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The hallmark eye movement (EM) bursts that occur during Rapid Eye Movement (REM) sleep are markers of consolidation for procedural memory involving novel cognitive strategies and problem-solving skills. Examination of the brain activity associated with EMs during REM sleep might elucidate the processes involved in memory consolidation, and may uncover the functional significance of REM sleep and EMs themselves. Participants performed a REM-dependent, novel procedural problem-solving task (i.e., the Tower of Hanoi; ToH) before and after intervals of either overnight sleep (n=20) or a daytime 8-hour wake period (n=20). In addition, event-related spectral perturbation (ERSP) of the electroencephalogram (EEG) time-locked to EMs occurring either in bursts (i.e., phasic REM), or in isolation (i.e., tonic REM), were compared to sleep on a non-learning control night. ToH improvement was greater following sleep compared to wakefulness. During sleep, frontal-central theta (~2-8 Hz) and central-parietal-occipital sensorimotor rhythm (SMR) activity (~8-16 Hz) time-locked to EMs, were greater on the ToH night vs. control night, and during phasic REM sleep, were both positively correlated with overnight memory improvements. Furthermore, SMR power during tonic REM increased significantly from the control night to ToH night, but was relatively stable from night-to-night during phasic REM. These results suggest that EMs are markers of learning-related increases in theta and SMR during phasic and tonic REM sleep. Phasic and tonic REM sleep may be functionally distinct in terms of their contribution to procedural memory consolidation.

A set of numerical and analytical models is presented to predict the growth and contraction of grain-boundary creep cavities in binary self-healing alloys. In such alloys, the healing is realised by preferential precipitation of supersaturated solutes at the free surface of the cavity. The cavity grows due to the diffusional flux of vacancies towards the cavity, which is driven by the stress gradient along the grain boundary. Upon deposition of healing solute atoms on the cavity wall, effectively vacancies are removed from the cavity due to the inverse Kirkendall effect. The competition between the inward and outward vacancy fluxes results in a time-dependent filling ratio (i.e. the fraction of the vacancies removed from the original cavity) of the creep cavity. It is found that for stress levels lower than a critical stress σcr, the filling ratio can proceed to unity, i.e. to complete filling and annihilation of the pore. For applied stresses higher than σcr, complete filling is not achieved and the open volume of the creep cavity will continue to grow once a maximum filling ratio is reached at the critical time tcr. The critical stress σcr, critical time tcr, and time for complete filling th (if fully filling is achievable) are derived from the models for different combinations of parameters. The results from the analytical model and from previous nanotomography experiments are compared and are found to be in good agreement. Graphical abstract

Hiv-besmetting heeft wereldwijd een prevalentie van 0,8%, een jaarlijkse incidentie en een sterfte van respectievelijk 2,7 miljoen en 2,0 miljoen mensen. Ongeacht ras en socio-economische status gaat hiv-besmetting gepaard met stigmatisering en discriminatie. Deze casus beschrijft een minderjarige patiente wier ouders bij opname niet vertelden dat ze hiv-positief was. Wij bespreken het medisch-ethisch dilemma met betrekking tot het verzwijgen van een hiv-positieve status en de culturele verschillen die bij deze beslissing een rol spelen. De stigmatisering en discriminatie van de hiv-geinfecteerde heeft verscheidene gevolgen. Zo kan dit leiden tot schending van de mensenrechten, voornamelijk die gerelateerd zijn aan toegang tot de gezondheidszorg en geschikte medische behandeling. Dit kan een reden zijn om ernstige ziekten zoals hiv-besmetting te verzwijgen voor zowel familieleden als gezondheidszorgmedewerkers. In Nederland heeft zowel de arts als de patient een informatieplicht volgens de Wet op de geneeskundige behandelingsovereenkomst (WGBO). Het verzwijgen van een positieve hiv-status kan meerdere nadelige gevolgen hebben, zowel voor de patient als voor hulpverleners

The increase in O2 tension after birth is a major factor stimulating ductus arteriosus (DA) constriction and closure. Here we studied the role of the mitochondrial electron transport chain (ETC) as sensor, H2O2 as mediator, and voltage-gated potassium (KV) channels and Rho kinase as effectors of O2-induced contraction in the chicken DA during fetal development. Switching from 0% to 21% O2 contracted the pulmonary side of the mature DA (mature pDA) but had no effect in immature pDA and relaxed the aortic side of the mature DA (mature aDA). This contraction of the pDA was attenuated by inhibitors of the mitochondrial ETC and by the H2O2 scavenger polyethylene glycol (PEG)-catalase. Moreover, O2 increased reactive oxygen species (ROS) production, measured with the fluorescent probes dihydroethidium and 2′,7′-dichlorofluorescein, only in mature pDA. The H2O2 analog t-butyl-hydroperoxide mimicked the responses to O2 in the three vessels. In contrast to immature pDA cells, mature pDA cells exhibited high-amplitude O2-sensitive potassium currents. The KV channel blocker 4-aminopyridine prevented the current inhibition elicited by O2. The L-type Ca2+ (CaL) channel blocker nifedipine and the Rho kinase inhibitors Y-27632 and hydroxyfasudil induced a similar relaxation when mature pDA were stimulated with O2 or H2O2. Moreover, the sensitivity to these drugs increased with maturation. Our results indicate the presence of a common mechanism for O2 sensing/signaling in mammalian and nonmammalian DA and favor the idea that, rather than a single mechanism, a parallel maturation of the sensor and effectors is critical for O2 sensitivity appearance during development.

Vaginal microbiome (VMB) dysbiosis is associated with increased acquisition of HIV. Cervicovaginal inflammation and other changes to the mucosal barrier are thought to have important roles but human data are scarce. We compared the human cervicovaginal proteome by mass spectrometry of 50 Rwandan female sex workers who had previously been clustered into four VMB groups using a 16S phylogenetic microarray; in order of increasing bacterial diversity: Lactobacillus crispatus-dominated VMB (group 1), Lactobacillus iners-dominated VMB (group 2), moderate dysbiosis (group 3), and severe dysbiosis (group 4). We compared relative protein abundances among these VMB groups using targeted (abundance of pre-defined mucosal barrier proteins) and untargeted (differentially abundant proteins among all human proteins identified) approaches. With increasing bacterial diversity, we found: mucus alterations (increasing mucin 5B and 5AC), cytoskeleton alterations (increasing actin-organizing proteins; decreasing keratins and cornified envelope proteins), increasing lactate dehydrogenase A/B as markers of cell death, increasing proteolytic activity (increasing proteasome core complex proteins/proteases; decreasing antiproteases), altered antimicrobial peptide balance (increasing psoriasin, calprotectin, and histones; decreasing lysozyme and ubiquitin), increasing pro-inflammatory cytokines, and decreasing immunoglobulins immunoglobulin G1/2. Although temporal relationships cannot be derived, our findings support the hypothesis that dysbiosis causes cervicovaginal inflammation and other detrimental changes to the mucosal barrier.

Summary. Background and objectives: Elevated levels of factor (F)VIII are associated with an increased risk of thrombosis. FVIII levels are determined mainly by von Willebrand factor (VWF). We have investigated the contribution of secretion and clearance rates to the elevated VWF antigen (VWF:Ag) and to the risk of thrombosis. VWF is secreted in equimolar amounts with its propeptide, which has a shorter half-life. VWF propeptide can be used as a measure of VWF secretion and allows estimation of the VWF half-life. Methods and results: We have measured VWF propeptide, VWF:Ag, FVIII:Ag and FVIII activity (FVIII:C) in the Leiden Thrombophilia Study. In controls, high VWF propeptide was associated with high VWF:Ag, FVIII:Ag and FVIII:C. In contrast to mature VWF:Ag, VWF propeptide was not influenced by blood groups. Using an ELISA-based assay we have shown that VWF propeptide lacks ABO antigens. Levels were higher in men and increased with age. A long VWF half-life was also associated with high VWF:Ag, FVIII:Ag and FVIII:C. The VWF half-life was influenced by blood group (10 h in O vs. 12 h in non-O individuals), but not by sex, and only slightly by age. VWF propeptide was higher in thrombosis patients than in controls. The VWF half-life was similar in patients and controls (11.4 and 11.1 h, respectively). Conclusions: Both secretion and clearance rates are important determinants of VWF and FVIII levels. However, mainly high VWF and FVIII levels caused by increased secretion seem to be associated with thrombosis. ABO blood group influences the clearance rates of VWF rather than VWF secretion rates.

Thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels exhibit a large interindividual variability in which genetic control seems to play a major role. However, recent reports have questioned the association between TAFI concentration and genotype, suggesting that variable antibody reactivity towards TAFI isoforms, particularly the Thr325Ile polymorphism (1040C/T), may lead to artefacts in TAFI antigen levels. In order to compare assay outcome we determined plasma TAFI levels in 92 healthy individuals, using an enzyme-linked immunosorbent assay (ELISA) (commercial antibodies), an electroimmunoassay (in-house antibodies) and a commercial chromogenic assay (Actichrome® TAFI). Each individual was genotyped for the -438A/G and 1040C/T polymorphisms in the TAFI gene. TAFI levels were significantly associated with genotype in both antigen and chromogenic assays. All assays displayed significant correlations with each other. Linear regression and Bland-Altman agreement analysis in the genotype subgroups showed that neither the genotype nor the concentration affected the relationship between the Actichrome® TAFI and the electroimmunoassay. In contrast, the ELISA/Actichrome® TAFI and the ELISA/electroimmunoassay relationships were concentration- and genotype-dependent. Our results demonstrate that artefacts may arise when measuring TAFI antigen levels by ELISA. Nevertheless, the electroimmunoassay and the Actichrome® TAFI assay support a genotype-related variation of TAFI concentration. © 2004 Blackwell Publishing Ltd. Chemicals / CAS: Carboxypeptidase U, EC 3.4.17.20

We report the first known case of supero-inferior ventricles with a superior morphologically left ventricle and an inferior morphologically right ventricle. This 2 1/2-year-old boy also had dextrocardia, double-outlet right ventricle [S,L,L], right-sided mitral atresia, left-sided tricuspid regurgitation, a large conoventricular type of ventricular septal defect, and pulmonary outflow tract stenosis. This very rare form of superoinferior ventricles appears to be due to excessive levorotation (approximately equal to 170 degrees) of discordant L-loop ventricles.

Determine the incidence of patients at risk for contrast-induced nephropathy (CIN), the incidence of CIN and mid-term effects (renal replacement therapy/deathone month) to measure the impact of CIN in a general patient population undergoing intravenous contrast-enhanced computed tomography (CECT).We conducted a prospective study in consecutive patients undergoing intravenous CECT from October 2012 to May 2013. Data were obtained through scripted interviews and the electronic patient records. Presence of risk factors and kidney function before and after CECT and the follow-up for one month were evaluated.We included 998 patients (mean age: 60 years). Estimated GFR was ≥ 60 ml/mg/1.72 m2 in 886 (88.8%) patients, 30-59 ml/mg/1.72 m2 in 108 (10.8%) patients and30 ml/min/1.73 m2 in 4 (0.4%) patients. We found diabetes mellitus in 137 (13.7%), anaemia in 70 (7.0%) congestive heart failure in 92 (9.2%), peripheral arterial disease in 34 (3.4%), age75 years in 126 (12.6%) patients and 301 (30.2%) used nephrotoxic medication. Fifty-eight (5.8%) patients were at risk for CIN; 35 (60.3%) risk patients received intravenous prophylactic hydration. Of the hydrated patients, 11 underwent follow-up within one week; of the non-hydrated patients seven underwent follow-up within one week. Two (2/58: 3.4%) patients developed CIN (increased serum creatinine ≥ 44 μmol/l or ≥ 25%); there was no difference between hydrated and non-hydrated patients (1/35:1/23). The incidence of renal replacement therapy and death within one month was zero for both.The number of patients at risk is low. CIN incidence is low, even in patients not receiving prophylactic hydration. No patients received renal replacement therapy or died. The impact of CIN is low. Extensive CIN prevention guidelines seem superfluous.

Nowadays many wind turbines use a doubly fed induction machine (DFIM) as a generator (DFIG). The brushless DFIM (BDFIM), however, has increased fault handling capabilities and suffers less from reliability issues. This paper presents a different method of analytically evaluating the BDFIM. This is done by analyzing the flux density produced by the two stator windings and the interaction with the nested loops of the rotor. Subsequently FEM is used to verify the analytical findings and analyze the behavior of the machine. Additionally several design parameters of the BDFIM such as the pole pair combinations and the number of loops per nest are evaluated. General rules of thumb regarding these design parameters are presented.

Hypertriglyceridemia (HTG) is an independent risk factor for cardiovascular disease (CVD). Hemostatic variables [factor VII antigen (FVIIag), factor VII coagulant activity (FVIIc), activated factor VII (FVIIa), free and endothelial-associated (EC) tissue factor pathway inhibitor (TFPI) antigen, pre- and post-heparin total TFPI activity, EC-TFPI activity, prothrombin fragment 1 + 2 (F1 + 2), fibrinogen and D-dimer] were compared between 18 HTG patients and 20 controls to investigate whether HTG is associated with alterations in the extrinsic pathway and whether such alterations create a procoagulant state, as expressed by F1 + 2 and D-dimer levels. In addition, the effects of bezafibrate therapy (6 weeks, 400 mg/day) on these variables were studied in 18 HTG patients in a double-blind, placebo-controlled, cross-over study. FVIIag, FVIIc, free TFPI and fibrinogen were significantly higher in HTG patients (by 44, 30, 45 and 31%, respectively; all P < 0.02), while FVIIa, EC-TFPIag and activity, total TFPI activities, F1 + 2 and D-dimer levels were similar in patients and controls. Bezafibrate reduced serum TG and fibrinogen levels (by 62 and 20%, respectively; both P < 0.001), whereas the other hemostatic variables were unaffected. In conclusion, the observed alterations in the extrinsic pathway in HTG are not associated with a procoagulant state. In contrast, the presence of elevated fibrinogen levels in HTG might enhance the risk for CVD. Bezafibrate therapy improved the adverse lipid profile and decreased fibrinogen levels in HTG patients.

The objective of this study was to evaluate the osmotic drying kinetics of cylindrical slices of apples as influenced by particle size at different concentrations of sucrose solutions and different temperatures. Osmotic drying was carried out, with cut apple cylinders of three different sizes (12, 17 and 20mm diameter), all with a length to diameter ratio of 1:1, in a well agitated large tank containing the osmotic solution at the desired temperature. The solution to fruit volume ratio was kept greater than 60. A central composite rotatable design (CCRD) was used with dive levels of sucrose concentrations (34–63°Brix) and five temperatures (34–66°C). Kinetic parameters included weight loss, moisture loss, solids gain, rates of moisture loss and solids gain generally increased with increasing treatment time, temperature and concentration of osmotic solution, and decreased with an increase in sample size. The parameter “osmotic drying time to achieve a given moisture loss” obviously showed the opposite. Com...

The name of the third author was spelled incorrectly. The correct name is: N.H. van Mil. The correct Citation is: Stolk L, Bouwland-Both MI, van Mil NH, Verbiest MMPJ, Eilers PHC, et al. (2013) Epigenetic Profiles in Children with a Neural Tube Defect; A Case-Control Study in Two Populations. PLoS ONE 8(11): e78462. doi:10.1371/journal.pone.0078462.

We have performed specific-heat measurements on the heavy-fermion superconductor URu2Si2 in magnetic fields up to 17.5 T. A sharp peak in the specific heat signals the antiferromagnetic transition at TN517.5 K, which shifts to lower temperatures in applied magnetic fields. In order to describe the specific heat below TN , we have used the characteristic features of the excitation spectrum measured by neutron scattering. The relative field dependence of the antiferromagnetic transition temperature TN and the energy gap D in the magnetic excitation spectrum can be described by a single scaling relation of the form @12(B/B0) # . The scaling field of 48.5 T is close to the metamagnetic transition field B*540 T, where the heavy-fermion state is suppressed. @S0163-1829~97!05746-9#

Erlotinib is used to treat patients with non-small cell lung cancer (NSCLC). The use of this tyrosine kinase inhibitor can result in interstitial lung disease, but the aetiology of this phenomenon is not clear.A 68-year-old man with NSCLC, who had been undergoing treatment with erlotinib (150 mg daily) for the previous two weeks, presented with dyspnoea. A chest x-ray revealed infiltrates for which we started broad-spectrum antibiotics, high dose glucocorticoids and oxygen supplementation; erlotinib was discontinued. Despite these measures, the patient died of respiratory failure. Autopsy showed diffuse alveolar damage; the blood cultures taken while the patient was still alive and the post-mortem lung cultures were negative. The alveolar damage was possibly a consequence of the use of erlotinib.Clinicians should be alert to worsening pulmonary symptoms without signs of infection in patients using erlotinib. Discontinuation of erlotinib and glucocorticoid treatment should be considered until alveolar damage caused by the use of erlotinib can be excluded.

The superconducting phase diagram ofUPt 3, as determined by accurate dilatometry as function of temperature and magnetic field (B‖c andB⊥c), exhibits three superconducting phases which meet in a tetracritical point. We show that the measured phase diagrams are thermodynamically stable and that all four phase lines are of second order. Via Ehrenfest relations the pressure dependence of the various phases has been determined. The so-calledC phase is the most stable phase under uniaxial pressure along the c-axis (p c>2.5 kbar). The resulting phase diagram in thep c -T plane yields stringent constraints on the fourth order coupling constants in the Ginzburg-Landau scenario of a vector superconducting order parameter coupled to a symmetry breaking field.

Flinsenberg TWH, van der Sterren S, van Cleef ANH, Schuurman MJ, Agren P, Villamor E. Effects of sex and estrogen on chicken ductus arteriosus reactivity. Am J Physiol Regul Integr Comp Physiol 298: R1217-R1224, 2010. First published February 17, 2010; doi: 10.1152/ajpregu.00839.2009.-Sex hormones have an important influence on cardiovascular physiology and pathophysiology and sex differences in vascular reactivity have been widely demonstrated. In the present study we hypothesized 1) the presence of sexual dimorphism in chicken ductus arteriosus (DA) responsiveness to contractile and relaxant stimuli and 2) that estrogens are vasoactive in the chicken DA. In vitro contractions (assessed with a wire myograph) induced by normoxia, KCl, 4-aminopyridine, norepinephrine, phenylephrine, U46619, or endothelin-1, as well as relaxations induced by ACh, sodium nitroprusside, BAY 41-2272, PGE2, isoproterenol, forskolin, Y-27632, and hydroxyfasudil were not significantly different between males and females. The estrogen 17 beta-estradiol elicited concentration-dependent relaxation of KCl-, phenylephrine, and oxygen-induced active tone in male and female chicken DA. The stereoisomer 17 alpha-estradiol showed lesser relaxant effects, and the selective estrogen receptor (ER) agonists 4,4',4 ''-(4-propyl-[H-1]pyrazole-1,3,5-triyl)tris-phenol (ER alpha) and 2,3-bis(4-hydroxyphenyl)-propionitrile (ER alpha) did not show any effect. There were no sex differences in the responses to estrogen. Endothelium removal or the presence of the soluble guanylate cyclase inhibitor ODQ, the K+ channel blockers tetraethylammonium, glibenclamide, and charybdotoxin, or the ER antagonist fulvestrant did not modify 17 beta-estradiol-induced relaxation. CaCl2 (30 mu M-10 mM) induced concentration-dependent contraction in DA rings depolarized by 62.5 mM KCl or stimulated with 21% O-2 in Ca2+-free medium. Preincubation with 17 beta-estradiol or the L-type Ca2+ channel blocker nifedipine produced an inhibition of CaCl2-induced contractions. In conclusion, there are no sex-related differences in chicken DA reactivity. The estrogen 17 beta-estradiol induces an endothelium-independent relaxation of chicken DA that is not mediated by ER activation. This relaxant effect is, at least partially, due to inhibition of Ca2+ entry from extracellular space.

We have developed a retroviral-vector system for the transfer and expression of a cloned blood clotting factor VIII cDNA. Since inclusion of the complete cDNA into existing vectors is precluded by its large size, we deleted most codons for the B-domain, which is also excised during in vivo maturation of factor VIII. When inserted into the retroviral vector M5-neoR (Laker, C., Stocking, C., Bergholtz, V., Hess, N., DeLamarter, J. F., and Ostertag, W. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, 8458-8462), the sequence was shown to be efficiently expressed in murine fibroblast cell lines, as well as in primary human skin fibroblasts. Upon infection of murine fibroblast cell lines, clones containing only a single copy of the integrated vector-provirus secreted up to 125 milliunits of factor VIII antigen/10(6) cells/day. Equivalent amounts were found in a factor VIII activity assay, which signifies that the factor VIII protein secreted by the infected fibroblasts is fully functional. Primary human skin fibroblasts infected with the vector virus secreted up to 30 milliunits/10(6) cells/day.

Introduction Vaginal microbiome (VMB) dysbiosis is associated with increased acquisition of HIV and sexually transmitted infections (STIs). Cervicovaginal inflammation and other changes to the mucosal barrier are thought to play important roles but human data are scarce. In this study, we compared the cervicovaginal proteome among women with different VMB compositions. Methods Cervicovaginal lavages of 50 Rwandan female sex workers with known VMB composition were selected for human proteome analysis using mass-spectrometry. These women were previously clustered into four VMB groups in order of increasing bacterial diversity: group 1 had a Lactobacillus crispatus-dominated VMB; group 2 a L. iners -dominated VMB; group 3 moderate dysbiosis; and group 4 severe dysbiosis. We compared relative protein abundances among these VMB groups using targeted (abundance of pre-defined mucosal barrier proteins) and untargeted (differentially abundant proteins among all human proteins identified) approaches. Results With increasing bacterial diversity, we found: mucus alterations (increasing mucin 5B and 5AC), cytoskeleton alterations (increasing actin-organising proteins; decreasing keratins and cornified envelope proteins), increasing cell death (using LDHA/B as biomarkers of cell death), altered proteolytic activity (increasing proteasome core complex proteins/proteases; decreasing antiproteases), altered antimicrobial peptide balance (increasing psoriasin, calprotectin, and histones; decreasing lysozyme and ubiquitin), increasing proinflammatory cytokines, and decreasing immunoglobulins IgG1/2. Conclusion The VMB is strongly associated with the cervicovaginal human proteome in this cohort of Rwandan women at high risk of HIV and other STIs. Although temporal relationships cannot be derived, our findings support the hypothesis that dysbiosis causes cervicovaginal inflammation and other detrimental changes to the mucosal barrier that may lead to increased HIV/STI acquisition. Disclosure of interest statement This work was funded by the Institute of Infection and Global Health of the University of Liverpool, the Aids Fonds Netherlands (project number 201102), European and Developing Countries Clinical Trials Partnership (project number CT.2005.33070.001) and the European Commission (CHAARM consortium). The authors declare no conflicts of interest.

Thrombin activatable fibrinolysis inhibitor (TAFI) antigen levels exhibit a large interindividual variability in which genetic control seems to play a major role. However, recent reports have questioned the association between TAFI concentration and genotype, suggesting that variable antibody reactivity towards TAFI isoforms, particularly the Thr325Ile polymorphism (1040C/T), may lead to artefacts in TAFI antigen levels. In order to compare assay outcome we determined plasma TAFI levels in 92 healthy individuals, using an enzyme-linked immunosorbent assay (ELISA) (commercial antibodies), an electroimmunoassay (in-house antibodies) and a commercial chromogenic assay (Actichrome TAFI). Each individual was genotyped for the -438A/G and 1040C/T polymorphisms in the TAFI gene. TAFI levels were significantly associated with genotype in both antigen and chromogenic assays. All assays displayed significant correlations with each other. Linear regression and Bland-Altman agreement analysis in the genotype subgroups showed that neither the genotype nor the concentration affected the relationship between the Actichrome TAFI and the electroimmunoassay. In contrast, the ELISA/Actichrome TAFI and the ELISA/electroimmunoassay relationships were concentration- and genotype-dependent. Our results demonstrate that artefacts may arise when measuring TAFI antigen levels by ELISA. Nevertheless, the electroimmunoassay and the Actichrome TAFI assay support a genotype-related variation of TAFI concentration.

A 56-year-old woman without structural heart disease had an ECG typical of Brugada syndrome. Syncope occurred due to monomorphic VT with left bundle branch block (LBBB) morphology. At electrophysiological study, VT with the same morphology was inducible.

The aim of this pilot study was to examine the usefulness of the Dutch version of the Arthritis Impact Measurement Scales 2 (D-AIMS2)in assessing the health status of Dutch individuals with haemophilia. Sixty-eight individuals with mild, moderate, and severe haemophilia attending our clinic for their annual check-up participated. They first completed the Canadian Occupational Performance Measure (COPM). The D-AIMS2 was filled in afterwards at home. With the COPM, individuals rated their specific problematic activities of daily life (ADL), as well as the severity and importance of each problem. The D-AIMS2 is a comprehensive, self-administered questionnaire that evaluates functional health status. Fifty-seven individuals completed and returned the D-AIMS2. Reliability analysis demonstrated good internal consistency for the scales (Cronbach's alpha=0.76-1.00), as well as for the components (alpha=0.80-0.88), except for the component 'social interaction' (alpha=0.44). Criterion validity of the D-AIMS2 was assessed by comparison with COPM outcomes; 80% of the problematic ADLs were included in the questionnaire, 20% were missing. Correlations between the D-AIMS2 components 'physical health' and 'symptoms' with predicted scores of those individuals by a highly experienced physiotherapist (r=0.63 and 0.53, respectively) substantiated its concurrent validity. Based on these results we concluded that the D-AIMS2, with minor adjustments, can be an appropriate tool for assessing the health status of Dutch haemophilia patients.

We report an unusual case of cutaneous nephrocolonic fistula caused by a renal calculus with perirenal infection. The diagnosis was made by fistulography and computed tomography, after which nephrectomy and resection of the descending colon were successful. We also review the literature on cutaneous nephrocolonic fistulas.

AIMS—To investigate the efficacy of azithromycin in patients with ocular toxoplasmosis. METHODS—11 immunocompetent patients with ocular toxoplasmosis were treated with azithromycin (500 mg the first day, followed by 250 mg/day for 5 weeks). Ocular and systemic examinations were performed during active retinitis episodes and all patients were followed for at least 1 year. RESULTS—The intraocular inflammation disappeared within 4 weeks in seven patients, including two cases with progressive retinitis despite previous treatment with pyrimethamine, sulphadiazine, and folinic acid. Recurrence of retinitis occurred in three patients (27%) within the first year of follow up. No systemic side effects of azithromycin were encountered. CONCLUSION—These results indicate that although azithromycin cannot prevent recurrent disease it may be an effective alternative for patients with ocular toxoplasmosis who cannot tolerate standard therapies. Keywords: azithromycin; ocular toxoplasmosis

CAS: blood clotting factor 11, 9013-55-2; thrombin, 9002-04-4; tissue plasminogen activator, 105913-11-9; protein C, 60202-16-6; Carboxypeptidase U, 3.4.17.20; Protein C; Tissue Plasminogen Activator, 3.4.21.68

There is a need to judge general exercise tolerance in children with cystic fibrosis (CF) under normal daily activity conditions and -when more extensive testing is required-in an exercise laboratory in a specialized center. We investigated the reproducibility, validity, and criterion for a 6-minute walking test, which simulates normal childhood activities. In Part A, we evaluated the reproducibility of a 6-minute walking test in 23 children (12 girls and 11 boys; ages 11.1 +/- 2.2 years; range, 8.2 15.6 years) with mild symptoms of CF [forced expiratory volume in 1 second (FEV1) 94.4 +/- 16.5% of predicted values (range, 60.6-129.7); body weight Z-score -0.71 +/- 0.81 (range, -1.73-0.93)]. The subjects performed two standardized 6-minute walking tests with 1 week between tests. There was no significant difference between the two walking distances reached (737 +/- 85 versus 742 +/- 90 meters; P = 0.56), and there was a strong correlation between the two walking distances reached by the individuals (r = 0.90, P0.0001). In Part B, the validity of the walking test was evaluated in 15 children (6 girls and 9 boys; ages 14.5 +/- 2.0 years; range, 10.2-16.9 years) with moderate symptoms of CF [FEV1 = 58 +/- 16.0% of predicted values, (range, 41.1-89.4); RV/TLC ratio = 46.3 +/- 6.5% (range, 31.6-57.2); body weight Z-score: -1.29 +/- 0.60 (range, -2.20-0.14)]. They underwent standardized maximum incremental exercise testing on a cycle ergometer and a 6-minute walking test. Postexertional lactate values exceeded threshold values (as described in the literature) in all patients but one. Correlation analysis (Pearson) showed a significant correlation between the walking distance reached (WD = 697 +/- 104 meters), and the maximum workload (Wmax = 118 +/- 44 watt; r = 0.76, P0.001) or the maximum oxygen uptake (1,688 +/- 495 ml; r = 0.76, P0.001), the latter two being determined on a cycle ergometer, RV/TLC% showed a significant negative correlation (r = -0.72, P0.01) with WD. Stepwise multiple regression analysis showed a multiple regression coefficient of R = 0.84 (P0.001) for Wmax and RV/TLC % as the independent variables vs. WD as the dependent variable. We conclude that the 6-minute walking test is a valid and useful test in children with mild to moderate symptoms of CF to assess their exercise tolerance and endurance. Exercise test results correlated negatively with pulmonary hyperinflation expressed by the RV/TLC ratio.

Alcohol abuse is a major problem among adolescents, and has both acute, potentially lethal, and long-term harmful effects. The authors describe an adolescent who was in a subcomatose condition after binge drinking. His serum alcohol concentration was 3.7 g/l. The next morning, before transfer to the paediatric ward, he developed a third-degree atrioventricular (AV) block without cardiac output while his infusion needle was removed. This recovered spontaneously after a precordial thump. Retrospectively, electrocardiography showed an increasing PR prolongation (200–300 ms) before the removal of the infusion needle. ECG recordings several hours later showed a first-degree AV block, which was no longer seen during follow-up, 1 month later. The authors conclude that acute alcohol poisoning has the potential to prolong the PR interval in young, healthy adolescents without pre-existing first-degree AV block and provoke a third-degree AV block after vagal stimulation. It is yet another potential danger of acute alcohol intoxication in this age group.

To compare patterns of reverse systolic flow in pulmonary arteries in children with dilated and normal pulmonary arteries.Retrospective survey.Tertiary pediatric cardiology referral centre.Colour Doppler images were reviewed on 45 children, aged three months to 17 years, with normal or dilated main pulmonary arteries. The patients included were unoperated, and had isolated lesions and good parasternal short axis colour Doppler images of the main pulmonary artery with no significant pulmonary insufficiency. There were 19 patients with idiopathic dilation of the pulmonary artery, seven with moderate sized atrial septal defect, seven with moderate pulmonary valve stenosis, two with pulmonary hypertension and 10 children who were normal. Reverse flow was identified by adjacent red and blue areas without aliasing.Reverse systolic flow extending into early diastole was seen in 27 of the 35 patients and in two of 10 normals (P = 0.003). The main pulmonary artery was substantially dilated in the patient group compared with normals.Significant reverse systolic flow was found in main pulmonary arteries dilated idiopathically, or from pressure or volume overload. Reverse flow may be related to excessive capacitance of the main pulmonary artery in these patients.

In a recent issue of Blood, Henry et al[1][1] reported the identification of several single nucleotide polymorphisms (SNPs) in the promoter and 3′ untranslated region of the thrombin-activatable fibrinolysis inhibitor (TAFI) gene. They also investigated the 505A/G SNP in the coding region of the

We have investigated the peripheral myelin protein gene, PMP-22, in a family with Charcot-Marie-Tooth disease type 1A (CMT1A). The DNA duplication commonly found in CMT1A was absent in this family, but strong linkage existed between the disease and the CMT1A marker VAW409R3 on chromosome 17p11.2. We found a point mutation in PMP-22 which was completely linked with the disease. The mutation, a proline for leucine substitution in the first putative transmembrane domain, is identical to that recently found in the Trembler-J mouse. The presence of this PMP-22 defect in this CMT1A family and the location of PMP-22 within the DNA duplication associated with CMT1A suggest that both structural alteration and overexpression of PMP-22 may lead to the disease.

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with a DNA duplication at chromosome 17p11.2. In view of the point mutation in the gene for peripheral myelin protein pmp-22/gas-3 in Trembler mice, a murine model for CMT1A, we have analysed whether this gene is altered in CMT1A. Here we show that the human homologue of the murine pmp-22 gene is located within the CMT1A DNA duplication, which is a direct repeat and does not interrupt the coding region of PMP-22. Expression of PMP-22 in CMT1A fibroblasts is similar to expression in control fibroblasts. Increased gene dosage or altered PMP-22 expression in the peripheral nervous system are therefore possible mechanisms by which PMP-22 is involved in CMT1A.

Since the ovine model is the most commonly used for foetal haemodynamic investigation it was felt important 1) to investigate the technical difficulties involved with ultrasound fetal cardiac imaging in this species and 2) to establish normal reference values for ovine cardiac and umbilical blood flow velocity measurements. Both two-dimensional and pulsed Doppler techniques were used for this assessment in 25 unsedated ewes. All morphological features described in human features to identify the ventricular cavities could be found in the ovine fetus with the two-dimensional echocardiogram. Specific differences included a flatten thorax as visualized from the lateral position, the mesocardial position of the heart, and a large left azygos vein behind the left atrium draining blood into a dilated coronary sinus. The mean peak velocities (cm/sec) of the early diastolic wave (E) and the atrial wave (A), along with their calculated ratio, were not statistically different between the two atrio-ventricular valves (E: 30.6 +/- 6.6, 31.2 +/- 6.1; A: 43.0 +/- 8.3, 41.6 +/- 8.0; E/A: .72, .76 for mitral and tricuspid valves respectively). A significant difference was observed between the acceleration times of the blood ejected into the aorta and the pulmonary artery, with the time interval being shorter in the pulmonary artery (Aorta: 0.052 +/- 0.011; Pulmonary artery: 0.037 +/- 0.009 s). A mean pulsatility index of the umbilical artery of 0.89 was recorded. The data recorded in this study should serve as a reference base for further non-invasive studies of the ovine foetal circulatory system using the ultrasound technique.

Seven patients underwent cardiac transplantation at Ste-Justine Hospital between June 1984 and October 1988 (age 3-16 years). Indices derived from M-mode echocardiography--left ventricular mass (LVM), isovolumetric relaxation time (IRT), shortening fraction (SF), velocity of circumferential fiber shortening (VCF), ejection fraction (EF), LV pre-ejection period/ejection time (PEP/ET), isometric contraction time (ICT)--and electrocardiography--summation of potentials (Sum Pot)--were used as non-invasive markers of rejection (367 studies), while rejection status was monitored by serial endomyocardial biopsy (55 biopsies). Spontaneous variation of such indices, as defined by the 90% distribution interval of their variation when biopsy was unchanged, was found to be important: -20% to +28% for IRT, -30% to +28% for LVM, -30% to 32% for Sum Pot, -32% to 42% for PEP/ET, etc. Using limits of spontaneous variation such as thresholds, none of the studied indices could consistently predict the 2 biopsy-documented episodes of rejection or the 7 episodes of improvement. Among all the studied indices, IRT was the most promising, correctly predicting 1 of the episodes of rejection and almost predicting the 2nd. Remeasurement of all M-mode tracings by an unique observer, following strict rules to maximize reproducibility, did not decrease the spontaneous variation of these indices, nor did it improve their performance as predictors of changes in the rejection status. These results warrant the continuing search for other non-invasive methods for accurate monitoring of the rejection status.