N-glycome profile levels relate to silent brain infarcts in a cohort of hypertensives

Background: Silent brain infarcts (SBIs) are highly prevalent in the aged population and relate to the occurrence of further stroke and dementia. Serum N-glycome levels have been previously associated with aging and they might be related as well to the presence of SBIs and age-related white matter hyperintensities. Methods and Results: We determined the serum N-glycome profile in a cohort study comprising 972 subjects and evaluated the relationship between N-glycome levels and the presence and number of SBIs and with age-related white matter hyperintensities grades, assessed by brain magnetic resonance imaging. Decreasing concentrations of bigalacto core-alpha-1,6-fucosylated biantennary glycan and increasing concentrations of branching alpha-1,3-fucosylated triantennary glycan remained as independent predictors of SBIs (odds ratio 0.4, 95% CI 0.3-0.7 and odds ratio 1.8, 95% CI 1-3.2, respectively), after controlling for the presence of age and classic vascular risk factors. A similar pattern was found to be related to an increasing number of SBIs and white matter hyperintensities grade. Conclusions: N-glycome levels might be potentially useful as biomarkers for the presence of silent cerebrovascular disease

EVALUATING THE MICROBIOME TO BOOST RECOVERY FROM STROKE: THE EMBRS STUDY

Accumulating evidence suggests that gut microbes modulate brain plasticity via the bidirectional gut-brain axis and may play a role in stroke rehabilitation. A severely imbalanced microbial community has been shown to occur following stroke, causing a systemic flood of neuro- and immunomodulatory substances due to increased gut permeability and decreased gut motility. Here we measure post-stroke increased gut dysbiosis and how it correlates with gut permeability and subsequent cognitive impairment. We recruited 12 participants with acute stroke, 12 healthy control participants, and 18 participants who had risk factors for stroke, but had not had a stroke. We measured the gut microbiome with whole shotgun sequencing on stool samples. We measured cognitive and emotional health with MRI imaging and the NIH toolbox. We normalized all variables and used linear regression methods to identify gut microbial levels associations with cognitive and emotional assessments. Beta diversity analysis revealed that the bacteria populations of the stroke group were statistically dissimilar from the risk factors and healthy control groups. Relative abundance analysis revealed notable decreases in butyrate-producing microbial taxa. The stroke group had higher levels of the leaky gut marker alpha-1-antitrypsin than the control groups, and roseburia species were negatively correlated with alpha-1-antitrypsin. Several Actinobacteria species were associated with cerebral blood flow and white matter integrity in areas of the brain responsible for language, learning, and memory. Stroke participants scored lower on the picture vocabulary and list sorting tests than those in the control groups. Stroke participants who had higher levels of roseburia performed better on the picture vocabulary task. We found that microbial communities are disrupted in a stroke population. Many of the disrupted bacteria have previously been reported to have correlates to health and disease. This preparatory study will lay the foundation for the development of therapeutics targeting the gut following stroke

Exploring the Effects of Hemodialysis on Renal and Hepatic Blood Flow and Function using CT Perfusion Imaging

Hemodialysis (HD) is the most common form of renal replacement therapy for end-stage renal disease. However, patients develop complications that are driven by HD-induced circulatory stress from rapidly removing large fluid volumes during HD, making various vascular beds vulnerable to ischemia. By assessing how HD-induced circulatory stress affects different organs, it may be possible to characterize the mechanisms behind these complications and evaluate therapeutic interventions. This thesis aims to explore how HD affects renal and hepatic blood flow and function using CT perfusion imaging. For this work, patients received either standard or cooled HD first in a two-visit, crossover study design, where imaging was performed before, during and after each HD session. Residual renal function is linked to improved clinical outcomes, yet characteristically declines upon HD initiation. In the first thesis project, we determined that renal perfusion deceases during HD, which could be an early manifestation of HD-mediated residual renal function loss. Although the liver normally clears endotoxin, increased circulating endotoxin levels have been found in HD patients. In the second thesis project, we showed that concurrent hepatic perfusion redistribution and decreased liver function during HD are likely responsible for increased circulating toxin levels. Dialysate cooling is a low-cost, feasible intervention that ameliorates HD-induced circulatory stress. In the first and second thesis projects, we found that cooling trended towards mitigating the drop in renal perfusion during HD and ameliorating the changes in liver perfusion and function during HD. If it were possible to accurately assess glomerular filtration rate (GFR) in HD patients, HD prescriptions could be adjusted in accordance with residual renal function to preserve remaining function. In the third thesis project, we extended the CT perfusion technique to measure GFR in HD patients, yielding physiologically realistic GFR values, thus demonstrating the feasibility of this approach in terms of reliability and accuracy. These findings help explain residual renal function loss and endotoxemia in HD patients, and showcases the protective potential of dialysate cooling. In addition, this work demonstrates the benefit of using CT perfusion as a functional imaging technique to further characterize and evaluate therapies for end-stage renal disease pathologies

Smoking and Second Hand Smoking in Adolescents with Chronic Kidney Disease: A Report from the Chronic Kidney Disease in Children (CKiD) Cohort Study

The goal of this study was to determine the prevalence of smoking and second hand smoking [SHS] in adolescents with CKD and their relationship to baseline parameters at enrollment in the CKiD, observational cohort study of 600 children (aged 1-16 yrs) with Schwartz estimated GFR of 30-90 ml/min/1.73m2. 239 adolescents had self-report survey data on smoking and SHS exposure: 21 [9%] subjects had “ever” smoked a cigarette. Among them, 4 were current and 17 were former smokers. Hypertension was more prevalent in those that had “ever” smoked a cigarette (42%) compared to non-smokers (9%), p\u3c0.01. Among 218 non-smokers, 130 (59%) were male, 142 (65%) were Caucasian; 60 (28%) reported SHS exposure compared to 158 (72%) with no exposure. Non-smoker adolescents with SHS exposure were compared to those without SHS exposure. There was no racial, age, or gender differences between both groups. Baseline creatinine, diastolic hypertension, C reactive protein, lipid profile, GFR and hemoglobin were not statistically different. Significantly higher protein to creatinine ratio (0.90 vs. 0.53, p\u3c0.01) was observed in those exposed to SHS compared to those not exposed. Exposed adolescents were heavier than non-exposed adolescents (85th percentile vs. 55th percentile for BMI, p\u3c 0.01). Uncontrolled casual systolic hypertension was twice as prevalent among those exposed to SHS (16%) compared to those not exposed to SHS (7%), though the difference was not statistically significant (p= 0.07). Adjusted multivariate regression analysis [OR (95% CI)] showed that increased protein to creatinine ratio [1.34 (1.03, 1.75)] and higher BMI [1.14 (1.02, 1.29)] were independently associated with exposure to SHS among non-smoker adolescents. These results reveal that among adolescents with CKD, cigarette use is low and SHS is highly prevalent. The association of smoking with hypertension and SHS with increased proteinuria suggests a possible role of these factors in CKD progression and cardiovascular outcomes

Exploring Novel Intradialytic Techniques to Identify & Ameliorate of Hemodialysis-induced Myocardial Ischemic Injury

Patients with chronic kidney disease requiring hemodialysis to sustain life have extremely high rates of cardiovascular morbidity/mortality. This is both a consequence of the disease process and treatment. Hemodialysis induces systemic circulatory stress is largely due to the extracorporeal circuit and volume removal. The stress induced by intermitted hemodialysis is repetitive with cumulative cardiovascular effect and is the principal driver of heart failure and sudden death in this vulnerable population. The insults imposed by hemodialysis result in left ventricular regional wall motion abnormalities and lead to myocardial stunning with permanent damage to the vasculature and myocardium. Currently, the adversity caused by hemodialysis remains under appreciated and largely ignored. The aim of this thesis is to explore intradialytic methods to detect and ameliorate hemodialysis-induced circulatory stress (myocardial stunning). The utility of a non-invasive intradialytic hemodynamic monitoring system using photoplethysmography to detect hemodialysis-induced circulatory stress through the skin was explored. In this first thesis project, we determined that pulse strength, an output generated by PPG technology was associated with the development of myocardial stunning. Building on this initial finding, the second thesis project supported the significance of the pulse strength variable as a signal to the development of regional wall motion abnormalities/myocardial stunning during hemodialysis. Additionally, we determined that intradialytic changes in cutaneous perfusion were detected earlier in treatment and were directly associated with direct measures of global cardiac perfusion using intravenous contract/computerized tomography imaging. Both findings were associated with rates of ultrafiltration/fluid removal during dialysis (previously identified as principal drivers of hemodialysis-induced acute cardiac injury). Exercise pre-conditioning, a phenomenon that is cardio-protective against ischemic-reperfusion injury was explored, in the form of intradialytic exercise. In the third project, we found there to be a reduction in the number of treatment-induced regional wall motion abnormalities at the peak of hemodialysis stress when intradialytic exercise was incorporated into treatment. Moreover, any amount of exercise had an immediate influence with no detrimental effect on treatment tolerability. This work describes the utility and benefit of non-invasive microcirculatory monitoring for the early detection of hemodialysis-induced circulatory stress and demonstrates the pre-conditioning benefit that intradialytic exercise has on the reduction of myocardial stunning in the hemodialysis populatio

Pain Management

Pain Management - Current Issues and Opinions is written by international experts who cover a number of topics about current pain management problems, and gives the reader a glimpse into the future of pain treatment. Several chapters report original research, while others summarize clinical information with specific treatment options. The international mix of authors reflects the "casting of a broad net" to recruit authors on the cutting edge of their area of interest. Pain Management - Current Issues and Opinions is a must read for the up-to-date pain clinician

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions