Association of the insertion/deletion polymorphism of the angiotensin I-converting enzyme gene in patients of migraine with aura

Recently, several angiotensin I-converting enzyme (ACE) inhibitors and an angiotensin II receptor blocker were demonstrated to have a clinically important prophylactic effect in migraine. ACE is one of the key enzymes in the rennin-angiotensin-aldosterone system, which modulates vascular tension and blood pressure. In humans, serum ACE levels are strongly genetically determined. Individuals who were homozygous for the deletion (D) allele showed increased ACE activity levels. To investigate the role of ACE polymorphism in headache, we analyzed the ACE insertion (I)/deletion (D) genotypes of 54 patients suffering from migraine with aura (MwA), 122 from migraine without aura, 78 from tension-type headache (TH), and 248 non-headache healthy controls. The ACE D allele were significantly more frequent in the MwA than controls (p<0.01). The incidence of the D/D genotype in MwA (25.9%) was significantly higher than that in controls (12.5%; p<0.01; odds ratio=5.26, 95% confidence interval: 1.69-16.34, adjusted for age and gender). No differences in the remaining groups were found. Our results support the conclusion that the D allele and the D/D genotype in the ACE gene is a genetic risk factor for Japanese MwA. There seems to be a possible relationship between ACE activity and the pathogenesis of migraine.     

Optimum selection of an implantable secondary battery for an artificial heart by examination of the cycle life test

An implantable secondary battery is one of the key components in a total artificial heart system. Because a 2 year cycle life is required, the cycle life of the secondary battery as well as its charge and discharge properties are important parameters for selection of an appropriate battery. We carried out cycle life tests on four kinds of rechargeable batteries (a Ni-MH secondary battery, a Ni-Cd secondary battery, a Li-ion battery with a graphite anode, and a Li-ion battery with a nongraphitizable carbon electrode) to determine their suitability as implanted back-up batteries. Each of the batteries was charge/discharge cycled at 37 degrees C to 39 degrees C using a charge current of 1 C ampere, and they were each fully discharged under either pulsatile discharge loads, which mimicked pulsatile operation, or a nonpulsatile load equivalent to the average of the pulsatile loads. The two Li-ion batteries made by different manufacturers both met the minimum requirement of cycle life of more than 1,500 cycles, considering safety coefficient regardless of the discharge pattern. In addition, the temperature increase of these Li-ion batteries (3 degrees C) was lower than that of Ni-Cd and Ni-MH batteries (15-25 degrees C). Out of these four batteries, the two Li-ion batteries are the most suitable for use in a totally implantable artificial heart system.     

Expression of the alpha1D subunit of the L-type voltage gated calcium channel in human liver

Calcium channel blocker is useful for a variety of purposes and is effective for preventing hepatitis elicited by different inducers, suggesting its possible clinical application for treating hepatitis. The alpha1-subunit of the dihydropyridine-sensitive L-type calcium channel is a target of calcium channel blocker. For clinical application of calcium channel blocker, it is important to analyze the expression of the L-type calcium channel in the liver. However, the subtype of the L-type calcium channel alpha1-subunit expressed in the liver was not known. In the present study, the alpha1-subunit of the calcium channel expressed in human liver was systematically analyzed. The alpha1D subunit of the dihydropyridine-sensitive L-type voltage gated calcium channel is expressed relatively strongly in the liver and may play an important role in the liver.     

Cytogenetic and comparative genomic hybridization findings in four cases of breast cancer after neoadjuvant chemotherapy

To assess a potential common pattern of genetic alterations in chemotherapy-resistant tumors we analyzed four tumors from breast cancer patients (patients 1-4) after neoadjuvant chemotherapy, by comparative genome hybridization (CGH) and conventional chromosome banding analysis. All patients showed structural aberrations involving chromosomes 1, 5, 11, 16, and 17. In CGH analysis, the patients showed typical imbalances for ductal breast cancer: gains of 1q (3 patients), 5q (2 patients), 8q (3 patients), and X (4 patients) and losses of 1p33 approximately p36 (3 patients), 16q (3 patients), 17p (3 patients), 19 (4 patients), and 22q (4 patients). Other recurrent imbalances of atypical pattern for ductal breast cancer were gain of 4q21 approximately q32 (2 patients), 20q21 approximately q22 (2 patients), and 21 (2 patients) and loss of 20p (3 patients). Three patients showed involvement of several regions bearing genes of drug resistance (MDR1 [HUGO symbol: ABCB1], BCRP [HUGO symbol: ABCG2], MRP1 [HUGO symbol: ABCC1], RFC1); the fourth patient displayed an amplification in the region of MYC (alias c-myc), thus providing--at the level of the light microscope--an explanatory background for the ability of their tumors to survive anthracycline-, taxane- and cyclophosphamide-based chemotherapy. Conventional cytogenetic analysis and CGH displayed highly coincidental findings in the tumors of four patients after neoadjuvant chemotherapy for breast cancer.     

Dipole-tracing of 'awareness' attenuating the cortical components of somatosensory evoked potentials

Using the dipole-tracing method, the source generators of N18, P22 and P40 of the somatosensory evoked potential (SEP) were estimated as the equivalent dipole. After voluntary action of the thumb flexion, no changes were observed in N18 or P40, but the amplitude of P22 was suppressed. The after-effects of intention accompanied by a voluntary action or the subject's awareness that electrical stimulation will be given after the voluntary action were treated as 'awareness'. By subtracting the pure SEP from SEP during 'awareness', it was found that the equivalent dipole of 'awareness' of P22 was located at the same region of pure P22, but the vector was of opposite orientation. 'Awareness' attenuated the perceptive potential of SEP like P22 generated in the cortex.     

Helicobacter pylori urease suppresses bactericidal activity of peroxynitrite via carbon dioxide production

Helicobacter pylori can produce a persistent infection in the human stomach, where chronic and active inflammation, including the infiltration of phagocytes such as neutrophils and monocytes, is induced. H. pylori may have a defense system against the antimicrobial actions of phagocytes. We studied the defense mechanism of H. pylori against host-derived peroxynitrite (ONOO(-)), a bactericidal metabolite of nitric oxide, focusing on the role of H. pylori urease, which produces CO(2) and NH(3) from urea and is known to be an essential factor for colonization. The viability of H. pylori decreased in a time-dependent manner with continuous exposure to 1 microM ONOO(-), i.e., 0.2% of the initial bacteria remained after a 5-min treatment without urea. The bactericidal action of ONOO(-) against H. pylori was significantly attenuated by the addition of 10 mM urea, the substrate for urease, whereas ONOO(-)-induced killing of a urease-deficient mutant of H. pylori or Campylobacter jejuni, another microaerophilic bacterium lacking urease, was not affected by the addition of urea. Such a protective effect of urea was potentiated by supplementation with exogenous urease, and it was almost completely nullified by 10 microM flurofamide, a specific inhibitor of urease. The bactericidal action of ONOO(-) was also suppressed by the addition of 20 mM NaHCO(3) but not by the addition of 20 mM NH(3). In addition, the nitration of L-tyrosine of H. pylori after treatment with ONOO(-) was significantly reduced by the addition of urea or NaHCO(3), as assessed by high-performance liquid chromatography with electrochemical detection. These results suggest that H. pylori-associated urease functions to produce a potent ONOO(-) scavenger, CO(2)/HCO(3)(-), that defends the bacteria from ONOO(-) cytotoxicity. The protective effect of urease may thus facilitate sustained bacterial colonization in the infected gastric mucosa.     

Evidence in patients with systemic lupus erythematosus of the presence of antibodies against RNA-dependent DNA polymerase of baboon endogenous virus.

Immunoglobulin G (IgG) in six out of 30 patients with systemic lupus erythematosus (SLE) strongly inhibited the activity of RNA-dependent DNA polymerase (RDPase) of baboon endogenous virus, M7, while IgG obtained from scleroderma patients, rheumatoid arthritis patients and normal subjects was less reactive. Experiments with anti-human IgG and with IgG F (ab')2-bound immunoaffinity columns indicated that the inhibition of RDPase was antibody-mediated. The RDPase inhibiting activity of SLE IgG was considered not to be due to cross-reactions of anti-nuclear antibodies including anti-DNA, anti-ribonucleoprotein, anti-Sm and anti-SS.B antibodies. SLE IgG preferably inhibited the RDPase activity of baboon endogenous virus and a feline endogenous virus, RD114. These findings support the hypothesis that retrovirus(es) might be involved in SLE.     

Blockade of vascular endothelial cell growth factor receptor signaling is sufficient to completely prevent retinal neovascularization

Retinal vasculogenesis and ischemic retinopathies provide good model systems for study of vascular development and neovascularization (NV), respectively. Vascular endothelial cell growth factor (VEGF) has been implicated in the pathogenesis of retinal vasculogenesis and in the development of retinal NV in ischemic retinopathies. However, insulin-like growth factor-I and possibly other growth factors also participate in the development of retinal NV and intraocular injections of VEGF antagonists only partially inhibit retinal NV. One possible conclusion from these studies is that it is necessary to block other growth factors in addition to VEGF to achieve complete inhibition of retinal NV. We recently demonstrated that a partially selective kinase inhibitor, PKC412, that blocks phosphorylation by VEGF and platelet-derived growth factor (PDGF) receptors and several isoforms of protein kinase C (PKC), completely inhibits retinal NV. In this study, we have used three additional selective kinase inhibitors with different selectivity profiles to explore the signaling pathways involved in retinal NV. PTK787, a drug that blocks phosphorylation by VEGF and PDGF receptors, but not PKC, completely inhibited retinal NV in murine oxygen-induced ischemic retinopathy and partially inhibited retinal vascularization during development. CGP 57148 and CGP 53716, two drugs that block phosphorylation by PDGF receptors, but not VEGF receptors, had no significant effect on retinal NV. These data and our previously published study suggest that regardless of contributions by other growth factors, VEGF signaling plays a critical role in the pathogenesis of retinal NV. Inhibition of VEGF receptor kinase activity completely blocks retinal NV and is an excellent target for treatment of proliferative diabetic retinopathy and other ischemic retinopathies.     

Enhanced invasion of Tax-expressing fibroblasts into the basement membrane is repressed by phosphorylated ascorbate with simultaneous decreases in intracellular oxidative stress and NF-kappa B activation

Invasion of rat fibroblastic cells Rat-1 through Matrigel was shown to be promoted by transfection with tax gene of human T-cell leukemia virus type 1. We found that an oxidation-resistant type of vitamin C (Asc), Asc-2-O-phosphate (Asc2P), inhibited the invasion of the tax-transfected Rat-1 cells (W4 cells). Intracellular Asc (Ascin), after enzymatic dephosphorylation of administered Asc2P, was more abundant in W4 cells than in Rat-1 cells, and the ratio of dehydroascorbic acid versus Asc was increased in W4 cells but scarcely in Rat-1 cells, according to the enhanced level of intracellular reactive oxygen species (ROSin) in W4 cells. Asc2P notably repressed the increases in both ROSin and secretion of matrix metalloproteases (MMPs), but did not affect Tax protein expression in tax-transfectants. NF-kappa B activation, as evidenced by its translocation to the nucleus in W4 cells, was also repressed by Asc2P. Thus, the tax-promoted invasion together with the enhanced production of MMPs occurred with NF-kappa B activation and the increase in ROSin, both of which were effectively reduced by Asc2P. These findings indicate the therapeutic efficacy of Ascin-enriching agents for the prevention against tumor invasion in which ROSin plays a major role.     

A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy

Chromosome 1p36 deletion syndrome is characterized by hypotonia, moderate to severe developmental and growth retardation, and characteristic craniofacial dysmorphism. Muscle hypotonia and delayed motor development are almost constant features of the syndrome. We report a 4-year-old Japanese girl with 1p36 deletion syndrome whose muscle pathology showed congenital fiber type disproportion (CFTD) myopathy. This is the first case report of 1p36 deletion associated with CFTD. This association may indicate that one of the CFTD loci is located at 1p36. Ski proto-oncogene −/− mice have phenotypes that resemble some of the features observed in patients with 1p36 deletion syndrome. Because fluorescent in situ hybridization analysis revealed that the human SKI gene is deleted in our patient, some genes in 1p36, including SKI proto-oncogene, may be involved in muscle hypotonia and delayed motor development in this syndrome. Received: March 4, 2002 / Accepted: July 7, 2002