Pengaruh Kuat Arus Dan Waktu Pengelasan Pada Proses Las Titik (Spot Welding) Terhadap Kekuatan Tarik Dan Mikrostuktur Hasil Las Dari Baja Fasa Ganda (Feritte-Martensite)

This research was conducted to investigate the appropiate spot welding variable to get the maximum tensile strength. The highest of tensile strength referred as good quality of weldment.The plate was made from low carbon steel with phase ferrite and martensite. The current of welding used 0.9 kA, 1.6 kA, dan 1.85 kA with welding time were 0.25, 0.5 , 0.75 and 1 second. Mechanical properties testing done involved tensile strength to know shear strength of weld joint. Microstructure test used optical microscope.The results show that spot welding with thecurrent of 1.85kA and welding time of 1 second has the highest tensile strength (about 237.04N/mm2). On the other hand, the lowest tensile strength (150 N/mm2) was produced by combination of 0.9 kA and 0.25 second welding time. It was caused by recrystallization phasedeformation on steel

Population diversity of the genetically determined TTR expression in human tissues and its implications in TTR amyloidosis

BACKGROUND: Transthyretin (TTR) amyloidosis is a hereditary disease with a complex genotype-phenotype correlation. We conducted a literature survey to define the clinical landscape of TTR amyloidosis across populations worldwide. Then, we investigated whether the genetically determined TTR expression differs among human populations, contributing to the differences observed in patients. Polygenic scores for genetically determined TTR expression in 14 clinically relevant tissues were constructed using data from the GTEx (Genotype-Tissue Expression) project and tested in the samples from the 1,000 Genomes Project.RESULTS: We observed differences among the ancestral groups and, to a lesser extent, among the investigated populations within the ancestry groups. Scandinavian populations differed in their genetically determined TTR expression of skeletal muscle tissue with respect to Southern Europeans (p\u2009=\u20096.79*10-6). This is in line with epidemiological data related to Swedish and Portuguese TTR Val30Met endemic areas. Familial amyloidotic cardiomyopathy (TTR deposits occur primarily in heart tissues) presents clinical variability among human populations, a finding that agrees with the among-ancestry diversity of genetically determined TTR expression in heart tissues (i.e., Atrial Appendage p\u2009=\u20094.55*10-28; Left Ventricle p\u2009=\u20096.54*10-35).CONCLUSIONS: Genetically determined TTR expression varied across human populations. This might contribute to the genotype-phenotype correlation of TTR amyloidosis

Low Sensitivity of Bone Scintigraphy in Detecting Phe64Leu Mutation-Related Transthyretin Cardiac Amyloidosis

OBJECTIVES The aim of this study was to assess the diagnostic accuracy of bone scintigraphy in a large multicenter cohort of patients with cardiac amyloidotic involvement and Phe64Leu transthyretin (TTR) mutation. BACKGROUND Diagnostic accuracy of bone scintigraphy for transthyretin-related cardiac amyloidosis (TTR-CA) is considered extremely high, enabling this technique to be the noninvasive diagnostic standard for TTR-CA. Nevertheless, this approach has not been systematically validated across the entire spectrum of TTR mutations. METHODS A total of 55 patients with Phe64Leu TTR mutation were retrospectively analyzed and evaluated between 1993 and 2018 at 7 specialized Italian tertiary centers. Cardiac involvement was defined as presence of an end-diastolic interventricular septum thickness $12 mm, without other possible causes of left ventricular hypertrophy (i.e., arterial hypertension or valvulopathies). A technetium-99m (99mTc)-diphosphonate (DPD) or 99mTc-hydroxyl-methylenediphosphonate (HMDP) bone scintigraphy was reviewed, and visual scoring was evaluated according to Perugini's method. RESULTS Among 26 patients with definite cardiac involvement, 19 underwent 99mTc-DPD or 99mTc-HMDP bone scintigraphy. Of them, 17 (89.5%) patients had low or absent myocardial bone tracer uptake, whereas only 2 (10.5%) showed high-grade myocardial uptake. The sensitivity and the accuracy of bone scintigraphy in detecting TTR-CA were 10.5% and 37%, respectively. Patients with cardiac involvement and low or absent bone tracer uptake were similar to those with high-grade myocardial uptake in terms of age, sex, and electrocardiographic and echocardiographic findings. CONCLUSIONS The sensitivity of bone scintigraphy (DPD and HMDP) in detecting TTR-CA is extremely low in patients with Phe64Leu TTR mutation, suggesting the need to assess diagnostic accuracy of bone scintigraphy to identify cardiac involvement across a wider spectrum of TTR mutations. (c) 2020 by the American College of Cardiology Foundation

Real‐life experience with inotersen in hereditary transthyretin amyloidosis with late‐onset phenotype: data from an early‐access program in Italy

Background: Hereditary transthyretin amyloidosis (ATTRv) is a dominantly inherited, adult-onset, progressive and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene-silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After EMA approval in 2018, an early access program was opened in Italy, and in this article, we present the long-term outcome of a cohort of Italian ATTRv patients that received inotersen within this program. Methods: This is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early access program. The primary endpoint was safety. Secondary endpoints included change from baseline in FAP score, PND, NIS, CADT, Norfolk QoL-DN, troponin, NT-proBNP, IVS thickness, and BMI. Results: In total, twenty-three patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug-related hypotension, and amyloid-negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage only two patients worsened while the other 21 patients remained stable until the last follow-up available. Conclusions: The long-term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype-phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype-phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype-phenotype correlation of the disease