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Biomedical subjects

K M Chang

Publications and source records attributed to K M Chang.

At least 19 recordsLinked to original sources
PubMed2001

Determinants of viral clearance and persistence during acute hepatitis C virus infection.

The virological and immunological features of hepatitis C virus (HCV) infection were studied weekly for 6 months after accidental needlestick exposure in five health care workers, four of whom developed acute hepatitis that progressed to chronicity while one subject cleared the virus. In all subjects, viremia was first detectable within 1-2 weeks of inoculation, 1 month or more before the appearance of virus-specific T cells. The subject who cleared the virus experienced a prolonged episode of acute hepatitis that coincided with a CD38+ IFN-gamma- CD8+ T cell response to HCV and a small reduction in viremia. Subsequently, a strong CD4+ T cell response emerged and the CD8+ T cells became CD38- and started producing IFN-gamma in response to HCV, coinciding with a rapid 100,000-fold decrease in viremia that occurred without a corresponding surge of disease activity. Chronic infection developed in two subjects who failed to produce a significant T cell response and in two other subjects who initially mounted strong CD4+ T cell responses that ultimately waned. In all subjects, viremia was higher at the peak of acute hepatitis than it was when the disease began, and the disease improved during the viremia. These results provide the first insight into the host-virus relationship in humans during the incubation phase of acute HCV infection, and they provide the only insight to date into the virological and immunological characteristics of clinically asymptomatic acute HCV infection, the commonest manifestation of this disease. In addition, the results suggest that the vigor and quality of the antiviral T cell response determines the outcome of acute HCV infection, that the ability of HCV to outpace the T cell response may contribute to its tendency to persist; that the onset of hepatitis coincides with the onset of the CD8+ T cell response, that disease pathogenesis and viral clearance are mediated by different CD8+ T cell populations that control HCV by both cytolytic and noncytolytic mechanisms, and that there are different pathways to viral persistence in asymptomatic and symptomatic acute HCV infection.

Acute Disease↗
PubMed2001

Colonization and persistence of rough and smooth colony variants of Actinobacillus actinomycetemcomitans in the mouths of rats.

Fresh isolates of Actinobacillus actinomycetemcomitans (Aa) bind avidly to surfaces in vitro, but existing in vivo studies of the adherence of Aa are limited. This study had two goals: (1) to compare the oral colonization of two isogenic strains of Aa-CU1010, a clinical isolate that expresses the adherent phenotype, and CU1012, a minimally adherent laboratory variant-and (2) to check for phenotypic reversion of these strains in a clinical setting. Rifampicin-resistant strains, developed for tracking in Sprague-Dawley rats, were tested in vitro to determine their stability and binding. In study 1, after antibiotic suppression, six rats (group I) received CU1010 in their feed. The eight rats in group II received CU1012 in their feed and four were supplemented by oral swabbing and four by gastric gavage. Group III consisted of three sham-inoculated controls. All rats were inoculated for 4 days. Microbiological data were collected at 1, 4 and 8 weeks after inoculation. Supporting data were supplied by antibody titres and clinical measures of alveolar bone loss. Study 2 consisted of six rats in each of three groups as above, but tagged strains of Aa were delivered by food alone. At all time-points in both studies, Aa was absent before inoculation and controls had no Aa or antibody to Aa. In study 1, all six rats in group I yielded positive cultures for Aa at 8 weeks. In group II, five of eight had positive cultures for Aa at 1 week, two of eight at 4 weeks and none had Aa at 8 weeks (P < or =0.001). All six rats in group I had serum anti-Aa titres compared to group II, where titres were seen in four of eight rats (P < or =0.015). In vitro data paralleled those found in vivo. No phenotypic reversion of either strain was seen in vivo. In study 2, four of six rats in group I showed Aa and had titres to Aa, while no other animals showed Aa at any time. The model provides convincing evidence that, unlike laboratory variants, clinical isolates colonize, persist and integrate into an already established, albeit reduced, econiche.

Actinobacillus Infections↗
PubMed2001

Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection.

This study was performed to compare the vigor and phenotype of virus-specific CD4(+) and CD8(+) T-cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4(+) proliferative T-cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV-specific CD8(+) T-cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN-gamma) staining. Furthermore, although HCV-specific cytolytic CD8(+) memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV-infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV-specific memory CD8(+) T-cell response. HCV-specific CD8(+) T cells displayed a type 1 cytokine profile characterized by production of IFN-gamma despite persistent HCV viremia. The paradoxical observation that HCV-specific CD4(+) T cells survive and CD8(+) T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4(+) and CD8(+) T-cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8(+) effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus.

Adult↗
PubMed2001

Degenerate immunogenicity of an HLA-A2-restricted hepatitis B virus nucleocapsid cytotoxic T-lymphocyte epitope that is also presented by HLA-B51.

The recent identification of hepatitis B virus (HBV) epitopes restricted by multiple HLA alleles has greatly expanded the epitope repertoire available for T-cell-mediated therapeutic vaccine development. The HLA-B51-restricted peptide HBc19-27 is particularly interesting because it is located entirely within the HLA-A2-restricted HBc18-27 epitope. Here we show that HLA-B51-restricted cytotoxic T lymphocytes specific for HBc19-27 from a patient with acute HBV infection were also able to lyse HLA-B51-positive target cells pulsed with HBc18-27 and to produce gamma interferon when stimulated by that peptide, implying that HBc18-27 can be presented by HLA-B51 as well as by HLA-A2. These results demonstrate the concept of degenerate immunogenicity across HLA class supertype boundaries in a human viral disease setting. In addition, they could facilitate the development of an epitope-based therapeutic vaccine to terminate chronic HBV infection that could provide a broad and diverse population coverage with a single peptide.

Acute Disease↗
PubMed2001

Multiple myeloma associated with extramedullary plasmacytoma causing nerve root compression: a case report.

Multiple myeloma associated with extramedullary plasmacytoma at initial presentation is rare. We describe a 45-year-old female patient with an initial presentation of low back pain and right side L5, S1 radiculopathy. There was no evidence of vertebral involvement but an epidural tumor was found later during neurosurgical intervention. The final diagnosis was immunoglobulin G, kappa multiple myeloma complicated with spinal root compression by an extramedullary plasmacytoma. No osteolytic lesion was noted over the length of the spine. Pathology revealed high-grade plasmablastic myeloma. During the clinical course, the patient was refractory to induction chemotherapy, and there was progressive deterioration of renal function. Urinary tract infection by Morganella morganii and pulmonary infection of unknown cause developed 5 months later, and the patient died.

Female↗
PubMed2001

Clinical patterns among invasive pulmonary aspergillosis patients with and without recent intensive immunosuppressive therapy.

BACKGROUND AND PURPOSE: Invasive pulmonary aspergillosis (IPA) is usually an acute life-threatening infection in cancer patients receiving chemotherapy and in organ transplant recipients receiving immunosuppressive therapy. In some immunocompetent patients, IPA has a chronic and indolent clinical course. We compared the clinical patterns among IPA patients who had received recent intensive immunosuppressive therapy (RIIT) and those who had not (N-RIIT). METHODS: We reviewed the medical records of patients with a diagnosis of IPA made between 1992 and 1999. RIIT was defined as chemotherapy or high-dose corticosteroid therapy (at least 500 mg/d methylprednisolone, or equivalent, for at least 3 d) within 2 weeks before the onset of symptoms. RIIT patients were divided into those with and without malignancy. We compared clinical characteristics including age, sex, chest image patterns, diagnostic methods, culture results, treatment conditions, mortality, and recurrence rate in IPA patients: RIIT versus N-RIIT, and RIIT with and without malignancy. RESULTS: A total of 24 patients with IPA, 17 patients who had received RIIT and seven patients who had not (N-RIIT), were included. In the RIIT group, 11 patients had malignancy and six did not. No significant differences in gender, chest image patterns, diagnostic methods, and culture results were found between the RIIT and N-RIIT groups. The N-RIIT group was older and was treated significantly later after the onset of symptoms than the RIIT group (mean +/- standard deviation, SD, 89.43 +/- 129.47 vs 9.70 +/- 9.33 d, p = 0.018). Only one of the seven N-RIIT patients died, while nine of the 17 RIIT patients died (p = 0.08). Among the RIIT patients, five of the six without malignancy died, while four of the 11 patients with malignancy died. IPA recurred in seven of the eight RIIT patients, all of whom had malignancy, but in none of the six N-RIIT patients during a similar follow-up period (mean +/- SD, 16.3 +/- 18.9 vs 27.0 +/- 54.5 mo, p = 0.505). CONCLUSIONS: No differences were noted in image and culture studies between RIIT and N-RIIT IPA patients. RIIT IPA patients had acute and fulminant clinical courses, especially patients without malignancy, even though they received treatment with a mean duration of about 10 days starting from the onset of symptoms. All patients with malignancy undergoing further chemotherapy had recurrence of IPA. N-RIIT IPA patients had chronic clinical courses, a trend of lower mortality rate even with delayed diagnosis, and no recurrence.

Adult↗
PubMed2001

Cholestatic fibrosing hepatitis and hepatitis B after bone marrow transplantation.

In the setting of transplantation and chronic hepatitis B viral infection there is a unique histological feature termed cholestatic fibrosing hepatitis. The use of nucleoside analogues in the treatment of this condition has been successful. We describe a case of cholestatic fibrosing hepatitis, which occurred after intense immunosuppression for graft versus host disease in a patient with bone marrow transplantations. She was commenced on lamivudine therapy and showed good clinical, biochemical and virological response. However she succumbed due to sepsis.

Adult↗
PubMed2000

Endoscopic sinus surgery for ethmoid sinus meningioma.

Meningiomas in the ethmoid sinuses are a challenge to manage. A 50-year-old man suffered from a left olfactory groove meningioma. He underwent a bilateral craniotomy to remove the tumor mass in August, 1997. During the follow-up period, a tumor was found in the right posterior ethmoid sinus. Endoscopic sinus surgery was performed to remove the tumor mass in August, 1998. Pathologic examination of the mass revealed a meningioma. No intraoperative or postoperative complications occurred, except for an episode of seizure.

Endoscopy↗
PubMed1999

Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C.

The inverse relationship between peripheral blood CTL responsiveness to multiple hepatitis C virus (HCV) epitopes and viral titer in patients with persistent HCV infection suggests that enhancement of the CTL response might result in viral clearance. Since several HLA-A2-restricted HCV CTL epitopes are already known, we aimed to identify CTL epitopes restricted by other HLA types in an effort to expand the epitope repertoire available for T cell-mediated therapeutic vaccine development. Scanning of 14 different HCV genome sequences for the presence of conserved peptides containing the HLA-A3 and -B7 motifs revealed 9- to 10-mer peptides that were synthesized and assayed for binding to HLA-A3, -B7 supertype molecules. Peptides with good HLA-binding affinities and cross-reactivities with at least three of five most common molecules of each supertype were tested for the ability to stimulate a memory CTL response in the peripheral blood from selected HCV-infected patients and normal seronegative donors in vitro. We identified eight HLA-A3 supertype-restricted CTL epitopes and one HLA-B7 supertype-restricted CTL epitope that were recognized by infected patients but not by healthy seronegative donors. HLA class I serotyping of 158 chronically infected patients revealed that 80% expressed one or more of HLA molecules belong to either the A2, A3, or B7 supertypes. In conclusion, the epitopes, herein identified combined with previously defined HLA-A2-restricted CTL epitopes, should be useful for the design of an ethnically unbiased, therapeutic CTL vaccine for the treatment of patients with chronic HCV infection.

Acute Disease↗
PubMed1998

Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity.

Using short term CTL lines derived from HLA A2/Kb transgenic mice and IFN-gamma release assays we demonstrate that the NS4.1769 epitope, is generated from natural processing of the NS4 antigen, and presented in the context of the A2/Kb molecules. Interestingly, T cell recognition of the naturally processed form of the NS4. 1769 epitope was associated with significant IFN-gamma release, but no direct cytolytic activity. Epitopes of this phenotype might be of interest, in terms of therapy of chronic HCV infection by associating the benefit of localized lymphokine release with low or absent direct cytopathicity.

Animals↗
PubMed1998

De novo unbalanced translocation resulting in monosomy for proximal 14q and distal 4p in a fetus with intrauterine growth retardation, Wolf-Hirschhorn syndrome, hypertrophic cardiomyopathy, and partial hemihypoplasia.

We present the perinatal findings of a fetus with a de novo unbalanced chromosome translocation that resulted in monosomy for proximal 14q and monosomy for distal 4p. Prenatal sonographic examination at 27 weeks of gestation showed intrauterine growth retardation, microcephaly, cardiomegaly with arrhythmia, and asymmetry of the upper limbs. Genetic amniocentesis showed an abnormal karyotype of 45,XX,der(4)t(4;14)(p16.3;q12),-14. Linkage analysis of the family confirmed the maternal origin of the deletions. Molecular refinement of the deletion breakpoints indicated that the breakpoints at 4p16.3 and 14q12 were located between loci D4S403 (present) and D4S394 (absent), and between loci D14S252 (present) and D14S64 (absent), respectively. Necropsy showed dysmorphic features compatible with Wolf-Hirschhorn syndrome, hypertrophic cardiomyopathy, partial hemihypoplasia, and a normal brain without evidence of holoprosencephaly. Our case adds to the list of clinical phenotypes associated with the proximal regions of 14q.

Abnormalities, Multiple↗
PubMed1998

Clinical evaluation of electronic and manual constant force probes.

The objective of this study was to compare the measurements of an electronic controlled-force probe (FP) to that of a manual controlled-force probe (SP) and a conventional probe (CP). Twelve subjects were recruited. A quadrant with no missing teeth (excluding third molars) was selected. Probing depth was measured at 6 sites per tooth (mesiobuccal, buccal, distobuccal, mesiolingual, lingual, and distolingual) by two examiners (AK and KC) each using the three probes in the following sequence: FP, SP, and CP. The same measurements were repeated a week later by both examiners. The mean difference of measurements between CP and FP was 0.375 +/- 0.858 mm (P < 0.05), with 52.7% of the measurements within 0.5 mm and 80% within 1.0 mm. Correlation between measurements was high (0.7208) and significant (P < 0.001). The mean difference between SP and FP was 0.450 +/- 0.863 mm (P < 0.05), with 49.1% of the measurements within 0.5 mm and 76.9% within 1.0 mm. Correlation between measurements was high (0.7354) and significant (P < 0.001). The mean difference between CP and SP was -0.074 +/- 0.373 mm (P < 0.05), with 49.1% of the measurements within 0.5 mm and 76.9% within 1.0 mm. Correlation between measurements was high (0.95) and significant (P < 0.001). Intra-examiner differences varied for each examiner. For both examiners, the correlations for FP (AK = 0.77, KC = 0.46) were lower than that for CP (AK = 0.86, KC = 0.80) and SP (AK = 0.86, KC = 0.83). Inter-examiner comparisons showed that the correlation for FP (0.50) was lower than that for CP (0.85) and SP (0.86). The percentage of sites within 1 mm differences was less for FP (70%) than for CP (94%) or SP (94%). In conclusion, both CP and SP correlated well with FP. None of the three probes investigated completely eliminated probing errors. The CP and SP yielded more reproducible measurements than FP. Regardless of the type of probe used, probing measurements are subject to both intra- and interexaminer errors.

Adult↗
PubMed1998

Metastatic hepatocellular carcinoma presenting as hemocholecyst with perforation: a case report.

In case of hepatocellular carcinoma (HCC), the gallbladder is less frequently involved and metastasis to the gallbladder, together with its significant clinical manifestations, is rarely discussed in the literature in detail. HCC with metastasis to the gallbladder, initially presenting as gallbladder intraluminal hemorrhage and perforation, has not been previously reported. We present a case of HCC disclosed by emergency cholecystectomy for hemocholecyst with perforation. Evaluation of the possible metastatic mechanisms is also discussed.

Aged↗
PubMed1997

Immunological significance of cytotoxic T lymphocyte epitope variants in patients chronically infected by the hepatitis C virus.

This study was performed to test the hypothesis that cytotoxic T lymphocyte (CTL) selection of hepatitis C virus (HCV) escape variants plays a role in HCV persistence. The peripheral blood CTL responsiveness of patients with well-established chronic hepatitis C to a panel of 10 prototype HCV peptides (genotype 1a) was compared with the corresponding sequences encoded by the infecting viruses in each patient. Variant viral peptide sequences were threefold more frequent in the presence of a CTL response than in its absence, and CTL responses were detected nearly twice as often in association with variant rather than with prototype viral peptide sequences. Furthermore, over half of the patients were infected with potential CTL escape variants that contained nonimmunogenic and noncross-reactive variant peptides many of which displayed reduced HLA-binding affinity. Surprisingly, follow up analysis over a period of up to 46 mo revealed that, in contrast to the relatively high frequency of escape variants initially observed, the subsequent emergence rate of CTL escape variants was very low. Interestingly, the one escape variant that was detected proved to be a CTL antagonist. Collectively, these observations suggest that CTL selection of epitope variants may have occurred in these patients before their entrance into the study and that it may have played a role in HCV persistence. The low apparent rate of ongoing CTL selection in chronically infected patients, however, suggests that if CTL escape occurs during HCV infection it is probably an early event.

Adult↗
PubMed1997

Hepatitis C virus core and E2 protein expression in transgenic mice.

Transgenic mice have been produced that express the hepatitis C virus (HCV) core protein in the liver under the transcriptional control of the mouse major urinary protein promoter. These animals express the full length core protein in cytoplasm of their hepatocytes at levels comparable to those detected in naturally infected patients, without histological or biochemical evidence of liver disease or hepatocellular carcinoma. This contrasts with recent reports that HCV core protein can transform NIH 3T3 cells and cooperates with H-ras to transform primary rat fibroblasts in vitro. Coexpression of HCV core protein in double transgenic mice that replicate the hepatitis B virus (HBV) does not inhibit hepatocellular HBV gene expression or replication, contrary to reports that it inhibits HBV replication in HuH-7 cells after transient transfection in vitro. We have also produced transgenic mice in which a C-terminally truncated (aa384-715) glycosylated HCV E2 protein is expressed in the liver under the transcriptional control of the mouse albumin promoter. Despite the high level expression of HCV E2 protein, no evidence of liver disease was detected in these animals. These results suggest that the HCV core and E2 proteins are not cytopathic for the hepatocyte in vivo, and they represent an initial step in the development of a small animal model of HCV immunopathology.

Animals↗