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: Patients who feel involved in their treatment have better outcomes than those who do not.

Objective: To identify determinants of perceived patient involvement in obstetric care.

Methods: A retrospective study was undertaken in 1,452 (83%) of 1,750 women sampled in November 1995 from maternity wards of 14 general hospitals in Israel. A postal and telephone survey using a self-administered questionnaire included the following variables: hospital (identity number), patients' age, self-reported complications, previous deliveries, education, ethnicity, and number of obstetric interventions performed and/or considered. The main outcome measured was the reported involvement in decisions for obstetric interventions.

Results: Reported full involvement varied from 72% for epidural analgesia to 13% for forceps/vacuum extraction. Factor analysis identified two dimensions of perceived involvement: one for routine” interventions (enema, monitor­ing, IV line and episiotomy), which are performed in Israel mostly by midwives, and another for "special" interventions (forceps/vacuum extraction, epidural or other analgesia, and cesarian section) performed by physicians. Logistic regression identified hospitals, younger age, number of interventions, and Arab ethnicity as correlates of a perceived non-involvement in decisions for "special" interventions.

Conclusions: Clinical setting, age and ethnicity affected patient perception of involvement in decisions for obstetric interventions.

Background: Recent genetic susceptibility findings in Jews of Eastern European descent, commonly called Ashke­nazi Jews, have led to concerns that they may be stigmatized as being more cancer prone than other groups.

Objective: To examine the hypothesis that site-specific or all-cancer incidence and mortality rates are higher than expected in Ashkenazi Jews worldwide when compared with referent populations.

Methods: A MEDLINE search was performed using keywords "Jews", "cancer", "incidence" and "mortality" to identify studies directly relevant to the primary study question.

Results: Little evidence suggested that all-cancer inci­dence or mortality is higher in Ashkenazi Jews than in North American non-Hispanic whites. Ashkenazi Jewish men appear to have relatively low cancer rates, which may be due to lower tobacco use. Colorectal cancer was shown to disproportio­nately overburden Ashkenazi Jews, who may also be at increased risk for ovarian, pancreatic and stomach cancer, and non-Hodgkin’s lymphoma. Little evidence was found support­ing an elevated risk of breast cancer in Ashkenazi Jewish women. Rates of lung, cervical, penile and prostate cancers appear low in this population. Rate disparities were generally attributed to lifestyle differences, particularly diet and tobacco use, rather than to genetic predisposition.

Conclusions: Ashkenazi Jews do not appear to have a higher total cancer burden than comparable North American populations. Any cancer rate differentials in this group are more likely to be related to lifestyle and dietary factors than to genetics. However, colorectal cancer rates in Ashkenazi Jews may be the highest of any ethnic group in the world and cancer controllers should consider this when developing future screening, diagnostic and policy strategies.

Background: Case-control and prospective studies indicate that an elevated plasma homocysteine level is a powerful risk factor for atherosclerotic vascular diseases. Certain medications can induce hyperhomocystinemia, such as methotrexate, trimethoprim and anti-epileptic drugs. There are few reports indicating an interaction between lipid-lowering drugs (cholestyramine and niacin) and homocysteine. Recently, an interaction was shown between fenofibrate and benzafibrates (a fibric acid derivative) and homocysteine plasma levels.

Objectives: To evaluate the effects of different fibrates on plasma homocysteine levels and to measure the reversibility of this effect.

Methods and Results: We investigated the effects of ciprofibrate and bezafibrate on homocysteine levels in patients with type IV hyperlipidemia and/or low high density lipoprotein levels. While a 57% increase in homocysteine was detected in the ciprofibrate-treated group (n=26), a 17% reduction n homocysteine was detected in the group treated with bezafibrate (n=12). The increase in homocysteine in the ciprofibrate-treated group was sustained for the 12 weeks of treatment and was partially reversible after 6 weeks of discontinuing the ciprofibrate therapy.

Conclusions: These results indicate that an increase In plasma homocysteine levels following administration of flbrates is not a class effect, at least in its magnitude. Moreover, it is reversible upon discontinuation of the treatment.
 

Background: The impact of repeated surgical resection on the survivorship of patients with malignant astrocytomas is an issue of some controversy in the medical literature.

Objectives: To clarify this issue through a retrospective analysis of treatment outcomes in a brain tumor clinic.

Methods: The patient records from the Brain Tumor Clinic at Hahnemann University Hospital for the period 1988 to 2000 were reviewed. From these, 112 cases of glioblastoma multiforme and 50 cases of anaplastic astrocytoma were chosen for analysis.

Results: The group of patients with glioblastomas showed a median survival of 415 days. When analyzed as subgroups based on the number of surgical resections, the median survival was 393 days in the group with biopsy only, 380 days in the group with one surgical resection, and 548 days in the group with two or three resections. Using the Kaplan-Meier method to generate survival plots and the log rank test to compare groups, repeat debulking was found to be a significant predictor of survival (P= 0.1 73). The group of patients with anaplastic astrocytomas showed a median survival of 1,311 days. When analyzed by subgroups, the patients with biopsy only had a median survival of 544 days, those with one debulking 1,589 days and those with two or three debulkings 1,421 days. There was a trend toward increased survival with debulking and the log rank test again showed statistical significance (P 0.1998).

Conclusions: This study indicates that repeated surgical resections offer increased survival for both glioblastomas and anaplastic astrocytomas.