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The concept of cardiorenal syndrome (CRS) has been established more than 10 years ago. Five distinct types of CRS have been defined. In CRS type 3, acute kidney injury (AKI) induces cardiac complications such as ventricular decompensation due to arrhythmias, myocardial ischemia, or fluid retention with or without arterial hypertension. The risk of cardiovascular events in AKI has been known for many years, even long before the introduction of the CRS concept. However, epidemiological and clinical studies published in recent years increasingly emphasized CRS type 3 (and the remaining four types also) as separate entity which requires particular therapeutic attention in an interdisciplinary manner. However, only a limited number of experimental studies specifically addressed CRS type 3 so far. Our review aims to summarize experimental studies on the pathological mechanisms in CRS type 3.The following search criteria were employed in order to identify articles published on the topic: "cardiorenal syndrome 3" OR "cardiorenal syndrome type 3" OR "CRS type 3" OR "CRS 3" AND "experimental" OR "mouse" OR "mice" OR "rats" OR "animals"; additional criteria were "myocardium" AND "ischemia" AND "kidney" OR "renal". By applying the search criteria mentioned earlier, 10 references were finally selected.By applying the search strategy, 10 experimental studies were finally selected. All included cardiac outcome analysis in AKI animals. The data clearly provide evidence for cardiac complications that evolve independently from excretory kidney dysfunction. Pathological processes that emerge in the heart of animals subjected to renal ischemia involve inflammation, a dysbalance of redox components, pro-apoptotic processes, and mitochondrial dysfunction.The findings may explain why AKI increases the risk of acute cardiac complications even if dialysis treatment has been initiated.

Interleukin-33 (IL-33), a member of the IL-1 family, is critically involved in the modulation of the activity of a diverse range of immunocompetent cells. Essential roles have been implicated in cardioprotection, in both innate and adaptive immune responses in mucosal organs, and in the maintenance of adipose tissue cells. Over the past 10 years, several studies evaluated the usability of IL-33 as a biomarker in diseases of inflammatory and noninflammatory origin. Our group is currently evaluating the predictive role of serum IL-33 in acute kidney injury (AKI). The aim of the article is to discuss selected studies on IL-33 in different diseases and its potential role as a biomarker molecule.

Cardiorenal syndromes (CRS) have increasingly been recognized as distinct disorders that affect the heart and kidneys simultaneously, either with acute or chronic onset. The different types share common pathophysiological characteristics. The concept "cardiorenal" shall emphasize the inter- or even multidisciplinary approach to respective patients. Anticongestive therapy becomes mandatory in many subjects that suffer from CRS. In recent years, the role of dialysis treatment in a broader sense has been investigated in CRS in more detail. We performed a search for studies related to the topic in the following databases: MEDLINE, PROSPERO, and Web of Science. The following keywords were used for reference identification: "CRS", "cardiorenal syndrome", "dialysis", "hemodialysis", "hemofiltration", "renal replacement therapy", "kidney replacement therapy", "peritoneal dialysis", and "aquapheresis". Finally, a total number of 22 studies, partly performed as retrospective cohort studies, and partly designed as prospective investigations, were included. The selected studies evaluated different modes of peritoneal dialysis (PD) or of non-PD procedures including intermittent hemodialysis, continuous procedures, and so-called aquapheresis. Inclusion and outcome parameters were almost not comparable between selected trials. Some studies revealed dialysis as effective, with reasonable tolerability. Particularly so-called "pure" ultrafiltration (e.g., aquapheresis) was associated with higher rates of adverse events. Future studies should be designed in a more homogenous manner, particularly concerning the inclusion criteria, the respective dialysis procedure applied, and endpoints in the short- and long-term.

OBJECTIVES Aim of this cross-sectional study was to investigate oral health-related quality of life (OHRQoL) of patients with different rheumatic diseases. SUBJECTS AND METHODS Patients with rheumatic disease, including rheumatoid arthritis (RA), systemic lupus erythematodes (SLE), systemic sclerosis (SSc), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and vasculitis were included. OHRQoL was assessed with the German short form of oral health impact profile (OHIP G14). Age, disease duration, leukocytes, c-reactive protein (CRP) and haemoglobin counts were considered as disease related parameters. RESULTS A total of 356 patients, assigned to the groups RA (n = 218), SLE (n = 36), AS (n = 36), PsA (n = 33), vasculitis (n = 19) and SSc (n = 14) were included. The OHIP G14 sub-scale psychosocial impact differed significantly between groups (p = .02). The OHIP G14 sum score was also significantly different between groups (p

Introduction: The prediction of acute kidney injury (AKI)-related outcomes remains challenging. Herein we prospectively quantified soluble ST2 (sST2), the circulating isoform of the IL-33 receptor, in hospitalized patients with AKI. Methods: In-hospital subjects with AKI of various etiology were identified through the in-hospital AKI alert system of the Brandenburg University hospital. sST2 was measured within a maximum of 48 hours from the time of diagnosis of AKI. The following endpoints were defined: in-hospital death, dialysis, recovery of kidney function until demission. Results: In total, 151 individuals were included in the study. The in-hospital mortality was 16.6%, dialysis therapy became mandatory in 39.7%, no recovery of kidney function occurred in 27.8%. sST2 was significantly higher in nonsurvivors (p = 0.024) but did not differ in the two other endpoints. The level of sST2 increased significantly with the severity of AKI. Further differences were detected in subjects with heart insufficiency (lower sST2), and in patients that required ICU treatment, or ventilatory therapy, or vasopressors (all higher). Conclusions: The current study suggests sST2 as biomarker of “acute distress”: it predicts post-AKI survival and substantially increases in subjects with a higher degree of cumulative morbidity under acute circumstances (e.g., ICU therapy, vasopressor administration).

Background: Acute kidney injury (AKI) significantly worsens the prognosis of hospitalized patients. Diabetes mellitus (DM) affects a growing number of individuals in the western world. DM subjects are at a higher risk for acquiring AKI during the stay at the hospital. The current study intended to quantify serum levels of specific immunomodulatory cytokines in diabetic mice suffering from AKI. Methods: DM was induced in male C57/Bl6N mice by systemic injections of beta cell-toxic streptozotocin. Animals underwent bilateral renal ischemia (45 min) 6 weeks later. Results: Post-ischemic diabetic mice showed significantly differing serum concentrations of the majority of all analytes as compared to untreated controls and non-diabetic (post-ischemic) animals. Conclusions: Together, our data suggest DM-associated immune activation in AKI. One may suppose that inadequate stimulation of the humoral/cellular immune response potentially contributes to the higher ischemia susceptibility of the organ in DM. J Clin Med Res. 2019;11(10):720-724 doi: https://doi.org/10.14740/jocmr3852

Background. Acute kidney injury substantially worsens the prognosis of hospitalized patients. The Brandenburg Medical School was founded in 2014, and a nephrology section was opened in summer 2017. The aim of the study was to analyze AKI epidemiology and outcomes in one of two university hospitals belonging to the medical school. The period of interest dated from January to December 2015. Methods. The investigation was designed as a single-center, retrospective cohort study at the Brandenburg Hospital of the Brandenburg Medical School. All in-hospital patients treated between January and the end of December 2015 were included. AKI was defined as specified in the 2012 published KDIGO criteria (criteria 1 and 2). Four parameters were evaluated in particular: AKI incidence, in-hospital mortality, frequency of renal replacement therapy, and renal recovery during the stay at the hospital. Results. A total number of 5,300 patients were included in the analysis. AKI was diagnosed in 490 subjects (10.1%). The in-hospital mortality was 26%. The following conditions/parameters significantly differed between survivors (s) and nonsurviving (ns) subjects: duration of in-hospital treatment (s > ns), AKI onset (outpatient vs. in-hospital) (outpatient in s > ns), dialysis due to AKI (s

Background: The aim of this cross-sectional study was to investigate potential associations between periodontal inflamed surface area (PISA) and tooth loss with disease-related parameters in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Methods: Patients who attended the Department of Nephrology and Rheumatology, University Medical Centre Goettingen, Germany, were included. The oral examination comprised the detection of the number of remaining teeth and periodontal condition based on staging and grading matrix. Based on periodontal pockets with positive bleeding on probing, the periodontal inflamed surface area (PISA) was determined. Disease related parameters were extracted from the patients’ records. Results: In total, 101 (RA) and 32 participants (AS) were included. Patients with RA had 22.85 ± 4.26 and AS patients 24.34 ± 5.47 remaining teeth (p &lt, 0.01). Periodontitis stage III and IV was present in 91% (RA) and 81.2% (AS) of patients (p = 0.04). Associations between PISA and disease-related parameters were not found in both groups (p &gt, 0.05). In RA, a higher age (p &lt, 0.01), C-reactive protein (p = 0.02), disease activity (p &lt, 0.01) and prednisolone intake (p &lt, 0.01) were associated with fewer remaining teeth. In AS, a higher age (p = 0.02) and increased Bath Ankylosing Spondylitis Metrology Index (p = 0.02) were associated with a lower number of remaining teeth. Conclusions: Tooth loss is associated with disease activity, especially in RA individuals. Dental care to prevent tooth loss might be recommendable to positively influence oral health condition and disease activity in RA and SA patients.

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.

Background Endothelial Progenitor Cells have been shown as effective tool in experimental AKI. Several pharmacological strategies for improving EPC-mediated AKI protection were identified in recent years. Aim of the current study was to analyze consequences of constitutive Atg5 activation in murine EPCs, utilized for AKI therapy. Methods Ischemic AKI was induced in male C57/Bl6N mice. Cultured murine EPCs were systemically injected post-ischemia, either natively or after Atg5 transfection (Adenovirus-based approach). Mice were analyzed 48 h and 6 weeks later. Results Both, native and transfected EPCs (EPCsAtg5) improved persisting kidney dysfunction at week 6, such effects were more pronounced after injecting EPCsAtg5. While matrix deposition and mesenchymal transdifferentiation of endothelial cells remained unaffected by cell therapy, EPCs, particularly EPCsAtg5 completely prevented the post-ischemic loss of peritubular capillaries. The cells finally augmented the augophagocytic flux in endothelial cells. Conclusions Constitutive Atg5 activation augments AKI-protective effects of murine EPCs. The exact clinical consequences need to be determined.

Background and Aims Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. Cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies performed in recent years utilized Pro-angiogenic Cells (PACs). Autophagy (AP) is commonly regarded as process of en-dogenous self-defense. The AP cascade, which may be stimulated by either substrate deprivation or certain exogenous / endogenous stressors, involves the activation of numerous proteins, the so-called Autophagy-related proteins (Atg proteins). Among these, Atg5 has been suggested to play a key role in augmenting AP. The current study evaluated whether selective Atg5 activation in syngeneic murine PACs may result in improved cell-mediated AKI protection. Method Cultured murine PACs were selectively transfected for Atg5. Successful transfection was verified by detecting red fluorescing cells. AKI was induced in male C57/Bl6N mice (8-12 weeks) by bilateral renal ischemia (IRI - 40 minutes). Transfected cells were i.v. injected post-ischemia. Mice were analyzed 48 hours and 6 weeks later. Results IRI induced significant kidney excretory dysfunction as reflected by higher serum cystatin C levels (48 hours and 6 weeks). Cell administration (either native or after transfection) did not improve AKI outcomes at 48 hours. At 6 weeks, injection of native cells resulted in lower serum cystatin C, this effect was even more pronounced if transcfected cells were applied. Conclusion Together, our data show that selective Atg5 overexpression in murine PACs sub-stantially augments cell-mediated AKI protection in the long-term. Thus, a new strategy for improving AKI protective effects of PACs has been identified.

Background and Aims Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on so-called Proangiogenic Cells (PACs). Mechanisms that contribute to PAC-mediated AKI protection include production / secretion of extracellular vesicles (EV). 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 EV and / or the secretome alone. Method 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 melatonine, Angiopoietin-1 or -2, or with Bone Morphogenetic Protein-5 (BMP-5) for one hour, respectively. The four mediators were chosen since previous own studies showed improved PAC-mediated AKI protection after cell preconditioning with these substances. PAC-derived EV and the vesicle-depleted supernatant were subsequently collected and i.v. injected post-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 EV, collected from native PACs. The following conditions worsened post-ischemic renal function even further: EV+Ang-1, EV+BMP-5, EV+melatonin, and EV+secretome+Ang-1. Conclusion Together, our data show that PAC-mediated AKI protection substantially depends on the availability of cell-derived EV. The secretome, either collected from native or preconditioned cells does not prevent mice from ischemia-induced dysfunction. However, since previous data showed improved AKI-protection by PACs after cell preconditioning with certain mediators (Ang-1 and -2, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection. We suggest, that the mere presence of intact cells in the post-ischemic tissue is necessary for improving functional and structural outcome parameters under certain conditions.

Background: Acute Kidney Injury (AKI) significantly worsens the prognosis of hospitalized patients. In recent years, cell-based strategies have been established as reliable option for improving AKI outcomes in experimental AKI. Own studies focused on 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 melatonine, 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 post-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 post-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, melatonine, BMP-5), other than exclusively vesicle-dependent mechanisms must be involved in PAC-mediated AKI protection.

Objectives: The aim of this systematic review was to assess the oral-health-related quality of life (OHRQoL) of adult patients with rheumatic diseases. Material and Methods: A systematic literature search was performed, including clinical studies on adults (aged at least 18 years) with a verified diagnosis of rheumatic disease. Results: 26 out of 41 clinical studies including rheumatoid arthritis (RA, seven studies), systemic sclerosis (SSc, five), Sjögren syndrome (SS, eight), Behcet disease (BD, four), systemic lupus erythematosus (SLE, one) and ankylosing spondylitis (AS, one) were found. In 15 studies, a healthy control group was recruited. The short form of the Oral Health Impact Profile (OHIP 14) was most frequently applied. The majority of studies (14/15) reported worse OHRQoL in patients with rheumatic disease compared to healthy individuals. In particular, patients with SS (salivary flow and composition) or BD (oral ulcers) showed a relation between OHRQoL and disease-specific oral manifestations. Most studies investigating subscales of OHRQoL (5/6) found the subscale physical disability to be predominantly affected in patients with rheumatic diseases. About half of the studies reported impaired psychosocial aspects. Conclusion: Patients with rheumatic diseases exhibit reduced OHRQoL, especially in diseases with oral manifestations like SS and BD. Physical affections due to oral diseases and psychosocial impairments caused by disease-related parameters must be recognized within patient-centered dental care.

Objectives: The aim of this systematic review was to assess the oral-health-related quality of life (OHRQoL) of adult patients with rheumatic diseases. Material and Methods: A systematic literature search was performed, including clinical studies on adults (aged at least 18 years) with a verified diagnosis of rheumatic disease. Results: 26 out of 41 clinical studies including rheumatoid arthritis (RA, seven studies), systemic sclerosis (SSc, five), Sjögren syndrome (SS, eight), Behcet disease (BD, four), systemic lupus erythematosus (SLE, one) and ankylosing spondylitis (AS, one) were found. In 15 studies, a healthy control group was recruited. The short form of the Oral Health Impact Profile (OHIP 14) was most frequently applied. The majority of studies (14/15) reported worse OHRQoL in patients with rheumatic disease compared to healthy individuals. In particular, patients with SS (salivary flow and composition) or BD (oral ulcers) showed a relation between OHRQoL and disease-specific oral manifestations. Most studies investigating subscales of OHRQoL (5/6) found the subscale physical disability to be predominantly affected in patients with rheumatic diseases. About half of the studies reported impaired psychosocial aspects. Conclusion: Patients with rheumatic diseases exhibit reduced OHRQoL, especially in diseases with oral manifestations like SS and BD. Physical affections due to oral diseases and psychosocial impairments caused by disease-related parameters must be recognized within patient-centered dental care.

Background Endothelial Progenitor Cells have been shown as effective tool in experimental AKI. Several pharmacological strategies for improving EPC-mediated AKI protection were identified in recent years. Aim of the current study was to analyze consequences of constitutive Atg5 activation in murine EPCs, utilized for AKI therapy.Methods Ischemic AKI was induced in male C57/Bl6N mice. Cultured murine EPCs were systemically injected post-ischemia, either natively or after Atg5 transfection (Adenovirus-based approach). Mice were analyzed 48 hours and 6 weeks later.Results Both, native and transfected EPCs (EPCsAtg5) improved persisting kidney dysfunction at week 6, such effects were more pronounced after injecting EPCsAtg5. While matrix deposition and mesenchymal transdifferentiation of endothelial cells remained unaffected by cell therapy, EPCs, particularly EPCsAtg5 completely prevented the post-ischemic loss of peritubular capillaries. The cells finally augmented the augophagocytic flux in endothelial cells.Conclusions Constitutive Atg5 activation augments AKI-protective effects of murine EPCs. The exact clinical consequences need to be determined.

Recent literature reveals worse periodontal health condition in ankylosing spondylitis (AS). However, roles of AS-related parameters, periodontal condition, and their association appear unclear. This cross-sectional study aimed at investigating dental and periodontal health as well as potentially periodontal pathogenic bacteria in patients with AS compared to healthy control subjects (HC). Dental examination comprised dental findings (DMF-T), periodontal probing depth (PPD), bleeding on probing, clinical attachment loss (CAL), papillary bleeding index, and microbiological analysis based on polymerase chain reaction of selected potentially periodontal pathogenic bacteria. Classification of periodontitis severity was based on PPD and/or CAL and divided into no/mild, moderate, and severe periodontitis. 52 participants with AS and 52 HC were included. 96% of the AS group and 75% of HC had moderate to severe periodontitis (moderate: AS = 26, HC = 34; severe: AS = 23, HC = 5; p

The aim of this cross-sectional study was to investigate oral health-related quality of life (OHRQoL) in patients with ankylosing spondylitis (AS) and its association to oral health as well as AS specific parameters. Patients with AS and a healthy control group (HC) were included and examined. The oral examination included decayed-, missing-, and filled-teeth index (DMF-T) as well as assessment of periodontal probing depth and clinical attachment loss to classify patients into healthy/mild, moderate, or severe periodontitis. Furthermore, the German short form of the oral health impact profile (OHIP G14) was used. A total of 50 patients each group (age: AS, 47.18 ± 15.67; HC, 55.82 ± 10.56; p

ZusammenfassungDie Akromegalie ist eine seltene Erkrankung, welche in den meisten Fällen aus einer hypophysären Überproduktion von Wachstumshormon (GH – Growth Hormone) resultiert. Der in der Folge anhaltende IGF-1(Insulin like Growth Factor-1)-Exzess bewirkt zahlreiche morphologische und metabolische Veränderungen des Organismus inklusive Organomegalie, arterieller Hypertonie und Diabetes mellitus. Insbesondere die kardiovaskuläre Morbidität nimmt zu, diese ist auch hauptverantwortlich für vermehrte Sterblichkeit der Betroffenen. Wiewohl nicht prognoseentscheidend, manifestiert sich die Erkrankung gleichfalls am Bewegungsapparat. Drei Komplikationen sind relevant: eine Arthropathie größerer Gelenke, lumbale Wirbelsäulenveränderungen sowie das Karpaltunnelsyndrom. Die Behandlung dieser Komplikationen unterscheidet sich nicht von der Therapie anderer Krankheitsmanifestationen: entscheidend ist die Beseitigung des GH-/IGF-1-Exzesses. Je früher die Diagnose gestellt und die Behandlung eingeleitet wird, desto besser ist die Prognose, sind doch ossäre/artikuläre Veränderungen in vielen Fällen irreversibel.

Background: Spondylarthritis (SpA) significantly affects sacroiliac, intervertebral and peripheral joints. Patients with SpA suffer from increased cardiovascular risk (CVR). The endothelial progenitor cell (EPC) system critically perpetuates vascular repair. The aim of the study was to evaluate circulating EPCs in axial (ax)SpA with special attention on parameters of disease activity and CVR. Methods: Disease activity and functional impairment were quantified in 50 axSpA patients by using standardized parameters (Bath ankylosing spondylitis disease activity index (BASDAI), C-reactive protein (CRP), finger-floor distance (FFD) and Ott’ sign). Circulating EPCs and EPC regeneration were analyzed (fluorescence-activated cell sorting (FACS) and colony-forming unit (CFU) assay). Serum vasomodulatory mediators were quantified by enzyme-linked immunosorbent assay (ELISA). Results: EPC colony numbers were lower in axSpA as compared to controls. Females displayed more colonies than males. In addition, fewer colonies were observed in smokers, in patients with a BASDAI of below 4 and in hypertension. Circulating CD133 + /KDR + cells did not differ between the groups. Follow-up analysis (33 months later) did not show any differences in gender, colony formation, CD133 + /KDR + cells or serum levels of vasomodulatory mediators if related to the categories of BASDAI, Ott’ sign or FFD. Conclusions: EPC colony formation is significantly affected in axSpA with particularly low levels in males. EPC-related parameters do not allow predicting disease activity-related or functional parameters nor are they useful for CVR assessment in SpA. J Clin Med Res. 2019;11(6):391-400 doi: https://doi.org/10.14740/jocmr3441w

High central blood pressure, augmentation index and pulse wave velocity are independent cardiovascular risk factors. Little is known of the effect of baroreflex activation therapy on central hemodynamics.In this prospective clinical trial, radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressure and hemodynamic indices (i.e. augmentation pressure, augmentation index, pulse wave velocity, systolic and diastolic pressure time integral, subendocardial viability index) at baseline and 6 months after starting baroreflex activation therapy in 25 patients with resistant hypertension.Apart from peripheral blood pressure reduction, 6 months of baroreflex activation therapy significantly reduced mean central aortic blood pressure from 109.7 ± 20.5 to 97.4 ± 18.8 mm Hg (P 0.01) and aortic pulse pressure from 62.9 ± 18.6 to 55.2 ± 16.0 mm Hg (P 0.01). Aortic augmentation pressure and augmentation index at a heart rate of 75 b.p.m. were significantly reduced by 4.3 ± 7.9 mm Hg (P = 0.01) and 3.5 ± 6.8% (P = 0.02). Additionally, pulse wave velocity decreased from 10.3 ± 2.6 to 8.6 ± 1.3 m/s (P 0.01) 6 months after starting baroreflex activation therapy. Systolic pressure time integral was significantly reduced (P = 0.03), whereas subendocardial viability index remained unchanged.Apart from peripheral blood pressure, baroreflex activation therapy reduces central blood pressure, augmentation index at a heart rate of 75 b.p.m. and pulse wave velocity in patients with resistant hypertension, suggesting strong potential to reduce cardiovascular risk.

BACKGROUND The aim of this cross-sectional study was to investigate clinical periodontal findings as well as prevalence of selected potentially periodontal pathogenic bacteria in patients with rheumatoid arthritis (RA) treated with different immunosuppressive rheumatic medications. METHODS One hundred sixty-eight patients with RA undergoing different immunosuppressive medications were included and divided into subgroups according to their medication, which was taken in the past 6 months, in detail, 1) non-steroidal anti-inflammatory drugs (NSAID) and glucocorticoids combined, and the following different disease modifying anti-rheumatic drugs (DMARDs): 2) methotrexate (MTX), 3) leflunomide, 4) MTX and TNF-α antagonists combined, 5) interleukin-6 (IL-6) antagonist, 6) MTX and rituximab combined, and 7) combination therapies of > 2 of these DMARDs. Periodontal examination consisted of papilla bleeding index (PBI), periodontal status with periodontal probing depth (PD), bleeding on probing (BOP), and clinical attachment loss (AL). Periodontitis was classified as none/mild, moderate, or severe. Samples obtained from gingival crevicular fluid were analyzed for presence of 11 periodontal pathogenic bacteria. RESULTS Patients with MTX + TNF-α antagonists therapy showed higher PBI and BOP values compared with leflunomide (P

Diabetic nephropathy is the most frequent single cause of end-stage renal disease in our society. Microvascular damage is a key event in diabetes-associated organ malfunction. Early endothelial outgrowth cells (eEOCs) act protective in murine acute kidney injury. The aim of the present study was to analyze consequences of eEOC treatment of murine diabetic nephropathy with special attention on endothelial-to-mesenchymal transdifferentiation, autophagy, senescence, and apoptosis. Male C57/Bl6N mice (8–12 wk old) were treated with streptozotocin for 5 consecutive days. Animals were injected with untreated or bone morphogenetic protein (BMP)-5-pretreated syngeneic murine eEOCs on days 2 and 5 after the last streptozotocin administration. Four, eight, and twelve weeks later, animals were analyzed for renal function, proteinuria, interstitial fibrosis, endothelial-to-mesenchymal transition, endothelial autophagy, and senescence. In addition, cultured mature murine endothelial cells were investigated for autophagy, senescence, and apoptosis in the presence of glycated collagen. Diabetes-associated renal dysfunction (4 and 8 wk) and proteinuria (8 wk) were partly preserved by systemic cell treatment. At 8 wk, antiproteinuric effects were even more pronounced after the injection of BMP-5-pretreated cells. The latter also decreased mesenchymal transdifferentiation of the endothelium. At 8 wk, intrarenal endothelial autophagy (BMP-5-treated cells) and senescence (native and BMP-5-treated cells) were reduced. Autophagy and senescence in/of cultured mature endothelial cells were dramatically reduced by eEOC supernatant (native and BMP-5). Endothelial apoptosis decreased after incubation with eEOC medium (native and BMP-5). eEOCs act protective in diabetic nephropathy, and such effects are significantly stimulated by BMP-5. The cells modulate endothelial senescence, autophagy, and apoptosis in a protective manner. Thus, the renal endothelium could serve as a therapeutic target in diabetes-associated kidney dysfunction.

Early endothelial outgrowth cells (eEOCs) protect mice from acute kidney injury (AKI). Peroxisome proliferator-activated receptor-alpha (PPAR-α) has been shown to mediate renoprotective effects under different experimental conditions. The aim of the study was to investigate consequences of fibrate treatment of murine eEOCs in a cell-based therapeutic approach to AKI. Male C57/Bl6N mice, subjected to unilateral renal ischemia (40 min) post-uninephrectomy, were systemically injected with 0.5 × 106 untreated or fenofibrate (FF 1, 5, 10 or 50 μm)/clofibrate (CF 1 mm) pretreated syngeneic murine eEOCs. Renal function and morphology were analyzed 48 h later. Cellular consequences of eEOC treatment with fibrates (FF 1, 5, 10, 50 μm, CF 1 mm) were evaluated using different in vitro assays (direct cell migration, apoptosis/necrosis, ELISA studies). Administration of untreated eEOCs did not protect mice from AKI. Injection of eEOCs treated with CF (1 mm) or FF 50 μm did not result in any protection from ischemia-induced renal dysfunction. In vitro analysis showed reduced cellular secretion of vasoprotective vascular endothelial growth factor (VEGF), an effect that was more pronounced with CF; FF increased percentages of apoptotic/necrotic eEOCs, and both substances failed to stimulate migration of cultured cells. With lower FF concentrations (1, 5, 10 μm) cell survival was increased and 10 μm FF stimulated VEGF secretion. In vivo administration of FF-treated eEOCs (10 μm) also did not result in any renoprotective effect. PPAR-α activation using fibrates does not stimulate renoprotective effects of syngeneic murine eEOCs in ischemic AKI, although lower fibrate concentrations significantly activate eEOCs in vitro.

Background and Objectives The aim of this clinical cross-sectional study was to determine the level of active matrix metalloproteinase-8 (aMMP-8) and periodontal pathogenic bacteria in gingival crevicular fluid in patients with rheumatoid arthritis (RA) with varying periodontal conditions. Material and Methods In total, 103 patients with RA and 104 healthy controls (HC) were included. The assessment of periodontal status included periodontal probing depth, bleeding on probing and clinical attachment loss. Periodontal disease was classified as healthy/mild, moderate or severe. For the determination of aMMP-8 levels using enzyme-linked immunosorbent assay and periodontal pathogenic bacteria using polymerase chain reaction, samples of gingival crevicular fluid were taken from the deepest gingival pockets. The statistical analyses used included a Mann–Whitney U-test, a chi-squared test or a Fisher's exact test, and the significance level was set at α = 5%. Results We found that 65% of patients with RA and 79% of HC had moderate to severe periodontal disease (p = 0.02). The prevalence of periodontal pathogens was almost equal (p > 0.05). Furthermore, depending on periodontal disease severity only minor differences in bacterial prevalence were detected. With increasing severity of periodontal disease, higher aMMP-8 levels were observed. Accordingly, a significant difference in patients with moderate periodontal disease (RA: 15.3 ± 13.8; HC: 9.1 ± 9.1; p ≤ 0.01) and severe periodontal disease (RA: 21.7 ± 13.3; HC: 13.1 ± 8.6; p = 0.07) was detected, with a greater tendency in the latter group. Conclusion The increased aMMP-8 levels in the RA group indicate that the presence of RA appears to have an influence on the host response at a comparable level of bacterial load and periodontal disease severity.

Early endothelial outgrowth cells (eEOCs) reproducibly have been shown to act protectively in acute ischemic kidney injury (AKI) and chronic kidney injury. Bone morphogenetic protein-5 (BMP-5) acted antifibrotically in human hypertensive nephropathy. The aim of the curent study was to analyze effects of BMP-5 treatment in an eEOC-based therapy of murine AKI and 5/6-nephrectomy. Male C57/Bl6N mice were either subjected to unilateral renal artery clamping postuninephrectomy or to 5/6-nephrectomy. Untreated or BMP-5-pretreated murine eEOCs were injected into recipient animals at the time of reperfusion (AKI) or at 2 and 5 days after 5/6-nephrectomy. Analysis of renal function and morphology was performed at 48 h and at 6 wk (AKI) or at 8 wk (5/6 model). Cellular consequences of eEOC treatment were evaluated using different in vitro assays. AKI was mitigated significantly by injecting BMP-5-pretreated eEOCs. Renal function was improved at 48 h and at 6 wk after cell therapy. In 5/6-nephrectomy, the cells failed to protect renal function, but proteinuria was reduced after administering untreated eEOCs. BMP-5 pretreatment resulted in aggravated proteinuria and renal fibrosis. In 5/6-nephrectomized animals, percentages of anti-smooth muscle actin+/CD31+ cells increased, indicating endothelial-mesenchymal transition (EnMT). In vitro analysis revealed increased cell migration and reduced cell apoptosis/necrosis. Paracrinic activity remained unaffected. BMP-5 acts as a potent eEOC agonist in murine AKI in the short and mid to long term. Cell effects in 5/6-nephrectomy are heterogenous, but untreated cells act antiproteinurically and antifibrotically without any impact on EnMT.

This study evaluates periodontal conditions and microbiologic findings and their influence on rheumatologic disease parameters in patients with rheumatoid arthritis (RA).One hundred and sixty-eight patients with RA were included. A healthy control group (HC, n = 168) was composed according to age, sex, and smoking habits. Rheumatologic data (duration of illness, Disease Activity Score 28, rheumatic factor [RF], anti-cyclic citrullinated peptide [aCCP], medications) were extracted from patients' records. Dental examination included: 1) dental findings (decayed, missing, and/or filled adult teeth [DMF-T] index); 2) gingival inflammation (papillary bleeding index [PBI]); and 3) periodontal status (probing depth [PD], attachment loss [AL]). Periodontal condition was classified as healthy/mild, moderate, or severe periodontitis. Subgingival biofilm was analyzed regarding 11 periodontopathogenic bacteria. Statistical analyses included: 1) Kolmogorov-Smirnov test; 2) Mann-Whitney U test; 3) Pearson χMean DMF-T was significantly higher in patients with RA (19.3 ± 4.8) than in HC group (16.9 ± 5.8), especially owing to number of missing teeth (RA = 6.0 ± 5.4, HC = 3.1 ± 3.3; P0.01). Patients with RA had a significantly higher proportion of increased PD (P0.01) and AL compared with HC group (P0.01). Moderate to severe periodontitis was noted in 98% of patients with RA and 82% of the HC group (P0.01). RF-positive patients with RA suffered from worse periodontal conditions than RF-negative patients (P = 0.01). Age, PBI, and presence of Treponema denticola (P0.03) are related to periodontal condition in patients with RA. Although not statistically significant, Porphyromonas gingivalis and Fusobacterium nucleatum occur in higher concentrations more often in aCCP-positive patients with RA (P = 0.06).Patients with RA had worse periodontal conditions than HC participants. Although a trend for higher F. nucleatum and P. gingivalis concentrations in aCCP-positive patients with RA was found, importance of periodontal pathogenic bacteria and rheumatoid parameters in the interrelationship between periodontitis and RA remains unclear.

The aim of this study was to evaluate the oral health-related quality of life (OHRQoL) in patients with rheumatoid arthritis (RA) depending on their oral health in comparison with healthy controls (HCs).One hundred three RA patients (55.5 years, female 58) were included. A healthy control group (HC n = 104; 56.7 years, female 68) was matched according to age, gender, and smoking habits. The OHRQoL was determined by Oral Health Impact Profile (OHIP)-G14 questionnaire. Oral examination included dental findings (DMF-T), gingival inflammation (PBI), periodontal probing depth (PPD), clinical attachment loss (CAL), and bleeding on probing (BOP). Based on CAL and/or PPD, periodontitis was categorized as healthy/mild, moderate, or severe.trend test (Cochran-Armitage) and Wilcoxon rank-sum test (α = 5%).For DMF-T (RA 17.6 ± 6.1, HC 16.0 ± 6.5) and PBI (RA 0.10 ± 0.18, HC 0.08 ± 0.18), no significant differences between both groups were found (p 0.05). Approximately 65% of RA group and 79% of HC group showed moderate to severe periodontitis (p = 0.02); RA patients showed significantly higher BOP values (p 0.01). OHRQoL was significantly worse in RA group compared to HC group (mean OHIP value RA = 7.3 ± 7.2, HC = 1.6 ± 2.1; p 0.001). In the HC group, a significant effect of DMF-T, M-T, and PD on OHRQoL was detected (p 0.01), whereas in the RA group, no influence was determined (p 0.05).RA patients showed a worse OHRQoL than HC patients, which was independent of dental and periodontal conditions. RA patients require a more intensive care in consideration of dental, medical, and psychological factors.Interdisciplinary collaboration between dentists and rheumatologists is necessary, whereby psychological factors should be considered.

Acute renal failure (ARF) severely worsens prognosis of hospitalized patients. The most frequent cause of intrarenal ARF is transient or prolonged renal hypoperfusion (ischemia). Ischemia primarily affects the function and structure of tubular epithelial cells, which, in severe cases, is characterized by epithelial cell necrosis. Nevertheless, ischemia does not exclusively lead to alterations of epithelial cells but also causes interstitial inflammation and interstitial microvasculopathy. Both inflammation and microvasculopathy are particularly important in terms of postischemic kidney repair. Postischemic microvasculopathy is characterized by endothelial cell swelling with subsequent microvascular occlusion. Thus, reperfusion is inhibited (no-reflow phenomenon). Such endothelial cell dysfunction offers new therapeutic perspectives in ischemic ARF. Newer observations point towards the role of the so-called endothelial progenitor cells (EPCs) in the treatment of ARF. Systemic administration of EPCs to mice with bilateral renal ischemia mitigates postischemic endothelial cell dysfunction and protects animals from acute renal failure.

Endothelial progenitor cells (EPCs) protect kidneys from acute ischemic damage. The aim of this study was to identify “treatment parameters” that optimize an EPC-based therapy of acute ischemic renal failure. Male C57BL/6N mice underwent unilateral nephrectomy with simultaneous contralateral renal artery clamping for 30, 35, and 40 min. Tagged murine EPCs were systemically injected at the time of reperfusion. In some experiments, EPCs were pretreated with the Epac (exchange protein directly activated by cAMP-1) activator 8-pCPT-2′- O-Me-cAMP (Epac-1 Ac) and the integrin binding antagonist cyclic Arg-Gly-Asp peptide (cRGD). Injections of 106 EPCs after 30 and 35 min of renal ischemia protected animals from acute renal failure. The same effect occurred with 0.5×106 EPCs after a 35-min period of ischemia. If ischemia lasted for 40 min, 0.5×106 cells mice did not prevent acute renal failure. To analyze whether EPC integrin receptor activation would modify the cells' renoprotective activity, EPCs were pretreated with Epac-1 Ac. Such animals did not develop acute renal failure, even if ischemia lasted for 40 min. This effect was negated if the cells were pretreated with both Epac-1 Ac and cRGD. In kidneys from those animals medullopapillary EPCs were significantly accumulated. In vitro Epac-1 Ac preactivation of EPCs did not increase the overall expression intensity but induced a redistribution of β1-integrins toward the cell membranes. We conclude that EPC pretreatment with the integrin receptor activator 8-pCPT-2′- O-Me-cAMP augments the anti-ischemic potential of the cells.

Purpose of review To discuss most recently published studies on morphologic patterns and molecular mechanisms of stress-induced premature senescence (SIPS) of vascular endothelial cells. Recent findings Lysosomal dysfunction and impaired autophagy, which have been well established in replicative senescence, were also described in SIPS induced by advanced glycation end products (AGEs). Recently, strides were made to prevent and reverse senescence. The role of lysosomal dysfunction and Lamp-2A deficiency has been demonstrated in aging. Molecular analyses identified the role of sirtuin 1 in preventing cell senescence; shed light on the role of polycomb group (PcG) protein Bmi-1 in senescence. Additionally, intriguing data on the role of caveolin-1 in cell senescence have emerged. Summary In aging organisms and chronic diseases properly functioning tissue is replaced by senescent cells. Comparison between replicative senescence and SIPS indicates that replicative senescence is almost exclusively associated with the reduction of telomerase activity and attrition of telomeres, whereas SIPS does not require these events, thus conferring potential reversibility onto this process.

Endothelial cells subjected to glycated collagen I develop premature senescence within 3–5 days, as revealed by increased senescence-associated β-galactosidase activity, decreased proliferation, and an increase in cell size. Here, we analyzed the time course and possible mechanisms of this process. Lysosomal integrity studies revealed a rapid collapse of pH gradient and lysosomal permeabilization, detectable after 30 min, and preceded by the increased production of reactive oxygen species. Measurement of mitochondrial membrane potential after application of glycated collagen demonstrated that depolarization was delayed by 4 h compared with changes in lysosomal pH and permeability. Based on the above findings of lysosomal permeabilization, we hypothesized that the reduced activity of senescence-associated β-galactosidase could be responsible for the cellular accumulation of gangliosides, previously shown to induce cell senescence. After 5 days of exposure to glycated collagen, there was an increase in the levels of gangliosides GM3, GD1b, and GT1b, coincident with development of cell senescence. Treatment of endothelial cells with d- threo-EtDOP4, an inhibitor of glucosylceramide synthase, inhibited apoptosis, but not the development of senescence. In conclusion, collagen I modified by advanced glycation initially induces apoptosis of human umbilical vein endothelial cells. This process is initiated by the collapse of lysosomal pH and an increase in lysosomal permeability, with the subsequent mitochondrial depolarization and accumulation of gangliosides. Blockade of ganglioside synthesis suppresses apoptosis, but not senescence, which develops after 3 days of exposure to glycated collagen. These data imply a critical role for lysosomal permeabilization in triggering apoptosis of endothelial cells exposed to the diabetic milieu.

With the recent characterization of enzymes responsible for protein arginine methylation and demonstration that catabolic products of arginine methylation, such as asymmetric dimethylarginine (ADMA), are among the most powerful mechanisms of atherogenesis, developing endothelial dysfunction and cardiovascular complications in a variety of pathologic processes, the need for functional characterization of the methylation-demethylation processes becomes ever more urgent. Therefore, the aims of the present study were to refine the feedback regulation of protein arginine methylation using one of the heavily methylated proteins, an RNA-binding protein Sam68, as a prototype, to elucidate the relations between Sam68 methylation and tyrosine phosphorylation and the role of methylation in RNA binding and subcellular distribution, as well as the cellular consequences of reduced protein methylation. Screening pro-atherogenic substances known to induce endothelial dysfunction showed that ADMA did not affect the level of arginine methylation of Sam68, whereas peroxynitrite was a strong inhibitor of methylation. Advanced glycation-modified collagen I, which accumulates in diabetes and induces formation of peroxynitrite and premature endothelial cell senescence, also inhibited arginine methylation of Sam68. When the level of arginine methylation of Sam68 was pharmacologically reduced, this did not affect its RNA binding or degree of tyrosine phosphorylation, but resulted in the predominantly nuclear hypomethylation pattern. Furthermore, protein hypomethylation resulted in the increased rate of apoptosis and premature senescence. This data may offer an additional explanation for the proapoptotic and senescence-accelerating action of peroxynitrite, a potent inhibitor of protein methylation.

Understanding the nature of endogenous mechanisms for mobilization of stem/progenitor cells is predicated on the identification of injury-induced substances that are released from a damaged organ and capable of producing a distant effect. Although different substances that mobilize endothelial progenitor cells (EPCs) have been proposed, their potential to signal injury and afford postischemic renoprotection and repair remains obscure. Uric acid (UA) is consistently overproduced by ischemic tissues and has been shown to exert immunomodulatory functions. It was hypothesized that UA and/or its precursors might serve as injury signals that are capable of mobilizing EPCs in acute renal ischemia. Indeed, FVB/NJ mice that were subjected to acute renal ischemia showed a transient surge in UA level in the peripheral blood. Single-dose treatment with UA, as well as acute hyperuricemia induced by the inhibition of uricase, caused a robust mobilization of EPCs, whereas administration of adenosine or inosine seemed to lack this effect. Moreover, pretreatment of mice with a single dose of UA afforded significant renoprotection against ischemic injury. In animals with chronic hyperuricemia (induced by continuous 2-wk treatment with a uricase inhibitor oxonic acid), EPC mobilization was blunted and renoprotective effects were absent. In conclusion, acute elevation of UA acts as "physiologic," fast-acting endogenous mediator of EPC mobilization and renoprotection, consistent with its novel function in pharmacologic preconditioning. Both of these actions are lacking in mice with chronic hyperuricemia. In summary, a transient surge in UA concentration may serve as a universal herald of tissue injury to accelerate the recruitment of EPCs.

Metabolic syndrome leads to accelerated development of macro- and microvasculopathy culminating in cardiovascular and renal complications. Using cultured endothelial cells and Zucker diabetic fat rats, we and others have demonstrated that endothelial cells undergo stress-induced premature senescence characterized by the decreased nitric oxide generation and enhanced production of peroxynitrite, in association with the increased expression of p53 and p16INK4a and accumulation of 3-nitrotyrosine-modified proteins. We reasoned that the combination of oxidative and nitrosative stress could be the cause of observed phenotypic switch in endothelial cells and employed for its prevention a selenoorganic compound, ebselen, endowed with both the antioxidant and peroxynitrite scavenging properties. Chronic therapy with ebselen resulted in the decline of the number of prematurely senescent endothelial cells and prevention of macro- and microvascular (renal) complications of metabolic syndrome. Instituting this therapy early after development of vasculopathy resulted in its amelioration. Based on these findings we propose that (a) oxidative and nitrosative stress are critical for the development of cardiovascular complications in metabolic syndrome, (b) stress-induced premature senescence of vascular endothelium represents a mechanistic link between the stressors and macro- and microvasculopathy, and (c) both can be prevented and partially reversed by antioxidant and peroxynitrite scavenging therapies.

This brief overview describes the physiology of lipid (membrane) rafts in the vascular endothelium, methods for detection of these domains and perturbations they undergo in pathophysiological conditions associated with cardiovascular disease and development of endothelial dysfunction. Specifically, emphasis is placed on the actions of oxidative stress, proatherogenic lipid mediators, advanced glycation end products and changes in flow and shear stress in perturbations in the expression of components of membrane rafts and signaling through eNOS and receptors localized to them.

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.