24-h Plasma Research Articles

Normal-range urinary albumin excretion associates with blood pressure and renal electrolyte handling in pregnancy.

Albuminuria in the pathological range is a significant predictor of preeclampsia. In healthy persons, high normal urinary albumin predicts a later incidence of hypertension and is associated with salt sensitivity of blood pressure. We hypothesized that in pregnancy urinary albumin in the normal range associates with blood pressure through activation of distal Na+ reabsorption and renal salt retention by plasma factors cofiltered with albumin. We analyzed 24-h urine collections and plasma samples from gestational week 29 of 560 pregnant women from the Odense Child Cohort, a Danish population-based cohort. Plasma and urinary aldosterone were measured by ELISA. Plasma and urinary Na+, K+, Cl-, and creatinine were also determined. Predictive values of urinary albumin were assessed by linear mixed, multiple, and Cox regression analyses. Primary outcomes were blood pressure and renal electrolyte handling. Twenty-four-hour urinary albumin excretion at gestational week 29 associated with gestational blood pressure trajectory, with adjusted β coefficients (95% confidence intervals) for each 10-fold increase in urinary albumin as follows: 5.71 (1.60 to 9.81) mmHg for systolic blood pressure and 4.39 (1.41 to 7.38) mmHg for diastolic blood pressure. Urinary albumin was inversely associated with fractional excretion rates of Na+, K+, and Cl-, with adjusted β coefficients (95% confidence intervals) for each 10-fold increase in urine albumin as follows: -0.25 (-0.35 to -0.14), -5.06 (-6.81 to -3.30), and -0.28 (-0.41 to -0.15), respectively. In conclusion, at gestational week 29, urinary albumin excretion in the normal range associated with blood pressure and renal electrolyte handling independent of potential confounders.

Overnight/first-morning urine free metanephrines and methoxytyramine for diagnosis of pheochromocytoma and paraganglioma: is this an option?

Sympathoadrenal activity is decreased during overnight rest. This study assessed whether urinary-free normetanephrine, metanephrine and methoxytyramine in overnight/first-morning urine collections might offer an alternative to measurements in 24-h collections or plasma for diagnosis of pheochromocytoma and paraganglioma (PPGL). Prospective multicenter cross-sectional diagnostic study involving 706 patients tested for PPGL, in whom tumors were confirmed in 79 and excluded in 627 after follow-up. Another 335 age- and sex-matched volunteers were included for reference purposes. Catecholamines and their free O-methylated metabolites were measured in 24-h collections divided according to waking and sleeping hours and normalized to creatinine. Plasma metabolites from blood sampled after supine rest were measured for comparison. Urinary outputs of norepinephrine, normetanephrine, epinephrine and metanephrine in the reference population were respectively 50 (48-52)%, 35 (32-37)%, 76 (74-78)% and 15 (12-17)% lower following overnight than daytime collections. Patients in whom PPGLs were excluded showed 28 (26-30)% and 6 (3-9)% day-to-night falls in normetanephrine and metanephrine, while patients with PPGLs showed no significant day-to-night falls in metabolites. Urinary methoxytyramine was consistently unchanged from day to night. According to receiver-operating characteristic curves, diagnostic accuracy of metabolite measurements in overnight/first-morning urine samples did not differ from measurements in 24-h urine collections, but was lower for both than for plasma. Using optimized reference intervals, diagnostic specificity was higher for overnight than daytime collections at similar sensitivities. Measurements of urinary-free catecholamine metabolites in first-morning/overnight urine collections offer an alternative for diagnosis of PPGL to 24-h collections but remain less accurate than plasma measurements.

Glucose levels are stable in stored blood and plasma samples of cultured female African catfish (Clarias gariepinus)

Glucose is utilized by fish as one of the sources of energy. It is a physiological parameter useful in the determination of the general health condition of cultured fish. The aim of this study was to determine the stability of plasma and blood glucose concentration, stored at different temperatures (4 °C and 30 °C) for 72 h. Two (2) milliliters of blood was collected via the caudal abdominal venipuncture of 10 female catfishes purchased. The fish were 8 months of age and were kept in plastic ponds at the Faculty of Veterinary Medicine, University of Nigeria. Blood was collected in blood tubes containing K2EDTA. Plasma was harvested from 1 mL of K2EDTA blood sample following centrifugation. Glucose concentration was determined using the Accu-Chek glucometer. Whole blood and plasma were analyzed immediately (0 h), and then after storage at 4 °C and 30 °C at 24 h, 48 h, and 72 h. Comparisons to the whole blood samples (0 h) stored at 30 °C revealed a significant (p 0.05) differences in the 24-h, 48-h, and 72-h plasma glucose concentration were observed. Therefore, whole blood and plasma stored at 4 °C for 72 h and plasma stored at 30 °C for 24 h can be used for glucose determinations in the female African catfish.

Left atrial myocardial dysfunction in patients with primary aldosteronism as assessed by speckle-tracking echocardiography.

We investigated the left atrial myocardial deformation in patients with primary aldosteronism using the speckle-tracking echocardiographic (STE) strain imaging technique. Our study included 107 primary aldosteronism patients [52 aldosterone-producing adenoma (APA) and 55 idiopathic hyperaldosteronism (IHA)] and 50 primary hypertensive patients. We performed conventional echocardiography to measure left atrial volume and ejection fraction, and STE to estimate left atrial myocardial deformation including peak velocity, strain and strain rate and calculate the ratio of E/e' to left atrial strain during left ventricular systole as the left atrial stiffness index. Patients with APA, compared with those with IHA and primary hypertension had a significantly (P < 0.001) lower serum potassium concentration and higher 24-h urinary aldosterone excretion and plasma aldosterone-to-renin ratio. Patients with APA had a significantly (P < 0.01) larger maximal, precontraction, and minimal left atrial volumes and lower total, active and passive left atrial emptying fractions than those with IHA and primary hypertension. Among the three groups, patients with APA showed lowest left atrial velocity, strain, and strain rate during ventricular systole, early diastole and late diastole (P < 0.05) and highest left atrial stiffness index (P < 0.001). In unadjusted analysis, the left atrial strain, strain rate and stiffness index were significantly (P < 0.05) associated with plasma aldosterone concentration and urinary aldosterone excretion. After adjustment for various confounding factors, these associations remained statistically significant for urinary aldosterone excretion (P < 0.05) but not plasma aldosterone concentration (P ≥ 0.05). Patients with primary aldosteronism, especially APA, had impaired left atrial deformation mechanics and increased left atrial stiffness, providing a promising insight into early detection of subclinical left atrial dysfunction by strain echocardiography.

Impact of Daily Antiperspirant Use on the Systemic Aluminum Exposure: An Experimental Intervention Study

Background and Objectives: Adverse health effects such as neurotoxic and carcinogenic effects through aluminum from cosmetic products have been repeatedly discussed. The dermal uptake and impact on the systemic aluminum load is still poorly understood. Therefore, we investigated the effect of daily antiperspirant use on the systemic aluminum load under real-life conditions. Methods: 21 healthy subjects meeting certain selection criteria to ensure a low systemic aluminum background load were asked to use a commercial aluminum-containing antiperspirant for 14 days. A questionnaire enquired about shaving habits and other sources of aluminum. Aluminum levels were measured before and after the exposure in 24-h urine and plasma using atomic absorption spectroscopy. Urine samples (n = 6) with <700 mg/day creatinine excretion or more than 30% difference in 24-h creatinine excretion were excluded from further analysis. Results: No significant increase in plasma aluminum concentration or total excreted aluminum per day before and after exposure was measurable. No sample exceeded the reference values of the general population (maximum: 9.42 µg/g creatinine and 2.1 µg/L plasma). Shaving habits did not have a significant influence on the systemic aluminum load. Also, no correlation between the total amount of antiperspirant applied and the systemic aluminum level could be demonstrated. Conclusions: No measurable contribution to the overall systemically available aluminum load due to daily use of an antiperspirant for 14 days could be shown, but real-life data concerning long-term use or higher concentrations are still lacking. Considering toxicological occupational exposure data, adverse neurotoxic changes are unlikely in the case of urinary excretion of <50 µg aluminum/g creatinine (= no observed adverse effect level), even following long-term exposure.

Mechanism of Action of Inhaled Insulin on Whole Body Glucose Metabolism in Subjects with Type 2 Diabetes Mellitus

In the current study we investigate the mechanisms of action of short acting inhaled insulin Exubera®, on hepatic glucose production (HGP), plasma glucose and free fatty acid (FFA) concentrations. 11 T2D (Type 2 Diabetes) subjects (age = 53 ± 3 years) were studied at baseline (BAS) and after 16-weeks of Exubera® treatment. At BAS and after 16-weeks subjects received: measurement of HGP (3-3H-glucose); oral glucose tolerance test (OGTT); and a 24-h plasma glucose (24-h PG) profile. At end of study (EOS) we observed a significant decrease in fasting plasma glucose (FPG, 215 ± 15 to 137 ± 11 mg/dl), 2-hour plasma glucose (2-h PG, 309 ± 9 to 264 ± 11 mg/dl), glycated hemoglobin (HbA1c, 10.3 ± 0.5% to 7.5 ± 0.3%,), mean 24-h PG profile (212 ± 17 to 141 ± 8 mg/dl), FFA fasting (665 ± 106 to 479 ± 61 μM), post-OGTT (433 ± 83 to 239 ± 28 μM), and triglyceride (213 ± 39 to 120 ± 14 mg/dl), while high density cholesterol (HDL-C) increased (35 ± 3 to 47 ± 9 mg/dl). The basal HGP decreased significantly and the insulin secretion/insulin resistance (disposition) index increased significantly. There were no episodes of hypoglycemia and no change in pulmonary function at EOS. After 16-weeks of inhaled insulin Exubera® we observed a marked improvement in glycemic control by decreasing HGP and 24-h PG profile, and decreased FFA and triglyceride concentrations.

Association of hypokalemia with cortisol and ACTH levels in Cushing's disease.

Hypokalemia is a common feature in patients with Cushing's syndrome (CS). Whether the occurrence of hypokalemia is associated with cortisol and adrenocorticotropic hormone (ACTH) levels is still unclear. Approximately 80% of cases of endogenous CS are due to Cushing's disease (CD). The purpose of this study was to determine the association of hypokalemia with cortisol and ACTH levels in patients with CD. The retrospective study included 195 patients with CD referred to our medical center from January 2011 to December 2017. The results show that 25.64% (50/195) of the patients had hypokalemia. The 24-h urinary free cortisol (UFC) and plasma cortisol levels were significantly higher in patients with hypokalemia than those with normokalemia (P < 0.05). Plasma ACTH levels were similar between the patients with hypokalemia and normokalemia (P > 0.05). Cortisol levels were negatively correlated with plasma potassium levels (08:00: r=-0.344 (P < 0.01), 00:00: r=-0.435 (P < 0.01); 24-h UFC: r=-0.281 (P < 0.05)). There was no significant correlation between the plasma ACTH and potassium (08:00: r=-0.093 (P > 0.05), 00:00: r=-0.184 (P > 0.050)). Our current data suggest that cortisol level, instead of ACTH level, is correlated with plasma potassium level. A high cortisol level may be the principal cause of hypokalemia.

Bioavailability and Pharmacokinetics of Once-Daily Amantadine Extended-Release Tablets in Healthy Volunteers: Results from Three Randomized, Crossover, Open-Label, Phase 1 Studies.

IntroductionIn February 2018, OS320—an amantadine extended-release (ER) tablet formulation with once-daily morning administration—was approved for the treatment of Parkinson’s disease and drug-induced extrapyramidal reactions in adults. The purpose of this study was to describe three phase 1 studies that assessed the pharmacokinetics (PK) and bioavailability of amantadine ER in healthy adult volunteers.MethodsStudy 1 was an open-label, four-treatment, single-dose, crossover study comparing amantadine ER 129, 193, and 258 mg tablets with an equivalent dose of immediate-release (IR) amantadine 40 mg/5 mL syrup. Study 2 was an open-label, single-dose, crossover food-effect study with amantadine ER 258 mg. Study 3 was an open-label, multiple-dose, crossover study comparing amantadine ER and amantadine IR syrup.ResultsAmantadine ER displayed a steady release of amantadine, with the peak amantadine concentration occurring at ~ 7.5 h postdose or in the middle of the day (following a morning dose) with steady-state administration. Administration of amantadine ER 258 mg with a high-fat meal did not affect amantadine bioavailability. Amantadine plasma exposure increased proportionally with increasing doses, and at steady state, amantadine exposure from an amantadine ER 258-mg tablet was bioequivalent to twice-daily 129-mg amantadine IR syrup.ConclusionThe PK profile of amantadine ER 129-mg, 193-mg, and 258-mg tablets allows for once-daily dosing in the morning; the 24-h average amantadine plasma concentration is equivalent to that for the same daily dose of IR amantadine administered twice daily.FundingOsmotica Pharmaceutical US LLC.

Tadalafil nanocomposites as a dry powder formulation for inhalation, a new strategy for pulmonary arterial hypertension treatment

Tadalafil (a phosphodiesterase-5 inhibitor) is a choice for treatment of pulmonary arterial hypertension (PAH) that is known as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest and ≥30 mmHg during exercise with reduced cardiac output. The aim of this study was to prepare inhalable tadalafil nanocomposites as a dry powder formulation by spray drying technique for increasing bioavailability and treatment efficacy, as well as decreasing systemic side effects.The D-optimal design was used for optimization of formulation parameters. Microparticle size, morphology, crystallinity, density, solubility, redispersion (%), and in-vitro inhalation performance of tadalafil nanocomposites were investigated as physicochemical characteristics. Pharmacokinetic parameters were also evaluated in plasma and lung tissue of Wistar rats after intratracheal insufflation and compared with a control group receiving an oral tadalafil marketed product (dose = 10 mg/kg).The suggested optimum formulation contained stable amorphous particles with almost rounded shape and corrugated surface that were completely redispersed in the lung simulated medium with the mass median geometric diameter of 3.2 μm, density of 1.4 g/cm3, fine particle fraction based on emitted dose (%) of 57.2 ± 6.5%, and 13.7-fold enhancement in dissolution rate. In-vivo studies showed that the ratio of AUC0–24h lung/AUC0–24h plasma, achieved in the treated group after intratracheal insufflation, was significantly higher than the control group that means high local drug concentration and more efficacy. Besides, plasma data analysis indicated high value of MRT (2.3-fold) and tmax (3.7-fold) after intratracheal insufflation of tadalafil nanocomposites in comparison with the conventional oral route, indicating longer retention of tadalafil molecules in the lungs and their slower entry to the systemic blood circulation. In conclusion, it seems that inhalable tadalafil nanocomposites can be introduced as an alternative to oral tadalafil in the treatment of PAH.

Peritoneal Protein Clearance Is a Function of Local Inflammation and Membrane Area Whereas Systemic Inflammation and Comorbidity Predict Survival of Incident Peritoneal Dialysis Patients.

It is not clear whether the association of increased peritoneal protein clearance (PPCl) with worse survival on peritoneal dialysis (PD) is a consequence of either local or systemic inflammation or indicative of generalized endothelial dysfunction associated with comorbidity. To investigate this we determined the relationship of PPCl to comorbidity, membrane area (equivalent to low molecular weight peritoneal solute transport rate), local and systemic inflammation and hypoalbuminaemia, and for each of these with patient survival. 257 incident patients from three GLOBAL Fluid Study centers were included in this analysis. Clinical profiles were collected at baseline along with a peritoneal equilibration test, 24-h dialysate protein and paired plasma and dialysate cytokine measurements. Although peritoneal protein clearance was associated with increased age and severe comorbidity on univariate analysis, only dialysate IL-6, peritoneal solute transport rate, plasma albumin and cardiac comorbidities (ischaemic heart disease and left ventricular dysfunction) were independent explanatory variables on multivariate analysis. While peritoneal protein clearance and daily peritoneal protein loss were associated with survival in univariate analysis, on multivariate analysis only plasma IL-6, age, residual kidney function, comorbidity, and plasma albumin were independent predictors. Peritoneal protein clearance is primarily a function of peritoneal membrane area and local membrane inflammation. The association with comorbidity and survival is predominantly explained by its inverse relationship to hypoalbuminaemia, especially in diabetics.

Relations of combat stress and posttraumatic stress disorder to 24-h plasma and cerebrospinal fluid interleukin-6 levels and circadian rhythmicity

BackgroundAcute and chronic stress can lead to a dysregulation of the immune response. Growing evidence suggests peripheral immune dysregulation and low-grade systemic inflammation in posttraumatic stress disorder (PTSD), with numerous reports of elevated plasma interleukin-6 (IL-6) levels. However, only a few studies have assessed IL-6 levels in the cerebrospinal fluid (CSF). Most of those have used single time-point measurements, and thus cannot take circadian level variability and CSF-plasma IL-6 correlations into account. MethodsThis study used time-matched, sequential 24-h plasma and CSF measurements to investigate the effects of combat stress and PTSD on physiologic levels and biorhythmicity of IL-6 in 35 male study volunteers, divided in 3 groups: (PTSD = 12, combat controls, CC = 12, and non-deployed healthy controls, HC = 11). ResultsOur findings show no differences in diurnal mean concentrations of plasma and CSF IL-6 across the three comparison groups. However, a significantly blunted circadian rhythm of plasma IL-6 across 24 h was observed in all combat-zone deployed participants, with or without PTSD, in comparison to HC. CSF IL-6 rhythmicity was unaffected by combat deployment or PTSD. ConclusionsAlthough no significant group differences in mean IL-6 concentration in either CSF or plasma over a 24-h timeframe was observed, we provide first evidence for a disrupted peripheral IL-6 circadian rhythm as a sequel of combat deployment, with this disruption occurring in both PTSD and CC groups. The plasma IL-6 circadian blunting remains to be replicated and its cause elucidated in future research.

Similar Variability of Fasting and 24-h Self-Measured Plasma Glucose (SMPG) with Insulin Glargine 300 U/mL (Gla-300) vs. Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve Adults with T2DM—The Randomized BRIGHT Trial

BRIGHT was an open-label, randomized, parallel-group, 24-week study in insulin naïve participants with uncontrolled T2DM, investigating efficacy and safety of Gla-300 and IDeg-100. Participants were randomized to Gla-300 or IDeg-100, titrated to a target fasting SMPG of 80-100 mg/dL. The primary objective (non-inferiority of Gla-300 vs. IDeg-100 in HbA1c change from baseline to week 24) was met. Secondary endpoints, presented here, included change in variability of fasting and 24-h SMPG. Eight-point SMPG profiles were similar for both groups at week 24. Mean baseline coefficient of variation (CV) of ≥3 fasting SMPG measurements over 7 days was 13.73% and 14.63% for Gla-300 and IDeg-100, respectively. Change in fasting SMPG variability (SE) to week 24 was 1.49% (0.39) and 1.97% (0.39) for Gla-300 and IDeg-100 (least squares [LS] mean difference [95% CI] −0.48 [−1.49 to 0.53]) (Figure a). Mean baseline CVs for 8-point profiles (24-h SMPG) were 22.60% and 23.41% for Gla-300 and IDeg-100. Mean change in 24-h SMPG variability (SE) was 3.70% (0.59) and 3.95% (0.60) for Gla-300 and IDeg-100 at week 24 (LS mean difference −0.25 [−1.72 to 1.22]) (Figure b). In summary, Gla-300 and IDeg-100 had similar variability of fasting and 24-hour SMPG over the 24-week treatment period in BRIGHT. Disclosure A.Y.Y. Cheng: Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Abbott. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Merck &amp; Co., Inc.. Speaker's Bureau; Self; Merck &amp; Co., Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Consultant; Self; Takeda Canada Inc.. Research Support; Self; Sanofi, Boehringer Ingelheim GmbH. R. Ritzel: Speaker's Bureau; Self; AstraZeneca. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Consultant; Self; Servier. Speaker's Bureau; Self; Bristol-Myers Squibb Company, Merck Sharp &amp; Dohme Corp., Boehringer Ingelheim GmbH, Eli Lilly and Company, Novartis Pharmaceuticals Corporation. Z. Bosnyak: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. E. Boelle-Le Corfec: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. A.M. Cali: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. X. Wang: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson &amp; Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker's Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. R. Roussel: Advisory Panel; Self; AbbVie Inc., Abbott, Eli Lilly and Company, Sanofi, Novo Nordisk A/S, AstraZeneca. Speaker's Bureau; Self; Servier. Consultant; Self; Bayer AG. Advisory Panel; Self; Merck Sharp &amp; Dohme Corp.. Research Support; Self; Amgen Inc., Sanofi, Novo Nordisk A/S, Danone Research. Stock/Shareholder; Self; Iriade. Advisory Panel; Self; Physiogenex S.A.S. G.B. Bolli: Speaker's Bureau; Self; Menarini Group, Sanofi. Research Support; Self; Sanofi.

IL-33 receptor ST2 deficiency attenuates renal ischaemia–reperfusion injury in euglycaemic, but not streptozotocin-induced hyperglycaemic mice

AimKidney hypoxia can predispose to the development of acute and chronic renal failure in diabetes. Ischaemia–reperfusion injury (IRI) causes inflammation, and diabetes is known to exacerbate this inflammatory response in the kidney, whereas alarmin IL-33 could act as an innate immune mediator during kidney IRI. Thus, the present study examined the impact of genetic IL-33 receptor ST2 deficiency (ST2−/−) on renal IRI in euglycaemic and hyperglycaemic mice. MethodsHyperglycaemia was induced with streptozotocin (STZ) in adult male C57BL/6JRj wild-type (WT) mice and ST2−/− mice. Unilateral renal IRI was achieved 3months after STZ treatment by left kidney nephrectomy (non-ischaemic control kidney) and clamping of the right renal artery for 32min in STZ- and vehicle-treated animals. At 24h after reperfusion, renal function and injury were determined by levels of plasma creatinine, blood urea nitrogen (BUN) and histological tubule scores. Also, in a complementary pilot clinical study, soluble ST2 concentrations were compared in diabetics and non-diabetics. ResultsUrinary albumin was significantly increased in STZ-induced hyperglycaemic mice, regardless of genotypic background. At 24h post-ischaemia, plasma creatinine, BUN and tubular injury were significantly reduced in ST2−/− mice compared with vehicle-treated WT mice, but this protective effect was lost in the STZ-induced hyperglycaemic ST2−/− animals. Plasma concentrations of soluble ST2 were significantly greater in type 2 diabetes patients vs non-diabetics. ConclusionOur data suggest that the IL-33/ST2 pathway exerts differential effects depending on the glucose environment, opening-up new avenues for future research on alarmins and diabetes in ischaemia-related diseases.

Reproducibility and relative validity of a food frequency questionnaire to estimate intake of dietary phylloquinone and menaquinones.

This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status. In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross-sectionally among 507 postmenopausal women. Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (rs=0.28) than men (rs=0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long-chain menaquinones showed good relative validity (rs=0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (rs=0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (rs=-0.09 (-0.18; -0.01)) and long-chain menaquinones (rs=-0.13 (-0.21; -0.04)), but not with short-chain menaquinones (rs=-0.04 (-0.13; 0.05)). The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake.

Comparative Pharmacodynamics of Telavancin and Vancomycin in the Neutropenic Murine Thigh and Lung Infection Models against Staphylococcus aureus.

The pharmacodynamics of telavancin and vancomycin were compared using neutropenic murine thigh and lung infection models. Four Staphylococcus aureus strains were included. The telavancin MIC ranged from 0.06 to 0.25 mg/liter, and the vancomycin MIC ranged from 1 to 4 mg/liter. The plasma pharmacokinetics of escalating doses (1.25, 5, 20, and 80 mg/kg of body weight) of telavancin and vancomycin were linear over the dose range. Epithelial lining fluid (ELF) pharmacokinetics for each drug revealed that penetration into the ELF mirrored the percentage of the free fraction (the fraction not protein bound) in plasma for each drug. Telavancin (0.3125 to 80 mg/kg/6 h) and vancomycin (0.3125 to 1,280 mg/kg/6 h) were administered by the subcutaneous route in treatment studies. Dose-dependent bactericidal activity against all four strains was observed in both models. A sigmoid maximum-effect model was used to determine the area under the concentration-time curve (AUC)/MIC exposure associated with net stasis and 1-log10 kill relative to the burden at the start of therapy. The 24-h plasma free drug AUC (fAUC)/MIC values associated with stasis and 1-log kill were remarkably congruent. Net stasis for telavancin was noted at fAUC/MIC values of 83 and 40.4 in the thigh and lung, respectively, and 1-log kill was noted at fAUC/MIC values of 215 and 76.4, respectively. For vancomycin, the fAUC/MIC values for stasis were 77.9 and 45.3, respectively, and those for 1-log kill were 282 and 113, respectively. The 24-h ELF total drug AUC/MIC targets in the lung model were very similar to the 24-h plasma free drug AUC/MIC targets for each drug. Integration of human pharmacokinetic data for telavancin, the results of the MIC distribution studies, and the pharmacodynamic targets identified in this study suggests that the current dosing regimen of telavancin is optimized to obtain drug exposures sufficient to treat S. aureus infections.

In Vivo Pharmacodynamic Evaluation of Omadacycline (PTK 0796) against Streptococcus pneumoniae in the Murine Pneumonia Model.

Omadacycline is a novel aminomethylcycline antibiotic in clinical development for community-acquired bacterial pneumonia (CABP). We used a neutropenic murine pneumonia infection model to characterize the in vivo pharmacodynamic activity of omadacycline against Streptococcus pneumoniae Four strains with various phenotypic resistances to other antimicrobials, including tetracyclines, were utilized. Drug concentration measurements were performed in the plasma and epithelial lining fluid (ELF) after administration of 0.5, 2, 8, and 32 mg/kg. Pharmacokinetic parameters were calculated using a noncompartmental model and were linear over the dose range. Penetration into ELF ranged from 72 to 102%. Omadacycline demonstrated net cidal activity in relation to the initial burden against all four strains. The pharmacokinetic/pharmacodynamic index AUC/MIC correlated well with efficacy (R2 = 0.74). The plasma 24-h static dose AUC/MIC values were 16 to 20 (24-h ELF AUC/MIC of 14 to 18). A 1-log10 kill was achieved at 24-h plasma AUC/MIC values of 6.1 to 180 (24-h ELF AUC/MIC values 6.0 to 200). A 2-log10 kill was achieved at 24-h plasma AUC/MIC values of 19 to 56 (24-h ELF AUC/MIC of 17 to 47). The targets identified in this study in combination with in vitro potency and favorable human pharmacokinetics make omadacycline an attractive candidate for further development and study in patients with CABP.

Hyperinsulinemia and elevated systolic blood pressure independently predict white matter hyperintensities with associated cognitive decrement in the middle-aged offspring of dementia patients.

Cerebrovascular disease is an independent risk factor for dementia that may also be synergistic with Alzheimer's disease. In recent years attention has switched from cerebral infarcts to microvascular disease as the primary cause of cerebrovascular cognitive decline, with damage to the white matter the primary mechanism. Uncertainties remain regarding the risks posed by different types vascular threat, the extent to which cerebrovascular damage occurs in middle age, and whether relatively "normal" amounts of white matter damage are accompanied by meaningful degrees of cognitive decline. We explored these issues via laboratory, cardiovascular, cognitive, and magnetic resonance imaging (MRI) data in 67 middle-aged cognitively normal offspring of dementia patients. The sample was enriched for vascular risk. Plasma insulin, 24-h systolic blood pressure, body mass index, age, and % small dense LDL cholesterol were the strongest correlates of MRI white matter hyperintensity (WMH) volume. With shared variance controlled for, 24h systolic BP, plasma insulin, and age remained as significant predictors of WMH volume. An interaction variable (24h BP * insulin) did not improve the prediction of WMH. WMH volume correlated negatively with cognition. No evidence for an ApoE ε4 effect emerged for either WMH or cognition. Hypertension and hyperinsulinemia appear to pose independent, consequential threats to the cerebral small vessel vasculature in middle age, reflected in the presence of areas of WMH on MRI scans. Our data show that even modest WMH volumes in middle age are associated with cognitive decrement, underscoring the importance of aggressive treatment and lifestyle modifications to address vascular risk throughout adulthood.

Urinary potassium excretion, renal ammoniagenesis, and risk of graft failure and mortality in renal transplant recipients

Background: Renal transplant recipients (RTRs) have commonly been urged to limit their potassium intake during renal insufficiency and may adhere to this principle after transplantation. Importantly, in experimental animal models, low dietary potassium intake induces kidney injury through stimulation of ammoniagenesis. In humans, low potassium intake is an established risk factor for high blood pressure.Objective: We hypothesized that low 24-h urinary potassium excretion [UKV; urinary potassium concentration × volume], the gold standard for assessment of dietary potassium intake, represents a risk factor for graft failure and mortality in RTRs. In secondary analyses, we aimed to investigate whether these associations could be explained by ammoniagenesis, plasma potassium, or blood pressure.Design: In a prospective cohort of 705 RTRs, we assessed dietary potassium intake by a single 24-h UKV and food-frequency questionnaires. Cox regression analyses were used to investigate prospective associations with outcome.Results: We included 705 stable RTRs (mean ± SD age: 53 ± 13 y; 57% men) at 5.4 y (IQR: 1.9–12.0 y) after transplantation and 253 kidney donors. Mean ± SD UKV was 73 ± 24 mmol/24 h in RTRs compared with 85 ± 25 mmol/24 h in kidney donors. During follow-up for 3.1 y (IQR: 2.7–3.9 y), 45 RTRs developed graft failure and 83 died. RTRs in the lowest sex-specific tertile of UKV (women, <55 mmol/24 h; men, <65 mmol/24 h) had an increased risk of graft failure (HR: 3.70; 95% CI: 1.64, 8.34) and risk of mortality (HR; 2.66; 95% CI: 1.53, 4.61), independent of potential confounders. In causal path analyses, 24-h urinary ammonia excretion, plasma potassium, and blood pressure did not affect these associations.Conclusions: Our results indicate that low UKV is associated with a higher risk of graft failure and mortality in RTRs. Specific attention for adequate potassium intake after transplantation seems warranted. This trial was registered at clinicaltrials.gov as NCT02811835.

"Micromegaly": an update on the prevalence of acromegaly with apparently normal GH secretion in the modern era.

Approximately 25% of cases of clinically active acromegaly cases treated in our academic center between 1996 and 2000, were diagnosed in patients who had elevated plasma IGF-1 levels, but apparently "normal" 24-h mean plasma GH levels. The current study served to update the data for patients with acromegaly referred to our facility, after increasing awareness of this "normal" GH subpopulation throughout the medical community. A retrospective chart review was conducted on 157 patients with acromegaly who underwent resection of a confirmed somatotroph pituitary adenoma at the University of Michigan Health System between the dates of 1 Jan 2001 to 23 Sept 2015. Overall prevalence of acromegalic patients with "normal" GH levels, defined as GH <4.7ng/mL, was 31%. Over time, the percentage of patients with "normal" GH at diagnosis did not decline: 26% from 2001 to 2005, 19% from 2006 to 2010, and 47% from 2011 to 2015. Mean pituitary tumor size was 1.8±0.1cm for the group with elevated GH, and 1.2±0.1cm for the group with "normal" GH (p<0.001). Percent microadenomas was higher in a group with "normal" GH as compared to those with elevated GH (48 vs. 12%, p<0.001), and tumors >2cm in the maximal diameter were encountered more frequently in the group with elevated GH (43 vs. 14%, p<0.001). Our data show that a substantial percentage of patients with clinical acromegaly have "normal" GH, and therefore strengthens the growing body of evidence which supports the leading role of IGF-1 levels in diagnostic evaluation. At the present time, questions about the natural course of "micromegaly" and treatment benefits compared to the subpopulation with elevated GH levels remain unanswered, but research continues to build on our understanding of the heterogeneous population of individuals.

Dietary Route of Exposure for Rabbit Developmental Toxicity Studies.

Dietary administration is a relevant route of oral exposure for regulatory toxicity studies of agrochemicals as it mimics potential human intake of the chemical via treated crops and commodities. Moreover, dietary administration of test compounds during a developmental toxicity study can deliver a prolonged and stable systemic exposure to the embryo or fetus at all stages of development. In this study, strategies were employed to optimize rabbit test material consumption via diet. Comparative toxicokinetic profiles of gavage versus dietary administration were evaluated in pregnant or non-pregnant New Zealand White rabbits for 2 novel agrochemicals with different plasma half-lives of elimination (sulfoxaflor, t½ = 13.5 h and halauxifen, t½ = 1 h). Dietary administration of sulfoxaflor resulted in stable 24-h plasma concentrations, whereas gavage administration resulted in a 3-fold fluctuation in plasma levels between Cmax and Cmin Dietary administration of sulfoxaflor resulted in a 2-fold higher nominal and diurnal systemic dose when compared with gavage dosing due to Cmax-related maternal toxicity following gavage. Results with the shorter half-life molecule, halauxifen, were more striking with a 6-fold diurnal fluctuation by the dietary route compared with a 368-fold fluctuation between Cmax and Cmin by gavage. Furthermore, plasma halauxifen was detectable only up to 12 h following gavage but up to 24 h following dietary administration. Finally, the presence of these compounds in fetal blood samples was demonstrated, confirming that dietary exposure is appropriate for achieving fetal exposure. Collectively, the results of these studies support the use of dietary exposure in rabbit developmental toxicity studies.