Impairment of muscular endothelial cell regeneration in dermatomyositis.

Background and aim: Inflammatory myopathies are heterogeneous in terms of etiology, (immuno)pathology, and clinical findings. Endothelial cell injury, as it occurs in DM, is a common feature of numerous inflammatory and non-inflammatory vascular diseases. Vascular regeneration is mediated by both local and blood-derived mechanisms, such as the mobilization and activation of so-called proangiogenic cells (PACs) or early endothelial progenitor cells (eEPCs). The current study aimed to evaluate parameters of eEPC integrity in dermatomyositis (DM), compared to necrotizing myopathy (NM) and to non-myopathic controls. Methods: Blood samples from DM and NM patients were compared to non-myositis controls and analyzed for the following parameters: circulating CD133+/VEGFR-2+ cells, number of colony-forming unit endothelial cells (CFU-ECs), concentrations of angiopoietin 1, vascular endothelial growth factor (VEGF), and CXCL-16. Muscle biopsies from DM and NM subjects underwent immunofluorescence analysis for CXCR6, nestin, and CD31 (PECAM-1). Finally, myotubes, derived from healthy donors, were stimulated with serum samples from DM and NM patients, subsequently followed by RT-PCR for the following candidates: IL-1ß, IL-6, nestin, and CD31. Results: Seventeen (17) DM patients, 7 NM patients, and 40 non-myositis controls were included. CD133+/VEGFR-2+ cells did not differ between the groups. Both DM and NM patients showed lower CFU-ECs than controls. In DM, intramuscular CD31 abundances were significantly reduced, which indicated vascular rarefaction. Muscular CXCR6 was elevated in both diseases. Circulating CXCL-16 was higher in DM and NM in contrast, compared to controls. Serum from patients with DM but not NM induced a profound upregulation of mRNS expression of CD31 and IL-6 in cultured myotubes. Conclusion: Our study demonstrates the loss of intramuscular microvessels in DM, accompanied by endothelial activation in DM and NM. Vascular regeneration was impaired in DM and NM. The findings suggest a role for inflammation-associated vascular damage in the pathogenesis of DM.

PAC-Mediated AKI Protection Is Critically Mediated but Does Not Exclusively Depend on Cell-Derived Microvesicles.

INTRODUCTION: Acute kidney injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as a reliable option for improving AKI outcomes in experimental AKI. Our previous studies focused on the so-called proangiogenic cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production/secretion of extracellular vesicles (MV, microvesicles). In addition, the cells most likely act by paracrinic processes (secretome). The current study evaluated whether AKI may be preventable by the administration of either PAC-derived MV and/or the secretome alone. METHODS: AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI-40 minutes). Syngeneic murine PACs were stimulated with either melatonin, angiopoietin-1 or -2, or with bone morphogenetic protein-5 (BMP-5) for one hour, respectively. PAC-derived MV and the vesicle-depleted supernatant were subsequently collected and i.v.-injected after ischemia. Mice were analyzed 48 hours later. RESULTS: IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels. The only measure that improved AKI was the injection of MV, collected from native PACs. The following conditions worsened after ischemic renal function even further: MV + Ang-1, MV + BMP-5, MV + melatonin, and MV + secretome + Ang-1. CONCLUSION: Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived MV. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonin, BMP-5), mechanisms other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

Analysis of Direct Effects of the CB1 Receptor Antagonist Rimonabant on Fatty Acid Oxidation and Glycogenolysis in Liver and Muscle Cells in vitro.

Recent pharmacological findings regarding rimonabant, an anorectic and cannabinoid type 1 receptor (CB1R) antagonist, strongly suggest that some of its effects on the metabolic parameters and energy balance in rats are not related to the centrally mediated reduction in caloric intake. Instead, they may be associated with acute induction of glycogenolysis in the liver, in combination with transient increase in glucose oxidation and persistent increase in fat oxidation. It is possible that rimonabant produced direct short- or long-term stimulatory effect on these processes in primary and cultured rat cells. Rimonabant slightly stimulated ß-oxidation of long-chain fatty acids in cultured rat myocytes overexpressing glucose transporter isoform 4, as well as activated phosphorylation of adenosine monophosphate-dependent protein kinase (AMPK) in primary rat hepatocytes upon long-term incubation. However, short-term action of rimonabant failed to stimulate ß-oxidation in myocytes, myotubes, and hepatocytes, as well as to upregulate AMPK phosphorylation, glycogenolysis, and cAMP levels in hepatocytes. As a consequence, the acute effects of rimonabant on hepatic glycogen content (reduction) and total energy expenditure (increase) in rats fed with a standard diet cannot be explained by direct stimulation of glycogenolysis and fatty acid oxidation in muscles and liver. Rather, these effects seem to be centrally mediated.

Rituximab in routine care of severe active rheumatoid arthritis : A prospective, non-interventional study in Germany.

OBJECTIVE: To assess safety, effectiveness and onset of effect of rituximab (RTX) in routine clinical treatment of severe, active rheumatoid arthritis (RA). METHODS: Prospective, multi-centre, non-interventional study in rheumatological outpatient clinics or private practices in Germany. RTX-naïve adult patients were to receive RTX according to marketing authorisation and at their physician's discretion. Also according to their physician's discretion, patients could receive a second cycle of RTX (re-treatment = treatment continuation). Major outcome was the change in Disease Activity Score based on 28-joints count and erythrocyte sedimentation rate (DAS28-ESR) over 24 weeks and during 6 months of re-treatment. RESULTS: Overall, 1653 patients received at least one cycle RTX; 99.2% of these had received disease-modifying antirheumatic drugs (DMARD) pre-treatment and 75.5% anti-tumor necrosis factor(TNF)­α pre-treatment. After a mean interval of 8.0 months, 820 patients received RTX re-treatment. Mean DAS28-ESR decreased from 5.3 at baseline to 3.8 after 24 weeks (-1.5 [95% confidence interval, CI: -1.6; -1.4]), and from 4.1 at start of cycle 2 to 3.5 at study end (change from baseline: -1.8 [95% CI: -2.0; -1.7]). Improvements in DAS28-ESR and Health Assessment Questionnaire (HAQ) score occurred mainly during the first 12 weeks of RTX treatment, with further DAS28-ESR improvement until week 24 or month 6 of re-treatment. Improvements in DAS28-ESR and EULAR responses were more pronounced in seropositive patients. RF was a predictor of DAS28-ESR change to study end. Safety analysis showed the established profile of RTX. CONCLUSION: RTX was safe and effective in a real-life setting with rapid and sustained improvement in RA signs and symptoms.

Early endothelial progenitor cells and vascular stiffness in psoriasis and psoriatic arthritis.

BACKGROUND: Both psoriasis (Ps) and psoriasis arthritis (PsA) have been associated with increased cardiovascular risk. Also, both are characterized by increased neovascularization. Endothelial progenitor cells (EPCs) have been implicated in promoting vascular repair in ischemic diseases. The aim of the study was to correlate the EPC system with CV risk factors and with parameters of vascular stiffness in Ps and PsA. METHODS: Twenty-six healthy subjects, 30 patients with Ps, and 31 patients PsA were included in the study. eEPC regeneration was evaluated by a colony-forming assay, circulating eEPCs were measured by cytometric analysis. For vascular analysis, all subjects underwent quantification of pulse wave velocity (PWV) and augmentation index (AIX). RESULTS: Patients were categorized upon the duration of disease, severity of skin involvement (PASI-Ps), individual pain as reflected by the VAS (PsA), CRP values, and history of treatment with one or more biologicals. Regarding the eEPC system, no significant differences were observed between the respective categories. Correlation analyses between parameters of vascular stiffness (PWV and AIX) and patterns of colony formation/circulating eEPCs did not show any correlation at all. CONCLUSION: Parameters of vascular stiffness are not significantly deteriorated in Ps/PsA. Thus, pulse wave analysis may not be suitable for CVR assessment in certain autoimmune-mediated diseases. Regenerative activity of the eEPC system/circulating eEPC numbers are not altered in Ps/PsA. One may conclude that malfunctions of the eEPC are not substantially involved in perpetuating the micro-/macrovascular alterations in Ps/PsA.

Therapeutic response to glucocorticoids, anticoagulation and plasma exchange in a patient with primary antiphospholipid syndrome presenting with purpura fulminans.

We report the case of a 25-year-old female patient who presented with purpura fulminans as a manifestation of primary antiphospholipid syndrome. Purpura fulminans is considered a rare cutaneous manifestation of antiphospholipid syndrome. Most frequently, it occurs in the context of catastrophic antiphospholipid syndrome and is associated with significant morbidity and mortality, either due to loss of affected extremities or thromboembolic damage to internal organs. After insufficient efficacy of parenteral anticoagulation and oral glucocorticosteroid treatment, we escalated treatment to high-dose intravenous glucocorticosteroid and five consecutive sessions of plasma exchange with good and sustained clinical response. At follow-up six months after admission, skin manifestations had healed with scarring, and no additional thrombotic events had occurred. Plasma exchange may hold promise as a therapeutic option in refractory or severe cases of antiphospholipid syndrome-related purpura fulminans with extensive cutaneous necrosis, although evidence is limited.

Dialysis vintage time has the strongest correlation to psychosocial pattern of oral health-related quality of life - a multicentre cross-sectional study.

BACKGROUND: Aim of this cross-sectional, multicentre study was to investigate associations of dialysis vintage time in haemodialysis (CKD5D) patients with oral health-related quality of life (OHRQoL) and dental and periodontal treatment need. MATERIAL AND METHODS: CKD5D patients were divided into subgroups according to dialysis vintage time in different dialysis centres in Germany. OHRQoL was assessed with oral health impact profile (OHIP-G14). Dental treatment need was classified as presence of carious lesions. Periodontal treatment need was defined as periodontal screening index score (PSI) 3-4. RESULTS: In total, 190 participants were divided into the subgroups according to the time on CKD5D: 0 - 2 (n = 29), 3 - 5 (n = 35), 6 - 8 (n = 34), 9 - 12 (n = 29), 13 - 20 (n = 34) and >20 years (n = 29). The overall treatment need in the total cohort was 92% (dental 56%, periodontal 88%) with a total OHIP-G14 sum score of 4.17 [2; 0-5] without a significant correlation. Time on CKD5D was inversely correlated with the OHIP G14 score (p<0.01, R = -0.201). The pattern psychosocial impact was significantly associated with the dialysis duration (p<0.01) and showed a negative correlation to the OHIP-G14 (R = -0.283, Spearman's rho test p<0.01). For oral function also a negative correlation with OHIP-G14 was detected (Spearman's rho: -0.183). CONCLUSIONS: Patients with a prolonged dialysis vintage time show an improved OHRQoL, which might be mainly caused by the positive development of psychosocial pattern of OHRQoL. The oral health situation of HD patients seems unsatisfying, independently of dialysis vintage time and OHRQoL. Accordingly, an improvement in oral health situation of CKD5D patients is mandatory necessary. Thereby, consideration of psychosocial aspects especially at the beginning of CKD5D therapy and a sensitization regarding oral health issues with increasing vintage time might be recommendable.

Autophagy activation in circulating proangiogenic cells aggravates AKI in type I diabetes mellitus.

Acute kidney injury (AKI) occurs frequently in hospitals worldwide, but the therapeutic options are limited. Diabetes mellitus (DM) affects more and more people around the globe. The disease worsens the prognosis of AKI even further. In recent years, cell-based therapies have increasingly been applied in experimental AKI. The aim of the study was to utilize two established autophagy inducers for pharmacological preconditioning of so-called proangiogenic cells (PACs) in PAC treatment of diabetic AKI. Insulin-dependent DM was induced in male C57/Bl6N mice by intraperitoneal injections of streptozotocine. Six weeks later, animals underwent bilateral renal ischemia for 45 min, followed by intravenous injections of either native or zVAD (benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone)- or Z-Leu-Leu-Leu-al (MG132)-pretreated syngeneic murine PACs. Mice were analyzed 48 h (short term) and 6 wk (long term) later, respectively. DM worsened postischemic AKI, and PAC preconditioning with zVAD and MG132 resulted in a further decline of excretory kidney function. Injection of native PACs reduced fibrosis in nondiabetic mice, but cell preconditioning promoted interstitial matrix accumulation significantly. Both substances aggravated endothelial-to-mesenchymal transition (EndoMT) under diabetic conditions; these effects occurred either exclusively in the short (zVAD) or in the short and long term (MG132). Preconditioned cells stimulated the autophagocytic flux in intrarenal endothelial cells, and all experimental groups displayed increased endothelial abundances of senescence-associated ß-galactosidase, a marker of premature cell senescence. Pharmacological autophagy activation may not serve as an effective strategy for improving PAC competence in diabetic AKI in general. On the contrary, several outcome parameters (excretory function, fibrosis, EndoMT) may even be worsened.

Mosquitoes (Diptera: Culicidae) from crepuscular period in an Atlantic Forest area in Southern Brazil / Mosquitos (Diptera: Culicidae) do período crepuscular em área de Floresta Atlântica no sul do Brasil

Abstract Crepuscular period is one of the factors that may influence the biting activity of mosquitoes. Many of these insects have a peak activity in this period. The purpose of this study was to investigate the afternoon crepuscular activity of Culicidae in a remaining area of Atlantic Forest in western Santa Catarina, southern Brazil. Moreover, the possible influence of abiotic factors, the abundance and species richness were verified. In order to better analyze the influence of crepuscular period in specific composition and abundance of mosquitoes, the dusk was divided into three periods: pre-sunset, sunset and post-sunset. At the end of the study, nine hundred and eight four specimens distributed in 12 genera and 23 species were collected. Trichoprosopon pallidiventer (Lutz, 1905) (59.76%), Aedes crinifer (Theobald, 1903) (8.13%), Ae. scapularis (Rondani, 1848) (5.89%) were the most abundant species. Spring time presented the greatest abundance and species richness. During the study, among the three periods evaluated, pre-sunset had the greatest abundance and post-sunset the lowest. Pre-sunset and sunset had the greatest similarity between species. Regarding to the abiotic factors evaluated seven and 15 days before sampling, they did not present significant correlation for the three most abundant species. However, temperature had a positive correlation to these species. Moreover, the correlation between collected species and its possible role as vectors of etiological agents of diseases was discussed.

Resumo O período crepuscular é um dos fatores que pode influenciar na atividade hematofágica dos mosquitos. Muitos desses insetos iniciam ou terminam suas atividades nesse período. O objetivo deste trabalho foi estudar os Culicidae que ocorrem no crepúsculo vespertino em uma área de Floresta Atlântica no oeste de Santa Catarina, sul do Brasil. Além disso, foi analisada a possível influência de fatores abióticos, bem como abundância e riqueza de espécies. Para melhor avaliar a influência do período crepuscular na composição das espécies e na abundância destas, o crepúsculo foi dividido em três períodos: pré-crepúsculo, crepúsculo e pós-crepúsculo. Ao final do estudo foram coletados 984 exemplares distribuídos em 12 gêneros e 23 espécies. Trichoprosopon pallidiventer (Lutz, 1905) (59,76%), Aedes crinifer (Theobald, 1903) (8,13%) e Ae. scapularis (Rondani, 1848) (5,89%) foram as espécies mais abundantes. A maior abundância e riqueza de espécies se deram na primavera. Dentre os três períodos estudados, o pré-crepúsculo apresentou a maior abundância de mosquitos, em contrapartida, o pós-crepúsculo apresentou a menor abundância. Os períodos pré-crepuscular e crepuscular apresentaram maior similaridade entre si com relação à composição das espécies. Relacionando os fatores abióticos e as três espécies mais abundantes, não foi observada correlação significativa nos dados avaliados nos sete e 15 dias anteriores às coletas. Entretanto, a temperatura apresentou uma correlação positiva para estas três espécies. A relação entre as espécies coletadas e a potencial transmissão de agentes etiológicos causadores de doenças foi comentada.

Endothelial Colony Forming Cells (ECFCs) in murine AKI - implications for future cell-based therapies.

BACKGROUND: In recent years, early Endothelial Progenitor Cells (eEPCs) have been proven as effective tool in murine ischemic AKI and in diabetic nephropathy. The mechanisms of eEPC-mediated vasoprotection have been elucidated in detail. Besides producing a diverse range of humoral factors, the cells also act by secreting vasomodulatory microvesicles. Only few data in contrast have been published about the role of so-called Endothelial Colony Forming Cells (ECFCs - late EPCs) in ischemic AKI. We thus aimed to investigate ECFC effects on postischemic kidney function over several weeks. Our special interest focused on endothelial-to-mesenchymal transition (EndoMT), peritubular capillary density (PTCD), endothelial alpha-Tubulin (aT - cytoskeletal integrity), and endothelial p62 (marker of autophagocytic flux). METHODS: Eight to twelve weeks old male C57Bl/6 N mice were subjected to bilateral renal pedicle clamping for 35 or 45 min, respectively. Donor-derived syngeneic ECFCs (0.5 × 106) were i.v. injected at the end of ischemia. Animals were analyzed 1, 4 and 6 weeks later. RESULTS: Cell therapy improved kidney function exclusively at week 1 (35 and 45 min). Ischemia-induced fibrosis was diminished in all experimental groups by ECFCs, while PTCD loss remained unaffected. Significant EndoMT was detected in only two of 6 groups (35 min, week 4 and 45 min, week 6), ECFCs reduced EndoMT only in the latter. Endothelial aT declined under almost all experimental conditions and these effects were further aggravated by ECFCs. p62 was elevated in endothelial cells, more so after 45 than after 35 min of ischemia. Cell therapy did not modulate p62 abundances at any time point. CONCLUSION: A single dose of ECFCs administered shortly post-ischemia is capable to reduce interstitial fibrosis in the mid- to long-term whereas excretory dysfunction is improved only in a transient manner. There are certain differences in renal outcome parameters between eEPCs and ECFC. The latter do not prevent animals from peritubular capillary loss and they also do not further elevate endothelial p62. We conclude that differences between eEPCs and ECFCs result from certain mechanisms by which the cells act around and within vessels. Overall, ECFC treatment was not as efficient as eEPC therapy in preventing mice from ischemia-induced mid- to long-term damage.

Mosquitoes (Diptera: Culicidae) from crepuscular period in an Atlantic Forest area in Southern Brazil.

Crepuscular period is one of the factors that may influence the biting activity of mosquitoes. Many of these insects have a peak activity in this period. The purpose of this study was to investigate the afternoon crepuscular activity of Culicidae in a remaining area of Atlantic Forest in western Santa Catarina, southern Brazil. Moreover, the possible influence of abiotic factors, the abundance and species richness were verified. In order to better analyze the influence of crepuscular period in specific composition and abundance of mosquitoes, the dusk was divided into three periods: pre-sunset, sunset and post-sunset. At the end of the study, nine hundred and eight four specimens distributed in 12 genera and 23 species were collected. Trichoprosopon pallidiventer (Lutz, 1905) (59.76%), Aedes crinifer (Theobald, 1903) (8.13%), Ae. scapularis (Rondani, 1848) (5.89%) were the most abundant species. Spring time presented the greatest abundance and species richness. During the study, among the three periods evaluated, pre-sunset had the greatest abundance and post-sunset the lowest. Pre-sunset and sunset had the greatest similarity between species. Regarding to the abiotic factors evaluated seven and 15 days before sampling, they did not present significant correlation for the three most abundant species. However, temperature had a positive correlation to these species. Moreover, the correlation between collected species and its possible role as vectors of etiological agents of diseases was discussed.

Acute Kidney Injury in Diabetes Mellitus.

Diabetes mellitus (DM) significantly increases the overall morbidity and mortality, particularly by elevating the cardiovascular risk. The kidneys are severely affected as well, partly as a result of intrarenal athero- and arteriosclerosis but also due to noninflammatory glomerular damage (diabetic nephropathy). DM is the most frequent cause of end-stage renal disease in our society. Acute kidney injury (AKI) remains a clinical and prognostic problem of fundamental importance since incidences have been increased in recent years while mortality has not substantially been improved. As a matter of fact, not many studies particularly addressed the topic "AKI in diabetes mellitus." Aim of this article is to summarize AKI epidemiology and outcomes in DM and current recommendations on blood glucose control in the intensive care unit with regard to the risk for acquiring AKI, and finally several aspects related to postischemic microvasculopathy in AKI of diabetic patients shall be discussed. We intend to deal with this relevant topic, last but not least with regard to increasing incidences and prevalences of both disorders, AKI and DM.

Frequency of the Val1016Ile mutation on the kdr gene in Aedes aegypti (Diptera: Culicidae) in south Brazil.

Recently, the number of Aedes aegypti foci has increased in west of Santa Catarina, south Brazil, which has increased concern regarding mosquito-borne disease outbreaks such as dengue fever, Zika virus, and chikungunya. Therefore, it is important to monitor genetic resistance to insecticides through "knockdown resistance". Homozygosity (Ile/Ile) at position 1016 in the coding region of a voltage-dependent sodium channel gene (Nav) may induce resistance to pyrethroid insecticides. We evaluated the frequency of these alleles in A. aegypti in west Santa Catarina. In total, 349 specimens were obtained from the microregions of Joaçaba (31), Concórdia (35), Chapecó (154), and São Miguel do Oeste (129). We found that 109 individuals (31.0%) were homozygous for Val/Val, 102 (29.0%) were heterozygous for Val/Ile, and 138 (40.0%) were homozygous for Ile/Ile. The allele frequencies were similar for Val (0.455) and Ile (0.545). Joaçaba and Concórdia had the highest mutant allele frequencies (0.825 and 0.685, respectively). Therefore, these populations should be monitored for increases in pyrethroid resistance. The São Miguel do Oeste and Chapecó populations had similar frequencies of Val and Ile and were not in Hardy-Weinberg equilibrium, suggesting that a selection pressure or other evolutionary force has occurred. In conclusion, the observed frequency of Ile/Ile homozygous individuals in the region studied requires attention, because the implementation of controls using pyrethroid may increase the frequency of the mutant allele through the selection of resistant populations.

Early Endothelial Progenitor Cells (eEPCs) in systemic sclerosis (SSc) - dynamics of cellular regeneration and mesenchymal transdifferentiation.

BACKGROUND: Patients with systemic sclerosis (SSc) are endagered by tissue fibrosis and by microvasculopathy, with the latter caused by endothelial cell expansion/proliferation. SSc-associated fibrosis potentially results from mesenchymal transdifferentiation of endothelial cells. Early Endothelial Progenitor Cells (eEPCs) act proangiogenic under diverse conditions. Aim of the study was to analyze eEPC regeneration and mesenchymal transdifferentiation in patients with limited and diffuse SSs (lSSc and dSSc). METHODS: Patients with both, lSSc and dSSc were included into the study. The following parameters were evaluated: eEPC numbers and regeneration, concentrations of vasomodulatory mediators, mesenchymal properties of blood-derived eEPC. Serum samples of healthy subjects and SS patients were used for stimulation of cultured human eEPC, subsequently followed by analysis of mesenchymal cell characteristics and mobility. RESULTS: Twenty-nine patients were included into the study. Regenerative activity of blood-derived eEPCs did not differ between Controls and patients. Circulating eEPC were significantly lower in all patients with SSc, and in limited and diffuse SSc (lSSc/dSSc). Serum concentrations of promesenchymal TGF-b was elevated in all patients with SSc. Cultured mononuclear cells from SS patients displayed higher abundances of CD31 and of CD31 and aSMA combined. Finally, serum from SSc patients inhibited migration of cultured eEPCs and the cells showed lower sensitivity towards the endothelin antagonist Bosentan. CONCLUSIONS: The eEPC system, which represents an essential element of the endogenous vascular repair machinery is affected in SSc. The increased appearance of mesenchymal properties in eEPC may indicate that alterations of the cells potentially contribute to the accumulation of connective tissue and to vascular malfunction.

Oral health-related quality of life in patients on chronic haemodialysis and after kidney transplantation.

OBJECTIVES: The objective of the study was to evaluate oral health-related quality of life (OHRQoL) depending on dental and periodontal situation in patients on haemodialysis (HD) and after kidney transplantation (KTx) compared to healthy controls (HC). SUBJECTS AND METHODS: OHRQoL was assessed using the German short form of Oral Health Impact Profile (OHIP G14). Dental health was estimated using the decayed, missing and filled teeth index (DMF-T). Periodontal health was classified as healthy/mild or moderate/severe periodontitis. STATISTICAL ANALYSIS: Mann-Whitney U-test, Kruskal-Wallis test, chi-square test and Fisher's test. RESULTS: Eighty-seven HD patients, 39 KTx patients and 91 HC were included. Significant differences in DMF-T, D-T, M-T and F-T scores were identified between groups (P < 0.001). The prevalence of moderate/severe periodontitis was significantly higher in the HD and KTx group compared to HC (P = 0.002). Differences in OHIP G14 between groups were neither clinical relevant nor statistically significant (P = 0.199). A significant effect of DMF-T (P = 0.012), M-T (P < 0.001) and periodontitis (P = 0.023) on the OHIP G14 scores was identified only in HC. CONCLUSIONS: Improvement in dental care of HD and KTx patients is required. OHIP G14 values provide a subjectively considered low importance of oral health in HD and KTx patients, leading to need of motivation and sensitisation of these patients.

Postischemic microvasculopathy and endothelial progenitor cell-based therapy in ischemic AKI: update and perspectives.

Acute kidney injury (AKI) dramatically increases mortality of hospitalized patients. Incidences have been increased in recent years. The most frequent cause is transient renal hypoperfusion or ischemia which induces significant tubular cell dysfunction/damage. In addition, two further events take place: interstitial inflammation and microvasculopathy (MV). The latter evolves within minutes to hours postischemia and may result in permanent deterioration of the peritubular capillary network, ultimately increasing the risk for chronic kidney disease (CKD) in the long term. In recent years, our understanding of the molecular/cellular processes responsible for acute and sustained microvasculopathy has increasingly been expanded. The methodical approaches for visualizing impaired peritubular blood flow and increased vascular permeability have been optimized, even allowing the depiction of tissue abnormalities in a three-dimensional manner. In addition, endothelial dysfunction, a hallmark of MV, has increasingly been recognized as an inductor of both vascular malfunction and interstitial inflammation. In this regard, so-called regulated necrosis of the endothelium could potentially play a role in postischemic inflammation. Endothelial progenitor cells (EPCs), represented by at least two major subpopulations, have been shown to promote vascular repair in experimental AKI, not only in the short but also in the long term. The discussion about the true biology of the cells continues. It has been proposed that early EPCs are most likely myelomonocytic in nature, and thus they may simply be termed proangiogenic cells (PACs). Nevertheless, they reliably protect certain types of tissues/organs from ischemia-induced damage, mostly by modulating the perivascular microenvironment in an indirect manner. The aim of the present review is to summarize the current knowledge on postischemic MV and EPC-mediated renal repair.

The endothelial-to-mesenchymal transition and endothelial cilia in EPC-mediated postischemic kidney protection.

Renal ischemia induces peritubular capillary rarefication and fibrosis, with the latter partly resulting from the endothelial-to-mesenchymal transition (EndoMT). Endothelial cilia transmit blood flow-associated forces into the cell. Early endothelial progenitor cells (eEPCs) have been shown to protect mice from acute kidney injury in the short term. The aim of the present study was to analyze midterm consequences of eEPC treatment in the context of endothelial cilia and the EndoMT. Male C57/Bl6N mice were subjected to unilateral renal ischemia postuninephrectomy. Syngeneic murine eEPCs were systemically injected at the time of reperfusion. Animals were investigated 1, 4, and 6 wk later. Cultured mature endothelial cells were exposed to a variable flow with versus without eEPC supernatant incubation. Systemically injected eEPCs reduced serum creatinine levels at week 1 (35 and 45 min) and week 4 (45 min). Interstitial fibrosis was significantly diminished by cell treatment at all time points as well. The EndoMT was less pronounced at week 4 (35 min) and week 6 (45 min). eEPC supernatant reduced α-smooth muscle actin expression and α-tubulin abundance in flow-treated cultured mature endothelial cells, and percentages of cilium-positive cells increased. The loss of peritubular capillaries was prevented by eEPCs. Intrarenal endothelial α-tubulin decreased postischemia and was further reduced by eEPC administration. We conclude that eEPCs are capable of reorganizing the endothelial cytoskeleton in an indirect manner, ultimately resulting in stabilization of the endothelial ciliome. The investigation indicates an antimesenchymal role of endothelial cilia in the process of postischemic tissue fibrosis/EndoMT.

Activation of annexin A1 signalling in renal fibroblasts exerts antifibrotic effects.

AIM: The anti-inflammatory protein annexin A1 (AnxA1) and its formyl peptide receptor 2 (FPR2) have protective effects in organ fibrosis. Their role in chronic kidney disease (CKD) has not yet been elucidated. Our aim was to characterize the AnxA1/FPR2 system in models of renal fibrosis. METHODS: Rats were treated with angiotensin receptor antagonist during the nephrogenic period (ARAnp) to induce late-onset hypertensive nephropathy and fibrosis. Localization and regulation of AnxA1 and FPR2 were studied by quantitative real-time PCR and double labelling immunofluorescence. Biological effects of AnxA1 were studied in cultured renal fibroblasts from AnxA1(-/-) and wild-type mice. RESULTS: Angiotensin receptor antagonist during the nephrogenic period kidneys displayed matrix foci containing CD73(+) fibroblasts, alpha-smooth muscle actin (a-SMA)(+) myofibroblasts and CD68(+) macrophages. TGF-ß and AnxA1 mRNAs were ~threefold higher than in controls. AnxA1 was localized to macrophages and fibroblasts; myofibroblasts were negative. FPR2 was localized to fibroblasts, myofibroblasts, macrophages and endothelial cells. AnxA1 and FPR2 immunoreactive signals were increased in the foci, with fibroblasts and macrophages expressing both proteins. AnxA1(-/-) fibroblasts revealed higher α-SMA (sevenfold) and collagen 1A1 (Col1A1; 144-fold) mRNA levels than controls. Treatment of murine WT fibroblasts with TGF-ß (22.5 ng mL 24 h(-1)) increased mRNA levels of α-SMA (9.3-fold) and Col1A1 (fourfold). These increases were greatly attenuated upon overexpression of AnxA1 (1.5- and 1.7-fold, respectively; P < 0.05). Human fibroblasts reacted similarly when receiving the FPR2 inhibitor WRW4. CONCLUSION: Our results demonstrate that AnxA1 and FPR2 are abundantly expressed in the renal interstitium and modulate fibroblast phenotype and extracellular matrix synthesis activity.

[Interstitial nephritis in rheumatic diseases]. / Interstitielle Nephritis bei rheumatischen Erkrankungen.

Interstitial nephritis is responsible for about 12 % of end-stage renal disease in Germany. It comprises an etiologically heterogenous group of inflammatory renal disorders which primarily affect the renal interstitium and tubuli. Drugs, predominantly antibiotics, nonsteroidal anti-inflammatory drugs and proton pump inhibitors are causative in the majority of cases. Rheumatic diseases frequently affect the kidneys, either the glomeruli or the interstitial tissues. Inflammatory interstitial processes can be accompanied by complex functional tubular disorders. This review gives an overview about clinical and laboratory findings of interstitial nephritis in the context of rheumatic diseases. Sarcoidosis, tubulointerstitial nephritis and uveitis (TINU) syndrome, primary Sjogren's syndrome, and IgG4-related disease often show an interstitial nephritis when the kidneys are affected. Other diseases, such as systemic lupus erythematosus, systemic sclerosis, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, and granulomatosis with polyangiitis are more rarely associated with predominant interstitial nephritis. Glucocorticoids are the mainstay of therapy for most cases; in refractory cases or when side effects occur, second-line immunosuppressants such as mycophenolate mofetil, azathioprine and others, rarely biologics, can be used.