Evaluation of unfractionated heparin versus low-molecular-weight heparin and fondaparinux for pharmacologic venous thromboembolic prophylaxis in critically ill patients with cancer.

Essentials Critically ill cancer patients require pharmacologic prophylaxis for venous thromboembolism (VTE). Patients from 566 hospitals in the United States between 2010 and 2014 were included. Low-molecular-weight heparin (LMWH) prophylaxis was not associated in a reduction of VTE rates. LMWH prophylaxis was associated with a reduction in bleeding and heparin induced thrombocytopenia. SUMMARY: Background Critically ill patients with cancer are at increased risk of venous thromboembolism (VTE) from physical and cellular factors, requiring pharmacologic prophylaxis to reduce the risk of VTE. Objectives To assess whether low-molecular-weight heparin (LMWH) prophylaxis reduces in-hospital rates of VTE or improves clinical outcomes compared with unfractionated heparin (UFH) prophylaxis in critically ill patients with cancer. Methods We used a propensity-matched comparative-effectiveness cohort from the Premier Database. Patients aged 18 years or older with a primary diagnosis of cancer, intensive care unit admission and VTE prophylaxis within 2 days of admission between 1 January 2010 and 31 December 2014 were included. Patients were divided into LMWH or UFH prophylaxis groups. Results A total of 103 798 patients were included; 75 321 (72.6%) patients received LMWH and 28 477 (27.4%) patients received UFH. Propensity analysis matched (2 : 1) 42 343 LMWH patients and 21 218 UFH patients. Overall, LMWH was not associated with a decreased incidence of VTE (5.32% vs. 5.50%). LMWH prophylaxis was associated with a reduction in pulmonary embolism (0.70% vs. 0.99%), significant bleeding (13.3% vs. 14.8%) and heparin-induced thrombocytopenia (HIT) (0.06% vs. 0.19%). In non-metastatic solid disease, LMWH was associated with decreased VTE (4.27% vs. 4.84%) and PE (0.47% vs. 0.95%). Conclusions The use of an LMWH for VTE prophylaxis was not associated with a reduction in the incidence of in-hospital VTE as compared with UFH, but was associated with significant reductions in PE, clinically important bleeding events, and incidence of HIT in critically ill patients with cancer.

Predictors of cardiovascular events and associated mortality within two years of kidney transplantation.

BACKGROUND: Cardiovascular disease is the most common cause of death after renal transplantation. Furthermore, acute coronary syndrome (ACS) attributable to coronary artery disease (CAD) accounts for the majority of deaths due to cardiovascular disease posttransplant. While renal transplantation is the treatment of choice for end-stage renal disease, understanding the causes of graft and patient loss is exceedingly important to improve outcomes. METHODS: This observational case-controlled study included 780 patients who underwent a kidney transplant between 1989 and 2001 who experienced early ACS (within 2 years). Patients were compared with controls matched for gender, year of transplant, and age. The primary outcome was the occurrence of an ACS event within 2 years after renal transplantation. RESULTS: Cardiovascular disease was the most common cause of death, with all 13 cardiovascular deaths due to CAD. An additional 15 episodes of nonfatal ACS episodes occurred. Thirty-seven percent of early ACS occurred perioperatively, the majority in the first 3 posttransplant months. On multivariate analysis, diabetes (OR [odds ratio] 5.56; P = .0007), smoking (OR 3.56; P = .034), and prior transplant (OR 2.81; P = .047) were associated with early ACS. CONCLUSIONS: Diabetes, smoking, and prior transplant were significantly associated with early ACS. The majority of events occurred perioperatively or within 3 months of transplant, highlighting the importance of improved screening and perioperative management.

Measurement of decay parameters for Xi- --> Lambda pi- decay.

Based on 1.35 x 10(6) polarized Xi(-) events, we measure the parameter phi(Xi) to be -1.61 degrees +/-2.66 degrees +/-0.37 degrees for the Xi(-)-->Lambda pi(-) decay. New results for the parameters beta(Xi) and gamma(Xi) are also presented. Assuming that the CP-violating phase difference is negligible, we deduce the strong phase difference between the P-wave and S-wave amplitudes of the Lambda pi final state to be 3.17 degrees +/-5.28 degrees +/-0.73 degrees, reducing the uncertainty in estimating the level of CP violation in Xi-hyperon decay.

Effects of water temperature and salinity on parathyroid hormone-related protein in the circulation and tissues of elasmobranchs.

Parathyroid hormone-related protein (PTHrP) is a hypercalcemic factor in mammals. The PTHrP antigen has been localized in both bony and cartilaginous fish tissues. Sites of localization included gills, skin and kidney, organs involved in osmoregulation. Physiological and localization experiments were carried out in elasmobranchs to dissect PTHrP's possible role in osmoregulation. The effects of alterations in the external environment on PTHrP in sharks were examined by keeping juvenile animals under conditions of increased temperature or decreased salinity. There were no alterations in the PTHrP levels in either the circulation or tissues. Significant correlations between plasma PTHrP, electrolyte and urea levels were seen in the pretreatment samples. The localization of PTHrP by immunohistochemistry and in situ hybridization revealed conserved sites of distribution from elasmobranchs to mammals, including skin, kidney, muscle and skeleton.

Noncommutative D-brane in a nonconstant NS-NS B field background.

We show that, when the field strength H of the NS-NS B field does not vanish, the coordinates x and momenta p of open string end points satisfy a set of mixed commutation relations among themselves. Identifying x and p with the coordinates and derivatives of the D-brane world volume, we find a new type of noncommutative space which is very different from those associated with a constant B field background.

Immunodetection of parathyroid hormone-related protein in plasma and tissues of an elasmobranch (Scyliorhinus canicula).

We have used antiserum to human parathyroid hormone-related protein (PTHrP) (1-16) to examine tissues and plasma of the dogfish (Scyliorhinus canicula) for the presence of immunoreactive PTHrP (irPTHrP). The plasma contained high concentrations of irPTHrP (9.34 +/- 0.37 pM), comparable to levels in humans with hypercalcaemia of malignancy. Other tissues with irPTHrP included brain neurones; epithelial cells of the saccus vasculosus, kidney, rectal gland and choroid plexus; and cells of the pituitary pars distalis. PTHrP was not detected in gut, skin, oviduct, and gill epithelia, nor in branchial cartilage. The principal source(s) of plasma PTHrP is not known.

Parathyroid hormone-related protein is a factor in normal fish pituitary.

Using antibodies to the amino-terminal region of human parathyroid hormone-related protein (PTHrP) we have demonstrated PTHrP immunoreactivity in pituitaries and plasma of the sea bream (Sparus aurata). Pituitary cells at two distinct locations contained immunodetectable PTHrP; an anterior group in the rostral pars distalis which also contained immunoreactive thyroid stimulating hormone (TSH), and a posterior group lying at the border of the pars intermedia and proximal pars distalis between cells which stained with antibody to human corticotrophin-like intermediate lobe peptide. By Western blot analysis pituitary extracts contained two immunoreactive isoforms of PTHrP, one of 29 kDa and the other of 26 kDa. Media of pituitaries incubated for up to 14 days in Krebs-Ringer bicarbonate also had several isoforms of immunodetectable PTHrP, two of them corresponding to the 29- and 26-kDa molecular forms but there were in addition both larger and smaller molecules. The concentration of PTHrP in sea bream plasma was comparable with levels observed in human subjects with humoral hypercalcaemia of malignancy. There was no reaction between pituitary cells or pituitary extracts and antibody to human parathyroid hormone. Thus sea bream pituitary contains immunoreactive PTHrP, which appears to be released into medium during in vitro incubation and which may be a significant source of plasma immunoreactive PTHrP in vivo.

Parathyroid hormone-related protein: a possible endocrine function in lactation.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP), initially discovered as the factor responsible for the syndrome of humoral hypercalcaemia of malignancy, has also been found to be expressed in placenta, in pregnant uterus, in the fetus at many locations, and in the lactating mammary gland. This study sought to establish whether PTHrP reaches the maternal circulation when it is expressed in mammary tissue during lactation or in the maternal reproductive tract during gestation. DESIGN: Blood samples were collected from 53 subjects: 18 pregnant women in all stages of gestation, 19 lactating mothers and 16 non-lactating post-partum controls. MEASUREMENTS: PTHrP was measured using a specific and validated radioimmunoassay. Parathyroid hormone was measured by two-site immunoradiometric assay. Total calcium was measured by atomic absorption spectrophotometry. RESULTS: Circulating levels of PTHrP were readily detectable in 12 of 19 nursing mothers (range 2.7-7.8 pmol/l) but in none of the mothers who were bottle feeding. PTHrP was also detected in one of 18 pregnant subjects. Parathyroid hormone concentrations were lower in lactating mothers (2.3 +/- 1.0 pmol/l), than in non-lactating mothers (3.5 +/- 1.2 pmol/l) (P < 0.01). CONCLUSION: PTHrP reaches the maternal circulation during lactation in amounts which could produce a systemic effect.

Behavioral effects of U-78875, a quinoxalinone anxiolytic with potent benzodiazepine antagonist activity.

U-78875 (3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-(1-methylethyl) imidazo[1,5-a]-quinoxalin-4(5H)-one) is a chemically novel compound with a high affinity for the benzodiazepine receptors. It has anticonflict effects in both the Vogel and Cook-Davidson models of anxiety, with a potency similar to that of diazepam (1-3 mg/kg, i.p.). In unanesthetized rats implanted with cortical electrodes for EEG recording, i.p. injections of U-78875 (3-10 mg/kg) increased the EEG power density in frequencies above 12 Hz, and decreased EEG power at lower frequencies. This EEG effect is similar to that of diazepam, and was completely antagonized by pretreatment with flumazenil. In animal models measuring central nervous system depression, U-78875 is much weaker than diazepam. It produced minimal impairment of rotarod performance in rats at doses up to 30 mg/kg, but at lower doses completely reversed the impairment from 10 mg/kg of diazepam. In rats trained to avoid shocks in a shuttle box, U-78875 (3-10 mg/kg) increased avoidance responses and antagonized the suppression of avoidance from diazepam (10 mg/kg). In the mouse one-trial passive avoidance task, pretreatment with U-78875 (1-10 mg/kg) before training produced no anterograde amnesia, but completely blocked the amnesic effect from diazepam (10 mg/kg). The diazepam antagonist potency for U-78875 is 10 to 100 times that of flumazenil. This unusual profile of mixed agonist/antagonist activities suggests U-78875 to be a unique anxiolytic agent with a minimum of central nervous system depression.

Both competitive and non-competitive antagonists of N-methyl-D-aspartic acid disrupt brightness discrimination in rats.

Rats were trained to avoid or escape electric shocks in a symmetrical Y-maze by choosing to enter the brighter of two arms. Pretreatment with phencyclidine-like compounds disrupted brightness discrimination with greatly increased spontaneous locomotor activity between trials. The competitive antagonists of NMDA, 2-amino-7-phosphonoheptanoate (AP7) or 3-(+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) also disrupted brightness discrimination when injected into the cerebral ventricles, with no increase in movements between trials. The results suggest that the competitive antagonists of NMDA may impair sensory and cognitive functions in a manner similar to that produced by the phencyclidine-like compounds.

A specific antagonist of vasopressin produced plasma hyperosmolality and reduced ischemic-induced cerebral edema in rats.

Water diuresis was produced in rats after s.c. injections of d(CH2)5,D-Ile2,Ile4-AVP (compound 1) and d(CH2)5,Tyr(OEt)2Val4-AVP (compound 2). Compound 1 is known to be a more potent antagonist against the antidiuretic effect, while Compound 2 is a more potent antagonist against the vasopressor effect of vasopressin. Compound 1 (but not compound 2) also increased plasma osmolality significantly at the diuretic doses. In rats rendered ischemic of the forebrain by 4-hour occlusion of both common carotid arteries, the resulting increases in brain water were significantly reversed by the injection of compound 1. Compound 2 did not reduce the edema. The results suggests a novel approach to the treatment of cerebral edema.

Growing familiarity with the test situation augments the vigilance deficit of aged rats.

Quantitative EEG profiles of aged and of young-adult Fisher-344 rats were studied over 10 consecutive recording (3 h) sessions. The individual recording sessions were spaced regularly over a 6-week period. In the aged rats, in recordings from both the frontal cortex and dorsal hippocampus, the EEG characteristics of a vigilance deficit state increased in prominence up through 8 recording sessions before a stable level was reached. A similar trend was not seen in the young-adult rats; instead, these rats showed a stable level of spectral voltage output in both leads over the entire period of the 10 recording sessions. Thus, the aged rat brain appears to suffer from a vigilance deficit state which is revealed most clearly by testing under the basal conditions brought about by thoroughly familiarizing the subjects with the test environment.

Arousal deficit shown in aged rat's quantitative EEG and ameliorative action of pramiracetam compared to piracetam.

The basal EEG profile of the aged Fisher-344 rat was consistently different from that of the young rat, showing dominant high voltage slow-wave components. These slow waves were present in both the frontal cerebral cortex and dorsal hippocampus. Absent or greatly attenuated in the aged rat's hippocampal EEG was rhythmic theta activity, which was always dominant in the young awake rat's hippocampus. These EEG differences were clearly apparent only under basal test conditions, i.e., following habituation to the test situation. Pramiracetam sulfate acted strongly to normalize the aged rat's EEG, while the action of piracetam was weak and appeared to undergo tolerance development.

Pharmacologic therapeutic window of pramiracetam demonstrated in behavior, EEG, and single neuron firing rates.

Following oral or intravenous administration, a representative cognition activator drug, pramiracetam sulfate, is shown to have a pharmacologic therapeutic window at three different levels of study: learned behavior, gross EEG activity of the frontal cortex and hippocampus, and firing rate of single hippocampal neurons.

The effect of potassium on the intestinal transport of glucose.

The rate of absorption of glucose, galactose, and 3-0-methylglucose was studied in the rat's small intestine perfused in situ with isosmotic solutions containing these sugars and Na(2)SO(4) or K2SO(4). The presence of high [K(+)] in the lumen enhances absorption of glucose but not that of galactose or of 3-0-methylglucose. The potassium stimulation is apparent at higher glucose concentrations where primarily carrier-mediated diffusion is involved in the translocation. In this case potassium stimulates transport even if it is the only cation in the lumen. The potassium-stimulated intestine produces more glycogen with higher specific activity than the control gut. Lactic acid production by the intestine is markedly enhanced if the intestinal lumen is perfused with a solution containing glucose and high [K(+)]. It is concluded that potassium does not affect permeability or the specific sugar transport system of the gut, but enhances intracellular metabolic disappearance of glucose thereby creating a larger luminal intracellular concentration gradient which in turn enhances the rate of carrier-facilitated entry.