Brain uptake of radiolabeled N‐oleoyl‐dopamine in the rat

N‐acyl‐dopamines are a novel class of biologically active lipids that have recently been identified in the brain and have the potential to interact with neural signaling pathways. This study seeks to determine the ability of N‐oleoyl‐dopamine, a synthetic amide of oleic acid and dopamine, to cross the blood brain barrier. We determined the tissue content of radioactivity in selected brain regions, in a short‐run study design, following injections of [³H]N‐oleoyl‐dopamine (0.4 µCi) into the internal carotid artery in the rat. These results were compared with intracarotid injections of [³H]dopamine and with intravenous injections of both radiolabeled compounds. The level of radioactivity was determined using liquid scintillation and was expressed as the percentage of its total dose injected per gram of tissue. We found that the 15‐min brain uptake of radioactivity, with no distinct regional variations, amounted to about 6% following the intracarotid [³H]N‐oleoyl‐dopamine, which was a significant 3–4‐fold increase over that following similar administration of [³H]dopamine. Intravenous injections of [³H]N‐oleoyl‐dopamine gave a much smaller yield of radioactivity in brain tissue samples which was still severalfold greater than that for intravenous [³H]dopamine. Qualitative thin‐layered chromatography screening showed the presence of unchanged N‐oleoyl‐dopamine in the brain following injections. We conclude that N‐oleoyl‐dopamine has an appreciable ability to cross the blood‐brain barrier, which contrasts the limited transfer of dopamine alone. N‐oleoyl‐dopamine might exert physiological effects due to its known affinity for the central vanilloid receptors or to better satisfying the brain tissue demand for dopamine. The study suggests a potential pharmacological role for N‐oleoyl‐dopamine delivered exogenously in helping regulate the brain function. Drug Dev. Res. 60:217–224, 2003. © 2003 Wiley‐Liss, Inc.     

Diabetes in female rats; changes in liver microsomal aminopyrine N-demethylase and UDP-glucuronyl transferase activities

Short or long term diabetes in female rats produced remarkable activation of aminopyrine N-demethylation, inhibition of oestrone and p-nitrophenol glucuronidation and no changes in morphine UDP-glucuronyltransferase activity in vitro. Km and Vmax for these reactions were determined. Insulin treatment partially antagonized diabetes activation of aminopyrine N-demethylation: it restored decreased UDP-glucuronyltransferase activities for oestrone and p-nitrophenol only in long term and short term diabetes, respectively. Insulin also markedly inhibited morphine glucuronidation. Triton X-100 also displayed a differential pattern of activation for the glucuronidation reactions in liver microsomes of diabetic rats. Results suggest that diabetes in female rats may increase the actual amount of enzyme protein for aminopyrine metabolism and to decrease that for oestrone and p-nitrophenol.     

GABAergic mechanisms in morphine-induced hypothermia

Morphine produced a hypothermic effect in restrained rats which was antagonized by naloxone. This effect was completely inhibited by gamma-acetylenic-GABA, an inhibitor of GABA transaminase and by baclofen, a specific GABAB agonist. Pretreatment with diazepam, an agonist of the benzodiazepine receptor, partially inhibited morphine-induced hypothermia. Flumazenil, a benzodiazepine receptor blocker, potentiated the action of morphine on body temperature. A role of brain GABA in the thermoregulatory effects of morphine is proposed on the basis of these results.     

Treatment of breast cancer in elderly women: retrospective analysis of 111 wide lumpectomies performed in a day hospital regimen between 1982 and 1988.

Between 1982 and 1988, 111 elderly women with breast cancer but without clinical involvement of the axillary lymph nodes underwent wide lumpectomy in a Day Hospital regimen at the National Cancer Institute of Milan. The patients ranged in age from 70 to 92 years (median, 79). An adjuvant treatment was carried out in all but 9 cases: tamoxifen only in 84 cases, tamoxifen plus radiotherapy in 6 cases, radiotherapy alone in 12 cases. The median duration of follow-up was 44 months (range, 30-109 months). Four patients (3.6%) were lost to follow-up. In the remaining 107 patients, 10 local-regional relapses (9.1%) and 7 distant metastases (6.5%) occurred. Six patients died from the disease, 14 from unrelated conditions. This retrospective study showed that selected elderly patients with breast cancers can be treated successfully under local anesthesia on an outpatient basis. The treatment guarantees local control of the disease, meets the favor of elderly women and consequently improves their quality of life.     

Peritumoral lymphatic invasion in patients with node-negative mammary duct carcinoma.

Five hundred six consecutive cases of ductal infiltrating carcinoma of the breast (T1-T2,N0,M0) were evaluated to define the frequency of peritumoral lymphatic invasion (PLI) and verify its possible prognostic significance. Histologically, PLI was characterized by the presence of neoplastic emboli within vascular lumina lined by recognizable endothelial cells, adjacent to but outside the margins of the carcinoma. In routine histopathologic assessment the frequency of PLI was 68% whereas in a randomly selected group of 234 reviewed cases the frequency rose to 20%. Patients with routinely evaluated PLI had a worse prognosis than those without PLI with reference both to disease-free survival (P = 0.0001) and total survival rates (P = 0.0001). The difference for local recurrences was prognostically highly significant (P = 0.0001) and also significant for the development of metastases (P = 0.0576). In the reviewed material the difference in prognosis between PLI-positive and PLI-negative cases was not confirmed for total survival whereas the significance for the disease-free interval persisted. The assessment of PLI, carried out following strict histopathologic criteria, appears to select a group of node-negative breast cancer patients who have an increased risk of recurrences and might benefit from a treatment different from that reserved for node-negative and PLI-negative patients.     

Quantitative morphology of human glioblastoma multiforme microvessels: structural basis of blood-brain barrier defect

Summary Neoplastic invasion of the brain parenchyma results in a disruption of the ultrastructure of the blood vessel walls such that serum proteins extravasate into the surrounding tissue, resulting in cerebral edema. The structural changes involved are not well understood, since the pores through which serum constituents pass (permeability routes) in normal barrier vessels and in tumor vessels where the barrier is compromised, have not been extensively explored. In this study we investigate the ultrastructure of human brain microvessels in biopsied samples of control brain tissue and five glioblastoma multiforme tumors. Electron micrographs of a total of 78 vessels were analysed with computer assisted morphometry for ultrastructural evidence of permeability routes. Fenestrations in the endothelium were not seen. Pinocytotic vesicle number and arrangement did not differ significantly from that seen in control brain vessels. Interendothelial junctions with enlarged distensions (which may represent sections through transendothelial channels) were seen in some vessels from most tumors but not in control barrier vessels. In addition, large gaps in the endothelial layer were seen in less than two percent of tumor vessels. In conclusion, glioblastoma multiforme vessels in this study show subtle alterations in vessel morphology from that seen in controls. We suggest that the high vascular permeability and resultant brain edema seen in glioblastoma multiforme tumors is likely due to the presence of channels through interendothelial junctions, and rare but large breaks in the endothelial wall.     

Short-term response of brain tissue to cerebrospinal fluid shunts in vivo and in vitro.

The purpose of the studies was to determine how gross physical characteristics of cerebrospinal fluid (CSF) shunts and the cellular proliferative response to shunts contribute to shunt obstruction. Ventricular catheters with round holes, slots, and flanges were implanted into the lateral ventricles of rabbits for 4 weeks. All shunt designs were subject to ingrowth of tissue from the ventricle wall or choroid plexus. There were no qualitative or quantitative differences between normal and hydrocephalic rabbits. Astroglial cells from newborn mice were cultured on shunt catheters for 2 or 4 weeks. The growth of these cells was poor, probably because the cells cannot attach well to the silicone rubber substrate. Contact between the shunt catheter and vascularized brain tissue is the most important factor in the genesis of shunt obstruction.     

Heparin prevents stasis-induced thrombosis through protection of the venous endothelial cells: an electron microscopic study in rabbits

This study was performed to see whether or not protection of the endothelial cells contributes to the antithrombotic effects of heparin. New Zealand albino rabbits were subjected to jugular vein stasis by single caudal ligation for 2 h. Three treatments were given: saline (control group), heparin (0.2 mg/kg) 5 or 45 min before ligature of the vein. Groups of 6-8 animals were killed at 0, 5, 15, 30 and 120 min. The following parameters were determined: (1) involution and damage of the endothelial cells by scanning and transmission electron microscopy; (2) incidence and weight of thrombi in the lumens of the veins after 2 h stasis, and (3) effects of heparin on APTT and anti-Xa activity. In the control group, stasis caused a considerable involution of the endothelial cells in the first 30 min, followed by fibrin deposition and thrombus generation. Heparin strongly reduced the damage to the endothelial cells, with very evident protection of the cell membranes, and prevented thrombus generation: there were significant decreases in both incidence and weight of thrombi. These effects of heparin were evident both shortly after (maximal anticoagulant effect) and long after (no anticoagulant effect) pretreatment. We think that, under the experimental conditions we used, heparin prevented venous thrombosis at least partially by protection of the endothelial cells, through unknown mechanisms.