Detection of P2Y(14) protein in platelets and investigation of the role of P2Y(14) in platelet function in comparison with the EP(3) receptor

mRNA encoding the recently discovered P2Y(14) receptor has been reported in platelets, but the presence of P2Y(14) receptor protein and its functionality have not been studied. If P2Y(14) is expressed along with P2Y(1) and P2Y(12) receptors it may have a role in haemostasis. It was the objective of this study to investigate the presence of the P2Y(14) receptor in platelets and its role in platelet function. The effects of the agonist UDP-glucose were compared with those of sulprostone, a selective EP(3) receptor agonist. Expression of P2Y(14) receptor was investigated by immunoblotting and confocal microscopy. Platelet aggregation in platelet-rich plasma (PRP) and whole blood was measured using light absorbance and platelet counting. VASP phosphorylation was investigated using flow cytometry. Immunoblotting provided evidence for P2Y(14) receptor protein and microscopy confirmed its presence on platelets. Despite this, UDP-glucose (up to 100 muM) did not induce platelet aggregation in either PRP or whole blood, and did not potentiate aggregation induced by other agonists. P2Y(14) did not substitute for P2Y(12) in experiments using the P2Y(12) antagonist AR-C69931. No effect of UDP-glucose was seen on adenylate cyclase activity as measured by VASP phosphorylation. In contrast, sulprostone acting via the EP(3) receptor promoted platelet aggregation with effects on adenylate cyclase activity. EP(3) also partially substituted for P2Y(12) receptor. We have demonstrated the presence of P2Y(14) receptor protein in platelets, but no contribution of this receptor to several measures of platelet function has been observed. Further studies are necessary to determine whether the P2Y(14) receptor in platelets has any functionality.     

Grey matter abnormalities in trichotillomania: morphometric magnetic resonance imaging study

BACKGROUND: Trichotillomania (repetitive hair-pulling) is an Axis I psychiatric disorder whose neurobiological basis is incompletely understood. Whole-brain trichotillomania neuroimaging studies are lacking. AIMS: To investigate grey and white matter abnormalities over the whole brain in patients with trichotillomania. METHOD: Eighteen patients with DSM-IV trichotillomania and 19 healthy controls undertook structural magnetic resonance imaging after providing written informed consent. Differences in grey and white matter were investigated using computational morphometry. RESULTS: Patients with trichotillomania showed increased grey matter densities in the left striatum, left amygdalo-hippocampal formation, and multiple (including cingulate, supplementary motor, and frontal) cortical regions bilaterally. CONCLUSIONS: Trichotillomania was associated with structural grey matter changes in neural circuitry implicated in habit learning, cognition and affect regulation. These findings inform animal models of the disorder and highlight key regions of interest for future translational research.     

Increased α1D adrenergic receptor activity and protein expression in the urinary bladder of aged rats

Objectives  A possibility that aging affects (a) expression of the α1D-adrenergic receptor (AR1D), (b) AR1D-mediated contractions and (c) sympathetic innervation in the urinary bladder in rats was studied. Materials and methods  Contraction produced by phenylephrine and inhibition of these contractions by a non-selective α1-adrenergic antagonist prazosin and a selective AR1D antagonist BMY7378 were compared between 6- and 24-month-old Fisher rats. Expressions of VMAT and AR1D in the bladder were assessed by immunofluorescence and Western blot. Results  Phenylephrine-induced contractions were larger and inhibition of these contractions by BMY7378 was significantly greater in 24-month-old rats. Aging increased expression of AR1D in the bladder. Density of VMAT-immunoreactive neurites was decreased in smooth muscle but elevated in the suburothelial region of 24-month-old rats. Conclusions  The results suggest that influence of adrenergic activity on bladder contractility increases with aging is due to overexpression of the AR1D. Influence of adrenergic activity on the urothelial function may also be enhanced with aging.     

Toward understanding the influence of soil metals and sulfate content on plant thiols

Plants respond to increased concentrations of metals by a number of mechanisms, including chelation with phytochelatins (PCs). Soil specimens and plants (Veronica anagalis-aquatica, Typha domingensis, Cynodon dactylon, Chenopodium album, Rumex dentatus, Amaranthus gracilis, Chenopodium murale, Inula viscosa) leaves were collected from two sites in northern Jordan and subsequently metals (cadmium, copper, and lead), sulfate, and PC (from leaves) levels were determined. One of these sites was contaminated with metals and the other served as a control site. The contaminated site had elevated cadmium, copper, lead, and sulfate levels. This increase of metal and sulfate levels in the soil at the contaminated site correlated with a rise in plant total glutathione (GSH(T)) and cysteine (CYS(T)). These increases were not attributed to an elevation in total phytochelatin levels. However, a significant increase in the ratio of short-chain phytochelatins to the total phytochelatin stores was observed. The individual effects of metals and sulfate on glutathione, short-chain PCs and long-chain PCs levels were dissimilar.     

Withanolides from Jaborosa kurtzii

Two new withanolides were isolated and characterized from the aerial parts of Jaborosa kurtzii, namely, jaborosalactone 43 (1), with a spiranoid delta-lactone at C-22, and jaborosalactone 44 (2), a 12-oxowithanolide, which may function as a biosynthetic precursor to 1. These new compounds were fully characterized by a combination of spectroscopic methods. Compound 1 showed selective phytotoxicity toward a dicotyledon species, Lactuca sativa (lettuce).     

Education predicts quality of life among men with prostate cancer cared for in the Department of Veterans Affairs: a longitudinal quality of life analysis from CaPSURE

BACKGROUND: Previous findings have suggested that patient educational attainment is related to cancer stage at presentation and treatment for localized prostate cancer, but there is little information on education and quality of life outcomes. Patient education level and quality of life were examined among men diagnosed with prostate cancer and cared for within an equal-access health care system, the Department of Veterans Affairs Veterans Health Administration (VA). METHODS: Participants were 248 men with prostate cancer cared for in the VA and enrolled in CaPSURE. Repeated-measures analysis of variance was used to examine quality of life over time according to education level, controlling for age, ethnicity, income, site of clinical care, and year of diagnosis. RESULTS: Patients with lower levels of education tended to be younger, nonwhite, and have lower incomes. Controlling for age, ethnicity, income, year of diagnosis, and site, men with less formal education, compared with those with more, had worse functioning in the physical (P=.0248), role physical (P=.0048), role emotional (P=.0089), vitality (P=.0034), mental health (P=.0054), social function (P=.0056), and general health (P=.0002) domains and worse urinary (P=.003) and sexual (P=.0467) side effects. CONCLUSIONS: Men with less education experienced worse health-related quality of life across a wide range of domains and greater urinary and sexual symptoms than their peers who had more education. Clinicians should be aware that, even within an equal access to health care system, men with less education are vulnerable, having greater difficulty functioning in their daily lives after their prostate cancer treatment.     

Hemigramicidin-TEMPO conjugates: novel mitochondria-targeted anti-oxidants

Oxidative damage to various cellular constituents (such as, proteins and lipids) mediated by reactive oxygen species (ROS) is thought to be an important mechanism underlying the pathogenesis of a variety of acute and chronic diseases. Mitochondria are the main source of ROS within most cells. Accordingly, there is increasing interest in the development of pharmacological ROS scavengers, which are specifically targeted to and concentrated within mitochondria. Numerous compounds with these general characteristics have been synthesized and evaluated in a variety of in vitro and in vivo models of redox stress. Among the more promising of these mitochondria-targeted anti-oxidants are those that employ various peptides (or peptide-like moieties) derived from the antibiotic, gramicidin S, as the targeting construct and employ the stable free radical, 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl (4-NH(2)-TEMPO), as the ROS scavenging "payload." One of these hemigramicidin-TEMPO conjugates, XJB-5-131, has been shown to ameliorate intestinal mucosal injury and prolong survival in rats subjected to lethal hemorrhage.     

Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men

INTRODUCTION: Fibroblast growth factor (FGF-23) is a novel phosphaturic factor. Current data suggest that serum phosphate, dietary phosphate and 1,25 dihydroxyvitamin D regulate circulating FGF-23 levels in vivo. We examined if hypogonadism-induced increases in serum phosphate are associated with increases in circulating FGF-23 in healthy men in the absence of dietary manipulation. MATERIALS AND METHODS: 25 healthy men were administered goserelin acetate (GnRH analog) 3.6 mg subcutaneously every 4 weeks for 12 weeks to induce acute testosterone and estrogen deficiency. Subjects consumed an ad libitum diet. Morning fasting blood and urine samples were collected to measure serum phosphate, serum intact FGF-23, PTH, and the maximum tubular reabsorption of phosphate (T(m)P/GFR) at baseline, weeks 4 and 12. The changes in serum FGF-23 and phosphate at weeks 4 and 12 were compared to baseline using paired t-tests. RESULTS: Goserelin therapy decreased mean serum testosterone levels from 543+/-160 ng/dL to 33+/-15 ng/dL at week 4 (p<0.001), and to 20+/-10 ng/dL at week 12 (p<0.001). Serum phosphate increased significantly from 3.4+/-0.6 mg/dL to 3.9+/-0.4 mg/dL at week 4 (p=0.002), and to 4.3+/-0.4 mg/dL at week 12 (p<0.001). T(m)P/GFR increased significantly from 3.2+/-0.6 mg/dL to 3.6+/-0.5 mg/dL at week 4 (p<0.004), and to 4.1+/-0.6 mg/dL at week 12 (p<0.001). FGF-23 levels, however, did not change during the 12-week study. CONCLUSIONS: Gonadal steroid deprivation increased serum phosphate levels in men but did not affect serum FGF-23 concentrations. The absence of any change in circulating FGF-23 suggests that supraphysiologic levels of serum phosphate may be required to stimulate circulating FGF-23 or that FGF-23 production is primarily sensitive to changes in dietary phosphate or 1,25 dihydroxyvitamin D within this physiologic serum phosphate range.