PDE5 inhibition against acute renal ischemia reperfusion injury in rats: does vardenafil offer protection?

Purpose

To evaluate the effect of vardenafil on renal function after renal ischemia–reperfusion (IR) injury (IRI) in a rat model.

Materials and methods

Seventy-one Wistar rats were divided into 7 groups including (1) a vehicle-treated group, (2) a vehicle pretreated-IR group, (3–6) vardenafil pretreated-IR groups in doses of 0.02, 0.2, 2 and 20 μg/kg, respectively, (7) a group of IR followed by treatment with 2 μg/kg of vardenafil. Vardenafil or vehicle solution was administered one hour before unilateral nephrectomy and the induction of 45 min of ischemia on the contralateral kidney by clamping of renal pedicle. Four hours of reperfusion were allowed after renal ischemia. Studied parameters were serum creatinine, fractional excretion of sodium (FENa), and histological evaluation of renal specimens. In addition, renal tissue cGMP levels, ERK1/2 phosphorylation as well as renal function by renal scintigraphy were also evaluated.

Results

Administration of vardenafil before the induction of ischemia resulted in a significant reduction in creatinine and FENa levels as well as in less histological lesions observed in treated kidneys in comparison with the vehicle-treated group. The underlying mechanism of cytoprotection was cGMP depended and involved the phosphorylation of ERK proteins. Renal scintigraphy confirmed that PDE5 inhibition attenuates renal IRI.

Conclusions

Vardenafil attenuates renal IRI. Based on similar results from relevant studies on other PDE-5 inhibitors in renal and cardiac IRI, it can be assumed that all PDE-5 inhibitors share a common mechanism of cytoprotection.     

Enamel Matrix Derivative in Intrabony Defects: Prognostic Parameters of Clinical and Radiographic Treatment Outcomes

Background: The purpose of this retrospective case series study is to identify possible preoperative parameters that could predict postoperative probing depth (PD), clinical attachment level (CAL) gain, or radiographic defect resolution in intrabony defects treated with enamel matrix derivative (EMD). Methods: Sixty‐one chronic periodontitis patients, each contributing a 2‐ or 3‐wall intrabony defect treated with EMD, were included. Clinical parameters recorded included the following: PD; CAL; gingival margin position; supracrestal soft tissue (SST); surgical distances of cemento‐enamel junction (CEJ) to bone crest (CEJ‐BC), CEJ to base of the defect (CEJ‐BD), and BC to BD (BC‐BD); and depth of 2‐ and 3‐wall components. Radiographic parameters recorded included the following: CEJ‐BC, CEJ‐BD, BC‐BD distances, and radiographic defect angle. Postoperative assessments were performed at 12 months. Results: The probability of postoperative PD >4 mm increased 1.6‐fold (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.2 to 2.3) with each 1‐mm baseline PD increase. Baseline PD and surgical CEJ‐BD were statistically significant predictors of CAL gain; the greater the baseline PD (OR = 0.5; 95% CI = 0.3 to 0.8) and bone loss (OR = 0.6; 95% CI = 0.3 to 0.9), the less likely that postoperative CAL gain was ≤3 mm. Smoking and SST were significantly associated with defect resolution; failure to achieve ≥65% defect resolution was six‐fold greater for smokers (OR = 6.5; 95% CI = 1.7 to 24.5) and almost double (OR = 1.7; 95% CI = 1.1 to 2.8) for each millimeter of SST increase. Conclusion: In EMD‐treated intrabony defects, baseline PD predicts both CAL gain and postoperative PD. Smoking and SST are predictors of defect resolution.     

Levodopa‐induced dyskinesias in tyrosine hydroxylase deficiency

The objective of this study was to characterize levodopa (l‐ dopa)–induced dyskinesias in patients with tyrosine hydroxylase deficiency. Clinical observation was carried out on 6 patients who were diagnosed with tyrosine hydroxylase deficiency and were treated with escalating doses of l‐ dopa. All 6 patients showed l ‐dopa‐induced dyskinesias of variable intensity early in the course of treatment and regardless of the age of initiation. l ‐Dopa–induced dyskinesias were precipitated by increases in the dose of l ‐dopa and also by febrile illnesses and stress. They caused dysfunction and distress in 2 patients. The dyskinesias were improved by decreasing the l ‐dopa dose or by slowing its titration upward. Increasing the dose frequency was helpful in 2 patients, and introducing amantadine was helpful in another 2 patients. l ‐Dopa–induced dyskinesias are a common phenomenon in tyrosine hydroxylase deficiency. The current observations show that l‐ dopa–induced dyskinesias are frequent in a dopamine‐deficient state in the absence of nigrostriatal degeneration. Although l ‐dopa–induced dyskinesias in tyrosine hydroxylase deficiency are phenomenologically similar to those that occur in Parkinson's disease, they are different in a number of other respects, suggesting intrinsic differences in the pathophysiologic basis of l‐ dopa–induced dyskinesias in the 2 conditions. © 2013 Movement Disorder Society     

ESCAP CovCAP survey of heads of academic departments to assess the perceived initial (April/May 2020) impact of the COVID-19 pandemic on child and adolescent psychiatry services

In April 2020, the European Society for Child and Adolescent Psychiatry (ESCAP) Research Academy and the ESCAP Board launched the first of three scheduled surveys to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on child and adolescent psychiatry (CAP) services in Europe and to assess the abilities of CAP centers to meet the new challenges brought on by the crisis. The survey was a self-report questionnaire, using a multistage process, which was sent to 168 heads of academic CAP services in 24 European countries. Eighty-two responses (56 complete) from 20 countries, representing the subjective judgement of heads of CAP centers, were received between mid-April and mid-May 2020. Most respondents judged the impact of the crisis on the mental health of their patients as medium (52%) or strong (33%). A large majority of CAP services reported no COVID-19 positive cases among their inpatients and most respondents declared no or limited sick leaves in their team due to COVID-19. Outpatient, daycare, and inpatient units experienced closures or reductions in the number of treated patients throughout Europe. In addition, a lower referral rate was observed in most countries. Respondents considered that they were well equipped to handle COVID-19 patients despite a lack of protective equipment. Telemedicine was adopted by almost every team despite its sparse use prior to the crisis. Overall, these first results were surprisingly homogeneous, showing a substantially reduced patient load and a moderate effect of the COVID-19 crisis on psychopathology. The effect on the organization of CAP services appears profound. COVID-19 crisis has accelerated the adoption of new technologies, including telepsychiatry.

     

Altered peptide ligands induce quantitatively but not qualitatively different intracellular signals in primary thymocytes

Interaction of the T cell receptor (TCR) with peptide/major histocompatibility complexes (MHC) in the thymus is of critical importance for developing thymocytes. In a previous study, we described an antagonist peptide that inhibited negative selection of transgenic thymocytes induced by an agonist peptide. In this study we show that this antagonist peptide can induce positive selection of CD8⁺ thymocytes more efficiently than the agonist or the weak agonist peptides, whereas the opposite is true for their ability to cause negative selection. The intracellular signals induced in thymocytes by such peptides after TCR ligation was examined in CD4⁺8⁺ double-positive thymocytes from F5/β₂m^o/Rag-1^o transgenic mice. TCR ligation with either the agonist, weak agonist, or antagonist peptide variants resulted in hyperphosphorylation of CD3ζ, CD3, ZAP-70, Syk, Vav, SLP-76, and pp36–38. The extent of phosphorylation of these intracellular proteins correlated with the efficiency with which the peptide analogs induced apoptosis of immature thymocytes. Unexpectedly, there was no correlation between the upstream TCR signaling pathways analyzed and the capacity of the different peptides to induce positive selection.     

Anemia of chronic disease is the more frequent type of anemia seen in patients with chronic idiopathic neutropenia of adults

This study describes the frequency and the type of anemia seen in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). We found that NI-CINA patients had low hemoglobin levels and increased serum concentrations of erythropoietin (EPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The hemoglobin levels correlated positively with the number of circulating neutrophils and inversely with the levels of EPO and TNF-alpha but not of IL-1beta. Anemia, defined as the reduction of the hemoglobin below 12.0 g/dl for women and 13.3 g/dl for men, was found in 23 out of 148 patients studied, a proportion of 15.5%. Two of the anemic patients had iron deficiency anemia (8.7%), 11 had anemia of chronic disease (ACD; 47.8%) presenting with normal or slightly reduced erythrocytic indices, low serum iron, and increased serum ferritin, and the remaining ten had anemia of undefined pathogenesis (AUP; 43.5%) with normal or slightly decreased erythrocytic indices, serum iron ranging from 43 to 88 microg/dl, and ferritin values ranging from 12 to 50 ng/ml. We conclude that ACD is the more frequent type of anemia seen in patients with NI-CINA, and that pro-inflammatory cytokines, notably TNF-alpha, may be involved in the pathogenesis of both ACD and AUP, given that serum levels of the cytokine were significantly increased and that the EPO response to anemia was blunted in these patients. These findings further support our previously reported suggestion for the possible existence, in NI-CINA patients, of an unrecognized low-grade chronic inflammatory process that may be involved in the pathogenesis of the disorder.