The impact of ECG synchronization during acquisition of left­atrium computed tomography model on radiation dose and arrhythmia recurrence rate after catheter ablation of atrial fibrillation - a prospective, randomized study.

BACKGROUND: The impact of ECG gating during computed tomography (CT) acquisition of left atrium (LA) model on radiation dose, image quality and ablation event-free survival rate after catheter ablation (CA) of atrial fibrillation (AF) is not well defined. METHODS: Sixty-two patients with paroxysmal atrial fibrillation were randomized for two types of LA CT (with vs without ECG gating) before CA. Pulmonary veins isolation was performed in all patients. Patients were followed for 12 months after CA. RESULTS: There was no difference between the groups in CA length (131.61±32.57 vs 119.84±33.18 min; p=0.108), CA fluoroscopy time (4.48±2.19 vs 3.89±1.83 min; p=0.251), CA fluoroscopy dose (3.99±2.79 vs 3.91 vs2.91 Gy*cm2; p=0.735), visual data quality (1.77±0.88 vs 2.0±0.63; p=0.102) and registration error (2.42±0.72 vs 2.43±0.46 mm; p=0.612). We found a significant difference in CT Dose index (89.55±5.99 vs 19.19±4.33 mGy; p<0.0001) and Dose Length product (1438.87±147.75 vs 328.21±73.83 mGy*cm; p<0.0001). Twelve months after CA, 25 of 31 patients in the gated group and 24 of 31 patients in the non-gated group were free of AF (80.65 vs 77.42 %; p=0.838). CONCLUSION: ECG gating of computed tomography of LA before AF ablation burdens patients with a four times higher radiation dose while improving neither the quality of CT model or fusion of CT with the electroanatomic map. As a result, it has no significant impact on arrhythmia recurrence rate after ablation (Tab. 3, Fig. 3, Ref. 25).

Down-regulation of the macrophage lineage through interaction with OX2 (CD200).

OX2 (CD200) is a broadly expressed membrane glycoprotein, shown here to be important for regulation of the macrophage lineage. In mice lacking CD200, macrophage lineage cells, including brain microglia, exhibited an activated phenotype and were more numerous. Upon facial nerve transection, damaged CD200-deficient neurons elicited an accelerated microglial response. Lack of CD200 resulted in a more rapid onset of experimental autoimmune encephalomyelitis (EAE). Outside the brain, disruption of CD200-CD200 receptor interaction precipitated susceptibility to collagen-induced arthritis (CIA) in mice normally resistant to this disease. Thus, in diverse tissues OX2 delivers an inhibitory signal for the macrophage lineage.

A humanized anti-CD3 antibody, HuM291, with low mitogenic activity, mediates complete and reversible T-cell depletion in chimpanzees.

BACKGROUND: An anti-CD3 antibody that reduces cytokine release syndrome (CRS) while maintaining immunosuppression would be a major advance in the treatment of acute allograft rejection. A humanized (Hu) anti-CD3 IgG2 Ab, HuM291 gamma2 M3 (HuM291; Protein Design Labs, Inc., Mountain View, CA), was engineered with mutations in the upper CH2 region of the Fc domain. The mutations were intended to reduce affinity for Fcgamma receptors, thought to be relevant to CRS. METHODS: In vitro studies using chimpanzee peripheral blood mononuclear cells (PBMCs) were conducted to characterize HuM291 and to establish an animal model. A multidose study was conducted in chimpanzees to evaluate the safety, pharmacokinetics, immunomodulatory activity, and immunogenicity of HuM291, when administered at doses ranging from 0.1 to 10 mg. RESULTS: HuM291 bound to and effectively downmodulated CD3 from chimpanzee PBMCs and stimulated substantially less cytokine secretion and proliferation of chimpanzee PBMCs compared with OKT3 (Orthoclone OKT3; Ortho Pharmaceutical Corp., Raritan, NJ). Multiple doses of HuM291 (0.1, 1.0, or 10 mg/dose) were not associated with adverse events, signs of toxicity, or CRS, despite cytokine release. HuM291 exhibited a long elimination t1/2 (81.5 hr) and, after three 10-mg doses, sustained serum concentrations > 1000 ng/ml were maintained for 1 week. Multiple 10-mg doses induced complete depletion of circulating CD2+CD3+ T cells for up to 10 days after the last dose; T cells recovered by Day 28. Anti-HuM291 Abs were observed in only 4 of 12 animals and were transient in 2 of those animals. CONCLUSIONS: In vitro, HuM291 is substantially less mitogenic than OKT3. In chimpanzees, HuM291 effectively depleted peripheral T cells without eliciting clinical signs of CRS, and recovered T cells were functionally normal.

HuM291, a humanized anti-CD3 antibody, is immunosuppressive to T cells while exhibiting reduced mitogenicity in vitro.

BACKGROUND: OKT3, a mouse monoclonal antibody (Ab) specific for the human CD3 complex on T cells, is a potent immunosuppressive agent used for the treatment of acute allograft rejection. The utility of the drug has been limited by a neutralizing anti-mouse Ab response and adverse side effects resulting from T cell activation and systemic cytokine release. T cell activation is caused by OKT3-mediated cross-linking of T cells and Fc receptor-bearing cells. Studies in the mouse model have shown that global T cell activation is not necessary for immunosuppression, as Fc receptor-nonbinding anti-CD3 Abs can suppress graft rejection in the absence of the activation effects seen with Fc receptor-binding Abs. Thus, a humanized anti-CD3 antibody with a low affinity for Fc receptors might improve immunosuppressive therapy by reducing the side effects associated with OKT3. METHODS: We developed a mouse monoclonal Ab, M291, which competes with OKT3 for binding to T cells. Humanized, complementary-determining region-grafted versions of M291 featuring various Fc were engineered, including a previously described IgG2 mutant deficient in Fc receptor binding (HuM291). RESULTS: Compared with OKT3 and HuM291-IgG1, HuM291 was significantly less mitogenic to T cells in vitro and induced the release of much lower levels of the cytokines tumor necrosis factor-alpha, interferon-gamma, and interleukin-10. Despite this reduction in T cell activation, HuM291 retained the ability to modulate the CD3 complex and inhibit the mixed lymphocyte reaction. CONCLUSIONS: When evaluated in vivo, HuM291 may be an immunosuppressive agent associated with less of the acute toxicity and immunogenicity seen with OKT3 therapy.

Activities of the triazole SCH 51048 against Coccidioides immitis in vitro and in vivo.

The activity of the novel triazole SCH 51048 was tested against Coccidioides immitis. SCH 51048 inhibited C. immitis in vitro; MICs for 13 isolates ranged from < or = 0.39 to 0.78 micrograms/ml, and minimum fungicidal concentrations ranged from < or = 0.39 to 1.6 micrograms/ml. In vivo, no mice treated with SCH 51048 at 2 to 50 mg/kg of body weight or 100 mg of fluconazole or itraconazole per kg died of systemic coccidioidomycosis, whereas 60 to 100% of the control mice died. SCH 51048 given at 25 or 50 mg/kg was curative, whereas fluconazole or itraconazole given at 100 mg/kg was not curative. Pharmacokinetic studies showed peak levels in serum of > 14 micrograms/ml, with an estimated half-life of > 12 h. SCH 51048 was 5- to 50-fold or more superior to fluconazole or itraconazole.

Therapy of systemic histoplasmosis in immunosuppressed mice with the triazole D0870.

Because histoplasmosis is a life-threatening disease in AIDS and other compromised patients, we examined the efficacy of D0870 (Zeneca) in immunosuppressed mice against systemic histoplasmosis. Oral therapy with fluconazole given once daily (QD) was ineffective in prolonging survival, whereas itraconazole given once or twice daily (BID), fluconazole given BID or D0870 given QD or given every other day (QOD) were efficacious (P < 0.001). Burdens of Histoplasma capsulatum in the liver and spleen of survivors showed that D0870 given QD or QOD and itraconazole given BID caused dose-responsive reduction of infectious burden. Infection was cleared more readily from the liver than from the spleen. Overall, D0870 was > or = 20-fold more efficacious than fluconazole or itraconazole and itraconazole was > ten-fold better than fluconazole for the treatment of systemic histoplasmosis in the immunosuppressed model.

A study of the prevalence of rotavirus infection in children with gastroenteritis admitted to an infectious diseases hospital.

In a 12 month survey of infants and children with gastroenteritis admitted to Fairfield Hospital, Melbourne, rotavirus was found in approximately 42% of patients. This virus was detected more often during the winter months, particularly in children aged between 12 months and 3 years. Detection of rotavirus by electron microscopy was found to be more sensitive than by counterimmunoelectrophoresis. Routine bacterial and viral studies revealed that bacterial pathogens and common enteric viruses were associated with relatively few cases of gastroenteritis. There is little doubt that rotavirus is the most important aetiological agent of acute gastroenteritis in yvirus is the most important aetiological agent of acute gastroenteritis in young children in Melbourne.

Down-regulation of poison ivy/oak-induced contact sensitivity by treatment with a class II MHC binding peptide:hapten conjugate.

Immune regulation of contact sensitivity to the poison ivy/oak catechol was studied at the level of class II MHC-restricted T cell recognition of hapten:peptide conjugates. In this study we have shown that 1) T cells from C3H/HeN (H-2k) mice, immunized with a synthetic I-Ak binding peptide coupled to 3-pentadecyl-catechol (PDC; a representative catechol in urushiol), recognized peptides derived from syngeneic cells linked to the same catechol; 2) T cells from draining lymph nodes of C3H/HeN mice skin-painted with PDC proliferated in response to a peptide carrier:PDC conjugate only when it was linked at the 7th, but not the 4th or the 10th, position on the peptide carrier; and 3) tolerization studies confirmed down-regulation of PDC-induced delayed-type hypersensitivity following treatment with a single I-Ak binding peptide carrying PDC covalently bound to a lysine residue at the middle (7th) TCR contact position. Tolerization with peptide:PDC conjugate resulted in abrogation of hapten-specific T cell proliferative responses that correlated with diminished IL-2 secretion. On the basis of these data we propose that it may be sufficient to couple the hapten at a single, well-chosen position on a carrier peptide to target a relevant population of T cells involved in contact sensitivity.