Israel Medical Association Journal

Mesenchymal stem cells, or mesenchymal stromal cells, have emerged as a major new cell technology with a diverse spectrum of potential clinical applications. MSCs[1] were originally conceived as stem/progenitor cells to rebuild diseased or damaged tissues. Over the last 14 years, since the first report of MSC infusions in patients, the cells have been shown to suppress graft vs. host disease, stimulate linear growth in a genetic disorder of bone, and foster engraftment of haplo-identical hematopoietic stem cells. In all cases, few, if any, MSCs were identified at the site of clinical activity. This experience suggests a remarkable clinical potential, but a different general mechanism of action. Systemically infused MSCs seem to exert a therapeutic effect effect through the release of cytokines that act on local, or perhaps distant, target tissues. Rather than serving as stem cells to repair tissues, they serve as cellular factories that secrete mediators to stimulate the repair of tissues or other beneficial effects. Since both the tissue source of MSCs and the ex vivo expansion system may significantly impact the cytokine expression profile, these parameters may be critically important determinants of clinical activity. Furthermore, cell processing protocols may be developed to optimize the cell product for a specific clinical indication. For example, MSC-like cells isolated from placenta and expanded in a three-dimensional bioreactor have recently been shown to increase blood flow in critical limb ischemia. Future efforts to understand the cytokine expression profile will undoubtedly expand the range of MSC clinical applications.

The incidence of aortic valve stenosis is growing rapidly in the elderly. Nonetheless, many symptomatic patients are not referred for surgery usually because of high surgical risk. Unfortunately, percutaneous balloon valvuloplasty is unsatisfactory due to high recurrence rates. In 2002, Cribier and colleagues were the first to describe percutaneous aortic valve implantation, opening a new era of aortic stenosis management. In the present review we report a patient treated by this novel method, discuss and assess how it is implanated, report the findings of studies conducted to date, and suggest future directions for percutaneous treatment of aortic valve disease.
 

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: Aural cholesteatoma is an epidermal cyst of the middle ear or mastoid that can only be eradicated by surgical resection. It is usually managed with radical or modified radical mastoidectomy. Clinical diagnosis of recurrent cholesteatoma in a closed postoperative cavity is difficult. Thus, the accepted protocol in most otologic centers for suspected recurrence consists of second-look procedures performed approximately 1 year after the initial surgery. Brain herniation into a post-mastoidectomy cavity is not rare and can be radiologically confused with cholesteatoma on the high resolution computed tomographic images of temporal bones that are carried out before second-look surgery.

Objectives: To present our experience with meningoceles that were confused with recurrent disease in patients who had undergone primary mastoidectomy for cholesteatoma and to support the use of magnetic resonance imaging as more suitable than CT in postoperative follow-up protocols for cholesteatoma.

Methods: We conducted a retrospective chart review of four patients.

Results: Axial CT sections demonstrated a soft tissue mass in the middle ear and mastoid in all four patients. Coronal reconstructions of CT scans showed a tympanic tegmen defect in two patients. CT failed to exclude cholesteatoma in any patient. Each underwent a second-look mastoidectomy and the only finding at surgery was meningocele in all four patients.

Conclusions: Echo-planar diffusion-weighted MRI can differentiate between brain tissue and cholesteatoma more accurately than CT. We recommend that otolaryngologists avoid unnecessary revision procedures by using the newest imaging modalities for more precise diagnosis of the patients who had undergone mastoidectomy for cholesteatoma in the past.
 

Background: Although unprotected left main coronary artery disease is considered by contemporary guidelines to be an indication for surgery, percutaneous coronary intervention may be necessary in patients at high surgical risk.

Objectives: To assess the outcome of angioplasty in the treatment of unprotected LMCA[1] disease.

Methods: Angiographic and clinical data were collected prospectively for all patients who underwent emergent or non-emergent (planned) therapeutic PCI[2] for unprotected LMCA disease at our center from 2003 to 2007. Baseline values were compared with findings at 1, 6 and 12 months after the procedure.

Results: The study group comprised 71 consecutive patients with a mean age of 74 ± 12 years; 63% were men, and 31% had diabetes. Forty-three patients had a planned procedure and 28 an emergent procedure. Mean EuroScore was 7.3 ± 3.6 (range 5–12). Forty-nine percent of the procedures were performed with bare metal stents and 51% with drug-eluting stents. Procedural success was achieved in 100% of cases. The overall mortality rate was 11.3% at 1 month, 18.3% at 6 months and 19.7% at 12 months. Elective PCI was associated with significantly lower mortality (2.3% vs. 25% at 1 month, 4.6% vs. 39% at 6 months and 6.9% vs. 39% at 12 months), and the use of drug-eluting stents was associated with lower rates of target vessel revascularization and major adverse cardiac events than use of bare metal stents (2.8% vs. 14% at 1 month, 8.3% vs. 43% at 6 and 12 months). Variables that correlated with increased mortality or MACE[3] at 6 and 12 months were cardiogenic shock, emergent PCI, ejection fraction < 35%, renal failure, distal left main stenosis location, and reference diameter < 3 mm.

Conclusions: PCI is a feasible and relatively safe therapeutic option for unprotected LMCA. The less favorable outcome of emergent compared to planned PCI is probably attributable to the overwhelming acute myocardial ischemic injury in emergent cases. The use of drug-eluting stents may improve the intermediate-term restenosis rate.

[1] LMCA = left main coronary artery

[2] PCI = percutaneous coronary intervention

Background: Venous thromboembolism is a well-recognized and relatively frequent complication of malignancy, whereas tumor thrombosis is a rare complication of solid cancers. Correct diagnosis of tumor thrombosis and its differentiation from VTE[1] can alter patient management and prevent unnecessary long-term anticoagulation treatment.

Objectives: To evaluate the contribution of 18F-fluorodeoxyglucose positron emission tomography/computed tomography to the diagnosis of tumor thrombosis and its differentiation from VTE.

Methods: PET/CT[2] scans from 11 patients with suspected tumor thrombosis were retrospectively evaluated. Suspicion arose from positive PET/CT in eight cases, or from findings on contrast-enhanced CT in three patients. Criteria for positivity of PET/CT included increased focal or linear uptake of 18F-FDG[3] in the involved vessel. Findings were categorized as PET/CT positive, or PET/CT negative and compared to contrast-enhanced or ultrasound Doppler, pathology where available, and clinical follow-up.

Results: Eight occult tumor thromboses were identified by PET/CT-positive scans. Underlying pathologies included pancreatic, colorectal, renal cell, and head-neck squamous cell carcinoma, as well as lymphoma (4 patients). Three thrombotic lesions on contrast-enhanced CT were PET/CT negative, due to VTE (2 patients) and leiomyomatosis. Accuracy of PET/CT to differentiate between tumor thrombosis and benign VTE was 100% in this small study.

Conclusions: Contrast-enhanced CT defines the extent of thrombotic lesions, while the functional information from PET/CT characterizes the lesions. It appears that PET/CT may be helpful in the diagnosis of occult tumor thrombosis and its differentiation from VTE.

Background: Mite allergy is an indoor allergen responsible for most respiratory allergies in the western world. Environmental control can modify disease activity in these patients.

Objectives: To examine the benefit of the Plasma Cluster^® device (Sharp, Japan) for inactivating and removing mites from the environment of patients diagnosed with either mite‑sensitive perennial allergic rhinitis or mite‑sensitive allergic asthma.

Methods: Patients with AR[1] (n=30) or AA[2] (n=10) were enrolled into a prospective open observational 8 week study. The first 2 weeks involved initial evaluation, the following 4 weeks consisted of active usage of the device, and the last 2 weeks were designated for follow‑up. Symptom scores (recorded daily by patients and during visits by physicians) were recorded and analyzed.

Results: Patients with AR experienced a significant (P < 0.05) reduction in nasal discharge, post‑nasal drip, nasal congestion, nasal itching, watery eyes, itchy eyes, headache, itchy ears, night disturbances and an improvement in general well‑being during the last 2 days of the study compared to baseline. Patients with AA reported significant (P < 0.05) reduction in dyspnea, wheezing and the need to avoid dust mites. There was a significant (P < 0.05) improvement in mean peak expiratory flow rate at study closure compared to baseline.

Conclusions: Short-term usage of the Plasma Cluster^® device resulted in considerable clinical improvement and increased peak expiratory flow rate in patients with AR or AA. The findings of this pilot study warrant longer and controlled studies to determine the value of this device in the treatment of various allergic disorders.

Background: High levels of plasma homocysteine constitute a risk for cardiovascular disease. Physical activity, known to reduce CVD[1] risk, has been related to levels of Hcy[2]. Recently, higher Hcy was shown to be associated with lower cardiovascular fitness in women but not in men.

Objectives: To further explore the relationship between cardiorespiratory fitness and plasma total homocysteine levels in a large cohort of adult males and females.

Methods: This cross-sectional study included 2576 fitness and Hcy examinations in adults (62% males) aged 30–59 years, randomly drawn from a population undergoing a periodic health examination in the Sheba Medical Center's Executive Screening Survey. Blood tests were collected for tHcy[3] and a sub-maximal exercise test was performed to estimate cardiorespiratory fitness. Information on CVD/CVD risk factors (coronary heart disease, cerebrovascular accident, diabetes, hypertension or dyslipidemia) was self-reported.

Results: Mean tHcy plasma levels were 14.4 ± 7.7 and 10.2 ± 3.0 µmol/ml, and mean maximal oxygen uptake 36.5 ± 11.7 and 29 2 ± 9.5 ml/kg/min for males and females, respectively. A multiple regression analysis, adjusting for age, body mass index and CVD/CVD risk factors, showed no association between cardiorespiratory fitness and level of tHcy in males (P = 0.09) or in females (P = 0.62).

Conclusions: In this sample no relationship was found between level of cardiorespiratory fitness and plasma tHcy in men or women. The inconsistency of findings and the small number of studies warrant further research of the association between cardiorespiratory fitness and tHcy, an association that may have clinical implications for the modifications of cardiovascular risk factors.

Background: A high incidence of abnormal pulmonary function tests has been reported in cross-sectional studies among patients with rheumatoid arthritis. Few patients have been enrolled in longitudinal studies.

Objectives: To perform PFT[1] in rheumatoid arthritic patients without pulmonary involvement and to identify variables related to changes in PFT over 5 years of follow-up.

Methods: Consecutive RA[2] patients underwent PFT according to American Thoracic Society recommendations. All surviving patients were advised to repeat the examination 5 years later.

Results: PFT was performed in 82 patients (21 men, 61 women). Their mean age was 55.7 (15.9) years and the mean RA duration was 11.1 (10) years. Five years later 15 patients (18.3%) had died. Among the 67 surviving patients, 38 (56.7%) agreed to participate in a follow-up study. The initial PFT revealed normal PFT in only 30 patients (36.6%); an obstructive ventilatory defect in 2 (2.4%), a small airway defect in 12 (17%), a restrictive ventilatory defect in 21 (25.6%), and reduced DLco in 17 (20.7%). Among the 38 patients participating in the 5 year follow-up study, 8 developed respiratory symptoms, one patient had a new obstructive ventilatory defect, one patient developed a restrictive ventilatory defect, and 5 patients had a newly developed small airway defect. The DLco had improved in 7 of the 8 patients who initially had reduced DLco, reaching normal values in 5 patients. Over the study period a new reduction in DLco was observed in 7 patients. Linear regression analyses failed to identify any patient or disease-specific characteristics that could predict a worsening in PFT. The absolute yearly decline in forced expiratory volume in 1 sec among our RA patients was 47 ml/year, a decline similar to that seen among current smokers.

Conclusions: Serial PFT among patients with RA is indicated and allows for earlier identification of various ventilatory defects. Small airways disturbance was a common finding among our RA patients.

Background: Foodborne Salmonella enterica outbreaks constitute both a threat to public health and an economic burden worldwide.

Objectives: To characterize the pathogen(s) involved and possible source of infection of an outbreak of acute gastroenteritis in a banqueting hall in Jerusalem.

Methods: We conducted interviews of guests and employees of the banqueting hall, and analyzed food items, samples from work surfaces and stool cultures.

Results: Of 770 persons participating in three events on 3 consecutive days at a single banqueting hall, 124 were interviewed and 75 reported symptoms. Salmonella enterica, serovar Enteritidis, phage type C-8, was isolated from: 10 stool cultures (eight guests, one symptomatic employee and one asymptomatic employee) and a sample of a mayonnaise-based egg salad. Pulsed-field gel electrophoresis[c1]  of the isolates revealed an identical pattern in the outbreak isolates, different from SE C-8 controls. A culture-positive, asymptomatic employee was linked to all three events. After a closure order, allowing for cleaning of the banqueting hall, revision of food preparation procedures and staff instruction on hygiene, the banqueting hall was reopened with no subsequent outbreaks.

Conclusions: It is often difficult to pinpoint the source of infection in S. enterica outbreaks. Using molecular subtyping methods, a link was confirmed between patients, a food handler, (presumably a carrier) and a food item – all showing an identical specific Salmonella enterica serovar Enteritidis. Testing asymptomatic as well as symptomatic food handlers in outbreak investigations is imperative. Pre- and post-hiring screening might be considered as preventive measures; hygiene and sanitation education are essential.

Ten years ago we published a review updating current knowledge on heart failure. We summarized that heart failure is a neuro-humoral and inflammatory syndrome, and that pro-inflammatory cytokines are involved in cardiac depression and in the complex syndrome of heart failure. We suggested that understanding the involvement of these cytokines may enable us to reverse cardiac depression and heart failure. Now we know that there are several mechanisms involved in this syndrome, including inflammation, nitric oxide-dependent pathways, apoptosis, reactive oxygen species, and mitochondrial energy metabolism. This review will focus on the up-to-date mechanistic aspects of heart failure, including clinical trials that have contributed to our better understanding of this entity.

Primary biliary cirrhosis is an autoimmune cholestatic liver disease characterized by humoral and cellular response directed at mitochondrial autoantigens, mainly the E2 component of the pyruvate dehydrogenase complex. The etiology of PBC[1], like most polygenic autoimmune diseases, belongs to the "complex" category, including genetic elements and environmental factors. Many environmental factors, such as xenobiotics, smoking, hormonal therapy, toxins, oxidative stress and recurrent urinary tract infections, are associated with PBC. Infectious agents can trigger autoimmunity via several mechanisms and are associated with various autoimmune diseases. A relationship between PBC and several infectious agents, and a possible role for Escherichia coli in the pathogenesis of PBC has been suggested. The identification of a culprit agent that induces or exacerbates PBC might have diagnostic and therapeutic implications. This review evaluates the evidence for an infectious agent role in the pathogenesis of PBC.