Eli Magen

CTLA-4 upregulation during HIV infection: association with anergy and possible target for therapeutic intervention.

Objective To study the role of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) during HIV infection. Methods Intracellular CTLA-4 expression, determined by flow-cytometry, and proliferative responses to HIV antigens, were studied in peripheral blood mononuclear cells (PBMC) from 93 HIV-1-infected [HIV(+)] patients and 40 HIV-1 seronegative controls. Results The proportions of CTLA-4 expressing CD4+ T cells were: (1) significantly higher in HIV(+) patients, 10.95 ± 0.66%, than in controls, 6 ± 0.45% (P < 0.0001); (2) inversely correlated to CD4+ counts (r = −0.67, P < 0.005, n = 16, drug-naive patients;r = −0.57, P < 0.0001, n = 77, HAART-treated patients); and (3) positively correlated to proportion of activated (HLA-DR+CD3+) (r = 0.53, P < 0.0001) and memory (CD45RO+CD4+) T cells (r = 0.46, P < 0.001). CD28 median fluorescence intensity in CTLA-4- cells was twice that in CTLA-4+ cells (140 ± 5.3 versus 70 ± 2.28, P < 0.00001), whereas cells low in CD28 and CD4, expressed more CTLA-4 (P < 0.0001). Higher proportion of CTLA-4+CD4+ cells expressed CCR5 and Ki-67, in comparison with CTLA-4-CD4+ cells, (65 ± 11.9 and 25 ± 7.5% versus 27 ± 8.9 and 3.7 ± 2%, P < 0.0001 and P < 0.01, respectively). Among HAART-treated patients, with viral load below detectable levels, CD4+ cells increase was inversely correlated to %CTLA-4+CD4+ cells (r = −0.5, P = 0.003, n = 39). Proliferation of PBMC to anti-CD3, gp-120 depleted HIV-1 antigen or HIV-1 p24 stimulation was inversely correlated with CTLA-4 levels (r = −0.68, P = 0.0035;r = −0.38, P = 0.04; and r = −0.43, P = 0.028, respectively). Conclusions (1) CTLA-4 is upregulated during HIV infection and may therefore account for CD4 T-cell decline and anergy in HIV-1 infection. (2) Increased levels of CTLA-4 may undermine immune responses and in the HAART-treated patient-immune reconstitution. (3) Blocking of CTLA-4 may offer a novel approach for immune-based therapy in HIV infection.

Eradication of Helicobacter pylori infection equally improves chronic urticaria with positive and negative autologous serum skin test.

Background:  The aim of the study was to examine effects of Helicobacter pylori eradication on chronic idiopathic urticaria (CU) with and without positive aulogous serum skin test (ASST).

Increased Mean Platelet Volume and C-Reactive Protein Levels in Patients With Chronic Urticaria With a Positive Autologous Serum Skin Test

Introduction:Activation of the coagulation cascade resulting in thrombin production is a prominent feature of exacerbations in chronic spontaneous urticaria (CU). Autologous serum skin test (ASST) causes wheal-and-flare reactions in 30% to 50% of CU cases. Objective:The aim of this study was to evaluate the clinical and laboratory data in patients with CU with positive and negative ASST. To understand the role of platelets in CU, we investigated the relation between CU clinical severity, platelet count and their mean platelet volume (MPV). Methods:Clinical and laboratory data were prospectively collected from 373 patients with CU who attended our Allergy and Clinical immunology Clinic during the period 2003 to 2007. The laboratory data were compared with 46 healthy subjects. Results:There were no significant differences in platelet counts between the groups, nevertheless the platelets in ASST-positive CU patients were characterized by a higher MPV (9.12 ± 1.25 fl), than that in ASST-negative patients (7.95 ± 1.08 fl; P = 0.039) and control group (7.72 ± 1.04 fl; P = 0.007). There was a significant positive correlation between CU severity score and MPV in ASST-positive patients (r = 0.44; P < 0.001) but not in ASST-negative patients. Higher levels of C-reactive protein (5.31 ± 2.74 mg/L) were measured in the ASST-positive CU group compared with the ASST-negative CU group (2.53 ± 1.27; P = 0.029) and the control group (2.34 ± 1.38; P = 0.003). Conclusion:CU with positive ASST is characterized with higher clinical severity, increased MPV and C-reactive protein.

Chronic Opisthorchis felineus infection attenuates atherosclerosis – An autopsy study

Previously, we proposed a hypothesis that chronic helminthic infection may have beneficial effects on the development of atherosclerosis. The aim of this study was to investigate an association between Opisthorchis felineus chronic helminthic infections with aortic atherosclerosis and serum total cholesterol. A series of medico-legal autopsy specimens collected in Khanty-Mansiisk (the region in Russia endemic for O. felineus) were studied to assess O. felineus worm burden in cadaver livers. The areas of atherosclerotic lesions in the cadaver aortas were measured by visual planimetry. A family history of cardiovascular disease, smoking, hypertension or diabetes was elicited, and serum total cholesterol levels examined. Three hundred and nineteen cadavers (280 (87.8%) males and 39 (12.2%) females) aged 20-72 years were divided into five age groups: (i) 20-29, (ii) 30-39, (iii) 40-49, (iv) 50-59 and (v) >60 years old. The O. felineus mean worm burden was 257±312 worms/liver. Infected subjects were categorised into three subgroups depending on the worm burden: mild (<100 worms), moderate (100-500 worms) and severe (>500 worms). Infected subjects had lower serum total cholesterol (mild worm burden, 186.4±25.6 mg/dl; moderate worm burden, 183.4±23.1mg/dl, P=0.002; severe worm burden, 170.6±25.1mg/dl, P<0.001) than non-infected subjects (201.1±21.2 mg/dl). The average percentage of aortic surface covered by fatty streaks, fibrotic plaques and complicated lesions was negatively related to worm burden in the infected subjects. Chronic helminthic infections was a negative predictor of aortic atherosclerosis; with an odds ratio of 1.72 (1.02-2.91), P=0.041 for all subjects; and 3.19 (1.35-7.58), P=0.008 for subjects aged >40 years old. Opisthorchis felineus chronic helminthic infectionswas found to be associated with lower serum total cholesterol levels and a significant attenuation of atherosclerosis.

BiPAP Ventilation as Assistance for Patients Presenting with Respiratory Distress in the Department of Emergency Medicine

AbstractBackground: Noninvasive ventilatory support (NIVS) is intended to provide ventilatory assistance for a wide range of respiratory disturbances. The use of NIVS for treatment of respiratory distress may be applicable in the emergency department (ED). It may prevent endotracheal intubation and, likewise, may favorably influence the course of the patient’s hospitalization, depending on the primary disease or ventilatory disturbance. Objective: To evaluate the efficacy of bilevel positive airway pressure (BiPAP) ventilation in patients with acute respiratory distress presenting in the ED. Methods: A prospective, uncontrolled, nonrandomized, nonblind study enrolled 30 patients. They were cooperative and hemodynamically stable, aged over 18 years, and presented with acute respiratory distress as defined by predetermined criteria. They were connected to a BiPAP machine through a face mask, using an initial pressure of 8/3cm H2O, which was gradually raised to 12/7cm H2O inspiratory positive airway pressure/expiratory positive airway pressure. Standard drugs, inhalation and oxygen therapies were administered as needed. The BiPAP was disconnected either upon relief of respiratory distress or on deterioration of the patient’s condition. Results: Of the 30 patients in the study, 19 had cardiogenic pulmonary edema, four had acute asthma, three had exacerbation of COPD, three had pneumonia and one had malignant pleural effusion. BiPAP was instituted subsequent to failure of standard therapies. Twenty-six patients were classified as responders to the BiPAP ventilation and four as nonresponders (three patients were intubated after 1 hour and one patient 24 hours, post BiPAP). The total length of stay (LOS) in the ED was 3–5 hours and the mean LOS in hospital was 4.1 ± 1.5 days, versus 6.5 ± 1.2 days in LOS reports of similar patients in the same hospital during 1999, who did not undergo BiPAP ventilation. No other complications were observed. Conclusions: We found BiPAP ventilation simple, safe, effective and well tolerated by patients in respiratory distress. The rate of endotracheal intubation after successful BiPAP ventilation was low. In carefully selected patients with respiratory distress, BiPAP ventilation may successfully replace endotracheal intubation.

Chronic Urticaria can be Triggered by Eradication of Helicobacter pylori

Participation of Helicobacter pylori (HP) in the pathogenesis of chronic spontaneous urticaria (CU) is subject to dispute, although its eradication proved to be effective for some patients.

The effect of l-thyroxine treatment on chronic idiopathic urticaria and autoimmune thyroiditis

Autoimmune thyroiditis (AT) is more prevalent in patients with chronic idiopathic urticaria CIU) than in the general population. Previous small studies without any controlled comparison reported that CIU remits in patients with CIU and AT treated with l‐thyroxine. To determine whether l‐thyroxine treatment can improve the clinical course of CIU in patients with the co‐occurrence of AT and CIU. A total of 749 patients with CIU were retrospectively studied. Clinical and laboratory evaluation and classification of chronic urticaria were performed according to the EAACI/GA(2)LEN/EDF/WAO guidelines. After l‐thyroxine treatment for 53 ± 19 days, euthyroidism was restored in all subjects. Urticaria activity score (UAS) was evaluated at baseline and after three and six months. The control group consisted of matched 44 euthyroid subjects with CIU. A total of 44 (5.9%) patients were diagnosed to have hypothyroidism related to AT. Autologous serum skin test (ASST) was found to be positive in 17 (38.6%) of them. There was no statistically significant difference in baseline UAS, between the ASST+ (3.94 ± 1.52) and the ASST− (3.63 ± 1.42; P = 0.27) hypothyroid subjects and the euthyroid CIU controls (3.73 ± 1.74). During the l‐thyroxine treatment, a significant reduction of UAS was observed in both hypothyroid ASST+ and ASST− subjects. However, the mean UAS after three and six months of l‐thyroxine treatment remained not significantly different from that in control euthyroid subjects with CIU. l‐Thyroxine treatment has no effect on the course of CIU in patients with CIU and AT.

Potential Link Between C3a, C3b and Endothelial Progenitor Cells in Resistant Hypertension

Introduction:Endothelial progenitor cells (EPC) and complement C3 are involved in the pathophysiology of arterial hypertension. C3a is the negative regulator of progenitor cells egress during their mobilization from bone marrow. Previously, higher plasma concentration of C3 was observed in resistant arterial hypertension (RAH) than in controlled arterial hypertension (CAH). Thus, we hypothesized that RAH would be associated with complement C3 activation and reduced number of circulating EPCs. Objective:To compare C3a, C3b and their correlation with circulating EPC in subjects with RAH and CAH. Methods:Blood pressure was measured by electronic sphygmomanometer. EPCs were identified as CD34+/CD133+/KDR+ cells by flow cytometry. C3a and C3b were determined using enzyme-linked immunosorbent assay (Quidel, CA). Results:RAH group (n = 20) and CAH group (n = 20) and 17 healthy individuals (control group) were recruited. In the RAH group, C3a (858.1 ± 70.6 &mgr;g/dL) was higher than in the CAH group (816.1 ± 123.3 &mgr;g/dL; P < 0.001), and in the control group (751.3 ± 98.8; P < 0.001), C3b (564.1 ± 54.7 &mgr;g/dL) was higher than in the CAH group (490.2 ± 58.5 &mgr;g/dL; P < 0.001). In control group (456.3 ± 98.8; P < 0.001), statistically significant negative correlation was observed between C3a and blood levels of EPC (r = −0.523, P = 0.018); statistically significant positive correlation was observed between systolic blood pressure and blood levels of C3a (r = 0.52, P = 0.02) and between systolic blood pressure and blood levels of C3b (r = 0.57, P = 0.009). Conclusion:RAH is characterized by higher levels of C3 component fragments and a negative correlation between circulating C3a and EPCs.

Circulating endothelial progenitor cells, Th1/Th2/Th17-related cytokines, and endothelial dysfunction in resistant hypertension.

Introduction:A possible link between chronic vascular inflammation and arterial hypertension is now an object of intensive studies. Objective:To compare Th1/Th2/Th17 cells-related cytokines, circulating endothelial progenitor cells (EPC), and endothelial function in subjects with resistant arterial hypertension (RAH) and controlled arterial hypertension (CAH). Methods:Blood pressure was measured by electronic sphygmomanometer. EPC were identified as CD34+/CD133+/kinase insert domain receptor (KDR)+ cells by flow cytometry. Th1/Th2/Th17 cells-related cytokines were identified using the Human Th1/Th2/Th17 Cytokines MultiAnalyte ELISArray Kit. Endothelium-dependent (FMD) vasodilatation of brachial artery was measured by Doppler ultrasound scanning. Results:RAH group (n = 20) and CAH group (n = 20) and 17 healthy individuals (control group) were recruited. In the RAH group, lower blood levels of EPC number (42.4 ± 16.7 cells/mL) and EPC% (0.19 ± 0.08%) were observed than in the CAH group (93.1 ± 88.7 cells/mL; P = 0.017; 0.27 ± 0.17; P = 0.036) and control group (68.5 ± 63.6 cells/mL; P < 0.001; 0.28 ± 0.17%; P = 0.003), respectively. Plasma transforming growth factor-β1 levels were significantly higher in the RAH group (1767 ± 364 pg/mL) than in the CAH group (1292 ± 349; P < 0.001) and in control group (1203 ± 419 pg/mL; P < 0.001). In the RAH group, statistically significant negative correlation was observed between systolic blood pressure and EPC% (r = −0.72, P < 0.01). FMD in the RAH group was significantly lower (5.5 ± 0.8%) than in the CAH group (9.2 ± 1.4; P < 0.001) and in healthy controls (10.1 ± 1.1%; P < 0.001). Conclusion:RAH is characterized by reduced circulating EPC, substantial endothelial dysfunction, and increased plasma transforming growth factor-β1 levels.

Selective IgE deficiency, immune dysregulation, and autoimmunity.

Selective IgE deficiency (IgED) is currently defined as a significant decrease in serum levels of IgE (<2 kIU/L) in a patient whose other immunoglobulin levels are normal. There are no published large-scale epidemiological studies regarding the prevalence of and clinical features of IgED. In the population-based case-control study, we investigated clinical and laboratory characteristics of patients with IgED. Case samples were drawn from all subjects (n = 18487), with serum total IgE measurement during 2012 at Leumit Health Care Services (Israel) and had serum total IgE of <2 kIU/L. The control group was randomly sampled from the remaining 18,261 subjects with a case-control ratio of four controls for each case (1:4). Comorbid diseases were identified by specific International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes given by the corresponding board-certificated physicians. Two hundred twenty-six subjects showed serum total IgE levels of <2 kIU/L; 68 (30.9%) were between the ages of 4 and 12 years (children) and 250 (69.1%) were ≥12 years old (adults). Matched control groups were selected for each age group. The children group was characterized by higher prevalence of asthma and hyperreactive airways disease; and both children and adult groups had significantly higher prevalence of chronic sinusitis, otitis media, autoimmune, and oncological diseases than their respective controls. Undetectable serum total IgE may serve as a marker of immune dysregulation and autoimmunity.