Experience with Surgical Excision in Childhood Pheochromocytoma

Pheochromocytoma is one of the potentially fatal causes of childhood hypertension. The study aims to analyze the results of our experiences in pheochromocytomas and the long-term results of its surgical treatment in children. The records of 15 children (11 boys, 4 girls) treated for pheochromocytoma in our unit during the period of 1984 and 2002 were reviewed retrospectively. The average age at surgery was 11.7 yr (range 6 yr 9 months-15 yr 7 months). Localized disease is defined as the cases without the invasion of surrounding tissue, regional disease as the invasion of surrounding tissue and metastatic disease as distant metastases. The mean follow-up after pheochromocytoma excision was 95 months (range 5 to 221 months). Tumors were located in the adrenal gland in 11 (bilaterally in 4) and extra-adrenally in 4. Localized disease occurred in 14 patients and regional disease in one. Only one patient was associated with von Hippel Lindau syndrome. Adrenalectomy or total excision of extra adrenal tumor was performed. Four patients (26.7%) recurred after the first operation (at 2 yr 9 months to 14 yr) and regional disease recurred in one patient three times. Early diagnosis, surgical excision, and long-term follow up are most important for the appropriate treatment of childhood pheochromocytoma

Role of Heparanase on Hepatic Uptake of Intestinal Derived Lipoprotein and Fatty Streak Formation in Mice

BACKGROUND: Heparanase modulates the level of heparan sulfate proteoglycans (HSPGs) which have an important role in multiple cellular processes. Recent studies indicate that HSPGs have an important function in hepatic lipoprotein handling and processes involving removal of lipoprotein particles. PRINCIPAL FINDINGS: To determine the effects of decreased HSPGs chain length on lipoprotein metabolism and atherosclerosis, transgenic mice over-expressing the human heparanase gene were studied. Hepatic lipid uptake in hpa-Tg mice were evaluated by giving transgenic mice oral fat loads and labeled retinol. Sections of aorta from mice over-expressing heparanase (hpa-Tg) and controls (C57/BL6) fed an atherogenic diet were examined for evidence of atherosclerosis. Heparanase over-expression results in reduced hepatic clearance of postprandial lipoproteins and higher levels of fasting and postprandial serum triglycerides. Heparanase over-expression also induces formation of fatty streaks in the aorta. The mean lesion cross-sectional area in heparanase over-expressing mice was almost 6 times higher when compared to control mice (23,984 µm(2)±5,922 vs. 4,189 µm(2)±1,130, p<0.001). CONCLUSIONS: Over-expression of heparanase demonstrates the importance of HSPGs for the uptake of intestinal derived lipoproteins and its role in the formation of fatty streaks

Syndecan 4 Is Involved in Mediating HCV Entry through Interaction with Lipoviral Particle-Associated Apolipoprotein E

Hepatitis C virus (HCV) is a major cause of liver disease worldwide and HCV infection represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. We sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. Using adenoviral vectors and siRNA to modulate apoE expression we show a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein expression. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Furthermore, a novel synthetic peptide that mimics apoE's HSPG-BD directly and competitively inhibits HCV infection. Genetic knockdown of the HSPG proteins syndecan (SDC) 1 and 4 revealed that SDC4 principally mediates HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatoma cells and establish infection. Targeting apoE-SDC interactions could be an alternative strategy for blocking HCV entry, a critical step in maintaining chronic HCV infection

Low Density Lipoprotein Receptor-Related Protein 1 Dependent Endosomal Trapping and Recycling of Apolipoprotein E

BACKGROUND: Lipoprotein receptors from the low density lipoprotein (LDL) receptor family are multifunctional membrane proteins which can efficiently mediate endocytosis and thereby facilitate lipoprotein clearance from the plasma. The biggest member of this family, the LDL receptor-related protein 1 (LRP1), facilitates the hepatic uptake of triglyceride-rich lipoproteins (TRL) via interaction with apolipoprotein E (apoE). In contrast to the classical LDL degradation pathway, TRL disintegrate in peripheral endosomes, and core lipids and apoB are targeted along the endocytic pathway for lysosomal degradation. Notably, TRL-derived apoE remains within recycling endosomes and is then mobilized by high density lipoproteins (HDL) for re-secretion. The aim of this study is to investigate the involvement of LRP1 in the regulation of apoE recycling. PRINCIPAL FINDINGS: Immunofluorescence studies indicate the LRP1-dependent trapping of apoE in EEA1-positive endosomes in human hepatoma cells. This processing is distinct from other LRP1 ligands such as RAP which is efficiently targeted to lysosomal compartments. Upon stimulation of HDL-induced recycling, apoE is released from LRP1-positive endosomes but is targeted to another, distinct population of early endosomes that contain HDL, but not LRP1. For subsequent analysis of the recycling capacity, we expressed the full-length human LRP1 and used an RNA interference approach to manipulate the expression levels of LRP1. In support of LRP1 determining the intracellular fate of apoE, overexpression of LRP1 significantly stimulated HDL-induced apoE recycling. Vice versa LRP1 knockdown in HEK293 cells and primary hepatocytes strongly reduced the efficiency of HDL to stimulate apoE secretion. CONCLUSION: We conclude that LRP1 enables apoE to accumulate in an early endosomal recycling compartment that serves as a pool for the intracellular formation and subsequent re-secretion of apoE-enriched HDL particles

Impulsiveness, postprandial blood glucose and glucoregulation affect measures of behavioral flexibility

Behavioral flexibility (BF) performance is influenced by both psychological and physiological factors. Recent evidence suggests that impulsivity and blood glucose can affect executive function, of which BF is a subdomain. Here, we hypothesized that impulsivity, fasting blood glucose (FBG), glucose changes (i.e. glucoregulation) from postprandial blood glucose (PBG) following the intake of a 15g glucose beverage could account for variability in BF performance. The Stroop Color-Word Test and the Wisconsin Card Sorting Test (WCST) were used as measures of BF, and the Barratt Impulsiveness Scale (BIS-11) to quantify participants’ impulsivity. In Study 1, neither impulsivity nor FBG could predict performance on the Stroop or the WCST. In Study 2, we tested whether blood glucose levels following the intake of a sugary drink, and absolute changes in glucose levels following the intake of the glucose beverage could better predict BF. Results showed that impulsivity and the difference in blood glucose between time 1 (postprandial) and time 2, but not blood glucose levels at time 2 per se could account for variation in performance on the WCST but not on the Stroop task. More specifically, lower impulsivity scores on the BIS-11, and smaller differences in blood glucose levels from time 1 to time 2 predicted a decrease in the number of total and perseverative errors on the WCST. Our results show that measures of impulsivity and glucoregulation can be used to predict BF. Importantly our data extend the work on glucose and cognition to a clinically relevant domain of cognition

Contending with Spiritual Reductionism: Demons, Shame, and Dividualising Experiences Among Evangelical Christians with Mental Distress

The belief that mental distress is caused by demons, sin, or generational curses is commonplace among many evangelical Christian communities. These beliefs may have positive or negative effects for individuals and groups. Phenomenological descriptions of these experiences and the subjective meanings associated with them, however, remain somewhat neglected in the literature. The current study employed semi-structured interviews with eight evangelical Christians in order to idiographically explore their experiences of mental distress in relation to their faith and wider communities. Through an interpretative phenomenological analysis, two superordinate themes were constructed: negative spiritualisation and negotiating the dialectic between faith and the lived experience of mental distress. Participants variously experienced a climate of negative spiritualisation, whereby their mental distress was demonised and dismissed, and they were further discouraged from seeking help in secular institutions and environments. Participants often considered such dismissals of their mental distress as unhelpful and stigmatising and experienced heightened feelings of shame and suffering as a result. Such discouragement also contributed to the process of othering and relational disconnection. Alongside a rejection of church teachings, which exclusively spiritualised psychological distress, participants negotiated a nuanced personal synthesis of faith, theology, and distress, which assumed a localised and idiographic significance. This synthesis included advocating for the uptake of aetiological accounts, which contextualised mental distress in terms of the whole person and resisted de-politicised, dichotomised, and individualistic narratives. Results are discussed in relation to a broad range of literature in the field, while further research suggestions are provided.N/

Glycosaminoglycan Binding Facilitates Entry of a Bacterial Pathogen into Central Nervous Systems

Certain microbes invade brain microvascular endothelial cells (BMECs) to breach the blood-brain barrier (BBB) and establish central nervous system (CNS) infection. Here we use the leading meningitis pathogen group B Streptococcus (GBS) together with insect and mammalian infection models to probe a potential role of glycosaminoglycan (GAG) interactions in the pathogenesis of CNS entry. Site-directed mutagenesis of a GAG-binding domain of the surface GBS alpha C protein impeded GBS penetration of the Drosophila BBB in vivo and diminished GBS adherence to and invasion of human BMECs in vitro. Conversely, genetic impairment of GAG expression in flies or mice reduced GBS dissemination into the brain. These complementary approaches identify a role for bacterial-GAG interactions in the pathogenesis of CNS infection. Our results also highlight how the simpler yet genetically conserved Drosophila GAG pathways can provide a model organism to screen candidate molecules that can interrupt pathogen-GAG interactions for future therapeutic applications

Requirements for Receptor Engagement during Infection by Adenovirus Complexed with Blood Coagulation Factor X

Human adenoviruses from multiple species bind to coagulation factor X (FX), yet the importance of this interaction in adenovirus dissemination is unknown. Upon contact with blood, vectors based on adenovirus serotype 5 (Ad5) binds to FX via the hexon protein with nanomolar affinity, leading to selective uptake of the complex into the liver and spleen. The Ad5:FX complex putatively targets heparan sulfate proteoglycans (HSPGs). The aim of this study was to elucidate the specific requirements for Ad5:FX-mediated cellular uptake in this high-affinity pathway, specifically the HSPG receptor requirements as well as the role of penton base-mediated integrin engagement in subsequent internalisation. Removal of HS sidechains by enzymatic digestion or competition with highly-sulfated heparins/heparan sulfates significantly decreased FX-mediated Ad5 cell binding in vitro and ex vivo. Removal of N-linked and, in particular, O-linked sulfate groups significantly attenuated the inhibitory capabilities of heparin, while the chemical inhibition of endogenous HSPG sulfation dose-dependently reduced FX-mediated Ad5 cellular uptake. Unlike native heparin, modified heparins lacking O- or N-linked sulfate groups were unable to inhibit Ad5 accumulation in the liver 1h after intravascular administration of adenovirus. Similar results were observed in vitro using Ad5 vectors possessing mutations ablating CAR- and/or αv integrin binding, demonstrating that attachment of the Ad5:FX complex to the cell surface involves HSPG sulfation. Interestingly, Ad5 vectors ablated for αv integrin binding showed markedly delayed cell entry, highlighting the need for an efficient post-attachment internalisation signal for optimal Ad5 uptake and transport following surface binding mediated through FX. This study therefore integrates the established model of αv integrin-dependent adenoviral infection with the high-affinity FX-mediated pathway. This has important implications for mechanisms that define organ targeting following contact of human adenoviruses with blood