Israel Medical Association Journal

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive death of motor neurons leading to fatal paralysis. The causes of ALS remain unknown; however, evidence supports the presence of autoimmune mechanisms contributing to pathogenesis. Although several environmental factors have been proposed, the only established risk factors are older age, male gender, and a family history of ALS. To date, there are no diagnostic test for ALS, and clinicians rely on the combination of upper motor neuron and lower motor neuron signs in the same body region. The aim of this paper was to provide a comprehensive review of current clinical literature with special focus on the role of autoimmunity in ALS, differential diagnosis, and available therapeutic approaches. Current evidence suggests a contribution of the innate immune system in ALS, with a role of microglial cell activation at the sites of neurodegeneration. The median time from symptom onset to diagnosis of ALS is 14 months, and this time estimate is mainly based on specific clinical signs and exclusion of ALS-like conditions. Several therapeutic approaches have been proposed, including immunosuppressive drugs, to reduce disease progression. Riluzole has been established as the only, although modestly effective, disease modifying therapy, extending mean patient survival by 3to 6 months. Recent advances in understanding the pathophysiology mechanisms of ALS encourage realistic hope for new treatment approaches. To date, the cornerstones of the management of patients with ALS are focused on symptom control, maintaining quality of life and improving survival.

Background: Fibromyalgia is a syndrome of unknown etiology that is characterized by widespread pain, which severely impairs quality of life. Several forms of occupational and alternative therapy have demonstrated beneficial effects in fibromyalgia patients.

Objective: To assess the effects of participation in a floral design course on physical and psychiatric symptoms in a cohort of fibromyalgia patients.

Methods: This study was conducted as an observational study. Women diagnosed with fibromyalgia over the age of 18 were recruited to participate in one of two 12-week flower design (floristry) courses. Demographic details, disease activity indices, and anxiety and depression scores were calculated for all participants at baseline, week 12, and study completion. Physical and mental health of the two groups were compared throughout the study time-points.

Results: The study was completed by 61 female fibromyalgia patients who were included in the final analyses; 31 patients participated in the first floristry course and 30 in the second. Significant improvements in the 36-Item Short Form Survey physical and mental health components, visual analog scale, Fibromyalgia Impact Questionnaire, Hamilton Anxiety Rating Scale, and Hamilton Depression Rating Scale scores for the entire study population and for each group separately could be seen following participation in each floristry course.

Conclusions: Participation in a floristry course may lead to a significant improvement in pain and psychiatric symptoms in fibromyalgia patients. These findings highlight the potential benefit of utilizing occupational therapy programs, such as a floristry course, for improving quality of life in fibromyalgia.

Serum rheumatoid factors are autoantibodies of different isotypes directed against the Fc fraction of immunoglobulin G (IgG) and represent paradigmatic autoantibodies that have been largely used in clinical practice for decades. Traditionally IgG has been associated with rheumatoid arthritis and more recently included also in the classification criteria for Sjӧgren’s syndrome. Researchers have established that rheumatoid factors are positive in a variety of infectious, autoimmune, and neoplastic disorders, thus requiring a comprehensive evaluation of seropositive patients. Of note, hepatitis B and C viruses represent a crossroad that includes the high rheumatoid factor seroprevalence and chronic inflammatory disease, as well as progression to non-Hodgkin's lymphomas. Chronic antigen stimulation is the likely common ground of these processes and rheumatoid factors may represent mere bystanders or drivers of pathology. Mixed cryoglobulinemia and lymphoproliferative disease are prime examples of the deleterious effects of rheumatoid factor-B cell activity, possibly associated with hepatitis B and C. More importantly, they show a clear association in a physiological host response to infection, chronic inflammation, and the slide toward autoimmunity and malignancy. The association between hepatitis B and C infections and the appearance of serum rheumatoid factors is further supported by prevalence data, which support a coexistence of these markers in a significant proportion of cases, with viral infections being frequent causes of rheumatoid factors in patients without a rheumatic condition. We provide a comprehensive overview of the known connections between hepatitis B and C infections and rheumatoid factors.

Background: Benign rolandic epilepsy or benign childhood epilepsy with centrotemporal spikes (BCECTS) is a common childhood epileptic syndrome. The syndrome resolves in adolescence, but 1–7% of patients have an atypical presentation, some of which require aggressive medical treatment. Early treatment may prevent complications and neurocognitive deterioration. Variants include Landau-Kleffner syndrome (LKS) and electrical status epilepticus during sleep (ESES).

Objectives: To determine data driven identification of risk factors and characterization of new subtypes of BCECTS based on anontology. To use data mining analysis and correlation between the identified groups and known clinical variants.

Methods: We conducted a retrospective cohort study comprised of 104 patients with a diagnosis of BCECTS and a minimum of 2 years of follow-up, between the years 2005 and 2017. The medical records were obtained from the epilepsy service unit of the pediatric neurology department at Dana–Dwek Hospital, Tel Aviv Sourasky Medical Center. We developed a BCECTS ontology and performed data preprocessing and analysis using the R Project for Statistical Computing (https://www.r-project.org/) and machine learning tools to identify risk factors and characterize subgroups.

Results: The ontology created a uniform and understandable infrastructure for research. With the ontology, a more precise characterization of clinical symptoms and EEG activity of BCECTS was possible. Risk factors for the development of severe atypical presentations were identified: electroencephalography (EEG) with spike wave (P < 0.05), EEG without evidence of left lateralization (P < 0.05), and EEG localization (centrotemporal, frontal, or frontotemporal) (P < 0.01).

Conclusions: Future use of the ontology infrastructure for expanding characterization for multicenter studies as well as future studies of the disease are needed. Identifying subgroups and adapting them to known clinical variants will enable identification of risk factors, improve prediction of disease progression, and facilitate adaptation of more accurate therapy. Early identification and frequent follow-up may have a significant impact on the prognosis of the atypical variants.

Background: Klotho is a transmembrane protein that can be shed and can act as a circulating hormone in three forms: soluble klotho (KL1 + KL2), KL1, and KL2. Klotho was discovered as a gene implicated in aging through inhibition of the IGF-I pathway. Our laboratory discovered the role of klotho as a tumor suppressor in breast cancer and other malignancies. Furthermore, we showed that the KL1 domain mediates this activity. Altered cancer cell metabolism is a hallmark of cancer and our lab demonstrated various effects of klotho on breast cancer cell metabolism. Thus, klotho inhibited glycolysis and activated adenosine monophosphate activating kinase (AMPK), an energy sensor pathway. Moreover, inhibition of AMPK reduced the tumor suppressor activity of klotho.

Objectives: To assess the effect of KL1 on breast tumor cells metabolism, as KL1 possesses the tumor suppressor activity of klotho.

Methods: We used MCF-7 breast cancer cells treated with soluble or over-expressed KL1 and klotho. Glycolysis was assessed by measuring mRNA levels of key glycolytic enzymes using reverse transcription polymerase chain reaction and by measuring lactate and glucose levels in media. The AMPK pathway was studied by monitoring AMPK phosphorylation as well as its down-stream target, acetyl-CoA carboxylase, using western blotting. Wound healing assay was used to assess cell migration.

Results: KL1 treatment reduced glycolytic enzymes mRNA levels and the activity of hexokinase, similar to klotho treatment. Furthermore, KL1 reduced glucose uptake and decreased lactate production. KL1 elevated phosphorylated acetyl-CoA carboxylase and phosphorylatedAMPK levels. Inhibition AMPK (using a mutant AMPK activator) stopped KL1 from inhibiting cell migration, suggesting AMPK underlies klotho’s tumor suppressor activity.

Conclusions: Our data indicate KL1 as a regulator of metabolic activity in breast cancer and suggest that metabolic alterations underlie KL1 tumor suppressor activities. Furthermore, as KL1 and klotho share a similar effect on cell metabolism, our results further support the central role KL1 domain plays in klotho’s tumor suppressor activity.

Background: In Israel, coronary heart disease mortality rates are significantly higher among the Arab population than the Jewish population. Dyslipidemia prevention should begin in childhood.

Objectives: To identify sociodemographic disparities in the preventive health measurement of lipid profile testing and lipoprotein levels among Israeli children and adolescents.

Methods: A cross-sectional analysis of 1.2 million children and adolescents insured by Clalit Health Services between 2007 and 2011 was conducted using sociodemographic data and serum lipid concentrations.

Results: Overall, 10.1% individuals had undergone lipid testing. Those with male sex (odds ratio [OR] = 0.813, 95% confidence interval [95%CI] 0.809–0.816), Arab ethnicity (OR = 0.952, 95%CI 0.941–0.963), and low socioeconomic status (SES) (OR = 0.740, 95%CI 0.728–0.752) were less likely to be tested. By 2010, differences among economic sectors narrowed and Arab children were more likely to be tested (OR = 1.039, 95%CI 1.035–1.044). Girls had higher total cholesterol, triglyceride, low-density lipoprotein-cholesterol, and non-high-density lipoprotein-cholesterol levels compared to boys (P < 0.001). Jewish children had higher cholesterol and low-density and high-density lipoprotein-cholesterol, as well as lower triglyceride levels than Arabs (P < 0.001). Children with low SES had lower cholesterol, low-density and high-density lipoprotein-cholesterol, and non-high-density lipoprotein-cholesterol levels (P < 0.001).

Conclusions: We found that boys, Arab children, and those with low SES were less likely to be tested. Over time there was a gradual reduction in these disparities. Publicly sponsored healthcare services can diminish disparities in the provision of preventive health among diverse socioeconomic groups that comprise the national population.

Background: Hysterectomy is common in the management of symptomatic uterine prolapse. Vaginal wall repair is often necessary, for which vaginal mesh remains a popular option.

Objectives: To evaluate the risk of mesh erosion following mesh-augmented vaginal prolapse repair, with or without concomitant vaginal hysterectomy.

Methods: This retrospective cohort comprised 70 women who underwent vaginal mesh-augmented pelvic organ prolapse repair from 2007 to 2010. Of the participants, 36 (51.4%) had a vaginal hysterectomy concomitant to the anterior and/or posterior vaginal mesh repair (hysterectomy group) and 34 (48.6%) underwent mesh repair without vaginal hysterectomy (no hysterectomy group).

Results: There were no inter-group differences in age, parity, menopausal state, hormonal use, or presenting symptoms. Previous prolapse repair surgery was much more common in the no hysterectomy group (29.4% vs. 5.5%, P = 0.01). Eleven patients (32.3%) in the no hysterectomy group had previously undergone hysterectomy. Anterior mesh repair was performed in 77.7% and 67.6% of hysterectomy and no hysterectomy patients, respectively. Posterior mesh repair was performed in 27.7% and 44.1%, respectively. One patient in the hysterectomy group underwent immediate removal of mesh due to infection. Surgically treated mesh erosion (limited local excision) occurred in three patients (8.3%) in the hysterectomy group (3, 16, and 18 months following surgery) and in two patients (5.8%) in the no hysterectomy group at 6 months following surgery (P = 0.67).

Conclusions: Vaginal mesh-augmentation concomitant with vaginal hysterectomy for pelvic organ prolapse repair does not carry an increased risk of erosion.

Background: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes.

Objectives: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA.

Methods: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394).

Results: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses.

Conclusions: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

Background: When a woman with an endometrioma presents with acute abdominal pain, it is unclear whether ovarian torsion should be suspected.

Objectives: To compare patient characteristics, imaging results, and surgical management of endometriomas in elective versus emergent surgeries.

Methods: This retrospective cohort study included women treated at our institution during the period 1990–2015 who presented with histologically verified endometrioma and who underwent either planned surgery or emergent surgery due to suspected adnexal torsion.

Results: Of 225 surgeries performed, 174 were elective and 51 emergent. Patients in the emergent group were significantly younger (33.9 ± 11.1 vs. 39.01 ± 10.9 years, P = 0.004). Abdominal pain was the main complaint of all the emergent surgery patients and the leading complaint in 21% of the elective surgery patients (P < 0.001), with right-sided predominance in both groups. Sonographic parameters were similar in both groups. Bilateral ovarian cysts were noted in 11.7% and 11.0% of emergent and elective patients, respectively (P = 0.87). Laboratory evaluation was notable for a higher white blood cell count and CA125 levels among emergent patients. All patients in the emergent group and 93% of patients in the elective group were managed laparoscopically. No cases of torsion were noted. The rate of intra-pelvic adhesions was similar in both groups (56.8% vs. 66.6%, P = 0.19).

Conclusions: Endometrioma may present with acute abdominal pain. However, adnexal torsion in these patients is rare. These cases can be managed using a minimally invasive approach, assuming an optimal surgical setting.

Background: Multidisciplinary biopsychosocial rehabilitation for patients presenting with rheumatic diseases has been shown to produce better results in a warm climate. Dead Sea Climatotherapy (DSC) has been successfully used for decades to treat many patients with rheumatic diseases.

Objectives: To evaluate the short-term improvement of Norwegian patients who presented with chronic pain following a multidisciplinary biopsychosocial approach to treatment combined with DSC. Both objective and subjective clinical parameters were evaluated.

Methods: This retrospective study included a statistical analysis of 938 patients presenting with rheumatoid arthritis and ankylosing spondylitis (n=105), osteoarthritis (n=342), fibromyalgia (n=374), and other orthopedic conditions (n=117). Clinical assessments were conducted before and after a 3 week treatment program at the Dead Sea.

Results: Six parameters improved significantly in the rheumatoid arthritis and ankylosing spondylitis group as well as in the osteoarthritis group. Five parameters in the fibromyalgia group improved, while two improved in the orthopedic conditions group. Overall, major significant changes occurred in the pain self-assessment, joint motility, and daily activities scores.

Conclusions: A 3-week multidisciplinary biopsychosocial program combined with DSC induced positive changes in the clinical parameters of Norwegian patients presenting with chronic musculoskeletal pain.

Background: Lower extremities ulcers (LEU) are associated with considerable morbidity and mortality. With longer life expectancy, the prevalence of LEU in developed countries is assumed to grow, necessitating an increased demand for treatment by specialists. 

Objectives: To compare the effectiveness of a telemedicine video conferencing modality with the conventional face-to-face treatment of LEU. 

Methods: The study was conducted in conjunction with a two-million member healthcare organization in Israel (Maccabi Healthcare Services). Consecutive visits of patients to wound care specialists during a 12-month observation period reviewed in 2015 were valuated. A nurse-assisted setting was implemented during all treatment sessions. The same specialist supervised patients in both modalities. 

Results: A sample of 111 patients (n=55 in the telemedicine group; n=56 in the face-to-face group) with 593 visits was analyzed. No significant difference in healing of LEU (78.2% in telemedicine vs. 75.0% in face-to-face) was detected, P = 0.823. A reduced number of visits in telemedicine (4.36 ± 2.36) compared to the face-to-face care (6.32 ± 4.17) was shown, P = 0.003. Non-inferiority of telemedicine demonstrated within the Δ = 15% range limits and 80% statistical power was demonstrated. 

Conclusions: Compared to the usual face-to-face method, synchronous video conferencing-based telemedicine may be a feasible and efficient method for LEU management. 

 

Background: Endothelial progenitor cells may have a role in ongoing endothelial repair. Impaired mobilization or depletion of these cells may contribute to progression of vascular disease. Our hypothesis was that endothelial progenitor cells would be suppressed in patients with acute cerebrovascular event based on our previous study that found severe endothelial dysfunction in those patients.

Objectives: To study the ability of patients with acute stroke to build colonies of endothelial progenitor cells.

Methods: We studied the number of colony-forming units of endothelial progenitor cells (CFU-EPCs) from the peripheral blood of 22 male patients with a first-time acute stroke (age 58.09 ± 9.8 years) and 13 healthy men (34 ± 6.7 years), 8 female patients with a first-time acute stroke (54.6 ± 10.3 years) and 6 healthy women (38.3 ± 11.6 years). Endothelium-dependent function was assessed by high-resolution ultrasonography of the brachial artery that measured the change in diameter of the artery by flow-mediated diameter percent change (FMD%). All patients had strokes demonstrated by a brain computed tomography (CT) scan done on admission. Peripheral blood was drawn soon after admission and was processed for endothelial progenitor cells in culture.

Results: Thirty patients without known cardiovascular risk factors and who did not take any medications were admitted with a first-time acute stroke. All demonstrated a strong correlation between CFU-EPCs grown in culture and endothelial dysfunction (r = 0.827, P < 0.01). Endothelial dysfunction with an FMD% of -2.2 ± 9.7% was noted in male patients vs. 17.5 ± 6.8% in healthy males (P = 0.0001), and -7.2 ± 10.1% in female patients vs. 25.1 ± 7.1% in healthy females (P = 0.0001). CFU-EPCs were 5.5 ± 6.3 in men with stroke vs. 23.75 ± 5.3 in healthy males (P = 0.0001), and 7.6 ± 4.9 in women with stroke vs. 22.25 ± 6.7 in healthy females (P = 0.0004).

Conclusions: Patients with acute stroke had an impaired ability to grow CFU-EPCs in culture and exhibited endothelial dysfunction. The novelty of this study was the discovery of the phenomenon of depressed numbers of EPCs and the poor ability to grow colonies of EPCs in the first 24 hours of the cerebrovascular event.

Background: Rheumatic mitral stenosis (MS) is a relatively rare diagnosis in the developed countries and its treatment during pregnancy is challenging due to hemodynamic changes. With the demographic changes due to recent waves of immigration an increase in the prevalence of rheumatic heart disease is expected.

Objective: To evaluate maternal and neonatal complications in patients with mitral stenosis.

Methods: During the years 2006–2017, 22 women who underwent 31 pregnancies were followed at the Sheba Medical Center in Israel. We collected on regarding hemodynamic changes and their clinical course. MS was classified as mild, moderate, or severe according to mitral valve area by echocardiography. Maternal and fetal adverse events were evaluated according to severity of MS and compared by Poisson regression modeling.

Results: MS was severe in 7 pregnancies (22.6%), moderate in 9 (29%), and mild in 15 (48.4%). Twenty patients were managed conservatively and 2 underwent a successful percutaneous mitral balloon valvuloplasty (PBMVP) during pregnancy. All pregnancies ended with a liveborn neonate and with no maternal mortality. Peak and mean mitral pressure gradients increased during pregnancy from 13.3 ± 5.3 to 18.6 ± 5.1 mmHg and from 5.9 ± 2.3 to 9.6 ± 3.4 mmHg respectively (P < 0.05). Eight pregnancies (25.8%) were complicated by pulmonary congestion, 2/15 (13.3%) with mild MS, 2/9 (22.2%) with moderate, and 4/7 (57.1%) with severe MS. The adverse event rate was higher among patients with severe MS compared with moderate and mild MS [hazard ratio (HR) 3.15, 95% confidence interval (95%CA) 1.04–9.52 and HR 4.06, 95%CI 1.4–11.19 respectively, P < 0.05]. Nine of 31 deliveries were vaginal; 6 of 22 cesarean sections (27.3%) were performed for cardiac indications.

Conclusions: The number of total adverse events were higher among patients with severe MS. Patients with moderate and mild MS should be treated attentively, but good obstetric and maternal outcome can be expected.