Israel Medical Association Journal

Background: Balneotherapy is an established treatment modality for musculoskeletal disease. However, few studies have examined the efficacy of spa therapy in elderly patients with degenerative spine and joint diseases.

Objectives: To assess the effects of balneotherapy on chronic musculoskeletal pain, functional capacity, and quality of life in elderly patients with osteoarthritis of the knee or chronic low back pain.

Methods: A total of 81 patients enrolled and the results of 76 were analyzed. Subjects underwent a 1 day course of 30 minute daily baths in mineral water. Changes were evaluated in the following parameters:  pain intensity, functional capacity, quality of life, use of non-steroidal anti-inflammatory or analgesic drugs, subjective disease severity perceived by the patients, investigator-rated disease severity, and severity of pain perceived by the patients.

Results: Compared to baseline, all monitored parameters were significantly improved by balneotherapy in both investigated groups. Moreover, the favorable effect was prolonged for 3 months after treatment.

Conclusions: This study showed that balneotherapy is an effective treatment modality for elderly patients with osteoarthritis of the knee or with chronic low back pain, and its benefits last for at least 3 months after treatment.
 

Background: As high dietary n-6 polyunsaturated fatty acids and n-6:n-3 PUFA[1] ratio may contribute to many western ailments, increasing n-3 PUFA in foods could be beneficial. The nutritional significance of n-3 PUFA-fortified egg vs. enzymatically competitive high n-6 PUFA diets is debatable.

Objectives: To evaluate the dietary contribution of 'field fortification' of eggs by adding n-3 PUFA to high n-6 PUFA hen feed and whether it meets consumer preferences.

Methods: Laying hens (n=3500) were fed n-3 PUFA-fortified (5% extruded linseed) feed or standard (control) feed for 5 weeks. Nutritional significance was evaluated for western (American, Israeli) populations.

Results: Compared to regular (control) eggs, fortified eggs yielded a 3.8-fold increase in total n-3 PUFA, 6.4-fold alpha-linolenic acid (18:3), and 2.4-fold docohexaenoic acid 22:6). N-6:n-3 PUFA ratio decreased 3.6-fold, and n-6:n-3 long chain PUFA ratio threefold (P < 0.0003). Sensory evaluations were not significantly different. Egg cost increased by 1.0–1.5%. Fortified egg n-3 PUFA content averaged 14.3% of the current intake of Americans and 15.9% of Israelis – 9.8 and 10.5% of upper Dietary Reference Intakes, respectively. Egg DHA content averaged 32.9 and 41.1% of upper DRI[2]. Current cholesterol intakes average 281 and 263 mg/day (median 214 and 184 mg/day) including 0.7 and 0.5 egg/day; reported hypercholesterolemia rates are 17.7 and 16.5%, respectively.

Conclusions: Effective concentration and transformation of supplemental n-3 PUFA/LCPUFA[3] from feed to egg substantially enhanced egg n-3 PUFA %DRI, particularly of DHA[4], critical for health but often deficient. Such land-based n-3 PUFA/LCPUFA fortification may be applicable to high n-6 PUFA diets, fitting within cholesterol limitations and market criteria. It may contribute to general health and specific requirements (i.e., pregnancy and lactation), with possibilities of wide accessibility and standardization.

Background: In the western world, trauma is the leading cause of disability and mortality in the 1–39 years age group. Road accidents constitute the most frequent cause of mortality among children older than 1 year and falls from a height are the most frequent cause of injuries requiring hospitalization.

Objectives: To analyze the epidemiology and characteristics of severe pediatric trauma due to falls from a height in northern Israel. This analysis should aid in planning an effective intervention plan.

Methods: This observational study included all patients aged 0–14 who died or were admitted to an intensive care unit in northern Israel following a steep fall. Demographic and clinical data were collected retrospectively for 3 years and prospectively for 1 year.

Results: A total of 188 children were severely injured or died following such a fall, with an annual rate of 11.4 per 100,000 children. Over 85% of severe injuries due to falls occurred among non-Jewish children, with an incidence rate 6.36 times higher than among Jewish children (20.17 and 3.17 per 100,000 children, respectively). In the non-Jewish sector 93.7% of the falls occurred at or around the child’s home, mainly from staircases, balconies and roofs.

Conclusions: A very high incidence of severe trauma due to domestic falls from a height was found among non-Jewish children in northern Israel. Domestic falls represent an important epidemiological problem in the non-Jewish pediatric sector, and an effective prevention plan should include measures to modify parents’ attitudes towards safety issues and the creation of a safe domestic environment.
 

Objective: To provide comparative information in an international context on the level of outpatient drug expenditures in Israel, both total and those publicly financed, and to analyze how these have changed with time during the last decade.

Methods: Using definitions of the OECD (Organization of Economic Cooperation and Development), internationally comparable data on total expenditure and public expenditure on medicines in Israel are provided. The Israeli estimates are based on data from the Ministry of Health audited reports of financial activities of the health management organizations and from the family expenditure surveys carried out by the Central Bureau of Statistics. Per capita total and public expenditures in Israel are analyzed over time, as are their share of national expenditure on health and of gross domestic product. Israel expenditures are then compared with those for individual member countries of the OECD, as well as a 21 country average, from 1992 to 2002.

Results: Analysis of the Israeli expenditure data shows a considerable reduction in growth of per capita total and public expenditures on medicines since 1997. Growth in the share of total drug expenditure of NEH[1] and of GDP[2] has also been constrained since 1997. In an international context, per capita expenditure on medicines in Israel, particularly what is publicly financed, is one of the lowest. Furthermore, its share of NEH and GDP is also very low compared to other countries. This substantive gap in spending on medicines between Israel and other countries has increased since 1997.

Conclusions: Israel, a medium-income country with a lower than average level of expenditure on health compared to OECD countries, has a particularly low level of expenditure on medicines. Whereas the share of health expenditure of GDP in Israel is similar to the international average, the share of drug expenditure of GDP is well below the average. In addition to structural and longer-term factors contributing to Israel's low per capita spending on medicines, such as the young population and the apparently low level of actual prices paid by most institutional purchasers, recent years are witness to the growing impact of National Health Insurance budgetary pressures on HMOs[3] as well as continual increases in prescription cost sharing by patients. The impact is felt both on the demand side (higher co-payments, administrative and prescribing restrictions) and perhaps more crucially on the supply side (price competition, mainly from generics). Substantial extra public funding for the addition of new drugs to the NHI[4] basket in recent years has had no overall impact on these longer-term spending patterns.

Background: Open neural tube defects are among the most common malformations of the fetus. Secondary prevention by early diagnosis during pregnancy and abortion of affected fetuses result in a marked reduction of NTD incidence at birth. The dramatic effect of folic acid for primary prevention of these defects led to recommendations for folic acid supplementation in women of reproductive age.

Objective: To describe the epidemiologic features of NTD in Israel in 1999±2000.

Methods: A national registry of NTD was begun in 1999. During the years 1999±2000, a non-syndromic NTD was diagnosed in at least 394 pregnancies (166 anencephaly, 166 spina bifida, 43 encephalo-cele, and 19 with other types of NTD). The religious-ethnic affiliation was known in 392 cases (209 Jews and 183 non-Jews).

Results: Despite a marked decline in the rate of NTD at birth in the last few decades, the total rates during pregnancy did not change significantly, demonstrating that the changes were secondary to termination of affected pregnancies. At birth, NTD were almost four times more frequent among non-Jews (3.6 per 10,000 live births for anencephaly and 5.9 for spina bifida) than among Jews (anencephaly 1/10,000 live births, spina bifida 1.4/10,000 live births). The complete data of the registry showed an approximately twofold difference in the overall rates during pregnancy between Jews (anencephaly 5.3, spina bifida 4.6, total 11/10,000 live births) and non-Jews (anencephaly 8.8, spina bifida 10.3, total 22.3/10,000 live births). The registry demon-strated that the significant differences in NTD incidence observed at birth between Jews and non-Jews are secondary to a combined effect of a higher frequency of the malformations among non-Jews and a lower proportion of termination of affected pregnancies among non-Jews.

Conclusions: The data presented here will serve as a basis for evaluating the impact of the Ministry of Health recommendations for folic acid supplementation on the incidence of NTD.
 

Background: Experimental and clinical protocols are being developed for the cryopreservation of human hematopoietic progenitor cells. However, the effect of these procedures on the potential for HPC[1] to repopulate bone marrow is unknown.

Objectives: To examine the effect of cryopreservation on the ability of fetal human liver HPC, which include CD34+ cells and long-term culture-initiating cells, to repopulate immunodeficient non-obese diabetic/severe combined immunodeficiency mouse bone marrow.

Methods: Groups of sublethally irradiated NOD[2]/SCID[3] mice were injected intravenously with cryopreserved or freshly isolated fetal human liver HPC.

Results: Seven weeks after transplantation, flow cytometric analysis of bone marrow samples showed that mice that received the transplanted cells (either cryopreserved or freshly isolated) demonstrated both lymphoid and myeloid differentiation as well as the retention of a significant fraction of CD34+ cells. Conclusions: Cryopreserved fetal human liver-derived HPC appear to be capable of initiating human cell engraftment in NOD/SCID mouse bone marrow and open the possibility of using cryopreserved fetal human liver HPC for gene manipulation, gene transfusion therapy, and transplantation purposes.

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[1] HPC = hematopoietic progenitor cells

[2] NOD = non-obese diabetic

[3] SCID = severe combined immunodeficiency

Background: Elevated fibrinogen, considered an independent risk factor for coronary disease, stratifies an individual as high risk for coronary disease. A risk marker requires little intra-individual variability during a long period.

Objectives: To establish intra-individual variability of fibrinogen levels in patients with coronary disease.

Methods: We investigated fibrinogen levels prospectively in four blood samples drawn from 267 patients with a history of arterial disease (arterial group) and from 264 patients with cardiac valve replacements (valvular group). The samples were taken during the course of 78.7 and 78.8 days from the arterial and valvular groups respectively.

Results: Marked intra-individual dispersion with a reliability coefficient of 0.541 was found in the arterial group and 0.547 in the valvular group. The Bland-Altman test showed low probability to obtain similar results in different samples from the same individual. These results show large intra-individual variability, with similarities in the arterial as well as in the valvular group.

Conclusions: It is not possible to stratify a patient by a specific fibrinogen dosage.

Background: Decreased heparan sulfate proteoglycan content of the glomerular basement membrane has been described in proteinuric patients with diabetic nephropathy. Heparanase is an endo-b-D-glucuronidase that cleaves negatively charged heparan sulfate side chains in the basement membrane and extracellular matrix.

Objectives: To investigate whether urine from type I diabetic patients differs in heparanase activity from control subjects and whether resident glomerular cells could be the source of urinary heparanase.

Methods: Using soluble ³⁵S-HSPG[1] and sulfate-labeled extracellular matrix we assessed heparanase activity in human glomerular epithelial cells, rat mesangial cells, and urine from 73 type I diabetic patients. Heparanase activity resulted in the conversion of a high molecular weight sulfate-labeled HSPG into heparan sulfate degradation fragments as determined by gel filtration analysis.

Results: High heparanase activity was found in lysates of both epithelial and mesangial cells. Immunohistochemical staining localized the heparanase protein to both glomeruli capillaries and tubular epithelium. Heparanase activity was detected in the urine of 16% and 25% of the normoalbuminuric and microalbuminuric diabetic patients, respectively. Urine from 40 healthy individuals did not posses detectable heparanase. Urinary heparanase activity was associated with worse glycemic control.

Conclusion: We suggest that heparanase enzyme participates in the turnover of glomerular HSPG. Hyperglycemia enhances heparanase activity and/or secretion in some diabetic patients, resulting in the loss of albumin permselective properties of the GBM[2].

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[1] HSPG = heparan sulfate proteoglycan

[2] GBM = glomerular basement membrane

Background: Chronic childhood autoimmune hemolytic anemia is an uncommon disorder that is associated with significant morbidity. Treatment with high dose steroids, splenectomy and frequent blood transfusions results in a myriad of complications including growth failure, bone demineralization, Cushing’s syndrome, immunosuppression, and transfusional hemosiderosis.

Objectives: To investigate the efficacy of the monoclonal anti-CD20 antibody, rituximab, in treating children with AIHA[1].

Methods: Four children with chronic AIHA, including two with prior splenectomy, who were dependent on high dose steroids and refractory to other immunosuppressive regimens were treated with four to six weekly doses of rituximab at a dose of 375 mg/m².

Results: All four patients became transfusion-independent and were taken off prednisone completely. Adverse effects included infusion-related reactions that were mild, and infectious complications of Pneumocystis carinii pneumonia and varicella pneumonia.

Conclusions: Treatment with rituximab appears promising for refractory AIHA; it may obviate the need for prednisone and may result in sustained disease remissions in some patients.

Background: Cigarette smoking is a well-known risk factor for the development of endothelial dysfunction and the progression of atherosclerosis. Oxidative stress and inflammation have recently been implicated in endothelial dysfunction.

Objectives: To assess the concomitant contribution of polymorphonuclear leukocytes to systemic oxidative stress and inflammation in cigarette smokers.

Methods: The study group comprised 41 chronic cigarette-smoking, otherwise healthy males aged 45.0 ± 11.5 (range 31–67 years) and 41 male non-smokers aged 42.6 ± 11.3 (range 31–65) who served as the control group. The potential generation of oxidative stress was assessed by measuring the rate of superoxide release from separated, phorbol 12-myristate 13-acetate-stimulated PMNL[1] and by plasma levels of reduced (GSH) and oxidized (GSSG) glutathione. Inflammation was estimated indirectly by: a) determining the in vitro survival of PMNL, reflecting cell necrosis; b) in vivo peripheral PMNL counts, reflecting cell recruitment; and c) plasma alkaline phosphatase levels, indicating PMNL activation and degranulation.

Results: PMA[2]-stimulated PMNL from cigarette smokers released superoxide at a faster rate than PMNL from the controls. Smokers had decreased plasma GSH[3] and elevated GSSG[4] levels. In vitro incubation of control and smokers' PMNL in sera of smokers caused necrosis, while control sera improved smoker PMNL survival. Smokers' PMNL counts, although in the normal range, were significantly higher than those of controls. Plasma ALP[5] levels in smokers were significantly higher than in controls and correlated positively with superoxide release and PMNL counts.

Conclusions: Our study shows that PMNL in smokers are primed in vivo, contributing concomitantly to systemic oxidative stress and inflammation that predispose smokers to endothelial dysfunction, and explains in part the accelerated atherosclerosis found in smokers.

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[1] PMNL = polymorphonuclear leukocytes

[2] PMA = phorbol 12-myristate 13-acetate

[3] GSH = reduced glutathione

[4] GSSG = oxidized glutathione

[5] ALP = alkaline phosphatase

The leukocyte NADPH oxidase catalyzes the reduction of oxygen to O₂- (superoxide) at the expense of NADPH. The O₂- then dismutes to H₂O₂, which serves to oxidize Cl- to HOCl, a potent microbicidal agent that is used by leukocytes to kill invading microorganisms. This oxidation is catalyzed by myeloperoxidase. O₂ is also used to make other microbicidal oxidants, some in reactions with nitric oxide. The oxidase itself is highly complex, consisting of four unique subunits and Rac2. In the resting cell, two of the subunits, p22PHOX and gp91PHOX, are located in the membrane, and the other two, p47PHOX and p67PHOX, are in the cytosol. The electron-carrying components of the oxidase are

located in gp91PHOX; the NADPH binding site is generally regarded to be in gp91PHOX as well, but there is some evidence that it may be in p67PHOX. When the oxidase is activated, p47PHOX is phosphorylated at specific sites, and the cytosolic components plus Rac2 migrate to the membrane to assemble the active oxidase.

Chemokines and their receptors play regulatory roles in inflammatory reactions. Lipoprotein(a) is an atherogenic lipoprotein, however the mechanisms of its actions are not defined. Our interest in chemokines and their receptors was stimulated by the finding that incubation of Lp(a)[1] with human umbilical vein endothelial cells produced a conditioned medium that was chemotactic for human monocytes. Since infiltration of monocytes into the vessel wall is an early lesion in atherosclerosis, this finding provided a novel mechanism to explain the relationship between Lp(a) and atherosclerosis. The chemoattractant produced by HUVEC[2] was identified as CCL1/I-309, a CC chemokine previously reported to be secreted by stimulated monocytes/macrophages and T lymphocytes. CCR8, the CCL1 receptor, was identified on endothelial cells, and CCL1 was found to be a chemoattractant for these cells. Most recently we demonstrated functional CCR8 on human vascular smooth muscle cells and found that the Lp(a)-HUVEC conditioned medium is a chemoattractant for these cells. CCL1 increased metalloproteinase-2 production by HUVEC, an activity that enables these cells to remodel the vascular matrix. These studies suggest that CCR8 may play an important role in arterial wall pathology.

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[1] Lp(a) = lipoprotein(a)

[2] HUVEC = human umbilical vein endothelial cells

Systemic infection or inflammation causes a decrease in intestinal iron absorption and impairs the release of recycled iron from macrophages. Decreased availability of iron may deny this essential element to invading pathogens and may inhibit their multiplication and other metabolic processes but also results in anemia of chronic disease. This article reviews recent discoveries that shed light on the regulation of iron metabolism during infection and iron overload, and point to the central role of a newly discovered peptide, hepcidin. Evidence to date indicates that hepcidin is a negative regulator of intestinal iron absorption, placental iron transport, and the release of iron from macrophages that recycle iron from senescent red cells. It may also be the central mediator of iron sequestration during infections and inflammatory states and the mediator of anemia of chronic disease. Rapid progress in this area is a good example of the beneficial effects of improvements in peptide analysis and chemistry, advances in genomics, and the increasing use of transgenic mice to determine the function of newly discovered genes and proteins.