Antisense Cdk2 kinase oligodeoxynucleotide inhibits ICAM-1 expression in murine cardiac allograft arteriopathy.
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Animals↗
Biomedical subjects
M Aoki
Publications and source records attributed to M Aoki.
Recurrent dorsal angulation of the distal radius fracture during dynamic external fixation.
Thirty-three fractures of the distal radius treated with a dynamic external fixator (that allowed for wrist motion between 2 to 4 weeks after surgery) were analyzed, focusing on loss of fracture reduction during external fixation. Fractures with preoperative dorsal angulation greater than 20 degrees and those involving the distal radioulnar joint had a significantly larger loss of reduction of dorsal angulation (8.9 degrees and 6.9 degrees, respectively) than fractures with less severe preoperative dorsal angulation or those with an intact distal radioulnar joint (3.0 degrees and 2.6 degrees, respectively). In contrast, preoperative radial shortening (>2 mm) and involvement of the radiocarpal joint did not significantly increase the loss of dorsal angulation. Neither of the 2 dynamic external fixation systems studied consistently stabilized Colles' fractures with preoperative dorsal angulation of greater than 20 degrees or involvement of the distal radioulnar joint.
Adult↗
Enhancement of heat shock protein expression after transient ischemia in the preconditioned spinal cord of rabbits.
PURPOSE: This investigation was designed to evaluate the mechanism used to acquire a tolerance to spinal ischemia. We investigated inductions of the heat shock protein (HSP) 70 gene and protein in rabbit spinal cord with or without preconditioning. METHODS: Neurologic function, morphologic changes, and inductions of HSP70 messenger RNA (mRNA) and protein were compared in the cases of a 15-minute ischemia 2 days after sham treatment and a 15-minute ischemia 2 days after 10-minute preconditioning. RESULT: HSP70 mRNA was induced at 8 hours of reperfusion after a 15-minute ischemia 2 days after sham treatment. HSP70 protein was induced slightly in selective motor neuron cells at 8 hours of reperfusion, and about 70% of motor neuron cells showed selective cell death after 7 days of reperfusion (p < 0.01). On the other hand, large populations of the motor neuron cells survived at 7 days after the 15-minute ischemia that was applied at 2 days after preconditioning (p < 0.01). HSP70 mRNA was induced persistently as compared with the case of a 15-minute ischemia 2 days after sham treatment. The motor neuron cells strongly produced immunoreactive HSP70 from 8 hours to 2 days. CONCLUSION: Preconditioning with 10-minute ischemia enhanced and prolonged the HSP70 gene expression at both mRNA and protein levels and saved the motor neuron cells from subsequent lethal ischemia. These changes of HSP70 gene expression may play an important role in the acquisition of ischemic tolerance of motor neuron cells in rabbit spinal cord.
Animals↗
Effects of adenosine infusion with or without leukocyte depletion on recovery after hypothermic ischemia in neonatal lamb hearts.
OBJECTIVE: Leukocytes have been shown to have an important role in ischemia/reperfusion injury. Adenosine also reduced this ischemia/reperfusion injury. There is an interaction between adenosine and leukocyte via receptor mediated function. To determine whether beneficial effects of adenosine on reperfusion injury is mediated by changes in leukocyte function, we studied the effects of adenosine with and without leukocyte depletion during reperfusion on the functional recovery of the neonatal myocardium after cold cardioplegic arrest. MATERIALS AND METHODS: We infused adenosine (350 micromol/l) during the first 20 min of reperfusion for adenosine treated group and adenosine-leukocyte treated group. The other two groups were perfused with leukocyte treated blood or untreated blood. All the groups were subjected to 2 h of cold cardioplegic ischemia (n = 8 in each group). At 30 min of reperfusion, LV function was measured. Coronary blood flow and oxygen consumption (MVO2) were also measured to evaluate the metabolic recovery. RESULTS: Adenosine treated, adenosine-leukocyte treated, and leukocyte treated groups showed better functional recovery than the control group (maximum developed pressure: control = 74.6 +/- 5.6%, adenosine treated = 97.6 +/- 9.5%, adenosine-leukocyte treated = 98.5 +/- 5.6%, leukocyte treated = 82.5 +/- 6.0%. P < 0.05). Both adenosine treated and adenosine-leukocyte treated groups showed better recovery than leukocyte treated group (P < 0.05). Coronary blood flow was higher in adenosine-leukocyte treated group compared to other groups (P < 0.05). MVO2/beat was higher in adenosine treated, adenosine-leukocyte treated, and leukocyte treated groups than control group (P < 0.05). CONCLUSION: Adenosine, with or without leukocyte depletion, had similar beneficial effect on recovery of systolic and diastolic functions, which involved other mechanisms in addition to the leukocyte inhibitory effect.
Adenosine↗
Mitochondrial DNA analysis of Sporothrix schenckii in North and South America.
Mitochondrial DNA (mtDNA) types based on restriction fragment length polymorphism (RFLP) patterns with HaeIII were investigated in clinical isolates of Sporothrix schenckii in North and South America. In addition to 14 mtDNA types (Types 1-14) so far reported, six new mtDNA types, Types 15-20 were found in this study. Type 3 was divided into two subtypes, Subtype 3A and Subtype 3B based on RFLP with Msp1. Type 14 was also divided into three subtypes, Subtype 14A, Subtype 14B and Subtype 14C based on RFLP with Hha1. Nineteen isolates in the United States consisted of 1 isolate of Type 1, 12 of Type 2, 2 of Type 4, 3 of Type 14 (1 of Subtype 14B and 2 of Subtype 14C) and 1 of Type 15. Twenty nine isolates in Venezuela consisted of 13 of Type 3 (Subtype 3B), 6 of Type 4, 1 of Type 18, 3 of Type 19 and 6 of Type 20. Thirteen isolates in Argentina consisted of 2 of Type 3 (Subtype 3A), 4 of Type 4, 4 of Type 16 and 3 of Type 17. One isolate in Brazil was Type 3 (Subtype 3A). Based on the phylogeny of 20 mtDNA types (Types 1-20) constructed by estimating sequence divergences of mtDNA, mtDNA types were clustered into two groups: Group A (Types 1-3, Type 11 and Types 14-19) and Group B (Types 4-10, Types 12-13 and Type 20). These results suggest that S. schenckii isolates in North and South America mainly belong to Group A.
DNA, Fungal↗
Molecular analyses of the Cu/Zn superoxide dismutase gene in patients with familial amyotrophic lateral sclerosis (ALS) in Japan.
1. Amyotrophic lateral sclerosis (ALS) is a degenerative disorder characterized by selective damage to the neural system that mediates voluntary movement. Although the pathophysiologic process of ALS remains unknown, about 5 to 10% of cases are familial. According to genetic linkage studies, the familial ALS (FALS) gene has been mapped on chromosome 21 in some families and recent work identified some different missense mutations in the Cu/Zn superoxide dismutase gene in FALS families. 2. We recently identified five mutations in six FALS families. The mutations identified in our FALS families are H46R, L84V, I104F, S134N, and V148I. The H46R mutation that locates in the active site of Cu/Zn SOD gene is associated with two Japanese families with very slow progression of ALS. On the other hand, the L84V mutation associated with a rapidly progressive loss of motor function with predominant lower motor neuron manifestations. 3. In the family with the V148I, the phenotype of the patient varied very much among the affected members. One case had weakness of the lower extremities at first and died without bulbar paresis. The second case first noticed wasting of the upper limbs with bulbar symptoms, but the third had weakness of upper extremities without developing dysarthria nor dysphagia until death. These mutations account for 50% of all FALS families screened, although Cu/Zn SOD gene mutations are responsible for less than about 13-21% in the Western population. 4. Our results indicate that the progression of disease with mutations of Cu/Zn SOD is well correlated with each mutation. The exact mechanism by which the abnormal Cu/Zn SOD molecules selectively affect the function of motor neurons is still unknown.
Adult↗
Stress protein inductions after brain ischemia.
1. Hippocampal CA1 neurons are the most vulnerable to transient cerebral ischemia. However, the mechanism has not been fully understood. 2. The mRNAs for 72-kd (HSP72) and 73-kd (HSC73) heat shock proteins (HSPs), which are located mainly in the cytoplasm, were greatly induced together in CA1 cells, with a peak at 1-2 days in gerbils. However, immunoreactive HSP72 protein was only minimally expressed in CA1 neurons. 3. The mRNA for mitochondrial HSP60 began to increase at 3 hr in CA1 cells and was sustained until 1 day. 4. The level of mRNA for cytochrome c oxidase subunit I (COX-I) progressively decreased in CA1 neurons after a transient ischemia and completely disappeared at 7 days. The activity of cytochrome c oxidase (COX) protein also showed an early decrease in CA1 cells and was followed by a reduction in the level of COX-I DNA after 2 days. 5. These results suggest that HSP gene inductions were inhibited at the translational level but that mitochondrial DNA expression was disturbed at the transcriptional level. A disturbance of mitochondrial DNA expression could cause progressive failure of energy production of CA1 cells that eventually results in neuronal cell death.
Animals↗
Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.
Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).
Adult↗
Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene.
The senescent cell-derived inhibitor (sdi)-1 (p21) protein has been identified as a downstream mediator of the tumor suppressor p53 in the cell cycle regulation. In this study, we focused on the function of sdi-1 gene in inhibiting vascular smooth muscle cell (VSMC) proliferation after vein grafting in a rabbit model. To test the hypothesis, we transfected human sdi-1 gene by an intra-operative approach. Accompanied by markedly increased sdi-1 protein, the significant increase in PCNA-stained VSMCs in vein grafts was inhibited by transfection of sdi-1 gene. Moreover, at 2 weeks after transfection, transfer of sdi-1 gene resulted in a significant inhibition in neointimal formation, compared with control vector. Of importance, immunohistological studies determining the expression pattern of myosin heavy isoforms, adult type specific SM2 and embryonic specific SMemb/NMHC-B, demonstrated expression of the adult phenotype of VSMCs in the neointima of sdi-1 gene-transfected vein grafts at 2 weeks after the operation, while the neointima was predominantly composed of embryonic phenotype of VSMCs in the control grafts. Overall, these results demonstrate that a single intraluminal incubation of human sdi-1 gene can result in a significant inhibition of neointimal formation after vein grafting, associated with phenotypic change of VSMCs from neonatal to adult type in a rabbit model. Inhibition of hyperplasia in a graft model by transfection of sdi-1 gene may be due to the change in VSMC phenotype from neonatal to adult, in addition to the inhibition of VSMC growth.
Actins↗
Prevention of vestibular deafferentation-induced spontaneous nystagmus with pretreatment of Ca2+ channel/N-methyl-D-aspartic acid receptor antagonists in guinea pigs.
Involvement of Ca2+ channel and N-methyl-D-aspartic acid (NMDA) receptors with induction of the spontaneous nystagmus (SN) after unilateral labyrinthectomy (UL) was evaluated by examining the effect of verapamil and MK-801 in guinea pigs. An injection of verapamil or MK-801 before the intratympanic application of arsanilate significantly (p < 0.05) suppressed the frequency of the SN towards the arsanilate-applied side. The frequency of the SN towards the intact side in these drug-treated animals was much lower than in the control animals until 36 h after the application of arsanilate. In addition, 60 days subsequent to induction of the UL, application of the drug before we injected the arsanilate into the opposite middle ear suppressed the SN towards the second arsanilate-injected side, but not towards the first injection side. We suggest that Ca2+ channel and NMDA receptor may be involved in the induction of the SN, and that the pretreatment of their antagonists could be applied in preventing the vestibular deafferentation-induced SN.
Animals↗
Asymmetry of vestibular function induced by unidirectional visual-vestibular conflict.
We describe an attempt to model unilateral vestibular dysfunction in normal man by inducing vestibular asymmetry with exposure to long-term, unidirectional, visual-vestibular conflict. Subjects were exposed to pseudo-random (0.13, 0.2, 0.25, 0.3Hz; 77 degrees/s peak) oscillation in Yaw for 30 min whilst viewing a surrounding, whole field optokinetic drum which rotated with them when they were rotating rightwards and remained earth stationary when they rotated leftwards. Adaptation to this stimulus was assessed by combined tests of "goal-directed" vestibular-ocular reflex (VOR) and vestibular memory contingent saccades (VMCS) in 5 subjects and in a further 4 subjects by combined tests of perception of reorientation (a "navigation" task) and sinusoidal VOR at 0.1 and 0.32 Hz. The exposure induced a reduction in the gain of the VMCS and an underestimation of perceived amplitude of displacement when subjects were turned rightwards. VOR gain for rightwards movement was reduced more markedly at 0.1 Hz. No change was found in the goal-directed VOR gain. Thirty minutes after adaptation, the asymmetry of the VOR gain remained at 0.1 Hz, but vestibular perception recovered to normal. Asymmetrical adaptation can be achieved with short exposures and is more marked for low frequency stimuli. Modification reflex of vestibular functions endures longer than of perception of reorientation.
Adaptation, Physiological↗
Sex differences in marital and social adjustment.
A sample of 67 married Japanese men and 79 married Japanese women, ranging in age from 25 through 85 years, were interviewed to clarify the relationship between marital adjustment and social adjustment. For the whole sample, the total score of the Short Marital Adjustment Test (SMAT; Locke & Wallace, 1959) and its subcategories, dyadic consensus and satisfaction, was significantly correlated with 5 subcategory scores of the Social Adjustment Scale-II (SAS-II; Weissman, 1978): household adjustment (except the spouse), external family adjustment, work adjustment, social leisure adjustment, and general adjustment. These correlations were present also for the women; for the men, they were present only for social leisure adjustment and general adjustment. Among men, the dyadic consensus scores of the SMAT had stronger correlations with the social adjustment scores; among women, correlations with the marital satisfaction scores of the SMAT were stronger. Thus, marital adjustment may be a part of social adjustment for women, but the two may be discrete for men.
Adult↗
Primary cutaneous Langerhans cell histiocytosis in an adult.
A 76-year-old man with Langerhans cell histiocytosis was admitted with an asymptomatic, dark red nodule on his left buttock. Histologic examination of the nodule showed a dense dermal infiltrate of histiocytic cells with bean-shaped nuclei; these cells reacted with antibodies to S-100 and CD1a. Ultrastructural analysis showed Birbeck granules in the cytoplasm of the histiocytic cells. Inguinal lymph node involvement subsequently developed in the patient and cutaneous nodules recurred three times in the inguinal area. Four years have passed since he first was admitted to our hospital with the cutaneous nodule on his buttock, and he is doing well without any intensive treatment except wide excision of the nodules and inguinal lymph nodes. We believe this case should be classified as one of "benign" primary cutaneous Langerhans cell histiocytosis based on the clinical course.
Aged↗
Transcription factor decoy for nuclear factor-kappaB inhibits tumor necrosis factor-alpha-induced expression of interleukin-6 and intracellular adhesion molecule-1 in endothelial cells.
BACKGROUND: Several cytokines and adhesion molecules released from endothelium play an important role in inflammation, immune responses, and probably atherogenesis. OBJECTIVE: To determine whether the transcription factor nuclear factor-kappaB mediated expression of these genes involved in the inflammatory response of endothelial cells to tumor necrosis factor-alpha, by using transcription factor decoy oligodeoxynucleotides. DESIGN AND METHODS: We first transfected fluorescein isothiocyanate (FITC)-labeled double-stranded oligodeoxynucleotides into endothelial cells by a cationic liposome-mediated method of gene transfer. We then confirmed that the decoy oligodeoxynucleotides could block binding of nuclear factor-kappaB to its specific cis element effectively. In addition, we transfected the reporter gene chloramphenicol acetyltransferase driven by three repeated nuclear factor-kappaB binding sequences in the promoter and enhancer region. RESULTS: FITC-labeled oligodeoxynucleotides were detected in the nuclei of approximately 70% of the total cells. Tumor necrosis factor--stimulated expression of chloramphenicol acetyltransferase was partially inhibited by transfection of nuclear factor-kappaB decoy oligodeoxynucleotides, but not by transfection of scrambled oligodeoxynucleotides. Also nuclear factor-kappaB decoy oligodeoxynucleotides but not scrambled oligodeoxynucleotides inhibited tumor necrosis factor-induced expression of interleukin-6 and intracellular adhesion molecule-1 both at the messenger RNA and at protein level (assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay). CONCLUSION: Our results demonstrate that nuclear factor-kappaB decoy oligodeoxynucleotides transfected by cationic liposome method inhibited tumor necrosis factor--induced expression of interleukin-6 and intracellular adhesion molecule-1 in endothelial cells.
Animals↗
Mitochondrial DNA deletion is a predisposing cause for sensorineural hearing loss.
Composed of a postmitotic stable tissue, the inner ear is a target organ for mitochondrial DNA (mtDNA) mutation. To determine whether mtDNA mutation is a predisposing factor in patients with sensorineural hearing loss (SNHL), the authors assessed the mtDNA4977 deletion from 60 patients with SNHL and 47 normal control subjects. All cases had no past history of ototoxic or noise exposure, middle ear disease, or other known etiological factors for SNHL. DNA specimens extracted from peripheral blood leukocytes were used for detection of mtDNA4977 deletion by polymerase chain reaction. Patients with SNHL had a significantly higher rate of the mtDNA4977 deletion than did controls (75% vs. 30%, P < 0.0001). The detection rate of mtDNA4977 deletion was significantly increased with the deterioration of the hearing threshold. Aging did not influence the detection rate of mtDNA4977 deletion in either the control or SNHL group. The authors have described high detection rates of the mtDNA4977 deletion in patients with idiopathic bilateral SNHL and propose that at least some of the advanced SNHL cases should be categorized as mitochondrial oxidative phosphorylation diseases. This inference would offer novel possibilities for treatment and prevention of SNHL including presbycusis.
Adult↗
[Mycobacterial lung infection in 8 patients with AIDS: clinical and radiological features].
The prevalence of mycobacterial infection in AIDS patients has increased in Japan. This report describes details of the clinical and radiological features of eight AIDS patients with mycobacterial disease (6 with M. tuberculosis infection and 2 with M. kansasii infection) in our hospital during the period from October 1995 through February 1997. Six of the 8 were men, and two were women. The mean age was 36.5 years. Six were Japanese, one was from Myanmar, and one was Malaysian. The median CD4 positive T lymphocyte counts (CD4 count) at the time of diagnosis of the M. tuberculosis was 75.5 (range 14-569/microliter, and the M. kansasii was 21.5 (range 19-24)/microliter. Clinical findings and symptoms of all patients were non-specific, but almost all patients had a cough and fever. In the radiographic findings, the patients of the M. tuberculosis group presented multiple hilar and mediastinal lymphadenopathy, miliary shadow, and obstructive pneumonia. Both M. kansasii patients showed a multiple infiltration shadow. There were no drug resistant strains in M. tuberculosis except on isolate with moderate resistant. to Streptomycin. These observations suggest that AIDS-associated mycobacterial disease shows atypical clinical and radiological features in some cases, especially in advanced stages of AIDS. Therefore, we need to recognize the characteristics of the clinical and radiological features of the patients with mycobacterial diseases and AIDS.
AIDS-Related Opportunistic Infections↗
Antiherpesvirus activities of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (A-5021) in cell culture.
Antiherpetic activity of (1'S,2'R)-9-([1',2'-bis(hydroxymethyl)cycloprop-1'yl]methyl)guanine (A-5021) was compared with those of acyclovir (ACV) and penciclovir (PCV) in cell cultures. In a plaque reduction assay using a selection of human cells, A-5021 showed the most potent activity in all cells. Against clinical isolates of herpes simplex virus type 1 (HSV-1, n = 5) and type 2 (HSV-2, n = 6), mean 50% inhibitory concentrations (IC50s) for A-5021 were 0.013 and 0.15 microgram/ml, respectively, in MRC-5 cells. Corresponding IC50s for ACV were 0.22 and 0.30 microgram/ml, and those for PCV were 0.84 and 1.5 micrograms/ml, respectively. Against clinical isolates of varicella-zoster virus (VZV, n = 5), mean IC50s for A-5021, ACV, and PCV were 0.77, 5.2, and 14 micrograms/ml, respectively, in human embryonic lung (HEL) cells. A-5021 showed considerably more prolonged antiviral activity than ACV when infected cells were treated for a short time. The selectivity index, the ratio of 50% cytotoxic concentration to IC50, of A-5021 was superior to those of ACV and PCV for HSV-1 and almost comparable for HSV-2 and VZV. In a growth inhibition assay of murine granulocyte-macrophage progenitor cells, A-5021 showed the least inhibitory effect of the three compounds. These results show that A-5021 is a potent and selective antiviral agent against HSV-1, HSV-2, and VZV.
Animals↗
Inhibition of growth of human vascular smooth muscle cells by overexpression of p21 gene through induction of apoptosis.
The senescent cell-derived inhibitor (sdi)-1 protein (p21 product) has been identified as a downstream mediator of the tumor suppressor p53 in the regulation of cell cycle progression through a G1 phase checkpoint. Given the importance of cell cycle inhibition for the treatment of restenosis, in this study we focused on the function of p21 gene in inhibiting proliferation of vascular smooth muscle cells (VSMC). To test the hypothesis, we transfected human p21 gene into human aortic VSMC using hemagglutinating virus of Japan-liposome-mediated transfer. Initially, we examined the successful transfection of human p21 gene into VSMC. p21 protein was increased in VSMC transfected with p21 vector as compared with control vector. Accompanied by increased p21 protein, transfection of p21 vector resulted in a significant decrease in number of VSMC induced by 2% serum (P<.01). Although p21 has been reported to play an important role in the regulation of apoptosis in some cells, apoptosis mediated by p21 is still controversial. Therefore, we hypothesized that overexpression of p21 mediates apoptosis in human VSMC, in addition to the blockade of cell cycle progression. First, we assessed the concordance between morphologic analysis and apoptosis as determined by nuclear staining with Hoechst 33342. Cells transfected with p21 gene exhibited the characteristic features of cell shrinkage, membrane blebbing, and rounding that are typical of apoptotic death. Of greater interest, a significant increase in apoptotic cells was observed in VSMC transfected with p21 vector as compared with control vector (P<.01). These results were confirmed by the measurement of DNA fragmentation. Consistent with nuclear staining, DNA fragmentation in VSMC transfected with human p21 gene was significantly increased as compared with that in VSMC transfected with control vector (P<.05). To study the molecular mechanisms of apoptosis mediated by overexpression of p21 gene, the protein levels of bax, a promoter of apoptosis, and bcl-2, an inhibitor of apoptosis, were also measured by Western blotting. Overexpression of p21 gene significantly increased protein of bax (P<.05), whereas transfection of p21 gene did not alter bcl-2 protein. Importantly, the ratio of bax to bcl-2 was significantly increased in VSMC transfected with human p21 vector as compared with control vector (P<.05). Overall, these results demonstrated that inhibition of VSMC growth by overexpression of human p21 gene was accompanied by induction of apoptosis through an inappropriate increase in bax protein. These results suggest that regulation of cell cycle by p21 may be closely linked to programmed cell death/apoptosis in human VSMC.
Aorta↗