Astroglial Glutamate Transporter Deficiency Increases Synaptic Excitability and Leads to Pathological Repetitive Behaviors in Mice

An increase in the ratio of cellular excitation to inhibition (E/I ratio) has been proposed to underlie the pathogenesis of neuropsychiatric disorders, such as autism spectrum disorders (ASD), obsessive-compulsive disorder (OCD), and Tourette''s syndrome (TS). A proper E/I ratio is achieved via factors expressed in neuron and glia. In astrocytes, the glutamate transporter GLT1 is critical for regulating an E/I ratio. However, the role of GLT1 dysfunction in the pathogenesis of neuropsychiatric disorders remains unknown because mice with a complete deficiency of GLT1 exhibited seizures and premature death. Here, we show that astrocyte-specific GLT1 inducible knockout (GLAST^CreERT2/+/GLT1^flox/flox, iKO) mice exhibit pathological repetitive behaviors including excessive and injurious levels of self-grooming and tic-like head shakes. Electrophysiological studies reveal that excitatory transmission at corticostriatal synapse is normal in a basal state but is increased after repetitive stimulation. Furthermore, treatment with an N-methyl-D-aspartate (NMDA) receptor antagonist memantine ameliorated the pathological repetitive behaviors in iKO mice. These results suggest that astroglial GLT1 has a critical role in controlling the synaptic efficacy at corticostriatal synapses and its dysfunction causes pathological repetitive behaviors.     

A Case of Malignant Cystic Endocrine Tumor of the Pancreas

A malignant pancreatic endocrine tumor with a cystic appearance in a 66-yr-old woman was reported. Total pancreatectomy was performed under the diagnosis of cystadenocarcinoma. The tumor was large and cystic, but the solid portion of the tumor showed histologically a ribbon-like array of small uniform cells typical for endocrine tumors. Immunohistochemically, most tumor cells were immunoreactive for neuron-specific enolase, chromogranin, and Leu 7-epitope. Ultrastructurally, innumerable neurosecretory granules were demonstrated in the cytoplasm of most tumor cells. The patient survived for 5.5 yr after operation despite liver metastases, some of which also showed cystic appearances.     

A comparative clinical study of gallbladder tubular adenocarcinoma according to the grade of differentiation

Background We sought to elucidate differences in the clinical characteristics of gallbladder carcinoma according to the histological degree of glandular formation.Methods The subjects consisted of 66 autopsy cases out of 331 patients admitted for gallbladder carcinoma between 1975 and 2000. After identifying 49 tubular adenocarcinoma cases, we arbitrarily divided them into two categories: a well-differentiated type (group W; n = 41; well or moderately differentiated tubular adenocarcinoma), and a poorly differentiated type (group P, n = 8). The clinical features of the groups were compared.Results No significant differences were found with regard to sex, age, or serum carcinoembryonic antigen (CEA) levels between the two groups. Moreover, no intergroup difference was found in either the time interval from the initial symptoms to admission, or the grade of tumor progression on admission. Although the frequency of liver metastases on admission was similar in both groups, the frequency at autopsy was significantly higher in group W than in group P (73% vs 25%; P < 0.05). When survival was determined based on the duration after primary treatment, the longest and median periods were 48.7 months and 3.7 months, respectively, in group W, whereas none of the subjects in group P survived for over 2 months. This difference was statistically significant (P < 0.001).Conclusions Hematogenous metastasis was more prominent in group W. Poorly differentiated tubular adenocarcinoma can be closely associated with a poor prognosis.     

The revised Japanese clinical diagnostic criteria for chronic pancreatitis

In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients’ prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category.     

Docetaxel inhibits progression of human hepatoma cell line in vitro and is effective in advanced hepatocellular carcinoma

Background: Current chemotherapy for advanced hepatocellular carcinoma (HCC) is insufficient; only sorafenib has been proven to provide a modest survival benefit. A future direction of chemotherapy is to tailor treatment based on the chemosensitivity of each individual tumor. By doing so, only patients who stand to benefit from therapy will be exposed to potential side‐effects and morbidity. Although the use of docetaxel (DTX) for the treatment of lung, breast and gastric cancer has been reported, there are few reports about its use in the setting of HCC. Methods: To examine the efficacy of DTX for HCC, we established a human hepatoma cell line (TK cell) from the patient's malignant ascites from peritoneal carcinomatosis and treated it with DTX in vitro. Results: After we confirmed the efficacy of DTX in vitro, we treated our patient with DTX with positive results. Conclusion: In this study, we present a therapeutic approach by using DTX that supports the potential usefulness of personalized medicine in vitro and demonstrates it clinically.     

Effects of sucrose on plasma concentrations and urinary excretion of purine bases

To determine whether an increase in the plasma concentration of uric acid by sucrose intake is ascribable to enhanced purine degradation and/or decreased urinary excretion of uric acid, we measured the plasma concentrations of purine bases (uric acid, hypoxanthine, and xanthine) and uridine, as well as the urinary excretion of purine bases in 7 healthy subjects before and after administering sucrose at 1.5 g/kg of body weight in 2 related experiments, with and without an administration of 300 mg of allopurinol. In addition, in the control experiment without an administration of sugar and with an administration of 300 mg of allopurinol, we measured the same parameters in those 7 subjects. Without added allopurinol, sucrose increased the plasma concentration of uric acid by 11% (P<.01) as well as that of uridine, although it did not significantly increase the plasma concentrations of hypoxanthine and xanthine or the urinary excretion of uric acid. On the other hand, the plasma concentration and urinary excretion of hypoxanthine were increased by 2.4-fold (P<.05) and 3.42-fold (P<.05), respectively, and the plasma concentration of xanthine was increased by 1.2-fold (P<.05) together with an increase in the plasma concentration of uridine in the experiment with allopurinol administration. In contrast, the plasma concentration and urinary excretion of uric acid and the urinary excretion of xanthine were not increased. In addition, in the control experiment, all parameters did not change significantly. These results indicate that purine degradation enhanced by sucrose plays a major role in the increased plasma concentration of uric acid.