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Previous studies reported controversial results regarding the association between allergic disorders and attention deficit hyperactivity disorder (ADHD)/autism spectrum disorder (ASD). The aim of this article was to investigate whether allergic disorders are associated with ADHD/ASD in a large cohort of pediatric patients.A retrospective study using the pediatric (0-18 year) database (ICD-9-CM codes) of Clalit Health Services during the years (2000-2018). Diagnosis of all disorders was made by specialist physicians.A total of 117 022 consecutive non-selective allergic children diagnosed with one or more allergic disorder (asthma, rhinitis, conjunctivitis, skin, food, or drug allergy) and 116 968 non-allergic children were enrolled to our study. The mean follow-up period was 11 ± 6 years. The presence of allergic disorders in early childhood (mean age of allergic diagnosis 4.5 ± 4.3 years) in boys as well as in girls significantly increased the risk to develop ADHD (O.R 2.45, CI 2.39-2.51; p .0001), ASD (O.R 1.17, CI 1.08-1.27; p .0001), or both ADHD + ASD (O.R 1.5, CI 1.35-1.79; p .0001). Children with more than one allergic comorbidity revealed a much higher risk. In a multivariable analysis (adjusted for age at study entry, number of yearly visits, and gender), the risk of allergic children to develop ADHD and ADHD + ASD, but not ASD alone, remained significantly higher.Allergic disorder in early childhood significantly increased the risk to develop ADHD, and to a less extend ASD, in later life.

Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands. We investigated whether the tolerogenic peptide, hCDR1, that ameliorates lupus manifestations would have beneficial effects on pSS as well. The in vitro effects of hCDR1 on gene expression of pro-inflammatory cytokines and regulatory molecules were tested in peripheral blood mononuclear cells (PBMC) of 16 pSS patients. hCDR1, but not a control peptide, significantly reduced gene expression of IL-1β, TNF-α, MX-1 and BlyS and up-regulated immunosuppressive (TGF-β, FOXP3) molecules in PBMC of pSS patients. hCDR1 did not affect gene expression in patients with rheumatoid arthritis and anti-phospholipid syndrome. Further, hCDR1 up-regulated the expression of Indoleamine 2,3-dioxygenase (IDO) via elevation of TGF-β. IDO inhibition led to a significant decrease in the expression of FOXP3 which is crucial for the induction of T regulatory cells. Thus, hCDR1 is potential candidate for the specific treatment of pSS patients.

Introduction Semaphorin-4D (CD100), generated by CD4/CD8 T-cells and its receptor on B cells – CD72, play a role in immune regulation. Both have soluble forms - sCD100/sCD72. Methods sCD100 and sCD72 levels were determined by ELISA (MyBioSource, USA). Results 28 chronic HIV patients and 50 matched healthy volunteers participated in our study. Before treatment, CD4 T-cells counts were 267 ± 216 cells/mcl and viral load (VL) was 586,675 ± 1897,431 copies/ml. Two years following HAART, CD4 T-cells counts rose to 475 ± 264 cells/mcl and VL dropped to 2050 ± 10,539 copies/ml. CD8 T-cells counts were stable. sCD72 levels prior (4.13 ± 2.03 ng/ml) and following HAART (3.53 ± 2.01 ng/ml) were similar to control levels (4.51 ± 2.66 ng/ml). sCD100 levels before (40.47 ± 31.4 ng/ml) and following HAART (37.68 ± 29.44 ng/ml) were significantly lower compared to controls (99.67 ± 36.72 ng/ml) despite the significant increase in CD4 T-cells counts. Conclusions The permanent low levels of the immunoregulator sCD100 suggest a role for CD100 in the immune dysfunction and T cells exhaustion of HIV.

IgG-4 related sialadenitis is a head and neck manifestation of an IgG4-related systemic disease. Here, we report a case of a 60 year-old woman presenting with three meta-synchronous head neck masses in the course of five years: Bilateral submandibular gland masses and a hard palate mass. Final diagnosis of IgG-4 related sialadenitis was made following the first excision, yet the initial suspected diagnosis was of lymphoma. After another submandibular mass, the patient presented with a hard palate mass, eventually diagnosed as IgG-4 related sialadenitis. In conclusion, IgG-4 related sialadenitis not limited to the submandibular gland and may appear in minor salivary glands as well.

וֹndoleamine-2,3-dioxygenase (IDO) plays a role in immune regulation. Increased IDO activity was reported in systemic lupus erythematosus (SLE). We investigated the effects of the tolerogenic peptide hCDR1, shown to ameliorate lupus manifestations, on IDO gene expression. mRNA was prepared from splenocytes of hCDR1- treated SLE-afflicted (NZBxNZW)F1 mice, from blood samples of lupus patients, collected before and after their in vivo treatment with hCDR1 and from peripheral blood mononuclear cells (PBMC) of patients incubated with hCDR1. IDO gene expression was determined by real-time RT-PCR. hCDR1 significantly down-regulated IDO expression in SLE-affected mice and in lupus patients (treated in vivo and in vitro). No effects were observed in healthy donors or following treatment with a control peptide. Diminished IDO gene expression was associated with hCDR1 beneficial effects. Our results suggest that the hCDR1-induced FOXP3 expressing regulatory T cells in lupus are not driven by IDO but rather by other hCDR1 regulated pathways.

Upper extremity deep vein thrombosis (UEDVT) is defined as thrombosis of the deep venous system (subclavian, axillary, brachial, ulnar, and radial veins), which drains the upper extremities. It can be caused by thoracic outlet anatomic obstruction, such as Paget-Schroetter syndrome, (primary) or by central intravenous catheters (secondary). UEDVT may be asymptomatic or present with acute severe pain and arm swelling. Clinical suspicion should be confirmed by diagnostic imaging procedures such as duplex ultrasound, computed tomography scan, or magnetic resonance imaging. UEDVT is managed by anticoagulant treatment. In addition to that, early thrombolysis aimed at preventing post-deep vein thrombosis syndrome and thoracic outlet decompression surgery should be given to patients with primary UEDVT. Anticoagulation without thrombolysis is the treatment of choice for patients with catheter-related thrombosis. Mandatory functioning catheters can remain in place with anticoagulant treatment. All other catheters should be immediately removed. The management of patients with UEDVT requires an experience multidisciplinary team comprised of internists, radiologists, hematologists, and vascular surgeons. Understanding the risk factors for the development of UEDVT, the diagnostic procedures, and the treatment modalities will improve the outcome of those patients.

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.

Anti-BLyS treatment with the human belimumab monoclonal antibody was shown to be a safe and effective therapeutic modality in lupus patients with active disease (i.e., without significant neurological/renal involvement) despite standard treatment.To evaluate the "real-life" safety and efficacy of belimumab added to standard therapy in patents with active lupus in five Israeli medical centers.We conducted a retrospective open-labeled study of 36 lupus patients who received belimumab monthly for at least 1 year in addition to standard treatment. Laboratory tests (C3/C4, anti dsDNA autoantibodies, chemistry, urinalysis and complete blood count) were done every 3-4 months. Adverse events were obtained from patients' medical records. Efficacy assessment by the treating physicians was defined as excellent, good/partial, or no response.The study group comprised 36 lupus patients (8 males, 28 females) with a mean age of 41.6 } 12.2 years. Belimumab was given for a mean period of 2.3 } 1.7 years (range 1-7). None of the patients discontinued belimumab due to adverse events. Four patients (11.1%) had an infection related to belimumab. Only 5 patients (13.9%) stopped taking belimumab due to lack of efficacy. The response was excellent in 25 patients (69.5%) and good/partial in the other 6 (16.6%). Concomitantly, serological response (reduction of C3/C4 and anti-dsDNA autoantibodies) was also observed. Moreover, following belimumab treatment, there was a significant reduction in the usage of corticosteroids (from 100% to 27.7%) and immunosuppressive agents (from 83.3% to 8.3%).Belimumab, in addition to standard therapy, is a safe and effective treatment for active lupus patients.

Systemic lupus erythematosus (SLE) is a chronic multisystem disease in which various cell types and immunological pathways are dysregulated. Current therapies for SLE are based mainly on the use of non-specific immunosuppressive drugs that cause serious side effects. There is, therefore, an unmet need for novel therapeutic means with improved efficacy and lower toxicity. Based on recent better understanding of the pathogenesis of SLE, targeted biological therapies are under different stages of development. The latter include B-cell targeted treatments, agents directed against the B lymphocyte stimulator (BLyS), inhibitors of T cell activation as well as cytokine blocking means. Out of the latter, Belimumab was the first drug approved by the FDA for the treatment of SLE patients. In addition to the non-antigen specific agents that may affect the normal immune system as well, SLE-specific therapeutic means are under development. These are synthetic peptides (e.g. pConsensus, nucleosomal peptides, P140 and hCDR1) that are sequences of conserved regions of molecules involved in the pathogenesis of lupus. The peptides are tolerogenic T-cell epitopes that immunomodulate only cell types and pathways that play a role in the pathogenesis of SLE without interfering with normal immune functions. Two of the peptides (P140 and hCDR1) were tested in clinical trials and were reported to be safe and well tolerated. Thus, synthetic peptides are attractive potential means for the specific treatment of lupus patients. In this review we discuss the various biological treatments that have been developed for lupus with a special focus on the tolerogenic peptides.

Ritonavir, a protease inhibitor (PI), is commonly used in the treatment of HIV-1 infection. It is a potent inhibitor of the hepatic cytochrome P450 superfamily. Therefore, its usage with other PI medications leads to significant increases in the levels of the latter PI, which allows a reduction in pill burden. Intranasal and inhaled corticosteroids are widely used for the treatment of allergic rhinitis and asthma. Inhaled steroids do not usually lead to systemic adverse events, since their plasma concentrations are quite low due to extensive first-pass metabolism and clearance by CYP3A4. However, the coadministration of Ritonavir with inhaled (or intranasal) corticosteroids may result in an increase in the plasma corticosteroid levels due to the potent CYP3A4 inhibition by Ritonavir. This may cause Cushing's syndrome (laboratory and clinical) with adrenal suppression.Plasma cortisol and urinary-free cortisol levels were determined using immunoassays. In the Synacthen test, plasma cortisol levels were measured at time 0 as well as at times 60, 120, and 150 minutes following an intramuscular injection of 0.25 mg Synacthen.We present here three HIV-1 female patients aged 12, 55 and 65 years who developed iatrogenic Cushing's syndrome with adrenal suppression following the coadministration of Ritonavir and inhaled Fluticasone, both at the standard recommended doses.The coadministration of Ritonavir and Fluticasone at the recommended doses caused, in our three patients, iatrogenic Cushing's syndrome with adrenal suppression. We suggest that this adverse event is underdiagnosed and high clinical suspicion is needed for early diagnosis and prenention of Addisonian crises. Thus, Fluticasone treatment should be avoided in patients who are treated with Ritonavir. Alternative therapeutic options for asthma control such as oral Montelukast or bronchodilators alone should be considered.

Background. Centralized data collection and analytic tools facilitate tracing HIV transmission trends at the patient-population level with increasing resolution, complementing behavioral studies while avoiding sampling biases. By several measures, the rate of HIV infection among men who have sex with men (MSM) in Israel increased in the past several years more rapidly than was expected. We describe features of the data that connect this increase to behavioral changes. Methods. We retrospectively analyzed data from the national HIV reference laboratory and the national HIV and sexually transmitted infections registries. We examined changes in selected epidemiologic and clinical parameters and in the pattern of drug-resistant virus transmission among MSM in Israel. In particular, virus isolates from 296 MSM (23.8% of all MSM who received a diagnosis) were genotyped, drug-resistance conferring mutations were characterized, and phylogenetic trees were constructed. Results. Compared with earlier years, during 2007―2009 MSM were more often infected with drug-resistant virus before treatment initiation, were coinfected with syphilis, and received a diagnosis during acute retroviral syndrome. Phylogenetic analysis suggested frequent transmission of drug-resistant HIV by drug-treated individuals to >1 partner. Secondary transmission of resistant virus by drug-naive patients is also consistent with the phylogenetic patterns. In addition, non-B HIV subtypes began to appear among MSM. Conclusions. Together, our findings suggest that the sexual behavior of MSM, both HIV-infected and uninfected, has become riskier, contributing to the number of those seeking early clarification of status, to syphilis comorbidity, and to the spread of drug resistance. These findings call for action by public health planners and community-based organizations aimed at increasing awareness of the risks, bringing a change in attitude and establishing safe sex norms.

Objective A significant number of HIV-1 patients experience poor immune reconstitution despite long-term viral suppression with highly active antiretroviral therapy (immunological non-responders). The aims of the present study were to determine whether eradication of Helicobacter pylori could facilitate a better immune reconstitution in these patients. Methods Forty-nine immunological non-responder HIV-1 patients were evaluated by 13 C-urea breath test (UBT) for the presence of active H. pylori infection. They were all asymptomatic. The UBT was positive in 26 (53%) of them. Eleven patients (group 1) were treated with a combination of omeprazole 20mg bid, amoxicillin 1g bid and clarithromycin 500mg bid for 14 consecutive days. Eight weeks later, successful eradication was proven by a repeat negative UBT in all 11 patients. The remaining 15 (group 2) refused the H. pylori eradication treatment. All 26 patients were followed for 24 months and evaluated for blood CD4 and CD8 cell counts and percentages and for plasma HIV-1 viral load. Results At the time of H. pylori diagnosis and eradication (baseline), CD4 and CD8 cell counts were similar in both study groups. All 11 H. pylori eradicated patients (group 1) had a significant increase in CD4 cell count starting 3 months and peaking 12–18 months after H. pylori eradication. Thereafter, CD4 levels gradually declined. Nevertheless, 24 months after triple therapy it was significantly higher than prior to H. pylori eradication. Parallel reciprocal changes were observed in CD8 cell counts. There were no significant changes in either CD4 or CD8 cell counts in group 2 patients. None of the patients of group 1 demonstrated virological failure, while four (26.7%) group 2 patients experienced virological failure requiring change of highly active antiretroviral therapy (HAART) regimen. Conclusion Triple therapy for H. pylori eradication is associated with a significant, although possibly transient immune reconstitution in HAART-treated HIV-1 patients with viral suppression without immunological response.

Summary The re-emergence of syphilis among HIV-infected patients has been reported in recent years. We evaluated co-infection among heterosexual immigrants in an Israeli AIDS center. The records of 1060 HIV-infected patients were evaluated for positive syphilis serology between the years 2000 and 2005, and all seropositive patients were further evaluated. We found 150 HIV/syphilis co-infected patients (57% men, 93% of African origin), of who 135 were found to have late latent syphilis. Lumbar puncture (LP) was performed in 51 patients, 16 (31 %) had abnormal cerebrospinal fluid (CSF) compatible with neurosyphilis. Abnormal CSF correlated with the absence of previous anti-syphilis treatment, but not with CD4 count, viral load or Venereal Disease Research Laboratory titres. Penicillin was recommended to all patients according to their disease stages and 81 patients completed 12 months post-treatment follow-up. Twenty-one of 81 (26%) treatments were successful, 33 (41 %) showed ‘serofast reaction’ and 27 (33%) failed therapy. In conclusion, a high incidence of syphilis with CSF reactivity suggestive of neurosyphilis was observed in heterosexual Ethiopian HIV-infected patients. Thus, repeated serological screening and CSF evaluation seems to be indicated in these patients. Penicillin therapy resulted in ‘serofast reaction’ or treatment failure for most patients. More, intensive treatment might be needed for HIV/syphilis in co-infected patients, especially those with severe immune-deficiency and prolonged syphilis infection.

The objective of the study was to investigate the HIV-mother-to-child transmission (MTCT) rate in Israel. This was a retrospective study of HIV-infected pregnant women, mainly immigrants from Ethiopia, in six Israeli AIDS centres, in 2000–2005. Medical records of mothers and newborns were evaluated for HIV status, treatment and MTCT rates. Three hundred pregnancies of 241 HIV-infected women, resulting in 304 live births, were studied. In 86/241(36%) women, HIV diagnosis was made during the current pregnancy or shortly after labour. Thirty others were diagnosed during previous pregnancies. Highly active antiretroviral therapy (HAART) was prescribed in 76% of pregnancies. The mean viral load before labour was 23,000 ± 100,000 copies/mL with a mean CD4 of 406 ± 223 (range 4–1277) cells/mm3. Caesarian sections were preformed in 175/300 pregnancies (103/175 with viral load

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.

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.

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. 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. 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

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

B cell receptor (BCR) -mediated signals are enhanced when CD72 expression is deficient on B cells in autoimmune diseases. The significance of soluble CD72 (sCD72) has not been elucidated.Soluble CD72 was analyzed in the serum of 159 SLE patients, 40 rheumatoid arthritis (RA) patients, and 100 healthy individuals. Correlations between sCD72 and SLE disease activity (SLEDAI) were assessed.Soluble CD72 was found increased in SLE patients, when compared to both RA patients and healthy individuals (20.2 ± 1.2 ng/ml; 10.6 ± 4.6 ng/ml and 7.2 ± 3.3 ng/ml; p0.001). Soluble CD72 level was significantly higher in SLE patients with renal involvement than in patients without (31.8 ± 2.3 ng/ml vs 13.9 ± 0.9 ng/ml; p0.001) and also with the presence of auto-antibodies.Soluble CD72 is significantly increased in SLE patients mainly in those with renal involvement. Increased sCD72 may become a potential biomarker for renal involvement in SLE.

Background HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning. Methods We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998–2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods. Results Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes. Conclusions Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.

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 (NZB×NZW)F1female 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-γ and IL-10) and up-regulation of the immunosuppressive cytokine TGF-β, which substantially contributed to the suppressed autoreactivity. TGF-β 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-β.

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

In Israel,0.06% of the general population is infected with human immunodeficiency virus (HIV), with a much higher prevalence among specific groups. These groups are distinguished demographically by risk behavior category and by virus subtype. We investigated transmission of drug resistance within groups to assess the impact of these factors.Plasma samples from15% of all patients with new diagnoses of HIV infection were randomly collected between June 1999 and June 2003. Sequences from 176 drug-naive patients included 20 of subtype A, 20 of subtype AE, 2 of subtype AC, 29 of subtype B, 100 of subtype C, and 5 of subtype F.Major drug resistance mutations (protease: L90M; reverse transcriptase: M41L, K103N, V106M, M184V, Y181S, G190A, L210W, T215Y/F, and K219R) were detected in 1 subject with A subtype, 3 with subtype B, and 9 with subtype C. In addition, 1 subject with A subtypes, 2 with subtype B, and 10 with subtype C had secondary mutations (protease: M46I; reverse transcriptase: A98G, K101Q, and V108I). Only 1 patient had mutations associated with1 class of drugs. Among subjects who contracted HIV infection in Israel, 16 of 56 (1 of 7 with subtypes A or AE, 4 of 17 with subtype B, and 11 of 32 with subtype C; P=.7-1.0) carried resistant virus--a significantly higher proportion (P.001) than in subjects infected in other countries (10 of 120 infected).Drug-resistant virus was detected in 14.8% of patients with new diagnoses of HIV infection but in 28.6% of patients known to have been infected in Israel. The implications include a need for pretreatment resistance testing and for better programs aimed at prevention of transmission, directed particularly at patients. We did not find significant differences in transmission of resistant virus between those infected with subtypes B and C, despite the different demographic background. A conclusive analysis and interpretation should await a more extensive study.

SUMMARYA peptide based on the complementarity determining region (CDR)1 of a human monoclonal anti-DNA autoantibody (hCDR1) was shown to either prevent or treat an already established murine lupus in systemic lupus erythematosus (SLE)-prone mice or in mice with induced experimental SLE. The present study was undertaken to determine the therapeutic potential of hCDR1 in a model of lupus in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes (PBL) of patients with SLE. To this end, PBL obtained from lupus patients were injected intraperitoneally into two equal groups of SCID mice that were treated either with the hCDR1 (50 µg/mouse) once a week for 8 weeks, or with a control peptide. Mice were tested for human IgG levels, anti-dsDNA autoantibodies, anti-tetanus toxoid antibodies and proteinuria. At sacrifice, the kidneys of the successfully engrafted mice were assessed for human IgG and murine complement C3 deposits. Of the 58 mice transplanted with PBL of SLE patients, 38 (66%) were engrafted successfully. The mice that were treated with the control peptide developed human dsDNA-specific antibodies. Treatment with hCDR1 down-regulated the latter significantly. No significant effect of the treatment on the levels of anti-tetanus toxoid antibodies could be observed. Treatment with hCDR1 resulted in a significant amelioration of the clinical features manifested by proteinuria, human IgG complex deposits as well as deposits of murine complement C3. Thus, the hCDR1 peptide is a potential candidate for a novel specific treatment of SLE patients.

Myasthenia gravis (MG) is a T cell–dependent, antibody-mediated autoimmune disease. A dual altered peptide ligand (APL) that is composed of the tandemly arranged two single amino acid analogs of two myasthenogenic peptides was demonstrated to downregulate in vitro and in vivo murine MG associated autoreactive responses. Furthermore, treatment with the dual APL ameliorated the clinical manifestations of an established experimental autoimmune MG in mice. This study was undertaken in order to investigate the ability of the dual APL to immunomodulate MG-associated responses of peripheral blood lymphocytes (PBL) of patients with MG to the native autoantigen acetylcholine receptor (AChR). PBL of 22 of 27 patients with MG tested responded by proliferation to torpedo AChR. The proliferative responses of PBL of 21 of 22 responders were significantly inhibited by the dual APL. The inhibition was specific because a control peptide did not inhibit these proliferative responses. The dual APL also downregulated the levels of the secreted pathogenic cytokine IFN-γ in supernatants of stimulated PBL of 80% of the tested patients. The latter inhibitions correlated with an upregulated production of the immunosuppressive cytokine, tumor growth factor beta. Thus, the results of our study demonstrate that the dual APL is capable of downregulating in vitro autoreactive responses of patients with MG and suggest that this peptide is a potential candidate for a novel specific treatment of patients with MG.

OBJECTIVE: To report 2 cases of ticlopidine-induced cholestatic hepatitis, investigate its mechanism, and compare the observed main characteristics with those of the published cases. CASE SUMMARIES: Two patients developed prolonged cholestatic hepatitis after receiving ticlopidine following percutaneous coronary angioplasty, with complete remission during the follow-up period. T-cell stimulation by therapeutic concentration of ticlopidine was demonstrated in vitro in the patients, but not in healthy controls. DISCUSSION: Cholestatic hepatitis is a rare complication of the antiplatelet agent ticlopidine; several cases have been reported but few in the English literature. Our patients developed jaundice following treatment with ticlopidine and showed the clinical and laboratory characteristics of cholestatic hepatitis, which resolved after discontinuation of the drug. Hepatitis may develop weeks after discontinuation of the drug and may run a prolonged course, but complete remission was observed in all reported cases. An objective causality assessment revealed that the adverse drug event was probably related to the use of ticlopidine. The mechanisms of this ticlopidine-induced cholestasis are unclear. Immune mechanisms may be involved in the drug's hepatotoxicity, as suggested by the T-cell stimulation study reported here. CONCLUSIONS: Cholestatic hepatitis is a rare adverse effect of ticlopidine that may be immune mediated. Patients receiving the drug should be monitored with liver function tests along with complete blood cell counts. This complication will be observed even less often in the future as ticlopidine is being replaced by the newer antiplatelet agent clopidogrel.

SUMMARYTwo 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-β. 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.

The objective of this study was to develop a human lupus model. To this end we have established and compared two models: (1) severe combined immunodeficient (SCID) mice reconstituted with peripheral blood lymphocytes (PBL) of either systemic lupus erythematosus (SLE) patients or healthy controls and (2) lethally irradiated BALB/c mice radioprotected with bone marrow of SCID mice, to which human PBL were transferred (human/mouse chimera). Engraftment was successful in most (78.4%) recipient mice as determined by the levels of human IgG measured. In about 50% of either SCID mice or human/mouse chimeras that were successfully engrafted with PBL of SLE patients, significant anti-dsDNA autoantibodies, mostly of the IgG1 and IgG2 isotypes, were determined. Interestingly, in a significant number (84.5%) of recipients of PBL of the healthy controls, anti-dsDNA antibodies were observed as well, suggesting that PBL of at least some of the healthy controls have the potential to develop SLE-associated autoantibodies under the appropriate stimulatory conditions. Glomerular immune deposits (human IgG, mouse C3) were detected in 70–80% of SCID mice with human DNA specific antibodies and in a third of the human/ mouse chimeras. Thus, SLE serology and glomerular pathology were reproducibly demonstrated in two models of human SLE. These models should allow the evaluation of potential therapies for the treatment of lupus patients.

SummarySystemic lupus erythematosus (SLE) is an autoimmune disease characterized by the increased production of autoantibodies and by systemic clinical manifestations and damage to multiple organs. The aim of the present study was to analyse matrix metalloproteinase (MMP)-9 activity in sera of patients with active and inactive SLE in order to evaluate its role in the pathogenesis and course of the disease, as well as its diagnostic value. We measured activity levels of MMP-9 and MMP-2, using both gel zymography and activity assay kits, in sera of 40 SLE patients and of 25 healthy controls. We found that MMP-9 activity, but not MMP-2 activity, is significantly elevated in the sera of SLE patients compared with sera samples of healthy controls. High activity levels of MMP-9 were determined in sera of 68% of the SLE patients. Elevated levels of MMP-9 were correlated with the presence of discoid rash, Raynaud phenomenon, pneumonitis, mucosal ulcers and anti-phospholipid antibodies. Changes in activity levels of MMP-9, but not of MMP-2, were observed in sera of the same patient at different periods of the disease course. High levels of MMP-9 did not correlate with disease activity index (SLEDAI, BILAG) in female patients, but correlated with SLE activity in the group of male patients. The results of the present study suggest that MMP-9 plays a role in the pathogenesis of SLE.

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.

Chronic inflammation is thought to be important in the pathogenesis of atherosclerosis. Helicobacter pylori (H. pylori) is a common chronic infection of humans that has been definitely linked to peptic ulcer. The evidence implicating H. pylori with atherosclerosis is controversial. We decided to investigate an effect of H. pylori infection on the restenosis after coronary angioplasty. Ninety four patients who underwent PTCA and a subsequent repeat angiography were included in the study. The indications for angiography and repeat PTCA were determined by the attending cardiologist. H. pylori serology was determined by ELISA. Sixteen (17.2%) of the patients developed restenosis. Of these 16, 12 (75%) were H. pylori seropositive versus 44 (56.4%) of the 78 patients who did not develop restenosis, p = 0.13. There was no difference between the H. pylori positive and negative patients with respect to cholesterol level, hypertension, diabetes or peptic disease. There appears to be no relationship between H. pylori and the development of restenosis following PTCA.

IL-18 binding protein (IL-18BP) is a circulating antagonist of the proinflammatory Th1 cytokine IL-18. It effectively blocks IL-18 by forming a 1:1 high affinity (Kd=400 pM) complex, exhibiting a very low dissociation rate. We have developed a sandwich ELISA for IL-18BPa and determined its limit of detection (62 pg/ml). Interference by IL-18 and related cytokines, as well as cross reactivity with other IL-18BP isoforms (b, c, and d) were determined. Using this ELISA, we measured serum IL-18BPa in large cohorts of healthy individuals and in septic patients. Serum IL-18BPa in healthy individuals was 2.15+/-0.15 ng/ml (range 0.5-7 ng/ml). In sepsis, the level rose to 21.9+/-1.44 ng/ml (range 4-132 ng/ml). Total IL-18 was measured in the same sera by an electrochemiluminescence assay and free IL-18 was calculated based on the mass action law. Total IL-18 was low in healthy individuals (64+/-17 pg/ml) and most of it ( approximately 85%) was in its free form. Total IL-18 and IL-18BPa were both elevated in sepsis patients upon admission (1.5+/-0.4 ng/ml and 28.6+/-4.5 ng/ml, respectively). At these levels, most of the IL-18 is bound to IL-18BPa, however the remaining free IL-18 is still higher than in healthy individuals. We conclude that IL-18BPa considerably inhibits circulating IL-18 in sepsis. Yet, exogenous administration of IL-18BPa may further reduce circulating IL-18 activity.

We have examined the humoral and cellular responses of SLE patients to peptides based on the complementarity-determining regions (CDR) of a monoclonal anti-DNA antibody with a major idiotype-16/6 Id, in comparison to their responses to the whole 16/6 Id-bearing antibody. Sera of 63% of the SLE patients had antibodies that bound the 16/6 Id, 80% had antibodies to one of the CDR-based peptides, and 40% of the patients reacted with both CDRs. Sera of only a few controls reacted with either the 16/6 Id (6%) or the CDR based peptides (4%) (P < 0.01). Peripheral blood lymphocytes (PBL) of 39% of the patients proliferated in response to the 16/6 Id or to one of the CDR-based peptides (37%), while in the control group the proliferation rates were 66% to the 16/6 Id and 59% to one of the CDR-based peptides (P < 0.05). The correlation between (both) the humoral and cellular immune responses to the CDR-based peptides and to the 16/6 Id suggests the relevance of these peptides to the 16/6 Id and provides additional information on the pathogenic moiety of the latter antibody.

We conducted a retrospective serosurvey of 1,000 persons in Israel who had fever of undetermined cause to look for Ehrlichia chaffeensis antibodies. Four of five cases with antibodies reactive to E. chaffeensis were diagnosed in the summer, when ticks are more active. All patients had influenzalike symptoms with high fever. None of the cases was fatal. Three serum samples were also seroreactive for antibodies to E. canis, and one was also reactive to the human granulocytic ehrlichiosis (HGE) agent. The titer to the HGE agent in this patient was higher than the serum titer to E. chaffeensis, and the Western blot analysis also indicated that the HGE agent was the primary cause of infection. We present the first serologic evidence that the agents of human monocytic ehrlichiosis (HME) and HGE are present in Israel. Therefore, human ehrlichiosis should be included in the differential diagnoses for persons in Israel who have been exposed to ticks and have influenzalike symptoms.

We are living in an era in which AIDS is no longer a terminal disease. It has become a chronic treatable disease. HIV-1 patients are mostly treated in specialized clinics by specialists in cLinical immunology or infectious diseases. In Israel, there are seven authorized centers for the diagnosis and treatment of HIV/AIDS. The primary caregiver for patients (family physician or internist) has to know the risk factors, risk groups and cLinical situations which are highly related to HIV-1 infection. These situations obligate a high clinical suspicion for early detection and diagnosis of HIV-1 infection. Early diagnosis has high clinical, prognostic and even epidemiological value. In this review, we highlight the main clinical situations in which the primary care physician should conduct an HIV-1 test as part of the clinical and Laboratory workup performed on the patient.

The prevalence of allergic diseases has increased dramatically in the western world. In the last 2 decades, the frequency of asthma and allergic rhinitis has doubled. Allergen specific immunotherapy [SIT] has been used successfully for more than 100 years for the treatment of allergic disorders. Allergen SIT provides not only symptomatic relief, but it is potentially curative. The immunologic mechanisms of allergen SIT include all parts of the immune system. Regulatory T cells (TR1, Treg), have a major pivotal role in the success of immunotherapy. Along with the regulatory T cells, elevated suppressor cytokines (IL-10), suppression of TH2 cells, increasing titer of specific IgG4 and gradual decline in the number and function of basophils and mast cells also contribute to the success of the treatment (SIT). The above immune mechanisms are connected and related to each other acting at different times with the treatment with SIT. In this review we focused on the current knowledge and understanding of the different immune mechanisms which are involved in the success of SIT.

Cytokines play a major role in the innate and the adaptive immune responses. Since cytokines are very powerful messengers, several regulatory systems (in all levels: production, secretion, effect on target) control their action in order to prevent overstimulation of cytokines. Recently, a negative feedback of cytokine activity in the target cell, namely suppressor of cytokine signaling (SOCS) was defined. This regulatory system consist of 8 proteins (CIS.SOCS 1-7) n which each one of them specifically regulates one or more cytokines. Malfunction of the SOCS proteins may lead to unregulated activity of cytokines which may lead to the development of allergic and autoimmune disorders.

Major changes happened in the last decade in the HIV/AIDS pandemic. The disease is no longer limited to young age. Due to the effectiveness of HAART (Highly Active Anti-Retroviral Therapy) as well as new diagnosis in older age groups, many patients in AIDS centers are above 50 years of age.To determine the prevalence, demographics and clinical characteristics of newly diagnosed HIV/AIDS patients older than 50 years compared to younger newly diagnosed patients.Retrospective single center analysis of the demographics and clinical characterizations of 62 newly diagnosed HIV/AIDS patients over 50 years of age.The average age at diagnosis of the whole cohort was 39+/-16 years. There was a gradual increase in the age at diagnosis over the years, as well as the percent of patients above the age of 50 diagnosed with the disease. In comparison to younger patients, in the older group there were more males compared to females and less patients who acquired the HIV/AIDS in unprotected homosexual sex. Furthermore, CD4 cells counts were lower and viral load leveLs were higher at diagnosis in the older group. Despite good adherence, patients above the age of 50 don't achieve adequate immunological response and many are left with significant immunodeficiency (CD4200).The prevaLence of patients above the age of 50 Living with HIV/AIDS in Israel is rising. Programs aimed at prevention, education and screening for this unique group are mandatory. An AIDS center should adopt new programs and routines to cope with the increasing number of patients over the age of 50 Living with HIV/AIDS.