[Evaluation of the efficacy of medial open wedge high tibial osteotomy combined with anterior cruciate ligament reconstruction in the treatment of varus knee osteoarthritis with anterior cruciate ligament injury].

Objective: To evaluate the efficacy of medial open wedge high tibial osteotomy (MOWHTO) combined with anterior cruciate ligament (ACL) reconstruction in the treatment of varus knee osteoarthritis (OA) with ACL injury. Methods: A follow-up study. The study retrospectively analyzed the patients underwent MOWHTO combined with ACL reconstruction for treatment of varus knee OA with ACL injury in Tianjin Hospital between April 2018 and September 2022. The preoperative and postoperative posterior slope angle (PSA), hip-knee-ankle angle (HKA), visual analog scale (VAS) pain scores, Lysholm score, International Knee Documentation Committee (IKDC) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Tegner score were compared. The follow-up indicators were recorded at 6 weeks, 3 months and 1 year after operation, and the complications were recorded. Results: The study included 32 patients (23 males, 9 females) with a mean age of (50.7±8.4) years. The mean follow-up time was (21.2±4.8) months. PSA increased from 9.2°±1.8° preoperatively to 11.1°±2.4° postoperatively, and HKA increased from 168.7°±2.2° to 181.5°±2.2° (both P<0.01). The indicators such as VAS score (6.8±1.1 vs 1.8±0.4), Lysholm score (52.6±7.1 vs 82.0±6.4), IKDC score (64.7±6.2 vs 80.3±10.0), WOMAC score (51.8±6.3 vs 81.8±6.5), and Tegner score (1.9±0.6 vs 5.0±1.0) were all improved after the operation (all P<0.01). Complications occurred in 5 patients (15.6%), including hematomas, sensory abnormalities, intermuscular vein thrombosis and correction angle loss. Conclusion: MOWHTO combined with ACL reconstruction is a safe and effective approach for the treatment of varus knee OA with ACL injury.

The JNK signaling pathway against titanium-particle-induced osteoclastogenesis and bone resorption in vivo.

OBJECTIVE: The c-Jun N-terminal kinases (JNK) signaling pathway may be involved in the regulation of osteoclast development. The purpose of this investigation was to investigate whether SB600125, a JNK inhibitor, could attenuate titanium-particle-induced inflammatory osteolysis in vivo. MATERIALS AND METHODS: A total of 45 mice were randomly divided into a Sham group, a Titanium group, and a Titanium + JNK inhibitor group, 15 mice per group. After establishing an air pouch bone graft model, we injected phosphate-buffered saline (PBS), titanium particles, or titanium particles + JNK inhibitor into the air pouch of the three groups. The pouch membranes containing bone implants were taken for morphological and molecular analysis 14 days after the mice were sacrificed. RESULTS: General morphological structure observation results, Hematoxylin and Eosin (H&E)-Stained Sections, anti-tartaric acid phosphatase (TRAP) staining, and the transmission electron microscope showed that SB600125, by inhibiting the expression of JNK, attenuated titanium particle-induced inflammatory osteolysis (p<0.05). Immunohistochemical appearance results and reverse transcription-polymerase chain reaction (RT-PCR) results showed SB600125 reduced expression of IL-6, and TNF-α in osteolytic sites stimulated with wear debris (p<0.05). The Western blot results showed the expression of the p-JNK protein in the titanium particle + SB600125 group was significantly reduced compared to the titanium particle stimulation group (p<0.05). CONCLUSIONS: Interfering with the JNK signaling pathway may be beneficial in reducing osteolysis, providing a therapeutic target for preventing and treating aseptic loosening caused by debris-induced inflammatory osteolysis.

[Expression of SOX10 and GATA3 in breast cancer and their significance].

Objective: To investigate the expression characteristics of SOX10 and GATA3 in breast cancer and the value of their combination. Methods: A total of 360 breast cancer specimens with SOX10 immunohistochemical staining were collected from the Department of Pathology in Shenzhen People's Hospital from 2018 to 2021, including 268 cases with simultaneous SOX10 and GATA3 staining. The expression of SOX10 and GATA3 in primary and metastatic breast cancer was detected, and the correlations between SOX10 and GATA3 and the molecular types and clinicopathological features of breast cancer were compared, and the distribution differences among each group were statistically analyzed. Results: The overall expression of SOX10 and GATA3 in breast cancer were 25.8%(93/360) and 81.7%(219/268), and that in triple negative breast cancer (TNBC) were 83.3%(80/96) and 42.7%(32/75), respectively. SOX10 was strongly associated with TNBC (P<0.001), whereas GATA3 was highly expressed in luminal A, luminal B and HER2 over expression breast cancers (P<0.001). The expression of SOX10 and GATA3 was negatively correlated in TNBC, and the combined expression rates of SOX10 and GATA3 in breast cancer and TNBC could reach 97.8% (262/268) and 94.7%(71/75), respectively. In addition, the expression of SOX10 was closely correlated with high histological grade, high Ki-67 proliferation index and lymph node metastasis, and negatively correlated with AR. The expression of GATA3 was correlated with low histological grade and lymph node metastasis, and positively correlated with AR, and the difference was statistically significant. Conclusions: SOX10 is a sensitive marker of TNBC, while GATA3 is highly expressed in non-triple negative breast cancer. The two complementary, combined application of SOX10-GATA3 can improve the detection rate of breast cancer, especially TNBC. SOX10 is associated with malignant characteristics of the tumor, suggesting that SOX10 can be used as a prognostic marker and potential therapeutic target for breast cancer.

[Analysis of complications after medial opening wedge high tibial osteotomy].

Objective: To analyze the incidence of recent complications in patients with osteoarthritis of the knee (OA) after medial opening wedge high tibial osteotomy(MOWHTO) and its influence on clinical effect. Methods: The clinical data of 131 patients with knee OA who received MOWHTO at Department of Sports Medicine and Arthroscopy,Tianjin Hospital from April 2017 to September 2018 were analyzed retrospectively. There were 75 males and 56 females, aged (62.8±5.1) years (range:48 to 70 years). Complications and clinical outcomes of patients were recorded and the proximal medial angle of tibia (MPTA), the International Knee Documentation Committee Subjective Knee Form (IKDC), the Western Ontario and McMaster Universities(WOMAC) Osteoarthritis Index and Knee Injury and Osteoarthritis Outcome score(KOOS) were collected before and 1 year after operation and compared between complication group and non-complication group. Data were analyzed by paired-samples t test, independent samples t test and χ(2) test. Results: The follow-up time was (18.5±3.4) months (range:13 to 22 months). Complications occurred in 22 patients(16.8%), including 8 cases(6.1%) of hematoma, 5 cases(3.8%) of neurosensory abnormality, 4 cases(3.1%) of intramuscular venous thrombosis, 2 cases(1.5%) of deep venous thrombosis, 3 cases(2.3%) of loss of correction angle, 3 cases(2.3%) of superficial infection, 2 cases(1.5%) of deep infection, 2 cases(1.5%) of delayed union of fracture, 1 case(0.8%) of postoperative stiffness, 1 case (0.8%) of hinge point cortex fracture. There were no significant difference in MPTA ((86.5±2.0)° vs. (86.7±2.1)°, t=-0.41, P=0.68) , IKDC ((86.4±4.8) vs.(85.5±6.9), t=0.74, P=0.50) , WOMAC ((87.7±6.5) vs. (86.1±5.8), t=1.16, P=0.25). There were no significant difference in knee scores except for the KOOS pain score ((79.4±4.4) vs. (87.2±5.9), t=-5.90, P<0.01) and sports and recreation score ((83.2±3.0) vs. (88.0±4.7), t=-6.14, P<0.01) . Conclusion: Short-term complications of MOWHTO can be managed appropriately through early diagnosis and individualized treatment and have no significant negative effect on knee function recovery of patients.

[The surgical management of upper parapharyngeal regions].

Objective: To find proper the surgical approval and evaluate clinical efficacy to treat the tumor of upper parapharyngeal space involving the base of skull and intracranial skull. Method: The data of 9 cases from June 2013 and June 2018 were analyzed retrospectively including schwannoma in 6 cases, pleomorphic adenoma in 2 cases and hemangioma in 1 case. All cases received preoperative high resolution CT and MRI, some cases also did the DSA examination. Tumor invaded top of nasopharyngeal in 4 cases, the base of skull in 3 cases, and intraskull in 2 cases. 9 cases were treated with surgery alone. Surgical approach: transcervical approach (n=1), transcervical approach and mandibular fracture surgery(n=2), transoral approach(n=3), transnasal transpterygoid approach(n=2), transparotid gland approach(n=1). Result: Tumors in 8 cases were completely removed, and 1 case was performed by partial excision. Hemorrhage(>500 ml) occurred in 2 cases, tongue deflection and cerebrospinal fluid leakage occurred in 1 case. No death, tumor recurrence and wound infection was found. Conclusion: The position of benign upper parapharyngeal space tumors is deep and tumor often invade in the base of the skull and brain tissue. It is close to the important nerve, vessels of the skull base and meninges. The appropriate surgical approach should be selected according to the individual situation. The main point of the operation is complete the tumor resection with preserving or reconstructing the important function of the blood vessel and nerve.

Immune escape to PD-L1/PD-1 blockade: seven steps to success (or failure).

The emergence of programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1)-targeted therapy has demonstrated the importance of the PD-L1 : PD-1 interaction in inhibiting anticancer T-cell immunity in multiple human cancers, generating durable responses and extended overall survival. However, not all patients treated with PD-L1/PD-1-targeted therapy experience tumor shrinkage, durable responses, or prolonged survival. To extend such benefits to more cancer patients, it is necessary to understand why some patients experience primary or secondary immune escape, in which the immune response is incapable of eradicating all cancer cells. Understanding immune escape from PD-L1/PD-1-targeted therapy will be important to the development of rational immune-combination therapy and predictive diagnostics and to the identification of novel immune targets. Factors that likely relate to immune escape include the lack of strong cancer antigens or epitopes recognized by T cells, minimal activation of cancer-specific T cells, poor infiltration of T cells into tumors, downregulation of the major histocompatibility complex on cancer cells, and immunosuppressive factors and cells in the tumor microenvironment. Precisely identifying and understanding these mechanisms of immune escape in individual cancer patients will allow for personalized cancer immunotherapy, in which monotherapy and combination immunotherapy are chosen based on the presence of specific immune biology. This approach may enable treatment with immunotherapy without inducing immune escape, resulting in a larger proportion of patients obtaining clinical benefit.

Increased risk of hepatocellular carcinoma in chronic hepatitis C patients with new onset diabetes: a nation-wide cohort study.

BACKGROUND: The impact of diabetes for hepatocellular carcinoma (HCC) development in chronic hepatitis C (CHC) patients remains controversial. AIM: To investigate the risk of HCC in CHC patients who develop new onset diabetes. METHODS: We conducted a nation-wide cohort study by using Taiwanese National Health Insurance Research Database, which comprised of data from >99% of entire population. Among randomly sampled one million enrollees, 6251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in the patient who was given the diagnosis in the years 1999-2009 but not in 1997-1998. The cohorts of CHC with new onset diabetes (n = 1100) and 1:1 ratio age-, gender-, and inception point (onset date of diabetes) matched nondiabetes (n = 1087) were followed up from the inception point until the development of HCC, withdrawal from insurance, or December 2009. RESULTS: After adjustment for competing mortality, patients with new onset diabetes had a significantly higher cumulative incidence of HCC (Relative Risk = 1.544, 95% CI = 1.000-2.387, modified log-rank test, P = 0.047) as compared to those without. After adjustment for age, gender, cirrhosis, hyperlipidaemia, CHC treatment, diabetes treatment, comorbidity index, obesity and statins therapy by Cox proportional hazard model, diabetes was still an independent predictor for HCC (hazard ratio (HR) = 1.906, 95% CI = 1.102-3.295, P = 0.021). The risk for HCC was increased in those who were 40-59 years old, independent of other variables (HR = 3.086, 95% CI = 1.045-9.112, P = 0.041), and after adjustment for competing mortality (modified log-rank test, P = 0.009). CONCLUSION: Chronic hepatitis C patients who develop diabetes are at an increased risk of hepatocellular carcinoma over time.

Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with new onset diabetes: a nationwide cohort study.

BACKGROUND: Diabetes increases the risk of hepatocellular carcinoma (HCC), however, the time-relationship between hepatitis B virus and diabetes for the development of HCC remains unclear. AIM: To explore the risk of HCC in chronic hepatitis B patients with newly diagnosed diabetes. METHODS: We conducted a nationwide cohort study by using Taiwanese National Health Insurance Research Database, which covers over 99% of entire population. Among randomly sampled one million enrollees, 14 523 chronic hepatitis B patients were diagnosed in years 1997-2009. We defined new onset diabetes as patients who were given the diagnosis in the years 1999-2009, but not in 1997-1998. The cohorts of chronic hepatitis B with new onset diabetes (n = 2099) and 1:1 ratio age-, gender- and inception point (onset date of diabetes)- matched nondiabetes (n = 2080) were followed up from the inception point until development of HCC, withdrawal from insurance or December 2009. RESULTS: After adjustment for competing mortality, patients with new onset diabetes had a significantly higher cumulative incidence of HCC [relative risk = 1.628, 95% confidence interval (CI) = 1.114-2.378, modified log-rank test, P = 0.012] as compared to nondiabetes patients. After adjustment for age, gender, hyperlipidaemia, chronic hepatitis B treatment, statins therapy, cirrhosis, comorbidity index and obesity, diabetes was still an independent predictor for HCC (hazard ratio = 1.798, 95% CI = 1.194-2.707, P = 0.005). CONCLUSION: Chronic hepatitis B patients with newly diagnosed diabetes have an increased risk of hepatocellular carcinoma over time.

Microinjection of salusin-beta into the nucleus tractus solitarii inhibits cardiovascular function by suppressing presympathetic neurons in rostral ventrolateral medulla in rats.

Salusin-beta is newly identified bioactive peptide of 20 amino acids, which is widely distributed in hematopoietic system, endocrine system, and the central nervous system (CNS). Although salusin-beta extensively expressed in the CNS, the central cardiovascular functions of salusin-beta are unclear. Our main objective was to determine the cardiovascular effect of microinjection of salusin-beta into the nucleus tractus solitarii (NTS) in anesthetized rats. Bilateral or unilateral microinjection of salusin-beta (0.94-94 microg/rat) into the NTS dose-dependently decreased blood pressure and heart rate. Bilateral NTS microinjection of salusin-beta (9.4 microg/rat) did not alter baroreflex sensitivity. Prior application of the glutamate receptor antagonist kynurenic acid (0.19 microg/rat, n=9) into the NTS did not alter the salusin-beta (9.4 microg/rat) induced hypotension and bradycardia. However, pretreatment with the GABA receptor agonist muscimol (0.5 ng/rat) within the rostral ventrolateral medulla (RVLM) completely abolished the hypotension (-14+/-5 vs. -3+/-5 mm Hg, P<0.05) and bradycardia (-22+/-6 vs. -6+/-5 bpm, P<0.05) evoked by intra-NTS salusin-beta (9.4 microg/rat). In addition, we found that vagotomy didn't influence the actions of salusin-beta (9.4 microg/rat) in the NTS. In conclusion, our present study shows that microinjection of salusin-beta into the NTS significantly produces hypotension and bradycardia, presumably by suppressing the activities of presympathetic neurons in the RVLM.

Hepatitis B vaccination in children: the Taiwan experience.

The world's first nationwide hepatitis B virus (HBV) universal vaccination program for infants was launched in Taiwan in July, 1984. All infants received three to four doses plasma or recombinant HBV vaccines. In addition, infants of HBeAg-positive mothers received 0.5ml of hepatitis B immunoglobulin within 24hours after birth. The vaccination coverage rate is as high as 97%. Seroprevalence of hepatitis B surface antigen (HBsAg) declined from 9.8% (prevaccination period) to 0.6% in children in Taipei City after 20years of mass vaccination. The seropositive rates for HBsAg, antibody to HBsAg, and antibody to hepatitis B core antigen were 1.2%, 50.5%, and 3.7%, respectively, in those born after the vaccination program (<20years old) in 2004. In line with the decrease of chronic HBV infection, the incidence of hepatocellular carcinoma (HCC) also decreased in children in Taiwan. From 1981 to 1994, the incidence of HCC in 6- to 9-year-olds declined from 0.52/100,000 for those born between 1974 and 1984 to 0.13 for those born between 1984 and 1986 (p<0.001). We extended the observation to 2000, the incidence of HCC per 100,000 children declined from 0.54 to 0.20. The prevalence of a determinant mutants (amino acids 121-149 of HBsAg) in Taiwanese carrier children was 7.8% (eight out of 103) in 1984, increased to 19.6% (10 out of 51) in 1989, peaked at 28.1% (nince out of 32) in 1994, and remained stationary at 23.1% (three out of 13) and about 25% in 1999 and 2004, respectively; it was higher in those fully vaccinated compared with those not vaccinated. The other group of subjects who are susceptible to vaccine failure is the immunocompromized hosts. We observed some de novo HBV infection in children after liver transplantation. Despite of the success of hepatitis B immunization, childhood chronic HBV infection and HCC were not eliminated by the universal vaccination program. Among those HBsAg carriers born after the vaccination program, 89% of their mothers were found to be positive for HBsAg, indicating the importance of maternal transmission. This was also true in the mothers of children with HCC, of them 96% were HBsAg positive. After two decades of universal infant HBV vaccination, we found this program provides long-term protection for up to more than 20years, and a universal booster is not required for the primary HBV vaccinees before adulthood. Mother-to-child transmission, although largely diminished, is still the main cause for immunoprophylaxis failure. The emergence of escape mutant did not impose increased risk of chronic infection at present. Nevertheless, development of new vaccines may overcome the vaccine failure.

Vitamin D receptor gene polymorphisms and distinct clinical phenotypes of hepatitis B carriers in Taiwan.

Vitamin D exhibits immunomodulatory and antiproliferative effects through vitamin D receptor (VDR) in chronic infections and cancers. We genotyped the BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) polymorphisms of VDR gene in 250 Taiwanese chronic hepatitis B virus (HBV) carriers who were categorized into six phenotypes. After adjustment for age and sex, the frequencies of the VDR B/b, B/a, B/T, B/a/T in patients with hepatitis flare(s) were lower than those without (7 vs 20%, P=0.009; 1 vs 9%, P=0.004; 3 vs 10%, P=0.007; 1 vs 9%, P=0.005, respectively); in contrast, T/t, A/T, A/t, b/A/t were higher in flare(s) (8 vs 3%, P=0.003; 49 vs 34%, P=0.027; 2 vs 1%, P=0.004; 0.5 vs 0%, P=0.001, respectively). In addition, B/b, B/B, T/t, b/A, B/a, B/A, B/T, B/t, A/t, b/A/T, B/a/T, B/A/T, B/A/t, b/A/t were higher in patients positive for HBeAg. The distribution of VDR genotypes was comparable between patients with and without hepatocellular carcinoma (HCC). VDR gene polymorphisms are associated with distinct clinical phenotypes in Taiwanese HBV carriers but not with HCC development.

Characterization of interleukin 8 in woodchucks with chronic hepatitis B and hepatocellular carcinoma.

The eastern woodchuck, Marmota monax, represents a useful animal model to study hepatitis B virus infection in humans. However, immunological studies in this model have been impeded by a lack of basic information about the components of the immune system such as cytokines and chemokines. To clarify the role(s) of interleukin 8 (IL-8) in chronic hepatitis B and hepatocellular carcinoma (HCC) in the woodchuck model, we cloned and characterized the woodchuck IL-8 cDNA and genomic DNA. Sequence analysis revealed that the organization of the wk-IL-8 gene is similar to that of the human IL-8 gene and consists of four exons and three introns. Woodchuck IL-8 protein exhibits the conserved ELRCXC motif of IL-8 and shows 87, 82, 82 and 79% similarity with rabbit, ovine, bovine and human IL-8 proteins, respectively. The biological activity of wk-IL-8 was demonstrated using neutrophil chemotaxis assays. Wk-IL-8 could be readily detected in both tumor and non-tumor tissues with higher expression in the non-tumor tissues in most cases. The results from this study will facilitate the investigation of IL-8 in the immunopathogenesis of hepadnavirus-related diseases by the woodchuck model.

Lower serum viral loads in young patients with hepatitis-B-virus-related hepatocellular carcinoma.

Advanced age and high hepatitis B virus (HBV) DNA level are risk factors associated with the development of HBV-related hepatocellular carcinoma (HCC). However, little is known about the role of viral load in the carcinogenesis of HCC in young people. A total of 183 HBV-related HCC patients and 202 HBV carriers were therefore enrolled to compare serum viral loads in young (40 years of age) age groups. Other factors associated with the development of HCC were also analysed. The results showed that serum alanine aminotransferase (38.7 +/- 24.1 vs 58.4 +/- 65.4 IU/L, P = 0.006) and HBV DNA levels (log(10) titre: 4.20 +/- 1.33 vs 4.80 +/- 1.39, P = 0.053) were lower in young HCC patients than in old HCC patients. There was a positive correlation between age and serum HBV DNA level in HCC patients but a negative correlation in HBV carriers. Young HCC patients with HBV genotype B infection had higher viral loads than those with genotype C infection (log(10) titre: 4.79 +/- 1.34 vs 3.27 +/- 0.60, P = 0.001). By multivariate logistic regression analyses, high serum HBV DNA level was associated with the development of HCC in old patients [odds ratio (OR) 1.584, 95% confidence interval (CI) 1.075-2.333] rather than in young patients (OR 0.848, 95% CI 0.645-1.116). In conclusion, viral factors in association with the development of HBV-related HCC in young patients may be different from their old counterparts. The complicated interplay between host and virus could be responsible for the emergence and aggressive outcome of early-onset HCC.

Clinicopathological differences between hepatitis B viral genotype B- and C-related resectable hepatocellular carcinoma.

Clinical and pathogenic differences exist between hepatitis B viral (HBV) genotypes B and C, and genotype C has a higher risk of hepatocellular carcinoma (HCC) development than genotype B. The aim of this study was to investigate whether HBV genotypes B and C influence the clinicopathological features of patients with resectable HCC. Stored serum samples from 193 patients with resectable HBV-related HCC were tested for HBV genotypes by a molecular method. Of 193 patients undergoing resection of HCC, 107 (55%) and 86 (45%) were infected with genotypes B and C, respectively. Compared with genotype C patients, genotype B patients were less likely to be associated with liver cirrhosis (33%vs 51%, P = 0.01). Pathologically, genotype B patients had a higher rate of solitary tumour (94%vs 86%, P = 0.048) and more satellite nodules (22%vs 12%, P = 0.05) than genotype C patients. Our results indicate that genotype B-related HCC is less associated with liver cirrhosis and has a higher frequency of solitary tumour as well as more satellite nodules than genotype C-related HCC. These characteristics may contribute to the recurrence patterns and prognosis of HBV-related HCC in patients with genotype B or C infection.

Searching for HLA-DRB1*1206 in volunteer marrow donors in four US population groups.

The frequencies of DRB1*12 alleles were determined in four US population groups by DNA sequencing. Only DRB1*120101 (or DRB1*1206 or *1210) and DRB1*120201 alleles were identified, the latter primarily in the Asian American population. Additional testing of a subset of samples to detect the presence of DRB1*1206 found all of the alleles to be DRB1*120101 (or DRB1*1210). Retesting of six samples previously typed as DRB1*1206 found only DRB1*120101 (or DRB1*1210).

Correlation of interleukin-10 gene haplotype with hepatocellular carcinoma in Taiwan.

Polymorphisms in cytokine genes can influence immune responses, inflammation and tissue injury, and may affect the outcome of hepatitis B virus (HBV) infection. We analyzed single nucleotide polymorphisms (SNP) in the interleukin (IL)-10 gene among 344 HBV carriers and 208 patients with hepatocellular carcinoma (HCC). Genotypes and haplotypes were tested for association with HCC. IL-10/-592 C/C genotype was associated with a higher risk for HCC compared with IL-10/-592 A/C and A/A genotypes [odds ratio (OR): 2.1, 95% confidence interval (CI): 1.2-3.6]. IL-10/1927 A/A genotype was also associated with a higher risk for HCC compared with IL-10/1927 A/C and C/C genotypes (OR: 1.5, 95% CI: 1.0-2.2). Haplotype analysis revealed that the homozygosity of the C-A haplotype (defined by SNPs at positions -592 and 1927) of IL-10 gene conveys the highest risk for HCC among HBV carriers compared with the homozygosity for the A-C haplotype (OR: 2.6, 95% CI: 1.3-4.9). The results demonstrate that IL-10 gene polymorphism can affect the outcome of chronic HBV infection. Further studies are necessary to clarify how variation in the IL-10 gene affects IL-10 function and risk of HCC.

Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan.

Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.

Ribavirin enhances interferon-gamma levels in patients with chronic hepatitis C treated with interferon-alpha.

Some patients with chronic hepatitis C respond to interferon (IFN)-alpha treatment, and the efficiency can be improved by combining it with ribavirin. The mechanism of this improvement is unknown. To investigate the effects of these two regimens on the immune responses in 51 patients with chronic hepatitis C, we examined the hepatitis C core antigen-specific proliferative response and cytokine production profiles, natural killer (NK) cell cytotoxicity and cytotoxic T cell function during treatment. The results are as follows: (1) both viral clearance and biochemical normalization occurred more frequently in patients receiving combination therapy; (2) the function of NK cells increased after treatment in the responders of both groups (p < 0.05); (3) the level of IFN-gamma produced by hepatitis C core antigen-stimulated peripheral blood mononuclear cells was higher in patients receiving combination therapy, especially in responders; (4) the core antigen-specific proliferative response decreased after treatment, and (5) in addition, the core-specific cytotoxic T cell activities of five responder patients also increased significantly after therapy. In conclusion, enhancement of immune responses, especially those related to type-1 T helper cell activity, may contribute to better efficacy in combining ribavirin with IFN-alpha for treatment of chronic hepatitis C.

Functional measurement of hepatitis C virus core-specific CD8(+) T-cell responses in the livers or peripheral blood of patients by using autologous peripheral blood mononuclear cells as targets or stimulators.

As is widely recognized, CD8(+) cytotoxic T lymphocytes (CTLs) play a crucial role in hepatitis C virus (HCV) infection, both in pathogenesis of liver injury and in clearing the virus. CTL studies with HCV-infected patients have been difficult because of the relatively low frequency of CTL precursors in the peripheral blood and because the targeted epitopes vary depending on the human leukocyte antigen (HLA) types of the individuals. This study attempts to overcome these problems by assessing the feasibility of using autologous peripheral blood mononuclear cells (PBMCs) expressing viral antigens as stimulators or targets in order to monitor the CTL responses. Primary PBMCs were transduced using a retroviral vector pseudotyped with a vesicular stomatitis virus G glycoprotein expressing the HCV core gene. Additionally, the vector-transduced PBMCs were used as targets of CTL assays to measure the HCV core-specific CTL activities from the liver-infiltrating lymphocytes of six different HLA-type patients with chronic HCV infection. The core-expressing PBMCs also served as stimulators, allowing us to measure core-specific CD8(+) T-cell responses by intracellular gamma interferon staining of the peripheral blood of hepatitis C patients who had received treatment with alpha interferon plus ribavirin. This approach provides an efficient means of measuring antigen-specific CTL responses without HLA constraints.

Molecular cloning and expression of woodchuck granulocyte-macrophage colony stimulating factor.

Granulocyte-macrophage colony stimulating factor (GM-CSF) has immunoregulatory and antiviral effects, and may thus be promising for the treatment of chronic hepatitis B. Using woodchuck hepatitis virus (WHV)-infected woodchuck as an animal model to test the efficacy and safety of GM-CSF on the therapy of chronic hepatitis B, woodchuck GM-CSF will be required due to the apparent species-specific activity of GM-CSF. The cDNA of woodchuck GM-CSF was cloned using reverse transcription-polymerase chain reaction (RT-PCR) with primers deriving from highly conserved regions of GM-CSF genes from other species. The deduced amino acids, including the signal peptide, is 138 in length and its identities to human, murine, canine and bovine GM-CSFs are 63, 49, 63, and 63% respectively. The genomic DNA of woodchuck GM-CSF was also cloned by PCR. Its organization is highly homologous to that of human and murine GM-CSF genes, consisting of four exons and three introns. Cloned woodchuck GM-CSF was expressed transiently in 293T cells. The recombinant protein expressed was found to stimulate the growth and differentiation of woodchuck bone marrow cells, indicating the protein expressed by the cloned gene is functional. These results pave the way for future studies on the potential role of GM-CSF for the treatment of chronic hepatitis B by using this animal model.