The Present Indication and Future of Deep Brain Stimulation

The use of electrical stimulation to treat pain in human disease dates back to ancient Rome or Greece. Modern deep brain stimulation (DBS) was initially applied for pain treatment in the 1960s, and was later used to treat movement disorders in the 1990s. After recognition of DBS as a therapy for central nervous system (CNS) circuit disorders, DBS use showed drastic increase in terms of adaptability to disease and the patient’s population. More than 100,000 patients have received DBS therapy worldwide. The established indications for DBS are Parkinson’s disease, tremor, and dystonia, whereas global indications of DBS expanded to other neuronal diseases or disorders such as neuropathic pain, epilepsy, and tinnitus. DBS is also experimentally used to manage cognitive disorders and psychiatric diseases such as major depression, obsessive-compulsive disorder (OCD), Tourette’s syndrome, and eating disorders. The importance of ethics and conflicts surrounding the regulation and freedom of choice associated with the application of DBS therapy for new diseases or disorders is increasing. These debates are centered on the use of DBS to treat new diseases and disorders as well as its potential to enhance ability in normal healthy individuals. Here we present three issues that need to be addressed in the future: (1) elucidation of the mechanisms of DBS, (2) development of new DBS methods, and (3) miniaturization of the DBS system. With the use of DBS, functional neurosurgery entered into the new era that man can manage and control the brain circuit to treat intractable neuronal diseases and disorders.     

Fas-associated phosphatase-1 promotes Fas-mediated apoptosis in human colon cancer cells: Novel function of FAP-1

Background and Aim: Fas‐associated phosphatase‐1 (FAP‐1) has been thought as an inhibitor in Fas‐mediated apoptosis. Here, we investigated the role of FAP‐1 in Fas‐mediated apoptosis of human colon cancer cells. Method: The viability of four colon cancer cell lines treated with agonistic anti‐Fas antibody was determined using WST‐1 assay and cell death detection ELISA. pRc/CMV‐FAP‐1 was transfected to a FAP‐1‐negative, Fas‐resistant colon cancer cell line SW480 by lipofection and the clones expressing FAP‐1 protein were selected by limiting dilution. In the clones, expression of 550 genes was analyzed by cDNA microarrays. Protein expression of FAP‐1 and molecules related to apoptosis was examined by western blot. Results: We obtained two FAP‐1 overexpressed clones which were much more susceptible to Fas‐mediated apoptosis than control cells. In the clones, caspase 8 and caspase 3 were fully activated by agonistic anti‐Fas antibody treatment. Bcl‐2 family proteins were not related to the high susceptibility of these clones, because caspase 9 was not activated. Transfection of FAP‐1 did not suppress the survival actions of insulin‐like growth factor (IGF‐1) which enhanced survival signal through Akt phosphorylation. Upregulation in 21 genes and downregulation in 29 genes was revealed by cDNA arrays. We confirmed protein expression of p21 and phosphorylated p21 were much more enhanced in the clones than in control cells. Conclusions: Overexpression of FAP‐1 enhanced susceptibility to Fas‐mediated apoptosis in SW480 and upregulation of p21 may contribute to this phenomenon. Our results indicate a novel function of FAP‐1 in Fas‐mediated apoptosis of human colon cancer cells.     

Long-term administration of natural interferon-α in patients with chronic hepatitis C: Relationship to serum RNA concentration, HCV-RNA genotypes, histological changes and hepatitis C virus

To virologically assess the efficacy of interferon therapy in chronic hepatitis C, either 5 or 10 MU/day natural interferon-α (IFNα) was administered to 57 patients with chronic hepatitis C for 38 weeks. A complete and sustained response (CR-SR), as evidenced by the absence of serum hepatitis C virus (HCV)-RNA during the administration period and at 6 months after the final administration of IFNα and a normal GPT level at 6 months after final administration, occurred in 42.6% (23/54) of subjects. Liver tissue was histologically evaluated using the histological activity index (HAI) score before and after the administration period. In CR-SR cases, significant improvements (P <0.01) occurred in periportal necrosis, intralobular necrosis, portal inflammation and total score. A comparison, by HCV genotypes, revealed that CR-SR occurred in 60% (9/15) of subjects with type 2a and 30.3% (10/33) of subjects with type Ib. A comparison by virus concentration revealed that CR-SR occurred in 71.4% (15/21) of those subjects having a virus concentration of < 10⁵ copies/mL, but in only 24.2% (8/33) of those having a virus concentration of > 10⁵ copies/mL. Analysis by a multiple logistic model revealed a strong correlation between the therapeutic effect of interferon therapy and the pre-administration virus concentration (P=0.0061) and genotype (P=0.0015). These results suggest that the preadministration virus concentration and genotype are both key factors affecting the therapeutic effect of interferon therapy in chronic hepatitis C and that the therapeutic effect of interferon is satisfactorily high, irrespective of virus concentration, in subjects with type 2a HCV, but varies depending on virus concentration in subjects with type 1b.     

A case of intractable diarrhea firmly suspected to have autoimmune enteropathy

Protracted diarrhea with insulin dependent diabetes mellitus (DM) and hypothyroidism in a 9 month old Japanese girl who was firmly suspected to have autoimmune enteropathy (AIE) is reported. Her severe secretory diarrhea failed to respond to intensive antidiarrheic treatment and was gradually improved with steroid therapy. The circulating autoantibodies to enterocytes in her serum were detected by indirect immunofluorescence technique and the impaired suppressor T (Ts) cell function was proved by plaque forming assay using bead-separated CD4 or CD8 T cells together with CD19 B cells. The anti-enterocyte antibodies were exclusively of immunoglobulin M (IgM) class and were detected with the progress of the protracted diarrhea. Maximum antibody titer was obtained at the onset of DM and the disappearance of autoantibodies was associated with the resolution of the clinical symptoms and signs. The helper functions of adult CD4 T cells to induce Ig-secreting cells from adult and the patient were strikingly suppressed by adult CD8 T cells. However, the CD8 T cells from the patient lost the ability to inhibit the induction of these Ig-secreting cells when stimulated with adult CD4 T cells. Moreover, the patient's CD8 T cells stimulated rather than suppressed the induction of Ig-secreting cells from the patient when stimulated with the patient's CD4 T cells. These results suggest that the impaired Ts cell function in this patient might play some immunological role in the pathogenesis of AIE     

CASE REPORT: A case of primary ileal carcinoma in a young woman and a review of the Japanese literature

We report a case of primary ileal carcinoma in a young woman, which was diagnosed definitively before operation. A 29-year-old woman presented with abdominal pain, diarrhoea and bloody stools. Colonoscopic and radiographic studies revealed that there was a 7.5 × 7 cm tumour (well-differentiated adenocarcinoma) at the terminal ileum, forming an ulcerated lesion at the centre. The tumour had invaded the caecum, the right urinary tract, the right ovary and a portion of the sigmoid colon. Fifty-three cases of primary ileal carcinoma were reported in Japan between 1982 and 1994 and their clinical features are reviewed herein.     

Comparison of Behavioural Effects of Repeated Treatment with Methamphetamine plus Scopolamine and Methamphetamine Alone on Behavioural Sensitization and Conditioned Response

We investigated how repeated treatments with methamphetamine (4.0mgkg^?1, i.p.) plus scopolamine (0.5mgkg^?1, i.p.) and methamphetamine alone effected behavioural sensitization and conditioned response in rats. Repeated methamphetamine plus scopolamine treatment induced a more progressive and enduring enhancement of focused stereotyped behaviour than repeated methamphetamine treatment. Stereotyped behaviour induced by methamphetamine plus scopolamine was reproduced by challenge injections of methamphetamine plus scopolamine, methamphetamine, and to a lesser extent by scopolamine challenges. The methamphetamine plus scopolamine-sensitized rats were conditioned to a low frequency tone (300 Hz, 100 dB) associated with the drug state. They exhibited a conditioned response to pairings of the tone (conditioned stimulus) and placebo injections. However, they did not respond to the tone alone or the placebo injections alone. The methamphetamine-sensitized rats failed to demonstrate any conditioning; only the repeated methamphetamine plus scopolamine treatment induced sensitization to the drug-associated tone. Pairings of exteroceptive conditioned stimulus-interoceptive unconditioned stimulus associations may provide an important source for conditioning to the tone associated with the drug state. We conclude that behavioural sensitization may operate via a reciprocal balance between the dopaminergic and cholinergic inhibitory systems, in favour of a dopaminergic dominance. Conditioning to the drug-associated tone may be mediated via a reciprocal balance between the two transmitter systems.