Uncoupling Neogenin association with lipid rafts promotes neuronal survival and functional recovery after stroke

The dependence receptor Neogenin and its ligand, the repulsive guidance molecule a (RGMa), regulate apoptosis and axonal growth in the developing and the adult central nervous system (CNS). Here, we show that this pathway has also a critical role in neuronal death following stroke, and that providing RGMa to neurons blocks Neogenin-induced death. Interestingly, the Neogenin pro-death function following ischemic insult depends on Neogenin association with lipid rafts. Thus, a peptide that prevents Neogenin association with lipid rafts increased neuronal survival in several in vitro stroke models. In rats, a pro-survival effect was also observed in a model of ocular ischemia, as well as after middle cerebral artery occlusion (MCAO). Treatments that prevented Neogenin association with lipid rafts improved neuronal survival and the complexity of the neuronal network following occlusion of the middle artery. Toward the development of a treatment for stroke, we developed a human anti-RGMa antibody that also prevents Neogenin association with lipid rafts. We show that this antibody also protected CNS tissue from ischemic damage and that its application resulted in a significant functional improvement even when administrated 6 h after artery occlusion. Thus, our results draw attention to the role of Neogenin and lipid rafts as potential targets following stroke.Ischemic stroke is of major public health significance as it may lead to permanent loss-of-functions or death. This is due to the pronounced susceptibility of adult central nervous system (CNS) neurons to undergo apoptotic death when injured. Many clinical trials have focused on reducing excitotoxicity to ameliorate neuronal death in the penumbra.¹ However, the short duration of excitotoxicity following stroke does not allow for effective treatment in the clinic. There is emerging consensus that a better therapy should be obtained by (i) targeting the molecular mechanisms of apoptosis and (ii) using this knowledge to develop effective treatments that maintain adequate brain functions.²The transmembrane protein Neogenin is a dependence receptor that causes death or survival depending on ligand (repulsive guidance molecule a (RGMa)) absence or presence, respectively.^{3, 4} In cell cultures, as well as in the developing chick brain, Neogenin induces apoptosis in the absence of RGMa.³ Cell survival can be rescued either by addition of RGMa or by Neogenin silencing. We recently have demonstrated that RGMa can also rescue neuronal cell death following traumatic CNS injury.⁵ When retinal ganglion cell (RGC) axons were severed by optic nerve crush, injection of RGMa into the vitreous significantly increased cell survival.⁵ Thus, the Neogenin/RGMa pathway is involved in neuronal cell death following injury. More recent studies revealed that this pathway is involved in axonal regeneration following stroke. RGMa is upregulated in the penumbra of human patients who died of stroke.⁶ Interestingly, electrical stimulation downregulates RGMa expression, which correlates with an improved functional outcome following middle cerebral artery occlusion (MCAO).^{7, 8} Although Neogenin has been shown to be expressed in the injured brain following stroke,⁹ there is no direct evidence that it may have a role in the pathology of this disease.The plasma membrane of cells contains a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains, termed lipid rafts.¹⁰ One key difference between lipid rafts and the plasma membranes from which they are derived is lipid composition. Lipid rafts generally contain twice the amount of cholesterol than that found in the surrounding bilayer.¹⁰ We recently discovered that RGMa contains three sites of interaction with Neogenin.¹¹ Two of these sites interact with Neogenin to block axonal growth, whereas the third site, located in the most N-terminal portion of RGMa (N-Raft), binds the Neogenin immunoglobulin domain (4Ig), to regulate recruitment of Neogenin into lipid rafts. Treatment with either 4Ig or a newly generated monoclonal antibody (mAb) abolished Neogenin-induced cell death suggesting that Neogenin recruitment into rafts is essential for Neogenin-mediated apoptosis. In this study, we assessed the neuroprotective effects of RGMa, as well as, the effect of altering Neogenin association with lipid rafts after cerebral– and retinal–ischemic injuries.     

Immunological and nutritional factors in elderly people in low-level care and their association with mortality

Background

This study examines associations between markers of nutritional status and lymphocyte subsets and seeks to determine if lymphocyte profile is predictive of survival in elderly Australians residing in aged care facilities. Aged yet still ambulatory subjects (n?=?88, 73% female) living in low-level care and requiring minimal assistance were studied for 143 weeks. At baseline when participants were aged (mean?±?SD) 86.0?±?5.9 years, dietary intake was determined by 3-day weighed food record, body composition was assessed by dual energy X-ray absorptiometry (DXA) and a venous blood sample was taken.

Results

At baseline assessment, study participants were consuming nutrient-poor diets and most had symptoms of chronic disease. Although overweight, 40% exhibited sarcopenia. Markers of nutritional status did not relate closely to immune cell numbers (absolute or relative), which on average were within the normal range. Men had lower numbers of CD3⁺CD4⁺ cells (CD4⁺ T cells), a higher proportion of CD3^? CD16^± CD56^± (natural killer (NK) cells) and a higher ratio of NK: CD4⁺ T cells than women (all P?<?0.05). The main age-related changes evident were decreased T cells, particularly low CD4⁺ T cell counts, and increased numbers of CD19⁺ (B-cell) and NK cells. During the 143 week duration of follow-up, about one quarter of the study participants died, with death more likely in men than women (P?<?0.01). Poor survival was predicted by the presence of decreased numbers of CD4⁺ T cells (hazard ratio (HR) 0.919, P?<?0.01) and expanded numbers of NK cells (HR 1.085, P?<?0.05) in the blood, and therefore the presence of a high NK: CD4⁺ T cell ratio (HR 30.521, P?<?0.01).

Conclusions

The NK: CD4⁺ T cell ratio may potentially have clinical utility for predicting longevity in elderly populations. Further studies are needed in other elderly populations to confirm this finding.

     

Insights into cardiovascular risk and nutritional status in subjects with wheat-related disorders

Objective: Wheat-related disorders are a spectrum of disorders associated with different autoimmune and non-autoimmune diseases. However, it is unclear whether these wheat-related disorders lead to adverse health effects such as cardiovascular risk, nutritional deficiencies etc. The objective of the study was to explore the lipid profiles and the nutritional status of subjects with wheat-related disorders to understand the potential threat of wheat on cardiovascular risk and nutritional deficiency.

Method: A total of 1041 subjects who showed wheat-related symptoms were initially tested for the wheat protein antibody panel (Wheat Zoomer (WZ) panel and Coeliac Disease (CD) panel), then for cardiovascular panel and the micronutrient panel at Vibrant America Clinical Laboratory.

Results: Subjects with both Wheat Zoomer positivity (WZ+) and Coeliac Disease positivity (CD+) had significantly low levels of high-density lipoproteins (HDL) (279/483(57.8%) and 29/47(61.7%) respectively), but only subjects with WZ?+?had low levels of Apo A1 (44/424(9.5%)), and high levels of Omega 6 fatty acids (53/334(15.9%)). None of the micronutrients tested showed a significant imbalance in WZ?+?subjects.

Conclusion: Subjects with positive serology for WZ have deranged blood lipid profiles but did not show any significant micronutrient deficiency. Hence, our results showcase a significant association of wheat-related disorders to cardiovascular risk.     

Maternal grandmothers improve nutritional status and survival of children in rural Gambia

Hypotheses for the evolution of human female life-history characteristics have often focused on the social nature of human societies, which allows women to share the burden of childcare and provisioning amongst other members of their kin group. We test the hypothesis that child health and survival probabilities will be improved by the presence of kin using a longitudinal database from rural Gambia. We find that the only kin to improve the nutritional status of children significantly (apart from mothers) are maternal grandmothers, and that this is reflected in higher survival probabilities for children with living maternal grandmothers. There is also evidence that the reproductive status of the maternal grandmother influences child nutrition, with young children being taller in the presence of non-reproductive grandmothers than grandmothers who are still reproductively active. Paternal grandmothers and male kin, including fathers, have negligible impacts on the nutritional status and survival of children.     

Association between selenium nutritional status and metabolic risk factors in men with visceral obesity

Background and aimPrevious evidence has suggested an association between selenium and cardiovascular disease, which is main outcome of metabolic syndrome. The aim of this study was to examine possible correlation between selenium nutritional status and metabolic risk factors in men with visceral obesity.MethodsPlasma samples were collected from 123 Indonesian men with visceral obesity. Their metabolic risk factors and selenium nutritional status were analyzed. The eligible subjects (n = 78) were stratified according to the International Diabetes Federation: obese, obese plus one component, and obese plus two components or more. Obese plus two components or more were diagnostic criteria of metabolic syndrome. Pearson's correlation was performed to examine the correlation in each group.ResultsIn the obese group, selenium positively correlated with high-density lipoprotein (HDL) cholesterol (r = 0.390, P < 0.05) and with fatty acid binding protein-4 (FABP4) (r = 0.474, P < 0.05); glutathione peroxidase-3 (GPx3) activity was inversely correlated with FABP4 (r = ?467, P < 0.05). In the obese plus one component group, GPx3 activity positively correlated with HDL cholesterol (r = 0.413, P < 0.05). In the metabolic syndrome group, selenium negatively correlated with monocytes chemoattractant protein (MCP)-1 (r = ?0.429, P < 0.05).ConclusionsThese results show that the association between selenium nutritional status and metabolic risk factors is limited to particular group of obese men with or without metabolic syndrome.     

Anemia status,hemoglobin concentration and outcome after acute stroke: a cohort study

Background  

In the setting of an acute stroke, anemia has the potential to worsen brain ischemia, however, the relationship between the entire range of hemoglobin to long-term outcome is not well understood.     

Antioxidant status and oxidative stress at rest and in response to acute exercise in judokas and sedentary men

It is well recognized that acute strenuous exercise is accompanied by an increase in free-radical production and subsequent oxidative stress, in addition to changes in blood antioxidant status. Chronic exercise provides protection against exercise-induced oxidative stress by upregulating endogenous antioxidant defense systems. Little is known regarding the protective effect afforded by judo exercise. Therefore, we determined antioxidant and oxidative stress biomarkers at rest and in response to acute exercise in 10 competitive judokas and 10 sedentary subjects after mixed exercise (anaerobic followed by aerobic). The subjects performed a Wingate test, followed by 30 minutes of aerobic exercise performed at 60% of maximal aerobic power. Blood samples were taken, by an intravenous catheter, at rest (R), immediately after the physical exercise (P0), and at 5 (P5), 10 (P10), and 20 (P20) minutes postexercise. The measured parameters included the activity of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and glutathione reductase, in addition to α-tocopherol, and total antioxidant status. Malondialdehyde was measured as a representation of lipid peroxidation. At rest, the judokas had higher values for all antioxidant and oxidative stress markers as compared to the sedentary subjects (p < 0.05). Plasma concentrations of all parameters except for α-tocopherol increased significantly above resting values for both the judokas and sedentary subjects (p < 0.05) and remained elevated at 20 minutes postexercise. A significant postexercise decrease was observed for α-tocopherol (p < 0.05) at P20 for judokas and at P5 for sedentary subjects. These data indicate that competitive judo athletes have higher endogenous antioxidant protection compared to sedentary subjects. However, both groups of subjects experience an increase in exercise-induced oxidative stress that is not different.     

Are elderly people living alone an at risk group?

OBJECTIVE--To test the hypothesis that elderly people living alone are an at risk group with a high level of morbidity that makes high demands on health and social services. DESIGN--Secondary analysis of data from a community survey of 239 people aged 75 and over, identified from general practitioners'' age-sex registers. SETTING--Nine practices in the London boroughs of Brent and Islington. MAIN OUTCOME MEASURES--Scores on the mini-mental state examination; stated satisfaction with life; assessment of mobility; numbers of diagnoses of major physical problems; numbers of prescribed drugs taken; urinary incontinence; alcohol consumption; contacts with general practitioners and hospital outpatient and inpatient services; contact with community health and social services. RESULTS--There were significantly more women among those living alone (93/120 (78%) v 63/119 (53%); p < 0.0005) and the median age of elderly people living alone was higher (81 v 80; p < 0.04). Those living alone and those living with others showed no significant differences in measures of cognitive impairment, numbers of major physical diagnoses, impaired mobility, or use of general practitioner or hospital services. Stated satisfaction with life was somewhat higher in those living alone. Elderly people living alone were significantly more likely to have contact with chiropody, home help, and meals on wheels services and less likely to have someone they could contact in an emergency or at night. Living alone increased the likelihood of contact with one or more community health professionals (district nurses, health visitors, or chiropodists) considered as a group and also increased the likelihood of contact with social services as a whole. There was a tendency for more of those living alone than those living with others to have home visits from their general practitioners, but there were no significant differences in contact with hospital services between the two groups. CONCLUSIONS--Elderly people living alone do not have an excess of morbidity compared with those living with others and do not seem to be an at risk group requiring specifically targeted assessments. More help is needed to provide elderly people living alone with a point of contact in case of emergency.     

Impact of functional status at six months on long term survival in patients with ischaemic stroke: prospective cohort studies

Objective To estimate the impact on long term survival of functional status at six months after ischaemic stroke.Design Prospective cohort study.Settings Three cohorts: Oxfordshire community stroke project, Lothian stroke register, and the first international stroke trial (in the United Kingdom).Participants 7710 patients with ischaemic stroke registered between 1981 and 2000 and followed up for a maximum of 19 years.Main outcome measures Functional status at six months after stroke assessed with modified Rankin scale or “two simple questions.” Mortality during follow-up. Survival analysis with Kaplan-Meier curves, log rank test, and Cox’s regression model.Results In a combined analysis of all three cohorts, among patients who survived to assessment six months after the index stroke, the subsequent median length of survival among those independent in daily living and those dependent was 9.7 years (95% confidence interval 8.9 to 10.6) and 6.0 years (5.7 to 6.4), respectively. In a combined analysis of the Oxfordshire and Lothian cohorts, subsequent median survival fell progressively from 12.9 years (10.0 to 15.9) for patients with a Rankin score of 0-1 at six months after the stroke to 2.5 years (1.4 to 3.5) for patients with a Rankin score of 5. All previously stated differences in median survival were significant (log rank test P<0.001). The influence of functional outcome on survival remained significant (P<0.05) in each cohort after adjustment for relevant covariates (such as age, presence of atrial fibrillation, visible infarct on computed tomography, subtype of stroke) in a Cox’s regression model.Conclusion Functional status six months after an ischaemic stroke is associated with long term survival. Early interventions that reduce dependency at six months might have positive effects on long term survival.     

Genomic risk profiling of ischemic stroke: results of an international genome-wide association meta-analysis

Introduction

Familial aggregation of ischemic stroke derives from shared genetic and environmental factors. We present a meta-analysis of genome-wide association scans (GWAS) from 3 cohorts to identify the contribution of common variants to ischemic stroke risk.

Methods

This study involved 1464 ischemic stroke cases and 1932 controls. Cases were genotyped using the Illumina 610 or 660 genotyping arrays; controls, with Illumina HumanHap 550Kv1 or 550Kv3 genotyping arrays. Imputation was performed with the 1000 Genomes European ancestry haplotypes (August 2010 release) as a reference. A total of 5,156,597 single-nucleotide polymorphisms (SNPs) were incorporated into the fixed effects meta-analysis. All SNPs associated with ischemic stroke (P<1×10⁻⁵) were incorporated into a multivariate risk profile model.

Results

No SNP reached genome-wide significance for ischemic stroke (P<5×10⁻⁸). Secondary analysis identified a significant cumulative effect for age at onset of stroke (first versus fifth quintile of cumulative profiles based on SNPs associated with late onset, ß = 14.77 [10.85,18.68], P = 5.5×10⁻¹²), as well as a strong effect showing increased risk across samples with a high propensity for stroke among samples with enriched counts of suggestive risk alleles (P<5×10⁻⁶). Risk profile scores based only on genomic information offered little incremental prediction.

Discussion

There is little evidence of a common genetic variant contributing to moderate risk of ischemic stroke. Quintiles based on genetic loading of alleles associated with a younger age at onset of ischemic stroke revealed a significant difference in age at onset between those in the upper and lower quintiles. Using common variants from GWAS and imputation, genomic profiling remains inferior to family history of stroke for defining risk. Inclusion of genomic (rare variant) information may be required to improve clinical risk profiling.     

Antioxidant status in patients with psoriasis

Psoriasis is a chronic inflammatory skin disease with an unknown aetiology that has been associated with abnormal plasma lipid metabolism and oxidative stress. There are controversial results in the previous studies investigating oxidant/antioxidant systems in psoriasis. The aim of this work was to evaluate the plasma levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), total bilirubin (T. Bili), direct bilirubin (D. Bili), uric acid (UA), apolipoproteins (ApoA1 and ApoB), Lp(a) and activities of paraxonase 1 (PON1) in 100 patients with psoriasis and 100 controls, and to look for a correlation between these parameters in psoriasis. PON1, bilirubin and UA were measured spectrophotometrically, MDA by the high‐performance liquid chromatography method, apolipoproteins and Lp(a) by immunoprecipitation assays, and lipid and other biochemical parameters were determined by routine laboratory methods. In patients with psoriasis, there was a significant decrease in PON1, SOD and CAT activities (P < 0.05) and an increase in MDA levels (P < 0.01). Also, the levels of bilirubin (total and direct) and UA were decreased in patients with psoriasis but were not significant (P > 0.05). These results suggest that psoriasis was in a state of oxidative stress and that the protective effects of high‐density lipoprotein against atherosclerosis may be dependent on PON1 activity. Moreover, there is a negative correlation between antioxidant with Lp(a), apoB and MDA levels, suggesting that subjects with higher levels of Lp(a) and apoB and lower levels of antioxidant are more exposed to oxidative damage. These findings may explain in part the reported increase in cardiovascular mortality in psoriasis. Copyright © 2013 John Wiley & Sons, Ltd.     

The relationships between oral status, physical and mental health, nutritional status and diet type in elderly Japanese women with dementia

Objectives: To suggest methods for maintaining an adequate nutritional status for elderly patients with dementia by evaluating the relationships between oral status, physical and mental health, and feeding conditions. Background: Feeding difficulties in dementia patients are related to food intake, and failure to eat may be associated with weight loss in long‐term care facilities. The relationship between compromised oral function and diet is still unclear. Materials and methods: A cross‐sectional study of 94 elderly women with dementia (mean age 89.6 ± 5.6 years) from a nursing home was undertaken to investigate their oral, physical and mental and nutritional status. Results: There were significant differences in serum albumin (p = 0.0284), N‐ADL (p = 0.0005), NM scale (p = 0.0004) and HDS‐R (p = 0.0004) between denture wearers and non‐denture wearers. However, there were no significant differences in body mass index between denture wearers and non‐denture wearers. Conclusion: A suitable type of diet and assistance with feeding could maintain the nutritional status of elderly patients with dementia if they are still feeding themselves. The nutritional support team will benefit from the participation of a dentist.     

Examining the association between obstructive sleep apnea and cardiometabolic risk factors in the elderly

Purpose

Obstructive sleep apnea (OSA) and metabolic syndrome (MetS) are common chronic disorders associated with cardiovascular morbidity and mortality. The goal of our research is to identify the associations between OSA and MetS, including different components of MetS, in adults.

Methods

We used data from the 2007–2008 National Health and Nutrition Examination Survey, which included 5909 eligible subjects (2898 men, 3011 women), aged 20 and over, who had undergone a complete medical examination and had self-reported three OSA symptom items. The primary study outcome was possible obstructive sleep apnea (pOSA) and MetS components.

Results

Participants in the pOSA group had significantly more MetS components (p < 0.001). In the group aged ≥ 60 years, there was a stronger relationship between pOSA and MetS components. After additional adjustment, the odds ratios for pOSA among those with 2, 4, and 5 MetS components were 3.11, 3.19, and 4.89, respectively (p < 0.05).

Conclusions

In conclusion, our study indicates that the risk of pOSA is higher in association with increased MetS factors, particularly among the elderly. Leading a healthy lifestyle may help reduce OSA risk in elderly patients with MetS.

     

Growth and nutritional status of Tibetan children at high altitude

Growth and development are clearly affected by high-altitude exposure to hypoxia, nutritional stress, cold or a combination of these factors. Very little research has been conducted on the growth and nutritional status of children living on the Tibetan Plateau. The present study evaluated the environmental impact on human growth by analyzing anthropometric characteristics of Tibetan children aged 8-14, born and raised above 4000 m altitude on the Himalayan massif in the prefecture of Shegar in Tibet Autonomous Region. Data on anthropometric traits, never measured in this population, were collected and the nutritional status was assessed. A reference data set is provided for this population. There was no evidence of wasting but stunting was detected (28.3%). Children permanently exposed to the high-altitude environment above 4000 m present a phenotypic form of adaptation and a moderate reduction in linear growth. However, it is also necessary to consider the effects of socioeconomic deprivation.