Reviews for APASL guidelines: immunomodulator therapy of chronic hepatitis B

The primary aim of immunomodulator therapy is to help the natural human immune system to mount a defense against hepatitis B virus. IFN-α has been used for the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B for over two decades and has been shown to be effective in suppressing HBV replication and in inducing serological response leading to long-term clinical benefits. IFN-α has been used in patients with well-compensated cirrhosis with comparable or better response to that in non-cirrhotic patients. IFN-α therapy in patients with cirrhosis has a similar side effect profile as in those without cirrhosis. However, IFN-α is contraindicated in patients with overt or decompensated cirrhosis. Pegylated IFN-α has been shown to be effective in treatment of chronic hepatitis B with sustained response rate in about one-third of the treated patients. Peg IFN-α treatment in non-responders to lamivudine or adefovir dipivoxil showed similar response rate to that seen in naïve patients. Thymosin α₁ is effective in treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B with a significantly increasing virological response over time after therapy.     

The protease-antiprotease balance within the human lung: Implications for the pathogenesis of emphysema

Critical elements of the mechanisms of emphysema remain to be clarified. However, taken together, the existing evidence supports the concept that alveolar matrix destruction ensues as the regulatory interplay between oxidant and protease expression is subverted. The final common pathway of matrix destruction links the inherited and acquired forms of emphysema through the ultimate expression of unimpeded neutrophil elastase.     

Klotho protein activates the PKC pathway in the kidney and testis and suppresses 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression

Homozygous Klotho mutant (kl ^−/−) mice exhibit a variety of phenotypes resembling human aging, including arteriosclerosis, infertility, skin atrophy, osteoporosis, and short life span. Calcium abnormality, one of the phenotypes in kl ^−/− mice, is thought to be due to the elevated gene expression of 25-hydroxyvitamin D₃ 1α-hydroxylase in the kidney. We studied 25-hydroxyvitamin D₃ 1α-hydroxylase gene expression using a Klotho plasmid that we had previously constructed for Klotho protein production. It was found that Klotho protein medium upregulated cAMP and the PKC pathway, and suppressed 25-hydroxyvitamin D₃ 1α-hydroxylase in kidney cells. However, both cAMP and PKC are known to elevate 25-hydroxyvitamin D₃ 1α-hydroxylase gene expression, therefore, another unknown calcium regulation pathway using Klotho protein medium might exist. Furthermore, we found that activation of the PKC pathway by Klotho was observed only in the kidney and testis, where the Klotho gene is expressed, although activation of the cAMP pathway was observed in any kind of cell. These data suggest that calcium regulation through 25-hydroxyvitamin D₃ 1α-hydroxylase by Klotho depends on non-cAMP and a non-PKC pathway and that the Klotho protein may have different signaling pathways, depending on the Klotho gene expression in different cells and organs.     

Islet alpha-cells do not influence insulin secretion from beta-cells through cell-cell contact

Interactions between the endocrine cells in islets of Langerhans influence their secretory function, and disruption of islet structure results in impaired insulin secretory responses to both nutrient and non-nutrient stimuli. We have previously demonstrated that insulin-secreting MIN6 cells show enhanced secretory responses when grown as islet-like structures (pseudoislets) suggesting that homotypic cell–cell interactions between β-cells are important for normal function. We have now extended this experimental model to study the role of heterotypic interactions between insulin-expressing and glucagon-expressing cells by measuring the organization and secretory function of pseudoislets formed from MIN6 and αTC1 cells. The direct α-cell to β-cell contact in the heterogenous MIN6/αTC1 pseudoislets was sufficient to enable the formation of anatomically correct islet-like structures, with a central core of MIN6 cells surrounded by a periphery of αTC1 cells. However, the presence of αTC1 cells had no detectable effect on insulin secretory responses to nutrient or non-nutrient stimuli. In contrast, exogenous glucagon enhanced insulin secretion, in accordance with a paracrine role for α-cell-derived glucagon in the regulation of insulin secretion rather than direct, contact-mediated effects of α-cells on neighbouring β-cells.     

Decline in FEV1 in patients with PiZ alpha-1-antitrypsin deficiency: the Australian experience

OBJECTIVE: Alpha-1-antitrypsin (alpha1antitrypsin) deficiency is a rare hereditary disorder which characteristically presents with emphysema at an early age. The aim of the present study was to determine whether the rate of decline of lung function in alpha1antitrypsin-deficient subjects in Australia was similar to that found elsewhere. METHODOLOGY: Patients registered with the Australian Alpha-1-Antitrypsin Replacement Program were studied. All patients (n = 50) had a serum alpha1antitrypsin concentration of < 0.3 g/L and had had spirometry measured over at least 2 years. They were compared with a group of normal volunteers (hospital staff, n = 107) with normal alpha1antitrypsin levels and phenotypes and with no clinical history of lung disease. All had spirometry measured for periods ranging from 2 to 6 years. The rate of decline of forced expiratory volume in 1 s (FEV1) for each subject was calculated by least squares linear regression using FEV1 against the time from entry into the study. RESULTS: The group mean (+/- SD) rate of decline in FEV1 was significantly greater (P < 0.01) in the alpha1antitrypsin-deficient patients (88 +/- 71 mL/year) than for the normal controls (-15 +/- 48 mL/year). There was no difference in decline in FEV1 when the data was analysed for gender and for index versus non-index cases. CONCLUSION: The results confirm previous reports of an accelerated rate of decline of FEV1 in patients with alpha1antitrypsin deficiency. Our results indicate that the rate of decline of lung function in alpha1antitrypsin deficient subjects in Australia is similar to that found in reported series from elsewhere.