Hereditary and acquired C1-inhibitor-dependent angioedema: from pathophysiology to treatment

Uncontrolled generation of bradykinin (BK) due to insufficient levels of protease inhibitors controlling contact phase (CP) activation, increased activity of CP proteins, and/or inadequate degradation of BK into inactive peptides increases vascular permeability via BK-receptor 2 (BKR2) and results in subcutaneous and submucosal edema formation. Hereditary and acquired angioedema due to C1-inhibitor deficiency (C1-INH-HAE and -AAE) are diseases characterized by serious and potentially fatal attacks of subcutaneous and submucosal edemas of upper airways, facial structures, abdomen, and extremities, due to inadequate control of BK generation. A decreased activity of C1-inhibitor is the hallmark of C1-INH-HAE (types 1 and 2) due to a mutation in the C1-inhibitor gene, whereas the deficiency in C1-inhibitor in C1-INH-AAE is the result of autoimmune phenomena. In HAE with normal C1-inhibitor, a significant percentage of patients have an increased activity of factor XIIa due to a FXII mutation (FXII-HAE). Treatment of C1-inhibitor-dependent angioedema focuses on restoring control of BK generation by inhibition of CP proteases by correcting the balance between CP inhibitors and BK breakdown or by inhibition of BK-mediated effects at the BKR2 on endothelial cells. This review will address the pathophysiology, clinical picture, diagnosis and available treatment in C1-inhibitor-dependent angioedema focusing on BK-release and its regulation.

• Key Messages

• Inadequate control of bradykinin formation results in the formation of characteristic subcutaneous and submucosal edemas of the skin, upper airways, facial structures, abdomen and extremities as seen in hereditary and acquired C1-inhibitor-dependent angioedema.

• Diagnosis of hereditary and acquired C1-inhibitor-dependent angioedema may be troublesome as illustrated by the fact that there is a significant delay in diagnosis; a certain grade of suspicion is therefore crucial for quick diagnosis.

• Submucosal edema formation in hereditary and acquired C1-inhibitor-dependent angioedema is potentially life threatening and can occur at any age.

• To date effective therapies for acute and prophylactic treatment are available.

     

Survival and Racial Differences of Non-Small Cell Lung Cancer in the United States Military

BACKGROUND

Lung cancer is the leading cause of cancer-related death in the United States (US) Military and worldwide, with non-small cell lung cancer (NSCLC) accounting for 87 % of cases.

OBJECTIVES

Using a US military cohort who receives equal and open access to healthcare, we sought to examine demographic, clinical features and outcomes with NSCLC.

DESIGN AND PARTICIPANTS

We conducted a retrospective cohort analysis of 4,751 patients, aged ≥ 18 years and diagnosed with a first primary NSCLC between 1 January 2003 and 31 December 2013 in the US Department of Defense (DoD) cancer registry.

MAIN MEASURES

Differences by patient and disease characteristics were compared using Chi-square and t-test. Kaplan Meier curves and Cox proportional hazards regression assessed overall survival.

RESULTS

The mean age at diagnosis was 66 years, 64 % were male, 72 % were Caucasian, 41 % were diagnosed at early stage, 77 % received treatment and 82 % had a history of tobacco use. Mean age at diagnosis was highest among Caucasians (67 years) and lowest among African Americans (AA; 62 years). Asian/Pacific Islanders (PI) were more likely to be female (p < 0.0001), have adenocarcinoma histology (p = 0.0003) and less likely to have a history of tobacco use (p < 0.0001) compared to other racial/ethnic groups. In multivariable survival analysis, older age, male gender, increasing stage, not receiving treatment, and tobacco history were associated with higher mortality risk. Untreated patients exhibited a 39 % higher mortality risk compared to treated patients (HR = 1.39; 95%CI = 1.23–1.57). Compared to Caucasian patients, Asian/PIs demonstrated a 20 % lower risk of death (HR = 0.80; 95%CI = 0.66–0.96). There was no difference in mortality risk between AAs and Hispanics compared to Caucasians.

CONCLUSION

The lack of significant outcome disparity between AAs and Caucasians and the earlier stage at diagnosis than usually seen in civilian populations suggest that equal access to healthcare may play a role in early detection and survival.KEY WORDS: military, lung cancer, survival outcomes     

Immune profile of pediatric renal transplant recipients following alemtuzumab induction

The incidence of developing circulating anti-human leukocyte antigen antibodies and the kinetics of T cell depletion and recovery among pediatric renal transplant recipients who receive alemtuzumab induction therapy are unknown. In a collaborative endeavor to minimize maintenance immunosuppression in pediatric renal transplant recipients, we enrolled 35 participants from four centers and treated them with alemtuzumab induction therapy and a steroid-free, calcineurin-inhibitor–withdrawal maintenance regimen. At 3 months after transplant, there was greater depletion of CD4⁺ than CD8⁺ T cells within the total, naive, memory, and effector memory subsets, although depletion of the central memory subset was similar for CD4⁺ and CD8⁺ cells. Although CD8⁺ T cells recovered faster than CD4⁺ subsets overall, they failed to return to pretransplant levels by 24 months after transplant. There was no evidence for greater recovery of either CD4⁺ or CD8⁺ memory cells than naïve cells. Alemtuzumab relatively spared CD4⁺CD25⁺FoxP3⁺ regulatory T cells, resulting in a rise in their numbers relative to total CD4⁺ cells and a ratio that remained at least at pretransplant levels throughout the study period. Seven participants (20%) developed anti-human leukocyte antigen antibodies without adversely affecting allograft function or histology on 2-year biopsies. Long-term follow-up is underway to assess the potential benefits of this regimen in children.The effects of alemtuzumab on T cell subsets have been extensively studied in adults since its introduction in the 1990s. It has been associated with profound depletion of total T cells and differential recovery among T cell subsets, with early and near-complete recovery of CD8⁺ T cells, but late, partial recovery of CD4⁺ T cells.^1–3 CD4⁺ memory T cells were relatively spared compared with other CD4⁺ subsets; some investigators reported preferential sparing of central memory (T_CM) cells, whereas others observed preferential sparing of the effector memory (T_EM) subset. Emergence of the T_EM subset, whether identified peripherally or in the allograft, has been associated with acute rejection, raising concerns about the tolerogenic potential of alemtuzumab.^1–4 Although the use of alemtuzumab was not associated with an increase in either FoxP3 expression or regulatory T cell counts in vitro, both transient and sustained expansion of regulatory T cells were observed when alemtuzumab was used in association with sirolimus in vivo.^2,5,6 Notwithstanding this, however, the combination of alemtuzumab and sirolimus in protocols free of calcineurin inhibitor (CNI) was associated with rates of acute rejection exceeding 20%, with a humoral rejection rate as high as 62.5%.^7,8 In the absence of long-term CNI treatment, alemtuzumab-treated adults may therefore have a propensity to develop alloantibodies and antibody-mediated rejection.^9,10In contrast, there is a paucity of data regarding the use of alemtuzumab in pediatric solid organ transplantation.¹¹ From a clinical perspective, two small series investigating the outcomes of selected high-risk recipients of renal, liver, and intestinal transplants treated with alemtuzumab yielded conflicting results, whereas a recent series of 42 renal transplant recipients of living donor grafts reported few cases of acute rejection and excellent graft function up to 4 years after transplant.^12–14 From a mechanistic perspective, only one study reported T cell counts in a single pediatric patient, demonstrating profound and prolonged depletion of CD3⁺, CD4⁺, CD8⁺, and CD20⁺ cells, with counts only reaching 50% of their baseline levels 12 months after transplant.¹²In this study, we investigated the longitudinal immune profiles of pediatric renal transplant recipients treated with alemtuzumab induction therapy, followed by a CNI-withdrawal regimen. Specific aims were to characterize the depletion and recovery patterns of various T cell subsets and to screen for anti-human leukocyte antigen (anti-HLA) antibody development.     

Risks of nonchromosomal birth defects,small-for-gestational age birthweight,and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth

Journal of Assisted Reproduction and Genetics - Excess embryos transferred (ET) (&gt; plurality at birth) and fetal heartbeats (FHB) at 6 weeks’ gestation are associated with reductions...     

Effects of oral soy protein on markers of inflammation in postmenopausal women with mild hypercholesterolemia

Background Nitric oxide (NO) may protect arteries against atherosclerosis, as suggested by experimental studies. Estrogen therapy enhances the bioactivity of NO in the vasculature of healthy postmenopausal women, but is not acceptable for long-term use by many women. Observational studies have demonstrated beneficial cardiovascular effects of soy protein in premenopausal and postmenopausal women. We examined whether the consumption of isolated soy protein may improve markers of vascular inflammation in postmenopausal women with hypercholesterolemia. Methods and Results In a randomized, double-blind, placebo-controlled, crossover study, 24 postmenopausal women with hypercholesterolemia received 25 g of soy protein or a placebo daily for 6 weeks, with treatment periods separated by 1 month. Markers of vascular inflammation were measured by enzyme-linked immunosorbent assay methods, including: soluble interleukin-2 receptor (sIL-2r), E-selectin, P-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). There was no effect of soy protein in comparison with placebo on the inflammatory markers: the sIL-2r level was 942.2 ± 335.3 pg/mL with soy protein and 868.5 ± 226.9 pg/mL with placebo (P = .311); E-selectin was 39.6 ± 16.5 ng/mL with soy protein and 42.1 ± 17.6 ng/mL with placebo (P = .323); P-selectin was 157.9 ± 67.9 ng/mL with soy protein and 157.5 ± 47.6 ng/mL with placebo, (P = .977); ICAM-1 was 266.0 ± 81.3 ng/mL with soy protein and 252.5 ± 82.7 ng/mL with placebo (P = .435); VCAM-1 was 402.7 ± 102.1 ng/mL with soy protein and 416.4 ± 114.8 ng/mL with placebo (P = .53). Conclusions Consumption of 25 g of isolated soy protein daily for 6 weeks does not substantially affect markers of vascular inflammation in postmenopausal women with hypercholesterolemia. (Am Heart J 2003;145:e7.)