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T Kamada

Publications and source records attributed to T Kamada.

At least 307 records · Page 17Linked to original sources
PubMed1994

Beta-adrenergic stimulation disassembles microtubules in neonatal rat cultured cardiomyocytes through intracellular Ca2+ overload.

Catecholamine cardiotoxicity is attributable in part to Ca2+ overload. To test whether the cytoskeletal structures of microtubules in cardiomyocytes are reversibly injured by catecholamine through excessive Ca2+ influx, morphological changes in the microtubules of neonatal rat myocytes were studied by immunohistochemical technique during exposure to norepinephrine (NE). In intact myocytes, microtubules appeared as a filamentous network throughout the cytoplasm and around the nucleus. NE exposure (10 mumol/L) for > 30 minutes elicited microtubular disassembly in a duration-dependent fashion without any irreversible change in sarcomere structure, and this abnormality recovered within 24 hours after cessation of stimulation. Microtubular disruption scores obtained by semiquantitative assessment were significantly increased in a dose-dependent manner (10.8 +/- 4.0 in the control condition, 23.4 +/- 4.7 at 60 minutes with 10 mumol/L NE), whereas they were significantly attenuated by pretreatment with propranolol (100 mumol/L; score, 11.8 +/- 3.3) but not with phentolamine (100 mumol/L; score, 26.4 +/- 4.8). Isoproterenol (1 mumol/L) and denopamine (10 mumol/L) mimicked the effects of NE, but phenylephrine did not, indicating that NE-induced microtubular disassembly is mediated by beta 1-adrenergic receptor stimulation. This beta-adrenergic receptor-mediated insult was significantly attenuated by a decrease in Ca2+ concentration in the medium from 2 to 0.5 mmol/L and by pretreatment with diltiazem (1 mumol/L). In contrast, microtubular disassembly was induced by an increase in Ca2+ concentration in the medium and an administration of the Ca2+ ionophore A23187, even without beta-adrenergic receptor stimulation. Involvement of intracellular hypoxia and activation of Ca(2+)-calmodulin-dependent kinase or Ca(2+)-dependent neutral protease were excluded from possible mechanisms; however, inhibition of tubulin polymerization by excessive Ca2+ influx during beta-adrenergic receptor stimulation may be primarily involved. We conclude that microtubular structures that support cellular integrity are reversibly injured by beta-adrenergic receptor stimulation through excessive Ca2+ influx.

Adrenergic beta-Agonists↗
PubMed1994

Effects of hemodialysis on cerebral circulation evaluated by transcranial Doppler ultrasonography.

BACKGROUND AND PURPOSE: The effects of hemodialysis on the cerebral circulation of humans and the correlation between changes in blood flow velocity in the basal cerebral arteries and those of several physiological variables influenced by hemodialysis have been inadequately studied. METHODS: Blood flow velocities were obtained from the middle cerebral artery and the basilar artery by transcranial Doppler ultrasonography in 27 patients receiving chronic maintenance hemodialysis immediately before and after the procedure. Changes in body weight, hematocrit, blood pressure, and arterial blood gases were recorded simultaneously. RESULTS: There was a significant reduction in mean flow velocity in the middle cerebral artery (P < .01) and the basilar artery (P < .01) after hemodialysis. We observed a significant negative correlation between the relative change in mean flow velocity and the loss of weight after hemodialysis, the amount of fluid removed, and the increase in hematocrit in the middle cerebral artery and the basilar artery. CONCLUSIONS: Hemodialysis and the associated physiological changes can significantly affect the cerebral circulation. Blood flow velocities in the middle cerebral artery and the basilar artery decrease significantly with hemodialysis. The loss of body weight, the amount of fluid removed, and the change in hematocrit significantly correlate with the change in mean flow velocity. The transcranial Doppler method can effectively monitor rapid changes in the cerebral circulation during potentially harmful procedures.

Adult↗
PubMed1994

Asymptomatic carotid lesions and silent cerebral infarction.

BACKGROUND AND PURPOSE: Few studies have investigated the relationships between asymptomatic carotid lesions and silent infarcts confirmed on magnetic resonance imaging. METHODS: A consecutive series of 117 subjects (average age, 62 +/- 9.4 years) who were free from neurological deficit but had at least one established risk factor for stroke were investigated by B-mode carotid ultrasonography and magnetic resonance imaging of the brain. Carotid lesions were evaluated by plaque score, maximum percent stenosis, and the existence of ulcerated lesions. The relations between the carotid lesions and the incidence, size, or localization of the brain lesions were investigated. RESULTS: The incidence of silent infarcts was 42% in all subjects and significantly increased with advancing age (P < .05). Most lesions were smaller than 1 cm in diameter and were usually localized in the subcortical white matter or the basal ganglia. The percentage of subjects with infarcts increased significantly as the plaque score increased (P < .05) or when subjects had high-grade stenosis (P < .05) or ulcerated lesions (P < .01). These relationships were also noted in each decade of age. A higher incidence of larger lesions (> 1 cm) was found in the brain hemisphere ipsilateral to the carotid lesion, particularly in subjects with high-grade stenosis or ulcerated lesions (P < .01). Multivariate analysis indicated significant correlations with silent infarcts for age, hypertension, and plaque score. CONCLUSIONS: Both the severity and characteristics of asymptomatic carotid lesions estimated by B-mode ultrasonography were closely related to the appearance of silent infarcts. These results demonstrate that noninvasive assessment of carotid lesions can be useful in predicting the existence of silent cerebral infarction even in patients free from neurological deficits.

Adult↗
PubMed1994

Paradoxical embolism as a cause of ischemic stroke of uncertain etiology. A transcranial Doppler sonographic study.

BACKGROUND AND PURPOSE: This study was designed to test the hypothesis that paradoxical embolization would be a cause of embolic strokes and transient ischemic attacks in patients with stroke of uncertain etiology in all age groups. METHODS: Thirty patients who had stroke of uncertain etiology were studied. They were divided into the following three groups: 13 patients with sudden onset (group A), 11 patients with subacute onset (group B), and 6 asymptomatic stroke patients (group C). Eleven patients with stroke of obvious etiology (group D) and 11 normal healthy volunteers (group E) were also studied as controls. In all patients transcranial Doppler sonography and contrast echocardiography were recorded simultaneously after intravenous injection of the contrast medium. Findings of positive patient foramen ovale in contrast echocardiography or "chirp" sounds in transcranial Doppler sonography were defined as positive for paradoxical contrast embolization. Radioisotope phlebography of the lower extremities and pulmonary scintigraphy, using technetium-99 macroaggregated albumin, were performed in all 17 patients who had positive findings of paradoxical contrast embolization and in 12 patients whose findings were negative. RESULTS: Positive findings of paradoxical contrast embolization were found in 17 subjects by transcranial Doppler sonography but in only 8 on contrast echocardiography. These positive findings were detected more frequently in group A (77%) than in groups B, D, and E (9%, 18%, and 9%, respectively) (P < .05). In group C, 4 of 6 patients (67%) had positive findings. There were positive findings on both phlebography and pulmonary scintigraphy only in 6 group A patients, with positive findings of paradoxical contrast embolization. CONCLUSIONS: Transcranial Doppler sonography is a sensitive detector of right-to-left shunts. Paradoxical cerebral embolization might be frequent in patients with stroke of unknown etiology, especially when the stroke is of sudden onset.

Adult↗
PubMed1994

Evaluation of cerebral vasoreactivity by three-dimensional time-of-flight magnetic resonance angiography.

BACKGROUND AND PURPOSE: Cerebral vasoreactivity is an important indicator of the reserve capacity of the cerebral circulation. To make a quantitative analysis of cerebral vasoreactivity in individual major arterial territories, we evaluated the response to acetazolamide using three-dimensional time-of-flight magnetic resonance angiography. METHODS: We examined 10 healthy volunteers and 6 patients with unilateral stenosis of the middle cerebral artery by a 1.5-T superconducting magnetic resonance imaging system. After a baseline vascular image was obtained, each subject received 17 mg/kg IV of acetazolamide; a second scan was performed 20 minutes later. Using a generally available personal computer and image analysis software, we measured the areas of the individual major arteries on collapsed axial vascular images and then calculated the vasoreactivity. RESULTS: The average vasoreactivity of individual major cerebral arterial territories in the healthy volunteers was as follows: anterior cerebral artery complex, 33%; right middle cerebral artery, 71%; left middle cerebral artery, 74%; right posterior cerebral artery, 68%; and left posterior cerebral artery, 68%. In the patient group, the vasoreactivity of the stenotic middle cerebral arteries was significantly smaller than that of the nonstenotic arteries (P < .05). In addition, the nonstenotic middle cerebral arteries showed significantly less vasoreactivity than the right arteries of the healthy volunteers (P < .01). CONCLUSIONS: Three-dimensional time-of-flight magnetic resonance angiography can be used to quantitatively evaluate acetazolamide-induced vasoreactivity in individual major cerebral arterial territories.

Acetazolamide↗
PubMed1994

Mitogen-activated protein kinase and its activator are regulated by hypertonic stress in Madin-Darby canine kidney cells.

Madin-Darby canine kidney cells behave like the renal medulla and accumulate small organic solutes (osmolytes) in a hypertonic environment. The accumulation of osmolytes is primarily dependent on changes in gene expression of enzymes that synthesize osmolytes (sorbitol) or transporters that uptake them (myo-inositol, betaine, and taurine). The mechanism by which hypertonicity increases the transcription of these genes, however, remains unclear. Recently, it has been reported that yeast mitogen-activated protein (MAP) kinase and its activator, MAP kinase-kinase, are involved in osmosensing signal transduction and that mutants in these kinases fail to accumulate glycerol, a yeast osmolyte. No information is available in mammals regarding the role of MAP kinase in the cellular response to hypertonicity. We have examined whether MAP kinase and MAP kinase-kinase are regulated by extracellular osmolarity in Madin-Darby canine kidney cells. Both kinases were activated by hypertonic stress in a time- and osmolarity-dependent manner and reached their maximal activity within 10 min. Additionally, it was suggested that MAP kinase was activated in a protein kinase C-dependent manner. These results indicate that MAP kinase and MAP kinase-kinase(s) are regulated by extracellular osmolarity.

Animals↗
PubMed1994

Induction of manganese superoxide dismutase in rat cardiac myocytes increases tolerance to hypoxia 24 hours after preconditioning.

Manganese superoxide dismutase (Mn-SOD) is induced in ischemic hearts 24 h after ischemic preconditioning, when tolerance to ischemia is acquired. We examined the relationship between Mn-SOD induction and the protective effect of preconditioning using cultured rat cardiac myocytes. Exposure of cardiac myocytes to brief hypoxia (1 h) decreased creatine kinase release induced by sustained hypoxia (3 h) that follows when the sustained hypoxia was applied 24 h after hypoxic preconditioning (57% of that in cells without preconditioning). The activity and content of Mn-SOD in cardiac myocytes were increased 24 h after hypoxic preconditioning (activity, 170%; content, 139% compared with cells without preconditioning) coincidentally with the acquisition of tolerance to hypoxia. Mn-SOD mRNA was also increased 20-40 min after preconditioning. Antisense oligodeoxyribonucleotides corresponding to the initiation site of Mn-SOD translation inhibited the increases in the Mn-SOD content and activity and abolished the expected decrease in creatine kinase release induced by sustained hypoxia after 24 h of hypoxic preconditioning. Sense oligodeoxyribonucleotides did not abolish either Mn-SOD induction or tolerance to hypoxia. These results suggest that the induction of Mn-SOD in myocytes by preconditioning plays a pivotal role in the acquisition of tolerance to ischemia at a later phase (24 h) of ischemic preconditioning.

Adaptation, Physiological↗
PubMed1994

The lung-eardrum pathway in three treefrog and four dendrobatid frog species: some properties of sound transmission.

Frequency-response curves of the tympanum and lateral body wall (lung area) were measured by laser Doppler vibrometry in three treefrog (Smilisca baudini, Hyla cinerea, Osteopilus septentrionalis) and four dendrobatid frog (Dendrobates tinctorius, D. histrionicus, Epipedobates tricolor, E. azureiventris) species. The high-frequency cut-off of the body wall response was always lower than that of the tympanum. The best response frequencies of the lateral body wall were lower than those of the tympanum in some species (S. baudini, O. septentrionalis, D. tinctorius), while in the others they were rather similar. Best tympanic frequencies and best body wall response frequencies tended to differ more with increasing body size. Stimulation of the tympanum by sound transfer through 3.14 mm2 areas of the lateral body wall showed that the lung-eardrum pathway can be in two states, depending on breathing activity within the lungs: 44% (in Smilisca), 39% (in Hyla) and 31% (in Osteopilus) of the eardrum vibrations were 2.5-8 times (8-18 dB) larger when the frogs were breathing with the lungs compared with non-breathing conditions. The vibration amplitudes of the tympanum and lateral body wall of the treefrogs followed the same dependence on sound intensity, only absolute amplitudes differed between species. Our results suggest that the lung-eardrum pathway attenuates high-frequency components of species-specific calls and enhances low-frequency components. In addition, an amplitude modulation is imposed on the low frequencies during the rhythm of breathing.

Acoustic Stimulation↗
PubMed1994

Contribution of chamber compliance and left ventricular minimum pressure to abnormal left ventricular filling dynamics.

This study was designed to clarify whether changes in transmitral flow velocity patterns in left ventricular (LV) dysfunction are determined primarily by changes in left atrial (LA) pressure and LV relaxation, and, if not, to determine the contribution of changes in other parameters. Two levels of acute LV dysfunction were produced in 11 dogs by coronary microembolization, and pulsed Doppler transmitral flow velocity patterns and hemodynamic parameters were recorded. The mean ratio of peak early diastolic filling velocity (E) to peak late diastolic filling velocity decreased with mild LV dysfunction (LV end-diastolic pressure of between 12 and 17 mmHg), and redistribution of diastolic filling to early diastole was observed with severe LV dysfunction (LV end-diastolic pressure of > or = 18 mmHg). Changes in E correlated best with those in the LA-LV pressure gradient integral. Multiple linear regression analysis of the changes in possible determinants of the pressure gradient integral, i.e., LA to LV crossover pressure, LV time constant, LV minimum pressure, and LA and LV chamber compliance, yielded a highly significant correlation with the changes in E. However, analysis of only the changes in the crossover pressure and the time constant showed a very poor correlation. Thus, changes in chamber compliance and LV minimum pressure, in addition to the changes in LA pressure and LV relaxation, may significantly affect the changes in E that are associated with LV dysfunction.

Animals↗
PubMed1994

A characteristic change in ventilation mode during exertional dyspnea in patients with chronic heart failure.

Although exertional dyspnea is an important symptom limiting daily lives in patients with chronic heart failure, there is no objective assessment of this symptom. To characterize the exertional dyspnea, ventilatory responses to exercise were studied in relation to exertional dyspnea. Gas exchange data were obtained during a maximal bicycle exercise in 43 patients with chronic heart failure and 20 normal subjects. In addition to standard ventilatory variables, the ventilation mode was assessed from the tidal volume-ventilation rate (VT-f) relationship. The exercise was performed again after sublingual administration of 5 mg of isosorbide dinitrate. In normal subjects, the f and VT increased almost proportionally with exercise intensity. In 17 (85 percent) of 20 patients with exertional dyspnea, the VT-f relationship abruptly lost linearity at the onset of exertional dyspnea. This change resulted from an inadequate increase in VT and a further increase in f. In 8 of these 17 patients, isosorbide dinitrate improved exertional dyspnea with normalization of the VT-f relationship; however, in 9 patients whose dyspnea was not improved, the abnormal VT-f relationship was unaltered. Only 2 (9 percent) of 23 patients without exertional dyspnea showed the abnormal VT-f relationship. Other ventilatory variables were not different between patients with and without dyspnea. Thus, exertional dyspnea is characterized by simultaneous appearance of rapid and shallow ventilation. The VT-f relationship appears to be a simple and useful objective assessment of exertional dyspnea in patients with chronic heart failure.

Dyspnea↗
PubMed1994

In vivo osmoregulation of Na/myo-inositol cotransporter mRNA in rat kidney medulla.

myo-Inositol, a major compatible osmolyte in renal medulla, is accumulated in kidney-derived epithelial cells cultured in hypertonic media via Na/myoinositol cotransporter (SMIT). The altered medium osmolality of Madin-Darby canine kidney cells leads to changes in the transcription of the SMIT gene and mRNA abundance. To investigate whether SMIT is regulated by tonicity in vivo, renal medullary myoinositol and SMIT mRNA was measured in rats in hydrated and dehydrated states. Rats were divided into two groups: (1) hydrated rats, free access to 3% sucrose water; (2) dehydrated rats, 3 days of water deprivation. Urine sodium, potassium, urea, and osmolality in dehydrated rats were significantly higher than in hydrated rats. Renal medullary sodium, urea, and myo-inositol in dehydrated rats were significantly higher than in hydrated rats. Northern analysis revealed that there was a message hybridized to SMIT cDNA in the cortex and outer and inner medulla of the kidney. Compared with hydrated rats, SMIT mRNA in dehydrated rats was 2.6-fold higher in the outer medulla and 2.5-fold higher in the inner medulla. These results indicate that there is osmoregulatory SMIT in the outer and inner medulla of the kidney and that myo-inositol accumulation in this region is probably due to the increased expression of the SMIT gene.

Animals↗
PubMed1994

Atherosclerosis in carotid artery of young IDDM patients monitored by ultrasound high-resolution B-mode imaging.

Ultrasound high-resolution B-mode imaging was used to assess the carotid arteries in 105 patients with insulin-dependent diabetes mellitus (IDDM), 4-25 years of age, with duration of diabetes ranging from 0.5-17 years, 529 patients with non-insulin-dependent diabetes (NIDDM), 31-86 years of age, with duration of diabetes ranging from 0.5-49 years, and 104 nondiabetic healthy subjects, 7-76 years of age, to determine the intimal plus medial thickness (IMT) of the arterial wall. The IMT values for IDDM patients 10-19 years of age (0.525 +/- 0.123 mm, n = 68) or 20-25 years of age (0.696 +/- 0.124 mm, n = 14) were significantly greater than those in age-matched nondiabetic subjects (0.444 +/- 0.057 mm, n = 12, P = 0.01169; 0.538 +/- 0.098 mm, n = 34, P < 0.00006). NIDDM patients showed IMT values equivalent to those in normal adults > or = 20 years of age. Multiple regression analysis showed that IMT in IDDM patients was positively related to the duration of diabetes (P = 0.00061) as well as to age (P = 0.00046). No other possible risk factors, such as serum total cholesterol level, serum high-density lipoprotein (HDL)-cholesterol level, serum low-density lipoprotein-cholesterol level, serum triglycerides, serum lipoprotein(a) level, or systolic or diastolic blood pressure, have shown significant correlations with IMT in IDDM patients. However, non-HDL-cholesterol, smoking, and systolic hypertension were independently responsible for increases in IMT values of NIDDM patients as well as age and duration of diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Effects of hepatitis B virus antigens on interferon-gamma production of peripheral blood mononuclear cells from hepatitis B virus carriers and healthy individuals.

BACKGROUND: Although the precise mechanisms of persistent infection by hepatitis B virus are not yet known, several lines of studies suggest that hepatitis B e antigen in sera might modulate the immune response of the host. The aim of this study was to clarify the effects of hepatitis B virus antigen on cytokine production of lymphocytes. METHODS: We studied the effects of recombinant hepatitis B core antigen and surface antigen on interferon-gamma production of phytohemagglutinin-stimulated peripheral blood mononuclear cells from hepatitis B virus carriers and healthy individuals. Hepatitis B core antigen used in this study shared the antigenic site responsible for hepatitis B core and e antigen. RESULTS: Although pre-incubation of peripheral blood mononuclear cells with hepatitis B core/e antigen followed by stimulation with phytohemagglutinin significantly reduced the production of interferon-gamma, pre-incubation with hepatitis B surface antigen did not affect them. CONCLUSIONS: These results indicate that hepatitis B core/e antigen has the ability to inhibit interferon-gamma production of lectin-stimulated peripheral blood mononuclear cells in vitro, suggesting that secretion of hepatitis B e antigen into sera might be how hepatitis B virus escapes the immuno-surveillance system of the host.

Adult↗
PubMed1994

Immunohistochemical detection of Fas antigen in liver tissue of patients with chronic hepatitis C.

Apoptosis is a type of cell death that occurs in acute or chronic hepatitis. It has been suggested to be mediated through Fas antigen. To evaluate the role of apoptosis on liver injury of chronic hepatitis C, we studied the expressions of Fas antigen and hepatitis C virus antigen (core antigen) immunohistochemically. Forty liver biopsy samples from patients with type C chronic liver disease were immunostained for Fas antigen and hepatitis C virus antigen. Expression of Fas antigen was found mainly in the cytoplasm of hepatocytes, and these positive cells were found particularly among infiltrating lymphocytes at the advancing edges of "piecemeal necrosis." The histological activity index showed inflammation of both portal and periportal areas to be more severe in the Fas antigen-positive samples than in the Fas antigen-negative ones (p < 0.05 and p < 0.001, respectively). Furthermore, semiquantitative analysis revealed more expression of Fas antigen in the liver tissues with active inflammation than in those without it (p < 0.01). The prevalence of Fas antigen expression in the hepatitis C virus antigen-positive group was higher than that in the hepatitis C virus antigen-negative group (p < 0.05). Our findings suggest that Fas antigen expression (apoptosis) plays an important role in inflammation in the hepatitis C virus-infected liver, particularly in the active inflammation of chronic hepatitis C.

Adolescent↗
PubMed1994

Hepatitis C virus replication and antibody responses toward specific hepatitis C virus proteins.

We assessed the correlation between hepatitis C virus replication and antibody responses toward hepatitis C virus core (C22-3), NS3 (C33C), NS4 (5-1-1 and C100-3) and NS5 proteins in 59 virus carriers. The concentration of serum hepatitis C virus RNA was determined by a competitive reverse transcription-polymerase chain reaction assay. All 50 patients with high viremic levels of > or = 10(6) copies/mL had antibodies to C22-3 and C33C. Antibodies to 5-1-1, C100-3 and NS5 proteins were detected less frequently (p < 0.01) in 72% (36 of 50), 78% (39 of 50) and 84% (32 of 38) of such patients, respectively. As for the nine patients with low viremic levels of < 10(6) copies/mL, antibodies to C22-3, C33C, 5-1-1 and NS5 proteins were detected in only one patient (11%), which was significantly less than the frequency for highly viremic patients (p < 0.01). Antibody to C100-3 was also found less frequently in only four patients (44%) (p < 0.05). Thus, only four (44%) of the nine low viremic patients tested positive for any antibody compared with all 50 highly viremic patients (p < 0.01). These results indicate that highly viremic carriers can be detected by the presence of hepatitis C virus antibodies, but a considerable proportion of low viremic carriers may not show any serological evidence of hepatitis C virus infection.

Adult↗
PubMed1994

Increased serum hepatitis C virus RNA levels among alcoholic patients with chronic hepatitis C.

Hepatitis viruses and alcohol are major causes of liver disease. This study was aimed at investigating the effect of alcohol intake on the replication of hepatitis C virus and the efficacy of interferon therapy. Fifty-three patients who were histologically proved to have chronic hepatitis C were tested. Of these, 16 were diagnosed as habitual drinkers whose cumulative total consumption of alcohol was more than 100 kg or who had consumed at least 60 gm of ethanol daily for at least 5 yr. The quantities of hepatitis C virus RNA in serum were measured with a competitive assay that combined reverse transcription and polymerase chain reaction. The subjects received a 26-wk course of interferon-alpha therapy. There were no significant differences in age and ALT levels between habitual drinkers and nonhabitual drinkers. The titer of viral RNA (logarithmic transformed copy numbers per milliliter of serum) of habitual drinkers (8.5 +/- 0.5) was higher than that of nonhabitual drinkers (7.7 +/- 0.8) (p < 0.01). Neopterin levels in serum, a marker for the activation of cell-mediated immunity, were lower for habitual drinkers (5.7 +/- 1.5 pmol/ml) than for nonhabitual drinkers (8.1 +/- 5.0 pmol/ml) (p < 0.01). Eleven of the nonhabitual drinkers (30%) were long-term responders whose alanine aminotransferase levels remained within normal range during the 24 wk after interferon therapy, whereas only one (6%) of the habitual drinkers was a long-term responder (p = 0.06). These findings suggest that alcohol intake increases hepatitis C virus RNA levels in serum--at least in part--impairment of cellular immunity, and modulates the efficacy of interferon therapy.

Adult↗
PubMed1994

Influence of viral quasispecies on effectiveness of interferon therapy in chronic hepatitis C patients.

The quasispecies nature of hepatitis C virus genome distribution is most evident in hypervariable regions of the putative envelope 2 domain. Eight patients with chronic hepatitis C treated with interferon-alpha were studied as to heterogeneity of the hypervariable regions to clarify the implications of quasispecies. More than 10 recombinant clones generated from polymerase chain reaction-amplified products of the hypervariable regions were sequenced. The sets of clones derived from long-term responders before interferon therapy showed a significantly lower (p < 0.05) degree of sequence complexity of the hypervariable region 1 quasispecies than those from short-term ones or non-responders. The values of nucleotide diversity (the average number of nucleotide differences per site between two randomly chosen sequences) in hypervariable region 1 before interferon therapy were also significantly lower (p < 0.05) for long-term responders (mean, 2.31 x 10(-2)). In some cases, nucleotide diversity decreased remarkably during interferon therapy, whereas the values remained unchanged in other cases. In one interesting case, a short-term response was first noted with the nucleotide diversity decreasing from 13.98 x 10(-2) to 0.21 x 10(-2); namely, the diversity of the quasispecies was significantly reduced, and then a long-term response was observed after an additional course of interferon therapy. Thus, the degree of quasispecies' complexity and diversity of hypervariable region 1 was closely correlated with the responsiveness to interferon therapy in chronic hepatitis C patients, and thus may have some influence on interferon efficacy.

Adult↗