An 18-Year-Old Man with Idiopathic Non-cirrhotic Portal Hypertension

Non-Cirrhotic Portal Hypertension (NCPH) is a rare cause of hematemesis and melena. Like in cirrhotic patient, hematemesis in NCPH patient was caused by rupture of esophageal varices. But unlike in cirrhotic patient, in NCPH there are no sign of liver failure, because liver physiology is still normal. We reported case of male patient with NCPH that had hematemesis because of rupture of esophageal varices

Scleroderma-like Impairment in the Network of Telocytes/CD34+ Stromal Cells in the Experimental Mouse Model of Bleomycin-Induced Dermal Fibrosis

Considerable evidence accumulated over the past decade supports that telocytes (TCs)/CD34+ stromal cells represent an exclusive type of interstitial cells identifiable by transmission electron microscopy (TEM) or immunohistochemistry in various organs of the human body, including the skin. By means of their characteristic cellular extensions (telopodes), dermal TCs are arranged in networks intermingled with a multitude of neighboring cells and, hence, they are thought to contribute to skin homeostasis through both intercellular contacts and releasing extracellular vesicles. In this context, fibrotic skin lesions from patients with systemic sclerosis (SSc, scleroderma) appear to be characterized by a disruption of the dermal network of TCs, which has been ascribed to either cell degenerative processes or possible transformation into profibrotic myofibroblasts. In the present study, we utilized the well-established mouse model of bleomycin-induced scleroderma to gain further insights into the TC alterations found in cutaneous fibrosis. CD34 immunofluorescence revealed a severe impairment in the dermal network of TCs/CD34+ stromal cells in bleomycin-treated mice. CD31/CD34 double immunofluorescence confirmed that CD31−/CD34+ TC counts were greatly reduced in the skin of bleomycin-treated mice compared with control mice. Ultrastructural signs of TC injury were detected in the skin of bleomycin-treated mice by TEM. The analyses of skin samples from mice treated with bleomycin for different times by either TEM or double immunostaining and immunoblotting for the CD34/α-SMA antigens collectively suggested that, although a few TCs may transition to α-SMA+ myofibroblasts in the early disease stage, most of these cells rather undergo degeneration, and then are lost. Taken together, our data demonstrate that TC changes in the skin of bleomycin-treated mice mimic very closely those observed in human SSc skin, which makes this experimental model a suitable tool to (i) unravel the pathological mechanisms underlying TC damage and (ii) clarify the possible contribution of the TC loss to the development/progression of dermal fibrosis. In perspective, these findings may have important implications in the field of skin regenerative medicine

Angiogenic T cell expansion correlates with severity of peripheral vascular damage in systemic sclerosis

The mechanisms underlying endothelial cell injury and defective vascular repair in systemic sclerosis (SSc) remain unclear. Since the recently discovered angiogenic T cells (Tang) may have an important role in the repair of damaged endothelium, this study aimed to analyze the Tang population in relation to disease-related peripheral vascular features in SSc patients. Tang (CD3+CD31+CXCR4+) were quantified by flow cytometry in peripheral blood samples from 39 SSc patients and 18 healthy controls (HC). Circulating levels of the CXCR4 ligand stromal cell-derived factor (SDF)-1α and proangiogenic factors were assessed in paired serum samples by immunoassay. Serial skin sections from SSc patients and HC were subjected to CD3/CD31 and CD3/CXCR4 double immunofluorescence. Circulating Tang were significantly increased in SSc patients with digital ulcers (DU) compared either with SSc patients without DU or with HC. Tang levels were significantly higher in SSc patients with late nailfold videocapillaroscopy (NVC) pattern than in those with early/active NVC patterns and in HC. No difference in circulating Tang was found when comparing either SSc patients without DU or patients with early/active NVC patterns and HC. In SSc peripheral blood, Tang percentage was inversely correlated to levels of SDF-1α and CD34+CD133+VEGFR-2+ endothelial progenitor cells (EPC), and positively correlated to levels of vascular endothelial growth factor and matrix metalloproteinase-9. Tang were frequently detected in SSc dermal perivascular inflammatory infiltrates. In summary, our findings demonstrate for the first time that Tang cells are selectively expanded in the circulation of SSc patients displaying severe peripheral vascular complications like DU. In SSc, Tang may represent a potentially useful biomarker reflecting peripheral vascular damage severity. Tang expansion may be an ineffective attempt to compensate the need for increased angiogenesis and EPC function. Further studies are required to clarify the function of Tang cells and investigate the mechanisms responsible for their change in SSc

Pengaruh Suplementasi Curcuma Xanthorriza Pada Pasien Lupus Eritematosus Sistemik (Les) Dengan Hipovitamin D Yang Diberikan Vitamin D3 Terhadap Derajat Kelelahan (Fatigue), Kadar Il-6 Dan Tgf–Β1 Serum

PPDS I Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Brawijaya, Rumah Sakit Umum Daerah dr. Saiful Anwar Malang 2 Divisi Reumatologi dan Alergi Imunologi, Departemen Ilmu Penyakit Dalam Fakultas Kedokteran Universitas Brawijaya Malang, Rumah Sakit Umum Daerah dr. Saiful Anwar Malang Tujuan: Bagaimana pengaruh penambahan Curcuma xanthorriza pada pemberian vitamin D3 terhadap derajat kelelahan (fatigue) serta perubahan kadar sitokin IL-6 dan TGF-β1 pada pasien LES dengan hipovitamin D. Metode : Penelitian randomized double blind controlled trial pada 40 pasien LES yang rutin berobat di Poli Reumatologi RS Dr. Saiful Anwar Malang, 20 sampel mendapat softgel vitamin D3/Cholecalciferol 1200 IU/hari dan plasebo sedangkan 20 lainnya mendapat softgel vitamin D3/Cholecalciferol 1200 IU/hari dan tablet Curcuma xanthoriza 60mg/hari selama 3 bulan. Variabel yang dianalisis sebelum dan sesudah suplementasi adalah nilai FSS (Fatigue Severity Scale) dan VAS-F (Visual Analogue Scale-Fatigue), kadar vitamin D/ 25(OH)D diukur dalam serum dengan metoda Enzyme Immuno Assay dari DiaSorin dengan satuan ng/ml, kadar IL-6 dan TGF-β1 serum yang diukur dengan metode ELISA dari Biolegend dengan satuan pg/ml. Hasil: Pasien yang memenuhi kriteria inklusi dan eksklusi untuk kelompok plasebo adalah 20 orang dan kelompok Curcuma xanthorriza adalah 19 orang dimana 1 pasien dari kelompok Curcuma xanthorriza dropout karena ketidakpatuhan berobat. Terdapat peningkatan signifikan kadar vitamin D pada kedua kelompok tetapi tidak berbeda bermakna antara delta keduanya (p=0.166). Kadar vitamin D setelah suplementasi berbeda bermakna pada kelompok plasebo dibandingkan kelompok Curcuma xanthorriza (p=0.047*). Nilai FSS menurun signifikan tetapi tidak berbeda bermakna antara delta keduanya (p=0.300). Nilai VAS-F menurun signifikan pada kedua kelompok tetapi tidak berbeda bermakna antara delta keduanya (p=0.085). Kadar IL-6 menurun signifikan pada kedua kelompok tetapi tidak berbeda bermakna antara delta keduanya (p=0.061). Kadar TGF-β1 meningkat signifikan tetapi tidak berbeda bermakna antara delta keduanya (p=0.535). Terapat korelasi positif antara nilai FSS dan VAS-F dengan (p=0.001*, r=0.571), tetapi tidak didapatkan korelasi antara fatigue dengan IL-6 dan TGF-β1 serum. Kesimpulan: Pemberian Curcuma xanthorriza pada pemberian vitamin D3 bagi pasien LES yang hipovitamin D tidak berbeda bermakna dalam menurunkan derajat fatigue, menurunkan kadar IL-6, TGF-β1 serum dibandingkan pemberian vitamin D3 saja

The contribution of mesenchymal transitions to the pathogenesis of systemic sclerosis

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Recent Insights into Cellular and Molecular Mechanisms of Defective Angiogenesis in Systemic Sclerosis

In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. In this narrative review, we aimed to give a comprehensive overview of recent studies dealing with the cellular and molecular mechanisms underlying SSc defective angiogenesis and the related endothelial cell dysfunctions, mainly the endothelial-to-mesenchymal transition process. We also discussed potential novel vascular treatment strategies able to restore the angiogenic process and reduce the endothelial-to-mesenchymal transition in this complex disease

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

Systemic sclerosis (SSc, scleroderma) is a multifaceted rare connective tissue disease whose pathogenesis is dominated by immune dysregulation, small vessel vasculopathy, impaired angiogenesis, and both cutaneous and visceral fibrosis. Microvascular impairment represents the initial event of the disease, preceding fibrosis by months or years and accounting for the main disabling and/or life-threatening clinical manifestations, including telangiectasias, pitting scars, periungual microvascular abnormalities (e.g., giant capillaries, hemorrhages, avascular areas, ramified/bushy capillaries) clinically detectable by nailfold videocapillaroscopy, ischemic digital ulcers, pulmonary arterial hypertension, and scleroderma renal crisis. Despite a variety of available treatment options, treatment of SSc-related vascular disease remains problematic, even considering SSc etherogenity and the quite narrow therapeutic window. In this context, plenty of studies have highlighted the great usefulness in clinical practice of vascular biomarkers allowing clinicians to assess the evolution of the pathological process affecting the vessels, as well as to predict the prognosis and the response to therapy. The current narrative review provides an up-to-date overview of the main candidate vascular biomarkers that have been proposed for SSc, focusing on their main reported associations with characteristic clinical vascular features of the disease

Circulating Neurovascular Guidance Molecules and Their Relationship with Peripheral Microvascular Impairment in Systemic Sclerosis

Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease whose earliest clinical manifestations are microvascular tone dysregulation and peripheral microcirculatory abnormalities. Following previous evidence of an association between circulating neurovascular guidance molecules and SSc disturbed angiogenesis, here, we measured the levels of soluble neuropilin 1 (sNRP1), semaphorin 3E (Sema3E), and Slit2 by enzyme-linked immunosorbent assay in serum samples from a large case series of 166 SSc patients vs. 110 healthy controls. We focused on their possible correlation with vascular disease clinical features and applied logistic regression analysis to determine which of them could better reflect disease activity and severity. Our results demonstrate that, in SSc: (i) sNRP1 is significantly decreased, with lower sNRP1 serum levels correlating with the severity of nailfold videocapillaroscopy (NVC) abnormalities and the presence of ischemic digital ulcers (DUs); (ii) both Sema3E and Slit2 are increased, with Sema3E better reflecting early NVC abnormalities; and (iii) higher Sema3E correlates with the absence of DUs, while augmented Slit2 associates with the presence of DUs. Receiver operator characteristics curve analysis revealed that both circulating sNRP1 and Sema3E show a moderate diagnostic accuracy. Moreover, logistic regression analysis allowed to identify sNRP1 and Sema3E as more suitable independent biomarkers reflecting the activity and severity of SSc-related peripheral microvasculopathy