Israel Medical Association Journal

Background: The treatment of osteoporosis among postmenopausal women represents a major public health challenge since long-term therapy is needed to prevent fractures and chronic disability.

Objectives: To assess compliance with osteoporosis drug therapy among Israeli postmenopausal women treated with either a bisphosphonate (alendronate) or a selective estrogen receptor modulator (raloxifene); to identify factors affecting compliance among these patients; and to compare adherence to the treatment in these two groups.

Methods: Our study included 178 consecutive patients aged 67.41 ± 8.52 years who were treated for osteoporosis with alendronate or raloxifene in the Metabolic Bone Diseases Unit. All the patients received supplement with calcium carbonate 1,500 mg and 600 IU vitamin D daily. Compliance was assessed at a clinic visit 6 months after starting therapy.

Results: The dropout rate was 23% (41 patients): 20 patients (31%) in the raloxifene group and 21 (18%) in the alendronate group (P = 0.0041). The main reasons for dropout were side effects and/or non-compliance, 16 and 24 patients (39% and 58.53%), respectively. The most frequent side effect was abdominal pain in 9 patients (42.8%) who discontinued alendronate use. The reasons for non-compliance were a fear of side effects and high drug price in 6 (30%) and 4 (20%) patients respectively in the raloxifene group, and inconvenience caused by medication use in 3 (14.3%) patients in the alendronate group. Logistic regression analysis of factors that may influence compliance included age, previous fractures, family history of osteoporosis, bone density T-score less than -2.5, and presence and number of concomitant diseases. Age was the only statistically significant parameter in this model: 67.8 ± 8.8 in non-compliant versus 64.11 ± 7.4 in compliant patients (P = 0.029).

Conclusion: At least 20% of the patients discontinued chronic treatment for osteoporosis during the initial 6 months of therapy. The main reasons were gastrointestinal side effects in the alendronate group, and fear of side effects and high drug price in the raloxifene group. Older age was the only statistically significant factor influencing compliance.

Background: The humanized SCID mouse model is an attractive tool for testing gene therapy to combat human immunodeficiency virus infection in vivo.

Objectives: To devise a more specific gene therapy directed against HIV, replacing the formerly used interferon with either soluble CD4 molecule immunoadhesin (sCD4-IgG) and/or anti-gp41 monoclonal antibody (2F5), or negative transdominants (Tat, Rev).

Methods: Human monocytoid cell line (U937) was transfected with IFNa[1], b or g genes. 3T3 murine fibroblastic cell line was transfected with sCD4-IgG or 2F5, or both genes, and a human T4 cell line (CEM) was grafted to SCID mice. Negative transdominant genes (Tat, Rev or both) were also transduced in CEM T cell line. Animals were then challenged with HIV-1[2]. Viral load was followed.

Results: IFNa or b were potent anti-HIV, reducing viral load in vivo and inhibiting reverse transcriptase activity in human-removed cells from animals. sCD4-IgG immunoadhesin and gp41 monoclonal antibody resulted in a dramatic reduction of HIV-1 cellular and plasmatic viral load in humanized SCID mice. The simultaneous introduction of negative Tat and Rev genes resulted in a synergistic inhibition of HIV-1 replication in vivo.

Conclusions: Despite the marked reduction of HIV-1 propagation by IFN genes or by negative Tat and Rev transdominants, the gene therapy using soluble CD4 immunoadhesin or anti-gp41 was a more efficient preventive treatment against HIV infection.

Background: Transcobalamin II is a serum transport protein for vitamin B₁₂. Small variations in TC-II[1] affinity were recently linked to a high homocysteine level and increased frequency of neural tube defects. Complete absence of TC-II or total functional abnormality causes tissue vitamin B₁₂ deficiency resulting in a severe disease with megaloblastic anemia and immunologic and intestinal abnormalities in the first months of life. This condition was described in hereditary autosomal-recessive form. Low serum TC-II without any symptoms or clinical significance was noted in relatives of affected homozygotes.

Objectives: To study 23 members of a four-generation family with hereditary vitamin B₁₂ deficiency and neurologic disorders.

Methods: Thorough neurologic, hematologic and family studies were supplemented by transcobalamin studies in 20 family members.

Results: Partial TC-II deficiency was found in 19 subjects. Apo TC- II (free TC-II unbound to vitamin B₁₂) and total unsaturated B₁₂ binding capacity were low in all tested individuals but one, and holo TC-II (TC-II bound by vitamin B₁₂) was low in all family members. The presentation of the disease was chronic rather than acute. Early signs in children and young adults were dyslexia, decreased IQ, vertigo, plantar clonus and personality disorders. Interestingly, affected children and young adults had normal or slightly decreased serum vitamin B₁₂ levels but were not anemic. Low serum B₁₂ levels were measured in early adulthood. In mid-late adulthood megaloblastic anemia and subacute combined degeneration of the spinal cord were diagnosed. Treatment with B₁₂ injections resulted in a significant improvement. The pedigree is compatible with an autosomal-dominant transmission. This family study suggests a genetic heterogeneity of TC-II deficiency.

Conclusions: We report the first family with a hereditary transmitted condition of low serum TC-II (partial TC-II deficiency) associated with neurologic and mental manifestations in childhood. Partial TC-II deficiency may decrease the amount of stored cobalamin, resulting in increased susceptibility to impaired intestinal delivery of cobalamin and predisposing to clinically expressed megaloblastic anemia at a later age. Partial TC-II deficiency should be suspected in families with megaloblastic anemia and in individuals with neurologic and mental disturbances – despite normal serum vitamin B₁₂ levels. Low serum UBBC[2] and apo TC-II should confirm the diagnosis. Early vitamin B₁₂ therapy may prevent irreversible neurologic damage.

The human placenta is the interface between the mother and fetus in the uterus. Until recently it was generally believed that the uterus provides a protective environment for the fetus. It is now accepted that any chemical substance, including any therapeutic agent, administered to a mother is able to permeate across the placental barrier. Unfortunately, the placental transfer of substances and their distribution in the placenta is not well established. Understanding the structure of placental transporters and their function may serve as the ideal tool for drug development and the cure of mother and fetus during pregnancy.
 

Background: The lack of lactobacilli in the vagina of postmenopausal women due to estrogen deficiency plays an important role in the development of bacteriuria. In the last few years, the use of lactobacilli for the prevention of genitourinary infections has been explored using different probiotic strains.

Objectives: To evaluate the vaginal colonization by Lactobacillus rhamnosus GG in postmenopausal healthy women following oral administration of the bacteria in a yogurt base for 1 month, as a first step in evaluating the potential probiotic role of LGG[1] in the prevention of recurrent urinary tract infections.

Methods: One or two doses per day of yogurt containing 10⁹ colony forming units of LGG were administered orally to 42 postmenopausal healthy women for 1 month. Vaginal and rectal swabs were cultured at the beginning and end of the study.

Results: At the end of the study, the vaginas of only four women (9.5%) were colonized with LGG, at a very low number of bacteria, despite the fact that the gastrointestinal tracts of 33 women (78.6%) were colonized. There were no significant differences between one or two doses daily.

Conclusions: LGG should not be considered as a probiotic agent in urinary infections since it does not attach well to the vaginal epithelium.

Background:  Physicians’ decisions regarding provision of life-sustaining treatment may be influenced considerably by non-medical variables.

Objectives: To examine physicians’ attitudes towards end-of-life decisions in Israel, comparing them to those found in the United States.

Methods: A survey was conducted among members of the Israel Society of Critical Care Medicine using a questionnaire analogous to that used in a similar study in the USA.       

Results: Forty-three physicians (45%) responded, the majority of whom hold responsibility for withholding or withdrawing life-sustaining treatments. Preservation of life was considered the most important factor by 31 respondents (72%). The quality of life as viewed by the patient was generally considered less important than the quality of life as viewed by the physician. Twenty-one respondents (49%) considered withholding treatment more acceptable than withdrawing it. The main factors for decisions to withhold or withdraw therapy were a very low probability of survival of hospitalization, an irreversible acute disorder, and prior existence of chronic disorders. An almost similar percent of physicians (93% for Israel and 94% for the U.S.) apply Do Not Resuscitate orders in their intensive care units, but much less (28% vs. 95%) actually discuss these orders with the families of their patients.

Conclusions:  Critical care physicians in Israel place similar emphasis on the value of life as do their U.S. counterparts and assign DNR[1] orders with an incidence equaling that of the U.S. They differ from their U.S. counterparts in that they confer less significance to the will of the patient, and do not consult as much with families of patients regarding DNR orders.

Background: Among the various new technologies in the field of parathyroid surgery are intraoperative quick parathormone measurements.

Objectives: To evaluate the contribution of QPTH[1] measurements during parathyroidectomy to the achievement of higher success rates. 

Methods: QPTH assay using Immulite Turbo Intact PTH[2] was measured in 32 patients undergoing parathyroidectomy: 30 for primary and 2 for secondary hyperparathyroidism.  QPTH levels were measured at time 0 minutes (before incision) and at 10, 20, and 30 minutes after excision of the hyperfunctioning gland.  Only a drop of 60% or more from the 0’ level was considered to be a positive result.

Results: The mean QPTH level at time 0’ for PHPT[3] patients was 38.12 ± 25.15 pmol/L (range 9.1–118 pmol/L).  At 10 minutes post-excision of the hyperfunctioning gland (or glands), QPTH dropped by a mean of 73.80% to 9.89 ± 18.78 pmol/L. 

Conclusions: Intraoperative QPTH level measurement is helpful in parathyroid surgery.  A drop of 60% or more from 0’ level indicates a successful procedure, and further exploration should be avoided.

Background: Leukotriene antagonist therapy in asthmatic patients alleviates symptoms and improves exercise tolerance, however the effect of these drugs on bronchial provocation tests and exhaled nitric oxide levels are less clearly established.

Objective: To determine the effect of montelukast treatment on airway hyperresponsiveness to exercise, methacholine and adenosine-5’-monophosphate and on exhaled nitric oxide levels in steroid-naive asthmatics.

Methods: Following a 2 week run-in period, 20 mild to moderate asthmatics were enrolled in an open label 6 week trial of oral montelukast-sodium therapy. Bronchial hyperreactivity (exercise, methacholine and adenosine-5’-monophosphate challenges) and exhaled nitric oxide levels were measured before and after the 6 week period.

Results: Montelukast treatment resulted in a significant improvement in exercise tolerance: median DFEV₁ 20.0% (range 0–50) prior to treatment vs. 15.0% (range 0–50) post-treatment (P = 0.029). A significant difference was also observed for exhaled NO[1] following therapy: median NO 16.0 ppb (range 7–41) vs. 13.0 (range 4.8–26) (P = 0.016). No change was seen in baseline lung function tests (FEV₁, MEF₅₀) or in the bronchial responsiveness (PC₂₀) for methacholine and adenosine-5’-monophosphate.

Conclusions: This study demonstrates that the leukotriene antagonist, montelukast-sodium, reduces bronchial hyperreactivity in response to exercise and reduces exhaled nitric oxide levels but has little effect on bronchial responsiveness to methacholine and adenosine challenges.