Israel Medical Association Journal

Between the 1960s and 1980s, the main focus of biological research was nucleic acids and the translation of the coded information into proteins. Protein degradation was a neglected area and regarded by many as a scavenger, non-specific and end process. While it was known that proteins are turning over, the large extent and high specificity of the process - where distinct proteins have half-lives that range from a few minutes to several days - have not been appreciated. The discovery of the lysosome by Dr. Christian de Duve did not change this view significantly, as this organelle is involved mostly in the degradation of extra- and not intracellular proteins, and it was clear that lysosomal proteases, similar to those of the gastrointestinal tract, cannot be substrate specific. The discovery of the complex cascade of the ubiquitin pathway has changed this view dramatically. It is now clear that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a broad array of basic pathways during cell life and death. With the multitude of substrates targeted and processes involved, it is not surprising that aberrations in the pathway have been recently implicated in the pathogenesis of many diseases, certain malignancies and neurodegeneration among them. Degradation of a protein via the ubiquitin pathway involves two successive steps: a) conjugation of multiple ubiquitin moieties to the substrate, and b) degradation of the tagged protein by the downstream 263 proteasome complex with release of free and re-utilizable ubiquitin. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation and major key problems remain unsolved. Among these are the modes of specific and timed recognition of the myriad substrates of the system and the nature of the mechanisms that underlie aberrations in the system and pathogenesis of diseases.

Background: Previous data showed that new recombi­nant hepatitis B virus vaccine, which contains the S-protein component of the HBV surface together with the Pre-S₁ and Pre-S₂, is considerably more immunogenic than a second-generation recombinant I-IBV vaccine.

Objectives:To compare the immunogenicity and safety of a novel recombinant HBV vaccine S1, Pre-S₁ and Pre-S₂ protein components of the hepatitis B surface antigen - Bio­TM

Hep^TM 10 לg dose, to a licensed vaccine containing only the S-protein component - Engerix-B, 20 לg dose.

Methods: A prospective randomized study included 524 adults - 260 in the Bio-Hep group and 264 in the Engerix-B group. Both vaccines were administered in a three-dose regimen given at 0, 1 and 6 months, and adverse events were recorded on a diary card 5 days after each vaccination. lmmunogenicity was tested by measuring anti-hepatitis B surface antibody.

Results: One month after the third injection, 98% of the BioHep^TM subjects were found to be seroprotected vs. 85.1% of the Engerix-B group. In addition, the geometric mean titers were 2,203 mlU/ml and 326 mlU/ml in the Bio-Hep-B and Engerix-B groups respectively. An immunogenic advantage of Bio-Hep-B was suggested by the rapid onset of antibody response - 66.5% were seroconverted one month after the first injection as compared to 19.3% in the Engerix-B group. No unexpected adverse events were observed, and the recorded events were mild in both groups.

Conclusions: BioHepTM, a novel recombinant HBV vaccine containing 5, Pre-S₁ and Pre-S₂ protein components. at a lower dose, is safe and more immunogenic than the conventional HBV vaccine that contains only S protein.

Background: Previous studies have documented that reduction in QT dispersion after thrombolytic treatment in acute myocardial infarction depends on reperfusion status as well as infarct site. Primary percutaneous transluminal coronary angioplasty as compared with thrombolytic therapy has been shown to result in higher patency rates of the infarct vessel.

Objectives: To evaluate whether primary PTCA has a more favorable effect on reducing QT dispersion in patients with acute MI as compared to thrombolytic treatment.

Methods: The study population included 42 consecutive patients (33 men, mean age 58 ± 11 years) with acute Ml (24 anterior wall, 18 inferior wall) who were treated with primary PTCA (group A, n 21) or thrombolytic therapy (group B, n = 21) at 3.9+2 hours after symptom onset. QT intervals were measured before and 24 hours after treatment.

Results: On the admission electrocardiogram, patients with anterior Ml had higher values of QT and QTc dispersions than patients with inferior Ml (52±9 vs. 36±9 msec, R<0.05 and 61+4 vs. 56+4 msec, P=0.002, respectively). There was a significant reduction in QT and QTc dispersions from admission to 24 hours in all patients (from 50+9 to 37+9 msec, P<0.001 and from 59+5 to 42+5 msec, P<0.001. respectively), and also in group A (from 49±8 to 32±5 msec. P<0.001 and from 58+5 to 38+3 msec, P<0.001, respec­tively) and in group B patients (from 51+10 to 42+10 msec. P<0.01 and from 60±4 to 46±5 msec, P<0.001, respec­tively). QT and QTc dispersions were found to be shorter in group A at 24 hours after treatment than in group B (32 + 5 vs. 42+10 msec, P<0.001 and 38+3 vs. 46+5 msec, P<0.001. respectively).

Conclusions: Reperfusion therapy with primary PTCA or thrombolytic agents reduces QT and QTc dispersions in acute Ml. QT and QTc dispersions after reperfusion treatment are shorter with primary PTCA than with thrombolytic therapy.

Background: Hepatitis B is a major problem worldwide. Israel has intermediate endemicity for hepatitis B virus, and an annual carrier rate of 1-3%.

Objective: To evaluate both the prevalence of HBV infection among family members of HBV carriers and the competence of family practitioners in performing a compre­hensive assessment.

Methods: A total of 152 HB surface antigen-positive blood donors were discovered in our subdistrict during the years 1993-97. Their family physicians were questioned regarding the patients' family members. Specific information on 85 spouses and 200 children was also obtained.

Results: Among the 85 married carriers, 5 of the spouses (5.9%) were found to be HBsAg positive. None of the 200 children was HB5Ag positive. We found that in a third (n=52) of the patients, the sexual partner had never been tested by a primary care physician. Patients were not routinely tested for HB e antigen or anti-HBe antibodies. Neither the parents nor the siblings had undergone any serological evaluation. How­ever, most family members of the carriers had received an HBV vaccine from their family physicians.

Conclusions: Our findings show that horizontal transmis­sion of HBV among spouses of HBV carriers still exists. We did not find any vertical transmission, probably due to male predominance and previous vaccination. Family physicians should be trained to perform an extensive serological evalua­tion of family members of patients with chronic HBV infection, including parents and siblings, and should vaccinate sero­negative family members.

Background: Between 1970 and 1979, there was an increase in the incidence of viral hepatitis in Israel with a shift of peak incidence to an older age in the Jewish population, followed by a declining trend during the early 1980s. In July 1999 universal immunization of infants against hepatitis A was introduced.

Objective: To evaluate the chan-ges in the epidemiology of viral hepatitis A in Israel during the past decade.

Methods: Viral hepatitis is a notifiable disease in Israel and cases are reported to the regional health offices, which in turn provide summary reports to the Ministry of Health's Department of Epidemiology. The data in this study were derived from the summary reports and from results of seroprevalence studies.

Results: Following the increase in the incidence of reported viral hepatitis (mainly due to type A) between 1970 and 1979, the rates then stabilized and around 1984 began to decline until 1992. Since then there has been a slight increase. Whereas until 1987 the rates were consistently higher in the Jewish population. since then they are higher in the Arab population. The shift in the peak age-specific incidence from the 1-4 to the 5-9 year age group observed in the Jewish population around 1970 occurred 20 years later in the Arab population. The previously described seasonality is no longer evident. Recent seroprevalence studies indicate that by age 18 years only about 30-40% of the Jewish population have anti-hepatitis A antibodies.

Conclusions: The decline in the incidence of hepatitis probably reflects the changing socioeconomic condition occurring at different times in the two major population groups. Since hepatitis A accounts for almost all the acute viral hepatitis in Israel, the universal vaccination of infants introduced in 1999 should substantially lower the morbidity within the next few years.

The hepatitis C virus is an enveloped positive-sense single-stranded RNA virus, which has been classified into 6 major genotypes and over 100 subtypes. HCV replicates mainly in the hepatocyte. Recently, infectious HCV cDNA clones have been generated. Despite evidence that innate and adaptative humoral and cellular immune responses are activated as part of an antiviral defense, HCV has a remarkable ability to establish persistent infection. The analysis of viral kinetics using mathematical modeling shows a relative steady state without treatment, while an immediate biphasic HCV decline occurs in blood during successful treatment, the latter being predictive of clearance of HCV by the end of treatment.

Background: Alkaline tide is the transient increase in blood and urine pH following stimulation of gastric acid secretion. It is attributed to HC0₃ release from parietal cells in parallel with H+ secretion. The enzyme carbonic anhydrase is thought to be responsible for HC0₃ production from CO₂ and 0H in the parietal cell.

Objective: To examine the effect of pretreatment with the carbonic anhydrase inhibitor, acetazolamide, on the alkaline tide phenomenon.

Methods: Ten patients with dyspepsia and demonstrable alkaline tide were tested on three separate days. The pH and base excess were determined in arterialized venous blood before and 45 minutes after an intramuscular injection of pentagastrin. The pH of the urine was measured before and 120 mm after pentagastrin injection. Measurements were performed after pentagastrin alone on day 1 following pretreatment with acetazolamide 60 mm before pentagastrin on day 2, and after the administration of acetazolamide alone on day 3.

Results: Following the administration of pentagastrin alone, the blood base excess increased by 1.61 +0.2 mEq/L (mean + standard deviation) and the calculated alkaline tide at 45 mm was 33.99 ±4.49 mEq. On day 2 with prior adminis­tration of acetazolamide, base excess decreased by 0.21 + 0.39 mEq/L, and the calculated alkaline tide was -3.28±7.57 mEq, which was significantly lower than on day 1 (P=0 0001). On day 3, following acetazolamide alone, the base excess values decreased by 0.53~0.2 mEq/L and the alkaline tide was -10.05 +3.33 mEq there was no significant difference compared with day 2 (P= 0.44).

Conclusion: Pretreatment with acetazolamide abolished the alkaline tide induced by pentagastrin. This finding supports the view that carbonic anhydrase has a major role in the alkaline tide phenomenon.