Treatment With 90Y/177Lu-DOTATOC in Patients With Metastatic Adrenocortical Carcinoma Expressing Somatostatin Receptors.

CONTEXT: We investigated the role of Gallium 68 dodecanetetraacetic acid Tyr3-octreotide (68Ga-DOTATOC) positron emission tomography/computed tomography (PET/CT) in detecting somatostatin receptors (SSTRs) in 19 patients with metastatic adrenocortical carcinoma (ACC) and explored the activity of yttrium-90/lutetium-177 (90Y/177Lu-DOTATOC) peptide receptor radionuclide therapy (PRRT). CASE DESCRIPTION AND METHODS: 68Ga uptake in metastatic sites was scored in terms of intensity and anatomical uptake distribution of standard uptake value (SUV). Tissue expression of SSTR2A and SSTR5 was also evaluated by immunohistochemistry (IHC) on primary tumors. Eight (42%) patients displayed radiometabolic uptake of any-grade intensity with focal and limited distribution. Two (11%) patients displayed strong uptake in multiple lesions and were treated with PRRT. Both obtained an overall disease control lasting 4 and 12 months, respectively. CONCLUSIONS: ACC can express SSTRs as detected by IHC and 68Ga-DOTATOC PET. SSTRs-based PRRT may represent a potential treatment opportunity for a minority of patients with advanced ACC. This treatment modality deserves further investigation.

Congenic dissection of a major QTL for methamphetamine sensitivity implicates epistasis.

We previously used the C57BL/6J (B6) × A/J mouse chromosome substitution strain (CSS) panel to identify a major quantitative trait locus (QTL) on chromosome 11 influencing methamphetamine (MA)-induced locomotor activity. We then made an F(2) cross between CSS-11 and B6 and narrowed the locus (Bayes credible interval: 79-109 Mb) which was inherited dominantly and accounted for 14% of the phenotypic variance in the CSS panel. In the present study, we created congenic and subcongenic lines possessing heterozygous portions of this QTL to narrow the interval. We identified one line (84-96 Mb) that recapitulated the QTL, thus narrowing the region to 12 Mb. This interval also produced a small decrease in locomotor activity following prior saline treatment. When we generated subcongenic lines spanning the entire 12-Mb region, the phenotypic difference in MA sensitivity abruptly disappeared, suggesting an epistatic mechanism. We also evaluated the rewarding properties of MA (2 mg/kg, i.p.) in the 84- to 96-Mb congenic line using the conditioned place preference (CPP) test. We replicated the locomotor difference in the MA-paired CPP chamber yet observed no effect of genotype on MA-CPP, supporting the specificity of this QTL for MA-induced locomotor activity under these conditions. Lastly, to aid in prioritizing candidate genes responsible for this QTL, we used the Affymetrix GeneChip(®) Mouse Gene 1.0ST Array to identify genes containing expression QTLs (eQTL) in the striatum of drug-naÏve, congenic mice. These findings highlight the difficulty of using congenic lines to fine map QTLs and illustrate how epistasis may thwart such efforts.

Effect of time of administration on cholesterol-lowering by psyllium: a randomized cross-over study in normocholesterolemic or slightly hypercholesterolemic subjects.

BACKGROUND: Reports of the use of psyllium, largely in hypercholesterolemic men, have suggested that it lowers serum cholesterol as a result of the binding of bile acids in the intestinal lumen. Widespread advertisements have claimed an association between the use of soluble fibre from psyllium seed husk and a reduced risk of coronary heart disease. Given the purported mechanism of cholesterol-lowering by psyllium, we hypothesized that there would be a greater effect when psyllium is taken with breakfast than when taken at bedtime. Secondarily, we expected to confirm a cholesterol-lowering effect of psyllium in subjects with "average" cholesterol levels. METHODS: Sixteen men and 47 women ranging in age from 18 to 77 years [mean 53 +/- 13] with LDL cholesterol levels that were normal or slightly elevated but acceptable for subjects at low risk of coronary artery disease were recruited from general gastroenterology and low risk lipid clinics. Following a one month dietary stabilization period, they received an average daily dose of 12.7 g of psyllium hydrophilic mucilloid, in randomized order, for 8 weeks in the morning and 8 weeks in the evening. Change from baseline was determined for serum total cholesterol, LDL, HDL and triglycerides. RESULTS: Total cholesterol for the "AM first" group at baseline, 8 and 16 weeks was 5.76, 5.77 and 5.80 mmol/L and for the "PM first" group the corresponding values were 5.47, 5.61 and 5.57 mmol/L. No effect on any lipid parameter was demonstrated for the group as a whole or in any sub-group analysis. CONCLUSION: The timing of psyllium administration had no effect on cholesterol-lowering and, in fact, no cholesterol-lowering was observed. Conclusions regarding the effectiveness of psyllium for the prevention of heart disease in the population at large may be premature.

Celiac disease: diagnosis at laparoscopy.

A 27-year-old woman was found to have an abnormal small bowel at the time of an elective laparoscopic tubal ligation. Subsequent investigation revealed celiac disease to be the underlying cause. The changes identified are believed to reflect an increased intestinal blood flow, which has been identified in the diagnostic imaging literature to be associated with active celiac disease. Further study of this feature of celiac disease may provide additional insights into its pathophysiology.

Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter.

The dopamine transporter (DAT) critically regulates the duration of the cellular actions of dopamine and the extent to which dopamine diffuses in the extracellular space. We sought to determine whether the reportedly greater diffusion of dopamine in the rat prefrontal cortex (PFC) as compared with the striatum is associated with a more restricted axonal distribution of the cortical DAT protein. By light microscopy, avidin-biotin-peroxidase immunostaining for DAT was visualized in fibers that were densely distributed within the dorsolateral striatum and the superficial layers of the dorsal anterior cingulate cortex. In contrast, DAT-labeled axons were distributed only sparsely to the deep layers of the prelimbic cortex. By electron microscopy, DAT-immunoreactive profiles in the striatum and cingulate cortex included both varicose and intervaricose segments of axons. However, DAT-labeled processes in the prelimbic cortex were almost exclusively intervaricose axon segments. Immunolabeling for tyrosine hydroxylase in adjacent sections of the prelimbic cortex was localized to both varicosities and intervaricose segments of axons. These qualitative observations were supported by a quantitative assessment in which the diameter of immunoreactive profiles was used as a relative measure of whether varicose or intervaricose axon segments were labeled. These results suggest that considerable extracellular diffusion of dopamine in the prelimbic PFC may result, at least in part, from a paucity of DAT content in mesocortical dopamine axons, as well as a distribution of the DAT protein at a distance from synaptic release sites. The results further suggest that different populations of dopamine neurons selectively target the DAT to different subcellular locations.