Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease.

Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.

Thrombocytopenia and bleeding in dental procedures of patients with Gaucher disease.

The risk of bleeding during dental procedures may be increased in patients with Gaucher disease. We aimed to evaluate potential coagulation and platelet function abnormalities and targeted therapy accordingly. Patients with type 1 Gaucher disease who were treated at the Oral and Maxilo-Facial surgery clinic at Sheba Medical Center between 2003 and 2010 comprised the study cohort. Data collected included disease history, enzyme treatment, platelet counts, dental therapy and outcome. Bleeding was defined as excessive bleeding during or immediately following procedure. Coagulation studies and platelet function tests including aggregometry were performed on all patients. Dental procedures (n = 14, including eight teeth extractions, two crown lengthening procedures, one cyst enucleation and three deep dental scaling) of seven patients were studied. Mean platelet count prior to procedure was 73 K ± 14.8 mm(3). Patients bleeding risk score was calculated according to previous history of bleeding tendency, degree of thrombocytopenia, presence of comorbid coagulopathy and the type of dental procedure. Two patients with highest risk score received prophylactic platelet transfusions, three patients (medium-risk) received DDAVP preprocedure and all received systemic tranexamic acid, which was the only systemic therapy for low-risk patients. Meticulous surgical local haemostasis was applied. No excessive intra-operative or postoperative bleeding occurred. Patients with Gaucher disease who have thrombocytopenia and abnormal platelet function tests may be safely treated if meticulous haemostasis is applied along with systemic therapy as required. Platelet transfusions are not mandatory and should be applied considering the procedure-related risk and the patient's calculated haematological risk for bleeding.

Fibromyalgia and Gaucher's disease.

BACKGROUND: Patients with symptomatic Gaucher's disease sometimes have non-specific symptoms (such as general malaise with widespread musculoskeletal pains) that respond poorly to enzyme replacement treatment. These may indicate fibromyalgia syndrome; if so, other therapeutic options might be more appropriate. AIM: To identify patients with Gaucher's disease for whom fibromyalgia-specific therapy may be therapeutic. DESIGN: Questionnaire-based survey. METHODS: Adult patients (n = 109) with non-neuronopathic Gaucher's disease and adult healthy controls (n = 108) completed health-related questionnaires including the Fibromyalgia Impact Questionnaire, and underwent testing with a dolorimeter to ascertain sensitivity at 22 tender points. RESULTS: Six patients, but no controls, met the criteria for fibromyalgia. Patients with fibromyalgia had a significantly greater incidence of co-morbidities (p = 0.014) relative to other patients with Gaucher's disease; four suffered from bone involvement and were receiving enzyme therapy, but two were untreated. DISCUSSION: The presence of fibromyalgia-specific trigger points may result from multiple aetiologies, or may be an independently-sorting predisposition. Our findings cannot distinguish between these possibilities, but if fibromyalgia were the cause, enzyme replacement therapy would be expensive and inappropriate.

The interleukin-6 promoter polymorphism in Gaucher disease: a new modifier gene?

BACKGROUND: Individuals with Gaucher disease vary significantly with regard to degree of bone disease, but there are no predictive markers for severity of skeletal involvement. AIM: To determine the frequency of polymorphisms of interleukin-6 (IL-6) among patients with Gaucher disease, and the relationship to bone mineral density (BMD) and other markers of disease severity. DESIGN: Case-control study. METHODS: Genotyping for the 174G --> C promoter polymorphism of IL-6 was performed in adult patients with Gaucher disease for whom there was concurrent bone mineral density (BMD) data and in healthy Ashkenazi Jewish controls. RESULTS: The prevalence of allelic variants (58% G/G, 36% G/C, and 6% C/C) was similar in Ashkenazi Jewish adults with Gaucher disease as in Ashkenazi Jewish controls, but significantly different (p < 0.05) from that reported among Caucasians. No statistically significant correlation was found between IL-6 genotypes and BMD or markers of severity of Gaucher disease. Patients with the C/C genotype had relatively mild Gaucher disease. DISCUSSION: The IL-6 polymorphisms appear to be distributed differently in Ashkenazi Jews than among other Caucasians. In Gaucher disease, the C/C genotype may be associated with a milder Gaucher phenotype, and may serve as a mitigating genetic modifier.

Plasma chitotriosidase activity in patients with beta-thalassemia.

Variable increases in chitotriosidase levels have been reported in Italian patients with beta-thalassemia major and intermedia. We measured plasma chitotriosidase levels in Israeli patients with beta-thalassemia to ascertain its use as a universal marker of disease and/or response to therapy. Chitotriosidase levels in 39 adults (16-53 years; 30 with beta-thalassemia major, 9 with intermedia), and in 14 children (0.7-15 years; 12 with beta-thalassemia major, 2 with intermedia) were compared with other measures of disease, such as ferritin, hemoglobin, liver function tests, and genotype. Plasma chitotriosidase levels were normal (0.37 +/- 0.04 mU/mL) in all children. Twelve adults (31%) had elevated levels (>1.33 mU/mL): 11 patients (37%) with thalassemia major and 1 patient (11%) with thalassemia intermedia. A significant correlation was only found between plasma chitotriosidase levels and ferritin levels, and with mean number of transfusions per year. The patient with the highest chitotriosidase (1,440 nmol/mL/hr) had the highest ferritin (5,175 microg/L), required the most transfusions per year (40), and had abnormal liver tests. Normal chitotriosidase levels in the pediatric cohort and increased levels in only some adults may reflect status of iron overload in macrophages; thus there may be a role for monitoring chitotriosidase in patients with beta-thalassemia. Our results confirm results of the Italian cohort; however, in the latter, a more universal correlation was noted and chitotriosidase levels were much higher.

Ozone enema: a model of microscopic colitis in rats.

Ozone is one of the most powerful oxidants available, with many applications in industry and medicine. Medically relevant features of ozone include bacterial and virucidal properties, disinfection, sterilization, circulatory stimulation, and disruption of malignant cells. Ozone therapy is administered in various ways, including intravenously, intramuscularly, and intrarectally. The latter modality is used for the treatment of colitis and hepatitis. Our aim was to examine the effect of ozone water enema on normal and inflamed rat colonic mucosa. Ozone water (20 microg/ml) was prepared via ozone generator and administered intrarectally (0.5 ml) daily. Rats were killed one, three, and seven days after rectal ozone water administration, and their colons resected, rinsed, and weighed (grams per 10 cm). Damage was assessed macro- and microscopically and tissue processed for myeloperoxidase and nitric oxide synthase activity. Rats receiving saline served as controls. In an additional experiment colitis was induced by intrarectal iodoacetamide. Ozone therapy caused no macroscopic damage. Ozone therapy induced microscopic colitis, which lasted for at least a week and was accompanied by increase in segmental weight, myeloperoxidase and nitric oxide activity, and prostaglandin E2 generation. Ozone therapy had no protective effect on inflamed mucosa. In conclusion, ozone water therapy had a deleterious effect on normal colonic mucosa, suggesting intrarectal administration be reevaluated. Ozone water enema may serve as a model of microscopic colitis.

Effect of ozone on neutrophil function in vitro.

The application of ozone is widely practised as a form of alternative medicine, particularly in Germany and Eastern Europe. Ozone major autohemotherapy (the return of a small amount of a patient's blood to the circulation after ex vivo exposure to ozone) has been reported to have a therapeutic effect in various pathological conditions, including ischemic, infectious, autoimmune and neoplastic disorders. Ozone has an effect on the expression of cytokines, adhesion molecules and acute phase reactants, which are responsible in part for the respiratory inflammatory response observed after exposure to this gas. The purpose of the present study was to investigate the effect of ozone administration ex vivo, at a concentration commonly used in major autohemotherapy, on peripheral blood neutrophil function in vitro. Blood drawn from healthy volunteers was studied for neutrophil adhesion, chemotaxis and O-2 production before and after exposure to 30 microg/ml ozone. There was no significant difference in adhesion and chemotaxis of neutrophils exposed to ozone versus unexposed cells. O-2 production was minimally decreased (20.3 +/- 5.0 vs. 22.1 +/- 5.5 nmol/106 cells/10 min, respectively; P=0.01), a reduction of no clinical significance. This study confirms that major autohemotherapy with ozone is safe as far as neutrophil function is concerned. Combined with previous data, it seems that well-designed clinical trials to assess the efficacy of major autohemotherapy would pose no danger to blood cell populations, and should be encouraged.

Outcome of total hip arthroplasty in patients with Gaucher disease.

This retrospective survey includes 29 total hip arthroplasties (THAs) in 23 patients with Gaucher disease, with heterogeneous techniques, with various prostheses, and performed by 9 different surgical teams. THA was discouraged in patients with Gaucher disease because of a tendency toward infection, poor bone matrix because of Gaucher cell infiltration, and deterioration of matrix with disease progression. Subjective assessment of pain and function, objective examination of outcome, and radiologic signs of loosening after THA were evaluated. In primary THAs, there was enhancement of quality of life, allowing restoration of full participation in normal activities; function was improved; radiologic evidence of loosening was low; and there were no infections. In revisions, the results were not as good. THA is recommended in this population using criteria comparable to those in other patients, with equally good results.

Effect of ozone on red blood cell enzymes and intermediates.

Ozone autohemotherapy has been considered a form of alternative medicine and has not yet been subjected to the rigors of well-designed clinical trials. Despite encouraging anecdotal reports regarding the use of ozone in various disorders, there has been a concern that ozone per se may adversely affect red cell membranes and metabolites. The purpose of this study was to ascertain the effect of ozone administration at a concentration commonly used in autohemotherapy on a panel of red cell enzymes and intermediates, as well as its effect on red cell integrity. Since these parameters were unaffected by ozone, we suggest that clinical trials for the use of ozone autohemotherapy should be encouraged.

Cytokines in Gaucher's disease.

Gaucher's disease (GD) is characterized by hepatosplenomegaly, bone marrow infiltration, osteonecrosis, which may all be associated with the presence of pathological macrophages that contain undegraded glycosphingolipids. Levels of serum cytokines, which are soluble products of mononuclear phagocytes (MNP), were evaluated in 24 GD patients. Levels of interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and soluble interleukin-2 receptor (sIL-2R) in GD patients were significantly higher than in normal controls. We attempted to correlate cytokine levels with disease severity. Type I GD patients with more severe clinical manifestations had significantly higher levels of IL-1beta, IL-1Ra and IL-6, relative to type I patients with milder disease. Three patients homozygous for the 1448C mutation with neuropathic type III disease, had significantly higher levels of sIL-2R than type I patients or controls. We speculate that cytokine over-expression may relate to the pathophysiology of some of the clinical manifestations of GD. Thus, the elevated IL-1beta, TNF-alpha and IL-6 levels may induce the bone manifestations, the neutrophil chemotaxis and the increased incidence of hyper-gammaglobulinemia present in GD patients.

Gaucher's disease with valve calcification: possible role of Gaucher cells, bone matrix proteins and integrins.

Gaucher's disease, an autosomal recessive storage disease, leads to deposition of glucocerebrosides in various organs, especially those of the reticuloendothelial system. The heart is not thought to be frequently involved and studies of patients with cardiac involvement have concentrated on myocardial involvement. Despite careful prior investigation Gaucher cells have never been detected in the valves of these patients. Pathological findings of a patient with Gaucher's disease, type IIIc, with prominent cardiac valvular involvement are reported and, for the first time, the presence of Gaucher cells in the valve tissue is documented. There is evidence that the pathogenesis of the valvular injury may be by way of a cell-mediated mechanism involving bone matrix proteins and integrins.

Geographic variance in the frequency of the t(14;18) translocation in follicular lymphoma: an Israeli series compared to the world.

It has been suggested that differences in the frequency of the t(14;18) translocation in follicular lymphoma might explain ethno-geographic variation in the incidence of these tumors. We tested Israeli follicular lymphoma patients for the frequency of the t(14;18) translocation, and reviewed the published literature, comparing the frequency in our series with data from different parts of the world. Tissue specimens from 36 Israeli follicular lymphoma patients were tested for presence of the translocation by PCR amplification of the MBR breakpoint. Twenty-two of the 36 patients (61%) tested positive. A systematic search of the literature yielded 35 papers reporting the frequency of the t(14;18) translocation in follicular lymphoma. We analyzed cytogenetic data and molecular data separately. For each method, data were pooled from all studies within each of three geographical regions - USA, East Asia and Europe. Pooled data from cytogenetic studies show a low frequency of the translocation in the Far East (38%) compared to the USA (71%), with an intermediate frequency found in Europe (61%). Molecular studies show a similar frequency of the translocation in the Far East and Europe, significantly lower than the frequency in pooled data from American studies. The frequency in our Israeli series is relatively high, comparable to that detected in the USA. We suggest that the apparent geographical differences we describe are unlikely to be caused by a difference in the biology of the tumor, and are more likely due to technical and methodological factors. We conclude that it is unlikely that differences in the frequency of the t(14;18) translocation explain the difference in the epidemiology of lymphoma between East and West.

The nature and extent of jaw involvement in Gaucher disease: observations in a series of 28 patients.

A wide variety of osteoarticular pathoses plague the clinical course of many patients with Gaucher disease. Osseous lesions involving the jaws have been described, usually as isolated case reports. The purpose of this study was to ascertain the nature and extent of mandibulo-maxillofacial pathosis in 28 patients with documented Gaucher disease by means of panoramic radiography. Twenty-five of the 28 patients displayed radiographic evidence of jaw involvement. The most prevalent finding was gross widening of marrow spaces; frank radiolucencies, endosteal scalloping, cortical thinning, root resorption, and inferior displacement of the mandibular canal or effacement of its cortices were also seen. A previously unreported finding was delayed eruption of permanent teeth, which was seen in more than one half of the patients who were under 20 years of age. Osseous changes throughout the jaws may be more common than previously suspected and may alert the dentist to the presence of the disease.

Abdominal ultrasound findings mimicking hematological malignancies in a study of 218 Gaucher patients.

Gaucher disease, the most prevalent sphingolipidosis, generally presents with splenomegaly, anemia, and thrombocytopenia. Hence, hematologists are often the specialists involved in diagnosis and management of these patients. We present ultrasonographic characteristics in a cohort of 218 consecutive Gaucher patients evaluated in our clinic during the past 5 years. Our data emphasize the high prevalence of lesions mimicking hematological malignancies in Gaucher disease. One fifth of 184 non-splenectomized patients had intra-splenic lesions, 6% of all patients had similar lesions in the liver, and 32% of 34 splenectomized patients (but none of the other patients) had marked retroperitoneal or peri-portal lymphadenopathy. The presence of splenic lesions correlated with age and splenic size, but not with extent of bone involvement or genotype. Interestingly, they were not affected by reduction in splenomegaly following enzyme replacement therapy. The importance of these findings is to include Gaucher disease in the differential diagnosis of splenic or hepatic lesions, especially in Ashkenazi Jews. Conversely, they are relevant for follow-up of all Gaucher patients, including asymptomatic individuals, because of the reported increased incidence of hematological malignancies in Gaucher disease.

Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype.

Gaucher's disease is the most prevalent sphingolipid storage disease, characterised by substantial genetic and phenotypic variability. Cardiac manifestations are rare. We report 12 Arab Gaucher's disease patients, 2-20 years of age, who presented with oculomotor apraxia but only slight classic signs of the disease. All but the youngest had calcifications of the aortic or mitral valves or both. All these patients were homozygous for the rare point mutation D409H (1342C). Valvular calcifications increased with age and showed progression during 2 years of follow-up. Two of the oldest patients underwent aortic valve replacement, and one sibling had died suddenly at age 16, before this study, Corneal opacities were another common feature. The potentially fatal course of this Gaucher's disease variant, and the availability of a reliable PCR-based method for heterozygote detection, mean that population screening and genetic counselling in the geographic area at risk are important. Affected individuals should be closely monitored by echocardiography to gauge the need for valve replacement. The potential of enzyme replacement to prevent these cardiac complications cannot be ascertained at present, because of the high cost of therapy.

[Pneumatosis cystoides intestinalis of the splenic flexure].

We describe a case of pneumatosis cystoides intestinalis with unusual localization and radiologic features. Barium enema showed multiple, rounded, submucosal masses, which were polypoid and airless and were localized to a 20 cm segment of the splenic flexure. There was no extraluminal gas on X-ray. Puncture of these formations via colonoscopic biopsy did not result in deflation of air. Surgical resection was performed and the classical features of pneumatosis cystoides intestinalis were found. Isolated splenic flexure involvement in conjunction with atherosclerotic cardiovascular disease may suggest that pneumatosis cystoides intestinalis is a reparative process after ischemic injury.

Histomorphometric evaluation of reversible heparin-induced osteoporosis in pregnancy.

Transilial bone biopsy confirmed heparin-induced osteopenia in a 23-year-old postpartum patient. Histomorphometric measurements during the reversible stage of bone disease that followed discontinuation of the heparin sodium therapy revealed signs of recovery; these were superimposed on a loose trabecular structure typical of osteoporosis. The histomorphometric evidence of recovery correlated well with signs of clinical improvement. In the majority of patients, heparin therapy during pregnancy is innocuous; however, discontinuation of treatment is recommended at the earliest signs of osteoporosis.

Chronic cutaneous polyarteritis nodosa simulating recurrent thrombophlebitis.

A 30-year-old man who had 12 repeated hospital admissions within a period of 7 years for localized pain and swelling of the extremities is described. Excision biopsy of several subcutaneous lesions revealed histologic changes typical of polyarteritis nodosa (PN). Systemic disease was excluded because of a normal testicular biopsy, negative abdominal angiogram, and the lack of evidence for renal or other visceral involvement. Response to steroid therapy was excellent. Cutaneous PN is a distinct subset of polyarteritis with a chronic course and excellent prognosis. The present case underlines the need for a greater awareness, and for considering early biopsy of suspected lesions in patients with multiple episodes of apparent superficial thrombophlebitis.