Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.

Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were 'odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.

Analysis of air contrast barium enema, computed tomographic colonography, and colonoscopy: prospective comparison.

BACKGROUND: The usefulness of currently available colon imaging tests, including air contrast barium enema (ACBE), computed tomographic colonography (CTC), and colonoscopy, to detect colon polyps and cancers is uncertain. We aimed to assess the sensitivity of these three imaging tests. METHODS: Patients with faecal occult blood, haematochezia, iron-deficiency anaemia, or a family history of colon cancer underwent three separate colon-imaging studies--ACBE, followed 7-14 days later by CTC and colonoscopy on the same day. The primary outcome was detection of colonic polyps and cancers. Outcomes were assessed by building an aggregate view of the colon, taking into account results of all three tests. FINDINGS: 614 patients completed all three imaging tests. When analysed on a per-patient basis, for lesions 10 mm or larger in size (n=63), the sensitivity of ACBE was 48% (95% CI 35-61), CTC 59% (46-71, p=0.1083 for CTC vs ACBE), and colonoscopy 98% (91-100, p<0.0001 for colonoscopy vs CTC). For lesions 6-9 mm in size (n=116), sensitivity was 35% for ACBE (27-45), 51% for CTC (41-60, p=0.0080 for CTC vs ACBE), and 99% for colonoscopy (95-100, p<0.0001 for colonoscopy vs CTC). For lesions of 10 mm or larger in size, the specificity was greater for colonoscopy (0.996) than for either ACBE (0.90) or CTC (0.96) and declined for ACBE and CTC when smaller lesions were considered. INTERPRETATION: Colonoscopy was more sensitive than other tests, as currently undertaken, for detection of colonic polyps and cancers. These data have important implications for diagnostic use of colon imaging tests.

Comparison of patients' experiences during imaging tests of the colon.

BACKGROUND: Physical discomfort, anxiety, embarrassment, and other aspects of patient experience impact on future compliance for colonic imaging tests. Therefore, a prospective study was performed comparing patient experiences during air contrast barium enema (ACBE), flexible sigmoidoscopy, and colonoscopy. METHODS: Immediately after each procedure, patients completed a questionnaire assessing pretest anxiety, difficulty with preparation, pain, cramping, bloating, overall discomfort, loss of dignity, willingness to repeat the test, and overall satisfaction. A follow-up questionnaire was administered within 48 hours. Nurses and physicians also completed questionnaires to assess the provider impression of patient experience. RESULTS: Four hundred ten patients (80 ACBE, 202 sigmoidoscopy, 128 colonoscopy) were prospectively enrolled. Sigmoidoscopy caused more pain than ACBE (Odds ratio [OR] 2.64: 95% CI [1.63, 4.27]) or colonoscopy (OR 1.83: 95% CI [1.21, 2.77]). ACBE and colonoscopy did not differ in the degree of pain. Although overall satisfaction appeared to be similar for all tests, patients were less willing to repeat ACBE than sigmoidoscopy (OR 1.85: 95% CI [1.13, 3.02]) or colonoscopy (OR 1.82: 95% CI [1.07, 3.09]). Initial and follow-up pain ratings by patients were highly correlated (Spearman correlation 0.81); however, correlation of pain assessments between staff and patients was poor (Spearman correlation 0.48). CONCLUSIONS: Sigmoidoscopy was more painful than other colonic imaging modalities. Although ACBE and colonoscopy caused similar pain, patients were less willing to repeat ACBE. In aggregate, the data suggest that patients perceive colonoscopy as the most acceptable colonic imaging procedure. Better methods are required to allow staff to adequately assess discomfort experienced by patients during these procedures.

Successful use of recombinant tissue plasminogen activator in a patient with relapsing peritonitis.

Intraperitoneal (IP) administration of either streptokinase (SK) or urokinase (UK) has assumed an adjunctive role to antibiotic therapy in selected patients with relapsing peritonitis. In these circumstances, bacteria may be protected from antibiotics through sequestration in either fibrinous structures or biofilms within the lumen of the peritoneal dialysis (PD) catheter or the peritoneal cavity. In some cases, it appears that disruption of these sheltered microenvironments by thrombolytic agents facilitated eradication of the offending organism and obviated the need for catheter removal, replacement, or interim hemodialysis. Although IP SK has been generally well tolerated as additive therapy in relapsing peritonitis, sporadic reports of significant complications, such as abdominal pain, fever, and severe hypotension, have precluded its more widespread acceptance. The only other thrombolytic agent used in this setting, UK, is presently unavailable because of a manufacturing shortfall. Therefore, adjunctive thrombolytic therapy for relapsing peritonitis is currently restricted. To circumvent these limitations, we devised an IP tissue plasminogen activator (tPA) protocol to eliminate recurring infection in a patient undergoing chronic ambulatory PD. After a third episode of peritonitis caused by Enterobacter cloacae, treated twice previously with an adequate antibiotic regimen, we instilled 6 mL of tPA (1 mg/mL) into the PD catheter for a 2-hour dwell time. The treatment was well tolerated and, in conjunction with a third course of antibiotic therapy, has produced an infection-free interval of 8 months.

Dietary supplementation of selenomethionine reduces metastasis of melanoma cells in mice.

The present study investigated the effect of dietary supplementation of selenomethionine on pulmonary metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Mice were assigned to four groups of 15 each. They were fed a basal AIN93G diet and the basal diet supplemented with 2.5 ppm or 5 ppm selenium as selenomethionine or with 2.5 ppm selenium as selenite for two weeks before and after the intravenous injection of 0.5 x 10(5) tumor cells. At necropsy, the number and size of tumors that developed in the lungs were determined. The number of mice that had > or = 11 tumors was 13, 8, 8, and 6 (p < 0.02 compared with the control), and the median number of lung tumors was 64, 14, 12 (p < 0.05 compared with the control), and 8 (p < 0.01 compared with the control) in the control group and the groups with 2.5 ppm and 5 ppm selenium as selenomethionine and 2.5 ppm selenium as selenite. Dietary supplementation of selenomethionine decreased tumor cross-sectional area and tumor volume compared with the controls. At the same dietary level, selenite had a greater inhibitory effect on tumor size than selenomethionine. These results demonstrate that dietary supplementation of selenomethionine reduced experimental metastasis of melanoma cells in mice and inhibited the growth of metastatic tumors that formed in the lungs. It is concluded that selenomethionine is an active form of selenium that reduces experimental metastasis.

Soybean isoflavones reduce experimental metastasis in mice.

We investigated the effect of dietary supplementation with isoflavones on pulmonary metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Mice were fed a basal AIN-93G diet or the basal diet supplemented with the isoflavones genistein and daidzein at 113 micromol/kg, 225 micromol/kg, 450 micromol/kg, or 900 micromol/kg for 2 wk before and after the intravenous injection of 0.5 x 10(5) melanoma cells. At necropsy, the number and size of tumors that formed in the lungs were determined. The number of mice that had >15 lung tumors was 17 in the control group, and 16, 15, 13, and 10 in the groups fed isoflavones at 113 micromol/kg, 225 micromol/kg, 450 micromol/kg and 900 micromol/kg, respectively. The latter two were significantly different from the control (P

Dialysate iron therapy: infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis.

BACKGROUND: Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate. METHODS: Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group). RESULTS: Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups. CONCLUSIONS: Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.

Dietary flaxseed supplementation and experimental metastasis of melanoma cells in mice.

The present study investigated the effect of dietary supplementation of flaxseed, the richest source of lignans, on experimental metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Mice were fed a basal diet or the basal diet supplemented with 2.5, 5 or 10% flaxseed for 2 weeks before and after the intravenous injection of 0.75 x 10(5) melanoma cells. At necropsy, the number of tumors that developed in the lungs was counted, the cross-sectional area of tumors was measured and the volumes of tumors were calculated. The median number of tumors in mice fed the 2.5, 5 and 10% flaxseed-supplemented diets was 32, 54 and 63% lower than that of the controls, respectively. The addition of flaxseed to the diet also caused a dose-dependent decrease in the tumor cross-sectional area and the tumor volume. These results provide the first experimental evidence that flaxseed reduces metastasis and inhibits the growth of the metastatic secondary tumors in animals. It is concluded that flaxseed may be a useful nutritional adjuvant to prevent metastasis in cancer patients.

Morphine stimulates adrenocorticotropin and cortisol release in the late-term ovine fetus.

Opiates are widely used as obstetrical analgesics during pregnancy and, as such, their interactions with the fetal endocrine system may have important consequences. In this study, the effects of morphine administration to fetal sheep in utero on fetal plasma immunoreactive (ir)-ACTH and ir-cortisol were examined. At the lowest dose administered (0.6 mg/h, i.v.) morphine reduced, although not significantly, plasma ir-cortisol levels. A dose-dependent stimulation of cortisol release was observed with higher doses of morphine. Doses of 2.5 and 5.0 mg/h morphine resulted in a significant increase in ir-cortisol with a change from control levels equal to 9.6 +/- 1.1 ng/mL (p = 0.03) and 17.6 +/- 5.1 ng/mL (p = 0.03), respectively. This increase in plasma ir-cortisol was associated with a significant increase in ir-ACTH (111.8 +/- 23.2 pg/mL versus 42.8 +/- 5.1 pg/mL; p = 0.02) that was naloxone-reversible. These effects of morphine were observed in fetal lambs only > 125 d of gestation, suggesting a maturation of functional opioid receptors in the ovine fetal hypothalamic-pituitary-adrenal axis after this time.

Effect of dietary supplementation of selenite on pulmonary metastasis of melanoma cells in mice.

The purpose of the present study was to determine the effect of dietary supplementation of selenite on experimental pulmonary metastasis of B16BL6 murine melanoma cells in C57BL/6 mice by means of an intravenous injection model. Three groups of mice were fed a basal AIN-93G diet containing 0.1 ppm selenium (control group) or the basal diet supplemented with 2 or 4 ppm selenium as selenite (experimental groups). Mice were fed the diet for two weeks before and after the intravenous injection of 0.75 x 10(5) viable tumor cells. At necropsy the number of tumors that developed in the lungs and their cross-sectional area were determined, and tumor volume was calculated. In the control group, 12 of the 15 mice had > or = 1 lung tumors. In contrast, only 4 of the 15 mice in each of the selenite-supplemented groups had > or = 11 tumors. The incidence of metastasis in mice fed the control and the 2- and 4-ppm selenium diets was 93%, 73%, and 53%, respectively. The median number of lung tumors was 53, 1, and 1 in mice fed the basal and the 2- and 4-ppm selenium diets, respectively. Tumor cross-sectional area and tumor volume were significantly decreased in selenite-supplemented groups. These results demonstrate that dietary supplementation of selenite reduced pulmonary metastasis of B16BL6 melanoma cells in C57BL/6 mice and also inhibited the growth of the metastatic tumors that developed in the lungs. It is concluded that selenite may be a useful adjuvant to prevent metastatic diseases in cancer patients.

Effect of dietary supplementation of soybeans on experimental metastasis of melanoma cells in mice.

The purpose of the present study was to determine the effect of dietary supplementation of soybean protein isolate (SPI) on experimental metastasis of B16BL6 murine melanoma cells in C57BL/6 mice. Four groups of mice were fed a basal AIN-93G diet or the basal diet supplemented with 10%, 15%, or 20% SPI for two weeks before and after the intravenous injection of 0.75 x 10(5) cells. At necropsy the number of tumors that developed in the lungs and their cross-sectional area were determined, and tumor volume was calculated. In the control group, 12 of the 15 mice had > or = 11 lung tumors. In contrast, only 3 or 4 of the 15 mice fed the SPI diets had > or = 11 tumors. The incidence of metastasis was 93%, 60%, 53%, and 53%, and the median number of lung tumors was 53, 2, 2, and 1 in mice fed the basal, 10%, 15%, and 20% SPI diets, respectively. Tumor cross-sectional area and tumor volume of SPI groups were significantly decreased compared with the controls. These results demonstrate that dietary supplementation of SPI reduced pulmonary metastasis of B16BL6 cells in mice and inhibited the growth of tumors that developed in the lungs. It is concluded that soybeans may be a useful adjuvant for preventing metastatic diseases in cancer patients.

kappa-Opioid agonist, U50,488H, stimulates ovine fetal pituitary-adrenal function via hypothalamic arginine-vasopressin and corticotrophin-releasing factor.

The fetal hypothalamic-pituitary-adrenal axis is regulated by such factors as corticotrophin releasing factor, arginine vasopressin and the endogenous opioid peptides. The goal of this study was to determine whether activation of the kappa-opioid system can modulate ovine fetal pituitary-adrenal function. The highly selective kappa-opioid agonist, U50,488H ¿trans-(+/-)-3, 4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexy]benzeneacetamide ¿ (1 mg/kg, i.v.), was administered directly to the ovine fetus in utero and fetal plasma levels of immunoreactive adrenocorticotrophin (ir-ACTH) and cortisol (ir-cortisol) were measured via radioimmunoassay. U50,488H resulted in an immediate and highly significant (P = .00005) increase in ir-ACTH, with a concomitant, significant (P = .02) increase in ir-cortisol. The peak increase was 312.1 +/- 31.2 pg/ml and 17.9 +/- 5.4 ng/ml from predrug control values for ir-ACTH and ir-cortisol, respectively, at 60 min after administration of U50,488H. This stimulation was completely blocked by concurrent naloxone (12 mg/hr, i.v.) administration, indicating that U50,488H is acting at classical opioid receptors to elicit this effect. Pretreatment with antagonists of arginine vasopressin or corticotrophin releasing factor attenuated the U50,488H response and it was therefore concluded that U50,488H is most likely acting to modulate ir-ACTH and ir-cortisol levels through regulation of arginine vasopressin and corticotrophin releasing factor release via hypothalamic kappa-opioid receptors. The results of this study should aid in the design of obstetrical analgesics that will not alter the fetal stress response.

Effect of selenium compounds and thiols on human mammary tumor cells.

The effect on cell viability and growth rate of sodium selenite, selenocystine, sodium selenate, and selenomethionine at selenium concentrations of 6.25 and 12.5 uM was studied in vitro on cells of the human mammary tumor cell line HTB123/DU4475. Selenite and selenocystine affected both cell viability and growth rate of the tumor cells at these selenium concentrations. Selenite and selenocystine decreased intracellular glutathione concentrations, but did not affect tumor cell glutathione peroxidase activity. After six days of exposure to either selenate or selenomethionine, the viability of tumor cells remained stable, but cell growth, as measured by numbers of cells, was retarded. Neither selenate nor selenomethionine produced changes in concentrations of intracellular glutathione. The toxic effect of selenite on tumor cells was enhanced by addition of 0.25 mM glutathione to the growth medium. Preincubation of the tumor cells with 62.5 uM buthionine sulfoximine decreased cellular glutathione to 15% of controls at 24 h and enhanced the toxicity of selenite toward the tumor cells. Glutathione, 2-mercaptoethanol, and L-cysteine were all toxic to the tumor cells in a dose-dependent manner.