Changing Clinical Epidemiology of Plasmodium vivax Malaria as Transmission Decreases: Population-Based Prospective Panel Survey in the Brazilian Amazon.

BACKGROUND: Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to elicit symptoms change as transmission declines remains unclear. METHODS: We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention. RESULTS: We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission. CONCLUSIONS: P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases.

Epidemiology of COVID-19 after Emergence of SARS-CoV-2 Gamma Variant, Brazilian Amazon, 2020-2021.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Gamma variant has been hypothesized to cause more severe illness than previous variants, especially in children. Successive SARS-CoV-2 IgG serosurveys in the Brazilian Amazon showed that age-specific attack rates and proportions of symptomatic SARS-CoV-2 infections were similar before and after Gamma variant emergence.

A novel risk assessment tool for bovine respiratory disease in preweaned dairy calves.

Due to the increased morbidity and mortality of bovine respiratory disease (BRD) in dairy calves, as well as an increasing urgency for the judicious use of antimicrobials in farm animals, a comprehensive risk assessment tool for BRD in preweaned dairy calves has been designed based on a longitudinal and a cross-sectional study. As a multifactorial disease complex in which immune function stressors increase susceptibility to respiratory pathology, risk management programs for environmental and husbandry practices may be an effective approach for BRD control. Practices of known or suspected effect on BRD in preweaned calves have been explored in 2 large studies correlating management factors to BRD prevalence (BRD 100 study) and incidence (BRD 10K study) and forming the scores presented here. Priority was given to results from multivariable over univariable model estimates. However, when used, univariable model estimates were adjusted for confounders or stratified by effect modifiers if necessary. Regression coefficients were translated into scores, which are presented in a field-ready tool consisting of (1) a risk assessment questionnaire, which identifies the herd-specific risk factors and the risk scores associated with each; (2) the California BRD scoring system to estimate the BRD prevalence at the time of risk assessment for future comparison with the prevalence after interventions; and (3) the BRD control and prevention herd management plan, which can be used to plan and track the interventions identified. Scores for 100 dairies across California were used to benchmark a dairy's risk on a spectrum. With the help of the risk assessment tool, dairy producers, calf managers, and veterinarians may be able to adjust management factors that affect BRD risk on a farm and objectively monitor BRD prevalence before and after management interventions. As a result, the BRD risk assessment tool described here is the first comprehensive effort for herd-specific BRD control and prevention.

Regional management practices and prevalence of bovine respiratory disease in California's preweaned dairy calves.

The objective of this cross-sectional study was to estimate the prevalence of bovine respiratory disease (BRD) in California preweaned dairy calves and identify management practices that are associated with BRD. A convenience sample of 100 dairies in the 3 distinct dairy regions of California was surveyed. Regions evaluated were Northern California (NCA), northern San Joaquin Valley (NSJV), and greater Southern California (GSCA). A questionnaire on calf management practices and demographic information was administered via in-person interviews at each dairy and a random sample of preweaned calves was evaluated using the California BRD scoring system on the same day. Prevalence of BRD varied between the 3 dairy regions: 9.30% in NCA, 4.51% in NSJV, and 7.35% in GSCA. Breed was not associated with BRD prevalence at the statewide level, but differences in prevalence were observed between breeds across the regions with a higher prevalence in NCA for Jerseys and in GSCA for Holsteins, compared with NSJV. Prevalence of BRD was not different between organic and conventional dairies. Colostrum management practices, including heat treatment and feeding colostrum from multiparous cows, varied by region and were associated with lower BRD prevalence. Calves housed in group pens, a practice observed primarily in NCA, had a higher BRD prevalence than those in individual housing. Feeding salable milk was also more common in NCA and was associated with lower BRD prevalence. Ground and road surfaces adjacent to the calf raising area were also variable by region, and paved surfaces were associated with lower BRD prevalence. Management practices associated with BRD varied across the state and may be addressed to inform the adoption and implementation of potentially protective management decisions on California dairies and other regions with similar dairy systems.

Management factors associated with bovine respiratory disease in preweaned calves on California dairies: The BRD 100 study.

The objective of this cross-sectional study was to determine how management practices on California dairies may be associated with bovine respiratory disease (BRD) in preweaned calves. A convenience sample of 100 dairies throughout California, providing a study population of 4,636 calves, were visited between May 2014 and April 2016. During each farm visit, in-person interviews with the herd manager or calf caretaker were conducted to collect information about herd demographics, maternity pen, colostrum and calf management, herd vaccinations, and dust abatement. A random sample of preweaned calves was identified and evaluated for the presence of BRD using a standardized tool. A survey-adjusted generalized linear mixed model with a logit link function was fitted with calf as the unit of analysis and dairy as the random effect. Mean study herd size (±SE) was 1,718 (±189.9) cows. Survey-adjusted estimates of breed types in the sample were 81.6% (±0.6) Holstein, 13.1% (±0.4) Jersey, and 5.3% (±0.5) crossbred or other purebred breeds, and calf sex proportions were 73.8% (±1.0) female and 26.2% (±1.0) male. Overall survey-adjusted BRD prevalence in the study herds was 6.91% (±0.69). Housing factors positively associated with BRD were metal hutches compared with wood hutches [odds ratio (OR) = 11.19; 95% confidence interval (CI) = 2.80-44.78], calf-to-calf contact in calves >75 d of age (OR = 9.95, 95% CI = 1.50-65.86), feeding Holstein calves <2.84 L of milk or replacer per day (OR = 7.16, 95% CI = 1.23-41.68), and lagoon water used for flushing manure under hutches compared with no flush (OR = 12.06, 95% CI = 1.93-75.47). Providing extra shade over hutches (OR = 0.08; 95% CI = 0.02-0.37), feeding calves at least 90% saleable milk (OR = 0.27, 95% CI = 0.13-0.54) or pasteurized milk (OR = 0.10; 95% CI = 0.03-0.36), and feeding >5.68 L of milk or replacer per day to Jersey calves (OR = 0.04; 95% CI = 0.01-0.28) were negatively associated with BRD. Our study identified management practices on California dairies with variability and that may contribute to differences in BRD prevalence, which will be incorporated into a risk-assessment tool to control and prevent BRD in preweaned dairy calves.

Malaria Resilience in South America: Epidemiology, Vector Biology, and Immunology Insights from the Amazonian International Center of Excellence in Malaria Research Network in Peru and Brazil.

The 1990s saw the rapid reemergence of malaria in Amazonia, where it remains an important public health priority in South America. The Amazonian International Center of Excellence in Malaria Research (ICEMR) was designed to take a multidisciplinary approach toward identifying novel malaria control and elimination strategies. Based on geographically and epidemiologically distinct sites in the Northeastern Peruvian and Western Brazilian Amazon regions, synergistic projects integrate malaria epidemiology, vector biology, and immunology. The Amazonian ICEMR's overarching goal is to understand how human behavior and other sociodemographic features of human reservoirs of transmission-predominantly asymptomatically parasitemic people-interact with the major Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, and with human immune responses to maintain malaria resilience and continued endemicity in a hypoendemic setting. Here, we will review Amazonian ICEMR's achievements on the synergies among malaria epidemiology, Plasmodium-vector interactions, and immune response, and how those provide a roadmap for further research, and, most importantly, point toward how to achieve malaria control and elimination in the Americas.

Indications of proton-dominated cosmic-ray composition above 1.6 EeV.

We report studies of ultrahigh-energy cosmic-ray composition via analysis of depth of air shower maximum (X(max)), for air shower events collected by the High-Resolution Fly's Eye (HiRes) observatory. The HiRes data are consistent with a constant elongation rate d/d[log(E)] of 47.9+/-6.0(stat)+/-3.2(syst) g/cm2/decade for energies between 1.6 and 63 EeV, and are consistent with a predominantly protonic composition of cosmic rays when interpreted via the QGSJET01 and QGSJET-II high-energy hadronic interaction models. These measurements constrain models in which the galactic-to-extragalactic transition is the cause of the energy spectrum ankle at 4x10(18) eV.

Association between Mycobacterium avium subspecies paratuberculosis infection and milk production in two California dairies.

The association between Mycobacterium avium ssp. paratuberculosis (MAP) and milk production was estimated on 2 California dairies using longitudinal data from 5,926 cows. Both study herds had moderate MAP seroprevalence, housed cows in freestalls, and had Johne's disease control programs. Cow MAP status was determined using both serum ELISA and fecal culture results from cows tested at dry-off and from whole-herd tests. Potential confounders were evaluated based on a causal diagram. Mixed models with 2 functions (splines) for days in milk (DIM) representing milk production pre- and postpeak used in similar studies were further modified to use each cow's observed DIM at peak and lactation length. Cows that were seropositive produced 2.5kg less 4% fat-corrected milk (FCM) per day than their seronegative herdmates. In addition, cows that were fecal-culture positive by liquid culture and confirmed by PCR produced 2.2kg less 4% FCM per day than their fecal-culture negative herdmates. The decrease in milk production in MAP test-positive compared with test-negative cows started in the second lactation. A switch in MAP status in either ELISA or fecal culture results from positive to negative had no significant association with milk production. Modified DIM functions that used the observed DIM at peak had better model fit than another function that assumed a fixed peak at 60 DIM. Cows that tested positive for MAP on serum ELISA or fecal culture produced less milk than cows that tested negative, and the association between MAP and milk production was not confounded by mastitis, elevated somatic cell counts, or uterine or metabolic cow conditions.

Intensive glucose control and macrovascular outcomes in type 2 diabetes.

AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.

Measuring quality of care for rheumatic diseases using an electronic medical record.

OBJECTIVES: The objective of this study was twofold: (1) to determine how best to measure adherence with time-dependent quality indicators (QIs) related to laboratory monitoring, and (2) to assess the accuracy and efficiency of gathering QI adherence information from an electronic medical record (EMR). METHODS: A random sample of 100 patients were selected who had at least three visits with the diagnosis of rheumatoid arthritis (RA) at Brigham and Women's Hospital Arthritis Center in 2005. Using the EMR, it was determined whether patients had been prescribed a disease-modifying antirheumatic drug (DMARD) (QI #1) and if patients starting therapy received appropriate baseline laboratory testing (QI #2). For patients consistently prescribed a DMARD, adherence with follow-up testing (QI #3) was calculated using three different methods, the Calendar, Interval and Rolling Interval METHOD: . RESULTS: It was found that 97% of patients were prescribed a DMARD (QI #1) and baseline tests were completed in 50% of patients (QI #2). For follow-up testing (QI #3), mean adherence was 60% for the Calendar Method, 35% for the Interval Method, and 48% for the Rolling Interval Method. Using the Rolling Interval Method, adherence rates were similar across drug and laboratory testing type. CONCLUSIONS: Results for adherence with laboratory testing QIs for DMARD use differed depending on how the QIs were measured, suggesting that care must be taken in clearly defining methods. While EMRs will provide important opportunities for measuring adherence with QIs, they also present challenges that must be examined before widespread adoption of these data collection methods.

Inhibition of vasopressin action by atrial natriuretic factor.

Atrial natriuretic factor results in diuresis in animals and humans, perhaps because atrial natriuretic factor increases renal blood flow. The possibility that this diuresis is due to direct inhibition of renal tubular epithelial water transport was examined in rabbit collecting tubules perfused in vitro. Atriopeptin III inhibition of the hydraulic conductivity response to the hormone arginine vasopressin but not to either 3'5'-cyclic adenosine monophosphate or forskolin was found. These results suggest that atriopeptin III acts proximal to cyclic adenosine monophosphate formation to directly affect vasopressin-stimulated water transport in the mammalian nephron. They also suggest a potential role for inhibition by atrial natriuretic factor of the renal response to arginine vasopressin as a contributor to a diuretic state.

Calcium and bromide contents of natural waters.

The linear relation observed in a log Ca++ versus log Brplot for subsurface Cl- waters is attributed to ultrafiltration by shale of sea water and fresh water that have passed through sedimentary rocks since their formation. Reactions between these solutions and sedimentary minerals, particularly dolomitization, must have contributed additional Ca++ to solution.

Reliability of environmental sampling to quantify Mycobacterium avium subspecies paratuberculosis on California free-stall dairies.

The reliability of environmental sampling to quantify Mycobacterium avium ssp. paratuberculosis (MAP) based on collector and time was evaluated. Fecal slurry samples were collected using a standardized protocol simultaneously by 2 collectors of different experience levels. Samples were collected from 30 cow pens on 4 dairies every other day on 3 occasions while cow movements between pens were minimal. The 4 study herds had moderate MAP seroprevalence and were housed in free-stall dairies in central California. Results of testing the environmental samples for MAP using PCR and culture were strongly correlated. The reliability of environmental sampling simultaneously by different collectors as estimated by the intraclass correlation coefficient was excellent (81%) for PCR and good (67%) for culture and may justify comparison of quantitative results of samples collected by different investigators. The reliability of environmental sampling over a 5-d period was good (67 and 64% for PCR and culture results, respectively), which justifies the utility of environmental sampling to identify pens with a high MAP bioburden between routine cow pen changes on a dairy. Environmental sampling of free-stall pens using the standardized sampling protocol yielded comparable PCR and culture results across collectors with different experience levels and at different times within a 5-d period.

Multivariate MR biomarkers better predict cognitive dysfunction in mouse models of Alzheimer's disease.

To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.

Thyronamines are substrates for human liver sulfotransferases.

Sulfotransferases (SULTs) catalyze the sulfation of many endogenous compounds that include monoamine neurotransmitters, such as dopamine (DA), and thyroid hormones (iodothyronines). Decarboxylation of iodothyronines results in formation of thyronamines. In the mouse, thyronamines act rapidly in a nongenomic fashion to initiate hypothermia and decrease cardiac output and heart rate. These effects are attenuated after 1-4 h, and metabolism of thyronamines via sulfation may be a mechanism for termination of thyronamine action. We carried out this study to test thyronamine (T0AM), 3-iodothyronamine (T1AM), 3,5-diiodothyronamine (T2AM), and 3,5,3'-triiodothyronamine (T3AM) as substrates for human liver and cDNA-expressed SULT activities. We characterized several biochemical properties of SULTs using the thyronamines that acted as substrates for SULT activities in a human liver high-speed supernatant pool (n=3). T1AM led to the highest SULT activity. Activities with T0AM and T3AM were 10-fold lower, and there was no detectable activity with T2AM. Thyronamines were then tested as substrates with eight cDNA-expressed SULTs (1A1, 1A2, 1A3, 1C2, 1E1, 2A1, 2B1a, and 2B1b). Expressed SULT1A3 had the greatest activity with T0AM, T1AM, and T3AM, whereas SULT1A1 showed similar activity only with T3AM. Expressed SULT1E1 had low activity with each substrate. T1AM, the most active thyronamine pharmacologically, was associated with the greatest SULT activity of the thyronamines tested in the liver pool and in both the expressed SULT1A3 and SULT1E1 preparations. Our results support the conclusion that sulfation contributes to the metabolism of thyronamines in human liver and that SULT activities may regulate the physiological effects of endogenous thyronamines.

ATP receptor regulation of adenylate cyclase and protein kinase C activity in cultured renal LLC-PK1 cells.

In cultured intact LLC-PK1 renal epithelial cells, a nonhydrolyzable ATP analogue, ATP gamma S, inhibits AVP-stimulated cAMP formation. In LLC-PK1 membranes, several ATP analogues inhibit basal, GTP-, forskolin-, and AVP-stimulated adenylate cyclase activity in a dose-dependent manner. The rank order potency of inhibition by ATP analogues suggests that a P2y type of ATP receptor is involved in this inhibition. The compound ATP gamma S inhibits agonist-stimulated adenylate cyclase activity in solubilized and in isobutylmethylxanthine (IBMX) and quinacrine pretreated membranes, suggesting that ATP gamma S inhibition occurs independent of AVP and A1 adenosine receptors and of phospholipase A2 activity. The ATP gamma S inhibition of AVP-stimulated adenylate cyclase activity is not affected by pertussis toxin but is attenuated by GDP beta S, suggesting a possible role for a pertussis toxin insensitive G protein in the inhibition. Exposure of intact LLC-PK cells to ATP gamma S results in a significant increase in protein kinase C activity. However, neither of two protein kinase C inhibitors (staurosporine and H-7) prevents ATP gamma S inhibition of AVP-stimulated adenylate cyclase activity, suggesting that this inhibition occurs by a protein kinase C independent mechanism. These findings suggest the presence of functional P2y purinoceptors coupled to two signal transduction pathways in cultured renal epithelial cells. The effect of P2y purinoceptors to inhibit AVP-stimulated adenylate cyclase activity may be mediated, at least in part, by a pertussis toxin insensitive G protein.

Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.

On the mechanism of polyuria in potassium depletion. The role of polydipsia.

The association of potassium (K) depletion with polyuria and a concentrating defect is established, but the extent to which these defects could be secondary to an effect of low K on water intake has not been systematically investigated. To determine whether hypokalemia has a primary effect to increase thirst and whether any resultant polyuria and polydipsia contribute to the concentrating defect, we studied three groups of rats kept in metabolic cages for 15 days. The groups were set up as follows: group 1, normal diets and ad lib. fluids (n = 12); group 2, K-deficient diet on ad lib. fluids (n = 12); and group 3, K-deficient diet and fluid intake matched to group 1 (n = 14). Daily urine flow and urinary osmolality of groups 1 and 3 were not significantly different throughout the study. In contrast, as of day 6, group 2 rats consistently had a higher fluid intake (P < 0.0025), higher urine flow (P < 0.001), and lower urinary osmolality (P < 0.001) than the other two groups. These alterations in fluid intake and urine flow preceded a defect in maximal concentrating ability. On day 7, maximal urinary osmolality was 2,599+/-138 msmol/kg in rats on K-deficient intake and 2,567+/-142 msmol/kg in controls. To determine whether this primary polydipsia is itself responsible for the development of the concentrating defect, the three groups of rats were dehydrated on day 15. Despite different levels of fluid intake, maximal urinary osmolality was impaired equally in groups 2 and 3 (1,703 and 1,511 msmol/kg, respectively), as compared to rats in group 1 (2,414 msmol/kg), P < 0.001. We therefore conclude that K depletion stimulates thirst, and the resultant increase in water intake is largely responsible for the observed polyuria. After 15 days of a K-deficient diet, the impaired maximal urinary concentration in hypokalemia, however, was not related to increased water intake, since fluid restriction did not abolish the renal concentrating defect.

Evidence for an in vivo antagonism between vasopressin and prostaglandin in the mammalian kidney.

These studies were undertaken to examine whether an antagonism between vasopressin and prostaglandin occurs in vivo in the mammalian kidney. All experiments were performed in steroid-replaced hypophysectonized dogs undergoing a water diuresis. In the first group of studied the effect of two consecutive intravenous doses (100 mU) of vasopressin was examined. The second dose of vasopressin was preceded by an injection of the carrier solution for solubilizing indomethacin or neclofenamate. No enhancement of the antidiuretic effect of the second dose of vasopressin was observed as urinary osmolality (Uosm) increased from 92 +/- 5 to 252 +/- 18 mosmol/kg H2O (P less than 0.0001) after the first dose and from 109 +/- 8 to 209 +/- 10 mosmol/kg H2O (P less than 0.001) after the second dose of vasopressin. In another group of studies the second dose of vasopressin was preceded by the administration of a potent inhibitor of prostaglandin synthesis, indomethacin (2 mg/kg). The Uosm increased from 93 +/- 9 to 244 +/- 33 mosmol/kg H2O (P less than 0.001) after the first dose of vasopressin, but after the second dose of vasopressin the Uosm increased to a significantly greater degree from 106 +/- 14 to 702 +/- 69 mosmol/kg H2O (P less than 0.001). In a third group of studies the antidiuretic effect of the same 100-mU dose of vasopressin was examined before and after the administration of meclofenamate (2 mg/kg), an inhibitor of prostaglandin synthesis which is chemically dissimilar from indomethacin. Uosm increased from 83+/-7 to 216+/-16 mosmol/kg H2O (P less than 0.001) after the first dose and from 101 +/- 8 to 734 +/- 86 mosomol/kg H2O (P less than 0.001) after the second dose of vasopressin. As in the indomethacin studies this enhancement in the antidiuretic effects of vasopressin after inhibition of prostaglanding synthesis was highly significant (P less than 0.001). These results therefore implicate a physiological role of prostaglandin in modulating the hydroosmotic effect of vasopressin in the mammalian kidney.

Mechanism of effect of thoracic inferior vena cava constriction on renal water excretion.

Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (U(osm)) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (C(H2o)) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on U(osm) (87-104 mosmols/kg) and C(H2o) (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on U(osm) was not significant (65-79 mosmols/kg) although C(H2o) decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in C(H2o) and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither U(osm) nor C(H2o) when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on U(osm) is primarily vasopressin mediated while the effect on C(H2o) is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.