Opportunistic Infections in Biological Therapy, Risk and Prevention.

Patients being treated with biological therapies are at increased risk for serious infections, including opportunistic infections. Although more is known about opportunistic infection risk with older biologics, such as antitumor necrosis factor drugs, there is less knowledge of opportunistic infection risk with newer biological therapies. The incidence of certain opportunistic infections (tuberculosis, herpes zoster, pneumocystosis) has been rigorously evaluated in large observational studies. However, data are more limited for other infections (histoplasmosis, nontuberculous mycobacteria). Infectious morbidity and mortality may be preventable with screening and prophylaxis in select populations.

Buffer Standards for the Physiological pH of the Zwitterionic Compound, ACES from 5 to 55°C.

The values of the second dissociation constant pK2 and related thermodynamic quantities of [N-(2-acetamido)-2-aminoethanesulfonic acid] (ACES) have already been reported over the temperature range 5 to 55°C including 37°C. This paper reports the paH values of four chloride ion free buffer solutions and eight buffer solutions with I = 0.16 mol·kg -1, matching closely to that of the physiological sample. Conventional paH values for all twelve buffer solutions from 5 to 55°C, are reported. The residual liquid junction potential correction for two widely used temperatures, 25 and 37°C, has been made. The flowing-junction calomel cell method has been utilized to measure Ej , the liquid junction potential. The operational pH values for four buffer solutions at 25 and 37°C are calculated using the physiological phosphate buffer standard based on NBS/NIST convention. These solutions are recommended as pH standards in the pH range of 6.8 to 7.2 for physiological fluids.

First look at the effect of overexpression of TIGR/MYOC on the transcriptome of the human trabecular meshwork.

Wild-type TIGR/MYOC is a secreted protein implicated in the development of steroid glaucoma. Mutations in TIGR/MYOC have been linked to some patients who develop elevated intraocular pressure (IOP) and glaucoma. Because there is evidence of some other factors contributing to the TIGR/MYOC causative role in glaucoma, and because substantial increased levels of a particular cellular mRNA and protein might alter expression of other host genes, we began to investigate the effect of TIGR/MYOC overexpression on the transcriptome of human trabecular meshwork cells. We used a recombinant adenovirus carrying wild-type TIGR/MYOC cDNA, primary HTM cells, 300 viral particles per cell and U133 Affymetrix GeneChips. Our results indicate that 2361 out of the 22,284 genes (10.6%) were altered more than two-fold (p

Social and environmental influences on opioid sensitivity in rats: importance of an opioid's relative efficacy at the mu-receptor.

RATIONALE: Evidence indicates that social and environmental enrichment can influence the functional maturation of the central nervous system and may affect an organism's sensitivity to centrally acting drugs. OBJECTIVE: The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to mu-opioids possessing a range of relative efficacies at the mu-receptor. METHODS: Rats were obtained at weaning (21 days) and divided into two groups immediately upon arrival. Isolated rats were housed individually in opaque laboratory cages with no visual or tactile contact with other rats; enriched rats were housed socially in groups of four in large cages and given various novel objects on a daily basis. After 6 weeks under these conditions, the effects of morphine, levorphanol, buprenorphine, butorphanol, and nalbuphine were examined in the warm-water, tail-withdrawal procedure and the place-conditioning procedure. RESULTS: In the tail-withdrawal procedure, isolated and enriched rats did not differ in sensitivity to morphine (1.0-30 mg/kg) and levorphanol (0.3-10 mg/kg), but enriched rats were more sensitive to buprenorphine (0.03-3.0 mg/kg), butorphanol (0.3-30 mg/kg), and nalbuphine (0.3-30 mg/kg). In drug combination tests, butorphanol and nalbuphine antagonized the effects of morphine in isolated rats under conditions in which they produced high levels of antinociception in enriched rats. In the place-conditioning procedure, doses of 10 morphine and 3.0 levorphanol established a place preference in both groups of rats, whereas doses of 0.3 buprenorphine, 3.0 butorphanol, and 10 nalbuphine established a place preference only in enriched rats. CONCLUSIONS: These findings may be taken as evidence that enriched rats are more sensitive than isolated rats to the effects of lower-efficacy mu-opioids and that social and environmental enrichment leads to functional alterations in opioid receptor populations.

Sensitivity to the effects of a kappa opioid in rats with free access to exercise wheels: differential effects across behavioral measures.

It is well established that chronic exercise decreases sensitivity to mu opioid agonists; however, it is less clear what effects it has on kappa opioids. The purpose of the present study was to examine sensitivity to the effects of the selective, kappa opioid spiradoline in rats with free access to exercise wheels. Rats were obtained at weaning and randomly assigned to either standard polycarbonate cages (sedentary) or modified cages equipped with exercise wheels (exercise). After approximately 7 weeks under these conditions, sensitivity to the effects of spiradoline on tests of antinociception, locomotor activity, conditioned place preference, and diuresis were examined in both groups of rats. Sedentary rats were more sensitive than exercising rats to the antinociceptive effects of spiradoline, and this effect was observed at both low and high nociceptive intensities. In contrast, exercising rats were more sensitive than sedentary rats to the diuretic effects of spiradoline, and slightly more sensitive to spiradoline's effects in the conditioned place preference procedure. No differences in sensitivity were observed to the effects of spiradoline on locomotor activity. Sensitivity to the antinociceptive effects of spiradoline nonsignificantly increased in exercising rats that were reassigned to sedentary housing conditions, and changes in spiradoline sensitivity were correlated with exercise output in individual subjects. Collectively, these data suggest that exercise alters sensitivity to the behavioral effects of kappa opioids, but that the direction and magnitude of this effect depends on the behavioral measure examined.

Social and environmental enrichment enhances sensitivity to the effects of kappa opioids: studies on antinociception, diuresis and conditioned place preference.

Previous studies have reported that social and environmental enrichment can have a marked impact on the functional maturation of the central nervous system and may influence an organism's sensitivity to psychotropic drugs. The purpose of the present study was to examine the effects of social and environmental enrichment on sensitivity to drugs possessing activity at the kappa opioid receptor. Rats were obtained at weaning and randomly assigned to one of two housing conditions: isolated rats were housed individually with no visual or tactile contact with other rats; enriched rats were housed in groups of four in large cages and given various novel objects on a regular basis. After 7 weeks under these conditions, the effects of spiradoline, U69,593 and nalorphine were examined in the warm water, tail-withdrawal procedure. The effects of spiradoline were also examined on urine output and in the conditioned place preference procedure. Enriched rats were more sensitive to the antinociceptive effects of all the opioids examined in the tail-withdrawal procedure, and were more sensitive to the effects of spiradoline on urine output and in the conditioned place preference procedure. Following the conclusion of these tests, housing conditions were reassigned, such that isolated rats were transferred to enrichment cages, and enriched rats were transferred to isolation cages. After 7 weeks under these new conditions, the two groups were equally sensitive to the antinociceptive effects of spiradoline, indicating that the effects of the initial housing conditions were, in part, reversible. Collectively, these data suggest that enriched rats are more sensitive than isolated rats to the effects of kappa opioids, and that the kappa opioid receptor system is sensitive to social and environmental manipulations after weaning.

Interactions between opioids and cocaine on locomotor activity in rats: influence of an opioid's relative efficacy at the mu receptor.

RATIONALE: Cocaine and mu opioid agonists increase central dopamine concentrations and produce robust interactions at both neurochemical and behavioral levels. Although the interactions between cocaine and high-efficacy mu opioids have been well characterized, the interactions between cocaine and lower efficacy opioids have not been as extensively examined. OBJECTIVE: The purpose of this study was to examine the interactions between cocaine and opioids possessing a range of relative efficacy at the mu receptor. METHODS: Male, Long-Evans rats were habituated to an open-field, locomotor activity chamber, and the effects of cocaine and various opioids were tested under a cumulative dosing procedure. In this procedure, a selected dose of an opioid was administered during the first component of a session, with increasing doses of cocaine administered during subsequent components. RESULTS: When administered alone, cocaine produced dose-dependent increases in locomotor activity that was stable across 5 weeks of behavioral testing. The high-efficacy mu opioid levorphanol, and the low-efficacy opioids buprenorphine, butorphanol, nalbuphine and (-)-pentazocine, dose-dependently enhanced the effects of cocaine at doses that did not alter locomotor activity when administered alone. In contrast, the opioid antagonist naloxone, and to a lesser extent, the kappa opioid spiradoline attenuated the effects of cocaine at doses that did not alter locomotor activity when administered alone. Across an extensive dose range, the low-efficacy opioid nalorphine failed to alter cocaine's locomotor-activating effects. CONCLUSIONS: These data suggest that low-efficacy opioids possessing significant mu-agonist activity (e.g. buprenorphine, butorphanol, nalbuphine, (-)-pentazocine) may potentiate the effects of cocaine in a manner similar to that typically observed with high-efficacy mu opioids.