Familial amyotrophic lateral sclerosis with bulbar onset and a novel Asp101Tyr Cu/Zn superoxide dismutase gene mutation

We describe a patient with familial amyotrophic lateral sclerosis (FALS) in whom we identified a novel missense mutation in exon 4 (Asp101Tyr) of the Cu/Zn superoxide dismutase (SOD1) gene. The disease started with a bulbar symptom (rapidly progressive hoarseness) and at autopsy showed degenerative changes restricted to the upper and lower motor neuron systems (more strictly, with lower motor predominance, showing the most severe degeneration in the nucleus ambiguus). Occasional intracytoplasmic Lewy-body-like hyaline inclusions that were immunoreactive for ubiquitin and SOD1, but immunonegative for neurofilament protein, were found in the lower motor neurons. This is the first report of hoarseness as the initial manifestation of FALS. This SOD1 gene mutation may be associated with a particular clinicopathological phenotype.     

Comparison of once-daily nifedipine controlled-release with twice-daily nifedipine retard in the treatment of essential hypertension

AIMS: Nifedipine is a short-acting calcium antagonist formulated into several different oral preparations, each of which may have different effects on haemodynamics and autonomic nervous function. We compared the effects of nifedipine controlled-release (CR) and nifedipine retard on 24-h blood pressure, heart rate, rate-pressure product, and power spectral measures of heart rate variability in patients with essential hypertension. METHODS: After 4 weeks of a drug-free period, 25 patients were randomized to receive either once-daily treatment with nifedipine CR (20-40 mg daily; 12 patients) or twice-daily treatment with nifedipine retard (20-40 mg daily; 13 patients) for 12 weeks. The ambulatory blood pressure, heart rate, and ECG R-R intervals were measured during a 24-h period using a portable recorder (TM-2425) at the end of the drug-free and the treatment periods. A power-spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. RESULTS: Nifedipine CR and nifedipine retard reduced 24-h blood pressure significantly by 15.9 +/- 3.2 (SE)/8.7 +/- 1.4 mmHg and by 10.9 +/- 2.8/9.4 +/- 1.7 mmHg, respectively, after the 12-week treatment. Nifedipine CR did not change the 24-h heart rate significantly, while nifedipine retard increased it significantly by 3.9 +/- 2.1 beats min(-1). Nifedipine CR produced a significant reduction in rate-pressure product throughout a 24-h period, while nifedipine retard did not change the rate-pressure product significantly. In addition, nifedipine retard significantly decreased the 24-h and daytime average values of the LF and HF components, while nifedipine CR affected the nighttime LF component alone and did not change the HF component throughout a 24-h period. CONCLUSIONS: These results demonstrate that both nifedipine CR and nifedipine retard are effective as antihypertensive agents, but nifedipine CR has less influence on the autonomic nervous system and heart rate than nifedipine retard.     

Development of TCR alpha beta CD8 alpha alpha intestinal intraepithelial lymphocytes is promoted by interleukin-15-producing epithelial cells constitutively stimulated by gram-negative bacteria via TLR4

The microbes present in the intestine have a strong influence on the development and maturation of lymphoid organs. The cross-talk mechanisms between intestinal intraepithelial lymphocytes (i-IEL) and noninvasive microbes are still poorly understood. The influence of microbes and lipopolysaccharides on the development of i-IEL, especially the TCR alpha beta(+) CD8 alpha alpha subset, was investigated using the different TLR4-mutant mouse strains C3H/HeJ, BALB/lps(d), and C57BL/10ScCr. Intestinal epithelial cells (i-EC) from TLR4-mutant strains did not express interleukin (IL)-15 mRNA, while IL-15 mRNA expression in i-EC from the corresponding wild-type, C3H/He, BALB/c, and C57BL/10ScSn mice was detected. The development of TCR alpha beta(+) CD8 alpha alpha cells in i-IEL significantly decreased in TLR4-mutant mice compared with the corresponding wild-type mice, while other T cell subsets in i-IEL showed similar percentages in the TLR4-mutant and wild-type mice. Adult thymectomized (ATx-) and lethally irradiated C3H/HeJ mice reconstituted with T cell-depleted bone marrow cells from C3H/He mice showed a significantly lower percentage of TCR alpha beta CD8 alpha alpha i-IEL than ATx-C3H/He mice after transfer of C3H/HeJ BM cells. The percentage of TCR alpha beta CD8 alpha alpha i-IEL and IL-15 mRNA expression in i-EC from BALB/lps(d) mice did not increase during Salmonella typhimurium infection but was significantly enhanced during Listeria monocytogenes infection. Our findings suggest that LPS induces IL-15 production by i-EC, resulting in the development of TCR alpha beta CD8 alpha alpha i-IEL.     

The effect of a newly synthesized indazole compound, TAS-3-124, on experimental autoimmune disease

The effects of a newly synthesized compound, 6-acetoamido-1-acetyl-1-indazole (TAS-3-124), on autoimmune diseases were studied. We used animal models of collagen-induced arthritis (CIA) in mice and experimental autoimmune encephalomyelitis (EAE) in rats to evaluate the efficacy of TAS-3-124. TAS-3-124 at doses of 100 and 300 mg/kg p.o. inhibited the development of CIA, decreasing the swelling of fore- and hind-limbs and bone destruction in knee joints. This agent also suppressed the delayed type hypersensitivity reaction (DTH) against type II collagen. These effects were confirmed by histopathological examination and measurement of the expression of mRNA of proinflammatory cytokines in the knee joint. In addition, TAS-3-124 at a dose of 300 mg/kg inhibited the development of EAE and the DTH to myelin basic protein (MBP) in rats. Moreover, TAS-3-124 inhibited the production of proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and IL-6 but not T cell derived cytokines in mice. These demonstrate the efficacy of TAS-3-124 against experimental autoimmune disease, probably due to the suppression of the production of proinflammatory cytokines in the pathological lesion.     

Potentiation of cytotoxic activity in naïve and tumor-bearing mice by oral administration of hot-water extracts from Agaricus brazei fruiting bodies

When hot-water extracts of mushroom Agaricus brazei MURRILL fruiting bodies (Agaricus extracts) were administered orally into Meth A-bearing mice, tumor growth was significantly inhibited compared with controls given water orally. Treatment with Agaricus extracts for five successive days significantly increased natural killer activity of spleen cells in na?ve BALB/c mice. In Meth A-bearing BALB/c mice, Agaricus extracts enhanced the induction of antigen-specific cytotoxic T lymphocytes and interferon gamma production, indicating that Agaricus extracts potentiate cytotoxic activity in innate and adaptive immunity.