Fragmentation Of Elastic Fibers Research Articles

Whole exome sequencing identified three ABCC6 variants in two Pakistani families with pseudoxanthoma elasticum phenotype.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder of ectopic mineralization and fragmentation of elastic fibers in skin, eyes, cardiovascular and digestive system. PXE is caused by sequence variants in ABCC6, which encodes multidrug resistance-associated protein 6 (MRP6, also known as the ABCC6 protein). MRP6 is an important regulator of inorganic plasma pyrophosphate that acts as an inhibitor of ectopic mineralization observed in PXE patients with low inorganic plasma pyrophosphate levels. The current study was designed to investigate underlying genetic defect in two unrelated Pakistani families affected with PXE. Whole exome sequencing followed by Sanger sequencing was performed to identify causative variants. A novel homozygous frameshift variant (c.1799_1805dupGTCTGGT) was identified in one family and two previously reported missense variants (c.2294G > A and c.2974G > A) in compound heterozygous form in the other family. We identified ABCC6 variants that are likely cause of the PXE disease in the tested families. Genetic analysis of these families could be useful for pre-symptomatic diagnosis and genetic counselling of the affected families.

Cellular signaling in pseudoxanthoma elasticum: an update

Pseudoxanthoma elasticum is an autosomal recessive genodermatosis with variable expression, due to mutations in the ABCC6 or ENPP1 gene. It is characterized by elastic fiber mineralization and fragmentation, resulting in skin, eye and cardiovascular symptoms. Significant advances have been made in the last 20 years with respect to the phenotypic characterization and pathophysiological mechanisms leading to elastic fiber mineralization. Nonetheless, the substrates of the ABCC6 transporter - the main cause of PXE - remain currently unknown. Though the precise mechanisms linking the ABCC6 transporter to mineralization of the extracellular matrix are unclear, several studies have looked into the cellular consequences of ABCC6 deficiency in PXE patients and/or animal models. In this paper, we compile the evidence on cellular signaling in PXE, which seems to revolve mainly around TGF-βs, BMPs and inorganic pyrophosphate signaling cascades. Where conflicting results or fragmented data are present, we address these with novel signaling data. This way, we aim to better understand the up- and down-stream signaling of TGF-βs and BMPs in PXE and we demonstrate that ANKH deficiency can be an additional mechanism contributing to decreased serum PPi levels in PXE patients.

A case of papular elastorrhexis.

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Jiang M, Bu W, Chen X, Gu H. A case of papular elastorrhexis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2019;36(1):117-118. doi:10.5114/ada.2019.82832. APA Jiang, M., Bu, W., Chen, X., & Gu, H. (2019). A case of papular elastorrhexis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 36(1), 117-118. https://doi.org/10.5114/ada.2019.82832 Chicago Jiang, Meng, Wenbo Bu, Xu Chen, and Heng Gu. 2019. "A case of papular elastorrhexis". Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii 36 (1): 117-118. doi:10.5114/ada.2019.82832. Harvard Jiang, M., Bu, W., Chen, X., and Gu, H. (2019). A case of papular elastorrhexis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, 36(1), pp.117-118. https://doi.org/10.5114/ada.2019.82832 MLA Jiang, Meng et al. "A case of papular elastorrhexis." Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii, vol. 36, no. 1, 2019, pp. 117-118. doi:10.5114/ada.2019.82832. Vancouver Jiang M, Bu W, Chen X, Gu H. A case of papular elastorrhexis. Advances in Dermatology and Allergology/Postępy Dermatologii i Alergologii. 2019;36(1):117-118. doi:10.5114/ada.2019.82832.

PECULIARITIES OF MORPHOLOGICAL CHANGES OF ENDOTHELIOCYTES AND REMODELING OF THE ARTERIES UNDER THE EXPERIMENTAL HYPERCHOLESTEROLEMIA

Introduction: Under the conditions of experimental hypercholesterolemia, endothelial dysfunction develops with the morphological marker which is an increase in the number of blood-circulating desquamated endothelial cells (DEC), but this situation needs to be clarified in the development of this pathology in the age aspect. The aim: To find out the features of remodeling of endothelial cells and arteries of the hind limbs in the rats of pre-repopductive and reproductive age with experimental hypercholesterolemia. Materials and methods: The experimental group consisted of 16 animals with biochemically confirmed hypercholesterolemia, which were divided into 2 groups: group 1 - 8 animals, aged 2-3 months, weighing 150-170 grams and group 2 - 8 rats aged from 11 to 11 months weighing 230-250 gram. The control group consisted of rats of the same age of 8 animals in each. Results: Hypercholesterolemia causes damage to the vascular endothelium of the arteries, which is characterized by an increase in the number of desquamated endothelial cells in the peripheral blood. The most circulating blood in desquamated endothelial cells was detected in 45 days of study in animals of reproductive age, where the number of desquamated endothelial cells increased by 2.56 times, and in animals of pre-reproductive age - 2.35 times. Morphological changes were characterized by thickening of the intima of the arteries of the femur, knee and tibia due to swelling of the endothelial cells, their desquamation and proliferative changes in places of preserved vascular endothelium. In response to the deposition of lipids and PAS-positive substrates, cellular reactions appeared as weak lymphocytic infiltration. In addition to hyperlastosis, fragmentation of elastic fibers was revealed. Correlation of intima contributed to the narrowing of vascular lumen. Lipids, xanthoma cells and sour mucopolysaccharides were accumulated in the inner membrane of the arteries. In addition to lymphocytic infiltrates, the amount of collagen fibers in adventitia increased. Conclusions: Under conditions of hypercholesterolemia the number of desquamated endothelial cells in the blood increases, and arterial remodeling is characterized by manifestations of hypertrophic-neoplastic remodeling in rats of pre-reproductive age, and in reproductive animals there were sclerotic and inflammatory changes.

DEVELOPMENT OF OBLITERATION IN THE GREAT SAPHENOUS VEIN AFTER INFLUENCE OF HIGH-FREQUENCY ENDOVENOUS WELDING BY DATA OF MORPHOLOGICAL AND ULTRASONIC STUDIES

Acute ascending thrombophlebitis (AAT) of the great saphenous vein (GSV) is one of the problems in modern surgery. Study of morphological and ultrasonic changes in a thrombosed vein following the influence of high-frequency endovenous electrical welding and assessment of the efficacy of application of this method to treatment of acute ascending thrombophlebitis. During the period of 2016-2018, surgery departments of Kyiv City Hospital No. 8 provided surgical treatment for 52 male and female patients with AAT of the GSV, who underwent high-frequency endovenous electrical welding (EVEW) with help of an EK300M Svarmed apparatus. The patients’ age ranged from 19 to 78 years (their mean age was 51±2.63 years). According to the international CEAP (сlinical-etiological-anatomical-pathophysiological) classification, C2 was revealed in 4 cases, C3 in 19, C4 in 13, C5 in 9 and C6 in 7. Sections, prepared in compliance with standard methods, were morphologically examined. Photo archiving was made with use of a ZEISS light optical microscope (Germany) and «Axio Imager. A2» data processing system. Duplex ultrasonography (DUS) was performed with help of a TOSHIBA Nemio XG (Japan) device, equipped with a convex transducer having the working frequency of 3.5-5 MC and a linear transducer at a range of 7.5-12 MC. Ultrasonic studies were carried out 2-7 days after the operation. Remote results were assessed after 3, 6 and 12 months. Morphological examinations of vein preparations after EVEW with standard haematoxylin-eosin staining revealed homogenization of thrombotic masses in the venous lumen and a close relationship of the veins with the treated vascular wall; in the majority of examined cases, thrombotic masses totally obliterated the venous lumen. All the layers of the venous wall – internal, middle and external – coalesced into a single homogenous complex. Specific staining on elastic fibers revealed their total destruction in the internal and middle coats, thinning and fragmentation of elastic fibers in the adventitia. Total occlusion of the GSV was observed sonographically in 49 of 52 cases (94.24%) on days 2-7 after the influence of EVEW. Within 3-6 months, 3 cases (5.76%) developed some partial recanalization. During 9-12 months, colour mapping revealed preservation of some partial and haemodynamically insignificant recanalization in 2 cases (3.84%). One case (1.92%) developed the complete and haemodynamically significant recanalization of the whole welded segment of GSV. Analysis of ultrasonic studies showed that despite the total destruction of the whole venous wall during the first days after the influence of EVEW there were areas of parietal blood flow in 5.76% of cases. During a remote period of follow-up from 3 to 6 months the above changes could develop partial and haemodynamically insignificant recanalization in 3.84% of cases. Within the period of follow-up from 9 to 12 months those areas of blood flow could lead to the complete and haemodynamically significant recanalization of the welded GSV in 1.92% of cases. High-frequency EVEW of the thrombosed GSV in AAT caused the total destruction of thrombotic masses and all layers of the venous wall and made it possible to achieve the total obliteration of the welded vein in 94.24 % of cases.

Pebbled skin over axilla and umbilicus

Pseudoxanthoma elasticum or Gronblad–Strandberg syndrome is characterized by progressive calcification and degeneration of the elastic fibers throughout the body. They are noted in the second or third decade and comprise flat-topped, discrete-to-confluent yellowish papules in a linear or reticular pattern over flexures, and periumbilical skin giving a “cobblestone,” “plucked chicken skin,” or “Moroccan leather” appearance. We report a case of 13-year-old-child with yellowish pebbled skin over axilla and umbilicus. Angioid streaks were present on ophthalmological examination. On histopathology, fragmented and curled fibers were present in the dermis giving ravelled wool appearance. Von Kossa and Verhoeff-van gieson stain fibers stains showed calcified and fragmented elastic fibers in the mid-dermis.

Elastic Fiber Fragmentation Increases Transmural Hydraulic Conductance and Solute Transport in Mouse Arteries.

Transmural advective transport of solute and fluid was investigated in mouse carotid arteries with either a genetic knockout of fibulin-5 (Fbln5-/-) or treatment with elastase to determine the influence of a disrupted elastic fiber matrix on wall transport properties. Fibulin-5 is an important director of elastic fiber assembly. Arteries from Fbln5-/- mice have a loose, noncontinuous elastic fiber network and were hypothesized to have reduced resistance to advective transport. Experiments were carried out ex vivo at physiological pressure and axial stretch. Hydraulic conductance (LP) was measured to be 4.99 × 10-6±8.94 × 10-7, 3.18-5±1.13 × 10-5 (p < 0.01), and 3.57 × 10-5 ±1.77 × 10-5 (p < 0.01) mm·s-1·mmHg-1 for wild-type, Fbln5-/-, and elastase-treated carotids, respectively. Solute fluxes of 4, 70, and 150 kDa fluorescein isothiocyanate (FITC)-dextran were statistically increased in Fbln5-/- compared to wild-type by a factor of 4, 22, and 3, respectively. Similarly, elastase-treated carotids demonstrated a 27- and 13-fold increase in net solute flux of 70 and 150 kDa FITC-dextran, respectively, compared to untreated carotids, and 4 kDa FITC-dextran was unchanged between these groups. Solute uptake of 4 and 70 kDa FITC-dextran within Fbln5-/- carotids was decreased compared to wild-type for all investigated time points. These changes in transport properties of elastic fiber compromised arteries have important implications for the kinetics of biomolecules and pharmaceuticals in arterial tissue following elastic fiber degradation due to aging or vascular disease.

Effects of Elastase Digestion on the Murine Vaginal Wall Biaxial Mechanical Response.

Although the underlying mechanisms of pelvic organ prolapse (POP) remain unknown, disruption of elastic fiber metabolism within the vaginal wall extracellular matrix (ECM) has been highly implicated. It has been hypothesized that elastic fiber fragmentation correlates to decreased structural integrity and increased risk of prolapse; however, the mechanisms by which elastic fiber damage may contribute to prolapse are poorly understood. Furthermore, the role of elastic fibers in normal vaginal wall mechanics has not been fully ascertained. Therefore, the objective of this study is to investigate the contribution of elastic fibers to murine vaginal wall mechanics. Vaginal tissue from C57BL/6 female mice was mechanically tested using biaxial extension-inflation protocols before and after intraluminal exposure to elastase. Elastase digestion induced marked changes in the vaginal geometry, and biaxial mechanical properties, suggesting that elastic fibers may play an important role in vaginal wall mechanical function. Additionally, a constitutive model that considered two diagonal families of collagen fibers with a slight preference toward the circumferential direction described the data reasonably well before and after digestion. The present findings may be important to determine the underlying structural and mechanical mechanisms of POP, and aid in the development of growth and remodeling models for improved assessment and prediction of changes in structure-function relationships with prolapse development.

Structural characterization of the L0 cytoplasmic loop of human multidrug resistance protein 6 (MRP6)

ABCC6 is a member of the C subfamily of ATP-binding cassette transporters whose mutations are correlated to Pseudoxanthoma elasticum, an autosomal recessive, progressive disorder characterized by ectopic mineralization and fragmentation of elastic fibers. Structural studies of the entire protein have been hindered by its large size, membrane association, and domain complexity. Studies previously performed have contributed to shed light on the structure and function of the nucleotide binding domains and of the N-terminal region. Here we report the expression in E. coli of the polypeptide E205-G279 contained in the cytoplasmic L0 loop. For the first time structural studies in solution were performed. Far-UV CD spectra showed that L0 is structured, assuming predominantly α-helix in TFE solution and turns in phosphate buffer. Fluorescence spectra indicated some flexibility of the regions containing aromatic residues. 1H NMR spectroscopy identified three helical regions separated by more flexible regions.

Absence of LTBP-3 attenuates the aneurysmal phenotype but not spinal effects on the aorta in Marfan syndrome.

Fibrillin-1 is an elastin-associated glycoprotein that contributes to the long-term fatigue resistance of elastic fibers as well as to the bioavailability of transforming growth factor-beta (TGFβ) in arteries. Altered TGFβ bioavailability and/or signaling have been implicated in aneurysm development in Marfan syndrome (MFS), a multi-system condition resulting from mutations to the gene that encodes fibrillin-1. We recently showed that the absence of the latent transforming growth factor-beta binding protein-3 (LTBP-3) in fibrillin-1-deficient mice attenuates the fragmentation of elastic fibers and focal dilatations that are characteristic of aortic root aneurysms in MFS mice, at least to 12weeks of age. Here, we show further that the absence of LTBP-3 in this MFS mouse model improves the circumferential mechanical properties of the thoracic aorta, which appears to be fundamental in preventing or significantly delaying aneurysm development. Yet, a spinal deformity either remains or is exacerbated in the absence of LTBP-3 and seems to adversely affect the axial mechanical properties of the thoracic aorta, thus decreasing overall vascular function despite the absence of aneurysmal dilatation. Importantly, because of the smaller size of mice lacking LTBP-3, allometric scaling facilitates proper interpretation of aortic dimensions and thus the clinical phenotype. While this study demonstrates that LTBP-3/TGFβ directly affects the biomechanical function of the thoracic aorta, it highlights that spinal deformities in MFS might indirectly and adversely affect the overall aortic phenotype. There is a need, therefore, to consider together the vascular and skeletal effects in this syndromic disease.

Arterial tortuosity syndrome: 40 new families and literature review

PurposeWe delineate the clinical spectrum and describe the histology in arterial tortuosity syndrome (ATS), a rare connective tissue disorder characterized by tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10. MethodsWe retrospectively characterized 40 novel ATS families (50 patients) and reviewed the 52 previously reported patients. We performed histology and electron microscopy (EM) on skin and vascular biopsies and evaluated TGF-β signaling with immunohistochemistry for pSMAD2 and CTGF. ResultsStenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation. Thus far, no reports unequivocally document vascular dissections or ruptures. Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS) are frequently observed. Skin and vascular biopsies show fragmented elastic fibers (EF) and increased collagen deposition. EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality. Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling. ConclusionOur findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards. EM on skin biopsies shows disease-specific abnormalities.

COMPARATIVE CHARACTERISTIC OF MORPHOLOGICAL CHANGES AND PHENOTYPIC MARKERS OF DISPLASIA OF CONNECTIVE TISSUE IN CHILDREN WITH VARIOUS UROLOGICAL AND ANDROLOGICAL PATHOLOGY

The increase in the number of urological and andrological diseases associated with undifferentiated connective tissue dysplasia dictates the need to study this problem in childhood. The present study was aimed at analyzing the phenotypic manifestations of undifferentiated connective tissue dysplasia, as well as the severity of the morphological changes in its structures in children with various urological and andrological pathology, that constituted the main observation group. As a control group, children with a similar pathology of the genitourinary system without signs of mesenchymal insufficiency were examined. Comparative analysis of the detection of the number of phenotypic markers as one of the indicators of connective tissue dysplasia in children with various nosological forms from the urological department made it possible to determine the prevalence rate of the number of phenotypes in patients with hypospadia, varicocele and congenital edema of the testicle, and in the highest percentage of cases - in patients with hypospadias. Craniocephalic anomalies and small anomalies of the oral cavity were diagnosed most frequently. In a smaller percentage of cases, stigmata of the auricles and the osteoarticular system were identified. Phenotypic manifestations of dysplasia in the form of eye anomalies, pathology of the skin and its appendages - were noted even less often. The morphological confirmation of undifferentiated connective tissue dysplasia in the examined patients was the detection of dystrophy of collagen and elastic fibers, detected by means of microscopy. At the same time, a characteristic sign of dysplasia was the chaotic arrangement of collagen fibers, their thickening and discontinuity. Staining for elastin allowed detecting the uneven arrangement, curvature or fragmentation of elastic fibers. In the work, there was made a study of the features of morphological changes in connective tissue structures, depending on the nosological form. With this aim, we divided various histological signs of mesenchymal insufficiency, revealed during microscopy, in three degrees of the severity. Histological studies of connective tissue structures confirmed the predominance of more pronounced morphological manifestations of dysplasia in patients with hypospadias. They had severe dystrophic changes in 70% of cases, while such abnormalities in children operated for varicocele, were noted in every fourth biopsy, and in hydrops patients - only in 15% of cases. The study of collagen and elastic fibers of dermal preparations resected during surgical interventions in children with phimosis against the background of dysplasia syndrome showed no significant pathological changes. In biopsies of this group of patients, there were only minimal manifestations of mesenchymal insufficiency. In children with urological and andrological pathology without signs of undifferentiated dysplasia, morphological disturbances in structural components of connective tissue corresponding to mild severity were noted. Thus, the performed analysis of manifestations of connective tissue dysplasia in children with various urological and andrological pathology showed the prevalence of the number of phenotypic markers and the severity of morphological changes in children with hypospadias. Less severe manifestations of dysplasia were noted in patients with varicocele and hydrocele. The study of signs of connective tissue insufficiency in the group of patients with phimosis showed their minimal manifestations.

Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice

Fluoroquinolones are among the most commonly prescribed antibiotics. Recent clinical studies indicated an association between fluoroquinolone use and increased risk of aortic aneurysm and dissection (AAD). This alarming association has raised concern, especially in patients with AAD with risk of rupture and in individuals at risk for developing AAD. To examine the effect of ciprofloxacin on AAD development in mice. In a mouse model of moderate, sporadic AAD, 4-week-old male and female C57BL/6J mice were challenged with a high-fat diet and low-dose angiotensin infusion (1000 ng/min/kg). Control unchallenged mice were fed a normal diet and infused with saline. After randomization, challenged and unchallenged mice received ciprofloxacin (100 mg/kg/d) or vehicle through daily gavage during angiotensin or saline infusion. Aortic aneurysm and dissection development and aortic destruction were compared between mice. The direct effects of ciprofloxacin on aortic smooth muscle cells were examined in cultured cells. No notable aortic destruction was observed in unchallenged mice that received ciprofloxacin alone. Aortic challenge induced moderate aortic destruction with development of AAD in 17 of 38 mice (45%) and severe AAD in 9 (24%) but no rupture or death. However, challenged mice that received ciprofloxacin had severe aortic destruction and a significantly increased incidence of AAD (38 of 48 [79%]; P = .001; χ2 = 10.9), severe AAD (32 of 48 [67%]; P < .001; χ2 = 15.7), and rupture and premature death (7 of 48 [15%]; P = .01; χ2 = 6.0). The increased AAD incidence was observed in different aortic segments and was similar between male and female mice. Compared with aortic tissues from challenged control mice, those from challenged mice that received ciprofloxacin showed decreased expression of lysyl oxidase, an enzyme that is critical in the assembly and stabilization of elastic fibers and collagen. These aortas also showed increased matrix metalloproteinase levels and activity, elastic fiber fragmentation, and aortic cell injury. In cultured smooth muscle cells, ciprofloxacin treatment significantly reduced lysyl oxidase expression and activity, increased matrix metalloproteinase expression and activity, suppressed cell proliferation, and induced cell death. Furthermore, ciprofloxacin-a DNA topoisomerase inhibitor-caused nuclear and mitochondrial DNA damage and the release of DNA into the cytosol, subsequently inducing mitochondrial dysfunction, reactive oxygen species production, and activation of the cytosolic DNA sensor STING, which we further showed was involved in the suppression of lysyl oxidase expression and induction of matrix metalloproteinase expression. Ciprofloxacin increases susceptibility to aortic dissection and rupture in a mouse model of moderate, sporadic AAD. Ciprofloxacin should be used with caution in patients with aortic dilatation, as well as in those at high risk for AAD.

Pseudoxanthoma Elasticum: Beyond the Skin

The pseudoxanthoma elasticum (PXE) is a metabolic genetic disorder affecting connective tissue characterized by calcification and fragmentation of elastic fibers, which essentially affects the skin, the eyes and the cardiovascular system.

Free Gingival Graft versus Mucograft: Histological Evaluation.

INTRODUCTION:The correction of the gingival recession is of esthetical and functional significance, but the tissue regeneration can only be confirmed by a histological examination.AIM:This study aims to make a comparison between the free gingival graft and the autograft.MATERIAL AND METHODS:This study included 24 patients with single and multiple gingival recessions. Twelve patients were treated with a free gingival graft and the other twelve with a micrograft. Six months after the surgical procedure, a micro-punch biopsy of the transplantation area was performed. The tissue was histologically evaluated, graded in 4 categories: immature, mature, fragmented and edematous collagen tissue. The elastic fibres were also examined and graded in three categories: with a normal structure, fragmented rare and fragmented multiplied.RESULTS:Regarding the type of collagen tissue that was present, there was a significant difference between the two groups of patients, with a larger number of patients treated with a micrograft showing a presence of mature tissue, compared to the patients treated with a free gingival graft. A larger number of patients in both of the groups displayed elastic fibres with a rare fragmented structure; 33.3% of the patients showed a normal structure; 50% demonstrated a normal structure.CONCLUSION:The patients treated with a free gingival graft showed a larger presence of fragmented collagen tissue and fragmented elastic fibres, whereas a mature tissue was predominantly present in the surgical area where a Geistlich Mucograft was placed.

Redox stress in Marfan syndrome: Dissecting the role of the NADPH oxidase NOX4 in aortic aneurysm.

Marfan syndrome (MFS) is characterized by the formation of ascending aortic aneurysms resulting from altered assembly of extracellular matrix fibrillin-containing microfibrils and dysfunction of TGF-β signaling. Here we identify the molecular targets of redox stress in aortic aneurysms from MFS patients, and investigate the role of NOX4, whose expression is strongly induced by TGF-β, in aneurysm formation and progression in a murine model of MFS. Working models included aortae and cultured vascular smooth muscle cells (VSMC) from MFS patients, and a NOX4-deficient Marfan mouse model (Fbn1C1039G/+-Nox4-/-). Increased tyrosine nitration and reactive oxygen species levels were found in the tunica media of human aortic aneurysms and in cultured VSMC. Proteomic analysis identified nitrated and carbonylated proteins, which included smooth muscle α-actin (αSMA) and annexin A2. NOX4 immunostaining increased in the tunica media of human Marfan aorta and was transcriptionally overexpressed in VSMC. Fbn1C1039G/+-Nox4-/- mice aortas showed a reduction of fragmented elastic fibers, which was accompanied by an amelioration in the Marfan-associated enlargement of the aortic root. Increase in the contractile phenotype marker calponin in the tunica media of MFS mice aortas was abrogated in Fbn1C1039G/+-Nox4-/- mice. Endothelial dysfunction evaluated by myography in the Marfan ascending aorta was prevented by the absence of Nox4 or catalase-induced H2O2 decomposition. We conclude that redox stress occurs in MFS, whose targets are actin-based cytoskeleton members and regulators of extracellular matrix homeostasis. Likewise, NOX4 have an impact in the progression of the aortic dilation in MFS and in the structural organization of the aortic tunica media, the VSMC phenotypic modulation, and endothelial function.

Inborn Errors of Metabolism: Pseudoxanthoma Elasticum.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive multisystem disorder that involves the skin, GI tract, and heart, as well as the eye. It affects approximately 1 in 50,000 people worldwide and is seen twice as frequently in females as in males. Fundus findings include angioid streaks (Fig. 38.1), reticular macular dystrophy, speckled appearance temporal to the macula (peau d'orange, like the dimpled texture of an orange peel), drusen of the optic nerve, and vitelliform-like deposits. Peau d'orange may precede the development of an angioid streak. "Comets," with or without a tail, are seen as solitary subretinal, nodular white bodies of retinal pigment epithelium (RPE) atrophy, usually present in the mid periphery (Fig. 38.2). The tail points toward the optic disc. Patients sometimes develop choroidal neovascular membrane. Skin changes (plucked chicken-like appearance) occur on the flexure areas, including the neck and axilla, as well as increased skin laxity with excessive skin folding. Cardiovascular changes include accelerated atherosclerosis with occlusive vascular disease leading to angina, hypertension, restrictive cardiomyopathy, mitral valve prolapse, and others. Progressive calcification and fragmentation of elastic fibers in the skin, eye, and cardiovascular system is the underlying pathophysiology.

Pseudoxanthoma elastic

The pseudoxanthoma elasticum is a generalized disease of the connective tissue involving the skin, eyes and cardiovascular system triggering the fragmentation and calcification of elastic fibers. Usually occurs after puberty, the manifestations characteristics are small spots, circumscribed, yellowish, located on the neck, axilla and inguinal folds. Angioid streaks in the retina, tendency to hemorrhage and arterial insufficiency are the most common complications. This disease can be inherited as autosomal dominant or recessive. The treatment of ocular manifestations is through the [...]

Annular elastolytic giant cell granuloma: An atypical presentation

Annular elastolytic giant cell granuloma is a rare granulomatous disease with unknown pathogenesis. It clinically presents as single or multiple well-defined erythematous annular arciform serpiginous polycyclic plaque with indurated elevated borders and central atrophy in sun-exposed areas. It is found to have a causal association with conditions such as diabetes mellitus, T-cell leukemia, CD4 lymphoma, cutaneous amyloidosis, squamous cell carcinoma lung, sarcoidosis, and monoclonal gammopathy. On histopathology, characteristic “elastophagocytosis” of dermal elastic fibers by the multinucleated giant cells is seen. The presence of horizontally oriented fragmented elastic fibers is characteristic. There is no necrobiosis or mucin deposition, thus differentiating from granuloma annulare. We herein report a case of elderly male with type 2 diabetes mellitus who presented with asymptomatic multiple discrete erythematous shiny dome-shaped papules over anterior chest, abdomen, and back of 2-month duration. The diagnosis was confirmed by biopsy and thorough workup for associations was done. This case is reported due to the rarity of the disease, the atypical presentation, and the characteristic histopathology which lead to the diagnosis.

Pseudoxanthoma Elasticum-Like in β-Thalassemia Major, a matter of α-Klotho and Parathyroid Hormone?

Pseudoxanthoma elasticum-like (PXL) condition is one of the complications faced by patients with β-thalassemia major (β-TM). Histopathological features include abnormal, mineralized and fragmented elastic fibers in skin, eyes and arterial blood vessels (elastorrhexia). The pathogenesis of PXL lesions in β-TM is not yet completely understood. This study was aimed at analyzing a possible implication of α-Klotho in the clinical manifestation of PXL in patients with β-TM (30 with and 78 without PXL). A significant correlation was observed between Klotho, parathyroid hormone (PTH) and serum calcium (Ca). Our analysis seems to indicate α-Klotho and PTH as factors that can affect the development of PXL.