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Biomedical subjects

M Shindo

Publications and source records attributed to M Shindo.

At least 55 records · Page 3Linked to original sources
PubMed2000

Genomic variations in precore and cytotoxic T lymphocyte regions in chronic hepatitis B in relationship to interferon responsiveness.

AIMS: Treatment of chronic hepatitis B patients with interferon (IFN) alpha results in a sustained loss of viral replication in as many as 20-40% of cases. The resistance to antiviral treatment by some viruses is due to positive selection of variants harboring mutations that confer resistance. An HBV variant with a stop codon in the precore region (A1896 HBV) has been reported to be associated with the response to IFN therapy. Recently variations in amino acid residues 21 and 27 of the core protein that serve as either partial agonists or antagonists to cytotoxic T-lymphocyte (CTL) function have been demonstrated to affect response to IFN therapy. In this study, we investigated whether these genomic variations in precore and CTL regions can affect response to IFN therapy. PATIENTS: Twenty-three patients with chronic hepatitis B were treated with IFN alpha. Of these 23 patients, 6 were responders (defined as showing seroconversion to anti-HBe, loss of serum HBV DNA and normalization of serum aminotransferase levels), and the remaining 17 were non-responders. METHOD: A total of 75 serum samples (3 serial samples per patient collected before, at the end of therapy, and 6 months after therapy) were tested for core promoter and precore wildtype and mutant viral levels and for sequence in the CTL region. RESULTS: There were no significant differences in precore wildtype and mutant viral levels before therapy between responders and non-responders, and both viral levels significantly decreased equally when measured at the end of therapy. Approximately 90% of non-responders with HLA-A2 had no amino acid substitutions in the CTL region before therapy. IFN therapy did not induce any specific mutations in this region. CONCLUSION: These findings suggest that the precore wildtype and mutant had similar sensitivity to IFN, and that genomic variation in the CTL region does not appear to be associated with response to IFN therapy.

Adult↗
PubMed2000

Suppression of adjuvant arthritis of rats by a novel matrix metalloproteinase-inhibitor.

BAY 12-9566 (4-[4-(chlorophenyl)phenyl]-4-oxo-2S-(phenylthiomethyl) butanoic acid) is a newly developed, synthetic matrix metalloproteinase (MMP) inhibitor (MMPI) that selectively inhibits MMP-2, MMP-3 and MMP-9 isozymes. We study the effect of BAY 12-9566 on inflammation and cartilage destruction in adjuvant-induced arthritis (AA) in rats. Rats were injected with adjuvant and treated for 21 days with vehicle, Indomethacin or BAY 12-9566. AA was assessed: by measuring arthritic index, paw volume, urinary pyridinoline (Pyr) and deoxypyridinoline (Dpyr); by examining joint inflammation; and by microscopic morphometry of articular cartilages. Oral treatment of rats for 22 days with 50 mg kg(-1) body weight/d BAY 12-9566 showed decreased AA as determined by improvement in body weight gain (P<0.01), arthritic index (P<0.05) and swelling of paws contralateral to the adjuvant injection site (P<0.05). Neutrophil infiltration and collagen degradation were also significantly lower (P<0.01) in this treatment group. Cartilage destruction was successfully suppressed (P<0.01) in rats treated with either 50 mg kg(-1) body weight/d BAY 12-9566 or 1 mg kg(-1) body weight/d Indomethacin. These results indicate that BAY 12-9566 successfully suppressed inflammation and cartilage destruction in rats with AA. Moreover, these results also suggested that MMP-2, MMP-3 and MMP-9 are involved in arthritic diseases such as rheumatoid arthritis.

Amino Acids↗
PubMed2000

Fas-mediated apoptosis of peripheral blood mononuclear cells in patients with hepatitis C.

In the present study, we demonstrated that a close relationship exists between hepatitis C virus (HCV) infection of peripheral blood mononuclear cells (PBMCs) and cell-surface Fas expression in patients with hepatitis C, and showed the possibility of PBMCs apoptosis via a Fas-mediated system. The expression of Fas on PBMCs was found by flowcytometric analysis to be significantly increased in these patients. In addition, the treatment of patients' PBMCs with anti-Fas antibody induced cell death, with nuclear condensation and fragmentation and cellular DNA fragmentation. These data indicate that the patients' PBMCs expressed a large amount of functional Fas on the cell surface and were susceptible to stimulation against Fas, causing apoptotic cell death. We then quantified the serum-soluble Fas ligand (sFasL), which was known to bind to Fas and induce the apoptotic signals into the sensitized cells. The patients' serum sFasL levels were significantly higher than those of normal subjects and showed a good negative correlation with their PBMC number. To demonstrate the correlation between Fas expression and HCV infection, nested reverse transcriptase polymerase chain reaction (RT-PCR) was performed to detect HCV RNA. Interestingly, HCV RNA was preferentially detected from Fas-positive cells but not from Fas-negative cells, which had been isolated from PBMCs by magnetic beads. These results suggest that HCV infection of PBMCs might induce Fas expression and additional stimulation such as sFasL might induce apoptosis in these Fas-expressing cells. These mechanisms, in addition to hypersplenism, may explain the decrease in the number of PBMCs observed in patients with chronic hepatitis C.

Adult↗
PubMed2000

Facial reanimation with microneurovascular free flaps.

Numerous options are available for rehabilitation of chronic facial nerve paralysis, ranging from simple slings to complex procedures such as microneurovascular tissue transfer. Microneurovascular muscle transfer is generally indicated: 1) if the patient desires dynamic facial reanimation, particularly restoration of involuntary emotional facial expressions; 2) in the absence of distal facial nerve fibers or motor endplate function; 3) with an associated large soft tissue defect in the cheek; and 4) when other dynamic reanimation procedures have not been successful. The most commonly used free flaps for facial reanimation are gracilis, latissimus dorsi and inferior rectus abdominus muscle. When successfully performed free flaps yield excellent functional and aesthetic results in facial reanimation.

Anastomosis, Surgical↗
PubMed2000

Neuropathology of auditory agnosia following bilateral temporal lobe lesions: a case study.

Our patient was first diagnosed with auditory agnosia following his second cerebral vascular accident (CVA) in 1975 when he was 37 years old. Comprehensive follow-up examinations of auditory function were periodically conducted until his sudden death 15 years later. His brain was studied postmortem for neuropathology. Initial pure-tone audiometry revealed moderate sensorineural hearing loss in the right ear and mild sensorineural hearing loss in the left ear. However, repeated pure-tone audiometry revealed that thresholds became progressively poorer over time, bilaterally. Speech audiometry of both ears consistently revealed that the patient was unable to discriminate any monosyllabic words (i.e. speech intelligibility scores were 0%, bilaterally). In general, speech and hearing tests demonstrated that he could not comprehend spoken words, but could comprehend written commands and gestures. Postmortem neuropathological study of the left hemisphere revealed total defect and neuronal loss of the superior temporal gyrus, including Heschl's gyrus, and total gliosis of the medial geniculate body. In the right hemisphere, examination revealed subcortical necrosis, gliosis in the centre of the superior temporal gyrus and partial gliosis of the medial geniculate body. The pathological examination supports clinical results in which the patient's imperception of speech sounds, music and environmental sounds could be caused by progressive degeneration of bilateral medial geniculate bodies.

Adult↗
PubMed2000

Long-term follow-up of auditory agnosia as a sequel of herpes encephalitis in a child.

We report a pediatric patient with auditory agnosia as a sequel of herpes encephalitis. His early development was completely normal. He uttered three words at 12 months old. Disease onset was 1 year and 2 months of age. He was discharged from the hospital seemingly with no sequel; however, he could not recover his intelligible words even at age 2 years. He was diagnosed as having auditory agnosia caused by bilateral temporal lobe injury. We began to train him at once, individually and intensively. Adult patients with pure auditory agnosia followed by two episodes of temporal lobe infarction have impairment in central hearing but not inner language. Therefore, they can communicate by reading and writing. Moreover, impairment in hearing is not always severe and is often transient. However, despite long-term (more than 15 years) energetic education and almost normal intellectual ability (Performance IQ of Wechsler Intelligence Scale for Children-Revised was 91), our patient's language ability was extremely poor. Cerebral plasticity could not work fully on our patient, whose bilateral temporal lobe was severely injured in early childhood. The establishment of a systematic training method in such patients is an urgent objective in this field.

Adolescent↗
PubMed2000

Rate enhancement with high ratio of the monoalkylated product to the dialkylated product in the alkylation of the lithium enolate of 1-tetralone with reactive alkyl halides.

The reactions of the lithium enolate of 1-tetralone with reactive alkyl halides were examined in the absence and in the presence of 3 eq of various ligands for the lithium. It is shown that the rates of the reactions are enhanced greatly in the presence a tetradentate amine (1,1,4,7,10,10-hexamethyltriethylenetetramine), and the ratio of the monoalkylated product to the dialkylated product is increased under shorter reaction times.

Alkylation↗
PubMed2000

[Development of new synthetic method and function of ynolate anions].

Ynolates are carbanions having a triple bond in place of the double bond in enolate anions. Ynolates are ketene anion equivalents, thus ynolates introduce a ketene unit into substrates and the resulting products possess high reactivity. This allows ynolates to undergo unique reaction sequences. For the past 20 years, several methods for the generation of ynolates and their reactions have been developed. Recently, we have developed a novel efficient method for their generation via cleavage of ester dianions. Starting from this success, we have found new reactions of ynolate anions. Ynolate anions react with carbonyl compounds to give beta-lactone enolates, which are converted into olefins with high E-selectivity. It is noteworthy that high E-selectivity was achieved in the synthesis of tetrasubstituted olefins. Utilizing the strong nucleophilicity of the beta-lactone enolates, we have succeeded in the first tandem [2 + 2] cycloaddition-Dieckmann condensation to lead synthetically useful 2,3-disubstituted-2-cycloalkenones in good yields. Ynolate anions were found to react with N-sulfonyl aldimines to give beta-lactams. N-2-methoxyphenyl aldimines efficiently activate their cycloaddition of lithium ynolates via chelation to give beta-lactams and alpha,beta-unsaturated amides. We have demonstrated the high functionality of ynolate anions. Ynolate chemistry has begun and much remains to be discovered.

Aldehydes↗
PubMed2000

A novel synthetic triazolotriazepine derivative JTT-606 inhibits bone resorption by down-regulation of action and production of bone resorptive factors.

In the search for a new class of bone-sparing agents, we have conducted random screening of the domestic chemical library using 45Ca release assay from prelabeled cultured neonatal mouse calvariae and identified a novel synthetic triazolotriazepine JTT-606 as a candidate for a potent inhibitor of bone resorption. JTT-606 inhibited 45Ca release dose dependently not only in the control calvarial culture but also in the stimulated cultures by interleukin-1alpha (IL-1alpha), fibroblast growth factor 2 (FGF-2), and parathyroid hormone (PTH). JTT-606 also inhibited both basal and stimulated osteoclast-like (OCL) cell formation in the coculture of mouse osteoblastic cells and bone marrow cells dose dependently, indicating its inhibitory effect on osteoclast differentiation. Ex vivo OCL cell formation by cultured bone marrow cells collected from ovariectomized (OVX) mice also was decreased dose dependently by in vivo application of JTT-606 to a level similar to that from sham-operated mice. Furthermore, JTT-606 inhibited resorbed pit formation by isolated mature osteoclasts as well as by unfractionated bone cells derived from rabbit long bones in the control and FGF-2-stimulated cultures dose dependently, indicating both the direct and the indirect actions of JTT-606 on mature osteoclast function. In addition, JTT-606 reduced production of IL-1alpha, tumor necrosis factor alpha (TNF-alpha), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the human peripheral blood mononuclear cell culture. In vivo analyses of mature OVX rats revealed that the application of JTT-606 for 12 weeks increased the BMD of the lumbar spine and decreased the levels of serum osteocalcin and urine deoxypyridinoline to levels similar to those of 17beta-estradiol-treated OVX rats. We propose that JTT-606 may inhibit both osteoclast differentiation and function by down-regulating both the action and the production of bone resorptive factors. It is speculated that JTT-606 could be a potent agent for the treatment of osteopenic disorders with elevated osteoclastic bone resorption.

Animals↗
PubMed2000

Contributing factors influencing the functional outcome of floating knee injuries.

The purpose of the present study was to retrospectively review the floating knee injuries treated at our institute and to determine various factors, such as severity of soft-tissue or skeletal injuries, site of fractures, and treatment methods that may significantly influence the final functional result in these injuries. Between 1986 and 1996, 65 patients with 66 floating knee injuries were treated in our institution. Among 66 fractures of the femur, 19 (29%) were open. There were 43 open tibial fractures. Fifty cases were Fraser type I floating knee fractures, 7 were type IIa, 2 were type IIb, and 7 were type IIc. In 63 cases (95%), both bones had been surgically stabilized with interlocked nails, Ender pins, plates, screws with/without pinning, or external fixations. Final functional results were evaluated according to Karlström and Olerud's criteria. Satisfactory results were rated as cases with excellent or good results. The mean follow-up time was 16.6 months range, (12-50 months). We assessed various factors influencing functional results, including Fraser type, severity of open injury grade (Gustilo) in both fractures, combination of open/closed injuries, fracture types (AO/ASIF type), existence of multiple trauma, neurovascular injuries, polyskeletal trauma, and stabilizing method or operation timing of both fractures. Satisfactory rates in Fraser type I and type II were 64% and 25%, respectively (P= .02). The satisfactory rate in closed, grade I+II, and grade III injuries of the femoral fractures was 53.2%, 81.8%, and 25%, respectively (grade I+II vs. grade III: P < .03). There were no significant correlations between the functional result and the following factors: soft-tissue injuries of the tibia; the fracture pattern of both fractures; the combination of open/closed injuries in each fracture; injury severity score; the existence of neurovascular injuries and double femoral fractures; treatment methods; and operation timing. Severity of damage to the knee joint and open injuries in the thigh were found to be significant factors contributing to the functional outcome in floating knee injuries.

Adolescent↗
PubMed2000

Acute creatine loading enhances human growth hormone secretion.

BACKGROUND: The main objective of this study was to explore the effect of acute creatine (Cr) ingestion on the secretion of human growth hormone (GH). METHODS: In a comparative cross-sectional study, 6 healthy male subjects ingested in resting conditions a single dose of 20 g creatine (Cr-test) vs a control (c-test). During 6 hours the Cr, creatinine and GH concentrations in blood serum were measured after Cr ingestion (Cr-test). RESULTS: During the Cr-test, all subjects showed a significant stimulation of GH (p<0.05), but with a large interindividual variability in the GH response: the difference between Cr-test and c-test averaged 83% (SD 45%). For the majority of subjects the maximum GH concentration occurred between 2 hrs and 6 hrs after the acute Cr ingestion. CONCLUSIONS: In resting conditions and at high dosages Cr enhances GH secretion, mimicking the response of strong exercise which also stimulates GH secretion. Acute body weight gain and strength increase observed after Cr supplementation should consider the indirect anabolic property of Cr.

Creatinine↗
PubMed2000

[Evaluation of brain function: electrophysiology of the motor system].

To evaluate brain motor function, transcranial magnetic stimulation and supraspinal control of spinal reflexes are reviewed. Motor evoked potentials (MEPs) is facilitated after movement, depending on muscles (arm, hand) and movements (isometric, precise, repetitive, sequential), which indicates specialization of cortical mechanisms. EMG triphasic pattern in ballistic movement is delayed by magnetic stimulation, but the pattern itself is preserved. Ballistic and associated posture-adjusting movements are delayed by magnetic stimulation in the same way, and similar cortical mechanisms appear to be included. Patients with motor neglect, normal MEPs and remarkably prolonged silent period show inability to initiate movement for several seconds after magnetic stimulation, and strong and long-lasting intracortical inhibition are observed. Motor neglect can be produced by strong inhibitory inputs to the motor cortex. Neural plasticity is studied in patients with brain and peripheral lesions; ipsilateral MEPs, enlargement of muscle representation in the cortex, and contribution of descending pathways other than corticospinal tract are reported. Central control of spinal reflex activities is also important in motor control. Reflex circuits contribute to reciprocal inhibition and to selective contraction, or function as an attenuator of activity of the motoneurone pool. Neural plasticity after daily exercise is reported also at the segmental level.

Electrophysiology↗
PubMed1999

Acute creatine ingestion in human: consequences on serum creatine and creatinine concentrations.

The aim of the study was to explore the effect of an acute dose of creatine (Cr) ingestion on serum Cr and serum creatinine (Crn) concentrations. Sixteen healthy subjects ingested a single dose of Cr (20 g) followed by the measurement of serum Cr and Crn concentration for 3 h up to a maximum of 6 h (n=6). In response to Cr ingestion a large rise in serum Cr concentration was observed (by 50 folds) occurring approximately 2 1/2h after the ingestion (peak value of 2.17 +/- 0.66 mmol x l(-1)). We also found a moderate but significant rise in serum Crn concentration averaging 13 % after 3 h (peak value at 99.5 +/- 10.5 micromol x l(-1)). A dose response curve obtained in two case studies, in whom different doses of Cr were ingested (0, 2.5, 5, 10, 15, 20 g and 0, 10, 20, 30 g), showed that serum Cr concentration as well as the peak time increased linearly with Cr ingestion. In addition, acute Crn ingestion (5 g) resulted in a substantial increase in serum Crn concentration (by 10 folds) but led to a minor rise in serum Cr concentration (by 2 folds). These results suggest that when acute doses of Cr are ingested in humans, the degree of conversion of exogenous Cr to Crn in the stomach and the gut can be considered as negligible following the first 6 h of ingestion. However, further studies are required to explore the prolonged effect of Cr on Crn metabolism.

Administration, Oral↗
PubMed1999

Varying incidence of cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis C responding differently to interferon therapy.

BACKGROUND: To determine whether interferon (IFN) therapy can reduce incidence of the development of cirrhosis and hepatocellular carcinoma equally in patients with chronic hepatitis C virus (HCV) who responded differently to therapy, a retrospective analysis of 250 patients treated with IFN was conducted. METHODS: Two hundred and fifty patients with chronic HCV who were treated with IFN were classified into 3 groups based on serum aminotransferase levels during and after therapy with IFN-alpha: long term responders (n=93), short term responders (n=70), and nonresponders (n=87). Eighty-nine untreated patients served as a control group. The follow-up period was 4 years. Liver function tests, HCV RNA levels, and alpha-fetoprotein were measured each month. Imaging diagnosis was made every 6 months with ultrasonography and yearly with dynamic computed tomography. Serum and liver HCV RNA was assayed by reverse transcriptase-polymerase chain reaction and branched DNA probe. RESULTS: Of the 93 long term responders, 67 (72%) remained HCV RNA negative whereas 26 (28%) were HCV RNA positive. Further histologic improvement occurred only in HCV RNA negative long term responders. During the follow-up period, the overall annual incidence of cirrhosis in the 250 patients was decreased significantly compared with the control group, whereas the overall annual incidence of hepatocellular carcinoma was not. None of the long term responders but 5 (7%) short term responders and 33 (38%) nonresponders had disease progression to cirrhosis. No HCV RNA negative long term responders but 1 (3.8%) HCV RNA positive long term responder, 1 (1.4%) short term responder, and 14 (16%) nonresponders developed hepatocellular carcinoma. Long term and short term responders had significantly lower incidence of cirrhosis whereas nonresponders had significantly higher incidence of cirrhosis and hepatocellular carcinoma than the control group. Multivariate analysis showed that staging score, the presence of high viral levels, and lack of response to therapy significantly influenced the incidence of these events. CONCLUSIONS: These findings suggest that patients with chronic HCV responding differently to IFN therapy had different incidence of disease progression to cirrhosis and of the development of hepatocellular carcinoma, and that nonresponders should be regarded as a group at high risk for these events.

Antiviral Agents↗