Importance of neuropsychological evaluation after surgery in patients with unruptured cerebral aneurysms

BACKGROUND: We evaluated neuropsychological function before and after surgery in patients with unruptured cerebral aneurysms. METHODS: Neuropsychological functions in 43 patients with unruptured cerebral aneurysms were evaluated before and 1 month after surgery. The neuropsychological examination included the Mini-Mental State examination, "Kana-hiroi" test, Kohs Block Design test, and Miyake's Memory test. Then, if scores of even a single test were decreased 1 month after surgery, the tests were performed again 5 months later. In 24 of the 43 subjects, cerebral blood flow (CBF) was measured before and 1 month after surgery by single-photon emission tomography. RESULTS: The outcome in all patients was evaluated as good according to the Glasgow Outcome Score (GOS). In 17 (40%) of the 43 patients, neuropsychological function had deteriorated 1 month after surgery. The most sensitive test applied was the Miyake's Memory test. Of 14 patients with neuropsychological deterioration 1 month after surgery, 6 showed complete recovery, 5 showed partial recovery, and 3 still showed cognitive deterioration 6 months after surgery. Patients over 65 years old, those with anterior communicating artery aneurysms, those operated by interhemispheric approach, or those with systemic diseases showed a greater tendency toward a decline in postoperative neuropsychological function than the other patients. The postoperative CBF and vascular response in the frontal lobe of affected-side was decreased in cases showing cognitive deterioration. CONCLUSIONS: These results suggested that the neuropsychological outcomes after surgery for unruptured cerebral aneurysms were not satisfactory.     

Expression of heat shock protein (Hsp) 70 and Hsp 40 in gastric cancer

Heat shock proteins (Hsp) 70 and Hsp 40 are stress proteins that cooperate as chaperones in mammalian cells. We determined the expression of Hsp 70 and Hsp 40 in 81 gastric cancers. Immunoreactivities to Hsp 70 and Hsp 40 were detected in 67.9 and 22.2% of tumors, respectively. Immunohistochemical analysis showed enhanced Hsp 70 and Hsp 40 expression in gastric tumor tissue, relative to the surrounding normal tissue. Overexpression of Hsp 70 and Hsp 40 was also confirmed by immunoblotting. Among various clinicopathological parameters, low histopathological differentiation was associated with reduced expression of both proteins.     

Mutagenic events induced by 4-hydroxyequilin in supF shuttle vector plasmid propagated in human cells

Increased incidence of breast, ovarian and endometrial cancers are observed in women receiving estrogen replacement therapy (ERT). Equilin and equilenin are the major components of the widely prescribed drug used for ERT. These equine estrogens are metabolized primarily to 4-hydroxyequilin (4-OHEQ) and 4-hydroxyequilenin, respectively, which are autoxidized to react with DNA, resulting in the various DNA damages. To explore the mutagenic potential of equine estrogen metabolites, a double-stranded pMY189 shuttle vector carrying a bacteria suppressor tRNA gene, supF, was exposed to 4-OHEQ and transfected into human fibroblast. Plasmids containing mutations in the supF gene were detected with indicator bacteria and mutated colonies obtained were analyzed by automatic DNA sequencing. The proportion of plasmids with the mutated supF gene was increased dose-dependently. The majority of the 4-OHEQ-induced mutations were base substitutions (78%); another 22% were deletions and insertions. Among the base substitutions, 56% were single base substitutions and 19% were multiple base substitutions. The majority (86%) of the 4-OHEQ-induced single base substitutions occurred at the C:G site. C:G --> G:C and C:G --> A:T mutations were detected preferentially with lesser numbers of C:G --> T:A transitions. Sixty-two percent of base substitutions were observed particularly at C:G pairs in (5')-TC/AG-(5') sequences. Using (32)P-post-labeling/gel electrophoresis analysis, 4-OHEN-dC was a major adduct, followed by lesser amounts of 4-OHEN-dA adduct. Mutations observed at C:G pairs may result from 4-OHEN-dC adduct. These results indicated that 4-OHEQ is mutagenic, generating mutations primarily at C:G pairs in (5')-TC/AG-(5') sequences.     

Molecular mechanisms of angiogenesis in non-small cell lung cancer,and therapeutics targeting related molecules

Angiogenesis, neovascularization from pre-existing vasculature, is necessary to supply oxygen and nutrition for tumor growth in both primary and distant organs. It consists of sprouting and non-sprouting (the enlargement, splitting, and fusion of pre-existing vessels) processes, and both can occur concurrently. Growth of solid tumors, including non-small cell lung cancer (NSCLC), is usually dependent on angiogenesis, which is regulated by complex mechanisms involving various angiogenesis-related molecules. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most potent angiogenic molecules, regulates both angiogenesis and vascular permeability, and hence promotes tumor progression and development of malignant pleural effusions in NSCLC. Signals via epidermal growth factor receptor (EGFR) promote not only the tumor cell cycle, but also the process of angiogenesis. Therefore, these molecules are potential targets for anti-tumor vasculature therapy. Many agents targeting tumor vasculature have been developed, and several compounds have shown anti-tumor potential in pre-clinical studies. Their efficacy against NSCLC is currently being evaluated in clinical trials.     

The role of CD36 in peripheral nerve remyelination after crush injury

We previously demonstrated that the deficiency of class A macrophage scavenger receptor type I/II was involved in the delayed phagocytosis of degraded myelin by macrophages in class A macrophage scavenger receptor type I/II knockout mice after crush injury of the sciatic nerve [Naba et al. (2000) Exp. Neurol., 166, 83-89]. In order to elucidate the role of CD36, one of the scavenger receptors, here we inflicted crush injury to the sciatic nerves of CD36 knockout mice and investigated the remyelination after crush injury in comparison with that of class A macrophage scavenger receptor type I/II knockout mice. Although we previously reported a lot of onion-bulbs in class A macrophage scavenger receptor type I/II knockout mice at 3 weeks, the number of onion-bulbs was limited both in CD36 knockout mice and wild-type mice. In the morphometry, the remyelination was seriously delayed, and the infiltrating macrophages into the nerve fascicles were quite frequent in CD36 knockout mice compared with wild-type mice at 3 and 6 weeks postinjury. The immunohistochemistry with the monoclonal antibody reacted with oxidized phosphatidylcholine and oil red O staining were positive in wild-type mice, but were negative in CD36 knockout mice, suggesting that the oxidation of phosphatidylcholine and the generation of neutral lipids in macrophages were disturbed in CD36 knockout mice. We hypothesize that the delayed phagocytosis by macrophages and the defect in reuse of lipids from degraded myelin are related to seriously delayed remyelination and a small number of onion-bulbs in CD36 knockout mice.     

Interleukin-2-inducible Killer Activity and Its Regulation by Blood Monocytes from Autologous Lymphocytes of Lung Cancer Patients

The ability of blood lymphocytes of newly diagnosed lung cancer patients to respond to interleukin 2 (IL-2) to become IL-2-activated killer (LAK) cells and its regulation by autologous monocytes were examined. LAK activity was measured by ³¹Cr release assay. The abilities of lymphocytes among blood mononuclear cells (MNC) of subjects of different ages without malignancies to generate LAK activity against NK-cell resistant Daudi cells and lung adenocarcinoma (PC-9) cells were very similar. The LAK activity of blood MNC of lung cancer patients was also nearly the same as that of blood MNC of control subjects. There was no significant difference in IL-2-inducible LAK activity between MNC of patients with small cell lung cancer (SCLC) and those of patients with non-SCLC. Monocytes and lymphocytes were separated from blood MNC on a one-step Percoll gradient. Monocytes of lung cancer patients were found to augment in vitro induction of LAK activity by IL-2 of autologous blood lymphocytes. In contrast, endotoxin-stimulated monocytes suppressed LAK induction of autologous lymphocytes of cancer patients. These findings suggest that administration of IL-2 and LAK cells induced in vitro may be of benefit in the treatment of lung cancer.     

Differential effects of methylmercury on the synthesis of protein species in dorsal root ganglia of the rat

Dorsal root ganglia from control and methylmercury(MeHg)-treated rats were incubated in vitro with ³⁵S-methionine ant the proteins synthesized were analyzed by two-dimensional electrophoresis. The double labelling method, in which proteins of control dorsal root ganglia labelled in vitro with ³H-leucine were added to each of the two samples as an internal standard, was used to minimize unavoidable errors arising from the resolving procedure itself. The results obtained showed that the effect of MeHg on the synthesis of proteins in dorsal root ganglia was not uniform for individual protein species in the latent period of MeHg intoxication. Among 200 protein species investigated, 157 showed inhibition of synthesis close to that of the total proteins in the tissue (68% of the control). Among the remaining protein species, 20 showed real stimulation of synthesis, whereas 7 were moderately inhibited and 16 were inhibited more strongly than the total proteins in the tissue. These results suggest that the effect of MeHg on the synthetic rates for protein species in dorsal root ganglia differs with the species, and that unusual elevation or reduction of the synthesis of some protein species caused by MeHg may lead to impairment of normal nerve functions.This work was supported in part by a grant from the Japanese Environmental Agency     

Lasting increase in D1 dopamine receptors in the lateral part of the substantia nigra pars reticulata after subchronic methamphetamine administration

To examine the possible involvement of D₁ dopamine receptors in behavioral sensitization induced by subchronic methamphetamine (MAP) administration, regional D₁ receptors labeled with [³H]SCH 23390 were examined using binding assay and quantitative autoradiography. Rats received 4 mg/kg/day MAP (i.p.) for 14 days, and were decapitated after an abstinence period of 24 h, 7 days or 21 days. In MAP-treated rats, a significant decrease in K_d in the mesolimbic area was observed 24 h but not 7 days after the last injection. Neither K_d nor B_max changed in the striatum or medial prefrontal cortex of MAP-treated rats after any period of abstinence. Autoradiography revealed a significant increase in specific [³H]SCH 22390 binding in the lateral part of the substantia nigra pars reticulata (SNr) of MAP-treated rats. Since this increase lasted up to 21 days after cessation of subchronic MAP administration, it is suggested that lasting increase in the nigral D₁ receptors may be associated with the biological changes underlying MAP-induced behavioral sensitization.