Preliminary evidence of high prevalence of cerebral microbleeds in astronauts with spaceflight experience.

Long-duration spaceflight poses a variety of health risks to astronauts, largely resulting from extended exposure to microgravity and radiation. Here, we assessed the prevalence and incidence of cerebral microbleeds in sixteen astronauts before and after a typical 6-month mission on board the International Space Station Cerebral microbleeds are microhemorrhages in the brain, which are typically interpreted as early evidence of small vessel disease and have been associated with cognitive impairment. We identified evidence of higher-than-expected microbleed prevalence in astronauts with prior spaceflight experience. However, we did not identify a statistically significant increase in microbleed burden up to 7 months after spaceflight. Altogether, these preliminary findings suggest that spaceflight exposure may increase microbleed burden, but this influence may be indirect or occur over time courses that exceed 1 year. For health monitoring purposes, it may be valuable to acquire neuroimaging data that are able to detect the occurrence of microbleeds in astronauts following their spaceflight missions.

Treatment intensification in Kawasaki disease - current perspectives.

INTRODUCTION: Intravenous immunoglobulin is the standard of care in Kawasaki disease. However, a subset of patients exhibits resistance to intravenous immunoglobulin treatment, even when Kawasaki disease is promptly diagnosed and managed. While intravenous immunoglobulin reduces the occurrence of coronary artery abnormalities from 15-25% to 3-5%, it does not entirely eliminate the risk. Besides, management guidelines for non-coronary complications of Kawasaki disease, for instance, myocarditis, remain speculative. AREAS COVERED: Recent literature suggests that a subset of patients with Kawasaki disease may benefit from treatment intensification with drugs, such as corticosteroids, infliximab, anakinra, and/or ciclosporin. In this manuscript, we have reviewed recent advances in the management of Kawasaki disease, especially with regard to preemptive intensification of therapy in children at high risk of cardiac complications. A comprehensive search was made using Web of Science, Scopus, and PubMed databases to gather English articles published from 1967 to 2023 on the treatment of Kawasaki disease. We incorporated the following words in the search strategy: 'Kawasaki disease,' 'intravenous immunoglobulin/IVIg,' 'intravenous immunoglobulin/IVIg-resistant Kawasaki disease,' 'treatment intensification,' or 'primary intensification of treatment/therapy.' EXPERT OPINION: The 'high-risk' group in Kawasaki disease needs to be identified with early intensification of primary therapy for better coronary and myocardial outcomes.

Takes Two to Tangle: A Rare Case of Type IV Dual Left Anterior Descending Artery (LAD) and Dual Ostia of the LAD and Left Circumflex (LCx) Artery.

The dual left anterior descending (LAD) artery is a rare anatomic variant of the LAD artery that refers to the duplication of the LAD into a short and long LAD. These two vessels, differentiated based on their lengths, ultimately provide blood supply to the areas normally covered by the LAD. In this case report, we describe an unusual case of a type IV dual LAD system with an additional finding of a separate origin for the short LAD and left circumflex (LCx) artery. These two findings have not been reported together in the literature previously. During diagnostic procedures like coronary angiography or when interpreting cardiac imaging, awareness of these anomalies prevents confusion with pathological conditions such as coronary artery disease or stenosis. Additionally, it is crucial for cardiologists and surgeons to identify these aberrant vessels to avoid any wrongful interventions.

Microstructural white matter damage on MRI is associated with disease severity in Dutch-type cerebral amyloid angiopathy.

Peak width of skeletonized mean diffusivity (PSMD) is an emerging diffusion-MRI based marker to study subtle early alterations to white matter microstructure. We assessed PSMD over the clinical continuum in Dutch-type hereditary CAA (D-CAA) and its association with other CAA-related MRI-markers and cognitive symptoms. We included (pre)symptomatic D-CAA mutation-carriers and calculated PSMD from diffusion-MRI data. Associations between PSMD-levels, cognitive performance and CAA-related MRI-markers were assessed with linear regression models. We included 59 participants (25/34 presymptomatic/symptomatic; mean age 39/58 y). PSMD-levels increased with disease severity and were higher in symptomatic D-CAA mutation-carriers (median [range] 4.90 [2.77-9.50]mm2/s × 10-4) compared with presymptomatic mutation-carriers (2.62 [1.96-3.43]mm2/s × 10-4) p = <0.001. PSMD was positively correlated with age, CAA-SVD burden on MRI (adj.B [confidence interval] = 0.42 [0.16-0.67], p = 0.002), with number of cerebral microbleeds (adj.B = 0.30 [0.08-0.53], p = 0.009), and with both deep (adj.B = 0.46 [0.22-0.69], p = <0.001) and periventricular (adj.B = 0.38 [0.13-0.62], p = 0.004) white matter hyperintensities. Increasing PSMD was associated with decreasing Trail Making Test (TMT)-A performance (B = -0.42 [-0.69-0.14], p = 0.04. In D-CAA mutation-carriers microstructural white matter damage is associated with disease phase, CAA burden on MRI and cognitive impairment as reflected by a decrease in information processing speed. PSMD, as a global measure of alterations to the white matter microstructure, may be a useful tool to monitor disease progression in CAA.

Lecanemab demonstrates highly selective binding to Aß protofibrils isolated from Alzheimer's disease brains.

Recent advances in immunotherapeutic approaches to the treatment of Alzheimer's disease (AD) have increased the importance of understanding the exact binding preference of each amyloid-beta (Aß) antibody employed, since this determines both efficacy and risk for potentially serious adverse events known as amyloid-related imaging abnormalities. Lecanemab is a humanized IgG1 antibody that was developed to target the soluble Aß protofibril conformation. The present study prepared extracts of post mortem brain samples from AD patients and non-demented elderly controls, characterized the forms of Aß present, and investigated their interactions with lecanemab. Brain tissue samples were homogenized and extracted using tris-buffered saline. Aß levels and aggregation states in soluble and insoluble extracts, and in fractions prepared using size-exclusion chromatography or density gradient ultracentrifugation, were analyzed using combinations of immunoassay, immunoprecipitation (IP), and mass spectrometry. Lecanemab immunohistochemistry was also conducted in temporal cortex. The majority of temporal cortex Aß (98 %) was in the insoluble extract. Aß42 was the most abundant form present, particularly in AD subjects, and most soluble Aß42 was in soluble aggregated protofibrillar structures. Aß protofibril levels were much higher in AD subjects than in controls. Protofibrils captured by lecanemab-IP contained high levels of Aß42 and lecanemab bound to large, medium, and small Aß42 protofibrils in a concentration-dependent manner. Competitive IP showed that neither Aß40 monomers nor Aß40-enriched fibrils isolated from cerebral amyloid angiopathy reduced lecanemab's binding to Aß42 protofibrils. Immunohistochemistry showed that lecanemab bound readily to Aß plaques (diffuse and compact) and to intraneuronal Aß in AD temporal cortex. Taken together, these findings indicate that while lecanemab binds to Aß plaques, it preferentially targets soluble aggregated Aß protofibrils. These are largely composed of Aß42, and lecanemab binds less readily to the Aß40-enriched fibrils found in the cerebral vasculature. This is a promising binding profile because Aß42 protofibrils represent a key therapeutic target in AD, while a lack of binding to monomeric Aß and cerebral amyloid deposits should reduce peripheral antibody sequestration and minimize risk for adverse events.

The Role of Aging in Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is the cerebrovascular disease with the highest disability and mortality rates, causing severe damage to the health of patients and imposing a significant socioeconomic burden. Aging stands as a foremost risk factor for ICH, with a significant escalation in ICH incidence within the elderly demographic, highlighting a close association between ICH and aging. In recent years, with the acceleration of the "aging society" trend, exploring the intricate relationship between aging and ICH has become increasingly urgent and worthy of in-depth attention. We have summarized the characteristics of ICH in the elderly, reviewing how aging influences the onset and development of ICH by examining its etiology and the mechanisms of damage via ICH. Additionally, we explored the potential impacts of ICH on accelerated aging, including its effects on cognitive abilities, quality of life, and lifespan. This review aims to reveal the connection between aging and ICH, providing new ideas and insights for future ICH research.

Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease.

An expanded CAG repeat in the huntingtin gene (HTT) causes Huntington's disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and guide RNAs (gRNAs) efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without altering HTT mRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased in the liver by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion strategies in HD and potentially other repeat expansion disorders.

Case Report and Literature Review of an Anomalous Course of the Left Main Coronary Artery (LMCA) Arising From the Right Sinus of Valsalva (RSV) Presenting as Takotsubo Cardiomyopathy.

Takotsubo cardiomyopathy (TC) mimics myocardial infarction with symptoms like chest pain, electrocardiogram (EKG) changes, and elevated troponin levels, although it typically features normal coronary arteries upon angiography. While often asymptomatic, coronary artery anomalies (CAAs) can cause intermittent vasospasm and endothelial dysfunction, potentially inducing TC. We report the case of a 74-year-old female with a history of hypertension, hyperlipidemia, and peripheral artery disease, who presented with sudden onset chest pain. Initial EKG and elevated troponin suggested myocardial infarction. However, coronary angiography revealed an anomalous left main coronary artery (LMCA) originating from the right coronary artery (RCA), with no significant stenosis. Subsequent transthoracic echocardiography indicated TC, with the left ventricular ejection fraction improving from 35-40% to 60-65% within days. Cardiac computed tomography angiography (CCTA) revealed that the anomalous LMCA originated from the common trunk at the right sinus of Valsalva (RSV), which further continued as a large, dominant RCA. The LMCA branched into a small to moderate left anterior descending artery (LAD) and a non-dominant left circumflex artery (LCx). The LMCA followed a prepulmonic/anterior course, while the LCx took an interarterial course between the aorta and pulmonary artery. The patient was referred for further surgical evaluation. We conclude that the CAA was an incidental finding and was not related to underlying TC. Although rare, this case suggests a possible correlation between CAAs and a predisposition to stress-induced cardiomyopathy, warranting further investigation.

Cerebral amyloid angiopathy and the immune system.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of amyloid protein in the walls of cerebral blood vessels. This deposition of amyloid causes damage to the cerebral vasculature, resulting in blood-brain barrier disruption, cerebral hemorrhage, cognitive decline, and dementia. The role of the immune system in CAA is complex and not fully understood. While the immune system has a clear role in the rare inflammatory variants of CAA (CAA related inflammation and Abeta related angiitis), the more common variants of CAA also have immune system involvement. In a protective role, immune cells may facilitate the clearance of beta-amyloid from the cerebral vasculature. The immune system can also contribute to CAA pathology, promoting vascular injury, blood-brain barrier breakdown, inflammation, and progression of CAA. In this review, we summarize the role of the immune system in CAA, including the potential of immune based treatment strategies to slow vascular disease in CAA and associated cognitive impairment, white matter disease progression, and reduce the risk of cerebral hemorrhage. HIGHLIGHTS: The immune system has a role in cerebral amyloid angiopathy (CAA) which is summarized in this review. There is an inflammatory response to beta-amyloid that may contribute to brain injury and cognitive impairment. Immune cells may facilitate the clearance of beta-amyloid from the cerebral vasculature. Improved understanding of the immune system in CAA may afford novel treatment to improve outcomes in patients with CAA.

Coronary Artery Aneurysms and Acute Coronary Syndrome: An Interventionalist's Dilemma.

We report three cases of coronary artery aneurysm (CAA) in adults who presented with acute coronary syndrome. Two of these patients did not have traditional coronary artery disease risk factors. Management of CAA poses a significant challenge to interventionalists. We discuss the etiologic mechanisms, risk factors, pathophysiology, and diagnosis using angiography, intravascular ultrasound, and coronary computed tomography. We also highlight management options, including medical therapy and catheter-based interventions such as stenting, coil embolization, stent-assisted coil embolization, and surgical exclusion.

High-Throughput Genomics Identify Novel FBN1/2 Variants in Severe Neonatal Marfan Syndrome and Congenital Heart Defects.

Fibrillin-1 and fibrillin-2, encoded by FBN1 and FBN2, respectively, play significant roles in elastic fiber assembly, with pathogenic variants causing a diverse group of connective tissue disorders such as Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCD). Different genomic variations may lead to heterogeneous phenotypic features and functional consequences. Recent high-throughput sequencing modalities have allowed detection of novel variants that may guide the care for patients and inform the genetic counseling for their families. We performed clinical phenotyping for two newborn infants with complex congenital heart defects. For genetic investigations, we employed next-generation sequencing strategies including whole-genome Single-Nucleotide Polymorphism (SNP) microarray for infant A with valvular insufficiency, aortic sinus dilatation, hydronephrosis, and dysmorphic features, and Trio whole-exome sequencing (WES) for infant B with dextro-transposition of the great arteries (D-TGA) and both parents. Infant A is a term male with neonatal marfanoid features, left-sided hydronephrosis, and complex congenital heart defects including tricuspid regurgitation, aortic sinus dilatation, patent foramen ovale, patent ductus arteriosus, mitral regurgitation, tricuspid regurgitation, aortic regurgitation, and pulmonary sinus dilatation. He developed severe persistent pulmonary hypertension and worsening acute hypercapnic hypoxemic respiratory failure, and subsequently expired on day of life (DOL) 10 after compassionate extubation. Cytogenomic whole-genome SNP microarray analysis revealed a deletion within the FBN1 gene spanning exons 7-30, which overlapped with the exon deletion hotspot region associated with neonatal Marfan syndrome. Infant B is a term male prenatally diagnosed with isolated D-TGA. He required balloon atrial septostomy on DOL 0 and subsequent atrial switch operation, atrial septal defect repair, and patent ductus arteriosus ligation on DOL 5. Trio-WES revealed compound heterozygous c.518C>T and c.8230T>G variants in the FBN2 gene. Zygosity analysis confirmed each of the variants was inherited from one of the parents who were healthy heterozygous carriers. Since his cardiac repair at birth, he has been growing and developing well without any further hospitalization. Our study highlights novel FBN1/FBN2 variants and signifies the phenotype-genotype association in two infants affected with complex congenital heart defects with and without dysmorphic features. These findings speak to the importance of next-generation high-throughput genomics for novel variant detection and the phenotypic variability associated with FBN1/FBN2 variants, particularly in the neonatal period, which may significantly impact clinical care and family counseling.

Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities.

Therapeutic antibodies have been developed to target amyloid-beta (Aß), and some of these slow the progression of Alzheimer's disease (AD). However, they can also cause adverse events known as amyloid-related imaging abnormalities with edema (ARIA-E). We investigated therapeutic Aß antibody binding to cerebral amyloid angiopathy (CAA) fibrils isolated from human leptomeningeal tissue to study whether this related to the ARIA-E frequencies previously reported by clinical trials. The binding of Aß antibodies to CAA Aß fibrils was evaluated in vitro using immunoprecipitation, surface plasmon resonance, and direct binding assay. Marked differences in Aß antibody binding to CAA fibrils were observed. Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aß present. The findings of this study support the proposal that Aß antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aß-based immunotherapies.

Three major effects of APOEε4 on Aß immunotherapy induced ARIA.

The targeting of amyloid-beta (Aß) plaques therapeutically as one of the primary causes of Alzheimer's disease (AD) dementia has been an ongoing effort spanning decades. While some antibodies are extremely promising and have been moved out of clinical trials and into the clinic, most of these treatments show similar adverse effects in the form of cerebrovascular damage known as amyloid-related imaging abnormalities (ARIA). The two categories of ARIA are of major concern for patients, families, and prescribing physicians, with ARIA-E presenting as cerebral edema, and ARIA-H as cerebral hemorrhages (micro- and macro-). From preclinical and clinical trials, it has been observed that the greatest genetic risk factor for AD, APOEε4, is also a major risk factor for anti-Aß immunotherapy-induced ARIA. APOEε4 carriers represent a large population of AD patients, and, therefore, limits the broad adoption of these therapies across the AD population. In this review we detail three hypothesized mechanisms by which APOEε4 influences ARIA risk: (1) reduced cerebrovascular integrity, (2) increased neuroinflammation and immune dysregulation, and (3) elevated levels of CAA. The effects of APOEε4 on ARIA risk is clear, however, the underlying mechanisms require more research.

Flow-S: A Field-Deployable Device with Minimal Hands-On Effort to Concentrate and Quantify Schistosoma Circulating Anodic Antigen (CAA) from Large Urine Volumes.

A laboratory-based lateral flow (LF) test that utilizes up-converting reporter particles (UCP) for ultrasensitive quantification of Schistosoma circulating anodic antigen (CAA) in urine is a well-accepted test to identify active infection. However, this UCP-LF CAA test requires sample pre-treatment steps not compatible with field applications. Flow, a new low-cost disposable, allows integration of large-volume pre-concentration of urine analytes and LF detection into a single field-deployable device. We assessed a prototype Flow-Schistosoma (Flow-S) device with an integrated UCP-LF CAA test strip, omitting all laboratory-based steps, to enable diagnosis of active Schistosoma infection in the field using urine. Flow-S is designed for large-volume (5-20 mL) urine, applying passive paper-based filtration and antibody-based CAA concentration. Samples tested for schistosome infection were collected from women of reproductive age living in a Tanzania region where S. haematobium infection is endemic. Fifteen negative and fifteen positive urine samples, selected based on CAA levels quantified in paired serum, were analyzed with the prototype Flow-S. The current Flow-S prototype, with an analytical lower detection limit of 1 pg CAA/mL, produced results correlated with the laboratory-based UCP-LF CAA test. Urine precipitates occurred in frozen banked samples and affected accurate quantification; however, this should not occur in fresh urine. Based on the findings of this study, Flow-S appears suitable to replace the urine pre-treatment required for the laboratory-based UCP-LF CAA test, thus allowing true field-based applications with fresh urine samples. The urine precipitates observed with frozen samples, though less important given the goal of testing fresh urines, warrant additional investigation to evaluate methods for mitigation. Flow-S devices permit testing of pooled urine samples with applications for population stratified testing. A field test with fresh urine samples, a further optimized Flow-S device, and larger statistical power has been scheduled.

Neuropsychiatric symptoms with focus on apathy and irritability in sporadic and hereditary cerebral amyloid angiopathy.

BACKGROUND: Neuropsychiatric symptoms (NPS) may affect cognition, but their burden in cerebral amyloid angiopathy (CAA), one of the main causes of intracerebral hemorrhage (ICH) and dementia in the elderly, remains unclear. We investigated NPS, with emphasis on apathy and irritability in sporadic (sCAA) and Dutch-type hereditary (D-)CAA. METHODS: We included patients with sCAA and (pre)symptomatic D-CAA, and controls from four prospective cohort studies. We assessed NPS per group, stratified for history of ICH, using the informant-based Neuropsychiatric Inventory (NPI-Q), Starkstein Apathy scale (SAS), and Irritability Scale. We modeled the association of NPS with disease status, executive function, processing speed, and CAA-burden score on MRI and investigated sex-differences. RESULTS: We included 181 participants: 82 with sCAA (mean[SD] age 72[6] years, 44% women, 28% previous ICH), 56 with D-CAA (52[11] years, 54% women, n = 31[55%] presymptomatic), and 43 controls (69[9] years, 44% women). The NPI-Q NPS-count differed between patients and controls (sCAA-ICH+:adj.ß = 1.4[95%CI:0.6-2.3]; sCAA-ICH-:1.3[0.6-2.0]; symptomatic D-CAA:2.0[1.1-2.9]; presymptomatic D-CAA:1.2[0.1-2.2], control median:0[IQR:0-3]), but not between the different CAA-subgroups. Apathy and irritability were reported most frequently: n = 12[31%] sCAA, 19[37%] D-CAA had a high SAS-score; n = 12[29%] sCAA, 14[27%] D-CAA had a high Irritability Scale score. NPS-count was associated with decreased processing speed (adj.ß=-0.6[95%CI:-0.8;-0.4]) and executive function (adj.ß=-0.4[95%CI:-0.6;-0.1]), but not with radiological CAA-burden. Men had NPS more often than women. DISCUSSION: According to informants, one third to half of patients with CAA have NPS, mostly apathy, even in presymptomatic D-CAA and possibly with increased susceptibility in men. Neurologists should inform patients and caregivers of these disease consequences and treat or refer patients with NPS appropriately.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy.

BACKGROUND: Neurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking. We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA. METHODS: For this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aß40 and Aß42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups. RESULTS: We included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years). In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aß42 levels (P=0.01/0.02). CONCLUSIONS: GFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.

Increasing Analytical Quality by Designing a Thin-Layer Chromatography Scanner Method for the Determination of the Radiochemical Purity of Radiopharmaceutical Sodium Iodide 131I Oral Solution.

The goal of this study was to apply the principles of analytical quality by design (AQbD) to the analytical method for determining the radiochemical purity (PQR) of the radiopharmaceutical sodium iodide 131I oral solution, utilizing thin-layer chromatography (TLC) with a radio-TLC scanner, which also enables the evaluation of product quality. For AQbD, the analytical target profile (ATP), critical quality attributes (CQA), risk management, and the method operable design region (MODR) were defined through response surface methodology to optimize the method using MINITAB® 19 software. This study encompassed the establishment of a control strategy and the validation of the method, including the assessment of selectivity, linearity, precision, robustness, detection limit, quantification limit, range, and the stability of the sample solution. Under the experimental conditions, the method parameters of the TLC scanner were experimentally demonstrated and optimized with an injection volume of 3 µL, a radioactive concentration of 10 mCi/mL, and a carrier volume of 40 µL. Statistical analysis confirmed the method's selectivity for the 131I iodide band Rf of 0.8, a radiochemical impurity IO3- Rf of 0.6, a linearity from 6.0 to 22.0 mCi/mL, and an intermediate precision with a global relative standard deviation (RSD) of 0.624%. The method also exhibited robustness, with a global RSD of 0.101%, a detection limit of 0.09 mCi/mL, and a quantification limit of 0.53 Ci/mL, meeting the prescribed range and displaying stability over time (at 0, 2, and 20 h) with a global RSD of 0.362%, resulting in consistent outcomes. The development of a method based on AQbD facilitated the creation of a design space and an operational space, with comprehensive knowledge of the method's characteristics and limitations. Additionally, throughout all operations, compliance with the acceptance criteria was verified. The method's validity was confirmed under the established conditions, making it suitable for use in the manufacturing process of sodium iodide 131I and application in nuclear medicine services.

Arteriolar degeneration and stiffness in cerebral amyloid angiopathy are linked to ß-amyloid deposition and lysyl oxidase.

Cerebral amyloid angiopathy (CAA) is a vasculopathy characterized by vascular ß-amyloid (Aß) deposition on cerebral blood vessels. CAA is closely linked to Alzheimer's disease (AD) and intracerebral hemorrhage. CAA is associated with the loss of autoregulation in the brain, vascular rupture, and cognitive decline. To assess morphological and molecular changes associated with the degeneration of penetrating arterioles in CAA, we analyzed post-mortem human brain tissue from 26 patients with mild, moderate, and severe CAA end neurological controls. The tissue was optically cleared for three-dimensional light sheet microscopy, and morphological features were quantified using surface volume rendering. We stained Aß, vascular smooth muscle (VSM), lysyl oxidase (LOX), and vascular markers to visualize the relationship between degenerative morphological features, including vascular dilation, dolichoectasia (variability in lumenal diameter) and tortuosity, and the volumes of VSM, Aß, and LOX in arterioles. Atomic force microscopy (AFM) was used to assess arteriolar wall stiffness, and we identified a pattern of morphological features associated with degenerating arterioles in the cortex. The volume of VSM associated with the arteriole was reduced by around 80% in arterioles with severe CAA and around 60% in cases with mild/moderate CAA. This loss of VSM correlated with increased arteriolar diameter and variability of diameter, suggesting VSM loss contributes to arteriolar laxity. These vascular morphological features correlated strongly with Aß deposits. At sites of microhemorrhage, Aß was consistently present, although the morphology of the deposits changed from the typical organized ring shape to sharply contoured shards with marked dilation of the vessel. AFM showed that arteriolar walls with CAA were more than 400% stiffer than those without CAA. Finally, we characterized the association of vascular degeneration with LOX, finding strong associations with VSM loss and vascular degeneration. These results show an association between vascular Aß deposition, microvascular degeneration, and increased vascular stiffness, likely due to the combined effects of replacement of VSM by ß-amyloid, cross-linking of extracellular matrices (ECM) by LOX, and possibly fibrosis. This advanced microscopic imaging study clarifies the association between Aß deposition and vascular fragility. Restoration of physiologic ECM properties in penetrating arteries may yield a novel therapeutic strategy for CAA.

Cerebral amyloid angiopathy decades after red blood cell transfusions: a report of two cases from a prospective cohort.

BACKGROUND AND PURPOSE: Patients who underwent red blood cell (RBC) transfusion from donors who later developed multiple spontaneous intracerebral hemorrhages (ICHs) have recently been identified to have increased risk of ICH themselves. This increased risk of ICH was hypothesized to be related to iatrogenic cerebral amyloid angiopathy (iCAA) transmission. Two cases are presented who had RBC transfusion as an infant and presented with CAA at a relatively young age decades later. METHOD: Cases were identified by prospectively asking all patients at our CAA outpatient clinic (November 2023 to January 2024) about a medical history with RBC transfusion or history with a high likelihood for RBC transfusion (e.g., hemolytic disease, trauma with massive hemorrhage). Eligible patients were all diagnosed with CAA, CAA with concomitant hypertensive arteriopathy or iCAA, and without hereditary CAA. RESULTS: Between November 2023 and January 2024, 2/35 (6%, 95% confidence interval 2%-19%) outpatient clinic patients had a history of RBC transfusion and none had a high likelihood medical history. The cases presented at age 47 and 57 and had already developed severe CAA. CONCLUSIONS: Red blood cell transfusion might be a possible mechanism for iCAA; however, further prospective data collection and experimental evidence concerning blood transmission of amyloid-ß are needed.

History, Paranoia, Fragmentation1.

In his book Aion, Jung describes something like a quasi-Hegelian progressive historical realization of the Self in a perspective similar to Fernand Braudel's longue durée history. This article deals with a similar perspective, as it tries to focus on what we may call a "cultural complex" yet within its unfolding in historical time and belonging not to just one specific cultural group, but to a large cultural basin, which we may indicate as the "West". This complex marks the birth and development of modernity. The depth, pervasiveness and duration of this cultural complex permeates the lives and psychologies of all of those that are part of it. Therefore, every analytical project must take into account the underlying emotional, epistemic and social field within which this complex constellates. One of the main features of this (trans)cultural complex, strictly connected with the progressive fragmentation of the self and the transformation of the numinosum with its meaning-giving force, is paranoia. This article analyses the historical and cultural features that produce paranoia and fragmentation and determine paranoid symptoms and attitudes.

Dans son livre Aïon, Jung décrit quelque chose comme une réalisation historique progressive quasi hégélienne du Soi dans une perspective similaire à l'histoire de longue durée de Fernand Braudel. Cet article aborde une perspective semblable, car il tente de se concentrer sur ce que nous pouvons appeler un « complexe culturel ¼. Mais ici il s'agit de son déroulement dans le temps historique et de son appartenance non pas à un groupe culturel spécifique, mais à un grand bassin culturel, que nous pouvons désigner comme « l'Occident ¼. Ce complexe marque la naissance et le développement de la modernité. La profondeur, l'omniprésence et la durée de ce complexe culturel imprègnent la vie et la psychologie de tous ceux qui en font partie. Par conséquent, tout projet analytique doit prendre en compte le champ émotionnel, épistémique et social sous­jacent dans lequel ce complexe se constelle. L'une des principales caractéristiques de ce complexe (trans)culturel, étroitement lié à la fragmentation progressive du soi et à la transformation du numinosum et de sa capacité à donner du sens, c'est la paranoïa. Cet article analyse les caractéristiques historiques et culturelles qui produisent la paranoïa et la fragmentation et déterminent les symptômes et les attitudes paranoïdes.

En su libro 'Aion', Jung describe algo así como una realización histórica progresiva cuasi­hegeliana del Self en una perspectiva similar a la historia 'longue durée' de Fernand Braudel. El presente artículo aborda una perspectiva similar, ya que trata de centrarse en lo que podríamos denominar un "complejo cultural", pero dentro de su despliegue en el tiempo histórico y perteneciente no sólo a un grupo cultural concreto, sino a una gran cuenca cultural, que podríamos señalar como "Occidente". Este complejo marca el nacimiento y el desarrollo de la modernidad. La profundidad, la omnipresencia y la duración de este complejo cultural impregnan la vida y la psicología de todos los que forman parte de él. Por lo tanto, todo proyecto analítico debe tener en cuenta el campo emocional, epistémico y social subyacente en el que se inscribe este complejo. Uno de los principales rasgos de este complejo (trans)cultural, estrictamente relacionado con la progresiva fragmentación del self y la transformación de lo numinoso con su fuerza dadora de sentido, es la paranoia. Este artículo analiza los rasgos históricos y culturales que producen la paranoia y la fragmentación y determinan síntomas y actitudes paranoides.