Quantitative studies of human urinary excretion of uropontin. Uropontin is the urinary form of osteopontin, an aspartic acid-rich phosphorylated glycoprotein. Uropontin has been previously shown to ...be a potent inhibitor of the nucleation, growth and aggregation of calcium oxalate crystals and the binding of these crystals to renal epithelial cells. Quantitative data defining the excretion of this protein are necessary to determine its role in urinary stone formation. In the present studies, we determined uropontin excretion rates of normal humans. Urine samples were obtained under conditions of known dietary intake from young adult human volunteers with no history, radiographic or laboratory evidence of renal disease. Urinary concentrations of uropontin were measured by a sensitive ELISA employing an affinity purified polyclonal antiserum to uropontin. Thirteen normal subjects ingested a constant diet providing 1 gram of calcium, 1 gram of phosphorus, 150mEq of sodium and 1 gram of protein per kilogram of body wt per day during an eight day study period. The relationship of urinary volume to uropontin excretion was assessed by varying fluid intake on the last four days of the study to change the mean urine volume/24hr by > 500ml. Urine collected in six hour aliquots for eight days was analyzed for uropontin by ELISA, and for calcium, and creatinine. Daily uropontin excretion of 13 individual subjects was 3805 ± 1805 μg/24hr (mean ± 1 SD). The mean urinary levels (1.9 μg/ml) detected in the present study are sufficient for inhibition of crystallization; our previous studies have demonstrated that the nucleation, growth and aggregation of calcium oxalate crystals and their binding to renal cells in vitro are inhibited by this concentration of purified uropontin. In contrast to the regular pattern of diurnal variation of calcium excretion seen in most subjects, uropontin excretion showed no regularity of diurnal variation and was not directly related to either calcium or creatinine excretion or changes in urinary volume. However, uropontin concentration varied inversely with urine volume (P ≤ 0.001), so that the highest uropontin concentrations occurred when urine volume was the lowest. We conclude that the physiologic characteristic of an inverse relationship of uropontin concentration to urine volume favors protection from urinary crystallization of calcium oxalate by uropontin. Our quantitative definition of urinary uropontin excretion of normal adults provides the basis for the evaluation of uropontin excretion by individuals who have formed urinary stones.
Global Positioning System (GPS) observations between 1994 and 2000 at twenty‐two sites in the Lesser Antilles and northern South‐America indicate that the Caribbean plate, along its southern ...boundary, slips at a rate of 20.5±2 mm/a with an azimuth of N 84°±2°E at 65°W, relative to the South‐American plate. East of 68° W, 80% of the dextral slip is contained within a 80‐km wide shear zone centered on the El Pilar‐San Sebastián fault system. West of 68° W the plate boundary broadens to more than 300 km with dextral shear shared between the northeast trending Boconó fault (9–11 mm/a) in western Venezuelan, and an offshore system near the northern coast.
4-Vinyl-1-cyclohexene (VCH) is ovotoxic in B6C3F(1) mice but not in Fischer-344 rats, which can be partially attributed to greater formation of toxic epoxides from VCH in mice compared with rats. ...Since repeated exposure to VCH is necessary to cause ovotoxicity in mice, it is important to determine whether repeated exposure results in induction of cytochrome P450 (CYP) enzymes involved in its bioactivation. Hepatic microsomes prepared from mice or rats treated repeatedly with VCH demonstrated significantly increased VCH bioactivation in vitro, as assessed by VCH-1,2-epoxide, VCH-7,8-epoxide, or vinylcyclohexene diepoxide (VCD) formation. Mice and rats were then dosed with VCH, VCH-1,2-epoxide, or VCD for 10 days and measured for increases in hepatic microsomal CYP levels or activities. Total hepatic CYP levels were elevated only in microsomes from mice pretreated with VCH or VCH-1,2-epoxide. Immunoblotting analysis of microsomes from VCH-treated rodents revealed elevated levels of CYP2A and CYP2B in mice but not rats. VCH-1,2-epoxide pretreatment also increased CYP2B levels in the mouse. Activities toward specific substrates for CYP2A and CYP2B (coumarin and pentoxyresorufin, respectively) confirmed that VCH and VCH-1,2-epoxide pretreatments resulted in increased catalytic activities of CYP2A and CYP2B in the mouse but not the rat. Pretreatment with phenobarbital, a known inducer of CYP2A and CYP2B, increased VCH bioactivation in both species. Interestingly, metabolism studies with human CYP "Supersomes" reveal that, of eight isoforms tested, only human CYP2E1 and CYP2B6 were capable of significantly catalyzing VCH epoxidation, whereas CYP2B6, CYP2A6, CYP2E1, and CYP3A4 were capable of catalyzing the epoxidation of the monoepoxides.
The nosocomial pathogen
forms biofilms on medical devices that persist in the face of antifungals and host defenses. Echinocandins, the most effective antibiofilm drugs, have recently been shown to ...augment the activity of neutrophils against biofilms through an unknown mechanism. Here, we show that treatment of
biofilms with subinhibitory concentrations of echinocandins promotes the formation of neutrophil extracellular traps (NETs), structures of DNA, histones, and antimicrobial proteins with antifungal activity.
In order to test the hypothesis that an imbalance between energy requirement and energy supply regulates mitochondrial genes and ultimately mitochondrial biogenesis, energy supply was challenged in ...HepG2 cells by withdrawal of glucose from the culture medium, making the cells exclusively dependent on mitochondrial ATP production. Such cells showed a 2-fold increase of cytochrome c oxidase activity, elevated levels of mitochondrial DNA, mitochondrial DNA encoded mRNAs and proteins, as well as the nuclear encoded mitochondrial transcription factor A. Lactate production was significantly reduced and glutamine was consumed as an alternative substrate for oxidative metabolism. Long-term adapted cells formed exclusively monolayers, while they normally grow in multilayers forming tumor spheroids. Also, long-term adapted cells proliferated significantly faster. No differences for the ATP/ADP ratio were observed, indicating that this is not the primary signal initiating the adaptative processes. These results show that mitochondrial biogenesis and oxidative metabolism are stimulated in HepG2 cells grown in the absence of fermentable glucose, probably in order to compensate for the diminished supply of glycolytic ATP.
The selective non-peptide NK(1) receptor antagonist NKP608 has been shown to exert potent anxiolytic-like effects in the rat and gerbil social interaction tests. In vitro binding of NKP608 in ...cortical, striatal and rest-of-brain tissue samples from mice, rats and gerbils indicated comparable pIC(50) values for rats and mice (in all three tissues) and only slightly higher values for gerbils. It would therefore be expected that doses previously found to produce anxiolytic-like effects in rats and gerbils would also be active in mice. The present study evaluated NKP608 in one of the most widely-used animal models of anxiety, the mouse elevated plus-maze. Two consecutive experiments were conducted in which the effects of NKP608 (0.0003-10.0 mg/kg, p.o.) were compared to those produced by the prototypical benzodiazepine anxiolytic, chlordiazepoxide (CDP, 15 mg/kg, p.o.). Ethological scoring methods were used to provide comprehensive behavioural profiles for each compound. In both experiments, acute CDP treatment resulted in significant anxioselective effects, i.e., reductions in measures of open arm avoidance without any alteration in general activity levels (closed arm entries and rearing). Although the results of Experiment 1 (0.001-10.0 mg/kg NKP608) suggested a weak anxiolytic-like action of NKP608 at 0.001 mg/kg (significant increase in percent open arm entries), Experiment 2 failed both to replicate this effect or to find any behavioural activity at lower (0.0003 mg/kg) or higher (0.03 mg/kg) doses. Present findings suggest that the anxiolytic efficacy of this NK(1) receptor antagonist may be test-specific and thus limited to particular subtypes of anxiety. These new data are also discussed in relation to the general difficulty of relating the behavioural profiles of NK(1) receptor antagonists to their potency at NK(1) receptors.
A sedentary lifestyle, chronic inflammation and leukocytosis increase atherosclerosis; however, it remains unclear whether regular physical activity influences leukocyte production. Here we show that ...voluntary running decreases hematopoietic activity in mice. Exercise protects mice and humans with atherosclerosis from chronic leukocytosis but does not compromise emergency hematopoiesis in mice. Mechanistically, exercise diminishes leptin production in adipose tissue, augmenting quiescence-promoting hematopoietic niche factors in leptin-receptor-positive stromal bone marrow cells. Induced deletion of the leptin receptor in Prrx1-creER
; Lepr
mice reveals that leptin's effect on bone marrow niche cells regulates hematopoietic stem and progenitor cell (HSPC) proliferation and leukocyte production, as well as cardiovascular inflammation and outcomes. Whereas running wheel withdrawal quickly reverses leptin levels, the impact of exercise on leukocyte production and on the HSPC epigenome and transcriptome persists for several weeks. Together, these data show that physical activity alters HSPCs via modulation of their niche, reducing hematopoietic output of inflammatory leukocytes.
Social isolation and loneliness are associated with increased mortality and higher health care spending in older adults. Hearing loss is a common condition in older adults and impairs communication ...and social interactions. The objective of this review is to summarize the current state of the literature exploring the association between hearing loss and social isolation and/or loneliness.
PubMed, Embase, CINAHL Plus, PsycINFO, and the Cochrane Library.
Articles were screened for inclusion by 2 independent reviewers, with a third reviewer for adjudication. English-language studies of older adults with hearing loss that used a validated measure of social isolation or loneliness were included. A modified Newcastle-Ottawa Scale was used to assess the quality of the studies included in the review.
Of the 2495 identified studies, 14 were included in the review. Most of the studies (12/14) were cross-sectional. Despite the heterogeneity of assessment methods for hearing status (self-report or objective audiometry), loneliness, and social isolation, most multivariable-adjusted studies found that hearing loss was associated with higher risk of loneliness and social isolation. Several studies found an effect modification of gender such that among women, hearing loss was more strongly associated with loneliness and social isolation than among men.
Our findings that hearing loss is associated with loneliness and social isolation have important implications for the cognitive and psychosocial health of older adults. Future studies should investigate whether treating hearing loss can decrease loneliness and social isolation in older adults.
Chemotherapy-induced damage of hematopoietic stem and progenitor cells (HSPC) causes multi-lineage myelosuppression. Trilaciclib is an intravenous CDK4/6 inhibitor in development to proactively ...preserve HSPC and immune system function during chemotherapy (myelopreservation). Preclinically, trilaciclib transiently maintains HSPC in G1 arrest and protects them from chemotherapy damage, leading to faster hematopoietic recovery and enhanced antitumor immunity.
This was a phase Ib (open-label, dose-finding) and phase II (randomized, double-blind placebo-controlled) study of the safety, efficacy and PK of trilaciclib in combination with etoposide/carboplatin (E/P) therapy for treatment-naive extensive-stage small-cell lung cancer patients. Patients received trilaciclib or placebo before E/P on days 1-3 of each cycle. Select end points were prespecified to assess the effect of trilaciclib on myelosuppression and antitumor efficacy.
A total of 122 patients were enrolled, with 19 patients in part 1 and 75 patients in part 2 receiving study drug. Improvements were seen with trilaciclib in neutrophil, RBC (red blood cell) and lymphocyte measures. Safety on trilaciclib+E/P was improved with fewer ≥G3 adverse events (AEs) in trilaciclib (50%) versus placebo (83.8%), primarily due to less hematological toxicity. No trilaciclib-related ≥G3 AEs occurred. Antitumor efficacy assessment for trilaciclib versus placebo, respectively, showed: ORR (66.7% versus 56.8%, P = 0.3831); median PFS 6.2 versus 5.0 m; hazard ratio (HR) 0.71; P = 0.1695; and OS (10.9 versus 10.6 m; HR 0.87; P = 0.6107).
Trilaciclib demonstrated an improvement in the patient's tolerability of chemotherapy as shown by myelopreservation across multiple hematopoietic lineages resulting in fewer supportive care interventions and dose reductions, improved safety profile, and no detriment to antitumor efficacy. These data demonstrate strong proof-of-concept for trilaciclib's myelopreservation benefits.
NCT02499770.
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