Central catecholamine deficiency characterizes α-synucleinopathies such as Parkinson's disease. We hypothesized that cerebrospinal fluid levels of neuronal metabolites of catecholamines provide ...neurochemical biomarkers of these disorders. To test this hypothesis we measured cerebrospinal fluid levels of catechols including dopamine, norepinephrine and their main respective neuronal metabolites dihydroxyphenylacetic acid and dihydroxyphenylglycol in Parkinson's disease and two other synucleinopathies, multiple system atrophy and pure autonomic failure. Cerebrospinal fluid catechols were assayed in 146 subjects-108 synucleinopathy patients (34 Parkinson's disease, 54 multiple system atrophy, 20 pure autonomic failure) and 38 controls. In 14 patients cerebrospinal fluid was obtained before or within 2 years after the onset of parkinsonism. The Parkinson's disease, multiple system atrophy and pure autonomic failure groups all had lower cerebrospinal fluid dihydroxyphenylacetic acid 0.86 ± 0.09 (SEM), 1.00 ± 0.09, 1.32 ± 0.12 nmol/l than controls (2.15 ± 0.18 nmol/l; P < 0.0001; P < 0.0001; P = 0.0002). Dihydroxyphenylglycol was also lower in the three synucleinopathies (8.82 ± 0.44, 7.75 ± 0.42, 5.82 ± 0.65 nmol/l) than controls (11.0 ± 0.62 nmol/l; P = 0.009, P < 0.0001, P < 0.0001). Dihydroxyphenylacetic acid was lower and dihydroxyphenylglycol higher in Parkinson's disease than in pure autonomic failure. Dihydroxyphenylacetic acid was 100% sensitive at 89% specificity in separating patients with recent onset of parkinsonism from controls but was of no value in differentiating Parkinson's disease from multiple system atrophy. Synucleinopathies feature cerebrospinal fluid neurochemical evidence for central dopamine and norepinephrine deficiency. Parkinson's disease and pure autonomic failure involve differential dopaminergic versus noradrenergic lesions. Cerebrospinal fluid dihydroxyphenylacetic acid seems to provide a sensitive means to identify even early Parkinson's disease.
•Mode I and mode III fracture of plain and forta-ferro fiber reinforced concretes were studied using ENDB specimen.•Crack growth behavior of tested concrete was significantly dependent on the loading ...type and fiber content.•While KIc was greater than KIIIc for all tested concretes, the mode III fracture energy value was higher than mode I case.•Fiber reinforced concrete exhibited excellent post peak failure response under both modes I and III.
This paper investigates the mode I (i.e. tensile) and mode III (i.e. tearing) fracture behavior of concrete composites containing synthetic forta-ferro (SFF) fibers. By employing a simple and suitable test specimen called edge notched disc bend (ENDB) specimen, the effect of adding different percentages of SFF additive on fracture load, fracture toughness and work of fracture was studied experimentally under both pure mode I and pure mode III. A number of unique and useful experimental results were obtained in this research for crack growth resistance of plain and fiber reinforced composite concretes subjected to pure modes I and III loading conditions. It was observed that the fracture initiation and propagation stages are significantly affected by the SFF content. In comparison with the ordinary and plain cement concrete which is manufactured with no fiber additive, the SFF fiber reinforced concrete composite showed higher fracture toughness and work of fracture values. This demonstrates the improved performance of SFF fiber reinforced concretes against cracking under both tensile and tear loads. However, the fracture behavior of tested ENDB specimens made of concrete composites was dependent on the loading mode type (i.e. I or III) and also the SFF content. According to the experimental results the influence of SFF fibers on enhancing mode III fracture toughness was noticeably greater than the pure mode I case and for both loading modes the highest fracture toughness values (i.e. KIc and KIIIc) were obtained for those concrete composites containing 0.3% SFF. In addition, while the magnitude of KIc was greater than the corresponding value of KIIIc for all tested concrete composites, the fracture energy (or work of fracture) of mode III specimens were significantly higher than the mode I specimens. Indeed, the SFF fiber reinforced concrete composites exhibited excellent post peak failure response such that due to resistance of SFF fibers agains applied loads significant amount of energy was required for overall breakage of tested concretes. This ability can be considered as an advantage of SFF fiber reinforced concrete materials for designing earthquake-resistant structures.
We aimed to characterize in vivo α-synuclein (α-syn) aggregates in skin nerves to ascertain: 1) the optimal marker to identify them; 2) possible differences between synucleinopathies that may justify ...the clinical variability. We studied multiple skin nerve α-syn deposits in 44 patients with synucleinopathy: 15 idiopathic Parkinson's disease (IPD), 12 dementia with Lewy Bodies (DLB), 5 pure autonomic failure (PAF) and 12 multiple system atrophy (MSA). Ten healthy subjects were used as controls. Antibodies against native α-syn, C-terminal α-syn epitopes such as phosphorylation at serine 129 (p-syn) and to conformation-specific for α-syn mature amyloid fibrils (syn-F1) were used. We found that p-syn showed the highest sensitivity and specificity in disclosing skin α-syn deposits. In MSA abnormal deposits were only found in somatic fibers mainly at distal sites differently from PAF, IPD and DLB displaying α-syn deposits in autonomic fibers mainly at proximal sites. PAF and DLB showed the highest p-syn load with a widespread involvement of autonomic skin nerve fibers.
1) p-syn in skin nerves was the optimal marker for the in vivo diagnosis of synucleinopathies; 2) the localization and load differences of aggregates may help to identify specific diagnostic traits and support a different pathogenesis among synucleinopathies.
We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin ...antibodies.
In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions.
We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10x10(9) per liter before treatment to peak counts of greater than 100x10(9) per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period.
This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.).
α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous ...system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83
mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy.
Display omitted
•Direct Extraction of the Heteronuclear coupling with High abundant nuclei.•Magnitude of the coupling can be measure straightforward with separation within doublet.•Proposed method ...will helpful in understanding the structure and dynamics of modern organic chemistry.
Determination of dihedral angles from heteronuclear nJHX couplings (where n is 2, 3 or 4 and X stands for 31P, 19F, etc.) is very useful in structure elucidation. It is a challenging task to extract these couplings from 1D 1H NMR spectra due to the presence of a large number of nJHH and nJHX. Herein, we demonstrate the utility of two different pure shift NMR methods wherein 1H–1H multiplets are collapsed into singlets, revealing only nJHX in the spectrum. The benefit of DFT calculations for prediction of these couplings and congruence with their experimental counterparts is also demonstrated.
To report a case of pure red-cell aplasia secondary to pregnancy and to conduct a review of the literature regarding diagnosis and treatment, as well as maternal and perinatal prognosis.
This is the ...case of a 24-year-old patient at 34 weeks of gestation, referred to a regional public referral hospital due to anemia. Bone marrow biopsy was performed, leading to the diagnosis of pregnancy-related pure red-cell aplasia. The patient received serial red blood cell transfusions. Delivery by Cesarean section at term resulted in a healthy newborn. Hemoglobin values remained stable during the postoperative period. A literature search was conducted in Medline via PubMed, LILACS, SciELO and ScienceDirect using the terms "pregnancy" and "pure red-cell aplasia". Case reports, case series and literature reviews in English and Spanish published between January 1999 and January 2020 that report pregnant women with pure red-cell aplasia were included. Information on diagnosis, treatment and maternal and perinatal prognosis was collected. Three of the authors selected the studies by title and abstract; A descriptive synthesis is provided.
Overall, 828 titles were identified; of these,818 were discarded after reviewing the inclusions criteria. Ten articles were included: six case reports, three case reports with literature review, and one case report in the poster modality, for a total number of 10 reported cases. Diagnosis was based on low hemoglobin levels and compromised erythroid cell line in bone marrow biopsy. Treatment consists of red blood cell transfusions, with good maternal and fetal prognosis.
Diagnosis of pure red-cell aplasia during pregnancy requires bone marrow biopsy. With transfusion support, maternal perinatal prognosis is good. Further studies are required to assess the safety and efficacy of steroid use in this pregnancy-related condition.
PDF
