LDL receptor cooperates with LDL receptor-related protein in regulating plasma levels of coagulation factor VIII in vivo

Low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein (LRP) are members of the LDLR family of endocytic receptors. LRP recognizes a wide spectrum of structurally and functionally unrelated ligands, including coagulation factor VIII (FVIII). In contrast, the ligand specificity of LDLR is restricted to apolipoproteins E and B-100. Ligand binding to the LDLR family is inhibited by receptor-associated protein (RAP). We have previously reported that, apart from LRP, other RAP-sensitive mechanisms contribute to the regulation of FVIII in vivo. In the present study, we showed that the extracellular ligand-binding domain of LDLR interacts with FVIII in vitro and that binding was inhibited by RAP. The physiologic relevance of the FVIII-LDLR interaction was addressed using mouse models of LDLR or hepatic LRP deficiency. In the absence of hepatic LRP, LDLR played a dominant role in the regulation and clearance of FVIII in vivo. Furthermore, FVIII clearance was accelerated after adenovirus-mediated gene transfer of LDLR. The role of LDLR in FVIII catabolism was not secondary to increased plasma lipoproteins or to changes in lipoprotein profiles. We propose that LDLR acts in concert with LRP in regulating plasma levels of FVIII in vivo. This represents a previously unrecognized link between LDLR and hemostasis.     

Associations between alcohol intake and brain volumes in male and female moderate drinkers

BACKGROUND: Alcohol-dependent individuals have brain volume loss. Possibly, moderate drinkers who are not alcohol dependent have similar but less prominent brain damage. The authors investigated whether current or lifetime alcohol intake is related to volumes of total brain, cerebellum, ventricles, peripheral cerebrospinal fluid, and cerebral gray and white matter in moderate drinkers. METHODS: The relation between current or lifetime alcohol intake and brain volumes of 47 male moderate drinkers (current alcohol intake 20 drinks per week, lifetime alcohol intake 240 kg) and 44 female moderate drinkers (current alcohol intake 15 drinks per week, lifetime alcohol intake 170 kg), all without a personal or family history of alcohol dependence, was determined using high-resolution magnetic resonance images, corrected for intracranial volume, age, and sex. RESULTS: In males, mean lifetime alcohol intake was positively associated with cerebral white matter volume, particularly in the frontal region. In females, mean lifetime alcohol intake was not associated with brain volumes. Current alcohol intake was unrelated to brain volumes in either males or females. CONCLUSIONS: Neither current nor lifetime alcohol intake is associated with decreases in brain volumes in male or female moderate drinkers. Because all participants had a negative personal and family history of alcohol dependence, the current results relatively purely concern the effects of moderate alcohol intake on brain volumes.     

Intimate partner violence: associations with low infant birthweight in a South African birth cohort

Violence against women is a global public health problem. Exposure to intimate partner violence (IPV) during pregnancy has been associated with a number of adverse maternal and fetal outcomes, including delivery of a low birthweight (LBW) infant. However, there is a paucity of data from low-middle income countries (LMIC). We examined the association between antenatal IPV and subsequent LBW in a South African birth cohort. This study reports data from the Drakenstein Child Lung Health Study (DCLHS), a multidisciplinary birth cohort investigation of the influence of a number of antecedent risk factors on maternal and infant health outcomes over time. Pregnant women seeking antenatal care were recruited at two different primary care clinics in a low income, semi-rural area outside Cape Town, South Africa. Antenatal trauma exposure was assessed using the Childhood Trauma Questionnaire (CTQ) and an IPV assessment tool specifically designed for the purposes of this study. Potential confounding variables including maternal sociodemographics, pregnancy intention, partner support, biomedical and mental illness, substance use and psychosocial risk were also assessed. Bivariate and multiple regression analyses were performed to determine the association between IPV during pregnancy and delivery of an infant with LBW and/or low weight-for-age z (WAZ) scores. The final study sample comprised 263 mother-infant dyads. In multiple regression analyses, the model run was significant [r ² ?=?0.14 (adjusted r ² ?=?0.11, F(8, 212) = 4.16, p?=?0.0001]. Exposure to physical IPV occurring during the past year was found to be significantly associated with LBW [t?=??2.04, p?=?0.0429] when controlling for study site (clinic), maternal height, ethnicity, socioeconomic status, substance use and childhood trauma. A significant association with decreased WAZ scores was not demonstrated. Exposure of pregnant women to IPV may impact newborn health. Further research is needed in this field to assess the relevant underlying mechanisms, to inform public health policies and to develop appropriate trauma IPV interventions for LMIC settings.     

Effect of breastfeeding on immunogenicity of oral live-attenuated human rotavirus vaccine: a randomized trial in HIV-uninfected infants in Soweto,South Africa

Objective

To investigate the effect of abstention from breastfeeding, for an hour before and after each vaccination, on the immune responses of infants to two doses of rotavirus vaccine.

Methods

In Soweto, South Africa, mother–infant pairs who were uninfected with human immunodeficiency virus (HIV) were enrolled as they presented for the “6-week” immunizations of the infants. Each infant was randomly assigned to Group 1 – in which breastfeeding was deferred for at least 1 h before and after each dose of rotavirus vaccine – or Group 2 – in which unrestricted breastfeeding was encouraged. Enzyme-linked immunosorbent assays were used to evaluate the titres of rotavirus-specific IgA in samples of serum collected from each infant immediately before each vaccine dose and 1 month after the second dose. Among the infants, a fourfold or greater increase in titres of rotavirus-specific IgA following vaccination was considered indicative of seroconversion.

Findings

The evaluable infants in Group 1 (n = 98) were similar to those in Group 2 (n = 106) in their baseline demographic characteristics and their pre-vaccination titres of anti-rotavirus IgA. After the second vaccine doses, geometric mean titres of anti-rotavirus IgA in the sera of Group-1 infants were similar to those in the sera of Group-2 infants (P = 0.685) and the frequency of seroconversion in the Group-1 infants was similar to that in the Group-2 infants (P = 0.485).

Conclusion

Among HIV-uninfected South African infants, abstention from breastfeeding for at least 1 h before and after each vaccination dose had no significant effect on the infants’ immune response to a rotavirus vaccine.     

CD8 T cell immunity against human respiratory syncytial virus

Human respiratory syncytial virus (HRSV) was first discovered in the 1950s, but despite decades of research, a licensed vaccine against it is not available. Epidemiological studies indicate that antibodies directed against the fusion protein (F) partially correlate with protection. In addition, an F-specific monoclonal antibody is licensed as a prophylactic treatment in children who are at high risk of developing complications following HRSV infection. Therefore, most HRSV-oriented vaccination strategies focus on inducing a humoral immune response against F. In the quest for the development of a safe HRSV vaccine, the induction of a T cell immune response has received a lot less attention. T cell immunity directed against HRSV has not been associated unequivocally with protection against HRSV and CD4⁺ T helper cell responses may even worsen disease due to HRSV. However, many studies support a protective role for CD8⁺ T cells in clearance of HRSV from the lungs. In this review we highlight the clinical and experimental evidence in favor of a CD8⁺ T lymphocyte-based vaccination strategy to protect against HRSV. First, we describe how T cell responses and T cell memory are induced in the lungs upon respiratory viral infection. HRSV has evolved mechanisms that hamper CD8⁺ T cell priming and effector functions. We appraise the information on HRSV-specific CD8⁺ T cell immunity gained from laboratory mouse studies, taking into account the advantages and limitations of this animal model and, where possible, the accordance with clinical evidence. Finally, we focus on recent efforts to develop T cell based vaccines against HRSV.     

Optical coherence tomography: a quantitative tool to screen for papilledema in craniosynostosis

Purpose

Our aim was to evaluate if optical coherence tomography (OCT) can be used as an alternative for fundoscopy to screen for increased intracranial pressure (ICP) in children with craniosynostosis

Methods

We performed a prospective cohort study at the Dutch Craniofacial Centre. We included 38 patients with nonsyndromic scaphocephaly and Crouzon’s syndrome aged 3–8 years old, in whom we scored complaints suggestive of increased ICP and performed fundoscopy and OCT. Main outcome measures total retinal thickness (TRT) which was measured on 58 OCT scans.

Results

Forty-three percent of fundoscopies revealed pathologic changes of the papil in at least one eye. Retinal thickness was increased in patients with an abnormal fundoscopy as compared to patients with a normal papil (TRT p?<?0.001). Patients with Crouzon’s syndrome had a significantly increased retinal thickness as compared to patients with scaphocephaly (TRT p?<?0.001).

Conclusions

The current study demonstrates that OCT in children with craniosynostosis is feasible. It confirms that retinal thickness increases in case of papilledema. Given the quantitative character, OCT has a high potential as an alternative tool to screen for papilledema in craniosynostosis and other pediatric populations.     

Reliability and validity of a global question on self-reported chronic morbidity

Aim

A global question on chronic morbidity is included in many national health interview surveys. According to a recent EU Commission regulation, information on this item should be collected in all EU member states. However, little is known about the reliability and validity of such a question.

Subject and methods

The reliability of a global question on chronic morbidity was investigated among persons who participated in 2001 in both the Belgian health interview survey (HIS) and the national population census (n?=?2,871) by using kappa statistics and logistic regression. In addition, data from the HIS 2001 and 2004 (n?=?21,376) were used to study estimates and determinants of the sensitivity of this global chronic morbidity measure among people with specific chronic diseases.

Results

In terms of reliability, the kappa statistic showed only moderate agreement (0.559; 95 % CI 0.523–0.594). Additionally, the sensitivity of the global question on chronic morbidity ranged from 49.9 to 87.2 %, depending on the type of disease. A much higher sensitivity was observed among people who rated their health status to be moderate to bad (adjusted OR 3.85; 95 % CI 3.17–4.69).

Conclusion

Self-reported chronic morbidity, measured by a single and global question, is a reasonably reliable instrument to measure ill health. The global instrument provides useful information on the burden of disease, because it takes into account the relevance of the diseases for the people themselves.