groups. This effect of EGEE treatment was observed in the wild-type, but not in the Aldh2 knockout mice. Sperm motion from the cauda epididymides was not affected. On the other hand, the concentration of ethoxyacetic acid, a metabolite of EGEE, in 24 h pooled urine of EGEE-treated Aldh2 knockout mice was not significantly lower than that of the wild-type mice on most days of urine sampling. These results suggest that inactivation of the ALDH2 enzyme due to gene mutation may be linked to differences in the susceptibility to EGEE-induced sperm toxicity.


Plantar fasciitis: a degenerative process (fasciosis) without inflammation.
The authors review histologic findings from 50 cases of heel spur surgery for chronic plantar fasciitis. Findings include myxoid degeneration with fragmentation and degeneration of the plantar fascia and bone marrow vascular ectasia. Histologic findings are presented to support the thesis that "plantar fasciitis" is a degenerative fasciosis without inflammation, not a fasciitis. These findings suggest that treatment regimens such as serial corticosteroid injections into the plantar fascia should be reevaluated in the absence of inflammation and in light of their potential to induce plantar fascial rupture.


Improving the usefulness of evidence concerning the effectiveness of implementation strategies for knowledge products in primary healthcare: protocol for a series of systematic reviews.
The literature on the implementation of knowledge products is extensive. However, this literature is still difficult to interpret for policymakers and other stakeholders when faced with choosing implementation strategies likely to bring about successful change in their health systems. This work has the particularity to examine the scope of this literature, and to clarify the effectiveness of implementation strategies for different knowledge products. Consequently, we aim to (1) determine the strengths and weaknesses of existing literature overviews; (2) produce a detailed portrait of the literature on implementation strategies for various knowledge products; and (3) assess the effectiveness of implementation strategies for each knowledge product identified and classify them. We will use a three-phase approach consisting of a critical analysis of existing literature overviews, a systematic review of systematic reviews, and a series of systematic reviews and meta-analyses. We will follow the Cochrane Methodology for each of the three phases. Our eligibility criteria are defined following a PICOS approach: Population, individuals or stakeholders participating in healthcare delivery, specifically, healthcare providers, caregivers, and end users; Intervention, any type of strategy aiming to implement a knowledge product including, but not limited to, a decision support tool, a clinical practice guideline, a policy brief, or a decision-making tool, a one-pager, or a health intervention; Comparison, any comparator will be considered; Outcomes, phases 1 and 2-any outcome related to implementation strategies including, but not limited to, the measures of adherence/fidelity to the use of knowledge products, their acceptability, adoption, appropriateness, feasibility, adaptability, implementation costs, penetration/reach and sustainability; phase 3-any additional outcome related to patients (psychosocial, health behavioral, and clinical outcomes) or healthcare professionals (behavioral and performance outcomes); Setting, primary healthcare has to be covered. We will search MEDLINE (Ovid), EMBASE, Web of Science, PsycINFO, CINAHL, and the Cochrane Library from their inception onwards. For each phase, two reviewers will independently perform the selection of studies, data extraction, and assess their methodological quality. We will analyze extracted data, and perform narrative syntheses, and meta-analyses when possible. Our results could inform not only the overviews' methodology but also the development of an online platform for the implementation strategies of knowledge products. This platform could be useful for stakeholders in implementation science. Protocol registered on Open Science Framework, https://osf.io/eb8w2/.


Light scattered by a liquid crystal: a new quasi-thermal source.
The spatial and temporal coherence properties of laser light scattered by a liquid crystal cell under the application of an external dc field are studied. It is shown that the scattered field constitutes a source with very long coherence time. The coherence time can be changed by changing the value of the applied voltage, and the spatial coherence can be adjusted by varying the dimension of the illuminated spot on the cell. The effects produced when the length of correlation of fluctuations in the liquid crystal is not negligible with respect to the dimension of the spot in the cell are also studied. The scattered field is proposed as a new quasi-thermal source, alternative of the rotating ground glass disk.


Factors Associated With Early Discontinuation of Study Treatment in the Mammary Prevention.3 Breast Cancer Chemoprevention Trial.
Purpose Aromatase inhibitors are established breast cancer chemoprevention interventions. However, nonadherence remains a significant challenge. We investigated the association between worsening menopause-specific quality of life, baseline participant characteristics, and early treatment discontinuation within the Mammary Prevention.3 (MAP.3) breast cancer prevention trial. Methods In the MAP.3 randomized, placebo-controlled trial evaluating exemestane, participants completed the Menopause-Specific Quality of Life Questionnaire (MENQOL) at entry and at 6 months. Multivariable log-binomial regression was used to assess the associations of baseline participant characteristics and clinically meaningful worsening in menopause-specific quality of life (QOL) with treatment discontinuation at 1 year. Results Of the 4,501 participants eligible for this analysis, 724 (17%) discontinued assigned treatment within the first year of random assignment of treatment (19% of the exemestane group and 13% of the placebo group). Between 19% and 35% of women experienced a clinically meaningful worsening in the vasomotor, sexual, physical, and psychosocial domains of the MENQOL within 6 months of treatment initiation. Regardless of receiving exemestane or not, experiencing a worsening in any MENQOL domain or, especially, overall menopause-specific QOL, was associated with early treatment discontinuation (relative risk, 1.79; 95% CI, 1.53 to 2.10 for overall worsening). Assignment to exemestane, having a smoking history, and current employment also were significantly associated with early discontinuation. Conclusion Negative changes in menopause-specific QOL influence a woman's decision to stop chemoprevention therapy. Attention to such symptoms may improve QOL and potentially improve chemoprevention adherence.


Acquisition and loss of virulence-associated factors during genome evolution and speciation in three clades of Bordetella species.
The genus Bordetella consists of nine species that include important respiratory pathogens such as the 'classical' species B. bronchiseptica, B. pertussis and B. parapertussis and six more distantly related and less extensively studied species. Here we analyze sequence diversity and gene content of 128 genome sequences from all nine species with focus on the evolution of virulence-associated factors. Both genome-wide sequence-based and gene content-based phylogenetic trees divide the genus into three species clades. The phylogenies are congruent between species suggesting genus-wide co-evolution of sequence diversity and gene content, but less correlated within species, mainly because of strain-specific presence of many different prophages. We compared the genomes with focus on virulence-associated genes and identified multiple clade-specific, species-specific and strain-specific events of gene acquisition and gene loss, including genes encoding O-antigens, protein secretion systems and bacterial toxins. Gene loss was more frequent than gene gain throughout the evolution, and loss of hundreds of genes was associated with the origin of several species, including the recently evolved human-restricted B. pertussis and B. holmesii, B. parapertussis and the avian pathogen B. avium. Acquisition and loss of multiple genes drive the evolution and speciation in the genus Bordetella, including large scale gene loss associated with the origin of several species. Recent loss and functional inactivation of genes, including those encoding pertussis vaccine components and bacterial toxins, in individual strains emphasize ongoing evolution.


First-line treatment disruption among post-menopausal women with HR+/HER2- metastatic breast cancer: a retrospective US claims study.
This study assessed disruption of first-line treatments initiated after the approval of the first CDK 4/6 inhibitor, palbociclib, among post-menopausal women with HR+/HER2- metastatic breast cancer (mBC) in the US. Post-menopausal women with HR+/HER2- mBC who initiated first-line endocrine therapy or chemotherapy (index therapy) between February 3, 2015 (palbociclib approval date) and February 29, 2016 (end of data) were identified from the Symphony Source Lx database. Patients were required to have continuous quarterly activity (defined as ≥1 pharmacy or medical claim) for 12 months prior to and 1 month after the initiation of the index therapy (index date). Treatment disruption was defined as a treatment gap of ≥60 days or adding an agent after the original therapy. Kaplan-Meier analyses were conducted to estimate treatment disruption rates during the 6 months following the index date. Patients without treatment disruption were censored at the end of continuous quarterly activity or end of data. A total of 8,160 and 2,153 eligible patients initiated endocrine therapy or chemotherapy as their first-line mBC treatment, with a median follow-up of 6.7 and 7.6 months, respectively. The three most prevalent metastatic sites were bone (28.1-42.2%), liver (8.8-17.3%), and lung (8.6-9.5%). Overall, 37.7% (n = 3,074) of patients receiving endocrine therapy and 86.1% (n = 1,852) of patients receiving chemotherapy encountered treatment disruption at 6 months (log-rank test p < .05). Treatment disruption rates of first-line therapies were sub-optimal among post-menopausal women with HR+/HER2- mBC, primarily driven by chemotherapy users. New therapies or interventions are needed to reduce treatment disruption in this patient population.


The role of left atrial muscular bundles in catheter ablation of atrial fibrillation.
We sought to investigate the imaging of the left atrial (LA) muscular bundle and the relationship between the bundle and inducibility of tachyarrhythmia after pulmonary vein isolation (PVI). Noninducibility is used as a clinical end point of atrial substrate ablation after PVI. However, little is known about the role of the LA muscular bundles in tachyarrhythmia after PVI. Forty-three consecutive patients with paroxysmal atrial fibrillation who underwent catheter ablation were included. Bi-atrial isochronal mapping was performed with the NavX system (St. Jude Medical Inc., St. Paul, Minnesota) during sinus rhythm. After 4 PVI, inducible organized LA flutter with or without transforming to atrial fibrillation (AF) (LA flutter/AF) was ablated with additional lines at the roof and/or mitral isthmus. The existence of bilateral muscular bundles was an independent predictor of LA flutter/AF after PVI (p = 0.02). Patients with LA flutter/AF after PVI had a greater index of the double potentials (5.4 +/- 3.4% vs. 2.8 +/- 1.8%, p = 0.006) and interpotential interval (33 +/- 5 ms vs. 29 +/- 4 ms, p = 0.02) than without LA flutter/AF. The muscular bundles were identified in 28% patients using 16-slice multidetector computed tomography, which were identical to the isochrone map. Patients with noninducible LA flutter/AF after PVI plus the additional linear ablation had a lower recurrence rate as compared with the patients without it (19% vs. 75%, p = 0.02). Left atrial muscular bundles may provide a conduction block line and barrier, which is important for the formation of LA flutter/AF after PVI. The noninducibility of LA flutter/AF achieved after additional linear ablation may contribute to a better outcome in RF ablation of paroxysmal atrial fibrillation.


Housing assets and the socio-economic determinants of health and disability in old age.
The influence of socio-economic determinants among the elderly is a complex subject. Although they rely on pension income, the wealth that they have accumulated over their lifetime (primarily housing assets), jointly with housing-related determinants, could have a more significant effect on health production. Hence, owning a house has more potential than income for reducing health inequalities. This study makes use of a representative cross-sectional database on the Spanish population aged 55 or over. Using a continuous variable to measure health and a measure of disabilities in old age, the study explores some socio-economic determinants of health and disability and provides a breakdown of inequalities in socio-economic status and in aggregate individual health. The study's findings indicate that housing equity overrides the effect of income as a determinant of health and (absence of) disability in old age. Furthermore, housing assets account for more than 90% of socio-economic inequalities and 54% of inequalities in disability.


A defective signal peptide tethers the floury-2 zein to the endoplasmic reticulum membrane.
The maize (Zea mays L.) floury-2 (fl2) mutation is associated with a general decrease in storage protein synthesis, altered protein body morphology, and the synthesis of a novel 24-kD alpha-zein storage protein. Unlike storage proteins in normal kernels and the majority of storage proteins in fl2 kernels, the 24-kD alpha-zein contains a signal peptide that would normally be removed during protein synthesis and processing. The expected processing site of this alpha-zein reveals a putative mutation alanine-->valine (Ala-->Val) that is not found at other junctions between signal sequences and mature proteins. To investigate the impact of such a mutation on signal peptide cleavage, we have assayed the 24-kD fl2 alpha-zein in a co-translational processing system in vitro. Translation of RNA from fl2 kernels or synthetic RNA encoding the fl2 alpha-zein in the presence of microsomes yielded a 24-kD polypeptide. A normal signal peptide sequence, generated by site-directed mutagenesis, restored the capacity of the RNA to direct synthesis of a properly processed protein in a cell-free system. Both the fl2 alpha-zein and the fl2 alpha-zein (Val-->Ala) were translocated into the lumen of the endoplasmic reticulum. The processed fl2 alpha-zein (Val-->Ala) was localized in the soluble portion of the microsomes, whereas the fl2 alpha-zein co-fractionated with the microsomal membranes. By remaining anchored to protein body membranes during endosperm maturation, the fl2 zein may thus constrain storage protein packing and perturb protein body morphology.


The risk of sodium toxicity from bed accumulation to key species in the vermifiltration wastewater treatment process.
This study was undertaken to assess the toxicological risks from sodium accumulation in a vermifiltration wastewater treatment system to the key worm species, Eisenia fetida. The study found that sodium chloride (NaCl) is the more toxic of the common sodium salts found in wastewater to the worms. The research further found that the worms have an ability to detoxify NaCl although reproduction will be impaired if the worms are exposed to moderate concentrations of NaCl for a long period of time. The actual risk from NaCl toxicity in the vermifiltration process was low however. The low risk was due to the low solid-water partitioning constant of NaCl, which led to a very low predicted environmental concentration (PEC) for NaCl.


Standard osteopathic manipulative treatment acutely improves gait performance in patients with Parkinson's disease.
Patients with Parkinson's disease exhibit a variety of motor deficits which can ultimately result in complete disability. The primary objective of this study was to quantitatively evaluate the effect of osteopathic manipulative treatment (OMT) on the gait of patients with Parkinson's disease. Ten patients with idiopathic Parkinson's disease and a group of eight age-matched normal control subjects were subjected to an analysis of gait before and after a single session of an OMT protocol. A separate group of 10 patients with Parkinson's disease was given a sham-control procedure and tested in the same manner. In the treated group of patients with Parkinson's disease, statistically significant increases were observed in stride length, cadence, and the maximum velocities of upper and lower extremities after treatment. There were no significant differences observed in the control groups. The data demonstrate that a single session of an OMT protocol has an immediate impact on Parkinsonian gait. Osteopathic manipulation may be an effective physical treatment method in the management of movement deficits in patients with Parkinson's disease.


Diagnosis of distal cholangiocarcinoma after the removal of choledocholithiasis.
Background and Aim. Distal cholangiocarcinoma associated with choledocholithiasis has not been reported, and the causal relationship remains to be established. We evaluated diagnosis of distal cholangiocarcinoma diagnosed after the removal of choledocholithiasis. Patients and Methods. We assigned 9 cases of cholangiocarcinoma with choledocholithiasis to Group A. As a control group, 37 patients with cholangiocarcinoma without choledocholithiasis were assigned to Group B. Results. Abdominal pain at admission is the only significant difference between Group A and Group B (P = 0.001). All patients in Group A had gall bladder stones, compared with 7 patients (19%) in Group B (P < 0.01). Of the 9 patients in Group A, endoscopic retrade cholangiopancreatography (ERCP) detected normality in 2 patients (22%) and abnormalities in 7 patients (78%). Of the 32 patients in Group B, ERCP detected normality in 4 patients (13%) and abnormalities in 28 patients (88%) (P = 0.597). Intraductal ultrasonography (IDUS) detected a tumor in 8 patients in Group A, while in Group B, IDUS detected normality in 1 patient (3%) and tumors in 29 patients (97%) (P = 1.000). Conclusions. IDUS after stone removal may potentially help in the detection of unexpected tumors. Therefore, we believe that IDUS after stone removal will lead to improve outcome and prognosis.


Referrals to a regional allergy clinic - an eleven year audit.
Allergy is a serious and apparently increasing public health problem yet relatively little is known about the types of allergy seen in routine tertiary practice, including their spatial distribution, co-occurrence or referral patterns. This study reviewed referrals over an eleven year period to a regional allergy clinic that had a well defined geographical boundary. For those patients confirmed as having an allergy we explored: (i) differences over time and by demographics, (ii) types of allergy, (iii) co-occurrence, and (iv) spatial distributions. Data were extracted from consultant letters to GPs, from September 1998 to September 2009, for patients confirmed as having an allergy. Other data included referral statistics and population data by postcode. Simple descriptive analysis was used to describe types of allergy. We calculated 11 year standardised morbidity ratios for postcode districts and checked for spatial clustering. We present maps showing 11 year rates by postcode, and 'difference' maps which try to separate referral effect from possible environmental effect. Of 5778 referrals, 961 patients were diagnosed with an allergy. These were referred by a total of 672 different GPs. There were marked differences in referral patterns between GP practices and also individual GPs. The mean age of patients was 35 and there were considerably more females (65%) than males. Airborne allergies were the most frequent (623), and there were very high rates of co-occurrence of pollen, house dust mite, and animal hair allergies. Less than half (410) patients had a food allergy, with nuts, fruit, and seafood being the most common allergens. Fifteen percent (142) had both a food and a non-food allergy. Certain food allergies were more likely to co-occur, for example, patients allergic to dairy products were more likely to be allergic to egg.There were age differences by types of allergy; people referred with food allergies were on average 5 years younger than those with other allergies, and those allergic to nuts were much younger (26 Vs 38) than those with other food allergies.There was clear evidence for spatial clustering with marked clustering around the referral hospital. However, the geographical distribution varied between allergies; airborne (particularly pollen allergies) clustered in North Dartmoor and Exmoor, food allergies (particularly nut allergies) in the South Hams, and on small numbers, some indication of seafood allergy in the far south west of Cornwall and in the Padstow area. This study shows marked geographical differences in allergy referrals which are likely to reflect a combination of environmental factors and GP referral patterns. The data suggest that GPs may benefit from education and ongoing decision support and be supported by public education on the nature of allergy. It suggests further research into what happens to patients with allergy where there has been low use of tertiary services and further research into cross-reactivity and co-occurrence, and spatial distribution of allergy.


Health services costs and their determinants in women with fibromyalgia.
Patients with fibromyalgia (FM) use health services extensively. Knowledge about costs of FM is limited because of non-inclusiveness in assessing direct costs, because attempts to assess indirect costs are largely absent, and because determinants of costs have yet to be identified. We investigated the 6-month costs (direct and indirect) in women with primary FM, and we identified determinants of direct costs. Subjects (n = 180 women) completed a health resource questionnaire as well as measures of pain, psychological distress, comorbidity, and disability. Unit costs for resources were obtained from government, hospital, laboratory, and professional association sources. Regression modeling for 6-month direct cost included age, disability, comorbidity, pain intensity, psychological distress, education, and work status. The average 6-month direct cost was $CDN 2298 (SD 2303). The largest components were medications ($CDN 758; SD 654), complementary and alternative medicine (CAM; $CDN 398; SD 776), and diagnostic tests ($CDN 356; SD 580). Our most conservative estimate of average 6-month indirect cost was $CDN 5035 (SD 7439). Comorbidity and FM disability were statistically significant contributors to direct costs in the multivariate analysis. Costs increased by approximately 20% with each additional comorbid condition. Women with FM are high consumers of both conventional and CAM services. Our estimates of costs exceed those from most other studies; this may be due to our inclusion of a broader set of health services, medications, and indirect costs. Although in univariate analyses the number of comorbidities and indices of the effect of FM, psychological distress, and pain intensity were associated with higher direct cost, in a multiple regression analysis, only the measure of FM disability and the number of comorbidities were significant direct-cost determinants. FM also imposes important indirect costs, which were nearly 70% of the economic burden.


Blockade of tolerance to morphine analgesia by cocaine.
Tolerance to morphine analgesia was induced in male Sprague-Dawley rats by s.c. implantation of a morphine base pellet (75 mg) on the first and second day and determining the magnitude of tolerance 72 h after the first implant by s.c. injection of a test dose of morphine (5 mg/kg). Implantation of a cocaine hydrochloride pellet (25 mg), concurrently with morphine pellets or of a cocaine hydrochloride (50 mg) pellet after the development of tolerance, blocked both the development and expression of morphine analgesic tolerance. In morphine-pelleted animals pretreatment for 3 days with desipramine or zimelidine or phenoxybenzamine but not haloperidol produced no significant morphine tolerance. Pretreatment with a combination of desipramine and zimelidine, however, was as effective as cocaine in blocking morphine tolerance. Alpha-Methyl-p-tyrosine methyl ester counteracted the effect of cocaine in blocking morphine tolerance and potentiated the tolerance development. Blockade of morphine tolerance by cocaine was reinforced and facilitated by pretreatment with fenfluramine or p-chlorophenylalanine ethyl ester and to a lesser extent by clonidine and haloperidol. Acute administration of fenfluramine or zimelidine or a combination of desipramine and zimelidine or alpha-methyl-p-tyrosine methyl ester or p-chlorophenylalanine ethyl ester did not significantly affect morphine analgesia. The study suggests an important role of the concomitant depletion of both central noradrenaline and serotonin in the blockade of morphine tolerance by cocaine and stresses the importance of the counter-balancing functional relationship between these two neurotransmitters in the central nervous system.


Optical coherence tomography of traumatic aneurysms of the internal carotid artery: report of 2 cases.
The pathophysiology of extracranial traumatic aneurysm formation has not been fully elucidated. Intraarterial optical coherence tomography (OCT), an imaging modality capable of micrometer cross-sectional resolution, was used to evaluate patients presenting with saccular traumatic aneurysms of the internal carotid artery (ICA). Two consecutive trauma patients diagnosed with saccular traumatic aneurysms of the cervical ICA, per the institutional screening protocol for traumatic cerebrovascular injury, underwent digital subtraction angiography (DSA) with OCT. Optical coherence tomography demonstrated disruption of the intima with preservation and stretching of the more peripheral layers. In 1 patient the traumatic aneurysm was associated with thrombus formation and a separate, more proximal dissection not visible on CT angiography (CTA) or DSA. Imaging with OCT indicates that saccular traumatic aneurysms may develop from disruption of the intima with at least partial preservation of the media and adventitia. This provides in vivo evidence that saccular traumatic aneurysms result from a partial arterial wall tear rather than complete disruption. Interestingly, OCT was also able to detect arterial injury and thrombi not visible on CTA or DSA.


Circulating Placental Vesicles Carry HLA-DR in Pre-Eclampsia: A New Potential Marker of the Syndrome.
Pre-eclampsia (PE) is a common disorder of pregnancy that usually presents with hypertension and proteinuria. The clinical presentation arises from soluble factors released into the maternal circulation from the placenta owing to the stress of syncytiotrophoblast, consequence of defective placentation occurring in the first half of pregnancy. Reduced tolerance of the semiallogeneic fetus by the maternal immune system has been proposed as first trigger leading to poor placentation. We previously observed aberrant expression of human leukocyte antigen (HLA)-DR molecules in the syncytiotrophoblast of a subset of women with PE. Aim of this study was to investigate abnormal expression of circulating HLA-DR in syncytiotrophoblast-derived extracellular vesicles (STBEVs) in women with PE compared to normal pregnant women. peripheral venous blood was collected from 22 women with PE and 22 normal pregnant women. Circulating STBEVs were collected by ultra-centrifugation (120000 g) and analyzed for the expression of HLA-DR and placental alkaline phosphatase (PLAP), a specific marker of the placenta, by Western blot analysis and flow cytometry. circulating STBEVs positive for HLA-DR were observed in 64% of PE women while no HLA-DR positivity was detected in any of the controls (P<0.01). Aberrant expression of HLA-DR in circulating STBEVs is specifically associated to PE. Further studies are required: a) to define the role of aberrant placental expression of HLA-DR molecules in the pathogenesis of PE; b) evaluate a possible application of detecting circulating HLA-DR positive STBEVs in the diagnosis and prediction of PE in the first and second trimester of pregnancy.


Stability of Fucoxanthin in Pasteurized Skim and Whole Goat Milk.
Obesity has become a worldwide problem giving rise to several health issues. Fucoxanthin, a marine carotenoid with anti-obesity activity, has potential application as a biofunctional ingredient in human food. The objective of this study was to evaluate the thermal stability of fucoxanthin at pasteurization temperature and, subsequently, its storage stability in goat whole milk (WM) and skim milk (SM) at refrigeration temperature for four weeks. Additionally, the effect of supplementation of fucoxanthin on the composition of milk, pH, acidity, color, and lipid oxidation of WM and SM was evaluated during the four week storage period. Fresh goat WM and SM were supplemented with fucoxanthin at a concentration of 10.67 µg/mL (2.56 mg/240 mL of milk, one serving), pasteurized at 64 °C for 30 min and stored at 4 °C for four weeks. The quantification of fucoxanthin in WM and SM was performed every week using a HPLC method. Moreover, the effect of supplementation of fucoxanthin on the composition of WM and SM was evaluated by a LactiCheck milk analyzer, and the color was evaluated by reflectance using a HunterLab colorimeter. Lipid oxidation, as the 2-thiobarbituric acid-reactive substances (TBARS) at A532, was determined using a Spectramax Plus spectrophotometer during storage. Data were analyzed by a split-plot design using PROC MIXED of SAS. The recovery yields of fucoxanthin from the pasteurized WM and SM were 96.17 ± 1.5 % and 96.89 ± 1.5 %, respectively. Both milks exhibited high recovery yields of fucoxanthin. Fucoxanthin was stable in goat WM and SM during storage at 4 °C for four weeks. The addition of fucoxanthin, at the concentration reported to have an anti-obesity effect in humans, to pasteurized WM and SM did not affect the composition or the physicochemical properties of milks but influenced the color, especially increasing the yellowness in the samples. These results revealed that goat milk can be used as a suitable matrix for the supplementation of fucoxanthin as a biofunctional ingredient in human foods.


More than just IQ: school achievement is predicted by self-perceived abilities--but for genetic rather than environmental reasons.
Evidence suggests that children's self-perceptions of their abilities predict their school achievement even after one accounts for their tested cognitive ability (IQ). However, the roles of nature and nurture in the association between school achievement and self-perceived abilities (SPAs), independent of IQ, is unknown. Here we reveal that there are substantial genetic influences on SPAs and that there is genetic covariance between SPAs and achievement independent of IQ. Although it has been assumed that the origins of SPAs are environmental, this first genetic analysis of SPAs yielded a heritability of 51% in a sample of 3,785 pairs of twins, whereas shared environment accounted for only 2% of the variance in SPAs. Moreover, multivariate genetic analyses indicated that SPAs predict school achievement independently of IQ for genetic rather than environmental reasons. It should therefore be possible to identify "SPA genes" that predict school achievement independently of "IQ genes."


Conceptual model for assessment of inhalation exposure: defining modifying factors.
The present paper proposes a source-receptor model to schematically describe inhalation exposure to help understand the complex processes leading to inhalation of hazardous substances. The model considers a stepwise transfer of a contaminant from the source to the receptor. The conceptual model is constructed using three components, i.e. (i) the source, (ii) various transmission compartments and (iii) the receptor, and describes the contaminant's emission and its pattern of transport. Based on this conceptual model, a list of nine mutually independent principal modifying factors (MFs) is proposed: activity emission potential, substance emission potential, localized control, separation, segregation, dilution, worker behavior, surface contamination and respiratory protection. These MFs describe the exposure process at a high level of abstraction so that the model can be generically applicable. A list of exposure determinants underlying each of these principal MFs is proposed to describe the exposure process at a more detailed level. The presented conceptual model is developed in conjunction with an activity taxonomy as described in a separate paper. The proposed conceptual model and MFs should be seen as 'building blocks' for development of higher tier exposure models.


Hypomethylation is restricted to the D4Z4 repeat array in phenotypic FSHD.
Patients with facioscapulohumeral muscular dystrophy (FSHD) show a contraction of the D4Z4 repeat array in the subtelomere of chromosome 4q. This D4Z4 contraction is associated with significant allele-specific hypomethylation of the repeat. Hypomethylation of D4Z4 is also observed in patients with phenotypic FSHD without contraction of D4Z4 and in patients with the immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, an unrelated disease that does not present with muscular dystrophy and is in part caused by DNMT3B mutations. In order to identify the gene defect and to find the pathogenetic epigenetic pathway in phenotypic FSHD, we have aimed to identify the differences and commonalities in phenotypic FSHD and ICF by 1) investigation of DNA methylation of non-D4Z4 repeat arrays, 2) analysis of mitogen-stimulated lymphocytes to detect pericentromeric abnormalities involving chromosomes 1, 9, and 16, 3) determination of IgA, IgG, and IgM levels, and 4) mutational analysis of candidate genes to identify a second disease locus involved in the pathogenesis of phenotypic FSHD. Our results do not show epigenetic or phenotypic commonalities between phenotypic FSHD and ICF other than the earlier observed D4Z4 hypomethylation. We could not identify any mutations in the candidate genes tested for. Our data suggest that in phenotypic FSHD hypomethylation is restricted to D4Z4 and that phenotypic FSHD and ICF do not share a defect in the same molecular pathway.


Pathologic findings in novel influenza A (H1N1) virus ("Swine Flu") infection: contrasting clinical manifestations and lung pathology in two fatal cases.
Although novel influenza A (H1N1) virus infection has assumed pandemic proportions, there are few reports of the pathologic findings. Herein we describe the pathologic findings of novel influenza A (H1N1) infection based on findings in 2 autopsy cases. The first patient, a 36-year-old man, had flu-like symptoms; oseltamivir (Tamiflu) therapy was started 8 days after onset of symptoms, and he died on day 15 of his illness. At autopsy, the main finding was diffuse alveolar damage with extensive fresh intra-alveolar hemorrhage. The second patient, a 46-year-old woman with alcoholism, was found unresponsive in a basement and brought to the hospital intoxicated and confused. Her condition deteriorated rapidly, and she died 4 days after admission. The main autopsy finding was acute bronchopneumonia with gram-positive cocci, intermixed with diffuse alveolar damage. The pathologic findings in these contrasting cases of novel influenza A (H1N1) infection are similar to those previously described for seasonal influenza. The main pathologic abnormality in fatal cases is diffuse alveolar damage, but it may be overshadowed by an acute bacterial bronchopneumonia.


Impairment in extinction of contextual and cued fear following post-training whole-body irradiation.
Because of the use of radiation in cancer therapy, the risk of nuclear contamination from power plants, military conflicts, and terrorism, there is a compelling scientific and public health interest in the effects of environmental radiation exposure on brain function, in particular hippocampal function and learning and memory. Previous studies have emphasized changes in learning and memory following radiation exposure. These approaches have ignored the question of how radiation exposure might impact recently acquired memories, which might be acquired under traumatic circumstances (cancer treatment, nuclear disaster, etc.). To address the question of how radiation exposure might affect the processing and recall of recently acquired memories, we employed a fear conditioning paradigm wherein animals were trained, and subsequently irradiated (whole-body X-ray irradiation) 24 h later. Animals were given 2 weeks to recover, and were tested for retention and extinction of hippocampus-dependent contextual fear conditioning or hippocampus-independent cued fear conditioning. Exposure to irradiation following training was associated with reduced daily increases in body weights over the 22-days of the study and resulted in greater freezing levels and aberrant extinction 2 weeks later. This was also observed when the intensity of the training protocol was increased. Cued freezing levels and measures of anxiety 2 weeks after training were also higher in irradiated than sham-irradiated mice. In contrast to contextual freezing levels, cued freezing levels were even higher in irradiated mice receiving 5 shocks during training than sham-irradiated mice receiving 10 shocks during training. In addition, the effects of radiation on extinction of contextual fear were more profound than those on the extinction of cued fear. Thus, whole-body irradiation elevates contextual and cued fear memory recall.


Postoperative complications in children undergoing gastrostomy tube placement.
Gastrostomy tube placement is associated with frequent postoperative complications. The aims of this study were to 1) determine the incidence of postoperative gastrostomy complications and 2) determine if patient demographics, comorbidities, or operative technique could predict these complications. A retrospective review was conducted on children who underwent gastrostomy tube placement from June 2006 through August 2009. Patient demographics, comorbidities, operative technique, health care visits, and complications were collected. Data were analyzed by chi-squared analysis (P < 0.05 significant). One hundred and fifty-nine patients were evaluated, with the majority of patients <5 years of age (129/159). Ninety-four patients underwent open gastrostomy, 31 laparoscopic gastrostomy, and 34 laparoscopic-assisted gastrostomy. Granulation tissue was the most common postoperative complication, occurring in 58% of patients (93/159). The majority of patients with granulation tissue had full resolution by the fourth postoperative month. Tube dislodgement was the second most common complication, occurring 69 times in 44 of the patients (28%) and resulting in 59 emergency department (ED) visits. Overall, gastrostomy complications resulted in 100 ED and 462 clinic visits. Ninety-three percent (93/100) of ED visits resulted in discharge home from the ED. Gender, age, insurance status, and operative technique were not predictive of complications. Granulation tissue and tube dislodgement are the most common complications after gastrostomy placement in children. Gender, age, insurance status, and operative technique were not predictive of complications. Emergency department utilization is high in children with gastrostomy tubes.