Putative contribution of prostaglandin and bradykinin to muscle reflex hyperactivity in patients on Ace-inhibitor therapy for chronic heart failure.

AIMS: In patients with chronic heart failure (CHF), an overactive muscle ergoreceptor reflex (chemo-afferents sensitive to the products of muscle work) is thought to play an important role in the origin of dyspnoea. We sought to investigate whether raised intra-muscular prostaglandins (PG) and bradykinin, as estimated by levels within the venous effluent from exercising skeletal muscle may be involved in symptom generation through the stimulation of the ergoreflex. METHODS AND RESULTS: In 19 stable CHF patients and 12 normal controls, cardiopulmonary exercise capacity (peak O2 consumption [peak VO2]) and the ergoreflex contribution to ventilation (post-handgrip regional circulatory occlusion method) were measured. Venous resting and exercise plasma PGE2, PGF1alpha and bradykinin concentrations were assessed. Eleven patients on angiotensin converting enzyme inhibitors and 10 controls were challenged with ketoprofen infusion (to inhibit PG synthesis and bradykinin activity). Patients vs. controls presented lower exercise tolerance (peak VO2 15.9+/-0.7 vs. 33.0+/-1.3 mL/kg/min), an increased ventilatory response to exercise (VE/VCO2 slope 43+/-2 vs. 27+/-0.9) (p<0.0001 for all comparisons). The overactive ergoreflex of CHF (5.1+/-1.3 vs. 0.1+/-0.3 L/min) was significantly related to the increase in PGF1alpha (adjusted R2=0.34, p<0.005) but not PGE2 (adjusted R2=0.16, p>0.05). The increased PG and bradykinin productions both at rest and during exercise in CHF were attenuated after ketoprofen infusion, associated with ergoreflex reduction (-5.1+/-2.2 L/min, p<0.05 vs. saline). CONCLUSION: In CHF, overactive muscle ergoreflex is associated with elevated blood concentration of PG and bradykinin. Modulation of these metabolite concentrations acutely reduces the muscle ergoreflex activity, which suggests a causative role in triggering and/or mediating the ergoreflex response.     

High homocysteine and low folate concentrations in acute aortic dissection

Background

Biomarkers for monitoring progression and prognosis of thoracic aneurysm are of great interest. Homocysteine (Hcy) induces elastolysis in arterial media and may directly affect fibrillin-1 or collagen whereas lipoprotein (Lp) (a) inhibits elastolysis by reducing activation of matrix metallopeptidase-9.

Methods

We studied 31 consecutive patients with acute aortic dissection (AAD) admitted for emergency surgery (group I, 60 ± 13 years old, 25 men), 30 consecutive patients with chronic aneurysms of the ascending aorta (group II, 67 ± 12 years old, 24 men) and 20 healthy controls (group III, 58 ± 15 years old, 14 men). We evaluated Hcy, folate, B12, Lp(a) and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism at baseline.

Results

Hcy, folate and B12 differed significantly among the 3 studied groups (P = 0.016, P = 0.004 and P = 0.001, respectively). The levels of Hcy and B12 were significantly higher in group I compared to both groups II and III (P = 0.05 and P = 0.002, P < 0.001 and P = 0.017, respectively) and without significant differences between groups II and III (P = 0.083 and P = 0.124). Folate was significantly lower in group I compared to both groups II and III (P = 0.001 and P = 0.006, respectively) and without marked difference between groups II and III (P = 0.409). No significant difference was found in serum levels of Lp (a) (P = 0.074) or among the frequency of MTHFR C677T genotypes.

Conclusions

Patients with AAD present with higher Hcy and lower folate compared to both chronic aneurysms and controls.     

FIP1L1-PDGFRA molecular analysis in the differential diagnosis of eosinophilia

Background  

Primary eosinophlia associated with the FIP1L1-PDGFRA rearrangement represents a subset of chronic eosinophilic leukaemia (CEL) and affected patients are very sensitive to imatinib treatment. This study was undertaken in order to examine the prevalence and the associated clinicopathologic and genetic features of FIP1L1-PDGFRA rearrangement in a cohort of 15 adult patients presenting with profound eosinophilia (> 1.5 × 10⁹/L).     

Combined thirty-day exposure to thioacetamide and choline-deprivation alters serum antioxidant status and crucial brain enzyme activities in adult rats

Choline (Ch) is an essential nutrient that seems to be involved in a wide variety of metabolic reactions and functions that affect the nervous system, while thioacetamide (TAA) is a well-known hepatotoxic agent. The induction of prolonged Ch-deprivation (CD) in rats receiving TAA (through the drinking water) provides an experimental model of mild progressive hepatotoxicity that could simulate commonly-presented cases in clinical practice. In this respect, the aim of this study was to investigate the effects of a 30-day dietary CD and/or TAA administration (300 mg/L of drinking water) on the serum total antioxidant status (TAS) and the activities of brain acetylcholinesterase (AChE), Na⁺,K⁺-ATPase and Mg²⁺-ATPase of adult rats. Twenty male Wistar rats were divided into four groups: A (control), B (CD), C (TAA), D (CD+TAA). Dietary CD was provoked through the administration of Ch-deficient diet. Rats were sacrificed by decapitation at the end of the 30-day experimental period and whole brain enzymes were determined spectrophotometrically. Serum TAS was found significantly lowered by CD (−11% vs Control, p < 0.01) and CD+TAA administration (−19% vs Control, p < 0.001), but was not significantly altered due to TAA administration. The rat brain AChE activity was found significantly increased by TAA administration (+11% vs Control, p < 0.01), as well as by CD+TAA administration (+14% vs Control, p < 0.01). However, AChE was not found to be significantly altered by the 30-day dietary CD. On the other hand, CD caused a significant increase in brain Na⁺,K⁺-ATPase activity (+16% vs Control, p < 0.05) and had no significant effect on Mg²⁺-ATPase. Exposure to TAA had no significant effect on Na⁺,K⁺-ATPase, but inhibited Mg²⁺-ATPase (−20% vs Control, p < 0.05). When administered to CD rats, TAA caused a significant decrease in Na⁺,K⁺-ATPase activity (−41% vs Control, p < 0.001), but Mg²⁺-ATPase activity was maintained into control levels. Our data revealed that an adult-onset 30-day dietary-induced CD had no effect on AChE activity. Treatment with TAA not only reversed the stimulatory effect of CD on adult rat brain Na⁺,K⁺-ATPase, but caused a dramatic decrease in its activity (−41%). Previous studies have linked this inhibition with metabolic phenomena related to TAA-induced fulminant hepatic failure and encephalopathy. Our data suggest that CD (at least under the examined 30-day period) is an unfavorable background for the effect of TAA-induced hepatic damage on Na⁺,K⁺-ATPase activity (an enzyme involved in neuronal excitability, metabolic energy production and neurotransmission).     

Subendocardial viability ratio in patients with rheumatoid arthritis: comparison with healthy controls and identification of prognostic factors

Cardiac involvement is common in rheumatoid arthritis. Subendocardial viability ratio (SEVR) is a non-invasive measure of microvascular coronary perfusion, yet it remains unclear whether it is affected in rheumatoid arthritis patients. We additionally sought predictors of SEVR in rheumatoid arthritis among a wide range of disease-related parameters, cardiac and hemodynamic factors, and markers of atherosclerosis, arteriosclerosis, and endothelial dysfunction. SEVR was estimated in rheumatoid arthritis patients and healthy controls by applanation tonometry, which was also used to evaluate arterial stiffness (pulse wave velocity and augmentation index). In the rheumatoid arthritis group, carotid intima–media thickness (cIMT) was additionally estimated by ultrasound, cardiac and hemodynamic parameters by impedance cardiography, and endothelial dysfunction by measurement of asymmetric dimethylarginine (ADMA). In a total of 122 participants, SEVR was lower among 91 patients with rheumatoid arthritis compared to 31 controls (141.4 ± 21.9 vs 153.1 ± 18.7%, p = 0.009) and remained so among 29 rheumatoid arthritis patients without hypertension, diabetes, or cardiovascular diseases, compared to the control group (139.7 ± 21.7 vs 153.1 ± 18.7%, p = 0.013). SEVR did not significantly correlate with arterial stiffness, cIMT, ADMA, or disease-related parameters. Multivariate analysis revealed gender (p = 0.007), blood pressure (p = 0.028), heart rate (p = 0.025), cholesterol levels (p = 0.008), cardiac index (p < 0.001) and left ventricular ejection time (p = 0.004) as independent predictors of SEVR among patients with rheumatoid arthritis. Patients with rheumatoid arthritis exhibit lower values of SEVR compared to healthy individuals. Cardiac and hemodynamic parameters, rather than functional indices of endothelial and macrovascular dysfunction, may be useful as predictors of myocardial perfusion in rheumatoid arthritis.     

Significant peri-operative reduction in plasma osteopontin levels after coronary artery by-pass grafting

ObjectivesOsteopontin (OPN) is a multifunctional protein associated with vascular injury and has been linked to atherosclerosis and inflammation. We sought to investigate whether OPN changes in relation to coronary artery by-pass grafting (CABG) surgery.Design and methodsWe studied 50 consecutive patients (63 ± 10 years old, 6 women and 44 men) undergoing elective CABG. Plasma OPN levels were determined by an enzyme-linked immunosorbent assay at baseline and in 24 and 72 h, post-operatively. Cardiac enzymes — creatine kinase, the MB isoenzyme of creatine kinase, troponin-I- and C-reactive protein (CRP) were also determined at all three time points.ResultsOPN levels 72 h post-op decreased significantly compared to pre-op and 24 h post-op levels (p < 0.001) whereas there was no difference between the pre-op and first post-op values (p = 0.57). The relative change in OPN levels between pre-op and 72 h post-op correlated negatively with absolute troponin-I levels at 72 h post-op (? 0.51, p = 0.005). OPN levels 72 h post-op correlated significantly with CRP at baseline (r = 0.73, p = 0.002).ConclusionsOPN plasma concentrations decreased after CABG surgery in the early post-operative period. The significance of this observation needs further investigation.     

Predictors of impaired quality of life in patients with rheumatic diseases

Quality of life (QoL) is a complex outcome and rheumatologic patients typically exhibit several comorbidities with a negative impact. In this study, we analyzed with respect to QoL for the first time a wide range of physical and psychological factors, including individual, clinical and disease-related parameters, mental health disorders, sexual dysfunction, and cardiovascular comorbidities among consecutive rheumatologic patients. QoL was evaluated using the EuroQol 5D (EQ-5D) utility index. The Health Assessment Questionnaire (HAQ) Disability Index, and the HAQ Pain Visual Analogue Scale were used as measures of physical disability and arthritis-related pain, respectively. The Hamilton Anxiety Scale and Zung Self-Rating Depression Scale, the International Index of Erectile Function and the Female Sexual Functioning Index were completed by all patients. In total, 360 patients were included, 301 females and 59 males. In the univariate analysis, pain, physical disability (p?<?0.001 for both), disease duration (p?=?0.014), anxiety and depression (p?<?0.001 for both), as well as sexual dysfunction (p?=?0.001 for females, p?=?0.042 for males), correlated with QoL. Female sex (p?<?0.001), advanced age (p?=?0.029), lower educational level (p?=?0.005), and cardiovascular factors (hypertension, dyslipidemia, diabetes, lack of systemic exercise) also appeared to negatively affect QoL. However, in the multiple regression model, only anxiety, pain, physical disability (p?<?0.001 for all), and disease duration (p?=?0.019) remained significant predictors of QoL. The emotional side and the disease-related physiological mode of rheumatic diseases appear as major independent correlates of QoL among rheumatologic patients, who may thus benefit the most from combined supportive psychological and pain-relieving interventions.     

Burnout among Primary Care Providers and Staff: Evaluating the Association with Practice Adaptive Reserve and Individual Behaviors

BackgroundWorkplace burnout among healthcare professionals is a critical public health concern. Few studies have examined organizational and individual factors associated with burnout across healthcare professional groups.ObjectiveThe purpose of this study was to examine the association between practice adaptive reserve (PAR) and individual behavioural response to change and burnout among healthcare professionals in primary care.DesignThis cross-sectional study used survey data from 154 primary care practices participating in the EvidenceNOW Heart of Virginia Healthcare initiative.ParticipantsWe analysed data from 1279 healthcare professionals in Virginia. Our sample included physicians, advanced practice clinicians, clinical support staff and administrative staff.Main MeasuresWe used the PAR instrument to measure organizational capacity for change and the Change Diagnostic Index© (CDI) to measure individual behavioural response, which achieved a 76% response rate. Logistic regression analysis was used to estimate the effects of PAR and CDI on burnout.Key ResultsAs organizational capacity for change increased, burnout in healthcare professionals decreased by 51% (OR: 0.49; 95% CI, 0.33, 0.73). As healthcare professionals showed improved response toward change, burnout decreased by 84% (OR: 0.16; 95% CI, 0.11, 0.23). Analysis by healthcare professional type revealed a significant association between high organizational capacity for change, positive response to change and low burnout among administrative staff (OR: 2.92; 95% CI, 1.37, 6.24). Increased hours of work per week was associated with higher odds of burnout (OR: 1.07; 95% CI, 1.05, 1.10) across healthcare professional groups.ConclusionAs transformation efforts in primary care continue, it is critical to understand the influence of these initiatives on healthcare professionals’ well-being. Efforts to reduce burnout among healthcare professionals are needed at both a system and organizational level. Building organizational capacity for change, supporting providers and staff during major change and consideration of individual workload may reduce levels of burnout.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06367-z.KEY WORDS: adaptive reserve, burnout, practice transformation, primary care, well-being     

Effect of D-Mannitol on the Microstructure and Rheology of Non-Aqueous Carbopol Microgels

D-mannitol is a common polyol that is used as additive in pharmaceutical and personal care product formulations. We investigated its effect on the microstructure and rheology of novel non-aqueous Carbopol dispersions employing traditional and time-resolved rheological analysis. We considered two types of sample, (i) fresh (i.e., mannitol completely dissolved in solution) and aged (i.e., visible in crystalline form). The analysis of the intracycle rheological transitions that were observed for different samples revealed that, when completely dissolved in solution, mannitol does not alter the rheological behaviour of the Carbopol dispersions. This highlights that the chemical similarity of the additive with the molecules of the surrounding solvent allows preserving the swollen dimension and interparticle interactions of the Carbopol molecules. Conversely, when crystals are present, a hierarchical structure forms, consisting of a small dispersed phase (Carbopol) agglomerated around a big dispersed phase (crystals). In keeping with this microstructural picture, as the concentration of Carbopol reduces, the local dynamics of the crystals gradually start to control the integrity of the microstructure. Rheologically, this results in a higher elasticity of the suspensions at infinitesimal deformations, but a fragile yielding process at intermediate strains.