Israel Medical Association Journal

Background: Familial Mediterranean fever (FMF) is a recessively inherited disease with a variety of clinical presentations. The disease is associated with mutations in the FMF gene (MEFV), which encodes for the pyrin protein. The role of the E148Q pyrin mutation in the FMF phenotype remains inconclusive, and some authors even view it as a disease-insignificant polymorphism. The calculated change, imposed by this mutation on pyrin structure, may help to understand the role of this mutation

Objectives: To calculate the relative electrochemical effect of the E148Q mutation on the structure of pyrin protein.

Methods: The electronic properties of the wild-type pyrin molecule and its common mutated forms were computed for the full-length molecule and its segments, encoded by exons 2 and 10, using the HyperChem 7.5 program with one of the molecular mechanical methods (MM+). The change in the structure of the molecule, expressed as a change in energy gain, conferred by the mutations was determined.

Results: The E148Q mutation caused deviation from the wild-type pyrin segment encoded by exon 2 by 1.15% and from the whole pyrin molecule by 0.75%, comparable to the R202Q mutation and less than the M694V mutation which caused a deviation from the wild-type structure of the whole pyrin molecule by 1.5%.

Conclusions: A quantum-chemistry based model suggests that the structural effect of the E148Q mutation is indeed low, but not zero. 
 

Background: Ultraviolet B (UVB) rays are required by the skin for the production of vitamin D. The intensity of UVB at the Dead Sea area is the lowest in the world. Low vitamin D levels are often associated with musculoskeletal symptoms.

Objectives: To assess the effectiveness of climatotherapy at the Dead Sea on the production of vitamin D in Norwegian patients suffering from various rheumatic diseases and to investigate possible associations between increased vitamin D serum levels, musculoskeletal symptoms and disease severity.

Methods: Sixty Norwegian patients who came to the Dead Sea area for 21 days of medical rehabilitation were divided into three groups according to their diagnosis: chronic pain syndromes, i.e., low back pain or fibromyalgia (Group 1, n=33); rheumatoid arthritis (Group 2, n=16); and osteoarthritis (Group 3, n=11). Serum 25-hydroxyvitamin D (25-OH-D) levels were determined at arrival and prior to departure. The treatment protocol included daily sun exposure (climatotherapy), bathing in the Dead Sea and mineral spring water (balneotherapy), mud applications and fitness classes.

Results: 25-OH-D serum levels increased significantly from 71.3 ± 26.6 nM at arrival to 89.3 ± 23.2 nM prior to departure (P < 0.001). Adjusted for the initial levels of pain (assessed by a visual analog scale) and disease severity, a direct correlation was observed between increased 25-OH-D serum levels and pain reduction (P = 0.012) and reduction of disease severity (P = 0.02).

Conclusions: Climatotherapy at the Dead Sea induces significant changes in vitamin D. Increased 25-OH-D serum levels are associated with reduced musculoskeletal pain and disease severity.
 

Background: Rapid reperfusion of an infarct-related artery is crucial for the successful treatment of ST elevation myocardial infarction. Every effort should be made to shorten door-to-balloon time.

Objectives: To investigate whether bypassing the emergency room (ER) has a positive influence on door-to-balloon time in patients presenting with ST elevation myocardial infarction (STEMI) and whether the reduction in door-to-balloon time improves patients’ clinical outcome.

Methods: We analyzed data of 776 patients with STEMI[1] from the 2004 and the 2006 Acute Coronary Syndrome Israeli Survey (ACSIS) registry. The ACSIS[2] is a biennial survey on acute myocardial infarction performed in all 25 intensive cardiac care units in Israel during a 2-month period. Twenty-five percent of patients (193 of 776) arrived directly to the intensive cardiac care unit (ICCU) and 75% (583 of 776) were assessed first in the ER[3]. We compared door-to-balloon time, ejection fraction, 30 days MACE (major adverse cardiac and cerebrovascular events) and 30 days mortality in the two study groups.

Results: There was significantly shorter door-to-balloon time in the direct ICCU group as compared with the ER group (45 vs. 79 minutes, P < 0.002). Patients in the direct ICCU group were more likely to have door-to-balloon time of less than 90 minutes in accordance with ACC/AHA guidelines (88.7% vs. 59.2%, P < 0.0001). Moreover, patients in the direct ICCU group were less likely to have left ventricular ejection fraction < 30% (5.4% vs. 12.2%, P = 0.045) and less likely to have symptoms of overt congestive heart failure. Lastly, 30 days MACE[4] was significantly lower in the direct ICCU group (22 vs. 30%, P < 0.004).

Conclusions: There is significant reduction of the door-to-balloon time in the direct ICCU admission strategy. This reduction translates into improvement in clinical outcome of patients. It is reasonable to apply the direct ICCU strategy to patients with STEMI.

Background: Internet use by patients as a source of information on health and disease is expanding rapidly with obvious effects on the doctor-patient relationship. Many of these effects remain undocumented or are poorly understood.

Objectives: To assess the use of the internet  for health information by patients in primary care in Israel and their perception of the effects of internet use on their relationship with their doctor.

Methods: A cross-sectional survey was conducted among a convenience sample of patients visiting 10 primary care clinics in central Israel using a questionnaire developed for this survey. The survey examined attitudes to using the internet for health-related information and attitudes to sharing this information with doctors. Associations between demographic variables, internet use and patient satisfaction with the doctor’s response were tested using the chi-square statistic and t-tests.

Results: Completed questionnaires were received from 138 patients; the response rate was 69%. Patients in the study sample had a high rate of internet access (87%), with many using the internet as a source of health information (41%) although most patients using the internet never share this information with their doctor (81%). Among those who share information with the doctor, most felt that this has a positive effect on the relationship (87%). Few patients reported being referred to websites by the doctor (28%).

Conclusions: Internet use is prevalent in this population, though physicians may be unaware of this. Future study may examine the effects of doctors who ask patients actively about their internet use and inform them of relevant health information sources online.

There are major dilemmas regarding the optimal modalities for breast cancer screening. This is of particular relevance to Israel because of its high-risk population. It was suggested that an avenue for further research would be to incorporate advances in signal processing through the fast Padé transform (FPT) to magnetic resonance spectroscopy (MRS). We have now applied the FPT[1] to time signals that were generated according to in vitro MRS[2] data as encoded from extracted breast specimens from normal, non-infiltrated breast tissue, fibroadenoma and cancerous breast tissue. The FPT is shown to resolve and precisely quantify the physical resonances as encountered in normal versus benign versus malignant breast. The FPT unambiguously delineated and quantified diagnostically important metabolites such as lactate, as well as phosphocholine, which very closely overlaps with glycerophosphocholine and phosphoethanolamine, and may represent a magnetic resonance-visible molecular marker of breast cancer. These advantages of the FPT could clearly be of benefit for breast cancer diagnostics via MRS. This line of investigation should continue with encoded data from benign and malignant breast tissue, in vitro and in vivo. We anticipate that Padé-optimized MRS will reduce the false positive rates of MR-based modalities and further improve their sensitivity. Once this is achieved, and given that MR entails no exposure to ionizing radiation, new possibilities for screening and early detection emerge, especially for risk groups. For example, Padé-optimized MRS together with MR imaging could be used with greater surveillance frequency among younger women with high risk of breast cancer.

Background: Intravitreal injections of the anti-vascular endothelial growth factor (VEGF) drugs bevacizumab (Avastin®) and ranibizumab (Lucentis®) became the mainstay of treatment for various retinal pathologies, but there is no consensus among ophthalmologists on the precise use of these drugs.

Objectives: To describe the current application of anti-VEGF[1] drugs among retinal specialists in Israel.

Methods: A questionnaire was sent via email to all 62 members of the Israeli Society of Retinal Specialists. The survey included 34 questions on various aspects of the use of anti-VEGF drugs: diagnosis, treatment, follow-up of different retinal pathologies, and the measures taken for ensuring sterile administration of the intravitreal injections.

Results: Fifty members (80%) completed the survey. Most of them (56%) offered both bevacizumab and ranibizumab to their patients for age-related macular degeneration, but 70% were influenced by the patient’s socioeconomic status. Three consecutive monthly injections were usually recommended (58%) for the first 3 months, and treatment was extended as long as subretinal or intraretinal fluids persisted (57%). Over two-thirds (68%) switched the drugs after the 3-monthly series if the first one yielded no improvement in fluid status. The routine practice for intravitreal injection (> 80%) involved the wearing of sterile gloves, using an eyelid speculum, and administering povidone-iodine pretreatment and topical antibiotics after treatment.

Conclusions: Intravitreal VEGF administration varies widely among Israeli retinal specialists. The current survey is intended to assist Israeli ophthalmologists in establishing their own treatment strategy for patients with retinal pathologies.  

Background: Increased cardiovascular morbidity has become a leading cause of mortality in rheumatoid arthritis (RA). Tumor necrosis factor-alpha (TNFα) inhibitors may influence flow-mediated vasodilation (FMD) of the brachial artery, common carotid intima-media thickness (ccIMT) and arterial stiffness indicated by pulse-wave velocity (PWV) in RA.

Objectives: To assess the effects of adalimumab treatment on FMD[1], ccIMT[2] and PWV[3] in early RA[4].

Methods: Eight RA patients with a disease duration ≤ 1 year received 40 mg adalimumab subcutaneously every 2 weeks. Ultrasound was used to assess brachial FMD and ccIMT. PWV was determined by arteriograph. These parameters were correlated with C-reacive protein, vonWillebrand factor (vWF), immunoglobulin M (IgM)-rheumatoid factor (RF), anti-CCP levels and 28-joint Disease Activity Score (DAS28).

Results: Adalimumab therapy successfully ameliorated arthritis as it decreased CRP[5] levels (P = 0.04) and DAS28[6] (P < 0.0001). Endothelial function (FMD) improved in comparison to baseline (P < 0.05). ccIMT decreased after 24 weeks, indicating a mean 11.9% significant improvement (P = 0.002). Adalimumab relieved arterial stiffness (PWV) after 24 weeks. Although plasma vWF[7] levels decreased only non-significantly after 12 weeks of treatment, an inverse correlation was found between FMD and vWF (R = -0.643, P = 0.007). FMD also inversely correlated with CRP (R = -0.596, P = 0.015). CRP and vWF also correlated with each other (R = 0.598, P = 0.014). PWV and ccIMT showed a positive correlation (R = 0.735, P = 0.038).

Conclusions: Treatment with adalimumab exerted favorable effects on disease activity and endothelial dysfunction. It also ameliorated carotid atherosclerosis and arterial stiffness in patients with early RA. Early adalimumab therapy may have an important role in the prevention and management of vascular comorbidity in RA.

Background: Acute renal failure (ARF) is a common complication in critically ill children. It is known as an important predictor of morbidity and mortality in this population. Data on the factors affecting the choice of renal replacement therapy (RRT) modality and its impact on mortality of children with ARF[1] are limited.

Objectives: We retrospectively studied 115 children with ARF necessitating RRT[2] during the period 1995–2005 to evaluate the effect of several prognostic factors as well as RRT type on their immediate outcome.

Methods: The data collected from charts included demographics, primary disease, accompanying medical conditions, use of vasopressor support, indications for dialysis, RRT modality, and complications of dialysis. Categorical variables were analyzed using chi-square or Fisher’s exact tests. Variables associated with mortality (P < 0.1) at the univariable level were studied by a multivariable logistic regression model.

Results: The most common cause of ARF was congenital heart disease (n=75). RRT modalities included peritoneal dialysis (PD) (n=81), hemodialfiltration (HDF) (n=31) and intermittent hemodialysis (IHD) (n=18). Median RRT duration was 4 days (range 1–63 days). Overall mortality was 52.2%. IHD[3] was associated with the best survival rate (P < 0.01 vs. PD[4] and HDF[5]), while children treated with HDF had the worse outcome. Hemodynamic instability and systemic infections were associated with greater mortality, but the rate of these complications did not differ between the study groups.

Conclusions: Our results suggest that IHD[6] when applied to the right patient in an appropriate setting may be a safe and efficient RRT modality in children with ARF. Randomized prospective trials are needed to further evaluate the impact of different RRT modalities on outcome in children with ARF.

Background: Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia.

Objectives: To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999–2006.

Methods: We conducted a retrospective multi-institutional, non-randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL[1]-BFM[2]-95 protocol.

Results: At a median follow-up of 4 years (range 1–9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five (13.5%) patients relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA).

Conclusions: Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.

Background: One of the major concerns in performing nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) is the risk of tumor recurrence.

Objectives: To assess the rate, predictors and mechanisms of oncological failure in patients after NSS[1] for renal cancer.

Methods: Between 1993 and 2008 NSS was performed in 229 patients via flank incision. Only patients without metastases at diagnosis and minimal 12 months follow-up were included in the outcome analysis.

Results: During a mean follow-up of 45 ± 34 months (range 6–168 months) tumor recurrence was observed in 13 patients (5.6%). Mean follow-up time for detection of oncological failure was 51 months (range 6–132 months).  All patients with oncological failure were males, with a mean age of 61 years (median 58, range 51–74 years). The average size of the enucleated lesion was 5 cm (range 4–7 cm). Intraoperative frozen sections as well as postoperative final pathological examination of the surgical margins were negative in all recurrent cases. Mechanisms of recurrence were distant metastases (n=4), surgical scar implantation (n=2), perirenal fat recurrence (n=2), local renal recurrence at the surgical site (n=1), and new renal lesions (n=4). Predictors of oncological failure included warm ischemia time (P = 0.058), tumor size (P = 0.001), tumor location (central versus peripheral) (P = 0.015), and multifocality (P = 0.001).

Conclusions: Distant dissemination, seeding during surgery, residual disease and new growth are the mechanisms responsible for cancer relapse. Large central lesions, long warm ischemia time and multifocality were significant predictors of oncological failure.