Temporal aspects of affective states, physiological responses, and perceived exertion in competitive cycling time trials.

Athletes' affective states can vary dramatically before, during, and after competition. Further, intense affect is associated with physiological responses that may amplify biological reactions manifested from the execution of physical tasks underlying performance. Fluctuations in perceptual cues (eg, perceived exertion) and physiological responses (eg, blood lactate, heart rate) can influence performance and vary dramatically in relation to competition. However, the pattern of these fluctuations and potential associations between perceptual cues and biological responses may also diverge during task execution with differential implications for performance. Data collected from highly trained athletes (N = 25; Mage  = 25.4) during a competition (ie, maximum total distance) comprised of three 7-minute cycling time trials and were analyzed with longitudinal multilevel modeling. Results showed that affective states were negatively associated with perceived exertion at the within-person level and negatively associated with heart rate at the between-person level within each trial. Blood lactate and heart rate were positively associated at the between-person level, whereas heart rate was positively associated with perceived exertion at the within-person level. The anticipation of more pleasurable affective states predicted less decline in affective states, but not physiological responses, during each trial. Anticipated affective states prior to each trial were also associated with affective states upon its completion. These findings suggest associations among perceptual cues and physiological responses may differ depending on the level of analysis (between- vs. within-person level associations), and anticipated affective states prior to performance may influence affective states during and after task execution.

Are the Clinical Presentations (Phenotypes) of Gitelman's and Bartter's Syndromes Gene Mutations Driven by Their Effects on Intracellular pH, Their "pH" Enotype?

Gitelman's syndrome (GS) and Bartter's syndrome (BS) are rare inherited salt-losing tubulopathies whose variations in genotype do not correlate well with either clinical course or electrolyte requirements. Using GS/BS patients as nature's experiments, we found them to be a human model of endogenous Ang II antagonism with activated Renin-Angiotensin System (RAS), resulting in high Ang II levels with blunted cardiovascular effects. These patients are also characterized by increased and directly correlated levels of both Angiotensin Converting Enzyme 2 (ACE2) and Ang 1-7. Understanding the myriad of distinctive and frequently overlapping clinical presentations of GS/BS arises remains challenging. Efforts to find a treatment for COVID-19 has fueled a recent surge in interest in chloroquine/hydroxychloroquine and its effects. Of specific interest are chloroquine/hydroxychloroquine's ability to inhibit SARS-CoV infection by impairing ACE2, the SARS-CoV2 entry point, through terminal glycosylation via effects on TGN/post-Golgi pH homeostasis. Several different studies with a GS or a BS phenotype, along with a nonsyndromic form of X-linked intellectual disability linked to a mutated SLC9A7, provide additional evidence that specific gene defects can act via misregulation of TGN/post-Golgi pH homeostasis, which leads to a common mechanistic basis resulting in overlapping phenotypes. We suggest that linkage between the specific gene defects identified in GS and BS and the myriad of distinctive and frequently overlapping clinical findings may be the result of aberrant glycosylation of ACE2 driven by altered TGN/endosome system acidification caused by the metabolic alkalosis brought about by these salt-losing tubulopathies in addition to their altered intracellular calcium signaling due to a blunted second messenger induced intracellular calcium release that is, in turn, amplified by the RAS system.

Increased RBP4 in a human model of activated anti-atherosclerotic and antiremodelling defences.

BACKGROUND: Both increased and decreased levels of the adipokine retinol-binding protein 4 (RBP4) have been reported in cardiovascular disease, and levels of RBP4 have been related to diabetes, metabolic syndrome and cardiovascular risk. Recently, clear in vitro and ex vivo vasodilatory and inhibitory of platelet activation effects of RBP4 has been shown and a reduced RBP4 level was found in high cardiovascular risk patients, suggesting a potential cardiovascular protective role for increased levels of RBP4. PATIENTS AND METHODS: Plasma level of RBP4 (ELISA) was determined in a cohort of Bartter's and Gitelman's syndrome (BS/GS) patients, a human model of endogenous Ang II signalling antagonism and activation of anti-atherosclerotic and antiremodelling defenses, the opposite of cardiovascular risk patients, and in healthy normotensive subjects. Haem Oxygenase (OH)-1 protein level (sandwich immunoassay) as a potential mediator of RBP4 stimulation of PI3K/Akt pathway and flow-mediated dilation (FMD) as a measure of endothelium (NO)-dependent response have also been measured. RESULTS: RBP4 in BS/GS patients (40·59 ± 15·32 µg/mL vs. 25·05 ± 5·56, P = 0·011) along with HO-1 protein levels (9·44 ± 3·09 ng/mL vs. 5·49 ± 1·04, P = 0·003) and FMD (10·52% ± 2·22 vs. 7·99 ± 1·13 P = 0·006) were significantly increased compared with healthy normotensive subjects. CONCLUSIONS: The increase of RBP4 in BS/GS, a human model of endogenous Ang II signalling antagonism and activation of anti-atherosclerotic and antiremodelling defenses, the opposite of cardiovascular risk patient, found in concert with an increased NO-mediated vasodilation and HO-1 levels supports a protective role for this adipokine in vascular protection/cardiovascular risk.

Balancing Time for Health Behaviors: Associations of Time Perspective With Physical Activity and Weight Management in Older Adults.

PURPOSE: To examine associations between time perspective and health promotion behaviors of physical activity and weight management. DESIGN: Quantitative cross-sectional. SETTING: This study is part of the Betula project on aging, memory, and dementia in Northern Sweden. SUBJECTS: 417 older adults aged between 55 and 85 years. MEASURES: Swedish-Zimbardo Time Perspective Inventory; Physical Activity in the past year, past week, and in comparison with others of similar age; Weight Management = Body Mass Index (BMI; kg/m2). RESULTS: After controlling for age, sex, and years of education, hierarchical linear regression indicated a Balanced Time Perspective was significantly associated with more physical activity in the past year (P = .04), the past week (P < .001), and in comparison with others (P < .01). Past Negative time perspective was associated with less physical activity in the past year (P = .03), and in comparison with others (P = .03). Present Fatalistic was associated with less physical activity during the past week (P = .03), and in comparison with others (P = .01). Present Hedonistic was associated with more physical activity the past week (P = .03), and in comparison with others (P = .03). Past Negative was associated with higher BMI (P = .02), and Future Negative were associated with lower BMI (P = .01). Taken collectively, greater positivity and flexibility across time perspectives was associated with more physical activity, whereas negative oriented time perspectives related with less physical activity and poorer weight management. CONCLUSION: Time perspective can be associated with health behaviors in older adults and have implications for health across the lifespan. Health promotion interventions may target older adults' enjoyment of exercise and weight management in the present, rather than highlight potential negative health outcomes in the future.

"Every Cloud Has a Silver Lining": How Three Rare Diseases Defend Themselves from COVID-19 and What We Have Learnt from It.

The process of SARS-CoV-2 infection, responsible for the COVID-19 pandemic, is carried out through different steps, with the interaction between ACE2 and Spike protein (S) being crucial. Besides of that, the acidic environment of endosomes seems to play a relevant role in the virus uptake into cells and its intracellular replication. Patients affected by two rare genetic tubulopathies, Gitelman's and Bartter's Syndromes, and a rare genetic metabolic disease, Fabry Disease, have shown intrinsic protection from SARS-CoV-2 infection and COVID-19 on account of specific intrinsic features that interfere with the virus uptake into cells and its intracellular replication, which will be reported and discussed in this paper, providing interesting insights for present and future research.

Tracing angiotensin II's yin-yang effects on cardiovascular-renal pathophysiology.

Adverse changes in cardiovascular and renal systems are major contributors to overall morbidity and mortality. Human cardiovascular and renal systems exhibit a complex network of positive and negative feedback that is reflected in the control of vascular tone via angiotensin II (Ang II) based signaling. This review will examine in some depth, the multiple components and processes that control the status and reflect the health of these various cardiovascular and renal systems, such as pathways associated to monomeric G proteins, RhoA/Rho kinase system and ERK, oxidative stress and NO balance. It will specifically emphasize the "yin-yang" nature of Ang II signaling by comparing and contrasting the effects and activity of various systems, pathways and components found in hypertension to those found in Gitelman's and Bartter's syndromes (GS/BS), two rare autosomal recessive tubulopathies characterized by electrolytic imbalance, metabolic alkalosis, sodium wasting and prominent activation of the renin-angiotensin-aldosterone system. Notwithstanding the activation of the renin-angiotensin-aldosterone system, GS/BS are normo-hypotensive and protected from cardiovascular-renal remodeling and therefore can be considered the mirror image, the opposite of hypertension.

Oxidants and Cardiorenal Vascular Remodeling-Insights from Rare Genetic Tubulopathies: Bartter's and Gitelman's Syndromes.

Two human genetic tubulopathies, Bartter's (BS) and Gitelman's (GS) syndromes, have normo/hypotension and absent cardiac remodeling despite their apparent angiotensin system (RAS) activation. This seeming contradiction has led to an extensive investigation of BSGS patients, the result of which is that BSGS represents a mirror image of hypertension. BSGS's unique set of properties has then permitted their use as a human model to probe and characterize RAS system pathways and oxidative stress in cardiovascular and renal remodeling and pathophysiology. This review details the results using GSBS patients that provide a deeper understanding of Ang II signaling and its associated oxidants/oxidative stress in humans. By providing a more complete and complex picture of cardiovascular and renal remodeling pathways and processes, studies of GSBS can inform the identification and selection of new targets and therapies to treat these and other oxidant-related disorders.

A high-fat diet containing whole walnuts (Juglans regia) reduces tumour size and growth along with plasma insulin-like growth factor 1 in the transgenic adenocarcinoma of the mouse prostate model.

Prostate cancer (PCa) has been linked to fat intake, but the effects of both different dietary fat levels and types remain inconsistent and incompletely characterised. The effects on PCa in the transgenic adenocarcinoma of the mouse prostate (TRAMP) cancer model of an elevated fat (20 % of energy as fat) diet containing 155 g of whole walnuts were compared to those of an elevated fat (20 % of energy as soyabean oil) diet with matched macronutrients, tocopherols as well as a low-fat (8 % of energy as soyabean oil) diet. Mice, starting at 8 weeks of age, consumed one of the three different diets ad libitum; and prostates, livers and blood were obtained after 9, 18 or 24 weeks of feeding. No differences were observed in whole animal growth rates in either high-fat (HF) diet group, but prostate tumour weight and growth rate were reduced in the walnut diet group. Walnut diet group prostate weight, plasma insulin-like growth factor 1, resistin and LDL were lower at 18 weeks, while no statistically significant prostate weight differences by diet were seen at 9 or 24 weeks. Multiple metabolites in the livers differed by diet at 9 and 18 weeks. The walnut diet's beneficial effects probably represent the effects of whole walnuts' multiple constituents and not via a specific fatty acid or tocopherols. Moreover, as the two HF diets had dissimilar effects on prostate tumour growth rate and size, and yet had the same total fat and tocopherol composition and content, this suggests that these are not strongly linked to PCa growth.

The psychophysiological influence of exertion and affect on sport-specific cognitive and physical performance.

OBJECTIVES: The purpose of the present study was to examine differences in cognitive and physical performance, affective states, perceived exertion, and physiological responses between trials with cognitive, physical, or combined cognitive and physical load. DESIGN: Randomised cross-over trial. METHODS: Highly trained competitive orienteers (n = 15 men; n = 10 women) completed three randomised trials comprised of: (1) sport-specific cognitive tests; (2) 35-minute cycling time trial; and (3) combined sport-specific cognitive tests and 35-minute cycling time trial. Measures taken during the trials recorded affective states, perceived exertion, heart rate, blood lactate, cycling watts, as well as working memory, updating, planning and decision making. RESULTS: No significant differences in cognitive performance accuracy were observed within or across trials although reaction times improved within trials and were fastest in the combined trial. Blood lactate, heart rate, perceived exertion, negative affective states, and watts were highest in the physical trial. CONCLUSIONS: The combined load of undertaking sport-specific cognitive tests and a cycling time trial did not influence cognitive performance accuracy. Athletes produced greater watts when completing the physical task independently compared with the combined trial, however psychophysiological responses were worse. Further investigation is warranted to determine whether athletes' attentional focus underpins psychophysiological responses to dual-task sport performance.

PLCß1-SHP-2 complex, PLCß1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling?

BACKGROUND: Angiotensin II (Ang II) signaling occurs via two major receptors which activate non-receptor tyrosin kinases that then interact with protein tyrosin-phosphatases (PTPs) to regulate cell function. SHP-2 is one such important PTP that also functions as an adaptor to promote downstream signaling pathway. Its role in Ang II signaling remains to be clarified. RESULTS: Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLCß1 are present as a preformed complex. Complex PLCß1 is tyr-phosphorylated basally and Ang II increased SHP-2-PLCß1 complexes and caused complex associated PLCß1 tyr-phosphorylation to decline while complex associated SHP-2's tyr-phosphorylation increased and did so via the Ang II type 1 receptors as shown by Ang II type 1 receptor blocker losartan's effects. Moreover, Ang II induced both increased complex phosphatase activity and decreased complex associated PLCß1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2. CONCLUSIONS: Ang II signals are shown for the first time to involve a preformed SHP-2-PLCß1 complex. Changes in the complex's PLCß1 tyr-phosphorylation and SHP-2's tyr-phosphorylation as well as SHP-2-PLCß1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLCß1 tyr-phosphorylation requiring RGS-2. These findings might significantly expand the number and complexity of Ang II signaling pathways. Further studies are needed to delineate the role/s of this complex in the Ang II signaling system.

Hemodiafiltration with online regeneration of ultrafiltrate: effect on heme-oxygenase-1 and inducible subunit of nitric oxide synthase and implication for oxidative stress and inflammation.

Hemodiafiltration with regeneration of ultrafiltrate (HFR) has a positive impact on inflammation and oxidative stress (OxSt), risk factors for cardiovascular disease (CVD), the most common cause of excess morbidity and mortality for end-stage renal disease (ESRD) patients. However, studies have been of limited duration. This study extends our previous study of HFR effects by evaluating the effect on mononuclear cell protein expression of heme-oxygenase-1 (HO-1), induced by OxSt, and inducible subunit of nitric oxide synthase (iNOS), and plasma level of interleukin-1ß (Il-1ß) and oxidized low-density lipoproteins (OxLDL), marker of OxSt, for a 12-month period. Fourteen ESRD patients stable on hemodialysis over a period of at least 2 years and on conventional bicarbonate dialysis were switched to be treated with HFR. Blood samples were collected at baseline, after 3, 6, 9 and 12 months. HO-1 and iNOS protein expression were evaluated by Western blot, OxLDL by enzyme-linked immunosorbent assay (ELISA), and Il-1ß by enzyme amplified sensitivity immumoassay assay. HFR significantly increased HO-1 at the 9 and 12 months (ANOVA = P < 0.00001): 0.17 ± 0.11 (baseline) versus 0.48 ± 0.20, P < 0.043 and 0.59 ± 0.32, P < 0.004, respectively. Il-1ß declined (ANOVA = P < 0.0001) since the 3 months from 169.92 ± 92.39 pg/mL (baseline) to 39.03 ± 10.01 (12 months), P < 0.0001. HFR also reduced plasma OxLDL: 475.4 ± 110.8 ng/mL (baseline) versus 393.1 ± 101.9 ng/mL (12 months), P < 0.04. iNOS showed no changes upon HFR treatment. These results together with our previous results indicate that HFR improves OxSt and inflammation. Given the strong relationships between OxSt and inflammation with CVD, their reduction might provide a beneficial impact by reducing the risk of atherosclerotic CVD in dialysis patients.

Molecular biology-based assessment of vitamin E-coated dialyzer effects on oxidative stress, inflammation, and vascular remodeling.

Cardiovascular disease represents the most common cause for the excess of morbidity and mortality found in end-stage renal disease (ESRD) and has prompted the exploration of multiple approaches to improve outcomes in these patients. Cardiovascular risk factors such as increased oxidative stress (OxSt) and inflammation are found in ESRD patients. A vitamin E-coated dialyzer using polysulfone membranes has been suggested to have positive effects on these factors. This 1-year study evaluated in 25 ESRD patients under chronic dialysis, the effects of a vitamin E-coated membrane (VitabranE ViE) "ex vivo" on mononuclear cells, OxSt, and inflammation-related biochemical and molecular biology markers using a molecular biology approach. p22(phox), heme oxygenase (HO)-1, plasminogen activator inhibitor (PAI)-1 protein level, and phosphorylated extracellular signal-regulated kinase (pERK)1/2 status were evaluated at the beginning of the study, after 6 months and after 12 months by Western blot analysis and oxidized low-density lipoprotein (OxLDL) plasma level by enzyme-linked immunosorbent assay, alongside vascular remodeling assessment as measured by carotid intima-media thickness (IMT) in a subgroup of nine randomly selected patients. p22(phox), PAI-1, OxLDL, and pERK all decreased with VitabranE use, while HO-1 increased. Carotid IMT did not increase. Treatment with VitabranE significantly decreases the expression of proteins and markers relevant to OxSt and inflammation tightly associated with cardiovascular disease, and it appears highly likely that VitabranE use will provide a benefit in terms of cardiovascular protection.

Effect of olmesartan on oxidative stress in hypertensive patients: mechanistic support to clinical trials derived evidence.

The role of oxidative stress in the pathophysiology of hypertension and target organ damage is widely recognized. Using a molecular biology approach, we report, in essential hypertensive patients, the effect of the angiotensin II type 1 receptor blocker olmesartan on the mononuclear cell (PBMC) protein expression of major elements in the oxidative stress and vascular remodeling-related pathways, p22(phox) and HO-1, along with the phosphorylation state of ERK1/2 and plasma oxidized low-density lipoproteins (oxLDL). Twenty untreated essential hypertensive patients (range blood pressure: 142?156/94?98 mmHg) were treated with olmesartan medoxomil (20 mg/day for 6 months) and blood samples collected at baseline, 3 and 6 months for PBMC p22(phox) and HO-1 protein expression, phosphorylation state of ERK1/2 (western blot) and oxLDL level (ELISA) evaluations. Olmesartan normalized blood pressure since the third month (149 ? 4.7/94.88 ? 1.9 mmHg vs 137.89 ? 2.08/88.44 ? 2.0 at 3 months and vs 135.44 ? 2.18/85.78 ? 1.2 at 6 months, analysis of variance: p < 0.001). p22(phox) protein level declined at 3 months (7.10 ? 2.61 vs 9.32 ? 2.43 densitometric units (d.u.; p < 0.001), further declining at 6 months (4.55 ? 1.26 d.u., p < 0.001). HO-1 levels increased at 3 months (10.87 ? 1.92 vs 7.70 ? 0.71 d.u., p = 0.001) and remained elevated (11.11 ? 1.89 d.u., p = 0.001), without further increase at 6 months. Phosphorylated ERK1/2 declined at 3 months (3.94 ? 1.44 vs 5.62 ? 1.11 d.u., p = 0.001), further declining at 6 months (1.94 ? 0.87, p < 0.001). oxLDL significantly declined at 3 and 6 months. These results demonstrate that olmesartan inhibits oxidative stress. Given the involvement of oxidative stress and its signaling in atherogenesis, and the available evidence of olmesartan's vasoprotective, anti-inflammatory and antiatherosclerotic effects derived from clinical trials in humans, the results of our study provide a mechanistic rationale for the omelsartan's antioxidant and anti-inflammatory potential translation, in the long term, toward the antiatherosclerotic and antiremodeling effects reported on the clinical ground.

Salivary glands: a new player in phosphorus metabolism.

In uremic patients, hyperphosphatemia is associated with cardiovascular calcification and increased cardiovascular mortality. Despite the use of phosphate binders and dietary phosphate limitation in addition to dialysis, only 50% of dialysis patients achieve recommended serum phosphate levels. The identification of other approaches for serum phosphorus reduction is therefore necessary. We have approached this issue by taking into account the relationships between serum phosphate, kidney function, and saliva. Saliva was chosen because the anatomy and/or physiology of acini, the secretive units of salivary glands, shares similarities with that of the renal tubules. Salivary fluid contains electrolytes including phosphate that, when related with the amount of salivary secretion per day, raises the interest in identifying another possible approach for phosphorus removal in uremic patients. This article reports studies from our laboratory in the last 3 to 4 years, which have demonstrated a hyperphosphoric salivary content in patients with chronic renal failure and those with end-stage renal disease under chronic dialysis that, in patients with chronic renal failure, linearly correlates with serum phosphate in patients with chronic renal failure and negatively with GFR. The ingestion of the saliva and later its absorption in the intestinal tract starts a vicious circle between salivary phosphate secretion and fasting phosphate absorption, thereby worsening hyperphosphatemia. Therefore, salivary phosphate binding could be a useful approach to serum phosphate level reduction in dialysis patients. The reduction of salivary phosphate with the salivary phosphate binder, chitosan-loaded chewing gum, chewed during fasting periods, as an add-on to phosphate binders could lead to a better control of hyperphosphatemia, as demonstrated in our study, which confirms the importance of this approach.

Reduction of hyperphosphatemia is related with the reduction of C-reactive protein in dialysis patients. Study in sevelamer-resistant dialysis patients treated with chitosan chewing gum as salivary phosphate binder.

BACKGROUND: In end-stage renal disease (ESRD) hyperphosphatemia associates with vascular calcifications and cardiovascular events derived from endothelial dysfunction. In dialysis patients, C-reactive protein (CRP), a marker of inflammation, associates with cardiovascular mortality. Increased PO(4) concentration impairs endothelial integrity via induction of oxidative stress, and sevelamer, a phosphate binder, showed anti-inflammatory effect reducing CRP, which paralleled PO(4) reduction. To give support to a direct proinflammatory role of hyperphosphatemia "per se," we have considered previously studied dialysis patients with sevelamer-"resistant" hyperphosphatemia, who were treated with a chitosan-loaded chewing gum, as salivary phosphate binder, in addition to sevelamer, reduced serum PO(4) to normal, to retrospectively evaluate their CRP and the relationship with hyperphosphatemia and calcium × phosphate (Ca × PO(4)) product. PATIENTS AND METHODS: High sensitive (hs) CRP of 13 previously studied hemodialysis patients with sevelamer-resistant hyperphosphatemia was evaluated with immunonephelometry. RESULTS: Chitosan chewing gum use reduced hsCRP (from 1.38 ± 0.61 to 0.39 ± 0.16 mg/L after the gum, p < 0.0002), which returned to baseline after 4 weeks from gum discontinuation (1.25 ± 0.41). hsCRP reduction paralleled serum PO(4) reduction: from 7.60 ± 0.91 mg/dL to 5.18 ± 0.73 (after the gum) (p < 0.00001), returning to baseline (7.55 ± 0.75) after gum discontinuation. hsCRP reduction directly correlated with PO(4) reduction (p = 0.029). CONCLUSION: The relationship in sevelamer-resistant dialysis patients between the reduction of serum PO(4), induced by the chitosan-loaded chewing gum, and CRP reduction supports also in humans a proinflammatory role of hyperphosphatemia "per se" derived from "in vitro" studies. This further contributes to the high cardiovascular risk of ESRD patients making their serum phosphate in the normal range of vital importance.