Lack of effect of opioid peptides,morphine and naloxone on superoxide formation in human neutrophils and HL-60 leukemic cells

Summary There are controversial reports in the literature concerning the effects of opioids on superoxide (O ₂ ^– ) formation in phagocytes, these agents being either inhibitory or stimulatory. We re-examined this issue and compared the effects of the Chemotactic peptide, N-formyl-l,-methionyl-l-leucyl-l-phenylalanine (fMet-Leu-Phe), phorbol myristate acetate (PMA), ATP, platelet activating factor (PAF), cytochalasin B (CB) and prostaglandin E₁ (PGE₁) with those of various opioids on O ₂ ^– formation in human neutrophils and HL-60 leukemic cells under defined experimental conditions. In the presence of CB, fMet-Leu-Phe and PAF concentration-dependently activated O ₂ ^– formation in neutrophils with EC₅₀ values of 20 nM and 100 nM, respectively. In the absence of CB, fMet-Leu-Phe and PAF were much less effective. PAF synergistically enhanced O ₂ ^– formation induced by fMet-Leu-Phe. ATP at a concentration of 100 M and the opioids, methionine enkephalin, -endorphin, dynorphin, [d-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin, [d-Ala²-d-Leu⁵]-enkephalin and morphine at concentrations between 10 pM to 1 M did not activate O ₂ ^– formation. ATP but not \-endorphin potentiated fMet-Leu-Phe-induced O ₂ ^– formation. O ₂ ^– formation induced by a maximally stimulatory concentration of PMA (100 ng/ml) was enhanced by fMet-Leu-Phe but was unaffected by methionine enkephalin or PGE₁. PMA at a non-stimulatory concentration (2 ng/ml) potentiated the effect of fMet-Leu-Phe but did not induce responsiveness to PAF, ATP or -endorphin. PGE₁ strongly inhibited fMet-Leu-Phe-induced O ₂ ^– formation, whereas morphine, methionine enkephalin and the opioid antagonist, naloxone, were without effect. In HL-60 cells differentiated with dibutyryl cAMP, fMet-Leu-Phe, PAF and ATP but not -endorphin activated O ₂ ^– formation. Our results show that O ₂ ^– formation is differentially regulated by various classes of intercellular signal molecules and that opioids do not play a role in the regulation of O ₂ ^– formation. The precise definition of the experimental conditions and control experiments with established modulators of O ₂ ^– formation are essential to evaluate the role of opioids in the regulation of this effector system.Send offprint requests to R. Seifert at the above address     

Cationic-amphiphilic arpromidine-derived guanidines and a histamine trifluoromethyl-toluidide derivative may activate pertussis toxin-sensitive G-proteins by a receptor-independent mechanism

Formyl peptides activate superoxide anion (O₂ ^–) formation in human neutrophils and in HL-60 cells via pertussis toxin (PTX)-sensitive guanine nucleotide-binding proteins (G-proteins), and histamine (HA) mediates inhibition of O₂ ^– formation via H₂-receptors. We have studied the effects of lipophilic arpromidine-derived guanidines, which are potent, full H₂-receptor agonists in the guinea pig atrium, on O₂ ^– formation and on activation of G-proteins in HL-60 membranes and on purified G-proteins. We have also studied the effects of a HA trifluoromethyl-toluidide derivative (HTMT), a cationic-amphiphilic HA derivative which activates O₂ ^– formation in HL-60 cells through a mechanism which is independent of known HA receptor subtypes, on G-protein activation. Guanidines, at concentrations, up to 30 mol/l inhibited and, at concentrations above 30 mol/l, enhanced formyl peptide-induce O₂ ^– formation in neutrophils. In HL-60 cells, guanidines per se activated O₂ ^– formation. The stimulatory effects of guanidines on O₂ ^– formation were not inhibited by H₁- or H₂-receptor antagonists. In HL-60 membranes, guanidines and HTMT, activated high-affinity GTPase in a PTX-sensitive manner. These substances also increased GTP hydrolysis effected by transducin and G_i/G_o-proteins. Our data suggest that lipophilic guanidines and HTMT may act as receptor-independent activators of PTX-sensitive G-proteins, resulting in stimulation of O ₂ ^– formation.     

Pelvimetry and patient acceptability compared between open 0.5-T and closed 1.5-T MR systems

Our objective was to compare maternal pelvimetry and patient acceptability between open low-field (0.5-T) and closed 1.5-T MR systems. Thirty women referred for pelvimetry (pregnant: n=15) were scanned twice in the supine position, once in the vertical open system and once in the closed system. Each patient completed a comfort and acceptability questionnaire. Pelvimetric and questionnaire data were compared between systems. Total scan time was double in the open system (7:52±1:47 vs 3:12±1:20 min). Poor image quality in the open system prevented assessment of interspinous and intertuberous diameters in one woman and all measurements in another, both pregnant, with abdominal circumferences >120 cm. The open system was much more acceptable in terms of claustrophobia and confinement (both p<0.01). Claustrophobia interrupted one closed examination. Thirty-three percent of pregnant women in both systems reported fear of fetal harm. Sixty percent of all women preferred the open system, 7% the closed system, and 33% had no preference. Limits of agreement of 3–5% from the mean for all diameters confirmed good pelvimetric reproducibility. Women's preference for open-system MR pelvimetry is feasible with abdominal circumferences ≤120 cm. Electronic Publication     

Insulin-like Growth Factor and its Therapeutic Potential for Diabetes Complications - Mechanisms and Metabolic Links: A Review

BACKGROUNDThe insulin-like growth factor (IGF) system is an important system in normal physiological functioning of the body. In diabetes mellitus, alterations of IGF-binding protein (IGFBP) levels have been described, mainly in vascular complications.AIMThe aim of this review was to explore the role of the IGF system in reducing diabetes complications and its role as potential therapeutic target.RESULTSIGF-1 plays a role in neuronal growth and developmental processes. Low concentrations of IGF-1 have been associated with neuropathy and other diabetes complications. Moreover, impaired IGF synthesis and function may result in cellular senescence and impaired vascular endothelial proliferation, adhesion, and integration. Of note, high IGF-1 bioavailability may prevent or delay the inception of diabetes-associated complications in diabetes patients. The mechanism of normal functioning IGF-1 is induced by increasing nitric oxide synthesis and potassium ion channel opening in cardiovascular physiology, which improves impaired small blood vessel function and reduces the occurrence of diabetes complications associated with reduced concentrations of IGF-1.CONCLUSIONSIGF may be considered an alternative therapy for diabetes and diabetes-associated complications. Therefore, future studies should focus on the mechanism of action and therapeutic potential of IGFs in reducing the risk of development and progression of the disease in different clinical settings.     

Preoperative Nutritional Deficiencies in Severely Obese Bariatric Candidates are not Linked to Gastric Helicobacter pylori Infection

Severely obese subjects have been found to show a high prevalence of distinct nutritional deficiencies even without any bariatric intervention but the underlying reasons remain obscure. We tested the hypothesis that gastric Helicobacter pylori infection is associated with increased nutritional deficiency rates. Taking advantage of our large database, we identified 404 patients who had undergone a gastroscopy—as a standard diagnostic assessment before bariatric surgery—along with a histological examination of gastric mucosal biopsies with concurrent nutritional blood measurements. Eighty-five (21 %) of the obese patients included in the study displayed a gastric H. pylori infection. Sex distribution, age and body mass index did not differ between H. pylori+ and H. pylori? patients (P?>?0.29). Referring to nutritional markers, neither serum levels of total protein, albumin, calcium, phosphate, magnesium, ferritin, zinc, copper, vitamin B₁₂, folate and 25-OH vitamin D₃ nor respective deficiency rates differed between the H. pylori+ and H. pylori? patients group (all P?>?0.13). Overall, 49.5 % of the bariatric candidates displayed at least one nutritional deficiency. Our data confirm previous reports on high prevalences of nutritional deficiencies in severely obese subjects. However, they do not provide evidence for a contributing role of gastric H. pylori infection to these nutritional alterations.     

Comparison of preoperative continuation and discontinuation of aspirin in patients undergoing total hip or knee arthroplasty

Introduction

Preoperative discontinuation of aspirin (acetylsalicylic acid) can reduce bleeding risk but may increase the risk of perioperative cardiovascular events.

Materials and methods

We retrospectively assessed the impact of preoperative continuation versus discontinuation of aspirin compared with a control group in a cohort of 739 consecutive patients undergoing total hip (THA) (n = 396) or knee arthroplasty (TKA) (n = 343) at a tertiary hospital. Bleeding risk, local complications, orthopaedic outcome, and cardiac and cerebral complications were assessed.

Results

Four hundred and sixty-five patients did not receive antithrombotic or full-dose anticoagulant medication, 175 patients were taking low-dose aspirin, 99 vitamin K antagonists, clopidogrel, or a combination of these drugs. Of the patients taking aspirin, 139 discontinued and 36 continued aspirin. Blood loss and local bleeding complications were comparable in these two groups. TKA patients who continued aspirin more frequently showed marked knee swelling after 1 week than those discontinuing aspirin (35.1 vs. 81.3 %; p = 0.001). However, orthopaedic outcome did not differ significantly between the two groups. There was a trend towards an increased risk of cardiac complications in patients who discontinued aspirin (6.5 vs. 0.0 %; p = 0.107).

Conclusions

Continuation or discontinuation of aspirin did not show a statistically significant difference in the risk of relevant perioperative bleeding complications in our study. Continuation of aspirin was associated with a transitory increase in knee swelling, but had no effect on orthopaedic outcome. Continuation of aspirin may be associated with a favourable perioperative cardiac outcome. Our data support perioperative continuation of aspirin intake in patients undergoing THA or TKA.

     

The Effect of Financial Incentives on Quality Measures in the Treatment of Diabetes Mellitus: a Randomized Controlled Trial

BackgroundFinancial incentives are often used to improve quality of care in chronic care patients. However, the evidence concerning the effect of financial incentives is still inconclusive.ObjectiveTo test the effect of financial incentives on quality measures (QMs) in the treatment of patients with diabetes mellitus in primary care. We incentivized a clinical QM and a process QM to test the effect of financial incentives on different types of QMs and to investigate the spill-over effect on non-incentivized QMs.Design/ParticipantsParallel cluster randomized controlled trial based on electronic medical records database involving Swiss general practitioners (GPs). Practices were randomly allocated.InterventionAll participants received a bimonthly feedback report. The intervention group additionally received potential financial incentives on GP level depending on their performance.Main MeasuresBetween-group differences in proportions of patients fulfilling incentivized QM (process QM of annual HbA1c measurement and clinical QM of blood pressure level below 140/95 mmHg) after 12 months.Key ResultsSeventy-one GPs (median age 52 years, 72% male) from 43 different practices and subsequently 3838 patients with diabetes mellitus (median age 70 years, 57% male) were included. Proportions of patients with annual HbA1c measurements remained unchanged (intervention group decreased from 79.0 to 78.3%, control group from 81.5 to 81.0%, OR 1.09, 95% CI 0.90–1.32, p = 0.39). Proportions of patients with blood pressure below 140/95 improved from 49.9 to 52.5% in the intervention group and decreased from 51.2 to 49.0% in the control group (OR 1.16, 95% CI 0.99–1.36, p = 0.06). Proportions of non-incentivized process QMs increased significantly in the intervention group.ConclusionGP level financial incentives did not result in more frequent HbA1c measurements or in improved blood pressure control. Interestingly, we could confirm a spill-over effect on non-incentivized process QMs. Yet, the mechanism of spill-over effects of financial incentives is largely unclear.Trial RegistrationISRCTN13305645Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-021-06714-8.KEY WORDS: quality of care, improvement, financial incentives, diabetes mellitus, primary care, spill-over effect     

Elevated levels of the antimicrobial peptide LL‐37 in hidradenitis suppurativa are associated with a Th1/Th17 immune response

Hidradenitis suppurativa (HS) is an inflammatory skin disease with poorly understood immunopathogenic mechanisms. LL‐37 is an antimicrobial peptide, which is transcribed from the CAMP (cathelicidin antimicrobial peptide) gene. Previous reports showed upregulated levels of CAMP and LL‐37 in HS lesions, and therefore, the aim of this study was to compare levels of LL‐37 in HS to other inflammatory skin diseases and to establish immunomodulatory functions of LL‐37 in HS. We confirm an upregulation of the LL‐37 peptide in lesional HS skin with comparable levels as in psoriasis patients and are able to positively correlate the presence of LL‐37 in HS with the presence of T cells, macrophages, neutrophils, IFN‐γ, IL‐17, IL‐23, TNF‐α, IL‐32 and IL‐1β. Mechanistically, LL‐37 boosts the proliferation of unspecifically activated CD4⁺ T cells via an increased calcium signalling independent of antigen‐presenting cells. Targeting LL‐37 may therefore represent a new therapeutic option for the treatment of this recalcitrant disease, but it has to be kept in mind that LL‐37 also has an antimicrobial function.