Israel Medical Association Journal

Abstract

Background: Diabetes mellitus-related lower extremity amputation is a major complication severely affecting patient survival and quality of life.

Objectives: To analyze epidemiological and clinical trends in the incidence and survival of lower extremity amputations among diabetes patients.

Methods: We conducted a retrospective observational cohort study of 565 consecutive diabetes patients who underwent their first non-traumatic lower extremity amputation between January 2002 and December 2009.

Results: Major amputations were performed in 316 (55.9%) patients: 142 above the knee (25.1%) and 174 below (30.8%); 249 (44.1%) had a minor amputation. The incidence rates of amputations decreased from 2.9 to 2.1 per 1000 diabetes patients. Kaplan-Meier survival analysis showed that first year mortality rates were lower among patients with minor amputations (31.7% vs. 39.6%, P = 0.569). First year mortality rates following below-knee amputation were somewhat lower than above-knee amputation (33.1 vs.45.1%, respectively). Cox regression model of survival at 1 year after the procedure found that age (HR 1.06 per year, 95% CI 1.04–1.07, P < 0.001), above-knee amputation (HR 1.36, 95% CI 1.01–1.83, P = 0.045) and ischemic heart disease (HR 1.68, 95% CI 1.26–2.24, P < 0.001) significantly increased one year mortality risk.

Conclusions: In this population-based study the incidence rate of non-traumatic amputations in diabetes patients between January 2002 and December 2009 decreased slightly. However, one year mortality rates after the surgery did not decline and remained high, stressing the need for a multidisciplinary effort to prevent amputations in diabetes patients.

Abstract

Background: Scleroderma lung disease (ILD-SSc) is treated mainly with cyclophosphamide (CYC). The effectiveness of CYC was judged after 12–24 months in most reports.

Objectives: To analyze the effect of monthly intravenous CYC on pulmonary function tests including forced vital capacity (FVC) and diffusing lung capacity (DLCO), as well as Rodnan skin score (mRSS), during long-term follow-up.

Methods: We retrospectively collected the data on 26 ILD-SSc patients who began CYC treatments before 2007. Changes in FVC, DLCO and mRSS before treatment, and at 1, 4 and 7 years after completion of at least six monthly intravenous CYC treatments for ILD-SSc were analyzed.

Results: Mean cumulative CYC dose was 8.91 ± 3.25 G. More than 30% reduction in FVC (0%, 8%, and 31% of patients), DLCO (15%, 23%, 31%), and mRSS (31%, 54%, 62%) at years 1, 4 and 7 was registered. During the years 0–4 and 4–7, annual changes in FVC, DLCO and mRSS were 3.2 vs. 0.42% (P < 0.040), 4.6 vs. 0.89% (P < 0.001), and 1.8 vs. 0.2 (P = 0.002). The greatest annual FVC and DLCO reduction over the first 4 years correlated with mortality (P = 0.022). There were no differences in the main variables regarding doses of CYC (< 6 G and > 6 G).

Conclusions: In patients with ILD-SSc, CYC stabilized the reduction of FVC during treatment, but this effect was not persistent. The vascular characteristic of ILD-SSc (DLCO) was not affected by CYC treatment. CYC rapidly improved the mRSS. This effect could be achieved with at least 6 G of CYC. Higher rates of annual reduction in FVC and DLCO in the first 4 years indicate the narrow window of opportunity and raise the question regarding ongoing immunosuppression following CYC infusions.

 

Abstract

Background: Heart rate variability (HRV) analysis has been shown to be a predictor of sudden cardiac death and all-cause mortality in patients with cardiac disease.

Objectives: To examine whether newer HRV analysis algorithms, as used by the HeartTrends device, are superior to exercise stress testing (EST) for the detection of myocardial ischemia in patients without known coronary artery disease (CAD).

Methods: We present pilot data of the first 100 subjects enrolled in a clinical trial designed to evaluate the yield of short-term (1 hour) HRV testing for the detection of myocardial ischemia. The study population comprised subjects without known CAD referred to a tertiary medical center for EST with single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). All patients underwent a 1 hour electrocardiographic acquisition for HRV analysis with a HeartTrends device prior to EST with MPI. Sensitivity, specificity, and positive and negative predictive values (PPV and NPV, respectively) were calculated for EST and HRV analysis, using MPI as the gold standard for the non-invasive detection of myocardial ischemia.

Results: In this cohort 15% had a pathologic MPI result. HRV analysis showed superior sensitivity (85%), PPV (50%) and NPV (97%) as compared to standard EST (53%, 42%, 90%, respectively), while the specificity of the two tests was similar (86% and 85%, respectively). The close agreement between HRV and MPI was even more pronounced among patients > 65 years of age.

Conclusions: Our pilot data suggest that the diagnostic yield of the novel HeartTrends HRV algorithm is superior to conventional EST for the non-invasive detection of myocardial ischemia.

Background: The activated NLRP3 inflammasome is associated with the etiology of fibrotic diseases. The role of inflammasomes in SSc is still poorly understood.

Objectives: To determine the expression of NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) in the skin of patients with systemic sclerosis (SSc) and its relationship with pro-inflammatory cytokines and vascular mediators expression.

Methods: Skin biopsies were taken from 42 patients with either limited or diffuse SSc (21 lcSSc and 21 dcSSc), and from 13 healthy individuals. Using real-time polymerase chain reaction (PCR), the relative expression of caspase-1, IL-1β, IL-18, IL-33, TGF-β, ET-1, iNOS and eNOS genes, were measured. The location of NLRP3 and IL-1β were also determined by immunohistochemistry. Clinical characteristics were evaluated.

Results: The mean age of the patients was 49.3 ± 12.9 (lcSSc), 44.6 ±1 3.8 (dcSSc), and 45 ± 14.1 (healthy individuals). Compared to healthy individuals, the skin of both subtypes of SSc showed a significant increase (P < 0.05) in NLRP3, caspase-1, IL-1β, IL-18 and ET-1. Samples of lcSSc also showed a significant increase of eNOS (P < 0.029), iNOS (P < 0.04) and TGF-β (P < 0.05). Dermal fibrosis evaluated by modified Rodnan skin score (MRSS) had significant correlation with NLRP3, IL-1β, IL-18, and ET-1. Immunohistochemical analysis showed stronger staining of NLRP3 and IL-1β cytoplasmic expression in the keratinizing squamous epithelium of skin from SSc patients compared to controls.

Conclusions: This study identified NLRP3 over-expression in skin of patients with SSc. Skin thickness correlates positively with the NLRP3 inflammasome gene expression and with the vascular mediator and pro-fibrotic ET-1, suggesting that NLRP3 inflammasome plays a role in the pathophysiology of skin fibrosis in human SSc.

Background: New animal models provide insights into the pathogenesis of different types of inflammatory bowel disease as well as novel pathways for new therapeutic options. However, the scarcity of large animal models hinders the research and development of new surgical procedures and technological devices in inflammatory bowel disease surgery. Common small animal inducible models involve chemical agents that result in the development of acute intestinal inflammation.

Objectives: To assess a novel method for the induction of Crohn’s-like colitis using intramural injection of sclerosants in a porcine model.

Methods: Seven domestic pigs underwent several experimental protocols to assess the efficacy of intramural colonic injections of two different compounds (lauromacrogol, and phenol in almond oil). Twenty-five different large bowel segments were treated with intramural injections of the compounds. The animals were followed for 6 weeks, and treated colonic segments were resected for histopathological examination.

Results: Intramural injection of lauromacrogol resulted in non-specific, mild reactive foreign body changes only. Injection of various dosages of 5% phenol in almond oil caused a range of histopathological changes varying from focal fibrosis to Crohn’s-like reactions comprising acute and chronic infiltrates, mucosal ulceration and focal necrosis with enteric and lymphoid non-caseating granulomas.

Conclusions: Intramural colonic phenol in almond oil injection in pigs induces inflammatory reactions that histologically resemble Crohn's disease in humans. 

Background: A clavicular fracture accounts for 2.6%–5% of adult fractures. Fractures in the middle-third (OTA 15-B) represent 69%–82% of all clavicular fractures. There is no consensus among orthopedic surgeons regarding treatment for these fractures; many support conservative treatment even for displaced middle-third clavicular fractures, while others choose operative treatment.

Objectives: To assess the attitudes of orthopedic surgeons regarding treatment of displaced mid-shaft clavicular fractures.

Methods: We conducted a survey in which we interviewed orthopedic surgeons from various countries during the 2012 EFORT meeting in Berlin. The questionnaire included an X-ray of a displaced middle-third clavicular fracture, as well as questions regarding the surgeon’s proposed treatment plan.

Results: A total of 177 orthopedic surgeons completed the questionnaire; 49% preferred operative treatment for a displaced middle-third clavicular fracture. Among the orthopedic trauma specialists, 58% suggested operative treatment, as did 82% of shoulder specialists. Most surgeons preferred a locking plate for fixation.

Conclusions: The treatment approach for a displaced middle-third clavicular fracture seems to be evenly split between conservative and operative approaches. The tendency toward operative treatment was even more remarkable among orthopedic trauma specialists and shoulder specialists who completed the questionnaire. Most surgeons prefer a locking plate as a fixation system for this type of fracture. 

Background: Orofacial clefts are the most common craniofacial congenital malformations, with significant anatomic, ethnical, racial and gender differences.

Objectives: To investigate the prevalence, distribution and characteristic features of various types of non-syndromic clefts among Israeli Jews and Arabs.

Methods: We conducted a retrospective multi-center survey in 13 major hospitals in Israel for the period 1993–2005. To obtain the true prevalence and detailed clinical characteristics, data on liveborn infants with non-syndromic clefts were obtained from the Ministry of Health's National Birth Defect Registry and completed by chart reviews in the 13 surveyed hospitals.

Conclusions: The prevalence of non-syndromic clefts was 7.00/10,000 live births. The markedly higher rate in Arabs is related to the high rate of consanguinity. Both very young and old maternal age represents a higher risk of clefts in their offspring. 

Background: Intra-articular corticosteroid injection (IACI), a common procedure in juvenile idiopathic arthritis, is usually associated with anxiety and pain. In a previous study, we concluded that nitrous oxide (NO₂) provides effective and safe sedation for such procedures. Following the introduction of medical clowns in our hospital, we added them as an integral part of the team performing IACI.

Objectives: To prospectively evaluate the effect of a medical clown on pain perception during intra-articular corticosteroid injection for juvenile idiopathic arthritis using NO₂ conscious sedation.

Methods: Patients scheduled for IACI first met and interacted with the medical clown. During the procedure, the rheumatologist and the medical clown worked in parallel to create distraction. NO₂ was administered. The patient, parent, physician, medical clown and nurse completed a visual analog scale (0–10) for pain. Change in heart rate ≥ 15% was recorded to evaluate physiologic response to pain and stress.

Results: A total of 46 procedures were performed in 32 children: 23 girls, 9 boys, with a mean age of 10.9 ± 3.6 years. The median visual analog scale pain score for the patients, parents, physicians, medical clown and nurses was 2, 2, 1, 1 and 1, respectively. Five patients had increased heart rate and experienced increased pain.

Conclusions: Active participation of a medical clown during IACI with nitrous oxide for juvenile idiopathic arthritis further decreases pain and stress and results in a positive patient experience. 

Background: Non-mobilized peripheral blood contains mostly committed cells with limited numbers of early progenitors. Objectives: To enrich functional progenitor cells from healthy donors and ischemic heart disease patients by short-term culture of mononuclear cells with defined culture conditions.

Methods: Mononuclear cells obtained from healthy donors and ischemic heart disease patients were cultured for 7 days in a cytokine cocktail. We tested the multilineage differentiation capacities and phenotype of cultured cells.

Results: The short-term culture (7 days) of all study groups with a defined cytokine cocktail resulted in two distinct cell populations (adherent and non-adherent) that differed in their differentiation capacities as well as their cell surface markers. Cultured adherent cells showed higher differentiation potential and expressed endothelial and mesenchymal fibroblast-like surface markers as compared to fresh non-cultured mononuclear cells. The non-adherent cell fraction demonstrated high numbers of colony-forming units, indicating a higher differentiation potential of hematopoietic lineage.

Conclusions: This study proved the feasibility of increasing limited numbers of multipotent progenitor cells obtained from the non-mobilized peripheral blood of healthy donors and ischemic patients. Moreover, we found that each of the two enriched subpopulations (adherent and non-adherent) has a different differentiation potential (mesenchymal, endothelial and hematopoietic).