Efficacy of adalimumab therapy for life-threatening pulmonary vasculitis in Behçet's disease.

Inflammatory large-vessel vasculitis in Behçet's disease may cause life-threatening arterial aneurysms that are prone to rupture. We report a patient with Behçet's disease with right ventricular thrombus and large aneurysms of the pulmonary arteries that led to recurrent episodes of hemoptysis. Following relapses and only partial response to repeated courses of cyclophosphamide and steroids, the patient was treated with adalimumab (Humira) and is now in clinical remission for over 30 months, with regression of her pulmonary lesions. Anti-TNFα treatment is a potential therapeutic option in patients with life-threatening complications due to large-vessel vasculitis.

Intracardiac mass as initial cardiac manifestation of Behçet's disease: think before you cut.

Behçet's disease (BD) is a chronic multisystemic inflammatory disorder. Cardiac abnormalities including intracardiac thrombi have been described in up to 16% of cases. The clinical presentation of cardiac complications in BD may include fever, dyspnea, chest pain, hemoptysis, and edema. We present 2 cases of patients who underwent surgical excision of intracardiac masses thought to be intracardiac malignancies. Further pathological and clinical evaluation established intracardiac inflammatory masses due to BD as the final diagnosis. As intracardiac masses may be the presenting manifestation of BD, it is crucial for echocardiographers to consider BD in the differential diagnosis. A careful history and physical exam looking for signs and symptoms of BD is critical before considering surgical excision of unexplained intracardiac masses. If the final diagnosis is BD anti-inflammatory therapy should be considered the basis of treatment.

[Prevention and treatment of atherosclerosis and cardiovascular diseases].

Atherosclerosis is one of the main causes of morbidity and mortality world-wide and specifically in Israel. These guidelines update the previous guidelines of the Israeli Society for Research, Prevention and Treatment of Atherosclerosis, published in 2005. The need for an update is based on new scientific data published in recent years necessitating changes in the recommendations for preventing and treating atherosclerosis. These guidelines were written in collaboration between all the societies outlined here and the content of this statement was approved by the delegates of these societies. The recommendations were written taking into consideration guidelines published by other international medical societies and also the specific needs of the Israeli medical system. Due to limitations of space, in the current paper we present: assessment of cardiovascular risk, smoking cessation and the treatment of dyslipidemia. Other sections including: recommendations to the general population, nutritional and physical activity recommendations, treatment of hypertension, prevention of ischemic stroke and the metabolic syndrome are available at http://www.ima.org.il/harefuah.

CMV-related thrombocytopenia treated with foscarnet: a case series and review of the literature.

Severe thrombocytopenia as a complication of CMV infection in immune competent adults is uncommon with only a few cases reported in the literature. The mechanism of CMV-related thrombocytopenia is unclear, resulting in a wide range of treatments used. The use of the antiviral agent ganciclovir was reported in five cases, with variable results. The use of foscarnet, which does not share the myelosuppressive effects of ganciclovir, in adult immune competent patients has not been reported. We review the literature and report two cases of CMV-related thrombocytopenia that were treated with foscarnet. In both cases a recent acute infection with CMV was well established and viral eradication following treatment with foscarnet was demonstrated. In one patient thrombocytopenia resolved following treatment with foscarnet and viral eradication. In the other patient, thrombocytopenia resolved following splenectomy, which was performed after viral eradication. Due to the therapeutic consequences of this diagnosis, it may be worthwhile to perform CMV screening in selected patients with thrombocytopenia. In case CMV viremia is demonstrated, viral eradication seems to have a positive influence on the resolution of thrombocytopenia. Foscarnet is a reasonable first line anti CMV agent in this setting.

The relationship of plasminogen activator inhibitor-1 levels to the ST deviation pattern of acute myocardial infarction.

OBJECTIVES: Myocardial infarction (MI) may be classified as ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI). Procoagulants such as plasminogen activator inhibitor-1 (PAI-1) as well as markers of inflammation such as C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) are elevated in acute coronary syndromes. However, no study has examined whether levels of these markers differ in patients with STEMI as opposed to NSTEMI. We sought to determine whether there are differences in plasma levels of PAI-1, CRP, SAA or IL-6 in patients with STEMI compared to patients with NSTEMI. METHODS: Seventy-six consecutive patients presenting with acute MI (37 with STEMI and 39 with NSTEMI) were prospectively enrolled. Blood samples were obtained from patients within 6 h from presentation and plasma PAI-1, CRP, IL-6 and SAA concentrations were measured. RESULTS: Plasma levels of PAI-1 were significantly higher in patients with STEMI compared to NSTEMI: 85.7 +/- 5 vs. 61.3 +/- 5 ng/ml (p < 0.001), while CRP, SAA and IL-6 levels were not significantly different between STEMI and NSTEMI patients. CONCLUSIONS: Higher plasma PAI-1 levels in STEMI patients may contribute to the predilection of these patients to occlusive thrombi and STEMI.

ST deviation pattern in acute myocardial infarction is not related to lesion location.

BACKGROUND: In ST-elevation MI (STEMI) the culprit artery is usually occluded, whereas non-STEMI (NSTEMI) it is usually patent. The location of the ruptured plaque may influence MI type. We examine whether the distance from the coronary ostium to the culprit lesion is different in STEMI as compared to NSTEMI. METHODS: We selected patients who presented with an acute MI and underwent coronary angiography during hospitalization. The analysis included 754 patients of whom 514 had STEMI and 240 had NSTEMI. The distance from the coronary ostium to the site of thrombosis was measured. RESULTS: For both STEMI and NSTEMI patients the first 60 mm of the coronary artery contained 75% of the culprit lesions. There were no significant differences in median distances from the vessel ostium to the site of thrombosis as well. CONCLUSIONS: The distance from coronary ostium to culprit lesion is similar in STEMI and NSTEMI. Culprit lesion location does not appear to influence the development of STEMI as opposed to NSTEMI.

Role of naturally occurring CD4+ CD25+ regulatory T cells in experimental atherosclerosis.

OBJECTIVE: Naturally occurring CD4+ CD25+ regulatory T cells (Tregs) exert suppressive effects on effector CD4 cells and downregulate experimental autoimmune disorders. We investigated the importance and potential role of Tregs in murine atherogenesis. METHODS AND RESULTS: Tregs were investigated comparatively between aged and young apolipoprotein E-knockout (ApoE-KO) mice and age-matched C57BL/6 littermates. The effect of oxidized LDL (oxLDL) was tested on the functional suppressive properties of Tregs from ApoE-KO and C57BL/6 mice. Tregs, CD4+ CD25- cells, and saline were infused into ApoE-KO mice to study their effects on atherogenesis. Treg numbers were reduced in atherosclerotic compared with nonatherosclerotic ApoE-KO mice. The functional suppressive properties of Tregs from ApoE-KO mice were compromised in comparison with those from their C57BL/6 littermates. Thus, oxLDL attenuated the suppressive properties of Tregs from C57BL/6 mice and more so in ApoE-KO mice. Transfer of Tregs from age-matched ApoE-KO mice resulted in significant attenuation of atherosclerosis compared with that after delivery of CD4+ CD25+/- T cells or phosphate-buffered saline. CONCLUSIONS: CD4+ CD25+ Tregs may play a protective role in the progression of atherosclerosis and could be considered a therapeutic tool if results from human studies can solidify observations in murine models.

Brain natriuretic peptide levels predict perioperative events in cardiac patients undergoing noncardiac surgery: a prospective study.

OBJECTIVES: Brain natriuretic peptide (BNP) levels correlate with prognosis in patients with cardiac disease and may be useful in the risk stratification of cardiac patients undergoing noncardiac surgery (NCS). The objective of this study was to examine whether BNP levels predict perioperative events in cardiac patients undergoing NCS. METHODS: Patients undergoing NCS with at least 1 of the following criteria were included: a clinical history of congestive heart failure (CHF), ejection fraction <40%, or severe aortic stenosis. All patients underwent echocardiography and measurement of BNP performed using the ADVIA-Centaur BNP assay (Bayer HealthCare). Clinical endpoints were death, myocardial infarction or pulmonary congestion requiring intravenous diuretics at 30 days of follow-up. RESULTS: Forty-four patients were entered into the study; 15 patients (34%) developed cardiac postoperative complications. The mean BNP level was 1,366 +/- 1,420 pg/ml in patients with events and 167 +/- 194 pg/ml in patients without events, indicating a highly significant difference (p < 0.001). The ROC area under the curve was 0.91 (95% CI 0.83-0.99) with an optimal cutoff of >165 pg/ml (100% sensitivity, 70% specificity). CONCLUSIONS: BNP levels may predict perioperative complications in cardiac patients undergoing NCS, and the measurement of BNP should be considered to assess the preoperative cardiac risk.

Ockham's razor or Hickam's dictum: a right atrial mass following excision of left atrial myxoma.

We report a case of a 54-year-old man presenting with a right atrial mass 7 months after undergoing a left atrial myxoma excision surgery. The differential diagnosis included recurrent myxoma or thrombus. The patient underwent repeat open sternotomy on cardiopulmonary bypass. Histopathological evaluation of the mass revealed an organizing thrombus. This report is, to our knowledge, the first that demonstrates right atrial thrombus shortly following excision of left atrial myxoma.

Chronicle of a death foretold: a case of catastrophic vascular Behcet's disease.

A 20-year-old man with Behcet's disease characterized by recurrent arterial aneurysms presented with a new aortic root aneurysm. This patient previously had aneurysms of the coronary arteries and vein, as well as ruptured renal artery aneurysm. Chronic maintenance immunosuppressive therapy was recommended due to the catastrophic nature of the disease, which the patient refused to take. The patient died shortly after admission. This case demonstrates the unique catastrophic natural history of vascular Behcet's disease with recurrent life-threatening arterial events, and this case stresses the therapeutic dilemma of maintenance immunosuppressive therapy in selected patients.

ST-deviation patterns in recurrent myocardial infarctions.

Myocardial infarction (MI) may be classified as ST-elevation MI (STEMI) or non-STEMI (NSTEMI). We used the term "recurrent MI" (RMI) to denote repeat MI episodes in a particular patient in which a different coronary site is responsible for each episode. We investigated whether the type of RMI is more likely to be of the same type as the index MI or whether patients may have the 2 types of MI at random. The analysis included 305 patients who had >or=2 MI episodes. Acute MIs were classified as STEMI or NSTEMI. We attempted to include only MIs of native vessels, without the presence of extracardiac conditions that intensify myocardial ischemia. Most patients (76%) had repeat episodes of the same MI type, i.e., STEMI or NSTEMI. Recurrent STEMI occurred in 44% of patients, recurrent NSTEMI in 32%, and STEMI and NSTEMI in 24%. Thus, most patients with RMI episodes will have STEMIs or NSTEMIs but not the 2 types, suggesting a predilection of some patients to repeat episodes of occlusive thrombi and others to repeat episodes of nonocclusive thrombi.

Spleen rupture secondary to anticonvulsant hypersensitivity syndrome.

Anticonvulsant hypersensitivity syndrome (AHS) is a rare complication associated with the use of anti-epileptic medications. The syndrome's main symptoms are cutaneous eruptions, fever, hepatitis, and lymphadenopathy. We describe a 23-year-old woman who developed AHS 2 months after starting phenytoin therapy. She presented with fever, orofacial edema, skin rash, and lymphadenopathy. Four days after admission, she developed agonizing epigastric pain with diffuse epigastric tenderness. An abdominal CT scan demonstrated splenomegaly with a large, hypodense area involving the upper half of the spleen, consistent with splenic rupture. She was managed medically in an effort to avoid splenectomy. There are no other documented cases of spleen rupture linked to AHS. A possible mechanism is the alteration of lymphocytic function due to the accumulation of cytotoxic metabolites and infiltration of the spleen with lymphocytic cells, distending the capsule and predisposing it for rupture. We believe that the case presented here should increase awareness of the potentially life-threatening complications associated with AHS.

Physicians underdiagnose and undertreat obesity in ishemic heart disease patients: data from the HOLEM Study Group.

BACKGROUND: Obesity is an independent risk factor for ischemic heart disease and affects the status of other risk factors for cardiovascular disease. OBJECTIVE: To study the attitude of physicians to obesity by examining discharge letters of overweight patients with ischemic heart disease. METHODS: We used the HOLEM database for this analysis. The HOLEM project was designed to study the NCEP (National Cholesterol Education Program) guideline implementation among patients with IHD at hospital discharge. We documented the recording of risk factors and treatment recommendations for IHD by reviewing the discharge letters of 2994 IHD patients admitted to four central hospitals in Israel between 1998 and 2000. A follow-up visit was held 6-8 weeks after discharge, at which time the diagnosis of IHD was verified, risk factor status was checked, height and weight were measured and drug treatment was reviewed. RESULTS: Mean body mass index was 28.3 kg/m2 and 32% were obese (BMI > or = 30 kg/m2). Only 39.6% of the obese patients and 65.8% of the morbidly obese patients (BMI > or = 40 kg/m2) had "obesity" noted in their discharge letters, and weight loss recommendation was written in only 15% of the obese patients' discharge letters. Acute episodes like acute myocardial infarction and unstable angina did not influence the notation of obesity, and only BMI and the number of additional risk factors were positively correlated with the notation of this risk factor. CONCLUSIONS: Despite the importance of obesity, weight status was not noted and weight loss was not recommended in most of the discharge letters of obese IHD patients.

A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair.

OBJECTIVES: The goal of this study was to analyze the genetic disorder of a family with cardiomyopathy, skin disorder, and woolly hair. BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder causing arrhythmia and sudden cardiac death. We report a patient with familial autosomal recessive ARVD, woolly hair, and a pemphigous-like skin disorder with a new mutation in the desmoplakin gene. METHODS: Genomic deoxyribonucleic acid was extracted from the patient's blood and 12 first- and second-degree family members, and was amplified by polymerase chain reaction. Linkage analysis with polymorphic microsatellites was performed for 11 genes that code for structural desmosomal proteins. The genetic locus of the disease in this family was mapped to the chromosomal region 6p24 that contains the desmoplakin gene. Exons of the desmoplakin gene were analyzed by single-strand conformational polymorphism and direct sequencing. Confirmation of the mutation was carried out by restriction enzyme analysis. RESULTS: We identified in the patient a homozygous missense mutation in exon 24 of the desmoplakin gene, leading to a Gly2375Arg substitution in the C-terminal of the protein where the binding site to intermediate filaments is located. Eight of 12 family members without hair or skin abnormalities were heterozygous for this mutation. The remaining 4, as well as 90 unrelated healthy control individuals of the same ethnic origin, were homozygous for the normal allele. CONCLUSIONS: We have described a new mutation in the desmoplakin gene that causes familial ARVD. These findings suggest that desmosomal proteins play an important role in the integrity and function of the myocardium. Dysfunction of these proteins can lead to the development of cardiomyopathies and arrhythmias.

Transgenic expression of mammalian heparanase uncovers physiological functions of heparan sulfate in tissue morphogenesis, vascularization, and feeding behavior.

We have generated homozygous transgenic mice (hpa-tg) overexpressing human heparanase (endo-beta-D-glucuronidase) in all tissues and characterized the involvement of the enzyme in tissue morphogenesis, vascularization, and energy metabolism. Biochemical analysis of heparan sulfate (HS) isolated from newborn mice and adult tissues revealed a profound decrease in the size of HS chains derived from hpa-tg vs. control mice. Despite this, the mice appeared normal, were fertile, and exhibited a normal life span. A significant increase in the number of implanted embryos was noted in the hpa-tg vs. control mice. Overexpression of heparanase resulted in increased levels of urinary protein and creatinine, suggesting an effect on kidney function, reflected also by electron microscopy examination of the kidney tissue. The hpa-tg mice exhibited a reduced food consumption and body weight compared with control mice. The effect of heparanase on tissue remodeling and morphogenesis was best demonstrated by the phenotype of the hpa-tg mammary glands, showing excess branching and widening of ducts associated with enhanced neovascularization and disruption of the epithelial basement membrane. The hpa-tg mice exhibited an accelerated rate of hair growth, correlated with high expression of heparanase in hair follicle keratinocytes and increased vascularization. Altogether, characterization of the hpa-tg mice emphasizes the involvement of heparanase and HS in processes such as embryonic implantation, food consumption, tissue remodeling, and vascularization.

Gender gap in cerebrovascular accidents: comparison of the extent, severity, and risk factors in men and women aged 45-65.

BACKGROUND AND OBJECTIVE: Few data are available on sex differences among relatively young adult stroke patients. The aim of the present study is to analyze such differences in mortality, principal risk factors, and outcome measures among patients aged 45-65 with acute stroke. The identification of these differences is indispensable for developing optimal strategies for the prevention and care of this disease. METHODS AND RESULTS: Retrospective study of 114 women and 190 men, aged 45-65 years, hospitalized from 1990 to 1998 in the Hadassah Medical Centers with confirmed CVA. Medical background, clinical presentation, imaging results, risk factors, lifestyle information, and rehabilitative status data were retrieved from medical records. No gender differences were observed in clinical presentation or imaging studies. In-hospital mortality rate among women was higher than men, 13.2% vs. 5.8%. A significant gender gap in comorbidity with diabetes, hypertension, and hypercholesterolemia was found: 29.1% of women vs. 14.3% of men. Men more than women had a history of ischemic heart disease (35.8% vs. 21.9%) and smoking and alcohol consumption (43.9% vs. 16.4%; 6.9% vs. 0.9%). Use of rehabilitative services was similar between the sexes. CONCLUSIONS: This study shows marked gender differences among younger adult stroke patients. The concomitance of multiple risk factors in the women may have contributed to the observed higher mortality rate. Characterization of risk factors for CVA in both sexes may aid in developing prevention strategies to reduce stroke incidence in this age group.

Cardiovascular risk assessment and treatment to target low density lipoprotein levels in hospitalized ischemic heart disease patients: results of the HOLEM study.

BACKGROUND: Hypercholesterolemia control status is lacking throughout the western world. OBJECTIVES: To examine whether the treatment recommendations given to ischemic heart disease patients at hospital discharge are compatible with the guidelines of the Israeli medical societies and the U.S. National Cholesterol Education Program for coronary artery disease prevention; and to study the effects of brief educational sessions on the adherence of physicians with the guidelines. METHODS: We included consecutive IHD patients admitted to four central hospitals in Israel between 1998 and 2000. The study was conducted in two phases. In phase 1, we reviewed discharge letters to document treatment recommendations given to each patient. In phase 2 we educated the practitioners by reviewing the Israeli medical societies and the NCEP guidelines and the quality of their recommendations in phase 1, after which we reevaluated the discharge letters. RESULTS: The study included 2,994 patients: 627 in phase 1 and 2,367 in phase 2. Of the patients who needed cholesterol-lowering according to their low density lipoprotein levels, 37.4% were not prescribed such drugs at discharge (under-treatment group). This proportion was reduced by education to 26.6% (P < 0.001) in phase 2. Of the treated patients, 65.6% did not reach the target LDLgoal in phase 1 (under-dosage group) as compared to 60.2% in phase 2 (P = 0.23). In phase 2 there was an increase in the percent of patients reaching LDL levels <130 mg/day (69.3% vs. 63.8% of patients prescribed medication, P = 0.01), but the percent of patients reaching' LDL levels <100 was not different in phase 2 after adjusting for age and gender (the odds ratio for reaching target LDL was 1.16, with 95% confidence interval of 0.95-1.43). CONCLUSIONS: Physician recommendations to IHD patients discharged from hospital were suboptimal. We documented a high proportion of under-treated and under-dosaged patients. Brief educational sessions have a beneficial effect on the usage of statins; however, additional effort in guideline implementations is needed.

Inhibition of hepatic gluconeogenesis and enhanced glucose uptake contribute to the development of hypoglycemia in mice bearing interleukin-1beta- secreting tumor.

Mice bearing IL-1beta-secreting tumor were used to study the chronic effect of IL-1beta on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1beta gene. Serum IL-1beta levels increased exponentially with time. Secretion of IL-1beta from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1beta caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1beta. Glut-1 and Glut-4 mRNA levels in IL-1beta mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1beta. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1beta-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.

Licorice consumption causing severe hypokalemic paralysis.

Hypokalemic paralysis due to licorice consumption is extremely rare, with only 40 cases in the English literature describing paralysis secondary to exposure to licorice in candies, medications, chewing tobacco, and herbal preparations. We describe a patient who suffered life-threatening hypokalemic paralysis caused by consumption of licorice in the form of a tea sweetener superimposed on long-term consumption of licorice candy. Aggressive fluid and potassium replenishment produced complete and lasting recovery. To our knowledge, this is the first report of hypokalemic paralysis due to exposure to licorice as a tea sweetener, a common custom among the Arab population. The case emphasizes the importance of considering patients' cultural backgrounds and local customs, which often may lead the treating physician to the correct clinical diagnosis.

Thoracic manifestations of Behçet disease at CT.

Behçet disease is a multisystemic and chronic inflammatory disorder of unknown cause that is characterized by recurrent oral and genital ulcerations, ocular manifestations, and additional clinical manifestations in multiple organ systems. Behçet disease involving the chest can manifest as a wide spectrum of abnormalities. Although conventional chest radiography is commonly used for initial assessment, spiral computed tomography can demonstrate the entire spectrum of thoracic manifestations of Behçet disease, including abnormalities of the vessel lumen and wall, perivascular tissues, lung parenchyma, pleura, and mediastinal structures. Aneurysms of the pulmonary arteries, with or without thrombosis, are a typical manifestation of Behçet disease. Other manifestations include thrombosis, vasculitis, hemorrhage, infarction, and inflammation. Familiarity with these manifestations can be useful in the diagnosis of Behçet disease, helping to determine the cause of symptoms in patients who present with hemoptysis and guide the choice of appropriate therapy.