ifn-γ-dependent secretion of IL-10 from Th1 cells and microglia/macrophages contributes to functional recovery after spinal cord injury.

Transfer of type-1 helper T-conditioned (Th1-conditioned) cells promotes functional recovery with enhanced axonal remodeling after spinal cord injury (SCI). This study explored the molecular mechanisms underlying the beneficial effects of pro-inflammatory Th1-conditioned cells after SCI. The effect of Th1-conditioned cells from interferon-γ (ifn-γ) knockout mice (ifn-γ(-/-) Th1 cells) on the recovery after SCI was reduced. Transfer of Th1-conditioned cells led to the activation of microglia (MG) and macrophages (MΦs), with interleukin 10 (IL-10) upregulation. This upregulation of IL-10 was reduced when ifn-γ(-/-) Th1 cells were transferred. Intrathecal neutralization of IL-10 in the spinal cord attenuated the effects of Th1-conditioned cells. Further, IL-10 is robustly secreted from Th1-conditioned cells in an ifn-γ-dependent manner. Th1-conditioned cells from interleukin 10 knockout (il-10(-/-)) mice had no effects on recovery from SCI. These findings demonstrate that ifn-γ-dependent secretion of IL-10 from Th1 cells, as well as native MG/MΦs, is required for the promotion of motor recovery after SCI.

Neuronal ectopic expression of tyrosine hydroxylase in the mouse striatum by combined administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 3-nitropropionic acid.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a dopaminergic neurotoxin which inhibits mitochondrial complex I. 3-Nitropropionic acid (3-NPA) inhibits mitochondrial complex II and produces specific striatal lesions. In order to produce a combined striatal neuronal and dopaminergic afferent lesion, we administered both toxins simultaneously to the mouse. The combination brought about a lesion in the striatum that was not simply additive of the two combined toxins. Intriguingly, a group of striatal neurons became immunoreactive to tyrosine hydroxylase after day 1. Some of them were clearly visible up to the dendritic details. Immuno-electron microscopy indicated that the tyrosine hydroxylase-positive striatal neurons contained densely immunoreactive polyribosomes. Reverse transcriptase-polymerase chain reaction analysis indicated the up-regulation of tyrosine hydroxylase mRNA in the treated striatum. These neurons were also immunoreactive to aromatic L-amino acid decarboxylase.We conclude that the combined administration of MPTP and 3-NPA caused a more profound damage to the nigro-striatal dopaminergic system, and thus some striatal neurons capable of up-regulating tyrosine hydroxylase were induced to produce dopamine, probably to compensate for the dopamine depletion.

Apoptotic cells associated with Wallerian degeneration after experimental spinal cord injury: a possible mechanism of oligodendroglial death.

We have investigated the temporal and spatial profiles of apoptotic cells in an experimental transection spinal cord injury by the terminal deoxynucleotidyl transferase-mediated biotin-16-2'-deoxyuridine-5'-triphosphate nick-end labeling (TUNEL) method. Twenty-four hours postinjury, a numerous TUNEL-positive cells appeared both rostrally and caudally to the transection site. Those positive cells, however, gradually diminished in number by several days postinjury. In contrast, other TUNEL-positive cells were found scattered within the white matter remote from the lesion by the third day postinjury. These cells were typically embedded in or among vacuolated fibers, where they were identified in close proximity to the vacuolated space enclosed by myelin basic protein (MBP)-positive structures confirmed by TUNEL-MBP double staining. Because of their linear arrangement, these TUNEL-positive cells were considered interfascicular oligodendrocytes, a fact that was confirmed by the finding that some TUNEL-positive cells were also stained with CCI, a cell marker for oligodendrocyte. Electron microscopic studies revealed that the cells expressing apoptotic morphology were invariably encased in a space formed by myelin splitting. Although the biological significance of apoptotic interfascicular oligodendrocytes in the process of wallerian degeneration is yet to be determined, the finding of such profiles localized within degenerating myelin structures suggests that; oligodendrocytes may be "trapped" within rapidly swollen and disintegrating myelin lamellae, which isolates and perhaps predisposes them to death.

Differential activation of microglia after experimental spinal cord injury.

This study sought to experimentally clarify time-dependent, differential microglial activation at various spinal cord locations in response to injury. The spinal cords of Wistar rats were either sharply transected at the Th 11 or subjected to compression at the same site. Immediately to 4 weeks after injury, each spinal cord was fixed and cut into longitudinal frozen sections, and was immunostained with OX42 for resident and activated microglia, OX-6 for activated microglia, GFAP for activated astrocytes, and biotinylated BS-I, a lectin for both resident and activated microglia. From three to 24 hours after injury, we observed a narrow belt around the transection site in which OX42 positive microglia were dramatically reduced in number, or often absent. BS-I labeling of the zone disclosed the rapid transformation of those microglia possessing typical antler-like processes to macrophage-like cells. At day 1 and thereafter, the zone of reduced OX42 immunoreactivity was gradually replaced by macrophage-like OX42-positive round cells, and the lesion itself was ultimately capped by fibrogliotic scar tissue. By 2-4 weeks postinjury, another phase of microglial activation was observed in those white matter tracts undergoing Wallerian degeneration. These microglia characterized by the presence of newly-expressed MHC class II antigens. We posit that the decreased OX42 immunoreactivity suggests that CR3 is quickly saturated by activated iC3b and internalized, but not down-regulated. The trigger for this transformation most likely occurs through signaling by iC3b-saturated CR3. In contrast, microglia activation along those degenerating tracts undergoing Wallerian degeneration does not appear to be CR3-related, as the CR3 is upregulated. These observations indicate microglia have at least two different spatial and temporal patterns of activation. One is rapid and most likely involves the blood-borne complement activating system. The other accompanies Wallerian degeneration and is independent of the blood-borne complement system.

Longterm effects of hepatic arterial interleukin-2-based immunochemotherapy after potentially curative resection of colorectal liver metastases.

BACKGROUND: Our previous study of hepatic arterial infusion of interleukin-2 (IL-2)-based immunochemotherapy demonstrated a high response rate of patients with unresectable liver metastases. In this study, we applied this therapy to the prevention of liver recurrence in patients who underwent potentially curative resection of liver metastases. STUDY DESIGN: A pilot study was conducted of 18 patients with liver metastases from primary colorectal cancer who underwent potentially curative liver resection followed by adjuvant immunochemotherapy. The regimen consisted of a weekly hepatic arterial infusion of IL-2 (1.4-2.1 X 10(6) U) and 5-fluorouracil (250 mg) and a bolus of mitomycin C (2-4 mg) for 6 months. RESULTS: Among 18 patients, 14 are still alive with a median postoperative survival of 52 months (as of April 1998). The 5-year overall survival rate was 75%. Although recurrent cancer developed in 6 of the 18 patients, no patients had recurrence in the residual liver. This complete prevention of liver recurrence is believed to have contributed to the high 5-year survival rate (75%) as compared with the survival rate of patients treated with surgery alone (average, 30%-40%) or with several other forms of adjuvant therapy. CONCLUSIONS: Interleukin-2-based immunochemotherapy is useful in combination with liver resection for the prevention of liver recurrence in colorectal cancer patients with liver metastases. A multicenter randomized trial is recommended.

Adjuvant hepatic arterial IL-2 and MMC, 5-FU after curative resection of colorectal liver metastases.

BACKGROUND/AIMS: Based on our favorable results of interleukin-2-based immuno-chemotherapy in the treatment of unresectable liver metastases from colorectal cancer, we utilized this therapy for the prevention of liver recurrence after liver resection. MATERIALS AND METHODS: Eighteen patients with colon cancer metastatic to the liver underwent successful hepatic resection and adjuvant immunochemotherapy that included hepatic arterial infusion of interleukin-2 and mitomycin C, 5-fluorouracil. The regimen consisted of weekly interleukin-2 (1.4-2x 10(6) units), 5-fluorouracil (250 mg) by 2-hour infusion and bolus mitomycin C (4 mg) for 6 months. RESULTS: Fourteen of 18 patients are alive and disease-free with a median postoperative follow-up of 28.5 months. Recurrent cancer has developed in 4 of the 18 patients (22%). The site of first recurrence was the lung in three patients (17%) and the pelvis in one (6%); no patients recurred in the liver. CONCLUSIONS: We recommend this adjuvant immuno-chemotherapy for the prevention of liver recurrence after curative resection of colorectal liver metastases.

[A case of spontaneous arteriovenous fistula presenting as the partial oculomotor nerve palsy].

We report a case of partial oculomotor nerve palsy due to spontaneous arteriovenous fistula. A 62-year-old man noticed double vision on downward gaze and periorbital pain. Clinical examination revealed inability to move the left eye downwards and to the right, and also anisocoria. No conjunctival injection or proptosis was noted. Findings of computed tomographic scan, magnetic resonance imaging and magnetic resonance angiography of the orbits, cavernous sinus region and brainstem were all normal. Carotid angiography demonstrated arteriovenous fistula via the left ophthalmic artery, the dural branch of the left external carotid artery, and the dural branch of the right internal carotid artery. Partial oculomotor palsy in this case indicated that the left inferior branch of the oculomotor nerve was affected. Inferior branch palsy of the oculomotor nerve in spontaneous arteriovenous fistula has not been described in the literature, while it is reported in cases of trauma, tumor, or aneurysm of the cavernous sinus.

Increased peptidylglycine alpha-amidating monooxygenase activity in cerebrospinal fluid of patients with multiple sclerosis.

Peptidylglycine alpha-amidating monooxygenase (PAM) plays a key role in the biosynthesis of many biologically active neuronal and endocrine peptides that possess alpha-amide function at their C-terminus. Using D-Tyr-Val-Gly as the substrate, we measured PAM activity levels in the cerebrospinal fluid (CSF) and serum of patients with a variety of neurological diseases. PAM activity in the CSF was significantly increased in patients with multiple sclerosis (MS), especially during the active stage, compared with that in patients with other neurological diseases (p < 0.05). Levels of CSF PAM activity were not correlated with protein levels in CSF or with level of serum PAM activity. Since PAM is present not only in neurons but also in oligodendroglia, it is possible that the increase in CSF PAM activity in patients with MS may stem from massive demyelination and oligodendroglial destruction.

Use of personal computers for translation and publication of an anesthesia textbook.

We used personal computers extensively for translating and publishing in Japanese an anesthesia textbook originally written in English. The procedure included optical character recognition, scanning of figures, use of computer translation, use of electronic mail and computer type-setting. While these have individually been done previously, this is process of any medical textbook published in Japanese. The advantages of combining these technologies are good exchange of information among individual authors/translators, rapid translation process, preliminary visualization of the final product, and overall high quality of the published book.

Idiopathic AA amyloidosis manifested by autonomic neuropathy, vestibulocochleopathy, and lattice corneal dystrophy.

A 69-year-old Japanese woman with non-familial amyloidosis had polyneuropathy and profound autonomic neuropathy, and kappa chain monoclonal gammopathy. Immunohistopathological examination showed protein AA and protein AP in the amyloid deposits. She showed involvement of the vestibulocochlear nerve and lattice dystrophy of the cornea. Vestibulocochleopathy and corneal lattice dystrophy have been reported in familial amyloid polyneuropathy type IV, Finnish type, but never in non-familial amyloidosis.

Paraneoplastic cerebellar degeneration and limbic encephalitis in a patient with adenocarcinoma of the colon.

The rare association of two neurological paraneoplastic syndromes, paraneoplastic cerebellar degeneration and limbic encephalitis occurred in a 55 year old woman with a microscopic adenocarcinoma in a colonic polyp. Complete removal of the tumour by polypectomy brought about a favourable recovery from limbic encephalitis but the cerebellar ataxia remained. High titres of antineuronal nuclear antibody resembling anti-Hu were demonstrated in serum by immunohistochemistry using rat brain as a substrate. The antibody identified a protein band of 41 kDa on a Western immunoblot.

[Clinical and experimental studies on gastrointestinal motility following total colectomy: direct measurement (strain gauge force transducer method, barium method) and indirect measurement (hydrogen breath test, acetaminophen method)].

In a clinical study, we examined the clinical assessment of bowel function and lactulose hydrogen breath test in 14 patients after total colectomy. All patients within one year after ileostomy closure had 'poor' function and showed no increase of hydrogen breath gas concentration. 10 of 12 patients more than one year showed increase of hydrogen breath gas concentration, and 8 of them had 'fair' function. The oro-neorectal transit time (ONTT) in 'poor' group was shorter than in 'fair' group and control (p less than 0.05). The increase of hydrogen breath gas suggests changes of bacterial flora and colonization of the remained ileum. In an experimental study, we performed subtotal colectomy with the J-pouch reservoir in 11 dogs. We examined ONTT with barium method, gastric emptying with acetaminophen method, and gastrointestinal motility with strain gauge force transducers. Although ONTT at one month after operation had been shorter than control, ONTT at 3 and 6 months became longer than at one month. The gastric emptying after subtotal colectomy was significantly slower than control. Although the propagation velocity of interdigestive migrating complex (IMC) in the jejunum and ileum at 2 weeks had been faster than control, the velocity at 4 weeks and 3 months became slower than at 2 weeks. The frequency of IMC and prolonged propagated contraction in the J-pouch reservoir decreased. The specimen of J-pouch reservoir resected at 6 months showed villous atrophy, crypt elongation, decrease of muscle layers thickness and disappearance of solitary follicles. Therefore, the suppressed motility in each sites of the gastrointestinal tract, increase of anaerobic and colonization of the ileum implied 'adaptation' after total colectomy.

[Two cases of primary pulmonary non-Hodgkin lymphoma].

Two cases of primary pulmonary non-Hodgkin lymphoma were presented. Case one had diffuse, homogeneous consolidation with air bronchogram in rt. upper lobe. Case two had a mass-like shadow with air bronchogram in rt. middle lobe. Both had no significant symptom, pleural effusion and lymphadenopathy. Patients with this entity had good prognosis.

[A case of non-resectable thymoma which responded to the administration of adriamycin, vindesine and 5-FU].

Surgery and radiotherapy have been considered to be the primary therapies for malignant thymoma. However, the results of these therapies for invasive thymoma are poor. Recently, combination chemotherapy for invasive thymoma has been tried and good results have been reported. A 50-year-old female was admitted to our hospital. Her chest film showed a large anterior mediastinal tumor which was diagnosed as invasive thymoma. In order to remove the tumor, median sternotomy and 4th intercostal thoracotomy was done but the mass was found to have invaded to the adjacent tissues, and so only partial resection of the tumor was performed. Postoperatively, the patient was treated with Adriamycin, Vindesine and 5-FU, as a result of which the mass completely disappeared and CR was achieved. Our regimen, AVF, for non-resectable thymoma is therefore thought to be a potentially effective treatment.

Rapid alterations of the axon membrane in antibody-mediated demyelination.

Alterations of nodal and paranodal axolemma of the rat sciatic nerve were investigated in antigalactocerebroside serum-induced demyelination. A ferric ion-ferrocyanide (FeFCN) stain that appears to stain the regions with a high sodium channel density in nerve fibers was applied. When acute conduction block was initiated 20 to 180 minutes after the antiserum injection, myelin terminal loops began to be detached from the paranodal axolemma and reaction product of FeFCN stain originally localized at the nodes decreased in density and extended to the paranodal axolemma. By the time that complete conduction block was established, 5 hours after the injection, FeFCN stain was barely detectable around the nodal area. The loss of staining was associated with detachment and vesiculovacuolar degeneration of the paranodal myelin. This rapid deterioration and disappearance of normal cytochemical characteristics of the axolemma in the presence of only modest paranodal demyelination could be a morphological correlate of the loss of excitability of the axon membrane.