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Background: Delays in admitting patients to the ICU can defer the timely initiation of life-sustaining therapies and invasive monitoring, jeopardizing the success of the treatment. The current study aimed to assess the factors related to delays in admission times of critically ill patients transferred to the ICU using a proactive approach to admission process analysis. Methods: A specifically designed software was created to follow up, compare and measure the defined laps of the time to admission, implemented at the ICU for six months. Measurements included five time-lapse, referral department, and work shift at admission. Data of 1004 patients admitted to the ICU between July 2017 to January 2020 were analyzed in a retrospective observational study. Results: A significant shortening of time to admission before and after the intervention done by the institutional Quality Control Commission. The mean time to admission was shortened by 14 minutes, from a mean of 92.4 minutes to 78.6 minutes. Insights about the organizational factors delaying transfer provide meaningful information for future efficacy interventions. Conclusions: The current study shows the positive effect of a protracted follow-up of the complex process divided into several stations, where possible preventable situations can be found and modified. Trial registration: The study was approved by the Ashkelon Academic College Ethics Committee with a waiver of informed consent. (Approval # 25/1-2020).

Background Despite the COVID-19 pandemic, cardiovascular disease is still the main cause of death in developed countries. Of these deaths, acute coronary syndromes (ACS) account for a substantial percentage of deaths. Improvement in ACS outcomes, are achieved by reducing the time from symptom onset until reperfusion or total ischemic time (TIT). Nevertheless, due to the overwhelming reality at the beginning of the pandemic, acute coronary syndrome (ACS) care may have been compromised. Objectives We evaluated delays in TIT based on the date and timing of admissions in patients with STEMI, by a timeline follow-up form, before and during the current COVID-19 pandemic. Methods Between July 2018 and June 2020, two hundred and twelve patients diagnosed with ST-segment elevation myocardial infarction (STEMI) were admitted to our medical center. Upon presentation, cases were assigned a timeline report sheet and each time interval, from onset of symptoms to the catheterization lab, was documented. The information was later evaluated to study potential excessive delays throughout ACS management. Results Our data evidenced that during the COVID-19 pandemic ACS admissions were reduced by 34.54%, in addition to several in-hospital delays in patient's ACS management including delays in door-to-ECG time (9.43 ± 18.21 vs. 18.41 ± 28.34, p = 0.029), ECG-to-balloon (58.25 ± 22.59 vs. 74.39 ± 50.30, p = 0.004) and door-to-balloon time (57.41 ± 27.52 vs. 69.31 ± 54.14, p = 0.04). Conclusions During the pandemic a reduction in ACS admissions occurred in our hospital that accompanied with longer in-hospital TIT due to additional tests, triage, protocols to protect and prevent infection within hospital staff, and maintenance of adequate standards of care. However, door-to-balloon time was maintained under 90 min.

Background Pemphigus and bullous pemphigoid are two autoimmune diseases that have similar pathogenesis. Both have a genetic predisposition, which promotes the production of auto antibodies targeted against different components of the epidermal desmosome and hemidesmosome. Antiphospholipid antibodies (aPL) are heterogeneous group of antibodies found in patients with autoimmune diseases and inflammatory conditions and are associated with thrombotic events. Objective We sought to determine the expression profile of eight non classical aPLs in ABD patients. Methods A cohort of 266 serum samples of patients with pemphigus, bullous pemphigoid and controls was screened for the presence of eight aPL antibodies, using the Bio-Rad BioPlex™ 2200 system. Results Phosphatidylserine-beta-2-glycoprotein-I (aPS-β2GPI) and anti prothrombin complex (aPT-PT) serum profiles were significantly more prevalent among ABD patients; 20.7% patients with ABD compared to 5.9% of control patients were positive for aPS-β2GPI IgM. In addition, aPT-PT IgM was more prevalent among ABD patients (31% vs. 14.8%). Conclusion aPL auto antibodies are more prevalent in ABD. Any clinical association should be further determined.

Recent research in systemic lupus erythematosus (SLE) yielded new antigens and antibodies in SLE patients. We describe the various autoantibodies that can be detected in patients with SLE. A literature review, using the terms “autoantibody” and “systemic lupus erythematosus”, was conducted to search for articles on autoantibodies in SLE, their target antigens, association with disease activity and other clinical manifestations. One hundred and eighty autoantibodies were so far described in SLE patients. These include autoantibodies that target nuclear antigens, cytoplasmic antigens, cell membrane antigens, phospholipid-associated antigens, blood cells, endothelial cells, and nervous system antigens, plasma proteins, matrix proteins, and miscellaneous antigens. The target of an autoantibody, the autoantigen properties, autoantibody frequencies in SLE, as well as clinical associations, and correlation with disease activity are described for all 180 autoantibodies. SLE is so far the autoimmune disease with the largest number of detectable autoantibodies. Their production could be antigen-driven, the result of a polyclonal B cell activation, impaired apoptotic pathways, or the outcome of an idiotypic network dysregulation.

Antiphospholipid antibodies (aPL) may accompany a response to many infectious agents. The emergence of aPL may be transient or associated with the clinical picture of antiphospholipid syndrome (APS) with thrombosis, recurrent foetal loss, central nervous system, and other organ involvement. The most studied pathogenic aPL antibodies are directed to the β2-glycoprotein-I (β2GPI) molecule. Studies on experimental APS models proved that molecular mimicry between β2GPI-related synthetic peptides and structures within bacteria, viruses, and tetanus toxoid can induce experimental APS. Any explanation of how microbial infections might trigger APS must take into account the observation that all individuals appear to harbour potentially autoreactive lymphocytes, as well as natural aPL, but they remain innocuous unless somehow activated by a second hit. In this chapter, we discuss the association of aPL with infections, vaccines, and drugs, with molecular mimicry as a proposed cause for the development of APS.

The purpose of this study was to determine patients' survival after undergoing an early or delayed operation. We retrospectively assessed 1849 files of patients operated for proximal femoral fracture, divided into two diagnostic groups: intracapsular (n = 640) and extracapsular (n = 1209). 1163 (63%) were treated within 48 h from hospital admission and 686 (37%) were treated >48 h afterwards. Delayed operation in patients with intracapsular fractures was associated with a 1.8-fold excess risk for 1-year mortality (HR = 1.83, P = 0.008), while no effect was observed for patients with extracapsular fractures. Males had a higher HR for mortality in both diagnostic groups. Early surgical intervention is beneficial for intra-capsular femoral fractures; male gender and a high ASA score are associated with an increased mortality hazard risk.

The association between antiphospholipid antibodies (aPL) and multiple sclerosis (MS) has been suggested previously, but prior studies provided contradicting findings.To characterize the expression profile of eight classic and non-classic aPL in patients diagnosed with MS.Using the BioPlex 2200 immunoassay, we measured the levels of serum immunoglobulin (Ig)M and IgG isotypes of three classic aPL and five non-classic aPL in 98 subjects with MS and 237 healthy controls.Three non-classic aPL were significantly more prevalent among MS patients in comparison to the control group. These antibodies included IgM and IgG against phosphatidylserine-β2GPI (PS-B2), IgG prothrombin complex (PT-PT) and IgM prothrombin (PT). The positive results according to Bonferroni correction are PS-B2 IgG and PT-PT IgG. The remaining aPL profiles did not differ significantly between the two groups.An association between certain non-classic aPL and MS has been established. The specific role of these autoantibodies in the pathogenesis of the condition remains uncertain.

Pemphigus and bullous pemphigoid are two autoimmune diseases that have a similar pathogenesis. Both have a genetic predisposition which promotes the production of auto-antibodies targeted against different components of the epidermal desmosome and hemidesmosome. Environmental factors play an important role in the pathogenesis of this autoimmune disease. Among these, the role of infectious agents was debated as a causative factor. We sought to determine a possible connection between various infectious agents and autoimmune bullous disease (ABD). A cohort of 148 serum samples of patients with pemphigus, bullous pemphigoid and controls was screened for evidence of a prior infection with HBV, HCV, EBV, CMV, Helicobacter pylori, Toxoplasma gondii and Treponema pallidum, utilizing the Bio-Rad BioPlex 2200 system as well as ELISA assays to complete the panel. HBV, HCV, H. pylori, T. gondii and CMV were demonstrated to have significantly higher prevalence of antibodies in patients with pemphigus and bullous pemphigoid in comparison to controls. Among them, we found a novel association between H. pylori and ABD. Our study suggests a contributing role for HBV, HCV, H. pylori, T. gondii and CMV in inducing ABD in the genetically susceptible host.

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that has a late mortality phase owing mainly to cardiovascular manifestations. Atherosclerosis itself is characterized by inflammatory components, fulfilling the criteria of Witebsky and Rose for an autoimmune disease. SLE patients have increased risk for cardiovascular events, and these are the result of both atherosclerosis and thromboembolic events. Risk factors for atherosclerosis in SLE include "traditional" risk factors (mainly the Framingham risk factors), as well as disease-related factors including disease duration, steroid therapy, and renal disease, and inflammatory mechanisms that specifically contribute to enhanced atherosclerosis in SLE. These include specific antibodies to beta2GPI; anticardiolipin antibodies; anti-oxidized low-density lipoprotein; and antibodies to heat shock proteins, complement activation, impaired ability to activate TGF-beta1, and elevated levels of CRP. These findings stress the importance of surveillance and preventive strategies to control atherosclerosis in SLE.

Infections can act as environmental triggers that induce or promote systemic lupus erythematosus (SLE) in genetically predisposed individuals. New technologies, developed recently, enable simultaneous assessment of multiple antibodies. Antibodies to specific infectious agents may shed light into the mechanisms of induction of SLE. The aim of this study was to investigate the prevalence of seropositivity and the titers of antibodies to bacterial, viral, and parasitic agents in SLE patients compared with non-autoimmune controls. Sera from 260 individuals (120 SLE patients and 140 controls) were tested by the BioPlex 2200 Multiplexed Immunoassay method (BioRad) for the prevalence and titers of antibodies to eight infectious agents (Epstein—Barr virus: early antigen IgG, nuclear antigen IgG, viral capsid antigen IgG and IgM, heterophile IgM; cytomegalovirus IgG and IgM; Toxoplasma gondii IgG and IgM; rubella IgG and IgM; Treponema pallidum TPr15G, TPr17G, TPr47G; herpes simplex virus type 1 and 2 IgG; hepatitis C virus and hepatitis B core antibodies. Cytomegalovirus IgM and Epstein—Barr virus early antigen IgG (but not other Epstein—Barr virus antigens) were significantly more prevalent in SLE patients than in controls. Conversely, positive titers of hepatitis B core and rubella IgG antibodies were less prevalent in the SLE patients than in controls. Other differences in titer positivity prevalence were not detected between patients and controls. The titers of the cytomegalovirus IgM, Toxoplasma IgG, Epstein—Barr virus early antigen, and viral capsid antigen IgG antibodies were significantly higher in SLE compared with controls. Our data suggest the importance of previous exposure to infectious agents in the induction and the prevention of SLE. Lupus (2009) 18, 1129—1135.

Antiphospholipid syndrome is characterized by thrombosis and pregnancy loss. Infections are generally associated with autoimmune diseases, but in the setting of antiphospholipid syndrome this link has been suggested as having a pathogenic role. In this study, 98 patients with antiphospholipid syndrome were screened for antibodies directed to several infectious agents. The main finding in this study is the significantly higher prevalence of IgM antibodies to toxoplasma and rubella. This novel finding suggests that these infections might be associated with antiphospholipid syndrome. As autoimmune diseases and, in particular, antiphospholipid syndrome are associated with infections, mainly the catastrophic type of the syndrome, this finding implies that a current infection with these agents, i.e. toxoplasma and rubella, might either be related to the pathogenesis of antiphospholipid syndrome or alternatively to its manifestations. Lupus (2009) 18, 1149—1153.

Infections may act as environmental triggers for the induction of systemic lupus erythematosus (SLE). In this study, we determine the relationship between disease manifestations of SLE patients and the titers of five Epstein-Barr virus (EBV) Abs. We evaluated the titers of early antigen IgG (EAG), nuclear antigen IgG, viral capsid antigen (VCA) IgG and IgM, and heterophile IgM, using the BioPlex 2200 multiplexed immunoassay method in 260 sera (120 SLE patients and 140 controls). EAG titers were significantly elevated (P < 0.024) in patients with cutaneous symptoms and increased anti-Ro antibody titers (P < 0.005). VCA IgG titers were significantly elevated (P < 0.003) in patients with joint involvement. None of the titers differed by central nervous system or renal involvement or antiphospholipid syndrome. We conclude that exposure to EBV infection may predict a disease phenotype of mild SLE disease with cutaneous and joint manifestations and elevated titers of anti-Ro Abs.

The antiphospholipid syndrome (APS) is the most common acquired thrombophilia. It is characterized by venous and arterial thrombosis, recurrent pregnancy loss, and various other clinical manifestations in the presence of antiphospholipid antibodies (aPL). Like other autoimmune diseases, the etiology of APS derives from a combination of genetic and environmental factors. The most significant environmental factors in APS are infectious agents, followed by trauma and drugs. Infections can induce aPL and, in the catastrophic variant of APS, about one-third of cases are associated with a clear recent infection. On their formation, aPL have been clearly shown to be pathogenic, because they influence all arms of the coagulation system and because passive transfer and active immunization protocols have demonstrated. Therefore, in a genetically susceptible individual, exposure to one or more infectious agent can cause a molecular mimicry and result in the production of pathogenic aPL that can induce thrombosis and pregnancy loss. Identification of the epitopes within the beta-2-glycoprotein-I molecule that serves as the target for autoantibodies makes them the target for immunomodulation of the syndrome.

Patients having systemic rheumatic diseases constitute a small percentage of admissions to the medical intensive care units (ICUs). Dermatomyositis (DM) is one of the rheumatic diseases that have secondary complications that may lead to a critical illness requiring hospitalization in the ICU. Herein, we present the features, clinical course, and outcome of critically ill patients having DM who were admitted to the ICU. The medical records of six DM patients admitted to the ICU in a large tertiary hospital in a 12-year period were reviewed. The mean age of patients at time of admission to the ICU was 38 (range 16-37). Mean disease duration from diagnosis to admission to the ICU was 1.6 years (range 1 month-8 years), while the main reason for admission to the ICU was acute respiratory failure. Two of six patients died during the hospitalization. The main causes of death were respiratory complications and sepsis. The outcome of DM patients admitted to the ICU was generally not different from the outcome of other patients hospitalized in the ICU. The main reason for hospitalization was acute respiratory failure. As there are many reasons for respiratory failure in DM, an early diagnosis and aggressive appropriate treatment may help to further reduce the mortality in these patients.

Within the last year, a growing body of evidence for a distinct role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of ANCA-associated vasculitides (AAV) has developed. An experimental model of myeloperoxidase (MPO)-ANCA-associated vasculitis provided direct and convincing in vivo evidence that MPO-ANCA are primary pathogenic factors in small-vessel vasculitis by augmenting of leukocyte-vessel wall interaction and leukocyte-mediated vascular injury. Determination of bacterial lipopolysaccharide (LPS) effects on disease severity in a mouse model of anti-MPO-induced glomerulonephritis showed that ANCA and other proinflammatory stimuli of infectious origin acted in synergism in the development of destructive inflammation.

Received October 16, 2004; revision received June 4, 2005; accepted June 7, 2005. Atherosclerosis is a multifactorial process that commences in childhood but manifests clinically later in life. Atherosclerosis is increasingly considered an immune system–mediated process of the vascular system. The presence of macrophages and activated lymphocytes within atherosclerotic plaques supports the concept of atherosclerosis as an immune system–mediated inflammatory disorder.1,2 Inflammation can aggravate atherosclerosis via different mechanisms secondary to autoimmunity, infectious diseases, and other proatherogenic changes that occur during the inflammatory state. Autoimmune rheumatic diseases (AIRDs) are associated with higher rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be attributed to traditional risk factors for atherosclerosis and use of specific drugs, such as corticosteroids, but also might be the result of other autoimmune and inflammatory mechanisms that are aggravated in AIRDs. Several AIRDs exhibit increased overt cardiovascular disease (CVD) prevalence as well as findings of advanced subclinical atherosclerosis, which may precede the appearance of a clinical disease and thus be a target of early identification and preventive therapy. Cells of the immune system can be found within atherosclerotic plaques, which suggests that they have a role in the atherogenic process. Their migration and activation within the plaques can be secondary to various stimuli, including infectious agents.3 These cells probably aggravate atherosclerosis, because CD4+ and CD8+ T-cell depletion reduced fatty streak formation in C57BL/6 mice. In addition, after crossing of apolipoprotein E (ApoE)-knockout mice with immunodeficient scid/scid mice, the offspring had a 73% reduction in aortic fatty streak lesions compared with the immunocompetent apoE mice. Moreover, when CD4+ T cells were transferred from the immunocompetent to the immunodeficient mice, they increased lesion area in the latter by 164%.4 It is therefore not surprising that as in autoimmune diseases, the cellular components …

Recently, considerable data have accumulated concerning the role of the immune system in atherosclerosis (AS). Several immunomodulating strategies are being evaluated that might influence the process of AS including immunosuppressive therapy, immunization (vaccination) and induction of immune tolerance. This article reviews experimental studies using the induction of immune tolerance for the suppression of respective immune responses in animal models of AS. Induction of neonatal tolerance or mucosal tolerance using autoantigens involved in atherogenesis, such as heat shock protein-65 or beta2-glycoprotein I, could modify the course of AS in animal models. These observations are of considerable interest and need further evaluation in humans.

Intravenous immunoglobulin (IVIg) is administered for various indications and generally considered a safe therapy. Most of the adverse effects (AEs) associated with IVIg administration are mild and transient. The immediate AEs include headache, flushing, malaise, chest tightness, fever, chills, myalgia, fatigue, dyspnea, back pain, nausea, vomiting, diarrhea, blood pressure changes, tachycardia, and anaphylactic reactions, especially in IgA-deficient patients. Late AEs are rare and include acute renal failure, thromboembolic events, aseptic meningitis, neutropenia, and autoimmune hemolytic anemia, skin reactions, and rare events of arthritis. Pseudohyponatremia following IVIg is important to be recognized. Renal failure, usually oliguric and transient, occurs mostly on using sucrose-containing products owing to osmotic injury. Among high-risk patients who have a previous renal disease, dehydration, diabetes mellitus, advanced age, hypertension, hyperviscosity, or are treated by other nephrotoxic medications, administration of a non-sucrose-containing IVIg product after accomplishing hydration, in a low concentration and a slow infusion rate while supervising urine output and kidney function, is recommended. Thromboembolic complications occur because of hyperviscosity especially in patients having risk factors including advanced age, previous thromboembolic diseases, being bedridden, diabetes mellitus, hypertension, dyslipidemia, or those receiving high-dose IVIg in a rapid infusion rate. Immediate AEs can be treated by the slowing or temporary discontinuation of the infusion and symptomatic therapy with analgesics, nonsteroidal anti-inflammatory drugs, antihistamines, and glucocorticoids in more severe reactions. Slow infusion rate of low concentration of IVIg products and hydration, especially in high-risk patients, may prevent renal failure, thromboembolic events, and aseptic meningitis.

No information is available regarding the association between low plasma glucose levels and cause-specific and all-cause mortality in patients with coronary artery disease (CAD). We aimed to investigate the relationship between hypoglycaemia and all-cause, cardiovascular and cancer mortality in a large population of patients with CAD.Patients were recruited from the BIP (Bezafibrate Infarction Prevention) registry, a secondary prevention prospective multicentre randomized, placebo-controlled, double-blind trial aimed to assess the efficacy of bezafibrate in reduction of coronary events.The study included 14,670 CAD patients aged 45-74, divided into six groups: (1) hypoglycaemic (up to 69 mg/dl); (2) low normal (70-79 mg/dl); (3) euglycaemic (80-109 mg/dl); (4) impaired fasting glucose (IFG) (110-125 mg/dl); (5) borderline diabetics (126-139 mg/dl); (6) diabetics (or 140 mg/dl).Patients comprised 131 with hypoglycaemia (0.9%), 731 with low normal glucose (5%), 9308 euglycaemic (63.4%), 1577 with IFG (10.7%), 617 borderline diabetics (4.2%) and 2306 diabetics (15.7%). Over a mean 8-year follow-up, crude all-cause mortality was higher in both diabetic (31.8%) and hypoglycaemic groups (25.2%) as compared with euglycaemics (14.9%; P0.0001); CAD mortality was higher in diabetic and borderline groups (17.8 and 13.3%, respectively, versus 7.9% in euglycaemics; P0.0001). The highest prevalence of cancer mortality was documented in the hypoglycaemic group (6.1 versus 2.9% in euglycaemics; P0.02). Actuarial survival curves showed the lowest mortality in euglycaemic and low normal groups; the highest was seen in diabetic and hypoglycaemic patients. Intermediate values were found in borderline and IFG patients. After adjustment for variables, a significantly higher mortality rate was seen in hypoglycaemics when compared with euglycaemics (P0.0001). Hypoglycaemia was identified as a predictor of increased all-cause and cancer mortality with a hazard ratio (HR) of 1.84 [95% confidence interval (CI) 1.29-2.61] and 2.26 (95% CI 1.12-4.57), respectively, but not of increased CAD mortality, with HR 1.30 (95% CI 0.73-2.29).Over a mean 8-year follow-up, hypoglycaemia emerges as a marker for substantially increased all-cause and cancer mortality among patients with CAD presenting with low fasting glucose levels.

Objective: To evaluate traditional and non-traditional risk factors for subclinical atherosclerosis in systemic lupus erythematosus (SLE). Methods: A prospective cohort of 78 patients with SLE without overt atherosclerotic disease was studied. SLE clinical and laboratory parameters, disease activity and damage, treatment and traditional risk factors for atherosclerosis were evaluated. At baseline (T1) and after five years' follow up (T2), the serum levels of anti-oxidised palmitoyl arachidonoyl phosphocholine (oxPAPC), anti-heat shock protein 65, and anti-s2-glycoprotein I antibodies and C reactive protein were tested. At T2, intima-media thickness (IMT) was measured using duplex carotid sonography. Thickened intima, plaque, mean IMT (m-IMT), and maximum IMT (M-IMT) were assessed. Results: A thickened intima was seen in 22/78 (28%) patients and plaque in 13/78 (17%). M-IMT and m-IMT were (mean (SD)) 0.77 (0.34) mm and 0.55 (0.15) mm, respectively. Patients with carotid abnormalities were significantly older, had higher blood pressure and total serum cholesterol levels, and had taken a higher prednisone cumulative dosage than those without any lesions. The carotid abnormalities were associated with renal disease and ECLAM >2 at T1, and with azathioprine treatment. In multivariate analysis, age and cumulative prednisone dose were associated with carotid abnormalities; age, hypertension, and anti-oxPAPC at T2 were correlated with higher M-IMT and m-IMT. Conclusions: In patients with SLE some non-traditional risk factors for atherosclerosis were identified, the most important of which was the cumulative prednisone dose. The role of some traditional risk factors, such as age and hypertension, was also confirmed. The predictive value of the new immunological and inflammatory markers of atherosclerosis seems to be masked by some disease related features.

BACKGROUND The presence of antibodies to thyroglobulin (Tg) is associated with fetal loss even in the absence of thyroid dysfunction. The aim of this study was to examine whether active immunization with Tg could elicit anti-Tg autoantibodies and reproductive failure without interfering with thyroid function. METHODS BALB/c mice that were immunized with human Tg in complete Freund's adjuvant (CFA) or injected with only CFA were studied for the development of antibodies to Tg, T4, dsDNA, ssDNA and cardiolipin. Total T4, free T4 and thyroid-stimulating hormone (TSH) levels were also assessed before and during pregnancy. Percentages of resorbed fetuses (the equivalent to human missed abortion) were compared and autoantibody presence on the placentae and fetuses was examined. RESULTS Following immunization, high levels of anti-Tg were observed in mice immunized with Tg, compared with mice injected with CFA [0.83 +/- 0.23 versus 0.012 +/- 0.016 respectively; mean +/- SD optical density (OD) at 405 nm; P < 0.001]. The specificity of binding to Tg was confirmed by competition assay. Although total T4 levels were increased in comparison with control mice, this was associated with the presence of antibodies to T4. Indeed, free T4 levels and TSH were similar to control mice. Mice were killed after 14 days of pregnancy. The thyroid function and the histology of the thyroid glands were normal. Increased fetal wastage was found among the Tg-immunized mice compared with the CFA-injected mice (P = 0.04), with lower fetal and placental weights (fetal weights: 194 +/- 4 mg versus 240 +/- 6 mg; placental weights: 105 +/- 2 mg versus 130 +/- 3; P < 0.001 for both). Antibodies to Tg were demonstrated only on the placentae of Tg-immunized mice. CONCLUSION Immunization with Tg results in the production of Tg antibodies and fetal resorption. These effects occur in the absence of thyroid dysfunction.

The 10th International Congress on Antiphospholipid Antibodies (Sicily, Italy, September 29–October 3, 2002) (Fig. 1) provided enlightening aspects on the recent developments in antiphospholipid syndrome (APS) and antiphospholipid antibodies in more than 150 lectures and posters. Researchers from all aspects of medicine attended the meeting, implicating the systemic characteristics of APS. The important breakthroughs are summarized.

Purpose: Autoimmune factors are involved in some of the cases of reproductive failure. The aim of this paper is to discuss the association between autoantibodies and reproductive failure.

Antiphospholipid antibodies are the hallmark of the antiphospholipid syndrome which is characterized by thrombosis. There are currently data supporting an association between these autoantibodies and atherosclerosis as well. Human studies suggest that anti-cardiolipin and anti-beta2-glycoprotein-I antibodies are elevated in patients having coronary artery disease compared with controls. Anti-cardiolipin antibodies are also associated with typical chest pain, significant coronary artery stenosis on angiography and prediction of myocardial infarction. Laboratory studies and murine models support the pro-atherogenic role of these autoantibodies, as they are involved in uptake of oxidized LDL into macrophages, and immunization of mice with them results in enhanced atherosclerosis. There is some evidence that high anti-beta2-glycoprotein-I antibodies can present a risk factor for atherosclerosis, but more epidemiological data are required in order to confirm whether the pro-atherogenic properties of anti-phospholipid antibodies signifies an independent risk factor for atherosclerosis and its complications.

The identification of specific antimicrobial activity of intravenous immunoglobulin (IVIG) preparations against particular microbial pathogens can assist in determining their therapeutic potential for specific infectious diseases. We analysed five different commercial IVIG preparations for the presence of antibodies directed against a large panel of viral, bacterial, fungal and parasitic pathogens. All IVIG batches contained high activity against herpesviruses types 1, 2, 6 and 7, as well as against varicella zoster virus, Epstein-Barr virus (EBV), measles, mumps, rubella and parvovirus B19. Some IVIG batches also had a significant activity against adenovirus and Saint Louis encephalitis virus. The IVIGs held high activity against several bacterial pathogens, including Mycoplasma pneumonia, Chlamydia pneumonia, Helicobacter pylori and tetanus. No activity was found against various parasitic and fungal pathogens. Our findings may provide further support for the use of IVIG for the prevention and treatment of infections caused by specific viral and bacterial pathogens.

In recent years, it has become clear that the immune system has a major role in atherosclerosis development and progression. More specifically, atherosclerosis fulfills all four criteria to define a condition as being an autoimmune in nature. This association also suggests that modification of the immune response in atherosclerosis could affect this process. In this review, we summarize different aspects of immunomodulation in atherosclerosis. These include immunosuppression, active immunization, induction of tolerance, administration of intravenous immunoglobulin, gene therapy, cytokine network manipulation and statins.

Magnesium (Mg) modulates blood lipid levels, atherogenesis, and atherosclerosis in rabbits, when supplemented to diet. We have recently reported that a high concentration (50 g/L) of Mg sulfate fortification of drinking water attenuates atherogenesis in male and female LDL-receptor-deficient mice fed a high-cholesterol diet. The aims of the current study were to examine whether lower concentrations and another Mg salt could also have such an antiatherogenic effect. Thirty male LDL-receptor-deficient mice were divided into three groups (n=10 in each group). The mice received either distilled water or water fortified with 0.83 g or with 8.3 g Mg-chloride per liter. In the first (27 wk) and second (5 wk) stages of the experiment, the mice received normal chow and Western-type diet, respectively. Blood was drawn for determination of plasma Mg, calcium, and lipid levels. The extent of atherosclerotic lesions was determined at the aortic sinus. Magnesium-chloride fortification of drinking water did not result in higher plasma Mg concentrations, whereas a trend toward lower plasma calcium concentrations did not reach statistical significance. Even though plasma lipid levels were similar at the beginning and the end of the study, there were decreased plasma cholesterol and triglyceride levels in the Mg groups after stage I. The atherosclerosis extent at the aortic sinus was significantly decreased in the 8.3-g Mg-chloride/L group (23,437 +/- 10,083 micron2) compared with the control group (65,937 +/- 31,761 microm2). There was also a trend toward lower atherosclerosis extent at the aortic sinus in the 0.83-g Mg-chloride/L group. An additional Mg salt (Mg-chloride) fortification of drinking water is capable of inhibiting atherogenesis in male LDL-receptor-deficient mice. That is done in a lower concentration of Mg than previously reported.

The diagnosis of antiphospholipid syndrome (APS) is based on a combination of clinical and serological criteria. This review summarizes the literature regarding animal models of APS. Animal models of this syndrome help to elucidate pathogenic roles of the characteristic antiphospholipid antibodies in pregnancy morbidity, vascular thrombosis, neurologic disease and atherosclerosis. Furthermore, these models also provide measures to evaluate novel therapies for APS. These include bone-marrow transplantation, intravenous immunoglobulin, anticoagulation, interleukin-3, in addition to other therapies. Experimental induction and treatment of APS largely contributes to our understanding of the disease and to better management of its clinical characteristics.

The aim of this study was to develop a 2-stage evaluation and intervention program for control of methicillin-resistant Staphylococcus aureus (MRSA) in the hospital setting. The first stage included evaluation of MRSA prevalence throughout the entire hospital; the presence of MRSA was determined in patients or medical staff who had a high risk of carrying it (i.e. as a result of contact with surgical wounds). In the second stage, "contact isolation" (which included the use of gloves, hand washing before and after treatment of a patient and isolation of patients' personal belongings) was carried out in every patient from whom MRSA was isolated in 4 intervention departments-Surgery, Orthopaedics, General ICU and Neonatal ICU-while the same policy of attempting to isolate MRSA was maintained. Both stages lasted 7 months. A comparison between MRSA prevalence in the evaluation and intervention stages disclosed a decrease in MRSA isolates from 91 to 56 in the entire hospital (p = 0.2) and from 45 to 24 in the intervention departments (p = 0.05), respectively; while the number of patients with MRSA decreased from 87 to 55 in the entire hospital (p = 0.2) and from 45 to 18 in the intervention departments (p = 0.007). The number of patients treated with vancomycin decreased from 48 before intervention to 23 after "contact isolation" was started in the entire hospital (p = 0.02) and from 31 to 5 in the intervention departments (p = 0.001). These results provide additional evidence in favor of establishing a program to control MRSA spread.

Background: Autoimmune factors have been shown to play a role in atherosclerosis. The aim of this study is to correlate 5 autoantibodies (anticardiolipin, anti-CL, β2-glycoprotein-I, β2GPI, phosphatidylcholine, oxidized low-density lipoprotein, oxLDL, endothelial cell) with the presence of coronary heart disease, angiographic findings, and with coronary artery calcification. Methods: The levels of the 5 autoantibodies and a control antifibroblast line of 126 coronary heart disease patients and 20 healthy controls were measured. Fifty-one patients underwent coronary angiography, and 98 patients had coronary artery calcium determination using spiral computerized tomography (dual mode). Results: Levels of 3 autoantibodies (anti-CL, β2GPI, oxLDL) were significantly elevated in coronary heart disease patients compared with controls (p < 0.001,p = 0.001, p < 0.001, respectively). Within the subgroup of patients with significant coronary artery stenosis, anti-CL antibodies were also elevated (p = 0.008). No correlation was found between anti-CL, and anti-β2GPI autoantibody levels and coronary calcium scores as measured by spiral computerized tomography. However, anti-oxLDL antibodies were raised in patients with no calcification detected by spiral computerized tomography, compared with the patients with any coronary calcification (p = 0.046). Conclusion: Anti-CL, β2GPI and oxLDL antibodies are elevated in coronary heart disease patients regardless of coronary calcification.

Animal models of the relatively new antiphospholipid syndrome (APS) enabled researchers to understand disease pathogenesis and to test novel experimental therapeutic modalities. Animal models of APS include spontaneous genetic models and experimental induced models. The latter test more reliably the pathogenicity of antiphospholipid antibodies because the syndrome is induced in normal mice rather than being secondary to a preexisting autoimmune disease. Reports about animal models of APS in the recent year provide new insights into the pathogenesis of antiphospholipid antibodies and beta2-glycoprotein-I in reproductive failure, neurologic manifestations, thrombosis, and atherosclerosis. In addition, novel therapies that were successful in experimental APS included anti-idiotypes, oral tolerance, and specific peptides that bind to beta2-glycoprotein-I. Animal models provide the first step in development of novel therapies for patients with APS.

Objective. To review the role of intravenous immunoglobulin (IVIg) in antiphospholipid syndrome (APS). Methods. A literature search was carried out for the immunopathogenesis of APS, laboratory evidence for the beneficial effect of IVIg in APS, and the clinical use of IVIg in APS. Results. There is both laboratory and clinical evidence for the beneficial role of IVIg in APS. IVIg succeeded in in vitro inhibition of anticardiolipin antibodies and lupus anticoagulant, and in the amelioration of experimental APS. Although there are few case reports about IVIg therapy in the haematological manifestations of APS, most of the reports focus on the use of IVIg in the obstetric complications of APS. Hence, in several patient series the use of IVIg either solely or in combination with aspirin/heparin resulted in successful pregnancy outcome in the vast majority of APS patients with recurrent abortions. In addition, IVIg was also beneficial in antiphospholipid antibody-positive patients undergoing in vitro fertilization. Conclusion. APS, an autoimmune disease whose main features are vascular thrombosis and pregnancy morbidity, is a good candidate for immunotherapy with IVIg that contains antiidiotypes directed towards patients’ pathogenic antiphospholipid antibodies. Future research should determine when to use anticoagulation, IVIg or both in the treatment of APS. K : Antiphospholipid syndrome, Aspirin, Heparin, Intravenous immunoglobulin, Recurrent pregnancy loss.

Background: Intravenous immunoglobulin (IVIg) is a standard therapeutic modality for a few autoimmune diseases, such as immune thrombocytopenic purpura. However, in other hematologic autoimmune conditions its role is still controversial. Methods: Seven patients with either autoimmune hemolytic anemia, Evans’ syndrome, aplastic anemia, pure red cell aplasia, thrombotic thrombocytopenic purpura, or acquired factor VIII inhibitors were treated with a single course of high-dose (2 g/kg) IVIg. Results: A good response was observed in all seven patients, except the one with thrombotic thrombocytopenic purpura, and there were no adverse effects related to IVIg use. The literature reports on IVIg therapy in these conditions and the mechanisms of action of IVIg in autoimmune diseases are discussed. Conclusions: IVIg might be a useful agent in the treatment of several hematologic disorders other than immune thrombocytopenic purpura. Future aims of clinical research in this respect would be to identify the patient subgroups that might benefit more from IVIg in these conditions.

Objective: The renin-angiotensin system may play a role in the development of atherosclerosis. Nevertheless, different results from studies attempting to attenuate the process by inhibiting the converting enzyme were equivocal, and in those who succeeded, blood pressure was lowered and/or the lipid profile was improved in addition to the inhibition of the renin-angiotensin axis. The aim of this study is to investigate the effect of low doses of fosinopril, a converting enzyme inhibitor, on the development of atherosclerosis in LDL-receptor-deficient mice. Methods: Three groups of 15 mice were fed a high-fat, high-cholesterol western diet. The three study groups received either distilled water (control group), or water supplemented with fosinopril 0.01 mg/kg/day (low-dose group) or with 0.1 mg/kg/day (high-dose group). Plasma aldosterone levels and lipid profiles were measured at the beginning and at the end of the study. After 10 weeks, the mice were sacrificed and the extent of atherosclerosis was assessed at the aortic sinus. Results: Plasma aldosterone levels did not change in the control group, but decreased significantly in both treated groups from 74.7 to 39.3 ng/ml in the low-dose group (p < 0.003) and from 70.7 to 33.6 ng/ml in the high-dose group (p < 0.001). The lipid profile at the end of the study showed significantly lower levels of cholesterol and triglycerides in the high-dose group as compared to the low-dose group (p < 0.05). There was no difference between the three groups regarding the area of atherosclerosis at the aortic sinus: 157,000 ± 34,000, 130,000 ± 58,000 and 145,000 ± 26,000 µm2 in the control, low-dose and high-dose groups, respectively. Conclusion: Inhibition of the renin-angiotensin-aldosterone axis by itself does not prevent the development of early atherosclerosis in LDL-receptor-deficient mice.

Objective: As APS (antiphospholipid syndrome) can be either primary or secondary to a wide range of other conditions (such as autoimmune diseases, malignancies, infectious diseases, and drug-induced conditions) the aim of this study was to describe a novel overlap syndrome of APS. Methods: All patients diagnosed with either PM (polymytosis) or DM (dermatomytosis) who were treated in the Rheumatology Unit, Sheba Medical Center, were followed-up in the past 8 years for the appearance of a clinical manifestation of the APS, and conversely, patients with APS treated by us were clinically assessed for the presence of signs and symptoms of PM and DM. Both conditions were diagnosed according to accepted diagnostic criteria. Results: Three patients were found to have both APS and PM/DM. A patient with PM had transverse myelopathy, a patient with DM had pulmonary embolism, and a patient with PM had recurrent abortions, stroke, livedo reticularis and mitral regurgitation. Both patients with PM had also SLE (systemic lupus erythematosis). Conclusions: APS can be associated with a wide range of diseases. Future data would reveal which therapy is the best for the association of PM/DM with APS, and determine the pathogenesis and prognosis in patients with this association.

Objective: To test the clinical response of systemic lupus erythematosus (SLE) patients to intravenous immunoglobulins (IVIg), and whether the clinical response of IVIg treatment in SLE is accompanied by modification of SLE-associated autoantibodies/antibodies (Abs) and complement levels.Methods: Twenty SLE patients were treated with high-dose (2 g/kg) IVIg monthly, in a 5-d schedule. Each patient received between 1-8 treatment courses. They were evaluated for the clinical response, Systemic Lupus Activity Measure (SLAM) score before and after IVIg, levels of antinuclear antibody (ANA), dsDNA (double-stranded DNA), SS-A or SS-B, ENA (extractable nuclear antigens), C3and C4levels before and after the treatment, and before and after each treatment course.Results: A beneficial clinical response following IVIg treatment was noted in 17 out of 20 patients (85%). Few clinical manifestations responded more to treatment: arthritis, fever, thrombocytopenia, and neuropsychiatric lupus. In 9 patients evaluated before and after IVIg, mean SLAM score decreased from 19.3 ± 4.7 to 4 ± 2.9 (P < 0.0001). There was a tendency towards abnormal levels of complement and Abs before IVIg courses among the treatment responders compared with the non-responders, and similarly the former tended to have normalization of their abnormal levels more than the latter. These differences were found statistically significant only with respect to C4and SS-A or SS-B levels before IVIg courses.Conclusion: IVIg has a high response rate among SLE patients. A combination of clinical manifestations, Abs and complement levels may aid in the future in predicting who among SLE patients will benefit more from IVIg treatment.

Neuropsychiatric lupus includes extremely diverse clinical manifestations, ranging from mild cognitive dysfunction to a severe, life-threatening presentation. We report a 28-year-old patient with systemic lupus erythematosus who had persistent fever for 3 months, and developed within a few hours motor and sensory aphasia, rotator nystagmus with deviation of the eyes, and severe nuchal rigidity. An extensive series of imaging and laboratory tests were interpreted as normal, except for an elevated opening pressure at lumbar puncture, cerebrospinal fluid inflammatory findings, and asymmetrical cortical perfusion on single-photon emission computed tomography. The patient received one course of high-dose intravenous immunoglobulin (IVIg) and within 5 days her condition returned to that of 3 months before admission. The mechanisms of injury, along with the management of cerebral lupus and the mechanisms of action of IVIg, are discussed.

Background: Autoimmune vasculitides cannot always be controlled by steroids and immunosuppressive drugs. Intravenous immunoglobulin (IVIg) treatment was found beneficial in several vasculitides including systemic and organ–specific diseases. In this article we tested whether the beneficial clinical response of IVIg treatment in vasculitides was accompanied by a decrease in vasculitis–associated autoantibody levels. Methods: Ten patients diagnosed as having vasculitis were treated with high–dose (2 g/kg) IVIg monthly, in a 5–day schedule. In all the patients, other therapeutic measures failed to control disease progression prior to IVIg treatment. Each patient received between 1 and 6 treatment courses. All patients were evaluated for the levels of 5 autoantibodies (Abs) related to vasculitis before and after each treatment course. Results: In 6 out of the 10 patients, a beneficial clinical response followed IVIg treatment. Moreover, no treatment–related adverse effects were observed in any of the patients. Anti–myeloperoxidase antibodies and cytoplasmic–antineutrophil cytoplasmic antibodies levels decreased concomitantly with the clinical improvement observed in the patients with Churg–Strauss vasculitis and Wegener’s granulomatosis, respectively. Levels of cytoplasmic–antineutrophil cytoplasmic antibodies (ANCA) with specificity for bacteridial/permeability–increasing protein and human lysosomal–associated membrane protein increased after each treatment course, but returned to normal values before the following one. Conclusions: When other therapeutic measures, such as immunosuppressive therapy, fails to control disease manifestations in patients with vasculitides, IVIg is a possible effective intervention method with a high response rate. IVIg probably exerted its effects on disease progression via different mechanisms. Among these mechanisms, a decrease in relevant Ab levels is often found (probably by anti–idiotypes in IVIg), and thus ANCA levels are expected to associate with disease activity.

SummaryAnti-oxidised low-density lipoprotein (anti-oxLDL) antibodies are a heterogeneous group of autoantibodies including both pathogenic and protective subsets. Whereas in most studies the levels of anti-oxLDL antibodies were associated with enhanced atherosclerosis as evaluated by different methods, immunization with oxLDL leads to elevated levels of anti-oxLDL and protection against atherosclerosis. Anti-oxLDL can also be used for immunomodulation of atherosclerosis (i.e. possible therapeutic use of intravenous immunoglobulin, oral tolerance). More specific autoantibodies out of total anti-oxLDL should be selected, for instance, anti-oxLDL/beta-2-glycoprotein I complex, hence defining the fine-tuning of anti-oxLDL antibodies might detect which autoantibodies are pathogenic and which can be used therapeutically.

Objectives: To determine whether malignant thymoma is associated with high rates of concomitantly occurring autoimmune diseases. Methods: Sheba Medical Center computer records from 1966 to 1995 werereviewed to identify patients with malignant thymoma, either type I (invasive thymoma) or type II (thymic carcinoma). All patients who had malignant thymoma and autoimmune phenomena were analyzed. The diagnosis of thymic neoplasm was confirmed by two independent pathologists. The diagnosis of autoimmune diseases was based on both clinical and serological findings. Results: Six of 22 (27%) cases of malignant thymoma had an autoimmunedisease. Five patients had type I malignant thymoma and either myasthenia gravis (four patients) or Graves' disease (one patient). Only one patient had type II malignant thymoma with Sjbgren's syndrome. The diagnosis of autoimmune disease preceded the diagnosis of thymic neoplasm in four cases, and was diagnosed simultaneously in two. Conclusions: Malignant thymomas are highly associated with autoimmunediseases, as are benign thymomas. To our knowledge, we report the first documented cases of a patient with thymic carcinoma and Sjogren's syndrome, and another with invasive thymoma and Graves' disease.

The various therapeutic modalities which are found to be beneficial in experimental antiphospholipid syndrome include: bone marrow transplantation, anti-CD4 monoclonal antibodies, bromocriptine, intravenous immunoglobulins and anti-idiotypes, interleukin-3, and various anti-coagulant and anti-aggregate agents. The advantage of animal models is the ability to evaluate experimental treatments that cannot be tested directly on patients. In this paper, we review the effect of these agents on animal models of antiphospholipid syndrome, their mechanisms of action, and their clinical implications.

The antiphospholipid (APS) syndrome frequently includes severe pregnancy complications such as fetal wastage and recurrent spontaneous abortions. Animal models for APS in pregnancy can provide both an understanding of the pathogenic mechanisms of anti-phospholipid antibodies (aPL), and aid in the evaluation of various therapeutic modalities in APS. Animal models for APS include both spontaneously developed diseases, as is the case for secondary APS in mice with another autoimmune disease, and induced models of APS. The latter includes either passive induction of disease by antibodies infusion, or active induction via manipulation of the idiotypic network. This article summarizes the literature reports of animal models of APS in pregnancy, deal with the various possible mechanisms of action of aPL in pregnancy, and discuss the treatment options of women having pregnancy complications of APS.

To review case histories of patients in whom fibrosis played a significant role in the pathogenesis of their disease, and to determine whether intravenous gammaglobulin (IVIg) contributed to the regression of their fibrotic condition.Eight patients with excess fibrotic reaction in the course of diverse diseases were analysed; a tendency that reverted with different IVIg treatment options. Myelofibrosis was predominant in three patients (a patient with a myeloproliferative syndrome, one with systemic lupus erythematosus, and one with Sjögren's syndrome). Three patients had scleroderma as their main feature, one patient had hepatitis C cirrhosis, and one had idiopathic thrombocytopenic purpura.Fibrotic excess was reduced in all the patients by IVIg treatment. In five patients the disease as a whole benefited from the infusion of immunoglobulins.IVIg may enhance resorption of fibrosis and promote healing in patients with fibrotic associated disorders.

Gaucher's disease is characterized by increased incidence of several autoantibodies, but autoimmune phenomena are rare in Gaucher patients. We report the first occurrence of Gaucher's disease and antiphospholipid syndrome in the same patient. A 27-year-old woman with hepatosplenomegaly and thrombocytopenia who was diagnosed as having Gaucher's disease with the genotype 1226G/1226G developed Coombs'-positive hemolytic anemia, recurrent abortions, and a high titer of IgG and IgM anticardiolipin antibodies constituting the diagnosis of antiphospholipid syndrome. A successful pregnancy outcome was achieved by combined therapy with aspirin, low-molecular-weight heparin, prednisone, and enzyme replacement therapy with imiglucerase. The possible pathogenicity of antiphospholipid antibodies found in the sera of many asymptomatic Gaucher patients should be further clarified.

Objectives The Dead Sea, the deepest and most saline lake on earth, has been known from biblical times for its healing properties. The aim of this systematic review was to present critically the level of evidence for the claims of therapeutic effects of Dead Sea treatments in several rheumatologic diseases and psoriasis as well as to review these treatments' safety. Methods All articles cited in MEDLINE under the query, "Dead Sea," were reviewed. Results We found bona fide evidence that Dead Sea treatments are especially effective in psoriasis due to both the special characteristics of solar ultraviolet radiation in the Dead Sea and the Dead Sea water balneotherapy. Dead Sea mud and Dead Sea balneotherapy have been found to be beneficial in rheumatologic diseases, including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and knee osteoarthritis. In the safety analysis, we found no evidence for an increase in skin neoplasia, although skin actinic damage seems to be increased in patients treated in the Dead Sea. Dead Sea treatments do not lead to worsening of blood pressure. Substantial ingestion of Dead Sea water (generally in unusual near-drowning cases) is toxic and can result in cardiac rhythm disturbances because of electrolyte concentration abnormalities. Laboratory analysis of Dead Sea mud did not reveal mineral concentrations that could represent a health concern for their intended use. Conclusions Dead Sea treatments are beneficial in several rheumatologic diseases and psoriasis and have a good safety profile.