Israel Medical Association Journal

Background: Stem cell-based therapy is a promising approach for the treatment of neurodegenerative disease. In our laboratory, a novel protocol has been developed to induce bone marrow-derived mesenchymal stem cells into neurotrophic factor-secreting cells. These cells produce and secrete factors such as BDNF (brain-derived neurotrophic factor) and GDNF (glial-derived neurotrophic factor).

Objectives: To evaluate the migratory capacity and efficacy of NTF-SC[1] in animal models of Parkinson's disease and Huntington's disease.

Methods: MSCs[2] underwent two-phase medium-based induction. An efficacy study was conducted on the 6-hydroxydopamine-induced lesion, a rat model for Parkinson's disease. Cells were transplanted on the day of 6-OHDA[3] administration, and amphetamine-induced rotations were measured as a primary behavioral index. In a second experiment, migratory behavior was examined by transplanting cells a distance from a quinolinic acid-induced striatal lesion, a rat model for Huntington's disease. Migration, in vivo, was monitored using longitudinal magnetic resonance imaging scans followed by histology.

Results: NTF-SCs attenuated amphetamine-induced rotations by 45%. HPLC analysis demonstrated a marked decrease in dopamine depletion, post-cellular treatment. Moreover, histological assessments revealed that the engrafted cells migrated and acted to regenerate the damaged striatal dopaminergic nerve terminal network. In a preliminary work on an animal model for Huntington's disease, we demonstrated by high resolution MR images and correlating histology that induced cells migrated along the internal capsule towards the QA[4]-induced lesion.

Conclusions: The induced MSCs are a potential therapy for neurodegenerative diseases, due both to their NTF secretion and their ability to migrate towards the diseased tissue.

Background: Monitoring the rate of infections in individual centers that treat patients with hematological malignancies is of major importance. However, there are no uniform guidelines for infection surveillance.

Objectives: To describe the epidemiology of bacterial and fungal infections in a single hematology ward and to compare methods for reporting surveillance and infection rates in other centers in Israel.

Methods: We conducted a prospective surveillance of all patients admitted to our hematology ward, applying standard definitions for invasive fungal infections and adapting definitions for non-fungal infections. Incidence rates were calculated using patients, admissions, hospital days and neutropenia days. We performed a search for other reported surveillance studies in Israel.

Results: We detected 79 infectious episodes among 159 patients admitted to the hematology ward during 1 year. Using neutropenia days as the denominator for calculation of incidence discriminated best between patients at high and low risk for infection. The incidence of invasive fungal infections was 7, 10 and 18 per 1000 neutropenia days, among all patients, those with acute leukemia and those with acute leukemia undergoing induction therapy, respectively. Only 10 reports from Israel were identified, 6 of which were prospective. Our data could not be compared to these reports because of the varying definitions and denominators used.

Conclusions: Hematology centers should monitor infection rates and report them in a uniform methodology.
 

Background: There is currently no standard salvage chemotherapy for the 40–50% of patients with non-Hodgkin’s lymphoma who fail first-line treatment.

Objectives: To review the experience of a major tertiary medical center with DVIP (dexamethasone, etoposide, ifosfamide and cisplatin) salvage therapy for primary refractory/relapsing NHL[1].

Methods: We reviewed the records of all patients with NHL who received DVIP salvage therapy during the period 1993 to 2005.

Results: We identified 37 adult patients (mean age 56.3 years): 29 with aggressive lymphoma and 8 with indolent lymphoma. Mean event-free survival was 13.5 months (range 0–82 months), mean time between diagnosis and DVIP treatment 18.5 months (range 2–101), and mean number of DVIP cycles 1.9. Four patients (11%) achieved a complete response and 9 (24%) a partial response (overall response 35%). Consolidation with stem cell transplantation was used in 14 patients with aggressive lymphoma and 4 with indolent lymphoma; 14 patients, all with aggressive lymphoma, responded (12 complete, 2 partial). Of the 10 patients who underwent SCT[2] despite no response to salvage DVIP, 6 achieved a complete response. Five year overall survival from diagnosis for the whole sample was 39.4 ± 8.7%, and 5 year post-DVIP overall survival 37.6 ± 8.0%. On multivariate analysis, SCT was the strongest predictor of survival (relative risk 0.73, P < 0.0001) followed by a high score on the International Prognostic Index (RR[3] 3.71, P = 0.032).

Conclusions: DVIP salvage therapy for NHL was associated with a low response rate of 35% but a 5 year post-DVIP survival rate of 37.6%. Patients who are refractory to salvage treatment with DVIP might still be salvaged with SCT.

Background: Diseases causing increased pulmonary pressure will subsequently cause a dilation of the pulmonary arteries and right heart chambers.

Objectives: To assess the capability of computed tomography angiography and high resolution CT to diagnose and estimate the severity of pulmonary arterial hypertension as compared with standard means of right heart catheterization, echocardiography and pulmonary function tests.

Methods: The study included 38 patients with PHT[1] who underwent CT angiography and HRCT[2] as part of their routine evaluation. Diagnose included: primary PHT (n=20), Eisenmenger syndrome (n=6), scleroderma (n=3), thromboembolic disease (n=3), and others (n=6). Mean pulmonary artery pressure was 58 mmHg (range 39–92 mmHg) by catheterization and peak systolic pressure 79 mmHg (range 40–135) by echocardiography. Findings for the diameters of the main pulmonary artery and its main branches, the ascending aorta, the right atria and ventricle as well as the position of the interventricular septum were compared with 22 chest CT scans as compared to patients with no known clinical history of pulmonary hypertension, performed for other reasons (trauma, oncology follow-up) during the study period. Correlations were also calculated with recent right heart catheterization, echocardiography and pulmonary function tests of the study group.

Results: Mean main pulmonary artery diameter in the study group was 3.55 ± 0.66 cm, pulmonary artery/ascending aorta ratio 1.2 ± 0.29, right pulmonary artery 2.63 ± 0.49 cm, left pulmonary artery 2.57 ± 0.5 cm. All diameters were significantly different from the control group (P < 0.0001). Main and right pulmonary artery diameters correlated to the pressure measurement by echocardiography (P = 0.001). Bronchial collaterals were found in 11 patients (30%). The position of the interventricular septum correlated well with the echocardiography study.

Conclusions: The size of the main pulmonary artery on CT angiography has a good predictive value regarding the severity of PHT.

Background: The diagnosis of gastrointestinal stromal tumors is based on documentation of c-KIT and platelet-derived growth factor-alpha receptors or specific c-KIT mutations. Before the diagnosis of GIST[1] was possible, all cases had been classified as sarcomas or benign tumors.

Objectives: To identify cases of GIST formerly diagnosed as abdominal or retroperitoneal mesenchymal tumors.

Methods: We reviewed the archive material on all surgical cases diagnosed as gastrointestinal related malignant mesenchymal tumors or GIST in our medical center during the last decade (1995–2004).

Results: Sixty-eight cases of retroperitoneal soft tissue sarcoma were identified. Thirty-eight were reconfirmed to be GIST, 19 were newly diagnosed as GIST (the hidden cases), 8 cases were re-diagnosed as mesenchymal tumors, and 3 cases of sarcoma remained sarcomas. Of all the GIST tumors, c-KIT-positive and PDGFRα[2]-positive tumors were more characteristic of primary gastric tumors, while c-KIT-positive and PDGFRα-negative tumors were found in the colorectal area. The c-KIT-negative and PDGFRα-positive cases were of gastric origin.

Conclusions: Any c-KIT-negative malignant mesenchymal mass located near the proximal gastrointestinal tract should also be stained for PDGFRα to differentiate between GIST and other soft tissue sarcomas. Practically, formerly diagnosed abdominal or retroperitoneal soft tissue sarcomas should be reviewed to identify patients with misdiagnosed GIST and thereby avoid future unnecessary and ineffective chemotherapy.

Background: With the development of computer technology and the high-tech electronic industry over the past 30 years, the technological age is flourishing. New technologies are continually being introduced, but questions regarding the economic viability of these technologies should be addressed.

Objectives: To identify the medical technologies that are currently in use in different rehabilitation medicine settings in Israel

Methods: The TECHNO-R 2005 survey was conducted in two phases. Beginning in 2004, the first survey used a questionnaire with open questions relating to the different technologies in clinical use, including questions on their purpose, who operates the device (technician, physiotherapist, occupational therapist, physician, etc.), and a description of the treated patients. This questionnaire was sent to 31 rehabilitation medicine facilities in Israel. Due to difficulties in comprehension of the term “technology,” a second revised standardized questionnaire with closed-ended questions specifying diverse technologies was introduced in 2005. The responder had to mark from a list of 15 different medical technologies which were in use in his or her facility, as well as their purpose, who operates the device, and a description of the treated patients.

Results: Transcutaneous electrical nerve stimulation, the TILT bed, continuous passive movement, and therapeutic ultrasound were the most widely used technologies in rehabilitation medicine facilities. Monitoring of the sitting position in the wheelchair, at the bottom of the list, was found to be the least used technology (with 15.4% occurrence). Most of the technologies are used primarily for treatment purposes and to a lesser degree for diagnosis and research.

Conclusions: Our study poses a fundamental semantic and conceptual question regarding what kind of technologies are or should be part of the standard equipment of any accredited rehabilitation medicine facility for assessment, treatment and/or research. For this purpose, additional data are needed.
 

Background: The etiology of chest pain with normal epicardial coronary arteries (cardiac syndrome X) seems to be related to endothelial cell dysfunction. Multiple factors are implicated in the pathophysiology, including evelated levels of homocysteine in the blood. Mutations in the MTHFR gene are associated with evelated levels of homocysteine.

Objectives: To test whether abnormal homocysteine metabolism is associated with syndrome X.

Methods: Forty-two women with chest pain, positive stress test and normal coronary arteries (syndrome X) and 100 asymptomatic women (controls) were studied for the C677T mutation. Vitamin B12, folic acid, and plasma levels of homocysteine were also measured. Endothelial cell function was studied in 10 patients with syndrome X and homozygosity for C677T mutation, and in 10 matched healthy controls. Folic acid (5 mg daily) was prescribed to syndrome X patients after initial measurements of ECF[1]. Following 13 weeks of treatment, ECF and blood tests were repeated and compared to baseline measurements.

Results: Homozygosity for C677T mutation was doubled in syndrome X vs. control (33%, 14/42 vs. 16%, 16/100, P < 0.02), and homocysteine levels were increased (9.16 ± 2.4 vs. 8.06 ± 2.6 μmol/L, P = 0.02). In the 10 homozygous patients, homocysteine levels decreased significantly after treatment with 5 mg/day folic acid (10 ± 3.3 vs. 5.4 ± 1.1 µmol/L, P = 0.004). Abnormal baseline ECF improved after treatment with folic acid: flow-mediated dilatation was greater (11.3 ± 7.9% vs. 0.7 ± 4.5%, P < 0.002), as was nitroglycerin-mediated dilatation (15.2 ± 9.0% vs. 5.6 ± 6.4%, P < 0.003). Frequency of chest pain episodes was significantly reduced after 13 weeks of folic acid treatment.

Conclusion: Our findings establish the association between the C677T mutation, endothelial cell dysfunction and cardiac syndrome X, and provide a novel and simple therapy for a subset of patients with syndrome X and homozygosity for the C677T mutation.

Objectives: To assess the effects of the recently introduced co-payment for consultant specialist services on patients' utilization of these services in southern Israel.

Methods: Computerized utilization data on specialists' services for 6 months before and 6 months after initiation of co-payment were retrieved from the database of Israel's largest health management organization.

Results: A decrease of 4.5% was found in the total number of visits to Soroka Medical Center outpatient clinics and of 6.8% to community-based consultants. An increase of 20.1% was noted in the number of non-actualized visits at the outpatient clinics. A decrease of 6.2% in new visits was found in the hospital outpatient clinics and of 6.5% in community clinics. A logistic regression model showed that the residents of development towns and people aged 75+ and 12–34 were more likely not to keep a prescheduled appointment.

Conclusion: After introduction of a modest co-payment, a decrease in the total number of visits to specialists with an increase in "no-shows" was observed. The logistic regression model suggests that people of lower socioeconomic status are more likely not to keep a prescheduled appointment.

Background: Poliovirus rapidly evolves by nucleic acid substitutions and genetic recombination with other polioviruses and non-polio enteroviruses. Evolving oral poliovirus (Sabin strains) can rapidly revert to neurovirulence and undergo antigenic alterations.

Objectives: To evaluate the threat of vaccine-derived poliovirus (1–15% divergence from the respective Sabin strain) for a poliomyelitis-free population in a country with a long-standing routine vaccination program.

Methods: We characterized genetic and antigenic changes in OPV[1] strains isolated from sewage in Israel and evaluated intestinal immunity by measuring fecal excretion after OPV challenge of vaccinated children.

Results: Characterization of poliovirus from sewage revealed eight type 2 and three type 3 vaccine polioviruses that had replicated and started to evolve (vaccine that replicated and diverged by 0.5 to ≤ 1.0%) and nine highly diverged type 2 vaccine-derived polioviruses (1–15% divergence from the respective Sabin strain) with 8–14% divergence between the years 1998 and 2005. Six of the eleven VRPV[2] uniquely recombined with OPV and/or NPEV[3]. The nine VDPV[4] were epidemically related, genotypically neurovirulent, and had 10–15 amino acid substitutions in antigenic sites altering their antigenicity, but shared a single recombination. Type 2 OPV was excreted by 23% and 17% of infants challenged with OPV 3 months after partial immunization (two doses each of OPV and enhanced inactivated poliovirus) or full immunization (three doses of each) respectively, despite high humoral antibody titers.

Conclusions: Our findings, which show that OPV is excreted for a significant period by children with high humoral immunity, emphasize the long-term potential threat from VDPV in highly vaccinated populations. An adequate immunization program, combined with environmental surveillance, is necessary to prevent poliomyelitis and community transmission of poliovirus.