Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs

Brachytherapy by embolization with radiotherapeutic microspheres following intraarterial infusion of a radiosensitizer represents an attempt to combine several selective modalities into a more potent, focused attack on regionally confined tumors. In pursuit of this goal, we examined the ability of foxhounds with surgically implanted hepatic arterial (HA) delivery systems to tolerate a clinically relevant dosage of HA yttrium-90 (Y-90) by microsphere administration either alone or preceded by a 28-day constant HA infusion of either 5-bromo-2'-deoxyuridine (BUDR) or a control solution. Five dogs received BUDR (10 mg/kg/day) and five a control buffer infusion for 28 days immediately prior to the administration of Y-90-coated 15 micron resin microspheres (equivalent of 5000 rads to the entire liver) to each dog on day 31. In all animals, blood counts, bilirubin, amylase, appetite, weight, and behavior remained unchanged. Dogs receiving the microspheres after buffer infusion alone exhibited no hepatic enzyme alanine aminotransferase or alkaline phosphatase elevation. Alanine aminotransferase and alkaline phosphatase levels both rose during the third week of BUDR infusion, and while subsequent microsphere administration further increased enzyme levels, these levels had largely normalized by necropsy on day 82. At necropsy, the type and degree of hepatic toxicity among the animals receiving radioactive microspheres was comparable to that previously described in patients receiving external beam hepatic irradiation at conventional doses (2000-3000 rads). Also noted was a radiation-induced cholecystitis (due in large part to the gallbladder's total reliance on the hepatic artery for blood supply). One resin microsphere dog exhibited a small quantity of microspheres in the lungs causing focal radiation-induced granulomas suggesting the need to assess shunting of microspheres through the liver in clinical studies. Thus, HA Y-90 microspheres with BUDR can produce acceptable, nonlethal, and tolerable toxicities in this dog model suggesting that clinical studies of this combination are not likely to be contraindicated by synergistic toxicity. Although HA BUDR did not contribute significantly to the toxicity of the Y-90 microspheres, HA BUDR by itself administered uninterrupted for 4 weeks may, like HA FUDR (clinically), cause chemical hepatitis/cholangitis. The unexpected fragmentation of the resin spheres (albeit without myelosuppression) has led us to begin studies with a recently developed nondisruptible glass microsphere (ThereSphere) in which the Y-90 is part of the glass matrix and cannot leach.(ABSTRACT TRUNCATED AT 400 WORDS)     

Detailed Diurnal Rhythm of Sensitivity to Melatonin Injections in Turkish Hamsters, Mesocricetus brandti

A diurnal rhythm of sensitivity to exogenous melatonin was defined in adult male Turkish hamsters, Mesocricetus brandti. Melatonin was administered daily by subcutaneous injections (15 micrograms in 0.1 ml 10% ethanolic saline) for 10 weeks in animals exposed to 16 L:8 D. As in golden and Djungarian hamsters, two periods of melatonin sensitivity were identified. The first, in late afternoon, persisted for 6 hr, from 7 hr to 1 hr before lights off. The second period was briefer, of only 2 hr duration in the late night, terminating at the time of lights on. Melatonin injections given during these sensitive periods promoted testicular regression in most animals; melatonin administered at other times of the day was without effect on testicular function in most animals of these groups. Gonadal regression induced by properly timed melatonin injections was rapid, in many groups nearly complete in 6 to 7 weeks. The results are discussed in relation to the function of pineal melatonin in photoperiodic time measurement in hamsters.     

Rapid expansion and IL-4 expression by Leishmania-specific naive helper T cells in vivo

CD4 T cells are pivotal for effective immunity, yet their initial differentiation into effector subsets after infection remains poorly defined. We examined CD4 T cells specific for the immunodominant Leishmania major LACK antigen using MHC/peptide tetramers and IL-4 reporter mice. Comprising approximately 15 cells/lymph node in naive mice, LACK-specific T cells expanded over 100-fold, and 70% acquired IL-4 expression by 96 hr. Despite their pathogenic role in susceptible mice, LACK-specific precursor frequency, expansion, and IL-4 expression were comparable between susceptible and resistant mice. When injected with unrelated antigen, Leishmania efficiently activated IL-4 expression from naive antigen-specific T cells. CD4 subset polarization in this highly characterized model occurs independently from IL-4 expression by naive T cells, which is activated indiscriminately after parasitism.     

Cyclosporine metabolism by P450IIIA in rat enterocytes--another determinant of oral bioavailability?

Cyclosporine is converted to its major metabolites (M-17, M-1, and M-21) in human liver by enzymes belonging to the P450IIIA subfamily. These enzymes are also present in rat and human enterocytes; however, the possibility that CsA is metabolized in enterocytes has not been previously investigated. We therefore directly compared metabolism of 3H-CsA in microsomes prepared from liver and jejunal enterocytes. M-17, M-1, and M-21 were the major CsA metabolites produced by enterocyte microsomes. This metabolism appeared to be catalyzed by P450IIIA, because pretreatment of rats with the P450IIIA inducer dexamethasone significantly increased the rate of CsA metabolism in enterocyte microsomes and preincubation of enterocyte microsomes with anti-P450IIIA IgG inhibited the production of CsA metabolites by greater than 95%. To determine if enterocyte P450IIIA metabolizes CsA in vivo, rats were pretreated with the P450IIIA inducer dexamethasone, the P450IIIA inhibitor erythromycin, or vehicle alone. At laparotomy, 2 mg/kg of 3H-CsA was injected into a sealed loop of jejunum, and after collection of the mesenteric venous blood draining this segment for 45 min, the production of M-17 and M-1 was measured. In the control group, a mean of 3.9% of the recovered radioactivity was found as M-1 and M-17. In the rats pretreated with dexamethasone, a mean of 8.4% of the radioactivity was found as M-1 and M-17 (P less than 0.05 relative to control) and this decreased to 2.3% in the group pretreated with erythromycin (P = 0.08 relative to control). We conclude that P450IIIA in jejunal enterocytes readily metabolizes CsA. Furthermore, the metabolism of CsA by enterocytes in vivo is substantial and likely contributes to "first pass metabolism" of orally administered CsA. Our observations provide novel hypotheses to explain some important drug interactions and interpatient differences in CsA dosing requirements.     

Improving dietitians' teaching skills.

Many health professionals lack important teaching skills, perhaps adding to patient difficulties in understanding and adopting therapeutic diets. Research suggests that teaching skills improved after dietitians took a continuing education course entitled "Effective Patient Teaching." Our study tested whether dietitians' new skills would persist in the field and whether selected patient outcomes would differ as a result. Thirty staff dietitians from six urban hospitals were videotaped teaching patients, then randomly assigned to take the Effective Patient Teaching course or not (control group). Follow-up videotapes were made after 1 week, 1 month, and 3 months. After each teaching session, patient satisfaction and recall were assessed. Two judges rated 20 teaching skills, which were divided into four subsets for analysis. Repeated measures analyses of variance showed overall gains only for the group that took the Effective Patient Teaching course, which scored higher than the control group at 1 week and 1 month, but not at baseline or 3 months. Gains occurred in presentation skills and essential teaching functions. Throughout the study, interpersonal skills were high and adherence promotion skills were low for dietitians in both groups. Groups did not differ on patient satisfaction or recall. Improvements in dietitians' teaching skills translated to the field immediately after they completed the continuing education program, but not all gains were sustained after 3 months. We recommend that dietitians assess their teaching and adherence promotion skills, obtain training where warranted, and periodically reassess the application of those skills during patient teaching sessions.     

Testicular function and pelage color have different critical daylengths in the Djungarian hamster, Phodopus sungorus sungorus

Testicular function and pelage color are regulated by photoperiod in the Djungarian hamster. To investigate the critical daylengths of these functions, adult male hamsters were exposed to one of four photoperiods: 16 h of light, 8 h of darkness (16L:8D), 14L:10D, 12L:12D, or 10L:14D. 10L:14D and 12L:12D induced the winter molt and testicular regression, in contrast to 14L:10D which induced only the latter response, and 16L:8D which maintained the summer pelage and large testes. Melatonin injections administered 4, 2, or 0 h before lights-off to hamsters exposed to 16L:8D mimicked the effects in hamsters exposed to 10:14D, 12L:12D or 14L:10D, respectively, on pelage color and testicular weight. Based on previous observations, the elevated circulating melatonin levels resulting from these injections were expected to extend the endogenous melatonin peak. Thus, this finding suggests that the duration of circadian melatonin elevation is the critical parameter determining its effect not only on the gonads, but also on the pelage. Since 14L:10D induced testicular regression but not the winter molt, this study also investigated whether circulating FSH levels, known to affect testicular function, and PRL levels, which have been shown to affect pelage color, might be affected differently by 14L:10D. Both FSH and PRL levels were found to be suppressed in 14L:10D hamsters compared to those in 16L:8D hamsters, although the interval between the initial decrease and eventual recovery was less than that in 10L:14D hamsters. Thus, the differential responses of the pelage and gonads to 14L:10D do not appear to be based on selective suppression of FSH in this photoperiod. However, different responses to 14L:10D compared to 10L:14D may be related to the shorter period of suppression of both PRL and FSH by the 14L:10D daylengths.     

Hormone release is tied to changes in cell size in the osmoreceptive prolactin cell of a euryhaline teleost fish, the tilapia, Oreochromis mossambicus

Prolactin (PRL) cells from a teleost fish, the tilapia, Oreochromis mossambicus, facilitate the direct study of osmoreception. The release of two prolactins, PRL(188) and PRL(177), which act in freshwater osmoregulation in teleost fish, rises in vitro within 5 min after extracellular osmolality falls. An increase in cell size accompanied this rise. Cell size and PRL release also increased, albeit more slowly, following the partial replacement of medium NaCl (55 mOsmolal) with an equivalent concentration of urea, a membrane-permeant molecule. Similar replacement using mannitol, which is membrane-impermeant, elicits no response. These findings suggest that osmoreception is linked to changes in cell volume rather than to extracellular osmolality per se.     

Safety of peritoneal and pleural drain placement in pediatric stem cell transplant recipients with severe veno‐occlusive disease

Hepatic VOD (veno‐occlusive disease) is a serious complication of HSCT (hematopoietic stem cell transplantation) and has historically been associated with high mortality. This obstruction to hepatic flow often results in fluid collections in the peritoneal and pleural cavities. Catheter placement to drain ascites or pleural fluid may reduce intra‐abdominal hypertension and/or improve respiratory parameters. The safety of these interventions among critically ill, immunocompromised children is unknown. Among 32 HSCT recipients (2000–2012) with severe VOD, we assessed the primary outcome of procedural complication from peritoneal drain placement. Twenty‐four (75%) patients underwent peritoneal drain placement. No patient sustained visceral perforation or hemorrhage with drain placement. Overall mortality was 47% (n = 15). The procedure was not associated with increased overall mortality (p > 0.99). Eight (25%) peritoneal drains required replacement for malfunction. Of 24 patients with peritoneal drains, one (4%) patient had a positive culture from ascitic fluid. Eight (25%) patients underwent pleural drain placement. No pleural drain‐related procedural complication or infection occurred. Four (50%) of the eight patients with pleural drains had de‐escalation in oxygen requirement at drain removal, compared to time of placement. In this study, peritoneal and pleural drains were safe interventions for children with severe VOD.