Israel Medical Association Journal

Background: Foreign bodies are sometimes overlooked in the initial evaluation of soft tissue wounds in the emergency room setting. The physical examination identifies foreign bodies that are superficial enough to be seen or palpated, while radiographs reveal those that are radio-opaque. If these two criteria are not met, however, the foreign body may remain undetected. These patients present later with long-standing pain in the area of penetration sometimes associated with localized tenderness.

Objectives: To assess the role of ultrasonography in the diagnosis and management of patients with a suspected retained foreign body.

Methods: Ultrasound was used in 21 patients with suspected retained foreign bodies and the diagnosis was positive in 19. Fifteen underwent a surgical exploration in which the ultrasound was used as an adjunctive modality either pre- or intraoperatively to assist in the localization of the foreign body.

Results: All procedures were successful. No postoperative complications were recorded at an average follow-up of 2 years. Three patients gradually became asymptomatic and were left untreated. One patient was lost to follow-up.

Conclusion: Sonography is an extremely effective tool for the late diagnosis of retained foreign bodies in the soft tissues. We suggest that its availability in the emergency room may decrease the rate of misdiagnosis and avoid these unfortunate cases, although this remains tc be proven.
 

Background: The transfer of therapeutic genes into malignant brain tumors has been the subject of intense pre­clinical and clinical research in recent years. Most approaches have used direct intratumoral placement of a variety of vectors and genes, such as retroviruses or adenoviruses carrying drug-susceptibility genes, modified replication-competent herpes virus, and several vectors carrying tumor suppressor genes such as the p53 gene. However, clinical results have so far been disappointing, mainly due to the limited ability to effectively distribute the genetic material into the target cell population. Accordingly, alternative delivery approaches into the central nervous system, e.g., intravascular, are under investigation. Genetic vectors administered intravascularly are unlikely to penetrate the blood-brain barrier and transfer a gene into brain or tumor parenchyma. However, intravascular delivery of vectors may target endothelial cells lining the blood vessels of the brain. Since endothetial cells participate in a variety of physiological and pathological processes in the brain, their modulation by gene transfer may be used for a variety of therapeutic purposes. Angiogenically stimulated endothelial cells within tumors replicate rapidly and hence may become targets for retroviral-mediated gene transfer.

Objective: To assess the anti-tumor effect of transferring a drug-susceptibility gene into endothelial cells of the tumor vasculature.

Methods: As a model for this approach we delivered concentrated retroviral vectors carrying a drug-susceptibility gene via the internal carotid artery of rats with malignant brain tumors. The safety and efficacy of this approach, without and with subsequent treatment with a pro-drug (ganciclovir). was evaluated.

Results: No acute or long-term toxicity was observed after intraarterial infusion of the vector. Treatment with ganciclovir resulted in variable hemorrhagic necrosis of tumors, indicating preferential transduction of the angiogenically stimulated tumor vasculature. This was accompanied by severe toxicity caused by subarachnoid hemorrhage and intracerebral hemorrhage in vascular territories shared by the tumor and adjacent brain.

Conclusion: The data indicate that endothelial cells can be targeted by intraarterial delivery of retroviral vectors and can be used for devising new gene therapy strategies for the treatment of brain tumors.

Background: The free-to-total prostate-specificantigen ratio is the best marker for optimizing prostate cancer detection. The main problem with studies of percent free PSA is the variability of reported cutoff values.

Objectives: To evaluate the influence of prostate size on the ratio of free to total PSA.

Methods: The study group included 58 patients (mean age 66.4 years) with clinically localized prostate cancer treated surgically at our institution. Total PSA and free PSA levels were measured by a solid phase enzyme immunoassay test (Hoffman-La Roche, Basel, Switzerland). The percent free PSA was compared with prostate size as determined from the surgical specimen.

Results: A direct relation was noted between prostate size and the percent free PSA value (r=0.49, P=0.0001). Mean percentage free PSA was 9%0.004 in men with normal-sized gland while in men with large prostate (60 g) the average percent free PSA was 15.90.09 (P=0.001).

Conclusions: In patients with prostate cancer the percent free PSA level is influenced by the gland size. The larger the prostate the higher the proportion of the free PSA. Such information may have influence on the recommendation for prostate biopsy in screening programs for early detection of prostate cancer.

Background: Achondroplasia is the most frequent form of disproportionate short stature, characterized by rhizomelic shortening of the limbs. This disorder is inherited as an autosomal dominant trait, although most of the cases are sporadic, a result of a de novo mutation. A recurrent glycine to arginine mutation at codon 380 (G380R) in the transmembrane domain of the fibroblast growth factor receptor 3 gene was found to cause achondroplasia among different populations. This is most uncommon in other autosomal dominant genetic diseases.

Objectives: To determine whether this mutation is also common among Jewish patients from diverse ethnic groups and among the Arab population in Israel.

Methods: We examined the G380R mutation (G>A and G>C transition) and the mutation G375C (G>T transition at codon 375) in 31 sporadic patients and in one family diagnosed clinically to have achondroplasia.

Results: We found the G>A transition at codon 380 in 30 of our patients and the G>C transition in one patient. We were not able to detect any of the three mutations in two patients with an atypical form of achondroplasia.

Conclusions: Our results further support the unusual observation that nucleotide 1138 of the FGFR3 gene is the most mutable nucleotide discovered to date across different populations.

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FGFR3 = fibroblast growth factor receptor 3

Background: A high rate of consanguineous marriages exists within the Israeli Arab community, with approximately half occurring between first cousins. This contributes towards a high incidence of congenital malformations and autosomal recessive diseases, many of which are detectable at prenatal diagnosis.

Objectives: To assess the levels of both awareness and acceptance regarding prenatal diagnosis and termination of pregnancy among a group of Arab women in order to devise the optimal means of providing genetic counseling and general health services.

Methods: A total of 231 Arab women of childbearing age were interviewed 3 days postpartum to assess their knowledge of prenatal diagnosis and termination of pregnancy, their willingness to undergo prenatal diagnosis, and their opinions on termination of pregnancy in the event of a severely affected fetus.

Results: Half the women believed that prenatal testing is not an effective (or accurate) tool for diagnosing an affected fetus. A quarter had poor knowledge on prenatal diagnosis, and a quarter believed that prenatal diagnosis does provide the correct diagnosis. Ninety-five percent said they would agree to undergo prenatal diagnosis; and in the event of a severely affected fetus, 36% said they would agree to a termination of pregnancy, 57% said they would not, and 7% were undecided.

Conclusions: There is a need for special intervention programs, with guidance by health professionals, geneticists and religious authorities, that will inform this population on the increased risk associated with consanguinity, stress the importance and effectiveness of prenatal testing to identify severe congenital malformations, and help them to accept prenatal diagnosis and termination of pregnancy if indicated.

Background: Articular cartilage is incapable of undergoing self-repair since chondrocytes lose their mitotic ability as early as the first year of life. Defects in articular cartilage, especially in weight-bearing joints, will predictably deteriorate toward osteoarthritis.  No method has been found to prevent this deterioration. Drilling of the subchondral bone can lead to fibrocartilage formation and temporary repair that slowly degrades. Animal experiments indicate that introducing proliferating chondrocytes such as cultured articular chondrocytes can reliably reconstruct joint defects.

Objectives: To describe our clinical experience in culturing and transplanting autologous chondrocytes. 

Methods: Biopsies were obtained from 10 patients, aged 18–45, undergoing a routine arthroscopy in which a cartilage defect was identified with indications for cartilage transplantation. The biopsies were further processed to establish chondrocyte cultures. ACT was performed in 8 of the 10 patients because of persistent symptoms for at least 2 months post-arthroscopy. All patients (6 men and 2 women) had a grade IV cartilage defect in the medial or lateral femoral condyle, and three had a defect in the trochlear region as well. Biopsies were removed from the lateral rim of the superior aspect of the femur, and cells were cultured in a clean room. Following a 2 order of magnitude expansion, cells were implanted under a periosteal flap.

Results: The eight patients implanted with autologous cells were followed for 6 months to 5 years (average 1 year). Complaints of giving-way, effusion and joint locking resolved in all patients, and pain as assessed by the visual analogue score was reduced by an average of 50%. Follow-up magnetic resonance imaging studies in all patients revealed that the defects were filled with tissue having similar signal characteristics to cartilage.

Conclusions: Chondrocyte implantation is a procedure capable of restoring normal articular cartilage in cases with isolated joint defects. Pain can be predictably reduced, while joint locking and effusion are eliminated. The effect on osteoarthritis progression in humans has not yet been elucidated.

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ACT = autologous chondrocyte transplantation

Background: Spectral analysis of heart rate variability has been shown to be a reliable non-invasive test for quantitative assessment of cardiovascular autonomic regulatory responses, providing a window reflecting the interaction of sympathetic and parasympathetic tone. Alterations in autonomic function are associated with a variety of physiologic and pathophysiologic processes and may contribute substantially to morbidity and mortality. Our previous study shows that patients with post-traumatic stress disorder have significantly lower HRV compared to controls, reflecting a basal autonomic state characterized by increased sympathetic and decreased parasympathetic tone.

Objectives: To apply this tool to PTSD patients treated with selective serotonin re-uptake inhibitors in order to assess the impact of such treatment on the autonomic dysregulation characterizing these patients.

Methods: Standardized heart rate analysis was carried out in nine PTSD patients treated with SSRI agents and compared to that in a matched control group of nine healthy volunteers and in nine untreated PTSD patients, based on a 15 minute resting electrocardiogram.

Results: Our preliminary results show that the HRV parameters indicating autonomic dysregulation, which characterize PTSD patients at rest, are normalized in responding patients by use of SSRIs. Neither the clinical implications of these findings nor their physiological mechanisms are clear at present, although we presume that they reflect a central effect, since the peripheral autonomic effects of SSRIs are relatively negligible.   

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HRV = heart rate variability

PTSD = post-traumatic stress disorder

SSRI = selective serotonin re-uptake inhibitor

Background: Over a 12 month period, the Israel Transplant Center doubled the number of donors by assigning a nurse coordinator to each of 22 hospitals around the country and by using kidneys from elderly donors.

Objective: To evaluate the impact of our "marginal donors" policy on the results immediately following transplantation.

Methods: Between October 1997 and September 1998, 140 cadaveric kidney transplantations from 72 donors were performed in Israel. We defined two groups of recipients: patients with immediate graft function and patients with either delayed graft function requiring >1 week of dialysis post-transplant or with primary graft non-function. We compared the following parameters between groups: donor and recipient age and gender, cause of donor’s death, length of stay in the intensive care unit, vasopressor dosage and creatinine levels before harvesting, cold ischemic time, and the number of recipient grafts.

Results: There were 102 recipients (72.8%) with immediate graft function and 38 with either PNF (n=13, 9.3%) or DGF (n=25, 17.9%). On regression analysis, donor age >50 year and retransplantation were significant risk factors for PNF or DGF (odds ratio 4.4 and 2.8, respectively). Of the 56 kidneys from donors >50 years old, 21 (37.5%) developed either PNF (n=9) or DGF (n=12).

Conclusions: We conclude that kidneys from donors over age 50 are at increased risk for graft non-function or delayed function. Better assessment of functional capacity of kidneys from “aged” donors may help to choose appropriate donors from that pool.

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PNF = primary graft non-function

DGF = delayed graft function

Background: Growth retardation in childhood was only recently recognized as a prominent feature of Gaucher disease type 1, but there are few data on both the pubertal development and the final outcome of growth and sexual maturation.

Objective: To investigate the natural pattern of growth and puberty in patients with Gaucher disease type 1 and the effect of splenectomy and enzyme replacement therapy.

Methods: We retrospectively analyzed growth and puberty in 57 patients with Gaucher disease type 1; 52 were followed since childhood and/or prepuberty and 42 have reached sexual maturity and final height. In the analysis we considered severity of disease, time of splenectomy, and start of enzyme replacement therapy.

Results: Deceleration of growth at age 3–5 years was observed in 30 of 57 patients followed since early childhood while untreated: height-SDS decreased from -0.34±0.42 at age 0–3 years to -1.93±0.95 (P<0.01) at age 7–10 years and was more pronounced with severe disease. A high prevalence (59.6%) of delayed puberty, which was more frequent with severe disease, was observed in 47 patients followed before and throughout puberty. No primary endocrine pathology was found. All patients, untreated as well as treated, with growth and pubertal delay had a spontaneous catch-up, achieved full sexual maturation, and most (83.3%) reached a final height within the range of parental height–standard deviation score. Splenectomy (partial and/or total) performed in 20 patients while still growing had a beneficial effect on growth, which was temporary in some and did not affect puberty. ERT improved growth in 11 patients who started therapy before puberty, as evidenced by a progressive increase in the height-SDS, and seemed to normalize the onset of puberty.

Conclusions: Growth retardation in childhood and delay of puberty are characteristic of Gaucher disease type 1 and are more frequent with severe disease. There is a spontaneous catch-up later in life and most patients reach a final height within their genetic growth potential. Enzyme replacement therapy apparently normalizes growth and possibly also the onset of puberty.

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ERT = enzyme replacement therapy

SDS = standard deviation score

Background: The preconception and intraconception parameters that are relevant to outcome in women with underlying renal disease remain controversial.  

Objectives: To analyze the types and frequencies of short- and long-term (2 years after delivery) maternal and neonatal complications in 38 patients with primary renal disease (46 pregnancies), most of them with mild renal insufficiency.  

Methods: Logistic regression models were formulated to predict successful outcome.  

Results: Successful pregnancy outcome (live, healthy infant without severe handicap 2 years after delivery) was observed in 98% of the patients with primary renal disease. Factors found to be significantly predictive of successful outcome were absence of pre-existing hypertension, in addition to low preconception serum uric acid level.

Conclusions: Most women with primary renal disease who receive proper prenatal care have a successful pregnancy outcome. Worse pregnancy outcome was observed in women with moderate or severe renal failure. Fitted logistic models may provide useful guidelines for counseling women with preexisting renal disease about their prospects for a successful pregnancy in terms of immediate and long-term maternal and neonatal outcome.