The causes and mechanisms of disease responsible for this syndrome remain elusive.

Method of study  We report two cases of maternal deaths attributed to AFE: (1) one woman presented with spontaneous labor at term, developed intrapartum fever, and after delivery had sudden cardiovascular collapse and disseminated intravascular coagulation (DIC), leading to death; (2) another woman presented with preterm labor and foul-smelling amniotic fluid, underwent a Cesarean section for fetal distress, and also had postpartum cardiovascular collapse and DIC, leading to death. Results  Of Nutlin-3 research buy major importance is that in both cases, the maternal plasma concentration of tumor necrosis

factor-α at the time of admission to the hospital and when patients had no clinical evidence of infection was in the lethal range (a lethal range is considered to be above 0.1 ng/mL). Conclusion  We propose that subclinical intraamniotic infection may be a cause of postpartum cardiovascular collapse and DIC and resemble AFE. Thus, some patients with the clinical diagnosis of AFE may have infection/systemic inflammation as a mechanism of disease. These observations have implications for the understanding of the mechanisms of disease of patients who develop cardiovascular collapse and DIC, frequently attributed to AFE. It may be possible Selleckchem MG 132 to identify a subset of patients who have biochemical and immunological evidence of systemic inflammation at the time of admission, and before a catastrophic event occurs. “
“Regulatory B (Breg) cells have been shown to play a critical role in immune homeostasis and in autoimmunity models. We have recently demonstrated many that combined anti-T

cell immunoglobulin domain and mucin domain-1 and anti-CD45RB antibody treatment results in tolerance to full MHC-mismatched islet allografts in mice by generating Breg cells that are necessary for tolerance. Breg cells are antigen-specific and are capable of transferring tolerance to untreated, transplanted animals. Here, we demonstrate that adoptively transferred Breg cells require the presence of regulatory T (Treg) cells to establish tolerance, and that adoptive transfer of Breg cells increases the number of Treg cells. Interaction with Breg cells in vivo induces significantly more Foxp3 expression in CD4+CD25− T cells than with naive B cells. We also show that Breg cells express the TGF-β associated latency-associated peptide and that Breg-cell mediated graft prolongation post-adoptive transfer is abrogated by neutralization of TGF-β activity. Breg cells, like Treg cells, demonstrate preferential expression of both C-C chemokine receptor 6 and CXCR3.

Data are the mean ± SEM of at least three independent experiments, unless differently

specified. The Student’s t-test see more was used to determine result significance (p ≤ 0.05). This work was supported by grants from the: Associazione Italiana Ricerca sul Cancro (AIRC, “Code: IG – 10565 Funding source: 5 PER MILLE MIUR 2008 to L.V.; AIRC, Code: IG-9366” to M.G.); the European Network for Cancer Research in Children and Adolescents (ENCCA) to L.V.; Associazione Italiana Glicogenosi (AIG) to L.V.; Progetti di ricerca di Ateneo Università di Torino-Compagnia San Paolo, Special Project Microstructure and Nanostructure to M.G.; Regione Piemonte Progetti strategici Piattaforma innovativa Biotecnologie per le Scienze della Vita: Project IMMONC to F.N. F.R. was supported by a fellowships www.selleckchem.com/products/BAY-73-4506.html from AIRC. PBMCs and DCs were derived from the peripheral blood of healthy donors from the blood bank under an Institutional Review Board-approved protocol. The authors declare no financial or commercial conflict of interest. As a service to our authors and readers, this journal provides supporting

information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. “
“During the last two decades, the resurgence of tuberculosis (TB) has been documented in both developed and developing nations, and much of this increase in TB burden coincided with 4��8C human immunodeficiency virus (HIV) epidemics. Since then, the disease pattern has changed with a higher incidence of extrapulmonary tuberculosis (EPTB) as well as disseminated TB. EPTB cases include TB lymphadenitis, pleural TB, TB meningitis, osteoarticular TB, genitourinary TB, abdominal TB, cutaneous TB, ocular TB, TB pericarditis and breast TB, although any organ can be involved. Diagnosis of EPTB can be baffling, compelling a high index of suspicion owing to paucibacillary load in the biological specimens.

A negative smear for acid-fast bacilli, lack of granulomas on histopathology and failure to culture Mycobacterium tuberculosis do not exclude the diagnosis of EPTB. Novel diagnostic modalities such as nucleic acid amplification (NAA) can be useful in varied forms of EPTB. This review is primarily focused on the diagnosis of several clinical forms of EPTB by polymerase chain reaction (PCR) using different gene targets. Tuberculosis (TB) remains one of the leading infectious diseases throughout the world accounting for about 8.8 million incident cases in 2010 (Griffiths et al., 2010; WHO, 2011). India alone accounted for 2.0–2.5 million cases in 2010, thus contributing approximately 26% of all TB cases worldwide (WHO, 2011). According to National Tuberculosis Control Programmes (NTPs), 2.6 million new cases of sputum smear-positive pulmonary TB (PTB), 2.

To identify new potential growth factors, we compared the expression profile of IL-1β-stimulated ECs over 4, 8 and 16 h with non-stimulated ECs using oligonucleotide microarrays covering more than 46 000 transcripts. Most significant changes were detected after 4 h. Utilization of Gene Ontology annotation for the stimulated EC transcriptome indicated

multiple upregulated genes encoding extracellular proteins with a cell–cell signaling AZD2014 cost function. Using flow cytometry, delta, colony and cobblestone assays, we assessed the proliferative capacities of 11 gene products, i.e. IL-8, IL-32, FGF-18, osteoprotegerin, Gro 1–3, ENA78, GCP-2, CCL2 and CCL20, which are not known to induce HPC expansion. Notably, IL-32 and to a lesser degree osteoprotegerin and Gro 3 significantly induced the proliferation of HPCs. Furthermore, IL-32 attenuated chemotherapy-related BM cytotoxicities by increasing the number of HPCs in mice. Our findings confirm that the combination of microarrays and gene annotation helps to identify new hematopoietic growth factors. Endothelial cells (ECs) have been shown to support the proliferation LY2835219 in vivo of hematopoietic CD34+ progenitor cells by the constitutive

production of cytokines 1, 2. In previous studies, we demonstrated that ECs stimulated by TNF-α induced the generation of dendritic cells from CD34+ cells for more than 6 wk 3. ILs, on the other hand, very can also induce the proliferation of hematopoietic and myeloid progenitors 4. So far, GM-CSF and G-CSF are known to be secreted by IL-stimulated ECs 5. Other endothelial factors propagating progenitor expansion include stem cell factor (SCF) 6, leukemia inhibitory factor (LIF) 7 and IL-6 8, 9. Beyond the known cytokine scenario, ECs synthesize multiple other proteins 10, i.e. chemokines

of the C-X-C, C-C and TNF receptor superfamily; however, whether these factors can also support hematopoietic progenitor cell (HPC) expansion remains unknown. Notably, microarray technologies monitoring expression changes for thousands of genes have been the basis for several systematic studies of immune and stem cells and their involvement in a variety of processes 11–15. For example, microarrays of ECs helped to reveal unknown signaling pathways in the endothelial immune cascades 16, specify the role of inflammatory stimuli in neutrophil transmigration 17 and identify the effects of biochemical forces 18. Microarrays of cultured HPCs also defined detrimental components of engineered extracellular matrices 19. To use microarrays of feeder cells for the identification of new hematopoietic growth factors is another aspect. Choong et al., for example, discovered proliferin-2 after microarray analyses of several supportive stroma cell lines 20. Chute et al. used a similar approach when they discovered the hematopoietic activity of adrenomedullin expressed by human brain ECs 21.

Results were compared with phenotypic DST data. Nineteen different

mutation types to at least one of the drugs were found; six isolates (6%) were classified as MDR-TB, defined as resistance to at least rifampicin and isoniazid. The rates of concordance of the PCR with the phenotypic susceptibility test were 71.4, 54.5, and 44.4 for isoniazid, rifampicin, and ethambutol, respectively. These results highlight the importance of molecular epidemiology studies of tuberculosis in understudied regions with a tuberculosis burden to uncover the true prevalence of the selleck chemicals llc MDR-TB. The spread of multidrug-resistant tuberculosis (MDR-TB) due to emergence of multidrug-resistant Mycobacterium tuberculosis isolates has increased worldwide and reached epidemic proportions in many countries (Mokrousov et al., 2003). The increasing number of multidrug-resistant isolates over the years has complicated the control of several outbreaks of the disease (WHO, 2000a, b). MDR-TB is defined as resistant to at least rifampicin and isoniazid, which are the backbone of short-course chemotherapy for tuberculosis (Herrera-León et al., 2005). Therefore, immediate identification of these resistant isolates is very important for adjustments in treatment (Herrera-León et al., 2005;

Abe et al., 2008). Rifampicin was introduced in 1972 as an antituberculosis drug and has excellent EPZ-6438 molecular weight sterilizing activity. Rifampicin acts by binding to the β-subunit of RNA polymerase (rpoB) (Ramaswamy & Musser, Bay 11-7085 1998), the enzyme responsible for transcription and expression of mycobacterial genes, resulting in inhibition of the bacterial transcription activity and thereby killing the

organism. Mutations in the 81-bp core region of rpoB were reported to be responsible for resistance in at least 95% of isolates (Sekiguchi et al., 2007). This region is located between codons 507 and 533, with the most common changes in codons Ser531Leu, His526Tyr, and Asp516Val (González et al., 1999). Isoniazid enters the bacterial cell as a prodrug; it is then activated to a toxic substance in the cell by a catalase peroxidase encoded by the katG gene (Wang et al., 1998) and subsequently affects intracellular targets such as mycolic acid biosynthesis, an important component of the cell wall, which eventually results in loss of cellular integrity and the bacterial death. Ethambutol, a first-line-specific antituberculosis drug used in combination with other drugs, inhibits the incorporation of mycolic acids into the mycobacterial cell wall. Genetic and biochemical studies have shown that resistance to ethambutol is mediated by mutations in the embB gene, which encodes arabinosyl transferase, an integral membrane protein that is inhibited by the drug.

Conversely, IC-loaded red cells have been reported to interact with macrophages leading to production of the pro-inflammatory cytokine interleukin (IL)-1 [12]. The level of expression of CR1 on red cells is influenced by a variety of factors. There are known quantitative polymorphisms (H and L) that can result in

low (LL), medium (HL) or high (HH) expression [5]. In addition, the level of CR1 is known to decline with the age of red cells [13,14] and can vary with the age of the host [15], as well as his/her health status [16]. For instance, individuals with certain conditions leading to formation of ICs such as malaria or systemic lupus erythematosus (SLE) tend to have lower CR1 on their red cells [15–19]. The variability in the level of red cell CR1 expression suggests that individuals at selleck kinase inhibitor either end of the expression spectrum may suffer deleterious consequences of IC-mediated diseases. Low expressors may be less equipped to remove ICs from circulation, leading to IC deposition in tissues and the consequent inflammatory response. Conversely, high expressors may trap ICs on red cells too effectively which, under certain circumstances such as in the slow circulation of the spleen or in congested capillaries of malaria-infected individuals, may cross-link

Fcγ receptors on monocyte/macrophages leading to production of proinflammatory cytokines [9–11,20]. To investigate the dual role of red cell CR1 on modulating the IC-mediated production of tumour necrosis factor CAL-101 in vivo (TNF)-α by macrophages and how this is affected by the CR1 expression level, we selected individuals with low, medium and high red cell CR1 expression. We then measured the ability of their red cells to enhance or inhibit TNF-α production

by macrophages in vitro in the presence ICs. This study was part of a larger cross-sectional survey to study the relationship between red cell complement regulatory protein expression, age and C3b deposition [21]. It was approved by and executed in accordance with guidelines of the Human Use Research Committee of the Walter Reed Army Institute of Research and of the Kenya National Ethics Review Committee, Kenya Medical Research Institute. Informed consent was obtained Urocanase from each participant or from the parent or guardian of participants under 18 years of age. The study was carried out in Kombewa Division, a malaria holoendemic region of the Lake Victoria basin in western Kenya, where most individuals are of the Luo ethnic group. The eligibility criteria and screening procedures were detailed previously [21]. Briefly, any person resident in the study area, male or female, aged 45 years or younger was eligible to participate in the study. Only healthy, malaria-negative individuals, as confirmed by a standardized physical examination and thick and thin Giemsa-stained blood smears, served as blood donors.

8 nm. The incident laser-light was scattered by added dispersing particles (titandioxide parcticles, TiO2) in the perfusion fluid and resulted in a scattered-light. The TiO2 particles were used as tracer particles for the LDA measurements and followed the flow slip-free,

as previously described.[26] The scattered-light with the laser Doppler-signal was received in a photomultiplier and forwarded to a data processor. With the help of a 3-D Traversier-Table (x-y-z table equipped with a stepping motor) the model could be moved for the LDA-measurements. Velocity components axial (x-axis) and perpendicular (z-axis) to the recipient vessel were recorded at four defined cross-sections proximal, in and distal to the anastomosis. GDC-0068 chemical structure The specimen analyzed contained 20 arteries for analyses for each technique

check details and flow data were gained by the mean ± standard deviation of 7 circles of perfusion of the models. Velocity and pressure distributions were measured with the help of the LDA-system (BBC Goerz. Spectraphysics; Munich, Germany) and pressure transducers were positioned proximal and distal to the model (type P 11/0.5 bar; Hottinger Baldwin measurement technics; Darmstadt, Germany). The outgoing data from Doppler-signal-processor was forwarded to a data processor, using the graphically orientated DIAdem™ software (Version 8.0; National Instruments Corporation; Austin, TX). We used the data visualization and analysis software Tecplot (Version 10.0-0-7; Tecplot Inc.; Bellevue, WA 98015) for further evaluations. Data were analyzed with the ‘‘Statistical Package for the Social Sciences” (SPSS for Windows,

release 20, SPSS Inc., Chicago, IL). For differences of flow pattern in the silicone rubber models values were evaluated using the t-test in comparison between both groups containing both techniques as they were normally distributed. Differences were considered statistically significant for a two-sided p-value of less than 0.05. The main vessel’s diameter in the conventional technique and Opened End-to-Side technique model were 2.2 mm and 2.1 mm. The diameters of the branching vessel in both models were 1.6 mm. The flow rate proximal to the bifurcation was adjusted to 48 ml/min. Distal to the bifurcation the flow rate was divided into 36 ml/min in the main vessel and 12 ml/min in the branching vessel, resulting MRIP in a flow rate ratio of 3:1. Seven physiologic flow curve cycles were recorded and averaged at four defined cross-sections in both models. As an example the velocity distributions during the maximal systolic (90°) and diastolic phase (270°) for each model in all of the four measurement planes are presented in Figure 4. The Womersley parameter was smaller for this experimental setup in both models (Table 1). The maximal and minimal axial and perpendicular velocities during the systolic and diastolic phase in the all vessel components of each technique can be found in comparisons in Table 2 and illustrated in Figure 4.

In this study, we determined that the

excretory–secretory (ES) protein from the parasite Anisakis simplex could elicit neutrophil recruitment and IL-17 production. Interleukin-8 and CXCL1 are known 3-deazaneplanocin A mw to be typical neutrophil attractants in lung inflammation (15,25). In this study, we also determined that the expression of the CXCL1 gene was increased as a result of ES protein treatment. Interleukin-17 is generated and released as a free protein from T-lymphocytes of the memory (CD45RO+) subset (27). Linden suggested that IL-17 can recruit and activate neutrophils in the airways; this recruitment is mediated by the neutrophil chemoattractant IL-8, CXCL1 and macrophage inflammatory protein-2 (27). In this study, the level of IL-17 in the BALF of ES protein and OVA-treated mice was significantly higher than those in the OVA-only treatment group (Figure 1c). In addition, IL-17 producing cells were recruited to the lung and lung draining lymph node as the consequence of intranasal ES protein treatment (Figure 1d,e). The ES proteins were also determined to induce IL-6

that enhances the activation of Th17 cells, and gene expression in lung epithelial cells (Figure 2a). Therefore, Anisakis ES proteins may activate IL-17 producing Navitoclax mouse cells and neutrophil recruitment in the airway via an induction of IL-6 cytokine production in lung epithelial cells. These findings reveal that IL-17 plays a critical role in the Anisakis-associated allergic reaction. Shainheit et al. previously reported that schistosome egg-stimulated dendritic cells plus naive CD4

T cells from Bay 11-7085 CBA mice resulted in increased levels of pre-inflammatory cytokines, as well as IL-17 and the chemokines CXCL1, CXCL2 and CCL2. They demonstrated that after neutralization of IL-23 and IL-1, but not of IL-6 or IL-21, egg-induced IL-17 production was profoundly inhibited. They also emphasized that parasite recognition followed by a genetically determined innate pro-inflammatory response induces the development of Th17 cells, and thus controls the outcome of immunopathology in schistosomiasis (28). Specific recognition of conserved molecular motifs associated with different classes of pathogens – particularly viruses, bacteria, fungi and protozoa – by antigen presenting cells (APCs) can be mediated by pattern recognition receptors (PRRs) including the TLR, C-type lectin and Nod-like receptors (26). Toll-like receptors are important initiators of innate immune responses, owing to their ability to recognize a variety of microbial products harbouring pathogen-associated molecular patterns (PAMPs) (29). However, there are no apparent uniformly expressed PAMPs for helminth parasites, although a number of helminth-derived products have been shown to interact with innate immune cells and to modulate their functions.

Graph Pad Prism version 5.00 for Windows (GraphPad Software, USA) was employed. Welch correction was applied when different variances were observed. All experiments were repeated at least two times to test the reproducibility of results. S.G. and M.P.A. are Research Career Investigator from CONICET. A.A, L.I.O., A.P., A.E.C.S, A.P., and R.C.C. thank CONICET and SECYT for the fellowships granted. We thank Alejandra Romero, Pilar Crespo, Paula Abadie, and Fabricio Navarro for their skillful https://www.selleckchem.com/products/bay-57-1293.html technical assistance and would like to thank Dr. Paul Hobson,

native speaker, for revision of the manuscript. This work was supported with grants from Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) Argentina, and Secretaría de Ciencia y Tecnología de la Universidad

Nacional de Córdoba (SECYT-UNC). The authors declare no financial or commercial conflict of interest. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Figure S1: Suppressor mechanisms see more of splenic CD11b+Gr1+ from infected BALB/c mice. Splenocytes from infected mice (21-dpi) were activated with anti-CD3 (2 ug/ml) and anti-CD28 (1 ug/ml) Abs for 72 hs and cultured in the presence or absence of NOS inhibitor (L-NMMA), ROS scavenger (NAC) and arginase I inhibitor (nor-NOHA) . As controls, splenocytes from uninfected mice were stimulated with anti-CD3 and anti-CD28 Abs. Proliferation values are represented as cpm, measured by [3H] thymidine incorporation. Statistically significant differences are shown. Data are mean ± SEM (n:4) and represent one of the two independent experiments. Figure S2: No preferential action of 5FU treatment on MDSC subsets. Infected BALB/c mice were treated

learn more or not with 5FU at 15 days post infection. Splenocytes from both groups were stained with anti-CD11b, anti-Ly6G and anti-Ly6C Abs. The graphic on the left shows the percentages of monocytic (Ly6G-Ly6Chigh) and granulocytic (Ly6G+Ly6Clow) subpopulation of MDSC after 5FU treatment. On the right, representative FACS is showed. Data are mean ± SEM. Similar results were obtained in two experiments with four mice per group. Figure S3: Effect of 5FU treatment on leukocyte populations during T. cruzi infection. Infected BALB/c mice were treated or not with 5FU at 15 days post infection. A, Splenocytes from both group were stained with anti-CD3, anti CD4, anti-CD8 and anti CD19 Abs. The absolute number of lymphocytes population is indicated. There is no statistically significant difference between untreated and treated groups.

Indeed, several miRNAs have been associated with tissue hypoxia,84–87 which is recognized as an important contributor to the development of acute kidney injury (AKI) as well as progression of CKD, particularly in predisposing conditions such as diabetes and hypertension. Further BGB324 supplier studies are needed to examine if hypoxia-regulated miRNAs can serve as early biomarkers for AKI or progression of CKD. MiRNAs with roles, or differential expression, in EMT, inflammation, fibrosis and activation of renal stem cells may also be relevant biomarkers in these conditions.63,66,88 The discovery of plasma- or serum-derived miRNAs and free circulating exosomes that contain miRNAs

has opened up a new frontier in understanding their physiological or pathophysiological roles.81,89–92 Many of the most highly expressed miRNAs in microvesicles are thought to have roles in cellular differentiation. This has led to speculation that miRNAs in microvesicles circulate LY294002 nmr to target tissues and have an endocrine function.93 It has also been hypothesized that the circulating miRNAs play a part in cell-to-cell communication.81

Thus far, plasma- or serum-derived miRNA expression has yet to be reported in association with kidney diseases. MiRNA expression and clearance may be altered in renal failure but this area has not been studied. One study performed miRNA array analysis in cultured human proximal tubular (HK-2) cells exposed to control versus uraemic dialysate. Forty-eight miRNAs were deregulated of which 15 were upregulated and 33 downregulated, respectively. It is possible that the uraemic environment can alter miRNA expression.94 These new insights potentially may have broad ranging implications for the role of microRNAs in the pathogenesis of uraemia. Exosomes are 40–100 nm diameter membrane

vesicles of endocytic origin that are released by most cell types under both physiological and pathological conditions. They are taken up by surrounding host cells and therefore function to promote intercellular communication.95 Exosomes have now been identified in blood, urine and other body fluids.96 Tumours also release exosomes into peripheral circulation and exosomes can be isolated from the blood by differential centrifugation or enriched using cell surface DNA ligase markers such as epithelial cell adhesion molecule.91,92 Exosomes seem to be particularly rich in miRNAs.90 MiRNA expression profiling in exosomes of ovarian cancer patients revealed a high correlation to that of its tumour counterpart.91 These data suggest that miRNA expression profiles from circulating exosomes can be used as a surrogate marker for diagnostic or prognostic purposes. For a number of kidney diseases, miRNAs in peripheral circulation may serve as a measure of disease stage or for monitoring therapeutic response or disease recurrence. MicroRNAs have been detected in urine.

Instead, a surprising number of the experimental manipulations which increase microglial activation lead to enhanced clearance of the amyloid deposits. Both the literature and new data presented here suggest

that either classical or alternative activation of microglia can lead to enhanced amyloid clearance. However, a limited number of studies comparing the same treatments in amyloid-depositing vs. tau-depositing mice find the opposite effects. Treatments that benefit amyloid pathology accelerate tau pathology. This observation argues strongly that potential treatments be tested for impact on both amyloid and tau pathology before consideration of testing in humans. “
“Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. find more The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma. We used the spontaneously

hypertensive stroke-prone rat (SHRSP), the closest spontaneous Selleckchem Cilomilast experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCR and pathway analysis in two brain regions (frontal and mid-coronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks. We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), from vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus predating blood pressure elevation. ‘Neurological’

and ‘inflammatory’ pathways were more affected than ‘vascular’ functional pathways. This set of defects, although individually modest, when acting in combination could explain the SHRSP’s susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD. “
“Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls.