Abnormal Collagen Deposition Research Articles

Oral Submucous Fibrosis: A Review on Etiopathogenesis, Diagnosis, and Therapy.

Oral submucous fibrosis (OSF) is characterized by abnormal collagen deposition. It is a precancerous disorder and transforms into a malignant tumor in 1.5–15% of all cases. Symptoms include submucous fibrosis, ulceration, xerostomia, a burning sensation, and restricted mouth opening. All of these greatly interfere with patient quality of life. The present review introduces OSF from a molecular perspective and summarizes what is known about its underlying mechanisms, diagnostic biomarkers, and therapeutic interventions. In addition to the aggressive treatment of OSF, its prevention is also important. Future research should, therefore, focus on improving the oral health literacy of the patients susceptible to OSF.

Brain cytoplasmic RNA 1 suppresses smooth muscle differentiation and vascular development in mice

The cardiovascular system develops during the early stages of embryogenesis, and differentiation of smooth muscle cells (SMCs) is essential for that process. SMC differentiation is critically regulated by transforming growth factor (TGF)-β/SMAD family member 3 (SMAD3) signaling, but other regulators may also play a role. For example, long noncoding RNAs (lncRNAs) regulate various cellular activities and events, such as proliferation, differentiation, and apoptosis. However, whether long noncoding RNAs also regulate SMC differentiation remains largely unknown. Here, using the murine cell line C3H10T1/2, we found that brain cytoplasmic RNA 1 (BC1) is an important regulator of SMC differentiation. BC1 overexpression suppressed, whereas BC1 knockdown promoted, TGF-β-induced SMC differentiation, as indicated by altered cell morphology and expression of multiple SMC markers, including smooth muscle α-actin (αSMA), calponin, and smooth muscle 22α (SM22α). BC1 appeared to block SMAD3 activity and inhibit SMC marker gene transcription. Mechanistically, BC1 bound to SMAD3 via RNA SMAD-binding elements (rSBEs) and thus impeded TGF-β-induced SMAD3 translocation to the nucleus. This prevented SMAD3 from binding to SBEs in SMC marker gene promoters, an essential event in SMC marker transcription. In vivo, BC1 overexpression in mouse embryos impaired vascular SMC differentiation, leading to structural defects in the artery wall, such as random breaks in the elastic lamina, abnormal collagen deposition on SM fibers, and disorganized extracellular matrix proteins in the media of the neonatal aorta. Our results suggest that BC1 is a suppressor of SMC differentiation during vascular development.

Disruption of TFGβ-SMAD3 pathway by the nuclear receptor SHP mediates the antifibrotic activities of BAR704, a novel highly selective FXR ligand

Liver fibrosis, a major health concern worldwide, results from abnormal collagen deposition by activated hepatic stellate cells (HSCs) in an injured liver. The farnesoid-x-receptor (FXR) is a bile acid sensor that counteracts HSCs transdifferentiation. While targeting FXR holds promise, 6-ethyl-CDCA known as obeticholic acid, the first in class of FXR ligands, causes side effects, partially because the lack of selectivity toward GPBAR1, a putative itching receptor. Here, we describe the 3-deoxy-6-ethyl derivative of CDCA, BAR704, as a highly selective steroidal FXR agonist. MethodsLiver Fibrosis was induced in mice by carbon tetrachloride (CCl4). Main resultsIn transactivation assay BAR704 activated FXR with and EC50 of 967 nM while exerted no agonistic activity on other receptors including GPBAR1. In naïve mice, BAR704 modulated the expression of FXR target genes in the liver of wild type mice but not in FXR−/− mice. In cirrhotic mice, administration of BAR704, 15 mg/kg for 9 weeks, spared the liver biosynthetic activity (bilirubin and albumin plasma levels), reduced liver fibrosis score (Sirius red staining), expression of pro-fibrogenetic (Colα1α, TGFβ and αSMA) and inflammatory genes (IL-1β, TNFα) and portal pressure. From mechanistic stand point, we have found that exposure of LX2 cells, a human HSCs line, to BAR704 increased the transcription of the short heterodimer partner (SHP) and induced the binding of this nuclear receptor to SMAD3, thus abrogating the binding of phosho-SMAD3 to the TGFβ promoter. Conclusions and applications.BAR704 is a selective FXR agonist that reduces liver fibrosis by interfering with the TGFβ-SMAD3 pathway in HSCs. Selective FXR agonists may represent an attractive strategy for the treatment of liver fibrosis.

Schistosoma mansoni and endocarditis: from egg to free DNA detection in Egyptian patients and infected BALB/c mice.

With the growing incidence of closed schistosomiasis and uncommon presentations, there is a risk of the infection rate being underestimated. A study in Japan reported an unexplained case of endocarditis that was finally diagnosed as a complex Schistosoma japonicum infection; in the absence of advanced techniques, the diagnosis was delayed. We therefore set out to explore the incidence of Schistosoma mansoni in endocarditis patients coming from areas of Egypt where S. mansoni is endemic. We also investigated histopathological changes in the cardiac valves and the presence of cell-free parasite DNA (CFPD) in cardiac tissues of laboratory mice infected with S. mansoni. The study included 186 patients with the manifestations of infective endocarditis. Eggs were detected in the stool samples of 5.91% of patients. Seropositivity was reported in 23.66% of patients and antigen was detected in the urine samples of 10.21%. Using real-time polymerase chain reaction (PCR), CFPD was detected in the blood of 6.98% of the endocarditis patients and 95% of the infected mice, while the cardiac samples of 45% of the mice tested positive for CFPD (means ± SD = 1390.2 ± 283.65, 2158.72 ± 1103.1 and 5.71 ± 2.91, respectively). Histopathological examination revealed abnormal collagen deposition, inflammatory cells and haemorrhagic pigmentation in the heart sections. Despite the low incidence of S. mansoni infection in the studied cohort, the presence of CFPD in the cardiac tissue of infected mice makes it necessary to: (1) investigate the hazards of CFPD deposition in endothelium-rich organs; and (2) test the potential of CFPD to trigger tissue inflammation, abnormal proliferation or genome integration.

Collagenase Clostridium Histolyticum in the Treatment of Peyronie's Disease: Review of a Minimally Invasive Treatment Option.

Peyronie's disease (PD) is an inflammatory disorder characterized by an abnormal collagen deposition in the tunica albuginea of the penis, leading to fibrous and non-compliant plaques that can impede normal erection. Although pharmacological treatments are available, only intralesional injection therapy and surgical reconstruction have demonstrated tangible clinical efficacy in the management of this condition. Intralesional injection of collagenase clostridium histolyticum (CCH) has come to the forefront of minimally invasive treatment of PD. In this review, the authors provide an update on the safety, efficacy, and indications for CCH. The efficacy of CCH will be assessed on the basis of improvement in the severity of penile fibrosis, curvature, and pain. Numerous well-designed clinical trials and post-approval studies involving more than 1,500 patients have consistently demonstrated the efficacy and tolerability of CCH in the treatment of PD. CCH significantly decreases penile curvature and plaque consistency, as well as improves quality of life. Post-approval studies continue to demonstrate the efficacy of CCH despite broader inclusion criteria for treatment, such as the case with acute phase disease and atypical plaque deformities (i.e., ventral plaques, hourglass narrowing). CCH continues to be the gold standard for non-surgical management of stable phase PD, in the absence of strong evidence supporting oral therapy agents and ongoing evaluation of extracorporeal shockwave therapy. However, recent studies are beginning to provide precedent for the use of CCH in the management of acute phase and atypical PD.

Erroneus measurement of the intraocular pressure with the goldmann aplanation tonometry in fuchs endothelial corneal dystrophy

PurposeFuchs endothelial corneal dystrophy (FECD) is a bilateral, progressive, disease of the corneal endothelium. It's caused by an abnormal collagen deposition in Descemet membrane leading to progressive degeneration of endothelial cells. The loss of endothelial cells prevents the removal of water from the cornea, causing corneal edema. Later stages involve other layers corneal layers. It is most frequently a spontaneous disease although several autosomal dominant mutations have been reported.It has been described that corneal thickness influences the corneal biomechanics properties, leading to an erroneous measurement of the intraocular pressure (IOP) with the Goldmannn aplanation tonometry.MethodsWe report a patient diagnosed with FECD and his IOP was measured with Goldamann applanation tonometry (GAT) and Ocular Response Analyser (ORA). As well as corneal hysteresis (CH), corneal resistance factor (CRF) were recorded with the ORA. We have followed this patient for several years we also carried out corneal topographic maps and spectral domain optical coherence tomography (SD‐OCT) to complete the study.ResultsThe evolution of our patient showed a corneal edema related to an abnormal endothelium. We noticed that compensated IOP was significantly higher than GAT IOP and Goldmann IOP due to biomechanic changes secondary to corneal edema.ConclusionsIOP in patients with FECD and edema should be measured with ORA so compensated IOP is registered avoiding the underestimation of only GAT.

Band-like Acral Osteolysis in Limited Cutaneous Scleroderma

Abstract: Acral osteolysis is a well-recognized manifestation of scleroderma. Scleroderma is characterized by abnormal deposition of collagen and other extra cellular matrix macromolecules leading to vascular damage, inflammation and tissue fibrosis. Acral osteolysis in scleroderma occurs due to digital ischemia resulting from the vasculopathy. Treatment is directed towards providing symptomatic relief and prevention of complications. Here we present a case of band-like acral osteolysis seen in a patient of limited cutaneous scleroderma. Keywords: Osteolysis; Acral osteolysis; Scleroderma; Systemic sclerosis Introduction:Scleroderma is a multisystem connective tissue disorder that is characterised by abnormal deposition of collagen and other connective tissue macromolecules in the skin and multiple internal organs leading to inflammation and fibrosis. The exact etiology is unknown. Various genetic, infectious, and environmental factors have been implicated in the pathogenesis of scleroderma leading to vascular injury, fibrosis, and immune activation. The pathological pathways include vasculopathy and abnormalities in both humoral and cellular immunity. Osteolysis is a well-recognized manifestation of scleroderma. Here we report a case of band-like acral osteolysis seen in a patient of scleroderma. Clinical Presentation: A 25 years old female presented with a history of progressive tightening of the skin over her fingers and face for 3 years associated with phasic changes in skin colour (white, blue and red) typical of Raynaud’s phenomenon. On physical examination, the skin over her face appear stretched out, tight and shiny. The skin over the distal part of most her fingers also appear tight and stretched out. The tips of most of her fingers appear shortened (Figure 1). A test for antinuclear antibodies was positive with a titre of 1: 1280. Her Anticentromere antibodies were positive. A radiograph of both hands showed symmetrical band-like osteolysis of the diaphysis of distal phalanges suggestive of acral osteolysis (Figure 2). Echocardiography revealed a normal study. Further test were done that ruled out other organ systems involvement. Discussion: Acral osteolysis in scleroderma is thought to result from impaired blood flow due to vasculopathy resulting in digital ischemia and subsequent damage to the terminal phalanges [1]. It may also be a result of pressure changes due to the induration and tightening of the skin. Acral osteolysis can also be seen in various other pathological conditions such as diabetes mellitus, tabes dorsalis, leprosy, psoriasis, rheumatoid arthritis, exposure to vinyl chloride, following trauma or in association with hyperparathyroidism [2]. Treatment options are limited and is focused on providing symptomatic relief and preventing complications. Patients should avoid prolonged cold exposure and avoid digital or skin trauma. Calcium channel blockers and alpha receptor blockers may reduce the ischemia by promoting vasodilatation. Phosphodiesterase-5 inhibitors such as sildenafil may also help provide symptomatic relieve. The disease is, however, progressive in nature and currently there are no approved therapy aimed at retarding the vascular damage, fibrosis and altered immunological response. Current experimental therapies are based on immune-suppression and immune-modulation and include drugs like methotrexate, mycophenolate mofetil, D-penicillamine and rituximab. Tocilizumab, an interleukin-6 (IL-6) receptor antagonist was recently granted breakthrough therapy designation status for systemic sclerosis by the United States Food and Drug Administration (USFDA) [3]. Various other possible immune-inflammatory therapies are currently under study, including modulators of the profibrotic pathways [4]. The safety and possible toxicity of these agents remain a cause for concern.

Persistent Thrombopoietin Mimetic Induced Myelofibrosis in a Woman with Chronic Refractory Immune Thrombocytopenia

BackgroundImmune thrombocytopenia (ITP) is a disease caused by autoimmune destruction and impaired production of platelets. It can be primary or secondary in origin. It manifests as isolated thrombocytopenia with platelet counts less than 100 x109/L. Therapy is typically initiated when the platelet counts fall to less than 20 to 30 x 109/L in asymptomatic patients to reduce the risk of bleeding. ITP that persists for greater than 12 months is classified as chronic and ITP that endures despite splenectomy is defined as refractory. Most therapeutic approaches, such as corticosteroids, target the pathologic platelet destruction. Thrombopoietin (Tpo) mimetics, on the other hand, enhance platelet production via stimulation of the Tpo receptor on megakaryocytes. Studies suggest that Tpo mimetics increase reticulin deposition in the bone marrow. Tpo mimetics are postulated to promote reticulin deposition through stimulation of cytokine production by megakaryocytes, including transforming growth factor beta. There are reports of myelofibrosis, with abnormal deposition of collagen and reticulin in bone marrow trephine biopsies of ITP patients treated with these agents. Tpo mimetic induced myelofibrosis however, is described as reversible upon cessation of Tpo based therapy in most reports. Here we present a case of myelofibrosis induced by sequential therapy with two high dose TPO mimetics, which was not reversed six months after discontinuation of the medications.Case ReportAn 87-year-old woman with chronic ITP resistant to multiple lines of therapy (prednisone, dexamethasone, rituximab, dapsone, mycofenylate mofetil, and splenectomy) was treated consecutively with two thrombopoietin (Tpo) mimetics, romiplostim and then eltrombopag. Bone marrow evaluation at diagnosis, prior to treatment with Tpo mimetics, showed megakaryocyte hyperplasia without evidence of fibrosis. There was no definitive evidence of an underlying clonal hematologic disorder.. The patient's course was complicated by gastrointestinal and intracranial hemorrhage. Tpo mimetics were introduced as fourth line therapy. ITP response to romiplostim and then to eltrombopag was initially encouraging but rapidly fleeting.The peak dose of romiplostim used was 10 mcg/kg/week and eltrombopag was used at a dose of 75 mg per day. While on eltrombopag and within six months of romiplostim, therapy, she developed persistent left-shifted leukocytosis and a peripheral blood film showing leukoerythroblastosis and dacrocytic erythrocytes. This prompted a bone marrow evaluation that confirmed myelofibrosis, with a dense and diffuse increase in reticulin content and focal bundles of collagen (MF 2 of 3). There was associated marrow hypercellularity, increased numbers of enlarged megakaryocytes, clustered megakaryocyte topography and extensive bone resorption and remodelling Eltrombopag was promptly discontinued and peripheral blood leukoerythroblastic picture improved. Repeat bone marrow evaluation 6 months after stopping therapy showed partial reversal of the abnormalities seen in the previous marrow, including a reduction in the extent of reticulin fibrosis without any evidence of collagen fibrosis (MF 1-2 of 3). These changes are shown in Figure 1.DiscussionChronic, refractory ITP is a challenging syndrome to treat, and the Tpo mimetics have emerged as an important therapeutic option for patients who have failed traditional therapies. Clinical experience with the relatively novel Tpo mimetic drug class is maturing as we obtain longitudinal data and reports about adverse effects like myelofibrosis. While the myelofibrosis in our patient improved upon cessation of Tpo mimetic therapy, it did not resolve entirely and persisted 6 months after stopping therapy. We hypothesize that the sequential use of high dose Tpo mimetic therapy may have contributed to the development and persistence of myelofibrosis in this patient. This report adds to the body of evidence suggesting that myelofibrosis is a serious and, potentially chronic, adverse effect of treatment with Tpo mimetics.TPO mimetic treatment and B) Grade 1-2 of 3 Myelofibrosis after cessation of TPO mimetic.Semiquantitative grading is based on the 2008 WHO classification.Images from left to right represent hematoxylin andeosin, reticulin, and trichrome stains. [Display omitted] DisclosuresSholzberg:CSL Behring: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Amgen: Honoraria.

Rosiglitazone modulates collagen deposition and metabolism in atherosclerotic plaques of fat-fed ApoE-knockout mice.

Abnormal collagen deposition, as well as collagen metabolism, plays a crucial role in the formation and progression of vulnerable atherosclerotic plaques (VAPs), which are susceptible to rupture. According to our previous findings, rosiglitazone, a thiazolidinedione, can promote the stability of atherosclerotic plaques in fat-fed ApoE-knockout mice; however, it is unknown whether it can modulate collagen deposition and metabolism in VAPs. The present study was designed to determine the effect of rosiglitazone on collagen deposition and metabolism in the plaques of fat-fed ApoE-knockout mice. Following 13 weeks of the high-fat diet, the mice were randomized into three groups (10 mice/group) and intragastrically administered rosiglitazone, simvastatin and distilled water, respectively, for a further 13 weeks. The category of the collagen present in the plaques was evaluated using the picro-Sirius red polarization method. Additionally, the protein expression of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in the plaques was determined using immunohistochemistry. The results showed that rosiglitazone reduced the lipid to collagen and type III to type I collagen ratios in the plaques, and these reductions were correlated with the reduction in the plaque MMP-9 to TIMP-1 ratio. These results suggest that rosiglitazone can modulate collagen deposition and metabolism and promote the stabilization of VAPs.

Fibrogenesis in Primary Myelofibrosis: Diagnostic, Clinical, and Therapeutic Implications.

Primary myelofibrosis is a stem cell-derived clonal malignancy characterized by unchecked proliferation of myeloid cells, resulting in bone marrow fibrosis, osteosclerosis, and pathologic angiogenesis. Bone marrow fibrosis (BMF) plays a central role in the pathophysiology of the disease. This review describes current issues regarding BMF in primary myelofibrosis, including the pathophysiology and impact of abnormal deposition of excess collagen and reticulin fibers in bone marrow spaces, the modified Bauermeister and the European Consensus grading systems of BMF, and the prognostic impact of BMF on the overall outcome of patients with primary myelofibrosis. The impact of novel therapeutic strategies, including JAK-STAT inhibitors and allogeneic stem cell transplant, on BMF is discussed.

A mouse model of endocardial fibroelastosis.

Endocardial fibroelastosis (EFE) is a pathologic condition of abnormal deposition of collagen and elastin within the endocardium of the heart. It is seen in conjunction with a variety of diseases including hypoplastic left heart syndrome and viral endocarditis. While an experimental model using heterotopic heart transplant in rats has been described, we sought to fully describe a mouse model that can be used to further elucidate the potential mechanisms of and treatments for EFE. The hearts of 2-day-old C57BL/6 mice were transplanted into the abdomen of 7-week-old C57BL/6 mice. At 2 weeks, the hearts were harvested and histologic analysis was performed using hematoxylin and eosin, Masson's trichrome, Russell-Movat's pentachrome, Picrosirius red, Hart's, Verhoeff-Van Gieson, and Weigert's Resorcin-Fuchsin stains. Additionally, one heart was analyzed using transmission electron microscopy (TEM). Specimens demonstrated abnormal accumulation of both collagen and elastin within the endocardium with occasional expansion into the myocardium. Heterogeneity in extracellular matrix deposition was noted in the histologic specimens. In addition, TEM demonstrated the presence of excess collagen within the endocardium. The heterotopic transplantation of an immature heart into a mouse results in changes consistent with EFE. This model is appropriate to investigate the etiology and treatment of EFE.

The use of triamcinolone combined with surgery in major ear keloid treatment: a personal two stages approach

Background Keloid is a fibroproliferative disorder characterized by an abnormal deposition of collagen within a wound. Despite an increased understanding of wound healing and collagen metabolism, the exact cause, the clinical behavior, and gold standard of treatment for keloids remain an enigma. There is no one right way of treatment, the results are variable, and the management of ear keloids can be difficult and frustrating both for patients and physicians. Traditional techniques include intralesional steroids, topical applications of silicone, vitamins, and segmental excision by lasers or surgery. The purposes of this article are to review the literature concerning the current therapies as well as to present the authors’ experience in the treatment of major ear keloids.

Increased Lysyl oxidase-like 2 (LOXL2) gene expression accurately designates advanced liver fibrosis induced by the Hepatitis C Virus (HCV) regardless race, blood specimen or co-infection with the Human Immunodeficiency Virus (HIV)

Background: The LOX gene encodes a member of the lysyl-oxidase (LOX) gene family, which is involved in biogenesis of connective tissue, and 4 LOX-like proteins (LOXL1 – 4) have been identified so far. This study was aimed to investigate gene expression of LOXL1 – 4 in association with fibrogenesis in Hepatitis C Virus (HCV) infected patients with and without co-infection with the Human Immundeficiency Virus (HIV) in peripheral blood mononuclear cells (PBMC), peripheral whole blood (PwB) and liver tissue (LT) samples. Materials and Methods: PwB samples from 34 therapy-naive patients (34/34 Caucasians, 18/34 males, 28/34 with HCV-genotype-1) with chronic HCV infection treated at the University Hospital Essen (Germany) and PBMC samples from 23 HIV/HCV co-infected subjects (11/23 African Americans and none Caucasian, 20/23 males, 23/23 with HCV-genotype-1) recruited at the NIAID/NIH (MD/U.S.A.) were enrolled in this study. Liver biopsies obtained at baseline were evaluated using the Batts-Ludwig staging (BL-S) system for HCV mono-infected patients and the Ishak score (IS) for HIV/HCV co-infected donors. 34 PwB and 23 PBMC samples (and 7 LT samples from HIV/HCV co-infected participants) were subjected to microarray analysis. For all statistical analyses (i.e. pair-wise group comparison) 1-way-ANOVA was performed. Overall, a P< 0.05 was considered significant. Results: PwB samples from 34 HCV mono-infected patients were grouped according to BL-S as early fibrosis (BL-S: 0 – 1, “EF”, N= 20,) and late fibrosis (BL-S: 2 – 4, “LF”, N= 14) and PBMC samples from 23 HIV/HCV co-infected patients were grouped based on IS as early fibrosis (IS: 0 – 2, “EF”, N= 20) and late fibrosis (IS: 3 – 6, “LF”, N= 14). We consistently detected significantly increased LOXL-2 gene expression levels in association with “LF” in HCV mono-infected patients (PwB, P< 0.041) and HIV/HCV co-infected subjects (PBMC, P< 0.038). In addition, linear regression analysis was performed between fibrosis grades (IS: 0 – 6) and LOXL1 – 4 gene expression levels measured in LT samples of 7 HIV/HCV co-infected subjects; here, a significant correlation was found only for LOXL1 (r= 0.8, P> 0.031). These results are currently being validated by quantitative real-time polymerase chain reaction (qRT-PCR). Conclusions: This study suggests significant involvement of LOX-like proteins, especially LOXL2, in the fibrogenic liver transformation process during chronic HCV infection. Previous research reported: 1. Association between increased mRNA levels of LOXL2 and type-III-procollagen in liver fibrosis in mice. 2. Abnormal deposition of collagen in hepatocytes obtained from humans with Wilson's disease. 3. LOXL2 involvement in fibroblast activation. These findings (1.-3.) along with the present data demonstrating consistent significance in two demographically very heterogeneous cohorts further highlight the pathogenic role suggested for LOXL in fibrogenesis and the importance of generating LOXL2-targeted therapies for the prevention/treatment of liver fibrosis.

Premature Collagen Fibril Formation, Fibroblast-Mast Cell Interactions and Mast Cell-Mediated Phagocytosis of Collagen in Keloids

Keloids are benign hyper-proliferative growths of fibrous tissue where increased fibroblast activity results in abnormal collagen deposition. Excessive inflammation is a characteristic feature of keloids, but little is known about the underlying ultrastructural features of keloids related to collagen processing, fibril and fiber formation, the interaction between fibroblasts and associated collagen fibers and mast cells. In this study, the ultrastructure of the dermis of keloid patients was evaluated using light and transmission electron microscopy techniques. Abnormal intracellular premature collagen fibril formation was observed. Phagocytosis of collagen fibrils by mast cells was a common ultrastructural feature of keloid tissue as was a close or direct association between fibroblasts and mast cells. Based on these findings and recent advances in knowledge related to collagen synthesis, fibril formation and processing, we hypothesize that keloid formation is primarily due to abnormal collagen synthesis where the consequent accumulation of collagen fibers causes increased mast cell recruitment and collagen phagocytosis. Subsequent release of mast cell-derived mediators then promotes further collagen synthesis. The observation of early formation in keloid tissue of premature insoluble collagen fibrils supports previous studies that enzymes such as procollagen C-proteinase are important early therapeutic targets.

A comprehensive review of erectile dysfunction in men with diabetes.

Erectile dysfunction (ED) is more common in men with diabetes (DM). Dependent on the selected population, age, DM type and duration, the prevalence of diabetic ED (DED) varies from 32 to 90%. In 12-30% of men ED is the first sign of diabetes, diagnosed later. Today men with diabetes live longer than ever, and develop more late diabetic complications. Having in mind also the global ageing of the world population all this data suggests an increasing number of men with DED in the future. The main factors playing in the complex pathogenesis of DED are diabetic neuropathy (oxidative stress, polyol pathway, advanced glycation end-products, nerve growth factor deficiency, dysfunction of protein kinase C, tissue remodeling, etc.), macrovascular arterial disease (endothelial dysfunction, abnormal collagen deposition and smooth muscle degeneration, dyslipidemia, arterial hypertension, veno-occlusive dysfunction, etc.), hypogonadism, structural remodeling of the corporeal tissue, psychogenic components and adverse drug reactions. The diagnostic process is based on the results of questionnaires, neurological, vascular (Doppler) and other more rarely used investigations.Because of the complex pathogenesis of DED diabetic men represent a "difficult" treatment group. The difficulties are from the "beginning", because patients do not talk about their problem spontaneously, and doctors do not ask about it. The treatment of DED should be team work, preferably including also specialists in sexual medicine. Psychological support and counseling of the couple is necessary in most cases. The general measures include implementation of a healthier lifestyle, improved glycemic-, lipids-, and arterial pressure control, and careful re-evaluation of the concomitant medications. The specific treatment includes as first line therapy the inhibitors of phosphodiesterase type 5 (PDE-5) with lesser effectiveness compared to non-DM men. There are rare studies with selected diabetic populations and even less with head-to-head comparisons between the PDE-5 inhibitors. Men with DM have a higher prevalence of hypogonadism. Testosterone replacement therapy should be started in symptomatic men with proven hypogonadism and no contraindications. Vacuum constriction devices and intracavernous or intraurethral applications of vasoactive drugs are the second line therapy. Vascular surgery rarely comes into consideration. The penile implant is the last and effective option in men with severe DED.

Polidocanol foam induces collagen deposition

Transcervical therapy with polidocanol foam (PF) causes tubal occlusion in nonhuman primates and is being studied as a method of nonsurgical permanent contraception (PMID:24560476). Tubal obstruction is correlated with an increase of fibrosis surrounding intramural tube where it passes through the uterine cornua. We hypothesized that the fibrosis contains an abnormal deposition of collagen in the extracellular matrix. Our objective in this study was to characterize collagen types in the zone of tubal obstruction.

Mesenchymal stem cells reduce intervertebral disc fibrosis and facilitate repair.

Intervertebral disc degeneration is associated with back pain and radiculopathy which, being a leading cause of disability, seriously affects the quality of life and presents a hefty burden to society. There is no effective intervention for the disease and the etiology remains unclear. Here, we show that disc degeneration exhibits features of fibrosis in humans and confirmed this in a puncture-induced disc degeneration (PDD) model in rabbit. Implantation of bone marrow-derived mesenchymal stem cells (MSCs) to PDD discs can inhibit fibrosis in the nucleus pulposus with effective preservation of mechanical properties and overall spinal function. We showed that the presence of MSCs can suppress abnormal deposition of collagen I in the nucleus pulposus, modulating profibrotic mediators MMP12 and HSP47, thus reducing collagen aggregation and maintaining proper fibrillar properties and function. As collagen fibrils can regulate progenitor cell activities, our finding provides new insight to the limited self-repair capability of the intervertebral disc and importantly the mechanism by which MSCs may potentiate tissue regeneration through regulating collagen fibrillogenesis in the context of fibrotic diseases.

Synthesis and functional characterization of a fluorescent peptide probe for non invasive imaging of collagen in live tissues

Targeted molecular imaging to detect changes in the structural and functional organization of tissues, at the molecular level, is a promising approach for effective and early diagnosis of diseases. Quantitative and qualitative changes in type I collagen, which is a major component in the extra cellular matrix (ECM) of skin and other vital organs like lung, liver, heart and kidneys, are often associated with the pathophysiology of these organs. We have synthesized a fluorescent probe that comprises collagelin, a specific collagen binding peptide, coupled to fluorescent porphyrin that can effectively detect abnormal deposition of collagen in live tissues by emitting fluorescence in the near infra red (NIR) region. In this report we have presented the methodology for coupling of 5-(4-carboxy phenyl)-10, 15, 20-triphenyl porphyrin (C-TPP) to the N-terminal of collagelin or to another mutant peptide (used as a control). We have evaluated the efficacy of these fluorescent peptides to detect collagen deposition in live normal and abnormal tissues. Our results strongly suggest that porphyrin-tagged collagelin can be used as an effective probe for the non invasive in vivo detection of tissue fibrosis, especially in the liver.

The effect of collagen–chitosan porous scaffold thickness on dermal regeneration in a one-stage grafting procedure

Dermal substitutes are used as dermal regeneration templates to reduce scar formation and improve wound healing. Unlike autografts, dermal substitutes lack normal vascular networks. The increased distance required for diffusion of oxygen and nutrients to the autograft following interpositioning of the substitute dramatically affects graft survival. To evaluate the effect of collagen–chitosan scaffold thickness on dermal regeneration, single-layer collagen–chitosan porous scaffolds of 0.5-, 1- and 2-mm thicknesses were fabricated and used to treat full-thickness wounds in a one-stage grafting procedure in a rat model. Skin-graft viability, wound contraction, histological changes, and wound tensile strength were evaluated. The results indicated that the distance for the diffusion of oxygen and nutrients to the autograft in the 2-mm-thick scaffold provided less support for graft take, which resulted in graft necrosis, extensive inflammatory reaction, marked foreign-body reaction (FBR), rapid scaffold degradation, and abnormal collagen deposition and remodeling. In contrast, the thinner scaffolds, especially of that 0.5-mm thickness, promoted earlier angiogenesis, ensuring skin-graft viability with a mild FBR, and ordered fibroblast infiltration and better collagen remodeling. It can be concluded that collagen–chitosan porous scaffolds with a thickness of <1mm are more suitable for dermal regeneration and can be used as dermal templates for treatment of dermal defects using a one-stage grafting procedure.

Neuropsychiatric Symptoms in Scleroderma

Systemic sclerosis (SSc; scleroderma), a rare disorder of connective tissue characterized by widespread organ dysfunction due to fibrosis and ischemia, is marked by the overproduction and abnormal deposition of collagen. The brain parenchyma itself is largely collagen-free and, thus, primary central nervous system (CNS) involvement in SSc is believed to be rare, although peripheral neuropathy is common. However, SSc is known to cause widespread microvascular damage, which may be a plausible mechanism for the neuropsychiatric symptoms of mood, anxiety, and cognitive disorders that have been documented in SSc patients. Thus, SSc may be a systemic cause of vascular cognitive impairment and should be considered in the diagnosis of vascular dementia. The current case report illustrates a potential vascular connection between SSc and neuropsychiatric symptoms. The classification of SSc includes limited and diffuse forms. The limited form includes the CREST variant, an acronym for Calcinosis, Raynaud phenomena, Esophageal dysmotility, Sclerodactyly, and Telangiectasias. The diffuse form features widespread collagen deposition resulting in dermatological thickening and fibrosis in the lungs, heart, kidneys, and gastrointestinal tract. However, CNS involvement has been less often documented. Although microangiopathy is the principal pathogenic marker of the disease, more recently some attention has also been paid to macrovascular abnormalities. Therefore, CNS manifestations in SSc may be due to primary cerebrovascular changes or hypertension. It is known that vascular dementia is a frequent consequence of small and/or large vessel disease. Many subtypes of vascular dementia have been described; however, regardless of the subtype, hypertension is the most common cause. Less common causes include hypoperfusion due to large vessel and/or cardiac disease and other systemic vasculopathic syndromes (e.g., polyarteritis nodosa) leading to multiple infarcts that can lead to vascular dementia. SSc, although perhaps even less common cause, may also manifest clinically as vascular cognitive impairment.