Founder effect of Fabry disease due to p.F113L mutation: Clinical profile of a late-onset phenotype.

BACKGROUND: Knowledge on clinical profiles of late-onset phenotypes of Fabry disease (FD) is essential to better define their natural history. Our study aims to demonstrate a founder effect of FD due to the GLA gene mutation c.337T>C (p.F113L) in the Portuguese region of Guimarães; and to characterize the clinical profile of this late-onset phenotype in a large cohort of genetically related adult patients, living in the same region. METHODS AND RESULTS: FD screening was performed in 150 adult patients with hypertrophic cardiomyopathy (HCM) and found 25 Fabry patients (16.6%). The p.F113L mutation was found in 21 of them, leading to a genealogy study and haplotype analysis of the p.F113L patients. Genealogy research revealed a 12-generation family tree with a common ancestor to p.F113L patients, suggesting a founder effect that was supported by haplotype findings. Pedigree analysis was performed and 120 consecutive p.F113L patients underwent a predefined diagnostic evaluation of FD multiorgan involvement. This late-onset phenotype was characterized by common and/or potentially severe cardiac manifestations (left ventricular hypertrophy 40.8%, atrial fibrillation 5%, non-sustained ventricular tachycardia 12.5%, atrioventricular block 18.3%, bifascicular block 13.4%). Extracardiac manifestations included albuminuria>30 mg/24 h 36.1%, chronic kidney disease≥G3 7.6%, brain white matter lesions 54.4%, stroke 3.3%, sensorineural deafness 44.5%, cornea verticillata 13.9%. Plasma lyso-GB3 was undetectable in females, regardless of clinical manifestations. CONCLUSION: A founder effect of FD due to p.F113L mutation was documented by genealogy and genetics in a Portuguese region. In this late-onset phenotype, although cardiac manifestations carry the highest prognostic impact, extracardiac involvement is common.

Joining of TiAl Alloy Using Novel Ag-Cu Sputtered Coated Ti Brazing Filler.

The aim of this study is to evaluate the potential use of titanium foil coated with sputtered silver and copper films as a novel brazing filler for joining TiAl alloys. For this purpose, a detailed microstructural characterization of the resulting brazing interfaces was carried out. The development of brazing fillers that allow the joining of TiAl alloys without compromising the service temperature is a fruitful prospect. Brazing experiments were performed in a vacuum at 900, 950, and 980°C, with a dwell time of 30 min. Microstructural characterization reveals that brazing joints can be obtained successfully at 950 and 980°C. The interface consists of a large central region of α-Ti with an amount of Al and Ti-Ag compound and thin layers, mainly composed of intermetallic compounds, formed close to the base material. A novel brazing filler consisting of Ti foil coated with sputtered Ag and Cu films inhibits the extensive formation of soft (Ag) zones or coarse brittle Ti-Al-(Cu,Ni) particles. Hence, the need for post-brazing heat treatments for the joining of TiAl alloys was avoided.

Microstructural Characterization of Carbon Nanotubes (CNTs)-Reinforced Nickel Matrix Nanocomposites.

This research focuses on the microstructural characterization of nickel matrix composites reinforced by carbon nanotubes (CNTs). The nanocomposites were produced by a conventional powder metallurgy process and the dispersion of CNTs and mixture with nickel powders was performed in a single step by ultrasonication. Microstructural characterization of Ni-CNT nanocomposites was performed by scanning and transmission electron microscopy, electron backscattered diffraction, high-resolution transmission electron microscopy, selected area electron diffraction, and fast Fourier transform analyses. This characterization revealed CNTs embedded in the nickel grains and mainly presented as clusters at the grain boundaries. CNTs hinder recrystallization during sintering, and dislocation cells and subgrains form as a result of the recovery process.

Microstructural Characterization of Aluminum-Carbon Nanotube Nanocomposites Produced Using Different Dispersion Methods.

This research focuses on characterization of the impact of dispersion methods on aluminum-carbon nanotubes (Al-CNTs) nanocomposite structure. Nanocomposites were produced by a conventional powder metallurgy process after the dispersion of the CNTs on the Al powders, using two approaches: (1) the dispersion of CNTs and mixture with Al powders were performed in a single step by ultrasonication; and (2) the CNTs were previously untangled by ultrasonication and then mixed with Al powders by ball milling. Microstructural characterization of Al-CNT nanocomposites was performed by optical microscopy, scanning and transmission electron microscopy, electron backscatter diffraction, and high-resolution transmission electron microscopy (HRTEM). Microstructural characterization revealed that the use of ball milling for mixing CNTs with Al powders promoted the formation of CNT clusters of reduced size, more uniformly dispersed in the matrix, and a nanocomposite of smaller grain size. However, the results of HRTEM and Raman spectroscopy show that ball milling causes higher damage to the CNT structure. The strengthening effect of the CNT is attested by the increase in hardness and tensile strength of the nanocomposites.

TEM and HRTEM characterization of TiAl diffusion bonds using Ni/Al nanolayers.

Diffusion bonding of TiAl alloys can be enhanced by the use of reactive nanolayer thin films as interlayers. Using these interlayers, it is possible to reduce the conventional bonding conditions (temperature, time, and pressure) and obtain sound and reliable joints. The microstructural characterization of the diffusion bond interfaces is a fundamental step toward understanding and identifying the bonding mechanisms and relating them to the strength of the joints. The interface of TiAl samples joined using Ni/Al nanolayers was characterized by transmission electron microscopy and scanning transmission electron microscopy. Microstructural characterization of the bond revealed that the interfaces consist of several thin layers of different composition and grain size (nanometric and micrometric). The bonding temperature (800, 900, or 1,000°C) determines the grain size and thickness of the layers present at the interface. Phase identification by high-resolution transmission electron microscopy combined with fast Fourier transform and electron energy-loss spectroscopy analyses reveals the presence of several intermetallic compounds: AlTiNi, NiAl, and Al2TiNi. For bonds produced at 800 and 900°C, nanometric grains of Ti were detected at the center of the interface.

Microstructural Characterization of Al/CNTs Nanocomposites after Cold Rolling.

The deformation behaviour of aluminium reinforced by carbon nanotubes (Al/CNTs) nanocomposites during cold rolling was investigated in this work. Deformation processes after production by conventional powder metallurgy routes may be an efficient approach to improve the microstructure and mechanical properties by decreasing the porosity. Metal matrix nanocomposites have enormous potential to produce advanced components, mainly in the mobility industry, with powder metallurgy being one of the most reported production processes. For this reason, it is increasingly important to study the deformation behaviour of nanocomposites. In this context, nanocomposites were produced via powder metallurgy. Advanced characterization techniques carried out the microstructural characterization of the as-received powders and produced nanocomposites. The microstructural characterization of the as-received powders and produced nanocomposites was carried out through optical microscopy (OM), and scanning and transmission electron microscopy (SEM and TEM), complemented by electron backscattered diffraction (EBSD). The powder metallurgy route followed by cold rolling is reliable for Al/CNTs nanocomposites. The microstructural characterization shows that the nanocomposites exhibit a different crystallographic orientation than the Al matrix. CNTs in the matrix influence grain rotation during sintering and deformation. Mechanical characterization revealed that during deformation, there is an initial decrease in the hardness and tensile strength for the Al/CNTs and Al matrix. The initial decrease was attributed to the Bauschinger effect being more significant for the nanocomposites. The difference in the mechanical properties of the nanocomposites and Al matrix was attributed to distinct texture evolution during cold rolling.

Clozapine-Induced Eosinophilia: a Case Report.

INTRODUCTION: Clozapine is an atypical antipsychotic drug eligible for treatment-resistant schizophrenia. It frequently represents the best and the only choice in resistant schizophrenia. However, its use is feared by many professionals due to its possible adverse effects, such as eosinophilia. CASE REPORT: We report a case of a young white male suffering from treatment-resistant schizophrenia who rapidly developed eosinophilia after starting clozapine. DISCUSSION: We present a case of a 26-year-old white man diagnosed with schizophrenia with poor clinical response to several antipsychotics owing to which clozapine was started. Psychotic symptoms improved dramatically but a progressively ascendant eosinophilia was reported during serial haematological analyses. The patient remained physically asymptomatic. An exhaustive assessment with ancillary diagnostic tests revealed no cause for eosinophilia. Thus, a diagnosis of clozapine-induced eosinophilia was made. The drug was discontinued and eosinophil count progressively returned to normal but psychotic symptoms worsened. CONCLUSIONS: Clozapine treatment is frequently feared due to its possible side effects and complications, delaying its use in refractory schizophrenia. Also, to our knowledge, there are no specific guidelines on how to manage haematological side effects such as eosinophilia. This is problematic as, in some cases, it may lead to an unnecessary withdrawal of clozapine with a worsening of psychotic symptoms. We present a brief discussion of the recent literature on the subject.

A patient with foot ulcer and severe metabolic alkalosis.

We report a case of triple acid-base disorder with metabolic alkalosis as the primary disorder in a 65-year-old man due to ingestion and application to leg ulcers of baking soda (calcium bicarbonate). The blood pH was 7.65 with hypochloremia, hypokalemia, and prerenal azotemia. He was treated with isotonic saline with K replacement, and the patient improved without any adverse clinical consequences. We discuss the causes, mechanisms, and management of Cl-responsive (depletion) metabolic alkalosis.

Joining of Ti6Al4V to Al2O3 Using Nanomultilayers.

Diffusion bonding of Ti6Al4V to Al2O3 using Ni/Ti reactive nanomultilayers as interlayer material was investigated. For this purpose, Ni/Ti multilayer thin films with 12, 25, and 60 nm modulation periods (bilayer thickness) were deposited by d.c. magnetron sputtering onto the base materials' surface. The joints were processed at 750 and 800 °C with a dwell time of 60 min and under a pressure of 5 MPa. Microstructural characterization of the interfaces was conducted by scanning electron microscopy (SEM) with energy-dispersive X-ray spectroscopy (EDS), and electron backscatter diffraction (EBSD). The mechanical characterization of the joints was performed by nanoindentation, and hardness and reduced Young's modulus distribution maps were obtained across the interfaces. The joints processed at 800 °C using the three modulation periods were successful, showing the feasibility of using these nanolayered films to improve the diffusion bonding of dissimilar materials. Using modulation periods of 25 and 60 nm, it was also possible to reduce the bonding temperature to 750 °C and obtain a sound interface. The interfaces are mainly composed of NiTi and NiTi2 phases. The nanoindentation experiments revealed that the hardness and reduced Young's modulus at the interfaces reflect the observed microstructure.

Heat-Treated Ni-CNT Nanocomposites Produced by Powder Metallurgy Route.

Nickel nanocomposites reinforced by carbon nanotubes (Ni-CNTs) are one of the possible candidates for applications in highly demanding industries such as the automotive and aerospace industries. As is well known, one of the limitations on the use of some materials in these applications is thermal stability. Some components in these industries are frequently subjected to high temperatures, which is crucial to understanding their microstructures and, consequently, their mechanical properties. For this reason, the main objective of this research is to understand the microstructural evolution of Ni-CNTs nanocomposites when subjected to heat treatment. The nanocomposites with varying levels of CNT content were produced by powder metallurgy, and unreinforced nickel was used for comparison purposes under the same conditions. The dispersion of CNTs, a critical aspect of nanocomposites production, was carried out by ultrasonication, which already proved its efficiency in previous research. The heat treatments were performed under high vacuum conditions at high temperatures (700 and 1100 °C for 30 and 120 min, respectively). Microhardness tests analyzed the mechanical properties while the extensive microstructural evaluation was conducted by combining advanced characterization techniques such as scanning electron microscopy (SEM) with electron backscatter diffraction (EBSD), transmission electron microscopy (TEM), and high-resolution TEM. The obtained results are promising and show that the presence of CNTs can contribute to the thermal stability of the Ni-CNT nanocomposites produced.

Investigation on the Strengthening Mechanisms of Nickel Matrix Nanocomposites.

The strengthening effect of carbon nanotubes (CNTs) in metal matrix nanocomposites occurs due to several mechanisms that act simultaneously. The possible strengthening mechanisms for metal matrix nanocomposites reinforced with CNTs consist of: (1) load transfer, (2) grain refinement and texture strengthening, (3) second phase strengthening, and (4) strain hardening. The main focus of this work is to identify the strengthening mechanisms that play a role in the case of the Ni-CNT nanocomposite produced by powder metallurgy. For the dispersion and mixing of the metallic powders with CNTs, two different routes were performed by ultrasonication and ball milling. The results indicated that four different strengthening mechanisms are present in the nanocomposites and had a different contribution to the final mechanical properties. The load transfer and the increase in dislocation density seem to strongly affect the properties and microstructure of the nanocomposite. The grain refinement and the presence of second phase particles have a small contribution in the strengthening of this nanocomposite, since the introduction of CNTs in the Ni matrix slightly affects the size and orientation of the grains in the matrix and a few nanometric particles of Ni3C were identified.

Clozapine-Induced Eosinophilia: a Case Report.

INTRODUCTION: Clozapine is an atypical antipsychotic drug eligible for treatment-resistant schizophrenia. It frequently represents the best and the only choice in resistant schizophrenia. However, its use is feared by many professionals due to its possible adverse effects, such as eosinophilia. CASE REPORT: We report a case of a young white male suffering from treatment-resistant schizophrenia who rapidly developed eosinophilia after starting clozapine. DISCUSSION: We present a case of a 26-year-old white man diagnosed with schizophrenia with poor clinical response to several antipsychotics owing to which clozapine was started. Psychotic symptoms improved dramatically but a progressively ascendant eosinophilia was reported during serial haematological analyses. The patient remained physically asymptomatic. An exhaustive assessment with ancillary diagnostic tests revealed no cause for eosinophilia. Thus, a diagnosis of clozapine-induced eosinophilia was made. The drug was discontinued and eosinophil count progressively returned to normal but psychotic symptoms worsened. CONCLUSIONS: Clozapine treatment is frequently feared due to its possible side effects and complications, delaying its use in refractory schizophrenia. Also, to our knowledge, there are no specific guidelines on how to manage haematological side effects such as eosinophilia. This is problematic as, in some cases, it may lead to an unnecessary withdrawal of clozapine with a worsening of psychotic symptoms. We present a brief discussion of the recent literature on the subject.

Seedless Cu Electroplating on Co-W Thin Films in Low pH Electrolyte: Early Stages of Formation.

The use of Ta/TaN barrier bilayer systems in electronic applications has been ubiquitous over the last decade. Alternative materials such as Co-W or Ru-W alloys have gathered interest as possible replacements due to their conjugation of favourable electrical properties and barrier layer efficiency at reduced thicknesses while enabling seedless Cu electroplating. The microstructure, morphology, and electrical properties of Cu films directly electrodeposited onto Co-W or Ru-W are important to assess, concomitant with their ability to withstand the electroplating baths/conditions. This work investigates the effects of the current application method and pH value of the electroplating solution on the electrocrystallisation behaviour of Cu deposited onto a Co-W barrier layer. The film structure, morphology, and chemical composition were studied by X-ray diffraction, scanning electron microscopy and atomic force microscopy, as well as photoelectron spectroscopy. The results show that the electrolyte solution at pH 1.8 is incapable of creating a compact Cu film over the Co-W layer in either pulsed or direct-current modes. At higher pH, a continuous film is formed. A mechanism is proposed for the nucleation and growth of Cu on Co-W, where a balance between Cu nucleation, growth, and preferential Co dissolution dictates the substrate area coverage and compactness of the electrodeposited films.

Effect of Morphology and Structure of MWCNTs on Metal Matrix Nanocomposites.

The effect of using different carbon nanotubes (CNTs) on the production of nanocomposites was evaluated in this work. The investigated CNTs were multi-walled carbon nanotubes (MWCNTs) with different morphologies and structures. The main objective was to relate the results reported by numerical simulation with the results obtained experimentally in order to validate these methodologies. A detailed characterization of CNTs was carried out to establish the different main characteristics, such as inner and outer diameters, defects, structure and the number of walls. Metal matrix nanocomposites were produced using the powder metallurgy route. The experimental results show that the morphology and structure of MWCNTs have a significant effect on the dispersion process for nanocomposite production. Straight CNTs with a larger diameter and with few defects allow for the production of nanocomposites with uniform dispersion and strong interface bonding, leading to a higher hardness value. In addition, the CNT introduction into a metal matrix induces a change in the deformation behavior that plays an important role in the strengthening mechanisms. Although some aspects are not considered in the molecular dynamic (MD) simulation, such as the CNT random orientation and CNT agglomeration, some comparative relationships can be performed in order to validate some methodologies. While the structure and morphology of the CNTs have a significant influence on the dispersion process, the influence of the diameter and the functionalization treatment on the properties of the nanocomposites is also identified. The experimental results show that the decrease in the diameter of the CNTs and the use of functionalized CNTs also contribute to the obtention of lower mechanical properties of the nanocomposites, as is pointed out in the results of MD carried out in nanocomposites.

Joining Alumina to Titanium Alloys Using Ag-Cu Sputter-Coated Ti Brazing Filler.

The joining of alumina (Al2O3) to γ-TiAl and Ti6Al4V alloys, using Ag-Cu sputter-coated Ti brazing filler foil, was investigated. Brazing experiments were performed at 980 °C for 30 min in vacuum. The microstructure and chemical composition of the brazed interfaces were analyzed by scanning electron microscopy and by energy dispersive X-ray spectroscopy, respectively. A microstructural characterization of joints revealed that sound multilayered interfaces were produced using this novel brazing filler. Both interfaces are composed mainly of α-Ti, along with Ti2(Ag,Cu) and TiAg intermetallics. In the case of the brazing of γ-TiAl alloys, α2-Ti3Al and γ-TiAl intermetallics are also detected at the interface. Bonding to Al2O3 is promoted by the formation of a quite hard Ti-rich layer, which may reach a hardness up to 1872 HV 0.01 and is possibly composed of a mixture of α-Ti and Ti oxides. Hardness distribution maps indicate that no segregation of either soft or brittle phases occurs at the central regions of the interfaces or near the base Ti alloys. In addition, a smooth hardness transition was established between the interface of Al2O3 to either γ-TiAl or Ti6Al4V alloys.

Natural history of the late-onset phenotype of Fabry disease due to the p.F113L mutation.

BACKGROUND: The common GLA gene mutation p.F113L causes late-onset phenotype of Fabry disease (FD) with predominant cardiac manifestations. A founder effect of FD due to this mutation was found in the Portuguese region of Guimarães. Our study aims to deepen the knowledge on the natural history of this late-onset variant. METHODS: 203 consecutive adult Fabry patients with p.F113L mutation (79 males; mean age 46 ± 18 years), from this region, were submitted at baseline to a predefined diagnostic protocol. The occurrence of FD manifestations was analyzed in each decade of age in both genders. RESULTS: In males, left ventricular hypertrophy (40.2%) and late gadolinium enhancement (21.4%) arose over 30 years; heart failure (HF) (21.9%), ventricular tachycardia (8.9%) and conduction disorders over 40 years; and bifascicular (13.1%) and complete atrioventricular blocks (5.9%) beyond 50 years of age. Cardiac manifestations occurred more commonly and 1-2 decades earlier in males; their frequency increased with age. Septum and posterior wall thickness, LV mass, QRS interval duration and pro-BNP levels increased with age in both genders. Mean survival free from HF (64 ± 1 vs. 76 ± 2 years) and pacemaker (71 ± 2 vs. 86 ± 1 years) was higher in females (p < .001). Albuminuria A2/A3 (33.7%), brain white matter lesions (50.3%) and sensorineural deafness (44.7%) arose before 30 years of age in both genders, increasing with age. Renal failure and stroke were rare. Lysosomal inclusions were demonstrated in podocytes of patients with proteinuria. CONCLUSION: This study improves the knowledge on natural history of late-onset variants of FD, carrying major impact on clinical decisions and guidelines.

EBSD Analysis of Metal Matrix Nanocomposite Microstructure Produced by Powder Metallurgy.

The development of metal nanocomposites reinforced by carbon nanotubes (CNTs) remains a focus of the scientific community due to the growing need to produce lightweight advanced materials with unique mechanical properties. However, for the successful production of these nanocomposites, there is a need to consolidate knowledge about how reinforcement influences the matrix microstructure and which are the strengthening mechanisms promoting the best properties. In this context, this investigation focuses on the study of the reinforcement effect on the microstructure of an Ni-CNT nanocomposites produced by powder metallurgy. The microstructural evolution was analysed by electron backscattered diffraction (EBSD). The EBSD results revealed that the dispersion/mixing and pressing processes induce plastic deformation in the as-received powders. The dislocation structures produced in those initial steps are partially eliminated in the sintering process due to the activation of recovery and recrystallization mechanisms. However, the presence of CNTs in the matrix has a significant effect on the dislocation annihilation, thus reducing the recovery of the dislocation structures.

Clozapine-Induced Eosinophilia: a Case Report

Introduction: Clozapine is an atypical antipsychotic drug eligible for treatment-resistant schizophrenia. It frequently represents the best and the only choice in resistant schizophrenia. However, its use is feared by many professionals due to its possible adverse effects, such as eosinophilia. Case report: We report a case of a young white male suffering from treatment-resistant schizophrenia who rapidly developed eosinophilia after starting clozapine. Discussion: We present a case of a 26-year-old white man diagnosed with schizophrenia with poor clinical response to several antipsychotics owing to which clozapine was started. Psychotic symptoms improved dramatically but a progressively ascendant eosinophilia was reported during serial haematological analyses. The patient remained physically asymptomatic. An exhaustive assessment with ancillary diagnostic tests revealed no cause for eosinophilia. Thus, a diagnosis of clozapine-induced eosinophilia was made. The drug was discontinued and eosinophil count progressively returned to normal but psychotic symptoms worsened. Conclusions: Clozapine treatment is frequently feared due to its possible side effects and complications, delaying its use in refractory schizophrenia. Also, to our knowledge, there are no specific guidelines on how to manage haematological side effects such as eosinophilia. This is problematic as, in some cases, it may lead to an unnecessary withdrawal of clozapine with a worsening of psychotic symptoms. We present a brief discussion of the recent literature on the subject.

Introducción: La clozapina es un fármaco antipsicótico atípico eligible para la esquizofrenia resistente al tratamiento. Con frecuencia representa la mejor y la única opción para la esquizofrenia resistente. Sin embargo, muchos profesionales temen utilizarla por sus posibles efectos adversos, como la eosinofilia. Reporte de caso: Se expone el caso de un joven blanco que sufre esquizofrenia resistente al tratamiento y desarrolló eosinofilia rápidamente tras comenzar el tratamiento con clozapina. Discusión: Varón de 26 años con diagnóstico de esquizofrenia y mala respuesta clínica a varios antipsicóticos, por lo que se inició clozapina. Los síntomas psicóticos mejoraron drásticamente, pero los análisis hematológicos seriados informaron una eosinofilia en ascenso progresivo. El paciente permaneció físicamente asintomático. Una evaluación exhaustiva con pruebas de diagnóstico complementarias no reveló ninguna causa de eosinofilia. Por lo tanto, se diagnosticó eosinofilia inducida por clozapina. Se suspendió el fármaco, el recuento de eosinófilos volvió progresivamente a la normalidad, pero los síntomas psicóticos empeoraron. Conclusiones: A menudo se teme tratar con clozapina por sus posibles efectos secundarios y sus complicaciones, lo cual retrasa su uso en la esquizofrenia refractaria. Además, hasta donde sabemos, no existen pautas específicas sobre cómo tratar los efectos secundarios hematológicos como la eosinofilia. Esto es problemático porque, en algunos casos, puede conducir a suspender innecesariamente la clozapina y que empeoren los síntomas psicóticos. Se presenta una breve discusión de la literatura reciente sobre el tema.