It is important to understand how the disease process affects the metabolic pathways in amyotrophic lateral sclerosis and whether these pathways can be manipulated to ameliorate disease progression. ...To analyse the basis of the metabolic defect in amyotrophic lateral sclerosis we used a phenotypic metabolic profiling approach. Using fibroblasts and reprogrammed induced astrocytes from C9orf72 and sporadic amyotrophic lateral sclerosis cases we measured the production rate of reduced nicotinamide adenine dinucleotides (NADH) from 91 potential energy substrates simultaneously. Our screening approach identified that C9orf72 and sporadic amyotrophic lateral sclerosis induced astrocytes have distinct metabolic profiles compared to controls and displayed a loss of metabolic flexibility that was not observed in fibroblast models. This loss of metabolic flexibility, involving defects in adenosine, fructose and glycogen metabolism, as well as disruptions in the membrane transport of mitochondrial specific energy substrates, contributed to increased starvation induced toxicity in C9orf72 induced astrocytes. A reduction in glycogen metabolism was attributed to loss of glycogen phosphorylase and phosphoglucomutase at the protein level in both C9orf72 induced astrocytes and induced neurons. In addition, we found alterations in the levels of fructose metabolism enzymes and a reduction in the methylglyoxal removal enzyme GLO1 in both C9orf72 and sporadic models of disease. Our data show that metabolic flexibility is important in the CNS in times of bioenergetic stress.
Using metabolic screening, Allen et al. identify an adenosine to inosine deamination defect in astrocytes from ALS patients. This defect is the result of reduced expression of adenosine deaminase, ...leading to increased susceptibility to adenosine-mediated toxicity. Astrocyte inosine supplementation reverses the motor neuron toxicity observed with patient astrocytes in co-culture.
Abstract
As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how the energy metabolic pathways are altered and whether they can be restored to slow disease progression. Possible approaches include increasing or rerouting catabolism of alternative fuel sources to supplement the glycolytic and mitochondrial pathways such as glycogen, ketone bodies and nucleosides. To analyse the basis of the catabolic defect in amyotrophic lateral sclerosis we used a novel phenotypic metabolic array. We profiled fibroblasts and induced neuronal progenitor-derived human induced astrocytes from C9orf72 amyotrophic lateral sclerosis patients compared to normal controls, measuring the rates of production of reduced nicotinamide adenine dinucleotides from 91 potential energy substrates. This approach shows for the first time that C9orf72 human induced astrocytes and fibroblasts have an adenosine to inosine deamination defect caused by reduction of adenosine deaminase, which is also observed in induced astrocytes from sporadic patients. Patient-derived induced astrocyte lines were more susceptible to adenosine-induced toxicity, which could be mimicked by inhibiting adenosine deaminase in control lines. Furthermore, adenosine deaminase inhibition in control induced astrocytes led to increased motor neuron toxicity in co-cultures, similar to the levels observed with patient derived induced astrocytes. Bypassing metabolically the adenosine deaminase defect by inosine supplementation was beneficial bioenergetically in vitro, increasing glycolytic energy output and leading to an increase in motor neuron survival in co-cultures with induced astrocytes. Inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis.
We examined the number, distribution, and immunoreactivity of the infracortical white matter neuronal population, also termed white matter interstitial cells (WMICs), in the brain of a lesser ape, ...the lar gibbon. Staining for neuronal nuclear marker (NeuN) revealed WMICs throughout the infracortical white matter, these cells being most numerous and dense close to cortical layer VI, decreasing significantly in density with depth in the white matter. Stereological analysis of NeuN‐immunopositive cells revealed a global estimate of ~67.5 million WMICs within the infracortical white matter of the gibbon brain, indicating that the WMICs are a numerically significant population, ~2.5% of the total cortical gray matter neurons that would be estimated for a primate brain the mass of that of the lar gibbon. Immunostaining revealed subpopulations of WMICs containing neuronal nitric oxide synthase (nNOS, ~7 million in number, with both small and large soma volumes), calretinin (~8.6 million in number, all of similar soma volume), very few WMICs containing parvalbumin, and no calbindin‐immunopositive neurons. These nNOS, calretinin, and parvalbumin immunopositive WMICs, presumably all inhibitory neurons, represent ~23.1% of the total WMIC population. As the white matter is affected in many cognitive conditions, such as schizophrenia, autism and also in neurodegenerative diseases, understanding these neurons across species is important for the translation of findings of neural dysfunction in animal models to humans. Furthermore, studies of WMICs in species such as apes provide a crucial phylogenetic context for understanding the evolution of these cell types in the human brain.
Immunohistochemical staining for neuronal nuclear marker (NeuN) reveals the subcortical white matter neurons, or white matter interstitial cells (WMICs), deep to the gray matter of the cerebral cortex of the superior lateral sulcus of the brain of the lar gibbon. Arrowheads indicate the GM/WM border; GM = gray matter, WM = white matter.
Tornadoes rank among the most destructive hazards to human life and property. In the United States, two regions known as Tornado Alley and Dixie Alley are particularly prone to tornadoes, but ...determining exactly where tornadoes will occur remains difficult. Examining the relationship between land surface heterogeneity (i.e. variations in topography, vegetation, and land cover) and tornado occurrence can provide insight into the spatial distribution of these storms. The objective of this study is to uncover the relationships between severe storm occurrence and land surface heterogeneity variables to determine (1) whether certain land heterogeneity variables exhibit a significant relationship with tornado occurrence, and (2) whether those relationships vary by region and storm strength. We delineate the spatial extent of Tornado Alley and Dixie Alley based on clusters of tornadic activity. We then use logistic regression to investigate how land heterogeneity factors are related to tornado formation of weakly and significantly tornadic storms. Using these relationships uncovered, we map tornado probability across the two regions. Regression results show that several land surface heterogeneity variables have a statistically significant relationship with tornado occurrence, but these relationships vary with region and storm severity, supporting the need for more local studies.
Objective To ascertain long term cardiovascular outcomes in patients whose chest pain remained undiagnosed six months after first presentation.Design Cohort study.Setting UK electronic health record ...database (CALIBER) linking primary care, secondary care, coronary registry, and death registry information.Participants 172 180 adults aged ≥18 from 223 general practices presenting with a first episode of recorded chest pain, classified from medical records as diagnosed (non-coronary condition or angina) or undiagnosed (cause unattributed) at first consultation between 2002 and 2009 and with no previous record of cardiovascular disease.Main outcome measures Fatal or non-fatal cardiovascular events over 5.5 years’ follow-up. Adjustments were made for age, sex, deprivation, body mass index, smoking status, year of index presentation, and previous records of diabetes or hypertension or previous prescriptions for lipid lowering drugs.Results At the index presentation, 72.4% of patients (124 688) did not have a cause attributed for their chest pain; 118 687 (95.2%) of these did not receive any type of cardiovascular diagnosis over the next six months. Only a minority of patients in all three groups (non-coronary 2.0% (769 of 39 232); unattributed 11.7% (14 582 of 124 688); angina 31.5% (2606 of 8260)) had a recorded cardiac diagnostic investigation in the first six months after presentation. The long term incidence of cardiovascular events was higher in those whose chest pain remained unattributed after six months (5126 of 109 628; 4.7%) compared with patients with an initial diagnosis of non-coronary pain (1073 of 36 097; 3.0%) (adjusted hazard ratios for 0.5-1 year after presentation: 1.95, 95% confidence interval 1.66 to 2.31; for 1-3 years: 1.35, 1.23 to 1.48); for 3-5.5 years: 1.21, 1.08 to 1.37). Owing to the larger number of patients in the unattributed group, there were more excess myocardial infarctions in the long term in this group (214 more than expected based on the rate in the non-coronary group) than in the angina group (132 more than expected). Patients who had cardiac diagnostic investigations in the first six months had a higher long term risk of cardiovascular events, regardless of the initial chest pain label. Incidence of unattributed chest pain and angina decreased between 2002 (124 per 10 000 person years and 13 per 10 000 person years, respectively) and 2009 (107 per 10 000 person years and 5 per 10 000 person years, respectively), but the incidence of chest pain attributed to a non-coronary cause remained stable (37-40 per 10 000 person years). Risk of cardiovascular events did not change over time.Conclusions Most patients with first onset chest pain do not have a diagnosis recorded at presentation or in the subsequent six months, including those who undergo cardiac investigations. These patients have an increased risk of cardiovascular events for at least five years. Efforts to better assess and reduce the cardiovascular risk of such patients are warranted.
Background Most adults presenting with chest pain will not receive a diagnosis and be recorded with unattributed chest pain. The objective was to assess if they have increased risk of cardiovascular ...disease compared with those with noncoronary chest pain and determine whether investigations and interventions are targeted at those at highest risk. Methods and Results We used records from general practices in England linked to hospitalization and mortality information. The study population included patients aged 18 years or over with a new record of chest pain with a noncoronary cause or unattributed between 2002 and 2018, and no cardiovascular disease recorded up to 6 months (diagnostic window) afterward. We compared risk of a future cardiovascular event by type of chest pain, adjusting for cardiovascular risk factors and alternative explanations for chest pain. We determined prevalence of cardiac diagnostic investigations and preventative medication during the diagnostic window in patients with estimated cardiovascular risk ≥10%. There were 375 240 patients with unattributed chest pain (245 329 noncoronary chest pain). There was an increased risk of cardiovascular events for patients with unattributed chest pain, highest in the first year (hazard ratio, 1.25 95% CI, 1.21-1.29), persistent up to 10 years. Patients with unattributed chest pain had consistently increased risk of myocardial infarction over time but no increased risk of stroke. Thirty percent of patients at higher risk were prescribed lipid-lowering medication. Conclusions Patients presenting to primary care with unattributed chest pain are at increased risk of cardiovascular events. Primary prevention to reduce cardiovascular events appears suboptimal in those at higher risk.
Abstract
Background
Patients presenting to primary care with chest pain are often not given a cause. Patients with such unattributed chest pain have an increased risk of future cardiovascular disease ...(CVD) compared to patients with diagnosed non-coronary chest pain. It is unknown whether risk factors for CVD determined in the general population are the same for the population with unattributed or non-coronary chest pain.
Purpose
To determine if key risk factors for a coronary event in patients with unattributed chest pain are similar to those for patients with non-coronary chest pain and previously identified in the general population.
Methods
The study used primary care information from the Clinical Practice Research Datalink Aurum linked to hospital inpatient and mortality data. Patients aged ≥18 years with an incident record of unattributed or non-coronary chest pain in 2002–2018 and no diagnosis of CVD were included. We included as potential risk factors those established for CVD in the general population and non-coronary explanations for chest pain. Flexible parametric models estimated hazard ratios (95% confidence intervals (CI)) between factors and incident coronary event (defined as myocardial infarction, angina, coronary heart disease, percutaneous intervention, and coronary artery bypass graft surgery).
Results
There were 375,240 patients with unattributed chest pain (53% female: mean age 49; 47% male: mean age 47) and 245,329 patients with non-coronary chest pain (58% female: mean age 47; 42% male: mean age 44). Median duration of follow-up was 5 years. In the unattributed chest pain group, there were 111 (95% CI: 109, 112) and 140 (138, 142) coronary events per 10,000 person-years in females and males, respectively. Lower rates of coronary event were observed in the non-coronary chest pain group (females: 73 (72, 75); males: 96 (94, 98)). Within females (Figure), in both chest pain groups the strongest risk factors were type I and type II diabetes, atrial fibrillation, and hypertension whereas no associations were observed for migraine and chronic kidney disease. Whilst alternative explanations for non-coronary chest pain also increased the risk of coronary events, associations were less strong than for established general population risk factors. Similar findings were found in males although family history of coronary event was a stronger risk factor in the non-coronary chest pain group compared to the unattributed chest pain group.
Conclusions
The pool of factors found to increase the risk of coronary events in patients presenting with recorded unattributed or non-coronary chest pain are similar but not identical to those identified for the general population. Further research is needed to develop prognostic models to identify patients at the most risk of a coronary event as models developed in the general population are unlikely to be applicable given the increased underlying risk of coronary events in these populations.
Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): Study funded by the British Heart Foundation, reference PG/19/46/34307. KJ also supported by matched funding awarded to the NIHR Applied Research Collaboration (West Midlands). Risk factors for coronary event
Abstract
Aims
Most adults presenting in primary care with chest pain symptoms will not receive a diagnosis (‘unattributed’ chest pain) but are at increased risk of cardiovascular events. To assess ...within patients with unattributed chest pain, risk factors for cardiovascular events and whether those at greatest risk of cardiovascular disease can be ascertained by an existing general population risk prediction model or by development of a new model.
Methods and results
The study used UK primary care electronic health records from the Clinical Practice Research Datalink linked to admitted hospitalizations. Study population was patients aged 18 plus with recorded unattributed chest pain 2002–2018. Cardiovascular risk prediction models were developed with external validation and comparison of performance to QRISK3, a general population risk prediction model. There were 374 917 patients with unattributed chest pain in the development data set. The strongest risk factors for cardiovascular disease included diabetes, atrial fibrillation, and hypertension. Risk was increased in males, patients of Asian ethnicity, those in more deprived areas, obese patients, and smokers. The final developed model had good predictive performance (external validation c-statistic 0.81, calibration slope 1.02). A model using a subset of key risk factors for cardiovascular disease gave nearly identical performance. QRISK3 underestimated cardiovascular risk.
Conclusion
Patients presenting with unattributed chest pain are at increased risk of cardiovascular events. It is feasible to accurately estimate individual risk using routinely recorded information in the primary care record, focusing on a small number of risk factors. Patients at highest risk could be targeted for preventative measures.
Lay Summary
It is known that patients with chest pain without a recognized cause are at increased risk of future cardiovascular events (for example, heart disease) and so this study aimed to find out whether those patients at greatest risk could be determined using information in their health records.
It is possible to accurately estimate a person’s risk of future cardiovascular events using the information entered into their health records, and this risk can be estimated using only a small number of factors.Patients at highest risk could now be targeted for management to help prevent future cardiovascular events.
Graphical Abstract
Graphical Abstract
Background Electronic health records (EHRs) have the potential to be used to produce detailed disease burden estimates. In this study we created disease estimates using national EHR for three high ...burden conditions, compared estimates between linked and unlinked datasets and produced stratified estimates by age, sex, ethnicity, socio-economic deprivation and geographical region. Methods EHRs containing primary care (Clinical Practice Research Datalink), secondary care (Hospital Episode Statistics) and mortality records (Office for National Statistics) were used. We used existing disease phenotyping algorithms to identify cases of cancer (breast, lung, colorectal and prostate), type 1 and 2 diabetes, and lower back pain. We calculated age-standardised incidence of first cancer, point prevalence for diabetes, and primary care consultation prevalence for low back pain. Results 7.2 million people contributing 45.3 million person-years of active follow-up between 2000–2014 were included. CPRD-HES combined and CPRD-HES-ONS combined lung and bowel cancer incidence estimates by sex were similar to cancer registry estimates. Linked CPRD-HES estimates for combined Type 1 and Type 2 diabetes were consistently higher than those of CPRD alone, with the difference steadily increasing over time from 0.26% (2.99% for CPRD-HES vs. 2.73 for CPRD) in 2002 to 0.58% (6.17% vs. 5.59) in 2013. Low back pain prevalence was highest in the most deprived quintile and when compared to the least deprived quintile the difference in prevalence increased over time between 2000 and 2013, with the largest difference of 27% (558.70 per 10,000 people vs 438.20) in 2013. Conclusions We use national EHRs to produce estimates of burden of disease to produce detailed estimates by deprivation, ethnicity and geographical region. National EHRs have the potential to improve disease burden estimates at a local and global level and may serve as more automated, timely and precise inputs for policy making and global burden of disease estimation.
Background: Electronic health records (EHRs) have the potential to be used to produce detailed disease burden estimates. In this study we created disease estimates using national EHR for three high ...burden conditions, compared estimates between linked and unlinked datasets and produced stratified estimates by age, sex, ethnicity, socio-economic deprivation and geographical region. Methods: EHRs containing primary care (Clinical Practice Research Datalink), secondary care (Hospital Episode Statistics) and mortality records (Office for National Statistics) were used. We used existing disease phenotyping algorithms to identify cases of cancer (breast, lung, colorectal and prostate), type 1 and 2 diabetes, and lower back pain. We calculated age-standardised incidence of first cancer, point prevalence for diabetes, and primary care consultation prevalence for low back pain. Results: 7.2 million people contributing 45.3 million person-years of active follow-up between 2000-2014 were included. CPRD-HES combined and CPRD-HES-ONS combined lung and bowel cancer incidence estimates by sex were similar to cancer registry estimates. Linked CPRD-HES estimates for combined Type 1 and Type 2 diabetes were consistently higher than those of CPRD alone, with the difference steadily increasing over time from 0.26% (2.99% for CPRD-HES vs. 2.73 for CPRD) in 2002 to 0.58% (6.17% vs. 5.59) in 2013. Low back pain prevalence was highest in the most deprived quintile and when compared to the least deprived quintile the difference in prevalence increased over time between 2000 and 2013, with the largest difference of 27% (558.70 per 10,000 people vs 438.20) in 2013. Conclusions: We use national EHRs to produce estimates of burden of disease to produce detailed estimates by deprivation, ethnicity and geographical region. National EHRs have the potential to improve disease burden estimates at a local and global level and may serve as more automated, timely and precise inputs for policy making and global burden of disease estimation.
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