Israel Medical Association Journal

Background: Genetic factors have been shown to play a major role in the development of peak bone mass, with hereditability accounting for about 50-85% of the variance in bone mass. Numerous candidate genes were proposed to be involved in osteoporosis, but the precise genes and their relative contribution remain unknown.

Objectives: To gain insight into the genetic basis of idiopathic low bone mineral density in Israeli patients by analyzing the impact of two candidate genes: polymorphism of the vitamin D receptor gene and polymorphism A986s in the calcium-sensing receptor gene.

Methods: We analyzed 86 Jewish Israeli patients with LBMD[1]: 38 premenopausal women and 48 men, and compared the allelic pattern distribution with that of the general population (126 men and 112 women). Genotyping of the VDR[2] gene was performed in three polymorphic sites using restriction enzymes, and allelic analysis of A986s polymorphism in the CaSR[3] gene was performed using the denaturing gradient gel electrophoresis technique.  

Reaults: In LBMD women the distributions of VDR alleres in Apal polymorphism were AA=7/28, Aa=16/28 and aa=5/28; in TaqI polymorphism TT=10/31, Tt=16/31 and tt=5/31; and in BsmI polymorphism BB=7/32, Bb=14/32 and 11/32. In LBMD men the distributions were AA=17/39, Aa=21/39 and aa=1/39; in TaqI polymorphism TT=12/42, Tt=23/42 and tt=7/42; and in BsmI polymorphism BB=12/41 Bb=18/41 and bb=11/41. The distributions of all these polymorphisms in the control groups were not significantly different. Adjusting for the independent age and gender parameters confirmed that these three polymorphisms of the VDR gene did not have a significant effect on bone mineral density. Thirty percent (24/79) of LBMD patients of either sex displayed heterozygosity of the CaSR A986s polymorphism, compared with 40 of 203 controls (19.7%) (P=0.059). Adjusting for age and gender in these patients revealed a significant difference in the femoral neck BMD[4] between homozygotes and heterozygotes (P=0.002). The age at menarche of the LBMD women was found to predict 61% of the variance of femoral neck BMD.

Conclusions: In Israeli Jewish men and premenopausal women VDR gene alleles do not seem to be associated with lower lumbar spine or femoral neck BMD. A trend towards heterozygosity for a CaSR polymorphism missense mutation was noted in the LBMD patients. Age at menarche in the LBMD women was found to be an important predictor of BMD. A significant difference was found between LBMD women and healthy control women towards heterozygosity for a CaSR polymorphism, as well between homozygotes and heterozygotes for a CaSR polymorphism in BMD. The significance of these findings and their applicability to a larger population awaits further studies.

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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: Inflammatory mediators, including cytokines and reactive oxygen species. are associated with the pathology of chronic liver disease. Hepatocytes are generally considered as targets but not producers of these important mediators.

Objectives: To investigate whether cells of hepatocellular lineage are a potential source of various cytokines we estimated the expression and secretion of tumor necrosis factor alpha, transforming growth factor beta 1 and interleukins I beta, 6 and 8 in the culture of well-differentiated human HepG2 cells treated for 24 hours with ethanol, acetaldehyde and lipopolysaccharide. Lipid peroxidation damage, glutathione content and glutathione perox­idase, catalase and superoxide dismutase activity were also determined.

Methods: HepG2 cells were treated for 24 hours with ethanol (50 mM), acetaldehyde (175 ìM) and LPS (1 ìg/ml). TNF-á, TGF­-â, L-1â, IL-6 and IL-8 mRNA were determined by reverse transcriptase polymerase chain reaction and secretion by en­zyme-linked immunoassay. Lipid peroxidation damage, glutathione content and antioxidant enzyme activities were determined spectrophotometrically.

Results: Exposure to ethanol for 24 hours induced the expression of TNF-á and TGF- â1. secretion of IL-1â and TGF-â₁ and decreased catalase activity. Acetaldehyde markedly increased TNF-á and IL-8 expression, stimulated IL-1â and IL-8 secretion, increased lipid peroxidation damage and decreased catalase activity, while LPS exposure induced the expression of TNF-á. TGF- â₁, IL-6 and IL-8, the secretion of TGF-â₁, IL-1â, IL-6 and IL-8, and a decrease in catalase activity. No change in GSH, GSHPx or SOD was found in any experimental condition.

Conclusions: The present studies confirm and extend the notion that hepatocytes respond to ethanol, acetaldehyde and LPS-producing cytokines. Oxidative stress produced by the toxic injury plays an important role in this response through up­regulation of inflammatory cytokines.

Background: inflammation is an important feature of atherosclerotic lesions and increased production of the actuephase reactant. The contribution of coagulation factor to the development of coronary artery disease has not yet been clearly established.

Objective: To test whether C-reactive protein, fibrinogen and antithrombin-III are associated with angiograpic CAD, history of myocardial infarction and extensive atherosclerotic involvement.

Methods: Blood samples were tested for CRP, fibrinogen and AT-III levels from 219 individuals undergoing coronary angiography.

Results: CRP was higher in patients with CAD (0.95 + 1.31, n=180, vs. 0.39 + 0.61 mg/dl, n=39, P<0.0001) and in those with a history of MI (1.07 + 1.64, n=96, vs. 0.65 + 0.72 mg/dl, n=84, P<0.05) than in control subjects. The patients who developed unstable angina had higher CRP levels than the patients with stable CAD (2.07 + 2/38, n=7, vs. 0.80 + 1.13 mg/dl, n=173, P<0.001).

Fibrinogen was significantly higher in patients with CAD (298 + 108 vs. 258 + 63 mg/dl, P<0.01). In patients with CAD, mean AT-III value was less than in patients without CAD, but this difference was found in CRP, fibrinogen and AT-III values among the patients with single, double or triple vessel disease.

Conclusion: CRP is elevated in patients with CAD and a history of MI. Elevated levels of CRP at the time of hospital admission is a predictive value for future ischemic events.

There is an association between higher levels of fibrinogen and CAD. The association of AT-III levels with CAD needs testing in further studies.
 

Background: Smoking is the most important preventable cause of chronic disease in the western world. Many smokers want to quit, but have difficulty overcoming the addictive effect of nicotine.

Objectives: To assess the quitting rate of smokers who participated in smoking cessation groups and to characterize predictors of success or failure over a 1-3 year follow-up period.

Methods: We studied 89 participants in 7 groups. Questionnaires were completed at baseline and after a follow-up period of 1 to 3 years. Smoking cessation was determined by self-report and a carbon monoxide breath test.

Results: Of the 89 participants in the support groups 76 (85%) were located. An intention-to-treat analysis was done for these participants. At follow-up 25 (33%) were non-smokers. There was a 95% agreement rate between self-report of smoking status and CO breath analysis. There were no differences between quitters and non-quitters in education level, gender, age at initiation of smoking, previous quit attempts, extent of participation in group meetings, concern about gaining weight, Fagerstrom index, or the number of close friends or relatives who smoke. Belief in one's ability to quit, satisfaction with group meetings, and spouse support were significantly associated with success (P<0.01).

Conclusions: The quit rate was 33%. Self-report is a reliable method for assessing smoking status. Smokers' belief in their ability to quit must be reinforced. Spouse participation in some group meetings may be beneficial, as may the involvement of a dietician and an expert on exercise. Follow-up "booster" meetings may also help.

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CO= carbon monoxide

* In partial fulfilment of the requirements for an MD degree.