Aim
Cystic fibrosis patients have an increased risk of developing metabolic alkalosis presumably as a result of altered renal HCO3− handling. In this study, we directly assess the kidneys’ ability to ...compensate for a chronic base‐load in the absence of functional CFTR.
Methods
Comprehensive urine and blood acid‐base analyses were done in anaesthetized WT mice or mice lacking either CFTR or pendrin, with or without 7 days of oral NaHCO3 loading. The in vivo experiments were complemented by a combination of immunoblotting and experiments with perfused isolated mouse cortical collecting ducts (CCD).
Results
Base‐loaded WT mice maintained acid‐base homeostasis by elevating urinary pH and HCO3− excretion and decreasing urinary net acid excretion. In contrast, pendrin KO mice and CFTR KO mice were unable to increase urinary pH and HCO3− excretion and unable to decrease urinary net acid excretion sufficiently and thus developed metabolic alkalosis in response to the same base‐load. The expression of pendrin was increased in response to the base‐load in WT mice with a paralleled increased pendrin function in the perfused CCD. In CFTR KO mice, 7 days of base‐loading did not upregulate pendrin expression and apical Cl−/HCO3− exchange function was strongly blunted in the CCD.
Conclusion
CFTR KO mice develop metabolic alkalosis during a chronic base‐load because they are unable to sufficiently elevate renal HCO3− excretion. This can be explained by markedly reduced pendrin function in the absence of CFTR.
Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has ...been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed “side population cells,” which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the “side population” phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.
A sixty‐day feeding trial was conducted to elucidate the effect of coated and uncoated crystalline amino acid mix (CAA) in Penaeus monodon. The control diet (CNT) was formulated with 250 g/kg ...fishmeal, and three more test diets were prepared by replacing 50% (125 g/kg) of fishmeal (w/w) using a blend of plant proteins with no supplementation of CAA (AA‐NL), supplementation of uncoated (AA‐NC) and coated (AA‐CT) CAA. The AA‐CT diet showed (p < .05) lower leaching of amino acids (1.13%) than other diets (2.78%–3.04%). DGC was high (p < .05) in shrimp fed on CNT and AA‐CT (1.48%–1.49%/day) than other groups (1.32%–1.37%/day). Of all the treatments, FCR was poor (p < .05) in AA‐NL (2.25). The dietary treatments did not influence survival (p = .841) and whole‐body composition. The peak of free amino acid was synchronized (60 min) between AA‐CT and CNT groups. The control group showed a higher nitrogen intake, oxygen consumption and O:N ratio and lower ammonia‐N excretion. Haemolymph indices varied (p < .05) among the dietary groups. As a result of the N‐metabolism study, the experimental diets were ranked as CNT>AA‐CT>AA‐NC. In conclusion, a blend of CAA could be effective in formulating low‐fishmeal diets and could replace 50% (125 g/kg) of dietary fishmeal using a plant protein mix in P. monodon.
Urinary metals are considered measures of long-term exposures of metals, such as cadmium (Cd). Some studies indicate reduced renal function may affect the urinary excretion of several metals in ...general population making assessments difficult.
To examine whether reduced renal function is associated with reduced urinary excretion of 12 metals or their metabolites and, in turn, an underestimated measure of Cd in general population.
We conducted analyses using data from the National Health and Nutrition Examination Survey (NHANES) 2003–2012. Multiple linear regression models were used to examine the associations between urinary metal levels and estimated glomerular filtration rate (eGFR). Restricted cubic spline regression models were used to evaluate the nonlinearity.
Urinary metal levels significantly increased (p < 0.001) with increasing eGFR, except for antimony (p = 0.172). Urinary levels of arsenic, dimethylarsonic acid, cobalt, molybdenum and tungsten increased linearly with eGFR, while Cd, lead, mercury, barium, cesium and thallium increased nonlinearly (p < 0.001) with eGFR. Based on a restricted cubic spline regression model, we found, corresponding to a fixed blood Cd adverse cutpoint of 5 μg/L, predicted urinary Cd cutpoints substantially varied from 0.78–1.21 μg/g for urinary Cd between those aged <40 years and who had chronic kidney disease and those aged 60 years or over with normal renal function, respectively.
Reduced renal function is associated with reduced urinary metals; and associations are also observed across the eGFR range not just in the reduced range. Urinary abnormal cutpoints of metals are likely dependent on eGFR and age. The associations between urinary exposure of metals and disease risk are likely underestimated without considering the modifying effect of renal function.
•Reduced renal function is associated with reduced urinary excretion of metals.•Urinary metals decrease with declining renal function linearly or non-linearly.•Urinary cutpoints of abnormal metals exposure are age and renal function dependent.•Our findings further support the hypothesis of reverse causality.•Modifying effect of renal function should be considered in health risk assessment.
Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma. Schistosomes have a complex life-cycle involving infections of ...an aquatic snail intermediate host and a definitive mammalian host. In humans, adult male and female worms lie within the vasculature. Here, they propagate and eggs are laid. These eggs must then be released from the host to continue the life cycle.
and
reside in the mesenteric circulation of the intestines with egg excreted in the feces. In contrast,
are present in the venus plexus of the bladder, expelling eggs in the urine. In an impressive case of exploitation of the host immune system, this process of Schistosome "eggs-iting" the host is immune dependent. In this article, we review the formation of the egg granuloma and explore how
eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces. We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism.
During drug discovery and prior to the first human dose of a novel candidate drug, the pharmacokinetic (PK) behavior of the drug in humans is predicted from preclinical data. This helps to inform the ...likelihood of achieving therapeutic exposures in early clinical development. Once clinical data are available, the observed human PK are compared with predictions, providing an opportunity to assess and refine prediction methods. Application of best practice in experimental data generation and predictive methodologies, and a focus on robust mechanistic understanding of the candidate drug disposition properties before nomination to clinical development, have led to maximizing the probability of successful PK predictions so that 83% of AstraZeneca drug development projects progress in the clinic with no PK issues; and 71% of key PK parameter predictions 64% of area under the curve (AUC) predictions; 78% of maximum concentration (Cmax) predictions; and 70% of half-life predictions are accurate to within twofold. Here, we discuss methods to predict human PK used by AstraZeneca, how these predictions are assessed and what can be learned from evaluating the predictions for 116 candidate drugs.
It is now universally recognized that an acceptable human PK profile increases the probability of a candidate drug becoming a successful therapy.A variety of tools are available to predict human PK behavior in advance of clinical data, including scaling clearance from in vitro metabolic stability data, and physiologically based scaling of volume of distribution.To improve PK prediction methods, it is crucial to continually assess the performance of predictions with first-time-in-human PK data for new candidate drugs.To date, AstraZeneca have compared observed PK to predictions for 116 candidate drugs, and since the launch of our five-dimensional framework in 2011, we have driven sustained improvements in the quality of PK predictions.
Heat stress has become a serious problem in poultry industry along with rising of the global temperatures. High environmental temperature causes deleterious impacts on physiology and immunology of ...poultry and impairs their productivity. Heat stress is linked to compromised productivity through a decline in growth rate, feed utilization, blood biochemistry and immunity. In addition, heat stress induced adverse effects on mineral balance of birds and the extent of such effects depended on the type of mineral and the severity of heat stress. Exposure of broilers to high temperature adversely affects mineral metabolism and their excretion route and reduced the retention of some minerals like P, Na, K, S, Mg, Mn, Zn and Cu. On the other hand, the effect of climate on intestinal microbiota has been described in a number of studies. Where, exposure to heat stress can also increase the colonization of Salmonella in the intestine and increase the susceptibility of birds to E. coli and change ileal contents. It is also characterized by decreased antioxidant enzymes in poultry species, resulting in increased oxidative stress that means presence of reactive oxygen species (ROS) in excess of the available antioxidant capacity of animal cells. However, further studies are still required to increase the information and knowledge of basic mechanisms associated with the consequences of heat stress on poultry. This article focuses on the scientific evidence available on the negative role of heat stress on physiological responses, biochemical blood parameters, immunity, antioxidant, mineral balance, acid-base balance, osmoregulation, body and rectal temperature, intestinal and ileal microbiota as well as the parameters related to thyroid, liver and kidney functions in some poultry species.
•Heat-related stress has become a serious problem in poultry industry.•Heat stress causes deleterious impacts on physiology and immunology.•High ambient temperature decreased antioxidant enzymes in poultry species.•Heat stress increased oxidative stress that means presence of ROS.•ROS altered many cellular macromolecules inducing oxidative damage to lipid and protein.
Background In China, high sodium and low potassium intakes result in elevated blood pressure, a major cause of cardiovascular disease, yet the intake estimates lack accuracy and nutritional ...strategies remain limited. Methods and Results We aimed to determine sodium and potassium intake by systematically searching for and quantitatively summarizing all published 24-hour urinary sodium and potassium data (ie, the most accurate method). MEDLINE , EMBASE , Scopus, China National Knowledge Infrastructure, and Wanfang were searched up to February 2019. All studies reporting 24-hour urinary sodium or potassium in China were included; hospitalized patients were excluded. Data were pooled using random-effects meta-analysis and heterogeneity was explored with meta-regression. Sodium data were reported in 70 studies (n=26 767), 59 of which also reported potassium (n=24 738). Mean sodium and potassium excretions were 86.99 mmol/24 h (95% CI , 69.88-104.10) and 14.65 mmol/24 h (95% CI , 11.10-18.20) in children aged 3 to 6 years, 151.09 mmol/24 h (95% CI , 131.55-170.63) and 25.23 mmol/24 h (95% CI , 22.37-28.10) in children aged 6 to 16 years, and 189.07 mmol/24 h (95% CI , 182.14-195.99) and 36.35 mmol/24 h (95% CI , 35.11-37.59) in adults aged >16 years. Compared with southern China, sodium intake was higher in northern China ( P<0.0001) but is declining ( P=0.0066). Conclusions Average sodium intake in all age groups across China is approximately double the recommended maximum limits, and potassium intake is less than half that recommended. Despite a decline, sodium intake in northern China is still among the highest in the world, and the North-South divide persists. Urgent action is needed to simultaneously reduce sodium and increase potassium intake across China.
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