Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Effect of Rehydration Fluid Osmolality on Plasma Volume and Vasopressin in Resting Dehydrated Men

Elevated plasma vasopressin concentration [PVP], which may act as a dipsogen, decreases promptly following the ingestion of fluids in many mammals including humans. The purpose for this study was to determine whether fluids of varied electrolyte and carbohydrate composition and osmolality (Osm] would modify post-drinking decreases in [PVP] which could be attributed to interaction with plasma volume (PV)- or fluid-electrolyte interactive hormones. Five men (23-41 yr, 78.0 +/- SD 8.2 kg), water deprived for 24 h, drank six fluids (12 ml/kg, at 16.5C in 4.0-6.2 min): water (30 m0sm/kg), NaCl (70 mOsm/kg), NaCl + NaCitrate (270 mOsm/kg), NaCl + 9.7% glucose (650 mOsm/kg), and two commercial drinks containing various ionic and carbohydrate contents (380 and 390 mOsm/kg). Blood (20 ml/sample) was drawn at -5 min before and at +3, +9, +15, +30, and +70 min after drinking. Heart rate, blood pressures, and plasma renin activity, {Na+], [K+], [Osm], aldosterone, atrial natriuretic peptide, and epinephrine concentrations were unchanged after drinking. Post-drinking [PVP] decreased from 1.7 - 3.7 pg/ml within 3 min with all fluids independently of their composition, [Osm], or delta PV; with maximal depression to 0.1-0.7 pg/ml (p<0.05) by 15 min. The continued [PVP] depression with all fluids from 15 to 70 min was accompanied by unchanged plasma (Osm] but 1.8-7.6% increases (p<0.05) in PV with 3) fluids (2 commercial and NaCitrate) and no change with the others. Percent changes in mean [PVP] and plasma norepinephrine concentrations [PNE] at 15 min correlated -0.70 (P<0.10) suggesting that about half the variability in [PVP I I depression was associated with [PNE]. Thus, part of the mechanism for post-drinking [PVP] depression may involve a drinking stimulated norepinephrine (neural) factor

Hypervolemia from Drinking Hyperhydration Solutions at Rest and Exercise

The mechanism of muscular fatigue from physical work and exercise (high metabolism) is not clear, but involves disturbances of muscle surface membrane excitation-contraction coupling from changes in sarcoplasmic reticulum Ca2+ release, cell H+ and Pi responses, and carbohydrate metabolism. Fatigue in people at rest (low metabolism) involves both psychological and physiological factors, probably in different proportions. One common factor appears to be the level and distribution of water and electrolytes within muscle cells and other vascular, interstitial, body fluid compartments. The vascular fluid volume, composed of plasma and red blood cells, is a primary regulatory factor for cardiovascular function; reduction of vascular volume (hypovolemia) and total body water (hypohydration) adversely affect exercise performance. Plasma volume and plasma ionic-osmotic constituent concentrations are also regulatory factors for body thermoregulation, which is often compromised from exercise induced hypovolemia and hypohydration. Rehydration of dehydrated people on earth is relatively easy with appropriate food (osmols), fluid, and a restful environment. But ad libitum drinking under stressful conditions; e.g., heat, exercise, or prior dehydration, results in involuntary dehydration defined as the delay in full fluid replacement (euhydration) during and following loss of body fluid. Astronauts, with their reduced total body water are euhydrated while in weightlessness, but become "dehydrated" during reentry and landing. Thus, people subjected to acute or chronic stress are probably somewhat "dehydrated" as well as fatigued. Many rehydration drinks are more concentrated (hypertonic-hyperosmotic) with respect to the normal plasma osmolality of 285 mOsm/kg H2O and more of the drink osmols are contributed by carbohydrates than by ionized substances. There have been few studies on the efficacy of various drink formulations for increasing body fluid compartment volumes, especially plasma volume, in rested hydrated subjects. Recent findings from our laboratory have indicated that drinks containing greater concentrations of ionized substances (Performance 1 and AstroAde) up to 157 mEq/L Na+ induced greater levels of hypervolemia in resting, moderately dehydrated men, and were also better than water for attenuating the characteristic hypovolemia during supine, submaximal, leg ergometer exercise

The constitutively active V2 receptor mutants conferring NSIAD are weakly sensitive to agonist and antagonist regulation.

Patients having the nephrogenic syndrome of inappropriate antidiuresis present either the R137C or R137L V2 mutated receptor. While the clinical features have been characterized, the molecular mechanisms of functioning of these two mutants remain elusive. In the present study, we compare the pharmacological properties of R137C and R137L mutants with the wild-type and the V2 D136A receptor, the latter being reported as a highly constitutively active receptor. We have performed binding studies, second messenger measurements and BRET experiments in order to evaluate the affinities of the ligands, their agonist and antagonist properties and the ability of the receptors to recruit beta-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the G(s) protein activation. In addition, these two mutants induce a constitutive beta-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of G(s) protein coupling and beta-arrestin recruitment. The small constitutive activities of the mutants and the weak regulation of their functioning by agonist suggest a poor ability of the antidiuretic function to be adapted to the external stimuli, giving to the environmental factors an importance which can explain some of the phenotypic variability in patients having NSIAD

Coupling properties of the wild-type and mutants receptors.

<p><b>a</b>, Basal, agonist induced and antagonist-inhibited cAMP accumulation was measured on cos 7 cells expressing wild-type or mutants receptors. Values of cAMP accumulation were normalized to the number of receptors expressed at the surface of the cells determined by ligand binding [3H]AVP. <b>b</b>, AVP dose-response experiments performed on cells expressing wild-type, R137C or R137L V2 receptor. <b>c</b>, effect of an inverse agonist, SR121463, on AVP-induced stimulation.</p

β-arrestin 1 recruitment to V2R studied by BRET.

<p><b>a</b>, For BRET measurements, V2 receptors and β-arrestin 1 were fused to Rluc and YFP proteins, respectively, and co-expressed in COS-7 cells treated or not with AVP for 45 minutes. <b>b</b>, AVP-induced β-arrestin 1 recruitment to either V2 wild-type, R137C, R137L or D136A mutants. Data are means±S.E.M of three independent experiments. <b>c</b>, Expression levels of BRET partners determined by Rluc luminescence and YFP fluorescence <b>d</b>, Dose-response of AVP-induced BRET after AVP stimulation for 45 minutes. <b>e</b>, BRET time-course: BRET increase between V2 receptors and β-arrestin 1 after AVP stimulation (1 µM) at the indicated time. Data are means±S.E.M of three independent experiments.</p

Pharmacological properties of the R137C and R137L V2 receptors compared to the those of the wild-type and D136A receptor.

*<p>: the values cannot be determined since the curves do not reach a plateau.</p>**<p>: values from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008383#pone.0008383-Morin2" target="_blank">[19]</a>.</p