Kirsten Alexandra Eberhardt

BDNF/TrkB signaling regulates HNK-1 carbohydrate expression in regenerating motor nerves and promotes functional recovery after peripheral nerve repair.

Functional recovery after peripheral nerve injury is often poor despite high regenerative capacity of peripheral neurons. In search for novel treatments, brief electrical stimulation of the acutely lesioned nerve has recently been identified as a clinically feasible approach increasing precision of axonal regrowth. The effects of this stimulation appear to be mediated by BDNF and its receptor, TrkB, but the down-stream effectors are unknown. A potential candidate is the HNK-1 carbohydrate known to be selectively reexpressed in motor but not sensory nerve branches of the mouse femoral nerve and to enhance growth of motor but not sensory axons in vitro. Here, we show that short-term low-frequency electrical stimulation (1 h, 20 Hz) of the lesioned and surgically repaired femoral nerve in wild-type mice causes a motor nerve-specific enhancement of HNK-1 expression correlating with previously reported acceleration of muscle reinnervation. Such enhanced HNK-1 expression was not observed after electrical stimulation in heterozygous BDNF or TrkB-deficient mice. Accordingly, the degree of proper reinnervation of the quadriceps muscle, as indicated by retrograde labeling of motoneurons, was reduced in TrkB+/- mice compared to wild-type littermates. Also, recovery of quadriceps muscle function, evaluated by a novel single-frame motion analysis approach, and axonal regrowth into the distal nerve stump, assessed morphologically, were considerably delayed in TrkB+/- mice. These findings indicate that BDNF/TrkB signaling is important for functional recovery after nerve repair and suggest that up-regulation of the HNK-1 glycan is linked to this phenomenon.

Impacts of lesion severity and tyrosine kinase receptor B deficiency on functional outcome of femoral nerve injury assessed by a novel single‐frame motion analysis in mice

Functional recovery after peripheral nerve injury is often poor. Comprehension of cellular and molecular mechanisms limiting or promoting restoration of function and design of efficient therapeutic approaches remain serious challenges for neuroscience and medicine. Progress has been restricted by the lack of reliable methods for evaluation of motor functions in laboratory animals. We describe a novel approach for assessment of muscle function in mice after femoral nerve damage, an injury causing impairment of knee extension. The functional deficit can be precisely estimated by angle and distance measurements on single video frames recorded during movements of the animals with or without body weight support. Using this method we describe here the precise time‐course and degree of functional recovery after femoral nerve crush and transection. In addition, we show that restoration of function is considerably impaired in mice with a reduced expression level of the tyrosine kinase receptor B, a cognate receptor for the neurotrophin brain‐derived neurotrophic factor. This finding is consistent with known functions of brain‐derived neurotrophic factor and tyrosine kinase receptor B and demonstrates the potential of the method. The principles of the approach are highly relevant for the development of novel functional assays in other peripheral and, in particular, central nervous system injury paradigms.

No association between antenatal common mental disorders in low-obstetric risk women and adverse birth outcomes in their offspring: results from the CDS study in Ghana and Côte D'Ivoire.

Background Evidence linking common mental disorders (CMD) in pregnant women to adverse birth outcomes is inconsistent, and studies often failed to control for pregnancy complications. This study aimed to explore the association between antenatal depression and anxiety symptoms and birth outcomes in a low-obstetric risk sample of mother/child dyads in Ghana and Côte d’Ivoire. Methods In 2010-2011, a prospective cohort of 1030 women in their third trimester in Ghana and Côte d’Ivoire was enrolled. Depression and anxiety were assessed in the third trimester using the Patient Health Questionnaire depression module and the 7-item Generalized Anxiety Disorder scale. 719 mother/child dyads were included in the analysis. We constructed multivariate regression models to estimate the association between CMD and low birth weight (LBW), and preterm birth (PTB) to control for potential confounders. Results The prevalence of depression and anxiety symptoms were 28.9% and 14.2% respectively. The mean birth weight was 3172.1g (SD 440.6) and the prevalence of LBW was 1.7%. The mean gestational age was 39.6 weeks and the proportion of PTB was 4%. Multivariate linear regression revealed no significant association between maternal depression (B=52.2, 95% CI -18.2 122.6, p=0.15) or anxiety (B=17.1, 95% CI -74.6 108.7, p=0.72) and birth weight. Yet, low socio-economic status, female sex of the child, and younger maternal age were associated with lower birth weight. Multivariate logistic regression suggested no significant association between maternal depression (OR: 2.1, 95% CI 0.8 5.6, p=0.15) or anxiety (OR: 1.8, 95% CI 0.6 5.5, p=0.29) with PTB. Conclusions Our data suggests that depression and/or anxiety in the 3rd trimester of pregnancy are not independent predictors of adverse birth outcomes in low obstetric risk women. The role of pregnancy complications as confounders or effect modifiers in studies of maternal CMD and their impact on birth outcomes should be investigated.

CD25+FoxP3+ memory CD4 T cells are frequent targets of HIV infection in vivo

ABSTRACT Interleukin 2 (IL-2) signaling through the IL-2 receptor alpha chain (CD25) facilitates HIV replication in vitro and facilitates homeostatic proliferation of CD25+ FoxP3+ CD4+ T cells. CD25+ FoxP3+ CD4+ T cells may therefore constitute a suitable subset for HIV infection and plasma virion production. CD25+ FoxP3+ CD4+ T cell frequencies, absolute numbers, and the expression of CCR5 and cell cycle marker Ki67 were studied in peripheral blood from HIV+ and HIV− study volunteers. Different memory CD4+ T cell subsets were then sorted for quantification of cell-associated HIV DNA and phylogenetic analyses of the highly variable EnvV1V3 region in comparison to plasma-derived virus sequences. In HIV+ subjects, 51% (median) of CD25+ FoxP3+ CD4+ T cells expressed the HIV coreceptor CCR5. Very high frequencies of Ki67+ cells were detected in CD25+ FoxP3+ memory CD4+ T cells (median, 27.6%) in comparison to CD25− FoxP3− memory CD4+ T cells (median, 4.1%; P < 0.0001). HIV DNA content was 15-fold higher in CD25+ FoxP3+ memory CD4+ T cells than in CD25− FoxP3− T cells (P = 0.003). EnvV1V3 sequences derived from CD25+ FoxP3+ memory CD4+ T cells did not preferentially cluster with plasma-derived sequences. Quasi-identical cell-plasma sequence pairs were rare, and their proportion decreased with the estimated HIV infection duration. These data suggest that specific cellular characteristics of CD25+ FoxP3+ memory CD4+ T cells might facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. The contribution of this cell population to plasma virion production remains unclear. IMPORTANCE Despite recent advances in the understanding of AIDS virus pathogenesis, which cell subsets support HIV infection and replication in vivo is incompletely understood. In vitro, the IL-2 signaling pathway and IL-2-dependent cell cycle induction are essential for HIV infection of stimulated T cells. CD25+ FoxP3+ memory CD4 T cells, often referred to as regulatory CD4 T cells, depend on IL-2 signaling for homeostatic proliferation in vivo. Our results show that CD25+ FoxP3+ memory CD4+ T cells often express the HIV coreceptor CCR5, are significantly more proliferative, and contain more HIV DNA than CD25− FoxP3− memory CD4 T cell subsets. The specific cellular characteristics of CD25+ FoxP3+ memory CD4+ T cells probably facilitate efficient HIV infection in vivo and passage of HIV DNA to cell progeny in the absence of active viral replication. However, the contribution of this cell subset to plasma viremia remains unclear.

Travelers to the FIFA world cup 2014 in Brazil: Health risks related to mass gatherings/sports events and implications for the Summer Olympic Games in Rio de Janeiro in 2016.

BACKGROUND Health threats during mass gatherings, such as the FIFA world cup 2014 differ from traditional health risks. The influence of event type, demographics of attendees and environmental conditions are still not fully understood. METHODS An observational, prospective case-control survey conducted at the Frankfurt international airport in Germany on 544 travelers to the FIFA world cup 2014 and 432 regular travelers to Brazil departing after the end of the world cup. RESULTS Travelers to the FIFA world cup 2014 were predominantly male whereas the gender distribution in the control group was more balanced. The majority in both groups obtained insect bites and sunburns as environmental risk factors. Every third traveler suffered from diarrheal complaints in both groups, whereas the proportion of travelers with flu-like symptoms was higher in the case group. Travelers to the FIFA world cup 2014 indicated alcohol intake and sexual contacts outside of a relationship more frequently than travelers in the control group. CONCLUSIONS The additional health risks of travelers to sporting events as the FIFA world cup 2014 should be addressed in addition to traditional health threats in pre-travel counseling for the Summer Olympic Games 2016 in Brazil.

Group B Streptococci serotype distribution in pregnant women in Ghana: assessment of potential coverage through future vaccines

Group B streptococcal (GBS) colonization of pregnant women can lead to subsequent infection of the new‐born and potentially fatal invasive disease. Data on GBS colonization prevalence and serotype distribution from Africa are scarce, although GBS‐related infections are estimated to contribute substantially to infant mortality. In recent years, GBS vaccine candidates provided promising results in phase I and II clinical trials. We aimed to assess the prevalence and serotype distribution of GBS in Ghana since this knowledge is a prerequisite for future evaluation of vaccine trials.

Helicobacter pylori Infection Is Associated with Higher CD4 T Cell Counts and Lower HIV-1 Viral Loads in ART-Naïve HIV-Positive Patients in Ghana.

Background Worldwide, there is a high co-endemicity of HIV and H. pylori infection and there is growing evidence that H. pylori co-infection is associated with parameters of HIV disease progression. The objective of this study was to investigate the prevalence of H. pylori infection, and the association with clinical, immunological and virological parameters in a large cohort of HIV-infected individuals and uninfected controls in a West African country. Methods HIV-patients (n = 1,095) and HIV-negative individuals (n = 107) were recruited at a university hospital in Ghana. H. pylori status was determined using stool antigen testing. HIV-related, clinical and socio-demographic parameters were recorded and analyzed according to H. pylori status. Results The prevalence of H. pylori infection was significantly lower in HIV-positive compared to HIV-negative individuals (51.5 vs. 88%, p<0.0001). In HIV patients, H. pylori prevalence decreased in parallel with CD4+ T cell counts. In ART-naïve HIV-infected individuals, but not in those taking ART, H. pylori infection was associated with higher CD4 cell counts (312 vs. 189 cells/μL, p<0.0001) and lower HIV-1 viral loads (4.92 vs. 5.21 log10 copies/mL, p = 0.006). The findings could not be explained by socio-demographic confounders or reported use of antibiotics. Having no access to tap water and higher CD4+ T cell counts were identified as risk factors for H. pylori infection. Conclusions H. pylori prevalence was inversely correlated with the degree of immunosuppression. In ART-naïve individuals, H. pylori infection is associated with favorable immunological and virological parameters. The underlying mechanisms for this association are unclear and warrant investigation.

Helicobacter pylori Coinfection Is Associated With Decreased Markers of Immune Activation in ART-Naive HIV-Positive and in HIV-Negative Individuals in Ghana

BACKGROUND Helicobacter pylori coinfection in human immunodeficiency virus (HIV) patients has been associated with higher CD4+ cell counts and lower HIV-1 viral loads, with the underlying mechanisms being unknown. The objective of this study was to investigate the impact of H. pylori infection on markers of T-cell activation in HIV-positive and HIV-negative individuals. METHODS In a cross-sectional, observational study, HIV patients (n = 457) and HIV-negative blood donors (n = 79) presenting to an HIV clinic in Ghana were enrolled. Data on clinical and sociodemographic parameters, CD4+/CD8+ T-cell counts, and HIV-1 viral load were recorded. Helicobacter pylori status was tested using a stool antigen test. Cell surface and intracellular markers related to T-cell immune activation and turnover were quantified by flow cytometry and compared according to HIV and H. pylori status. RESULTS Helicobacter pylori infection was associated with decreased markers of CD4+ T-cell activation (HLA-DR+CD38+CD4+; 22.55% vs 32.70%; P = .002), cell proliferation (Ki67; 15.10% vs 26.80%; P = .016), and immune exhaustion (PD-1; 32.45% vs 40.00%; P = .005) in 243 antiretroviral therapy (ART)-naive patients, but not in 214 patients on ART. In HIV-negative individuals, H. pylori infection was associated with decreased frequencies of activated CD4+ and CD8+ T cells (6.31% vs 10.40%; P = .014 and 18.70% vs 34.85%, P = .006, respectively). CONCLUSIONS Our findings suggest that H. pylori coinfection effectuates a systemic immune modulatory effect with decreased T-cell activation in HIV-positive, ART-naive patients but also in HIV-negative individuals. This finding might, in part, explain the observed association of H. pylori infection with favorable parameters of HIV disease progression. CLINICAL TRIALS REGISTRATION Clinicaltrials.gov NCT01897909.

Trajectories of maternal ante- and postpartum depressive symptoms and their association with child- and mother-related characteristics in a West African birth cohort study

Background The vast majority of research on mental health has been undertaken in high income countries. This study aimed at investigating the long-term course of maternal depressive symptoms and its association with various mother- and child-related characteristics in two West African lower middle income countries with focus on the relationship with long-term anxiety symptoms. Methods In the Child Development Study, a prospective birth cohort study in Côte d’Ivoire and Ghana, the 9-item Patient Health Questionnaire (PHQ-9) was answered by N = 776 women 3 months antepartum, and 3, 12, and 24 months postpartum between April 2010 and March 2014. Growth mixture modeling was used to identify distinct trajectories of depressive symptoms. Several psychosocial, obstetric, and sociodemographic characteristics were assessed and multinomial regression analysis was performed to investigate the influence of these variables on the different depression trajectories. Results We found three distinct classes of depressive symptoms that were characterized by an asymptomatic trajectory (91.5%), by recurrent risk (4.3%) and by postnatal risk (4.3%). The longitudinal course of depressive symptoms was strongly associated with anxiety symptoms (χ2 = 258.54, df = 6, p < 0.001; φ = .577). Among other factors, higher levels of anxiety, new pregnancy 2 years after birth, economic stress, and family stress were associated with the risk classes. Conclusions A substantial proportion of West African women in our sample developed unfavorable patterns of depressive symptoms during the vulnerable phase of pregnancy and early motherhood. Psychosocial factors, especially antepartum anxiety symptoms, played a decisive role in this process. Perceived economic hardship further exaggerated the mental health burden.