Tracer kinetic modeling of the 5-HT1A receptor ligand [carbonyl-11C]WAY-100635 for PET

[Carbonyl-11C]WAY-100635 is a promising PET radioligand for the 5-HT1A receptor, having demonstrated more favorable characteristics for in vivo imaging than the previously available [O-methyl-11C]WAY-100635. The current study evaluates different tracer kinetic modelling strategies for the quantification of 5-HT1A receptor binding in human brain. Mathematical modelling of the carbonyl-labeled radiotracer is investigated using compartmental structures, including both plasma input and reference tissue approaches. Furthermore, the application of basis function methods allows for the investigation of parametric imaging, providing functional maps of both delivery and binding of the radioligand. Parameter estimates of binding from normal volunteers indicate a low intra- versus a high intersubject variability. It is concluded that a simplified reference tissue approach may be used to quantify 5-HT1A binding either in terms of ROI data or as parametric images.     

Inositol 1,4,5-trisphosphate receptor function in neonatal cardiomyocytes

We have previously reported that the metabolism of inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) is altered when rat neonatal ventricular cardiomyocytes are isolated and cultured. In the current study we show that the mass content of Ins(1,4,5)P3 is lower in the isolated cells than in the intact tissue. However, the properties of the Ins(1,4,5)P3 receptors were not different in the two preparations and the isolated cells remained insensitive to Ins(1,4,5)P3 in terms of 45Ca2+ release. Thus, despite the altered pattern of metabolism of Ins(1,4,5)P3 in isolated neonatal cells, the properties of the receptors were similar to those reported in other myocardial preparations.     

Association analysis in an evolutionary context: cladistic analysis of the DRD2 locus to test for association with alcoholism

Recent clinical trials of adjuvant therapy for early stage breast cancer support two general observations. First, overall survival is not impacted by the extent of surgery. Low rates of axillary relapse in patients treated with total mastectomy alone combined with the availability of systemic therapy as a substitute for surgical control of the axilla mean that patients can often be spared the morbidity of axillary node dissection. In problematic cases, newer diagnostic approaches, such as sentinel node biopsy, can help in making appropriate treatment decisions. Second, systemic therapy can reduce the clinical manifestations of disease. The incorporation of more sophisticated approaches to predicting outcomes, to varying timing and dose of treatment, and to developing new modalities of treatment, including immunotherapy, will contribute to a general strategy aimed at reducing the tumor to a harmless parasite. These observations support a paradigm shift in our definition of 'adjuvant'. Rather than referring to the use of systemic therapy after the patient's known disease has been surgically removed, adjuvant therapy would be re-defined to refer to local therapy used to eradicate any residual tumor remaining after systemic therapy has been completed.     

Degradation chemistry of gemcitabine hydrochloride, a new antitumor agent

The anti-tumor agent gemcitabine hydrochloride, a beta-difluoronucleoside, is remarkably stable in the solid state. In 0.1 N HCI solution at 40 degrees C, deamination of gemcitabine occurs, yielding its uridine analogue. Approximately 86% of the initial gemcitabine remains after 4 weeks under these conditions. Cleavage of the N-glycosidic bond of gemcitabine or conversion to its alpha-anomer in 0.1 N HCI solution is not observed over a 4-week period. However, this work has shown that gemcitabine hydrochloride anomerizes in 0.1 N NaOH at 40 degrees C. Approximately 72% of the initial gemcitabine remains after 4 weeks under the basic conditions used. Uridine hydrolysis products are also formed under these conditions. The anormerization reaction, which is unusual under basic conditions, has been confirmed by characterization of the chromatographically isolated alpha-anomer by NMR and mass spectrometry. A mechanism involving an acyclic intermediate is proposed.     

Early gastric cancer and Helicobacter pylori: 34 years of experience at Charity Hospital in New Orleans

Good survival rates have been reported for resected early gastric adenocarcinoma (EGC) in patients found via screening procedures. However, the prevalence of Helicobacter pylori in EGC in unscreened populations is unclear. The major purpose of this investigation was to analyze the clinical experience and incidence of H. pylori in unscreened patients presenting with EGC at Charity Hospital over a 34-year period. From 1963 through 1997, the tumor registry at Charity Hospital compiled data on 2497 patients evaluated for gastric carcinoma. Of these patients, 26 (1%) had lesions that were confined to the mucosa or submucosa, i.e., T1N0M0 (American Joint Commission on Cancer classification). Pathology specimens and medical records were retrieved for confirmation of diagnosis and retrospective analysis for H. pylori. H. pylori was analyzed by Steiner staining and immunohistochemistry using a polyclonal antibody. EGC was detected in 12 men and 14 women with a mean age of 62 years. Upper gastrointestinal X-ray studies were performed on 19 of the 26 patients and failed to conclusively demonstrate a lesion in any case. Endoscopy was performed on 22 patients, and preoperative biopsies were positive in 95 per cent of these. Operative procedures included 2 local excisions and 22 subtotal and 2 total gastrectomies. No extended nodal dissections were performed. Microscopic evaluation revealed lesions limited to the mucosa in 63 per cent of cases and involving the submucosa in 37 per cent of the cases. Of the 14 patients evaluable of H. pylori, 79 per cent were positive for the bacterium. The status of 2 patients is unknown, and only 1 patient died of the original gastric cancer, for a disease-free survival of 96 per cent. The 5-year and 10-year overall survival rates were calculated to be 50 per cent and 21 per cent, respectively, when all causes of death were taken into consideration. Median follow-up of the survivors was 64 months. Resection of early gastric carcinoma in unscreened patients without extended lymphadenectomy yielded excellent results. H. pylori was present in 79 per cent of cases. These data suggest an association between H. pylori and EGC. Whether H. pylori infection is an etiologic factor in gastric cancer remains an area of active research.