Inhibition of hepatitis B virus DNA replicative intermediate forms by recombinant interferon-γ

AIM: To evaluate the in vitro anti-HBV activity of recombinant human IFN-γ, alone and in combination with lamivudine.METHODS: A recombinant baculovirus-HBV/HepG2 culture system was developed which could support productive HBV infection in vitro. Expression of HBsAg and HBeAg in infected HepG2 culture medium was detected by commercial enzyme immunoassays. HBV DNA replication intermediates were detected in infected cells by Southern hybridization and viral DNA load was determined by dot hybridization.RESULTS: IFN-γ at 0.1 to 5 μg/L efficiently down regulated HBsAg expression in transduced HepG2 cells.At 5 μg/L, IFN-γ also suppressed HBV DNA replication in these cells. While treatment with a combination of lamivudine and IFN-γ showed no additive effect,sequential treatment first with lamivudine and then IFN-γ was found to be promising. In this culture system the best HBV suppression was observed with a pulse of 2 μmol/L lamivudine for two days, followed by 1 μg/L IFN-γ for another four days. Compared to treatment with lamivudine alone, the sequential use of 0.2 μmol/L lamivudine for two days, followed by 5 μg/L IFN-γ for six days showed a 72% reduction in HBV cccDNA pool.CONCLUSION: This in vitro study warrants further evaluation of a combination of IFN-γ and lamivudine,especially in IFN-α non-responder chronic hepatitis B patients. A reduced duration of lamivudine treatment would also restrict the emergence of drug-resistant HBV mutants.     

Influence of quasispecies on virological responses and disease severity in patients with chronic hepatitis C

AIM： To elucidate the influence of quasispecies on virological response and disease severity in patients with chronic hepatitis C.
METHODS： Forty seven patients with hepatitis C [32 with chronic active hepatitis （CAH）, 9 with cirrhosis, and 6 with hepatocellular carcinoma （HCC）] were screened for the presence of quasispecies by single stranded conformational polymorphism （SSCP） analysis in the hypervariable region （HVR） and non-structural 5B （NS5B） viral genes of hepatitis C virus. The 41 patients excluding those with HCC were on therapy and followed up for a year with the determination of virological response and disease severity. Virus isolated from twenty three randomly selected patients （11 non-responders and 12 showing a sustained virological response） was sequenced for the assessment of mutations.
RESULTS： The occurrence of quasispecies was proportionately higher in patients with HCC and cirrhosis than in those with CAH, revealing a significant correlation between the molecular evolution of quasispecies and the severity of disease in patients with hepatitis C. The occurrence of complex quasispecies has a significant association （P 〈 0.05） with the non-responders, and leads to persistence of infection. Significant differences （P 〈 0.05） in viral load （log10 IU/mL） were observed among patients infected with complex quasispecies （CQS）, those infected with simple quasispecies （SQS） and those with no quasispecies （NQS）, after 12 wk （CQS-5.2 ± 2.3, SQS-3.2 ± 1.9, NQS-2.8 ± 2.4） and 24 wk （CQS-3.9 ± 2.2, SQS-3.0 ± 2.2, NQS-2.1 ± 2.3） in the HVR region. However, a statistically significant difference （P 〈 0.05） was observed between the viral loads of patients infected with CQS and those infected with NQS in NS5B viral gene after 24 wk （CQS-3.9 ± 2.2, SQS-3.0 ± 2.2, and NQS-2.1 ± 2.3） and 48 wk （CQS-3.1 ± 2.7, SQS-2.3 ± 2.4, NQS-2.0 ± 2.3） of therapy. Disease severity was significantly associated with viral load during th     

Endothelin as a therapeutic target in the treatment of cardiovascular disease

Endothelins, a family of peptides derived from the vascular endothelium and smooth muscle cells possess vasoconstrictor and mitogenic properties. By acting predominantly in a paracrine fashion, these peptides activate specific receptors and have protean effects in normal and diseased organ systems. The wide distribution of these receptors in various tissues mediate the multiplicity of physiologic actions attributed to endothelins. Much of our understanding about endothelins has come from the development of an array of receptor-specific and mixed receptor antagonists. Based on the promising results from animal studies, active research and drug development programs are under way to investigate the clinical potential of endothelin antagonism for treatment of cardiovascular disease.     

Pulmonary autograft mitral valve replacement: initial experience with the Ross II procedure

BACKGROUND: The renewed interest in mitral valve replacement with a pulmonary autograft encouraged us to perform this procedure in selected patients. METHODS AND RESULTS: From August 2000 to February 2002, 10 patients between 30 and 52 years of age with calcific mitral valvular disease underwent the Ross II procedure. Patients were either in New York Heart Association functional class III (7/10) or IV (3/10). Transthoracic echocardiography was done in all the patients to confirm the diagnosis. A pulmonary autograft was used to replace the diseased mitral valve. Intraoperative transesophageal echocardiography confirmed normal functioning of the autograft. There were 2 early deaths. The 8 survivors are in New York Heart Association functional class I with excellent autograft and homograft function at a follow-up of 2-20 months (mean 9 months). CONCLUSIONS: This procedure is a viable option for mitral valve replacement in patients with calcific mitral valve disease. However, the procedure is technically demanding and requires a valve bank.     

Weighted Coherence: A More Effective Measure Than Average Coherence

In this study, we evaluated the effectiveness of the statistic, Weighted Coherence in relation to the average or mean coherence in a particular frequency band after cross-spectral analysis. In time domain, correlation coefficient explains the relationship between two variables of interest, and a similar statistic in frequency domain using cross-spectral analysis is referred to as coherence, which is equivalent to the squared correlation coefficient and ranges from zero to unity. In this study, we show that weighted coherence is much more sensitive to various challenges within the same subject and also may be a more sensitive indicator of group differences in different frequency bands. Our data on normal subjects and patients with panic disorder during supine and standing postures during normal breathing, and also at different breathing rates throw new light on the sensitivity of this previously described novel index to quantify coherence between two related time series such as beat-to-beat heart rate and QT interval.     

Syncope in a middle aged male due to acute rheumatic fever

Rheumatic fever is a multi system disease which occurs following infection with group A beta hemolytic streptococcus. It is commonest in the age group of 5-15 years but can occur in adults also. First degree atrioventricular block is a common manifestation of acute rheumatic fever and is included in the Jones criteria but Wenckebacks phenomena and complete heart block are relatively rare manifestations of rheumatic fever. Syncope occurring in acute rheumatic fever is also infrequently reported. We report the case of a 38-year-old male with rheumatic carditis who had advanced atrioventricular block which resulted in syncope and required a temporary pacemaker insertion.     

Use of the stiff shaft,straight terumo glidewire in crossing stenotic aortic valves

One of the more difficult and time-consuming diagnostic procedures in the cardiac catheterization laboratory is retrograde crossing of the severely stenotic aortic valve. Whereas patients with advanced aortic stenosis tend to be complicated and elderly, lengthy procedures can lead to a higher incidence of thrombo-embolic and vascular complications and relatively greater procedural blood loss. This report concerns the use of the Terumo Glidewire to facilitate passage through stenotic and tortuous peripheral arteries. © 1993 Wiiey-Liss, Inc.     

Increased AT2R protein expression but not increased apoptosis during cardioprotection induced by AT1R blockade

BACKGROUND: The angiotensin II type 2 receptor (AT2R) is considered to be antigrowth and to mediate apoptosis in several cell types. Whether AT2R upregulation, associated with angiotensin II type 1 receptor (AT1R) blockade and cardioprotection after ischemia-reperfusion (IR), might not result in increased cardiomyocyte (CM) apoptosis has not been documented. OBJECTIVES: To determine whether increased AT2R protein expression, during AT1R blockade after acute IR, is associated with no increase in CM apoptosis. MATERIALS AND METHODS: The recovery of left ventricular (LV) mechanical function after acute IR (30 min of ischemia, 40 min of reperfusion) was measured in isolated Langendorff rat hearts following pretreatment with the AT1R antagonist candesartan (CN) (CN 10 nmol/L) for 40 min before ischemia. The authors established with an initial dose-response curve using escalating concentrations of CN that 10 nmol/L abrogated vasoconstriction induced by angiotensin II (0.1 mmol/L). AT1R and AT2R protein expression (Western immunoblot), CM apoptosis (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labelling assay and nuclear morphology) and apoptotic markers (Bax, Bcl-2, caspase-3, p53) were assessed in LV tissue. RESULTS: Compared with IR controls, CN improved peak systolic pressure, LV developed pressure and positive dp/dt, and increased AT2R (not AT1R) protein, but did not change the level of apoptosis or the expression of Bax, Bcl-2, caspase-3 or p53. CN also increased AT2R protein after ischemia alone but did not change CM apoptosis or expression of the markers. CONCLUSIONS: Increased AT2R protein expression during AT1R blockade after IR in the isolated Langendorff rat heart is associated with cardioprotection but no increase in CM apoptosis.