Solid-phase immunoglobulins IgG and IgM activate macrophages with solid-phase IgM acting via a novel scavenger receptor a pathway.

IgG may accelerate atherosclerosis via ligation of proinflammatory Fcγ receptors; however, IgM is unable to ligate FcγR and is often considered vasculoprotective. IgM aggravates ischemia-reperfusion injury, and solid-phase deposits of pure IgM, as seen with IgM-secreting neoplasms, are well known clinically to provoke vascular inflammation. We therefore examined the molecular mechanisms by which immunoglobulins can aggravate vascular inflammation, such as in atherosclerosis. We compared the ability of fluid- and solid-phase immunoglobulins to activate macrophages. Solid-phase immunoglobulins initiated prothrombotic and proinflammatory functions in human macrophages, including NF-κB p65 activation, H(2)O(2) secretion, macrophage-induced apoptosis, and tissue factor expression. Responses to solid-phase IgG (but not to IgM) were blocked by neutralizing antibodies to CD16 (FcγRIII), consistent with its known role. Macrophages from mice deficient in macrophage scavenger receptor A (SR-A; CD204) had absent IgM binding and no activation by solid-phase IgM. RNA interference-mediated knockdown of SR-A in human macrophages suppressed activation by solid-phase IgM. IgM binding to SR-A was demonstrated by both co-immunoprecipitation studies and the binding of fluorescently labeled IgM to SR-A-transfected cells. Immunoglobulins on solid-phase particles around macrophages were found in human plaques, increased in ruptured plaques compared with stable ones. These observations indicate that solid-phase IgM and IgG can activate macrophages and destabilize vulnerable plaques. Solid-phase IgM activates macrophages via a novel SR-A pathway.

Intrapleural injection of OK-432 as the primary in-utero treatment for fetal chylothorax.

Chylothorax is a rare congenital condition associated with significant perinatal mortality and morbidity. Previous treatments with repeated thoracocentesis or thoracoamniotic shunting were technically demanding, and associated with significant procedure-related complications and neonatal complications. Here we report the first successful case in Hong Kong treated by a simple and effective intervention, namely pleurodesis with OK-432, in a fetus presenting at 20 weeks of gestation with bilateral pleural effusion.

Decay-accelerating factor suppresses complement C3 activation and retards atherosclerosis in low-density lipoprotein receptor-deficient mice.

Decay-accelerating factor (DAF; CD55) is a membrane protein that regulates complement pathway activity at the level of C3. To test the hypothesis that DAF plays an essential role in limiting complement activation in the arterial wall and protecting from atherosclerosis, we crossed DAF gene targeted mice (daf-1(-/-)) with low-density lipoprotein-receptor deficient mice (Ldlr(-/-)). Daf-1(-/-)Ldlr(-/-) mice had more extensive en face Sudan IV staining of the thoracoabdominal aorta than Ldlr(-/-) mice, both following a 12-week period of low-fat diet or a high-fat diet. Aortic root lesions in daf-1(-/-)Ldlr(-/-) mice on a low-fat diet showed increased size and complexity. DAF deficiency increased deposition of C3d and C5b-9, indicating the importance of DAF for downstream complement regulation in the arterial wall. The acceleration of lesion development in the absence of DAF provides confirmation of the proinflammatory and proatherosclerotic potential of complement activation in the Ldlr(-/-) mouse model. Because upstream complement activation is potentially protective, this study underlines the importance of DAF in shielding the arterial wall from the atherogenic effects of complement.

Brief report: accelerated atherosclerosis in low-density lipoprotein receptor-deficient mice lacking the membrane-bound complement regulator CD59.

OBJECTIVE: Whereas studies in humans and animal models have suggested a role for complement activation in atherosclerosis, there has been little analysis of the importance of complement regulators. We tested the hypothesis that the terminal pathway inhibitor CD59 plays an essential role in limiting the proinflammatory effects of complement activation. METHODS AND RESULTS: CD59 gene targeted mice (CD59a(-/-)) mice were crossed with low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice. CD59-deficient Ldlr(-/-) mice had significantly more extensive en face Sudan IV staining of thoracoabdominal aorta than Ldlr(-/-) single knock-outs, both after a low-fat diet (6.51+/-0.36% versus 2.63+/-0.56%, P<0.001) or a high-fat diet (17.05+/-2.15% versus 7.69+/-1.17%, P<0.004). Accelerated lesion formation in CD59a(-/-)/Ldlr(-/-) mice on a high-fat diet was associated with increased lesional vascular smooth muscle cell (VSMC) number and fibrous cap formation. CONCLUSIONS: Our data show that CD59 deficiency accelerates the development of lesions and increases plaque VSMC composition. Assuming that the main function of CD59 is to prevent the development of C5b-9 membrane attack complexes, our observations are consistent with the terminal complement pathway having proatherogenic potential in the Ldlr(-/-) mouse model, and highlight the importance of complement regulation.

Use of birth weight threshold for macrosomia to identify fetuses at risk of shoulder dystocia among Chinese populations.

OBJECTIVE: To assess the incidence of macrosomia and the influence of birth weight on shoulder dystocia risk among a cohort of Chinese women. METHODS: A retrospective analysis was conducted of 80953 singleton deliveries recorded at the Prince of Wales Hospital, Hong Kong, between 1995 and 2009. The incidences of macrosomia (birth weight ≥ 4000 g) and shoulder dystocia were assessed by birth weight; risk factors for shoulder dystocia were examined by multiple logistic regression analysis. RESULTS: The incidence of macrosomia was 3.4%. The overall incidence of shoulder dystocia was 0.3%; however, the incidence rose with increasing birth weight. The odds ratio (OR) for a birth weight of 4000-4199 g was 22.40, while the OR for a birth weight of 4200 g or above was 76.10. Other independent risk factors for shoulder dystocia included instrumental delivery (OR 12.11), short stature (OR 2.16), maternal diabetes mellitus (OR 1.78), and obesity (OR 1.58). CONCLUSION: Although the overall incidences of macrosomia and shoulder dystocia were low, the risk of shoulder dystocia was strongly linked to increasing birth weight. International guidelines for elective cesarean delivery in suspected cases of macrosomia may not, therefore, apply to Chinese women.

External cephalic version does not increase the risk of intra-uterine death: a 17-year experience and literature review.

OBJECTIVE: To assess the risk of intra-uterine death (IUD) after external cephalic version (ECV). METHODS: In this retrospective cohort study, 1078 consecutive ECVs performed between January 1994 and March 2011 in an University teaching hospital were extracted from the computerized database to examine the risk of IUD after ECV. RESULTS: A total of 1078 consecutive ECVs were performed over the study period. The overall successful rate was 72.8%, the successful rate was 63.1% in nulliparous and 82.7% in multiparous, respectively (p < 0.001). There was no IUD identified within 24 h after the procedure and there was only one case of IUD (0.09%) that occurred 4 weeks after an uncomplicated ECV. CONCLUSIONS: ECV is a safe procedure that does not increase the risk of IUD within and after 24 h of enrollment irrespective of outcome of ECV. Our findings have important clinical implication in terms of patient counseling regarding the decision on term breech management.

Breastfeeding initiation: is this influenced by maternal hepatitis B infection?

OBJECTIVE: To elucidate the effect of hepatitis B virus (HBV) infection on breastfeeding uptake in Chinese mothers in an endemic region. PATIENTS AND METHODS: A retrospective cohort study on 63 885 consecutive pregnant delivered between January 1997 and June 2008, were extracted from computerized database to examine the relationship between breastfeeding uptake and maternal HBV status, adjusted for demographic factors. RESULTS: A total of 6593 (10.3%) women were hepatitis B surface antigen (HBsAg)-positive, with an annual prevalence of around 10%. In the study period, 29 869 (46.8%) practised breastfeeding, and its prevalence ranged from 35.4 to 54.8% with an increasing trend throughout the years (p < 0.001). HBsAg-positive mothers had a significantly lower rate of breastfeeding (39.2 vs. 47.6% p < 0.001). Multiparas had higher incidence of HBV infection (10.9 vs. 9.8%, p < 0.001) and lower breastfeeding rate (42.2% versus 51.0%, p < 0.001) when compared with primiparas. Among those factors, maternal HBV infection had the strongest negative association with breastfeeding (adjusted odd ratio (aOR) = 0.726, 95% confidence interval (CI): 0.689-0.765). CONCLUSIONS: Our results suggested maternal HBV infection was one of the factors for the persistently low breastfeeding rate in Hong Kong over the past decades. To promote breastfeeding, it is necessary to generate definitive data on its safety regarding to mother-to-child transmission (MTCT) of HBV in order to allay the fear and anxiety in HBsAg-positive mothers.

Determinants of hepatitis B vaccine uptake among pregnant Chinese women in Hong Kong.

OBJECTIVE: To determine the prevalence of a history of hepatitis B vaccination among pregnant Chinese women in Hong Kong, and to identify factors associated with vaccine uptake at their own expense. METHODS: A prospective, cross-sectional survey was conducted in a university obstetric unit in Hong Kong. Pregnant Chinese women who attended the prenatal clinic were invited to complete a self-administered questionnaire, which requested details of their history of hepatitis B vaccination and sociodemographic characteristics. RESULTS: The prevalence of hepatitis B vaccine uptake was 33%. The following factors were associated with higher hepatitis B vaccine uptake: employment as a healthcare worker; a higher education level; higher monthly family income; routine medical checkups; and premarital checkups. CONCLUSION: The findings suggest that the public has insufficient awareness of hepatitis B infection in the community and that providing better information and education to the general public is necessary.

KLF2-dependent, shear stress-induced expression of CD59: a novel cytoprotective mechanism against complement-mediated injury in the vasculature.

Complement activation may predispose to vascular injury and atherogenesis. The atheroprotective actions of unidirectional laminar shear stress led us to explore its influence on endothelial cell expression of complement inhibitory proteins CD59 and decay-accelerating factor. Human umbilical vein and aortic endothelial cells were exposed to laminar shear stress (12 dynes/cm(2)) or disturbed flow (+/- 5 dynes/cm(2) at 1Hz) in a parallel plate flow chamber. Laminar shear induced a flow rate-dependent increase in steady-state CD59 mRNA, reaching 4-fold at 12 dynes/cm(2). Following 24-48 h of laminar shear stress, cell surface expression of CD59 was up-regulated by 100%, whereas decay-accelerating factor expression was unchanged. The increase in CD59 following laminar shear was functionally significant, reducing C9 deposition and complement-mediated lysis of flow-conditioned endothelial cells by 50%. Although CD59 induction was independent of PI3-K, ERK1/2 and nitric oxide, an RNA interference approach demonstrated dependence upon an ERK5/KLF2 signaling pathway. In contrast to laminar shear stress, disturbed flow failed to induce endothelial cell CD59 protein expression. Likewise, CD59 expression on vascular endothelium was significantly higher in atheroresistant regions of the murine aorta exposed to unidirectional laminar shear stress, when compared with atheroprone areas exposed to disturbed flow. We propose that up-regulation of CD59 via ERK5/KLF2 activation leads to endothelial resistance to complement-mediated injury and protects from atherogenesis in regions of laminar shear stress.

Complement C1q reduces early atherosclerosis in low-density lipoprotein receptor-deficient mice.

We explored the role of the classic complement pathway in atherogenesis by intercrossing C1q-deficient mice (C1qa-/-) with low-density lipoprotein receptor knockout mice (Ldlr-/-). Mice were fed a normal rodent diet until 22 weeks of age. Aortic root lesions were threefold larger in C1qa-/-/Ldlr-/- mice compared with Ldlr-/- mice (3.72 +/- 1.0% aortic root versus 1.1 +/- 0.4%; mean +/- SEM, P < 0.001). Furthermore, the cellular composition of lesions in C1qa-/-/Ldlr-/- was more complex, with an increase in vascular smooth muscle cells. The greater aortic root lesion size in C1qa-/-/Ldlr-/- mice occurred despite a significant reduction in C5b-9 deposition per lesion unit area, suggesting the critical importance of proximal pathway activity. Apoptotic cells were readily detectable by cleaved caspase-3 staining, terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and electron microscopy in C1qa-/-/Ldlr-/-, whereas apoptotic cells were not detected in Ldlr-/- mice. This is the first direct demonstration of a role for the classic complement pathway in atherogenesis. The greater lesion size in C1qa-/-/Ldlr-/- mice is consistent with the emerging homeostatic role for C1q in the disposal of dying cells. This study suggests the importance of effective apoptotic cell removal for containing the size and complexity of early lesions in atherosclerosis.