Long-term dietary nitrate supplementation does not reduce renal cyst growth in experimental autosomal dominant polycystic kidney disease

Augmentation of endogenous nitric oxide (NO) synthesis, either by the classical L-arginine-NO synthase pathway, or the recently discovered entero-salivary nitrate-nitrite-NO system, may slow the progression of autosomal dominant polycystic kidney disease (ADPKD). To test this hypothesis, the expression of NO in human ADPKD cell lines (WT 9-7, WT 9-12), and the effect of L-arginine on an in vitro model of three-dimensional cyst growth using MDCK cells, was examined. In addition, groups of homozygous Pkd1RC/RC mice (a hypomorphic genetic ortholog of ADPKD) received either low, moderate or high dose sodium nitrate (0.1, 1 or 10 mmol/kg/day), or sodium chloride (vehicle; 10 mmol/kg/day), supplemented drinking water from postnatal month 1 to 9 (n = 12 per group). In vitro, intracellular NO, as assessed by DAF-2/DA fluorescence, was reduced by >70% in human ADPKD cell lines, and L-arginine and the NO donor, sodium nitroprusside, both attenuated in vitro cyst growth by up to 18%. In contrast, in Pkd1RC/RC mice, sodium nitrate supplementation increased serum nitrate/nitrite levels by ~25-fold in the high dose group (P<0.001), but kidney enlargement and percentage cyst area was not altered, regardless of dose. In conclusion, L-arginine has mild direct efficacy on reducing renal cyst growth in vitro, whereas long-term sodium nitrate supplementation was ineffective in vivo. These data suggest that the bioconversion of dietary nitrate to NO by the entero-salivary pathway may not be sufficient to influence the progression of renal cyst growth in ADPKD

The effect of incremental inclusion of whole grain wheat in the diet of growing turkeys on growth performance, feed conversion ratio, cecal health, and digesta characteristics

This study was conducted to determine the effects of adding incremental amounts of whole grain wheat (0, 100, and 200 g per kilogram of feed) to the diet of growing turkey poults on growth performance, feed efficiency, digesta pH, and the incidence of cecal distension. Seventy two, 6-wk-old commercial line turkeys were blocked by live weight and randomly allocated to 1 of 3 dietary treatment (n = 4 pens/treatment). Turkeys were offered their respective treatments for the duration of the study. Feed offered and refused and body weights were determined weekly. At 63 d of age 12 turkeys from each treatment were euthanized and crop contents were collected and weighed, pH of gizzard and cecal digesta measured, and ceca and cecal contents visually scored. At 84 d of age, all remaining turkeys were euthanized and the same sampling procedure repeated. Feed conversion ratio was poorer in those turkeys offered diets containing whole grain wheat (P < 0.05), declining quadratically (P < 0.005) as the proportion of whole grain wheat (WGW) in the diet increased. The proportion of WGW found in the crop post-mortem reflected whole wheat inclusion rates of the diets. The pH of gizzard contents at 63 d was lower in turkeys receiving diets supplemented with WGW, declining quadratically (P = 0.005) as the proportion of WGW in the diet increased. However, this difference in gizzard pH was not apparent at 84 d of age. Cecal content pH, cecal visual appearance scores, and cecal content visual appearance scores were not affected by the inclusion of WGW to the diet. The inclusion of WGW to the diets of growing turkeys reduces growth performance and feed efficiency suggesting that the addition of whole wheat may have reduced the nutritional quality of the diet as a whole

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Lithospheric structure in Central Eurasia derived from elevation, geoid anomaly and thermal analysis

We present new crustal and lithospheric thickness maps for Central Eurasia from the combination of elevation and geoid anomaly data and thermal analysis. The results are strongly constrained by numerous previous data based on seismological and seismic experiments, tomographic imaging and integrated geophysical studies. Our results indicate that high topography regions are associated with crustal thickening that is at a maximum below the Zagros, Himalaya, Tien Shan and the Tibetan Plateau. The stiffer continental blocks that remain undeformed within the continental collision areas are characterized by a slightly thickened crust and flat topography. Lithospheric thickness and crustal thickness show different patterns that highlight an important strain partitioning within the lithosphere. The Arabia¿Eurasia collision zone is characterized by a thick lithosphere underneath the Zagros belt, whereas a thin to non-existent lithospheric mantle is observed beneath the Iranian and Anatolian plateaus. Conversely, the India¿Eurasia collision zone is characterized by a very thick lithosphere below its southern part as a consequence of the underplating of the cold and stiff Indian lithosphere. Our new model presents great improvements compared to previous global models available for the region, and allows us to discuss major aspects related to the lithospheric structure and acting geodynamic processes in Central Eurasia.This research has been funded by DARIUS Consortium and projects ATIZA (CGL2009-09662-BTE), TECLA 564 (CGL2009-09662-BTE) and Consolider-Ingenio 2010 Topo-Iberia (CSD2006-00041). Some figures were 565 generated using GMT (Wessel and Smith, 1991)

Lithospheric and crustal structures in central Asia: New insghts on the Arabia/Eurasia and India/Eurasia collision zones using geoid anomaly, elevation and thermal analysis

Evolution of the Zagros-Makran Fold Belts, Darius Workshop, 14-15 may 2012, in Barcelona, Spai

Effect of Early and Delayed Commencement of Paricalcitol in Combination with Enalapril on the Progression of Experimental Polycystic Kidney Disease

Vitamin D secosteroids are intranuclear regulators of cellular growth and suppress the renin-angiotensin system. The aim of this study was to test the hypothesis that the vitamin D receptor agonist, paricalcitol (PC), either alone or with enalapril (E) (an angiotensin-converting enzyme inhibitor), reduces the progression of polycystic kidney disease. Preventative treatment of Lewis polycystic kidney (LPK) and Lewis control rats with PC (0.2 μg/kg i.p. 5 days/week) or vehicle from postnatal weeks 3 to 10 did not alter kidney enlargement. To evaluate the efficacy in established disease, LPK rats received either PC (0.8 μg/kg i.p; 3 days/week), vehicle, E (50 mg/L in water) or the combination of PC + E from weeks 10 to 20. In established disease, PC also did not alter the progression of kidney enlargement, kidney cyst growth or decline in renal function in LPK rats. Moreover, the higher dose of PC was associated with increased serum calcium and weight loss. However, in established disease, the combination of PC + E reduced systolic blood pressure and heart-body weight ratio compared to vehicle and E alone (p &lt; 0.05). In conclusion, the combination of PC + E attenuated cardiovascular disease but caused hypercalcaemia and did not alter kidney cyst growth in LPK rats

Lithospheric structure in Central Eurasia derived from elevation, geoid anomaly and thermal analysis

<p>We present new crustal and lithospheric thickness maps for Central Eurasia from the combination of elevation and geoid anomaly data and thermal analysis. The results are strongly constrained by numerous previous data based on seismological and seismic experiments, tomographic imaging and integrated geophysical studies. Our results indicate that high topography regions are associated with crustal thickening that is at a maximum below the Zagros, Himalaya, Tien Shan and the Tibetan Plateau. The stiffer continental blocks that remain undeformed within the continental collision areas are characterized by a slightly thickened crust and flat topography. Lithospheric thickness and crustal thickness show different patterns that highlight an important strain partitioning within the lithosphere. The Arabia–Eurasia collision zone is characterized by a thick lithosphere underneath the Zagros belt, whereas a thin to non-existent lithospheric mantle is observed beneath the Iranian and Anatolian plateaus. Conversely, the India–Eurasia collision zone is characterized by a very thick lithosphere below its southern part as a consequence of the underplating of the cold and stiff Indian lithosphere. Our new model presents great improvements compared to previous global models available for the region, and allows us to discuss major aspects related to the lithospheric structure and acting geodynamic processes in Central Eurasia. </p

Assessment of Dietary Sodium Intake Using the Scored Salt Questionnaire in Autosomal Dominant Polycystic Kidney Disease

The excess intake of dietary sodium is a key modifiable factor for reducing disease progression in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that the scored salt questionnaire (SSQ; a frequency questionnaire of nine sodium-rich food types) is a valid instrument to identify high dietary salt intake in ADPKD. The performance of the SSQ was evaluated in adults with ADPKD with an estimated glomerular filtration rate (eGFR) &ge; 30 mL/min/1.73 m2 during the screening visit of the PREVENT-ADPKD trial. High dietary sodium intake (HSI) was defined by a mean 24-h urinary sodium excretion &ge; 100 mmol/day from two collections. The median 24-h urine sodium excretion was 132 mmol/day (IQR: 112&ndash;172 mmol/d) (n = 75; mean age: 44.6 &plusmn; 11.5 years old; 53% female), and HSI (86.7% of total) was associated with male gender and higher BMI and systolic blood pressure (p &lt; 0.05). The SSQ score (73 &plusmn; 23; mean &plusmn; SD) was weakly correlated with log10 24-h urine sodium excretion (r = 0.29, p = 0.01). Receiving operating characteristic analysis showed that the optimal cut-off point in predicting HSI was an SSQ score of 74 (area under the curve 0.79; sensitivity 61.5%; specificity 90.0%; p &lt; 0.01). The evaluation of the SSQ in participants with a BMI &ge; 25 (n = 46) improved the sensitivity (100%) and the specificity (100%). Consumers with an SSQ score &ge; 74 (n = 41) had higher relative percentage intake of processed meats/seafood and flavourings added to cooking (p &lt; 0.05). In conclusion, the SSQ is a valid tool for identifying high dietary salt intake in ADPKD but its value proposition (over 24-h urinary sodium measurement) is that it may provide consumers and their healthcare providers with insight into the potential origin of sodium-rich food sources