Arterial Calcification due to Deficiency of CD73 (ACDC) results from mutations in the NT5E gene encoding the 5′ exonucleotidase, CD73. We now describe the third familial case of ACDC, including radiological and histopathological details of the arterial calcifications. The medial lesions involve the entire circumference of the elastic lamina, in contrast to the intimal plaque-like disease of atherosclerosis. The demonstration of broken and fragmented elastic fibers leading to generalized vascular calcification suggests an analogy to pseudoxanthoma elasticum (PXE), which exhibits similar histopathology. Classical PXE is caused by deficiency of ABCC6, a C type ABC transporter whose ligand is unknown. Other C type ABC proteins transport nucleotides, so the newly described role of adenosine in inhibiting vascular calcification, along with the similarity of ACDC and PXE with respect to vascular pathology, suggests that adenosine may be the ligand for ABCC6.
PF-10a was feasible to implement in a diverse RA population. It strongly correlates with the HAQ but has fewer ceiling effects and is responsive to changes in RA disease activity, suggesting its validity for use in routine clinical practice.
Summary. The function of lymphocytes, like platelets, has been shown to be inhibited by agents which increase intracellular cyclic AMP. Two high-affinity cAMP phosphodiesterases (PDEs), the cyclic GMP-inhibited cAMP phosphodiesterase, PDE3, and the cAMP-specific phosphodiesterase PDE4, are known to regulate cAMP concentration in haemopoietic cells by degrading cAMP to AMP. We characterized the relative contribution of the two PDEs to total lymphocyte PDE activity. We then determined which of the different gene products, PDE3A, typical of myocardium and platelets, or PDE3B, typical of adipocytes, were present in lymphocytes. The PDE3-specific inhibitor, milrinone, and the PDE4 inhibitor, rolipram, suppressed hydrolysis by 70% and 30% respectively, which indicated that both PDE4 and PDE3were present, and that PDE3 was predominant. RT-PCR yields the expected size fragment for the primer pair PDE3B and not for PDE3A. The DNA sequence obtained had > 95% identity with PDE3B. PDE3B appears to be the major cAMP PDE in lymphocytes. In contrast to human platelets, human lymphocytes appear to contain the PDE3B subtype. Since PDE3B in adipocytes is subject to hormonal regulation, lymphocytes may be similarly modulated. Understanding the role of cAMP regulation and the involvement of cAMP in lymphocyte function may have important implications in drug development.Keywords: phosphodiesterase, lymphocytes, cyclic AMP, milrinone, rolipram.Cyclic AMP, an important second messenger in cells, is maintained at steady state levels as a result of formation and destruction by adenylate cyclase and cAMP phosphodiesterases (PDEs) respectively. Currently, the group of PDEs isolated from mammalian tissues is divided into at least seven distinct classes, based on a variety of biochemical characteristics including their substrate specificity, response to selective inhibitors, mode of regulation and kinetic characteristics (Beavo et al, 1994). These classes appear to be coded for by related but distinct genes yet they share a conserved region of about 250 amino acids at the C terminal end (Charbonneau, 1990). This region demonstrates a homology of about 28-40% between classes and contains the catalytic domain (Charbonneau, 1990). The N terminal region of each class appears to be distinct and may contain the regulatory domain. Each class has at least two isotypes coded for by different genes or the product of differential mRNA splicing. Lymphocytes contain two high-affinity cAMP PDEs, the cyclic GMP-inhibited cAMP phosphodiesterase or PDE3 and the cAMP-specific phosphodiesterase or PDE 4 (Robicsek et al, 1991). In monocytes and neutrophils PDE4 predominates (Wright et al, 1990) whereas in platelets most of PDE activity is PDE3A (Degerman et al, 1994;Cheung et al, 1996). Two rat and two human enzymes have been cloned from heart (PDE3A) (Meacci et al, 1992) and adipocyte (PDE3B) (Taira et al, 1993), and their results show that the PDE3 class appears to have a conserved region of 44 amino acids at the C terminal end distinct from the catalytic re...
Background and Purpose: The management of unruptured intracranial aneurysms remains controversial. The decisions to treat are heavily informed by estimated risk of bleeding. However, these estimates are imprecise, and better methods for stratifying the risk or tailoring treatment strategy are badly needed. Here, we demonstrate an initial proof-of-principle concept for endovascular biopsy to identify the key molecular pathways and gene expression changes associated with aneurysm formation. We couple this technique with single cell RNA sequencing (scRNAseq) to develop a roadmap of the pathogenic changes of a dolichoectatic vertebrobasilar aneurysm in a patient with polyarteritis nodosa.Methods: Endovascular biopsy and fluorescence activated cell sorting was used to isolate the viable endothelial cells (ECs) using the established techniques. A single cell RNA sequencing (scRNAseq) was then performed on 24 aneurysmal ECs and 23 patient-matched non-aneurysmal ECs. An integrated panel of bioinformatic tools was applied to determine the differential gene expression, enriched signaling pathways, and cell subpopulations hypothesized to drive disease pathogenesis.Results: We identify a subset of 7 (29%) aneurysm-specific ECs with a distinct gene expression signature not found in the patient-matched control ECs. A gene set enrichment analysis identified these ECs to have increased the expression of genes regulating the leukocyte-endothelial cell adhesion, major histocompatibility complex (MHC) class I, T cell receptor recycling, tumor necrosis factor alpha (TNFα) response, and interferon gamma signaling. A histopathologic analysis of a different intracranial aneurysm that was later resected yielded a diagnosis of polyarteritis nodosa and positive staining for TNFα.Conclusions: We demonstrate feasibility of applying scRNAseq to the endovascular biopsy samples and identify a subpopulation of ECs associated with cerebral aneurysm in polyarteritis nodosa. Endovascular biopsy may be a safe method for deriving insight into the disease pathogenesis and tailoring the personalized treatment approaches to intracranial aneurysms.
Arterial calcification due to CD73 deficiency (ACDC) is a recently identified rare and debilitating adult-onset disorder caused by autosomal recessive NT5E gene mutations. ACDC is characterized by progressive and painful arterial calcifications primarily affecting the lower extremities, as well as calcifications affecting small joint capsules of the hands and feet. In this case report, the authors provide clinical follow-up for one of the first individuals identified by the National Institutes of Health (NIH) as having ACDC, focusing mainly on the imaging manifestations of periarticular joint mineralization, which are bilateral but slightly asymmetric, bulky up to the levels of the metacarpophalangeal and metatarsophalangeal joints, but smaller and more capsular in distribution at the proximal and distal interphalangeal joints, without erosive change or intra-articular mineralization. Differential considerations for similar appearing joint mineralization are provided.
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