The photoproduction of omega mesons on nuclei has been investigated using the Crystal Barrel/TAPS experiment at the ELSA tagged photon facility in Bonn. The aim is to study possible in-medium ...modifications of the omega meson via the reaction gamma + A --> omega + X --> pi(0)gamma + X('). Results obtained for Nb are compared to a reference measurement on a LH2 target. While for recoiling, long-lived mesons (pi(0), eta, and eta;(')), which decay outside of the nucleus, a difference in the line shape for the two data samples is not observed, we find a significant enhancement towards lower masses for omega mesons produced on the Nb target. For momenta less than 500 MeV/c an in-medium omega meson mass of M(medium) = 722(+4)(-4)(stat)+35-5(syst) MeV/c(2) has been deduced at an estimated average nuclear density of 0.6rho(0).
Quasifree photoproduction of eta mesons off nucleons bound in the deuteron has been measured with the CBELSA/TAPS detector for incident photon energies up to 2.5 GeV at the Bonn ELSA accelerator. The ...eta mesons have been detected in coincidence with recoil protons and recoil neutrons, which allows a detailed comparison of the quasifree n(gamma,eta)n and p(gamma,eta)p reactions. The excitation function for eta production off the neutron shows a pronounced bumplike structure at W=1.68 GeV (E{gamma} approximately 1 GeV), which is absent for the proton.
Information on hadron properties in the nuclear medium has been derived from the photoproduction of omega mesons on the nuclei C, Ca, Nb, and Pb using the Crystal Barrel/TAPS detector at the ELSA ...tagged photon facility in Bonn. The dependence of the omega-meson cross section on the nuclear mass number has been compared with three different types of models: a Glauber analysis, a Boltzmann-Uehling-Uhlenbeck analysis of the Giessen theory group, and a calculation by the Valencia theory group. In all three cases, the inelastic omega width is found to be 130-150 MeV/c(2) at normal nuclear matter density for an average 3-momentum of 1.1 GeV/c. In the rest frame of the omega meson, this inelastic omega width corresponds to a reduction of the omega lifetime by a factor approximately 30. For the first time, the momentum dependent omegaN cross section has been extracted from the experiment and is in the range of 70 mb.
Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A deficiency. The Fabry Registry is a global clinical effort to collect longitudinal data on FD. In the past, ...most “carrier” females were usually thought to be clinically unaffected. A systematic effort has been made to enroll all FD females, regardless of symptomology. Of the 1077 enrolled females in the Registry, 69.4% had symptoms and signs of FD. The median age at symptom onset among females was 13 years, and even though 84.1% had a positive family history, the diagnosis was not made until a median age of 31 years. Twenty percent experienced major cerebrovascular, cardiac, or renal events, at a median age of 46 years. Among adult females with estimated glomerular filtration rate (eGFR) data (
N
=
638), 62.5% had an eGFR <90
ml/min/1.73m
2 and 19.0% had eGFR <60
ml/min/1.73 m
2. Proteinuria ⩾300
mg/day was present in 39.0% of females, and 22.2% had >1 gram/day. Quality of life (QoL), as measured by the SF-36
® survey, was impaired at a later age than in males, but both genders experience significantly impaired QoL from the third decade of life onward. Thus, females with FD have a significant risk for major organ involvement and decreased QoL. Females should be regularly monitored for signs and symptoms of FD, and considered for enzyme replacement therapy.
Pregnancy is a cardiovascular and metabolic challenge to the human female body. This review summarizes current knowledge on the regulation of blood pressure and plasma volume in normal and ...hypertensive pregnant women. During pregnancy, systemic vascular resistance and blood pressure decrease, whereas cardiac output and blood volume increase to safeguard an adequate circulation in the utero-placental arterial bed. Hypertension affects 10% of all pregnancies and is accompanied by an increase in foetal and maternal morbidity and mortality. Hypertension in pregnancy includes a wide spectrum of conditions, including pre-eclampsia and eclampsia, pre-eclampsia superimposed on chronic hypertension, chronic hypertension, and gestational hypertension. Endothelial dysfunction, oxidative stress and an exaggerated inflammatory response are features related to hypertensive disorders. Microangiopathic disorders can easily mimic hypertensive disorders during pregnancy. Although they have some symptoms in common, they require another type of management.
To reduce the risk of maternal and foetal complications due to haemodynamic maladaptations, the current management includes rest at home or in the hospital, close monitoring of maternal and foetal signs and symptoms, early start of antihypertensive therapy, and timely delivery regarding maternal and foetal survival chances. Thresholds to initiate blood pressure lowering treatment during pregnancy are 160 mmHg systole or 110 mmHg diastole. Below these thresholds, treatment must be individualized because current evidence does not support aggressive medical interventions. Alpha-methyldopa and dihydropyridinic calcium channel blockers are among the recommended antihypertensives.
Fabry disease is an inherited X-linked disorder that presents during childhood in male and female patients. Young patients may initially experience pain, hypohidrosis, and gastrointestinal symptoms. ...Other manifestations of Fabry disease, such as renal and cardiac disease, manifest later in adolescence or adulthood. In the pediatric population, renal damage is typically subclinical and identifiable only through biopsy. Specialists from the United States with expertise in Fabry disease convened during 2013–2014 in order to develop these consensus guidelines about the management and treatment of children with Fabry disease. The presence of symptoms in boys and girls of any age is an indication to begin therapy. Early treatment before the onset of potentially irreversible vital organ pathology is ideal. Asymptomatic children with Fabry mutations should be followed closely for the development of renal, cardiac, neurological, or gastrointestinal signs, symptoms, or laboratory changes, which would warrant treatment initiation. A comprehensive care plan should be implemented by the treating physicians to guide the management of children with Fabry disease.
•We present consensus guidelines for the management of children with Fabry disease.•The presence of Fabry symptoms in boys and girls of any age is a strong indication for treatment initiation.•Treatment should be initiated before irreversible end-organ damage has occurred.•Asymptomatic children with Fabry mutations should be followed closely.•The management of Fabry disease requires a multidisciplinary care approach.
The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta.
Renal function was evaluated in 151 men and 62 ...women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression.
Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m(2)/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m(2)/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m(2)/year).
Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
Fabry disease (FD) is a rare, X-linked lysosomal storage disorder affecting both males and females caused by genetic abnormalities in the gene encoding the enzyme α-galactosidase A. FD-affected ...patients represent a highly variable clinical course with first symptoms already appearing in young age. The disease causes a progressive multiple organ dysfunction affecting mostly the heart, kidneys and nervous system, eventually leading to premature death. Disease-specific management of FD includes enzyme replacement therapy with agalsidase α and β or pharmacological oral chaperone migalastat. Migalastat is a low-molecular-mass iminosugar, that reversibly binds to active site of amenable enzyme variants, stabilizing their molecular structure and improving trafficking to the lysosome. Migalastat was approved in the EU in 2016 and is an effective therapy in the estimated 35-50% of all patients with FD with amenable GLA gene variants. This position statement is the first comprehensive review in Central and Eastern Europe of the current role of migalastat in the treatment of FD. The statement provides an overview of the pharmacology of migalastat and summarizes the current evidence from the clinical trial program regarding the safety and efficacy of the drug and its effects on organs typically involved in FD. The position paper also includes a practical guide for clinicians on the optimal selection of patients with FD who will benefit from migalastat treatment, recommendations on the optimal selection of diagnostic tests and the use of tools to identify patients with amenable GLA mutations. Areas for future migalastat clinical research have also been identified.
Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. ...Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients.
Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol.
Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%).
Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies. Clinical Trial Registration Information- URL: http://www.clinicaltrials.gov.Unique identifier: NCT00414583.
The initiation of enzyme-replacement therapy prior to the occurrence of substantial and irreversible organ damage in patients with Fabry disease is of critical importance. The Fabry Outcome Survey is ...an international disease registry of patients with a confirmed diagnosis of Fabry disease. In this study, data from the Fabry Outcome Survey were used for the assessment of the risks for cardiovascular and renal events in patients who received agalsidase alfa treatment.
Eligible patients were males and females aged ≥18 years with Fabry disease treated with agalsidase alfa. Cardiovascular events included myocardial infarction, left ventricular hypertrophy (LVH), heart failure, arrhythmia, conduction abnormality, and cardiac surgery. Renal events included dialysis, transplantation, and renal failure. Kaplan–Meier curves and log-rank tests were used for comparing event-free probabilities and time to first cardiovascular or renal event, from agalsidase alfa initiation to a maximum of 120 months, in patients with LVH versus normal left ventricular mass index (LVMI; ≤50 g/m2.7 in males and ≤48 g/m2.7 in females) at treatment initiation (baseline), and in patients with a low estimated glomerular filtration rate (eGFR; <90 mL/min/1.73 m2) versus normal eGFR at baseline. Multivariate Cox regression analysis was used for examining the association between key study variables and the risks for cardiovascular and renal events.
Among the 560 patients (269 males; 291 females) with available LVMI data, 306 (55%) had LVH and 254 (45%) had normal LVMI at baseline. The risk for a cardiovascular event was higher in the subgroup with LVH versus normal LVMI at baseline (hazard ratio HR = 1.57; 95% CI, 1.21–2.05; P < 0.001), but the risk for a renal event was similar between the 2 subgroups (HR = 1.90; 95% CI, 0.94–3.85; P = 0.074). Among the 1093 patients (551 males; 542 females) with available eGFR data, 433 (40%) had a low eGFR and 660 (60%) had a normal eGFR at baseline. The subgroup with a low eGFR at baseline had a significantly higher risk for a cardiovascular event (HR = 1.33; 95% CI, 1.04–1.70; P = 0.021) or a renal event (HR = 5.88; 95% CI, 2.73–12.68; P < 0.001) compared with patients with a normal eGFR at baseline.
In the present study, the presence of LVH and/or reduced renal function at agalsidase alfa initiation was associated with a significantly higher risk for a cardiovascular or renal event, indicating that cardiovascular and renal pathologies in Fabry disease may be inter-related. Early initiation of agalsidase alfa treatment prior to the onset of severe organ damage may improve outcomes. ClinicalTrials.gov identifier: NCT03289065.
•We assessed the risk of cardiovascular (CV) and renal events in Fabry patients.•Presence of LVH at ERT start was associated with higher risk of CV and renal events.•Reduced eGFR at ERT start was associated with higher risk of renal and CV events.•Cardiovascular and renal pathologies in Fabry disease may be inter-related.
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