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: Introduction: There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD) among HIV‐positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study. Methods: Participants were followed from study enrolment until the earliest of death, six months after last visit or February 1, 2015. Initiation of CVD interventions [lipid‐lowering drugs (LLDs), angiotensin‐converting enzyme inhibitors (ACEIs), anti‐hypertensives, invasive cardiovascular procedures (ICPs) were investigated and Poisson regression models calculated whether rates were lower among women than men, adjusting for potential confounders. Results: Women (n = 12,955) were generally at lower CVD risk than men (n = 36,094). Overall, initiation rates of CVD interventions were lower in women than men; LLDs: incidence rate 1.28 [1.21, 1.35] vs. 2.40 [2.34, 2.46]; ACEIs: 0.88 [0.82, 0.93] vs. 1.43 [1.39, 1.48]; anti‐hypertensives: 1.40 [1.33, 1.47] vs. 1.72 [1.68, 1.77] and ICPs: 0.08 [0.06, 0.10] vs. 0.30 [0.28, 0.32], and this was also true for most CVD interventions when exclusively considering periods of follow‐up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men (LLDs: relative rate 0.83 [0.78, 0.88]; ACEIs: 0.93 [0.86, 1.01]; ICPs: 0.54 [0.43, 0.68]), except for the receipt of anti‐hypertensives (1.17 [1.10, 1.25]). Conclusion: The use of most CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV‐positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions., Introduction HIV‐positive individuals are known to be at increased risk of cardiovascular disease (CVD) compared to the general population, partly due to an increased prevalence of some CVD risk factors, [...]

To evaluate hospitalization rates and causes among human immunodeficiency virus (HIV) patients in the late highly active antiretroviral therapy (HAART) era. Data during the years 2000 to 2012 were obtained from hospital/clinical charts. Hospitalizations were defined as a ≥24 hours hospital admission. Obstetric admissions were excluded. Causes of hospitalizations were defined as acquired immune deficiency syndrome (AIDS)-defining illnesses, AIDS-related diseases (HAART adverse events, metabolic complications and non-AIDS-defining tumors/infections), and non-HIV-related diseases. Hospitalization rates are presented as admissions per 100 patient years. The number of HIV patients (58% males) in our center increased from 521 in 2000 to 1169 in 2012. 1676 hospital admissions (in 557 patients) were observed during the years of the study. The mean number of admissions per hospitalized patient was 3 ± 3.39. Hospitalization rates of HIV patients declined significantly (18.4/100 in 2000, 9/100 patient years in 2012; P = .0001), but it was higher than the rates reported in the Israeli general population (X8.76 in 2000, X6.04 in 2012). Furthermore, hospitalizations for AIDS-defining illness declined (from 46.9% to 16.1%) whereas non-HIV-related hospitalizations increased (from 31.3% to 60.1%). Lower cluster of differentiation 4 (CD4) cell counts and older age, at the time of HIV diagnosis, were associated with higher rates of admissions (especially for AIDS-defining illnesses) and mortality. Hospitalization rates of HIV patients, especially for AIDS-defining illness, continue to decline in the late HAART era despite the increasing age of the patients, though it is still higher than that of the general population. Low CD4 cell counts and older age, at the time of HIV diagnosis, are associated with readmissions and mortality.

Rationale: The integrase inhibitor dolutegravir is now recommended as first-line treatment for HIV. A single case of myocarditis after treatment with dolutegravir was reported in the FLAMINGO trial. We present here 2 cases of severe myocarditis that occurred shortly after the initiation of dolutegravir treatment., Patients Concerns: The first case is a 45-year-old female who developed severe congestive heart failure and died, weeks after the initiation of dolutegravir treatment (for simplification of her antiretroviral regimen). The second case was a 51-year-old male who presented with effort dyspnea 3 weeks after the initiation of dolutegravir treatment and was later diagnosed as severe congestive heart failure. The treatment was changed and the patient survived, but he still suffers from severe heart failure with functional impairment., Diagnosis and Outcome: Patient 1 died, patient 2 suffers from severe heart failure., Lessons: We discuss here the possible relationship between the initiation of dolutegravir treatment and the development of lymphocytic myocarditis in our patients, and we suggest a possible mechanism., Competing Interests: The authors have no funding and conflicts of interest to disclose.

To characterize the clinical, virological, and immunological status at presentation as well as the outcome of patients diagnosed with HIV above the age of 50. A retrospective study of 418 patients newly diagnosed with HIV in 1 Israeli center, between the years 2004 and 2013. Patients with new HIV diagnosis ≥ 50 years of age defined as "older' and < 50 defined as "younger.' Patients were evaluated every 1 to 3 months (mean follow-up 53 ± 33 months). Patients with < 2 CD4/viral-load measurements or with < 1 year of follow-up were excluded. Time of HIV infection was estimated by HIV sequence ambiguity assay. Ambiguity index ≤ 0.43 indicated recent (≤ 1 year) HIV infection. Eighty nine (21%) patients were diagnosed with HIV at an older age. Those older patients presented with significant lower CD4 cell counts and higher viral-load compared with the younger patients. At the end of the study, the older patients had higher mortality rate (21% vs 3.5%; P < 0.001) and lower CD4 cell counts (381 ± 228 vs 483 ± 26 cells/μL; P < 0.001) compared with the younger patients. This difference was also observed between older and younger patients with similar CD4 cell counts and viral load at the time of HIV diagnosis and among patients with a recent (≤ 1 year) HIV infection. One-fifth of HIV patients are diagnosed at older age (≥ 50 years). Those older patients have less favorable outcome compared with the younger patients. This point to the need of educational and screening programs within older populations and for a closer follow-up of older HIV patients.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32-97), lowest in Northern Europe (median 44%, IQR 22-68%) and highest in Eastern Europe (median 99%, IQR 86-100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0-4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Background: Granulomatous lobular mastitis (GLM) is a rare disorder that can clinically mimic breast carcinoma. The recommendation for diagnosis and treatment of GLM has not yet been established., Objectives: To assess a series of GLM patients, including their clinical presentation, diagnosis, treatment and outcome., Methods: We retrospectively analyzed the clinical data and treatment of 17 female patients with biopsy-proven GLM. Breast tissue was obtained by a core needle biopsy (15 patients) or open biopsy (2 patients). Images were reviewed by an experienced radiologist., Results: The mean age of the patients at diagnosis was 44.6 ± 12.6 years. Five patients (29%) presented with bilateral disease, and seven (41%) presented with a mass, suggesting the initial diagnosis of breast carcinoma. Treatment comprised observation alone (23%), antibiotics (58.8%) and/or corticosteroids (with or without methotrexate) (35%). At the end of the study 70.6% of the patients demonstrated complete remission. None of the patients developed any systemic (granulomatous) disease or breast carcinoma during the follow-up period (4.7 ± 3.8 years)., Conclusions: Core needle biopsy is mandatory for the diagnosis of GLM and the exclusion of breast carcinoma. The recommended treatment modalities are observation alone or corticosteroids; surgery should be avoided. GLM is a benign disease with a high rate of resolution and complete remission.

Angiotensin-converting enzyme inhibitors (ACE-I) are widely used, effective, and well-tolerated antihypertensive agents. The mechanisms by which those agents act can cause side effects such as decreased blood pressure, hyperkalemia, and impaired renal function. ACE-I can induce cough in 5%-35% and angioedema in up to 0.7% of treated patients. Because cough and angioedema are considered class adverse effects, switching treatment to other ACE-I agents is not recommended. Angioedema due to ACE-I has a low fatality rate, although deaths have been reported when the angioedema involves the airways. Here, we review the role of bradykinin in the development of angioedema in patients treated with ACE-I, as well as the incidence, risk factors, clinical presentation, and available treatments for ACE-I-induced angioedema. We also discuss the risk for recurrence of angioedema after switching from ACE-I to angiotensin receptor blockers treatment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Type I interferons (IFN) are primarily regarded as an inhibitor of viral replication. However, type I IFN, mainly IFNalpha, plays a major role in activation of both the innate and adaptive immune systems. Systemic lupus erythematosus (SLE) is a chronic, multi-systemic, inflammatory autoimmune disease with undefined etiology. SLE is characterized by dysregulation of both the innate and the adaptive immune systems. An increased expression of type I IFN-regulated genes, termed IFN signature, has been reported in patients with SLE. We review here the role of IFNalpha in the pathogenesis and course of SLE and the possible role of IFNalpha inhibition as a novel treatment for lupus patients.

Current treatments for systemic lupus erythematosus (SLE) are effective in reducing morbidity and mortality but are not specific and have severe adverse effects. Based on understanding of the different dysregulated immunological pathways involved in SLE pathogenesis, specific targeted therapies were developed. This review presents the current and the near-future novel biological immune targeted treatments, such as B cell-targeted therapy, cytokine blockade, peptide-based treatments and other novel treatments for SLE.

Systemic lupus erythematosus is a multisystem disease of unknown etiology in which dysregulation of the innate and adaptive immune systems has a major effect in the pathogenesis of the disease. The treatment should be tailored for each patient according to how the disease manifests itself. Although there is no cure for systemic lupus erythematosus, the current treatment, using anti-inflammatory, antimalarial, and immunosuppressive agents, is fairly effective, but serious adverse events are possible. New biologic agents that target various components of the immune system recently have been developed for the treatment of patients with systemic lupus erythematosus., (Copyright 2010 Elsevier Inc. All rights reserved.)

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the production of autoantibodies particularly to nuclear antigens and by an abnormal production of proinflammatory cytokines. In the present study, we measured the levels of the proinflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of SLE patients at various stages of the disease. This is the first study to present IL-18BP levels in sera of SLE patients as well as the calculated, biologically active, free IL-18 concentrations that are most probably more relevant to the pathology of SLE. Sera from 48 unselective SLE patients (total of 195 samples) were obtained longitudinally with a mean follow-up period of 11.1 +/- 8.9 years and were compared to sera from 100 healthy volunteers. Circulating levels of IL-18, IL-18BP and free IL-18 in the SLE patients were significantly higher than the levels of healthy controls (5 fold, 6 fold and 3 fold for IL-18, IL-18BP and free IL-18, respectively) and correlated with disease activity as scored by SLEDAI-2K. Furthermore, these levels during active disease (SLEDAI-2K > or = 6) were higher compared to the levels measured in the sera of the same patients during remission or during mild disease (SLEDAI-2K 0-5). The high levels of IL-18 and IL-18BP in sera of active SLE patients suggest their possible role in the pathogenesis and course of the disease. However, despite the elevated levels of IL-18BP during active disease, free IL-18 remained more than 2 fold higher than the levels in healthy controls suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active SLE., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Interferon-gamma (IFN-gamma) plays a pathogenic role in systemic lupus erythematosus (SLE). Uncontrolled IFN-gamma signaling may result from a deficiency in the negative regulator, namely, suppressor of cytokine signaling-1 (SOCS-1). We investigated the activation status of IFN-gamma signaling pathway in SLE-afflicted (New-Zealand-BlackxNew-Zealand-White)F1 mice and determined its responsiveness when treating with a tolerogenic peptide, hCDR1, which ameliorates SLE. SOCS-1 was suppressed and pSTAT1 was enhanced in spleen-derived cells from SLE-affected mice as compared with healthy controls. Treatment with hCDR1 reversed the expression of these two molecules in association with clinical amelioration. In vitro stimulation with IFN-gamma resulted in elevated levels of SOCS-1 in cells from both vehicle and hCDR1-treated mice but this effect reached significance only in cells of the latter group, which also exhibited reduced levels of pSTAT1. Thus, SOCS-1 is diminished in SLE-affected mice, and treatment with hCDR1 results in its up-regulation thereby restoring control of IFN-gamma signaling pathway.

Systemic lupus erythematosus (SLE) is an autoimmune disease, resulting in inflammation and tissue damage. The precise etiology for SLE is so far unknown. It has been shown that the innate immunity plays a role in SLE pathogenesis. The innate immune system confers broad protection against pathogens by the secretion of broad-spectrum antibacterial and immunomodulatory substances named defensins. Recently, alpha-defensin, the products of neutrophils have been found to be upregulated at the mRNA and protein levels in SLE patients. In addition, increased antidefensin antibodies were found in sera of patients with SLE, but these levels decreased after therapy with corticosteroids. These recent findings suggest a role for defensins in the pathogenesis of SLE. Thus, activation and degranulation of neutrophils leads to alpha-defensin secretion in SLE patients. Given their immunomodulatory role, alpha-defensin secretion might activate the adaptive immune system leading to the stimulation of the immune system, as is manifested in SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by dysregulation of cytokines, apoptosis, and B- and T-cell functions. The tolerogenic peptide, hCDR1 (Edratide), ameliorated the clinical manifestations of murine lupus via down-regulation of pro-inflammatory cytokines and apoptosis, up-regulation of the immunosuppressive cytokine TGF-beta, and the induction of regulatory T-cells. In the present study, gene expression was determined in peripheral blood mononuclear cells of 9 lupus patients that were treated for 26 weeks with either hCDR1 (five patients), or placebo (four patients). Disease activity was assessed by SLEDAI-2K and the BILAG scores. Treatment with hCDR1 significantly down-regulated the mRNA expression of the pathogenic cytokines IL-1beta, TNF-alpha, IFN-gamma, and IL-10, of BLyS (B-lymphocyte stimulator) and of the pro-apoptotic molecules caspase-3 and caspase-8. In contrast, the treatment up-regulated in vivo gene expression of both TGF-beta and FoxP3. Furthermore, hCDR1 treatment resulted in a significant decrease in SLEDAI-2K (from 8.0+/-2.45 to 4.4+/-1.67; P=0.02) and BILAG (from 8.2+/-2.7 to 3.6+/-2.9; P=0.03) scores. Thus, the tolerogenic peptide hCDR1, immunomodulates, in vivo, the expression of genes that play a role in SLE, consequently restoring the global immune dysregulation of lupus patients. Hence, hCDR1 has a potential role as a novel disease-specific treatment for lupus patients.

Innate immunity plays a role in systemic lupus erythematosus (SLE). Our objective was to determine the levels of defensins, which are antimicrobial and immunomodulatory polypeptides, in SLE. Sera from SLE patients and healthy controls were tested for pro-inflammatory human beta-defensin 2 (hBD-2) and for alpha-defensin human neutrophil peptide 1 (HNP-1). hBD-2 could not be detected by enzyme-linked immunosorbent assay (ELISA) and its mRNA levels were low in SLE patients and similar to those found in controls. In contrast, the mean alpha-defensin level in the sera of all SLE patients (11.07 +/- 13.92 ng/microl) was significantly higher than that of controls (0.12 +/- 0.07 ng/microl). Moreover, 60% of patients demonstrated very high serum levels (18.5 +/- 13.36 ng/microl) and 50% showed elevated gene expression in polymorphonuclear cells. High alpha-defensin levels correlated with disease activity, but not with neutrophil count. Thus, activation and degranulation of neutrophils led to alpha-defensin secretion in SLE patients. Given the immunomodulatory role of alpha-defensins, it is possible that their secretion may activate the adaptive immune system leading to a systemic response.

A tolerogenic peptide, hCDR1, ameliorated murine lupus via the upregulation of functional regulatory cells and by immunomodulating cytokine production. In the present study we analyzed the ability of hCDR1 to similarly affect gene expression and regulatory T cells when incubated with peripheral blood mononuclear cells (PBMC) of lupus patients. To this end, peripheral blood mononuclear cells (PBMC) of 11 lupus patients and five gender- and age-matched healthy controls were cultured with hCDR1 or a control peptide. Gene expression and regulatory T-cells were assessed. hCDR1 significantly downregulated interleukin (IL)-1beta, interferon (IFN)-gamma, and IL-10 gene expression. Furthermore, hCDR1 upregulated the expression of the anti-apoptotic Bcl-xL molecule and downregulated the pro-apoptotic caspase-3, resulting in reduced rates of apoptosis. hCDR1 increased the expression of transforming growth factor (TGF)-beta, FoxP3 and the negative regulators Foxj1 and Foxo3a. No significant effects were observed using a control peptide or when PBMC of healthy donors were incubated with hCDR1. The elevated gene expression of FoxP3 was due to hCDR1-induced upregulation of TGF-beta, resulting in an increase of CD4+CD25+FoxP3+ functional, regulatory cells. The ability of the regulatory cells to diminish IFN-gamma expression and to upregulate TGF-beta was abrogated after the addition of a neutralizing anti-CD25 antibody, confirming their role in the beneficial effects of hCDR1.

Introduction: In the present study, we examined the levels of the pro-inflammatory cytokine IL-18 and its natural inhibitor, the IL-18 binding protein (IL-18BP), in sera of Wegener's granulomatosis (WG) patients at various stages of the disease., Patients and Methods: Sera from eight consecutive biopsy-proven systemic WG patients (four men and four women; age at diagnosis 58.4 +/- 13.8 years) were obtained longitudinally with a follow-up period of 55.2 +/- 30 months. Sera obtained from 50 healthy subjects were used as controls., Results and Discussion: Serum levels of IL-18, IL-18BP, and free IL-18 obtained during an active phase of the disease (Birmingham Vasculitis Activity Score, BVAS > 10) were more than twofold higher than levels in the same patients during inactive disease stages (BVAS < 5; P < 0.002; P < 0.006, and P < 0.03 for IL-18, IL-18BP, and free IL-18, respectively). During inactive stages, the levels of these markers were comparable to those of healthy controls. The elevated levels of IL-18 and IL-18BP in sera during active stages of disease suggest a possible role in the pathogenesis and course of the WG., Conclusion: Despite the elevated IL-18BP levels during active disease, free IL-18 remained higher than in the inactive disease stages, suggesting a potential benefit of administration of exogenous IL-18BP as a novel therapeutic approach for active WG.

Pulmonary arteriovenous malformation (PAVM) is a rare condition often associated with hereditary hemorrhagic telangiectasia. The association between PAVMs and brain abscesses has been previously reported, but abscesses at other locations are extremely rare. We present a 51-year-old woman with PAVM (without signs of hereditary hemorrhagic telangiectasia) and necrotizing fasciitis of her thigh and discuss the possible relationship between the 2 disorders.

We report here a patient with acute Q fever-related acalculous cholecystitis, who presented with prolonged fever, valvular abnormalities, and positive serology for Q fever phase 1 antigens, features suggesting chronic Q fever endocarditis. The pathogenesis of this rare presentation of Q fever is discussed.

Combination antiretroviral therapy (HAART) restores protective immune response and reduces morbidity and mortality in human immunodeficiency virus (HIV) infected patients, however this life-long therapy withholds many complications. In a subset of patients' immune reconstitution, after initiation of therapy, it is associated with a pathological inflammatory response leading to a paradoxical short term morbidity and even mortality, defined as the immune reconstitution inflammatory syndrome (IRIS). IRIS presents as clinical deterioration caused by restoration of the capacity to mount an inflammatory response against infectious and non-infections antigens. The inflammatory response can result in a spectrum of presentations ranging from mimicking acute infection to worsening of a treated opportunistic infection, malignant diseases or even an autoimmune disease. The mechanisms of IRIS remains to be evaluated, however in many cases redistribution of memory T cells can be demonstrated. Currently there are no laboratory tests or accepted criteria for the diagnosis of IRIS, which remains a diagnosis of exclusion. Recently, numerous groups have published studies regarding incidence, timing of onset, risk factors and therapy options for IRIS. This large resource of evidence may enable physicians to diagnose and treat patients more accurately. A consistent finding from different studies is that IRIS develops in a substantial percentage of HIV-infected patients receiving HAART. As the use of HAART increases worldwide, the care for patients receiving HAART will need to incorporate monitoring for and treating complications of IRIS.

We describe 3 cases of Mediterranean spotted fever (MSF) who presented with severe sepsis, in 2 of which the clinical diagnosis was unclear at presentation. In each case the diagnosis of MSF was made using a nested-PCR assay for Rickettsia conorii 17-kD protein gene. The nested-PCR based diagnosis preceded the serological results of MSF that were all negative at admission. The early diagnosis of MSF by specific PCR will facilitate an early institution of appropriate therapy, saving unnecessary tests and medications.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies and systemic clinical manifestations. In this study we investigated the beneficial effects on murine lupus accomplished by a peptide based on the sequence of the complementarity-determining region 1 of an anti-DNA autoantibody (hCDR1) when given alone or in combination with cyclophosphamide (CYC), and determined the mechanisms underlying those effects. SLE-afflicted (NZB x NZW) F(1) mice were treated for 12 weeks with injections of hCDR1, CYC or a combination of both drugs. We found that hCDR1 and CYC ameliorated serological and renal manifestations of the diseased mice, down-regulated interferon-gamma and interleukin-10, and up-regulated transforming growth factor-beta. These effects were associated with an increment of naive CD4(+) cells at the expense of the number of CD4(+) cells with the memory/activated phenotype. Further, the number of CD8(+) cells in the diseased mice was increased by the two drugs, resulting in a significant decrease in the CD4 : CD8 ratio. However, whereas the frequency and activity of CD4(+) CD25(+) CD45RB(low) regulatory T cells and the expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in CD4(+) cells were up-regulated by hCDR1 treatment, they were minimally affected following treatment with CYC. CTLA-4 played an important role in the activity of the hCDR1-induced CD4(+) CD25(+) cells as manifested by down-regulation of CD28 expression, decrease of activation-induced apoptosis, and modulation of the cytokine profile in CD4(+) CD25(-) cells derived from SLE-afflicted mice. Thus, although the two drugs have similar ameliorative effects, hCDR1 but not CYC elicits regulatory pathways that are of importance for tolerance induction in SLE.

Background: Patients with severe persistent asthma despite GINA 2002 step 4 treatment are at risk for asthma-related morbidity and mortality. This study constitutes the Israeli arm of the international INNOVATE study., Objectives: To determine the efficacy and safety of Xolair as an add-on treatment in patients with severe persistent asthma., Methods: Asthma patients (age 12-75 years) not controlled with high dose inhaled corticosteroids and long-active beta-2 agonists were randomized to receive either Xolair or placebo for 28 weeks in a double-blind study in two Israeli centers., Results: Thirty-three patients, 20 females and 13 males, mean age 54 +/- 11.7 years, were included in the Israeli arm of the INNOVATE study. There were neither major adverse events nor withdrawals from the study. Xolair (omalizumab) significantly reduced the rate of clinically significant asthma exacerbations (55% reduction) and all asthma-related emergency visits (53% reduction)., Conclusions: In patients with severe persistent difficult-to-treat asthma, despite regular treatment with LABA and inhaled corticosteroids (GINA 2002 step 4), Xolair is a safe and effective treatment.

Objective: To study two women who presented with internal jugular vein thrombosis that developed shortly after in vitro fertilization (IVF) therapy complicated by mild ovarian hyperstimulation syndrome (OHSS)., Methods: Evaluation of the past medical history, treatment, laboratory studies, and clinical outcome of both patients., Results: The two patients were found to be carriers for factor V Leiden mutation (FVLM). One was homozygote and the other heterozygote for that mutation. The genetic predisposition probably contributed to the development of an early thrombosis in these patients despite the mildness of their OHSS. In the homozygote patient, the dose of low molecular weight heparin was reduced due to vaginal bleeding. Afterwards, fetal loss due to an extensive placental infarction occurred. Infarction was confined to maternal side while the fetal side vessels were spared., Conclusion: We suggest that women of European descent, especially those with personal or familial history of thromboembolic events, should be screened for FVLM before IVF treatment. In those found to be carriers of FVLM, preventive anticoagulation should be considered.

Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies and systemic clinical manifestations. A peptide, designated hCDR1, based on the complementarity-determining region (CDR) 1 of an autoantibody, ameliorated the serological and clinical manifestations of lupus in both spontaneous and induced murine models of lupus. The objectives of the present study were to determine the mechanism(s) underlying the beneficial effects induced by hCDR1. Adoptive transfer of hCDR1-treated cells to systemic lupus erythematosus-afflicted (NZBxNZW)F1 female mice down-regulated all disease manifestations. hCDR1 treatment up-regulated (by 30-40%) CD4+CD25+ cells in association with CD45RBlow, cytotoxic T lymphocyte antigen 4, and Foxp3 expression. Depletion of the CD25+ cells diminished significantly the therapeutic effects of hCDR1, whereas administration of the enriched CD4+CD25+ cell population was beneficial to the diseased mice. Amelioration of disease manifestations was associated with down-regulation of the pathogenic cytokines (e.g., IFN-gamma and IL-10) and up-regulation of the immunosuppressive cytokine TGF-beta, which substantially contributed to the suppressed autoreactivity. TGF-beta was secreted by CD4+ cells that were affected by hCDR1-induced immunoregulatory cells. The hCDR1-induced CD4+CD25+ cells suppressed autoreactive CD4+ cells, resulting in reduced rates of activation-induced apoptosis. Thus, hCDR1 ameliorates lupus through the induction of CD4+CD25+ cells that suppress activation of the autoreactive cells and trigger the up-regulation of TGF-beta.

Background: Q fever is endemic in Israel, yet a large series describing the clinical spectrum of inpatients with acute Q fever in Israel is lacking., Objectives: To report on the clinical characteristics and outcome of hospitalized patients with acute Q fever in Israel., Methods: We conducted a retrospective study of 100 patients hospitalized in six medical centers, in whom acute Q fever was diagnosed by the presence of immunoglobulin G and M antibodies to phase II Coxiella burnetti antigens., Results: The mean age of the patients was 42.7 +/- 17.3 years with a male to female ratio of 1.6:1. Acute Q fever occurred throughout the year but was more common during the warm season. The most common clinical presentation was acute febrile disease (98%, mean length of fever 15.5 +/- 8.6 days), followed by hepatitis (67%) and pneumonia (32%). The prominent laboratory findings included: accelerated erythrocyte sedimentation rate, normal or low white blood count with many band forms, thrombocytopenia, and abnormal urinalysis. Although the diagnosis of acute Q fever was not known during the hospitalization in the majority of patients, about 80% of our patients received appropriate antibiotic therapy and all patients recovered., Conclusions: Patients with acute Q fever present with a typical clinical picture that enables clinical diagnosis and empiric therapy in most cases. The prognosis of hospitalized patients with acute Q fever is excellent.

A 43-year-old man developed a skin eruption characterized by 'macules with blisters' typical to Stevens-Johnson syndrome, as well as erosions of the lips and buccal mucosa, 2 weeks after he had started treatment with lamotrigine. He had a fever (39.6 degrees C), elevated liver enzymes and atypical lymphocytes in the peripheral blood. This undoubtedly reflects a case of Stevens-Johnson syndrome induced by lamotrigine, but it can also fulfill the criteria of anticonvulsant hypersensitivity syndrome or drug rash with eosinophilia and systemic signs. A case that precisely fits the definition of two syndromes that have different characteristics, different treatments and different prognoses indicates that there is a flaw in the classification.

Objective: To determine the prevalence of autoantibodies directed against an epitope of the glutamate/N-methyl-D-aspartic acid (NMDA) receptor subunit NR2A (which is highly expressed in human brain) in the sera of lupus patients, and to investigate the possible correlation of these antibodies with clinical and serological manifestations of systemic lupus erythematosus (SLE)., Methods: Sera were obtained from 109 consecutive SLE patients. Controls were 65 patients with myasthenia gravis, 19 with autoimmune polyendocrine syndrome type I (APS I), and 65 healthy donors. A 15 amino acid long peptide based on a sequence within the NR2A subunit of the NMDA/glutamate receptor was synthesised. Antibodies to this peptide were determined by enzyme linked immunosorbent assay. Antibodies against double stranded DNA (dsDNA) were measured by Chrithidia luciliae assay. Disease activity was determined using the SLE disease activity index (SLEDAI)., Results: Sera of 34/109 SLE patients (31%) reacted specifically with the NR2A peptide compared with only 4/65 myasthenia gravis patients (6.1%, p<0.001), 1/19 APS I patients (5.3%, p<0.02), and 3/65 healthy controls (4.6%, p<0.001). No correlation was found between the presence of NR2A and dsDNA or anti-cardiolipin specific autoantibodies. In addition, no significant correlation was observed between the presence of NR2A specific antibodies and the SLEDAI score or any lupus related clinical manifestations., Conclusions: A significant number of SLE patients (31%) have NR2A specific antibodies that do not correlate with anti-dsDNA antibodies. Additional studies of lupus patients with neurological disorders should elucidate the role of NR2A specific antibodies in lupus related CNS manifestations.

Fever of unknown origin (FUO) is defined as fever of more than 38.3 degrees C, the cause of which remains elusive after 1 week of intensive investigation. Most cases of FUO are restricted to infections, malignancies, and inflammatory diseases. FUO was previously reported as the presenting symptom of a few solid tumors such as lymphoma, renal cell carcinoma, and hepatocellular carcinoma. Colon carcinoma manifesting as FUO has been rarely reported. We describe three female patients who presented with classical FUO and microcytic anemia. As a control, we retrospectively evaluated 28 matched patients with carcinoma of colon and no fever. The evaluation included review of patient files, clinical and laboratory data, and pathologic specimens. In the three patients (mean age, 58 years) who presented with FUO and had left-sided colon carcinoma and microcytic anemia, pathologic evaluation of the tumor tissues demonstrated a severe organized inflammatory process forming abscesses in the pericolic fat. The 28 control matched patients showed no such histopathologic changes. In patients presenting with FUO, especially those who present with microcytic anemia, even with no bowel disturbances or elevated carcinoembryonic antigen levels, diagnostic workup should include a search for occult colorectal carcinoma. In our three cases, it appears that microabscesses in the pericolic fat are the cause of fever.

Opsoclonus myoclonus with ataxia (OMA) is a rare neurological disorder. The syndrome is characterized by involuntary, conjugate, multidirectional eye movements accompanied by involuntary movements of limb or face, and sometimes ataxia, dysarthria, irritability, dementia, altered level of consciousness and even death. OMA is associated with various etiologies including infectious, toxic, drug-related, vascular and paraneoplastic conditions. Paraneoplastic opsoclonus myoclonus with ataxia (POMA) is more common in patients over 40 years of age and is usually associated with lung (especially small cell), breast and ovarian cancer but has also been reported with many other cancers. The syndrome is thought to be mediated by autoantibodies directed against onconeural antigens that are expressed by the tumor as well as by neurons. Studies from several laboratories were able to demonstrate a role for the cellular response in the pathogenesis of POMA. The results for treatment of this syndrome have been disappointing, although aggressive multimodality immunosuppressive treatments have been used. This is a case study of a patient with POMA who clearly demonstrates the difficulties in the diagnosis and treatment of this syndrome.

We report here a case of an older woman, 90 years old on admission, who presented with general deterioration, fever, abdominal pain, large hepatic mass, and was found to have an extra-nodal large B-cell lymphoma of the liver. The patient was successfully treated with multi-agent chemotherapy and followed up for 2 years with no recurrence of the disease. To the best of our knowledge this is the oldest patient reported with such a primary extra-nodal hepatic lymphoma and a remarkably favourable response to chemotherapy.

Two peptides, based on the sequences of the complementarity-determining regions (CDR) 1 and 3 of a pathogenic murine monoclonal anti-DNA autoatibody that bears the 16/6 idiotype (Id), were shown to either prevent or treat an already established systemic lupus erythematosus (SLE) in two murine models of lupus. Two additional peptides based on the human monoclonal anti-DNA, 16/6 Id were synthesized. This study was undertaken in order to investigate the ability of the CDR-based peptides to immunomodulate SLE-associated responses of peripheral blood lymphocytes (PBL) of SLE patients. PBL of 24 of the 62 SLE patients tested proliferated in vitro following stimulation with the human 16/6 Id. Peptides based on the CDRs of both the human and murine anti-DNA autoantibodies inhibited efficiently and specifically the 16/6 Id-induced proliferation and IL-2 production. The latter inhibitions correlated with an up-regulated production (by 2.5-3.5-fold) of the immunosuppressive cytokine, TGF-beta. Overall, the results of our study demonstrate that the CDR-based peptides are capable of down-regulating in vitro autoreactive T cell responses of PBL of SLE patients. Thus, these peptides are potential candidates for a novel specific treatment of SLE patients.

Behçet's disease is a complex, multisystem disease first described in 1937 by the Turkish dermatologist, Hulusi Behçet. In his original description, Behçet referred to a symptom complex of recurrent oral aphthous ulcers, genital aphthae, and iritis that could lead to blindness. Today we know that Behçet's disease is much more than a "triad syndrome" and it may also involve the gastrointestinal, central nervous system and large vessels. As yet, there are no existing diagnostic laboratory tests or curative treatments for Behçet's disease. Howver, genetic studies have identified those who are at risk and newer molecular biologic investigations further elucidate the pathogenesis of the disease. The treatment of Behçet's disease depends on clinical manifestations and the severity of the disease. Although various therapeutic modalities have been employed for Behçet's disease, treatment is still unsatisfactory. Treatment modalities include local, systemic, or surgical approaches. Only limited success has been achieved with classic agents such as: colchicine, indomethacin, chlorambucil, and systemic corticosteroids. New therapeutic approaches have been introduced for Behçet's disease using cyclosporine, thalidomide, interferon, high-dose corticosteroids or cyclophosphamide therapy. In this article we summarized the clinical and diagnostic approach for Behçet's disease and the current therapy indicated for different clinical presentations of the disease.

In short-term studies, both in animals and in humans, fish oil seems to exert anti-inflammatory effects. However, these effects may vanish during long-term treatment. There is a possibility that in autoimmune diseases, supplementation of dietary n-3 fatty acids might lead to a decrease in the number of autoreactive T cells via apoptosis, as demonstrated in (NZBXNZW) F1 lupus mice [40]. Thus, the "fade away" effect might be due to regrowth of pathogenic autoreactive cells. In animal models of autoimmune diseases, diets high in n-3 fatty acids from fish oil increase survival and reduce disease severity in spontaneous autoantibody-mediated disease, while n-6 linoleic acid-rich diets appear to increase disease severity. The situation in human disease is probably more complex. Some of the discrepancy between studies can be attributed to methodologic problems. The effect of fish oil is dose, time and disease-dependent. Since the anti-inflammatory effects depend on the balance between n-3 and n-6 fatty acids, the relative proportion of EPA and DHA and possibly co-treatment with dietary vitamin E, the dose/effect ratio may vary between individuals. Furthermore, some animal studies demonstrating efficacy used very high doses that may be incompatible with human consumption. It seems that fish oil is only mildly effective in acute inflammation. In those chronic inflammatory disorders where it was found to be effective, several weeks are necessary to exhibit results. Yet, this mild anti-inflammatory effect, possibly through downregulation of pro-inflammatory cytokine production, leads to striking therapeutic improvement in critically ill patients. Fish oil supplementation seems advantageous especially in acute and chronic disorders where inappropriate activation of the immune system occurs. Fish oil has only a mild effect on active inflammation of diseases such as rheumatoid arthritis, SLE and Crohn's disease, but it could prevent relapse (in some of the studies). In diseases where the inflammation is mild, such as IgA nephropathy, fish oil may slow or even prevent disease progression. The above could explain the observation in some populations of a decreased incidence of inflammatory and autoimmune diseases [3], since the constant consumption of n-3 fatty acids could suppress any autoreactive (or hyper-reactive) T cells. However, if there is already an existing disease, increased consumption might not be beneficial over a long period. Therefore, the use of n-3 fatty acids can be recommended to the general healthy population, not only to prevent atherosclerosis but possibly also to reduce the risk of autoimmunity.