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Biomedicines May 2024Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several...
Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in this study. The median duration of drug treatment was over 20 months. The application of tSCS was performed during physical therapy for 20-40 min per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, and forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both type 2 and 3 SMA participants. The magnitude of functional changes was not associated with participant age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation on SMA.
PubMed: 38927369
DOI: 10.3390/biomedicines12061162 -
Journal of Cardiothoracic Surgery Jun 2024For acute type A aortic dissection involving the aortic root with root diameter no more than 45 mm, there are various aortic root repair techniques. In this study, a...
BACKGROUND
For acute type A aortic dissection involving the aortic root with root diameter no more than 45 mm, there are various aortic root repair techniques. In this study, a novel surgical technique using a pericardial autograft for aortic root repair was introduced. We described its surgical steps in detail and compare its clinical outcomes with direct suture technique.
METHODS
Between July 2017 and August 2022, 95 patients with acute type A aortic dissection who underwent aortic root repair were enrolled, including aortic root repair using pericardial autograft (group A, n = 49) or direct suture (group B, n = 46). The patient's clinical data were retrospectively analyzed, and a 5-year follow-up was conducted.
RESULTS
The 30-day mortality, re-exploration for bleeding, postoperative new-onset renal failure requiring continuous renal replacement therapy, stroke, and paraplegia occurred in 3%, 4%, 11%, 5%, and 2% of the overall patients, respectively. There was no significant difference in the 30-day mortality and complication rate between the two groups. The 30-day mortality and re-exploration for bleeding marked the primary endpoint events. Logistic regression analysis indicated that there was a significant correlation between the primary endpoint events and surgical technique (odds ratio, 0.002; 95% confidence interval, 0-0.159; P = 0.026). The aortic valve insufficiency of the two groups were significantly improved after operation (group A, P < 0.001; group B, P < 0.001). During follow-up, there was no significant difference in short-term survival between the two groups after surgery (log-rank P = 0.75), and all patients were free from reoperation for aortic disease.
CONCLUSIONS
Patients who underwent aortic root repair using pericardial autograft tended to have reduced 30-day mortality and a lower risk of re-exploration for bleeding. Using pericardial autograft for aortic root repair is a safe and useful approach for patients with acute type A aortic dissection involving the aortic root.
Topics: Humans; Aortic Dissection; Male; Female; Retrospective Studies; Middle Aged; Pericardium; Treatment Outcome; Autografts; Aortic Aneurysm, Thoracic; Aged; Acute Disease; Postoperative Complications; Blood Vessel Prosthesis Implantation; Transplantation, Autologous; Follow-Up Studies
PubMed: 38926836
DOI: 10.1186/s13019-024-02909-2 -
Alzheimer's Research & Therapy Jun 2024Although several cardiovascular, demographic, genetic and lifestyle factors have been associated with cognitive function, little is known about what type of cognitive...
BACKGROUND
Although several cardiovascular, demographic, genetic and lifestyle factors have been associated with cognitive function, little is known about what type of cognitive impairment they are associated with. The aim was to examine the associations between different risk factors and future memory and attention/executive functions, and their interaction with APOE genotype.
METHODS
Participants from a large, prospective, population-based, Swedish study were included (n = 3,229). Linear regression models were used to examine baseline hypertension, body mass index (BMI), long-term glucose levels (HbA), different lipid levels, physical activity, alcohol consumption, smoking, education, APOE genotype, age and sex. All models were adjusted for follow-up time and basic demographics, and, in a second step, all significant predictors were included to examine independent effects. Follow-up outcomes were memory and attention/executive functions.
RESULTS
The mean age at baseline was 56.1 (SD 5.7) years and 59.7% were women. The mean follow-up time was 17.4 (range 14.3-20.8) years. When examining independent effects, APOE ε4 genotype(p < 0.01), and higher HbA(p < 0.001), were associated with future low memory function. Higher BMI (p < 0.05), and HbA(p < 0.05), lower high-density lipoprotein cholesterol (HDL-C)(p < 0.05)and stroke(p < 0.001) were associated with future low attention/executive function. The strongest factors associated with both better memory and attention/executive functions were higher education and alcohol consumption. Further, significant interaction effects between predictors and APOE genotype were found. For memory function, the protective effects of education were greater among ɛ4-carriers(p < 0.05). For attention/executive function, the protective effects of alcohol were greater among ɛ2 or ɛ4-carriers(p < 0.05). Also, attention/executive function was lower among ɛ4-carriers with higher BMI(p < 0.05) and ɛ2-carriers with higher HbA1c-levels(p < 0.05).
CONCLUSIONS
Targeting cardiovascular risk factors in mid-life could have greater effect on future attention/executive functions rather than memory, whereas targeting diabetes could be beneficial for multiple cognitive domains. In addition, effects of different risk factors may vary depending on the APOE genotype. The varied cognitive profiles suggest that different mechanisms and brain regions are affected by the individual risk factors. Having detailed knowledge about the specific cognitive effects of different risk factors might be beneficial in preventive health counseling.
Topics: Humans; Female; Male; Middle Aged; Risk Factors; Follow-Up Studies; Prospective Studies; Sweden; Executive Function; Cognition; Attention; Body Mass Index; Memory; Glycated Hemoglobin; Aged; Alcohol Drinking; Genotype; Apolipoprotein E4; Neuropsychological Tests; Cognitive Dysfunction
PubMed: 38926747
DOI: 10.1186/s13195-024-01497-6 -
BMC Neuroscience Jun 2024Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This...
BACKGROUND
Astrocytes are the most abundant cell type of the central nervous system and are fundamentally involved in homeostasis, neuroprotection, and synaptic plasticity. This regulatory function of astrocytes on their neighboring cells in the healthy brain is subject of current research. In the ischemic brain we assume disease specific differences in astrocytic acting. The renin-angiotensin-aldosterone system regulates arterial blood pressure through endothelial cells and perivascular musculature. Moreover, astrocytes express angiotensin II type 1 and 2 receptors. However, their role in astrocytic function has not yet been fully elucidated. We hypothesized that the angiotensin II receptors impact astrocyte function as revealed in an in vitro system mimicking cerebral ischemia. Astrocytes derived from neonatal wistar rats were exposed to telmisartan (angiotensin II type 1 receptor-blocker) or PD123319 (angiotensin II type 2 receptor-blocker) under normal conditions (control) or deprivation from oxygen and glucose. Conditioned medium (CM) of astrocytes was harvested to elucidate astrocyte-mediated indirect effects on microglia and cortical neurons.
RESULT
The blockade of angiotensin II type 1 receptor by telmisartan increased the survival of astrocytes during ischemic conditions in vitro without affecting their proliferation rate or disturbing their expression of S100A10, a marker of activation. The inhibition of the angiotensin II type 2 receptor pathway by PD123319 resulted in both increased expression of S100A10 and proliferation rate. The CM of telmisartan-treated astrocytes reduced the expression of pro-inflammatory mediators with simultaneous increase of anti-inflammatory markers in microglia. Increased neuronal activity was observed after treatment of neurons with CM of telmisartan- as well as PD123319-stimulated astrocytes.
CONCLUSION
Data show that angiotensin II receptors have functional relevance for astrocytes that differs in healthy and ischemic conditions and effects surrounding microglia and neuronal activity via secretory signals. Above that, this work emphasizes the strong interference of the different cells in the CNS and that targeting astrocytes might serve as a therapeutic strategy to influence the acting of glia-neuronal network in de- and regenerative context.
Topics: Animals; Astrocytes; Rats, Wistar; Microglia; Receptor, Angiotensin, Type 2; Telmisartan; Angiotensin II Type 1 Receptor Blockers; Neurons; Receptor, Angiotensin, Type 1; Ischemic Stroke; Angiotensin II Type 2 Receptor Blockers; Rats; Cells, Cultured; Pyridines; Imidazoles; Animals, Newborn; Benzimidazoles; Cell Communication
PubMed: 38926677
DOI: 10.1186/s12868-024-00876-x -
Scientific Reports Jun 2024The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial...
The microbial communities of the oral cavity are important elements of oral and systemic health. With emerging evidence highlighting the heritability of oral bacterial microbiota, this study aimed to identify host genome variants that influence oral microbial traits. Using data from 16S rRNA gene amplicon sequencing, we performed genome-wide association studies with univariate and multivariate traits of the salivary microbiota from 610 unrelated adults from the Danish ADDITION-PRO cohort. We identified six single nucleotide polymorphisms (SNPs) in human genomes that showed associations with abundance of bacterial taxa at different taxonomical tiers (P < 5 × 10). Notably, SNP rs17793860 surpassed our study-wide significance threshold (P < 1.19 × 10). Additionally, rs4530093 was linked to bacterial beta diversity (P < 5 × 10). Out of these seven SNPs identified, six exerted effects on metabolic traits, including glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, the risk of type 2 diabetes and stroke. Our findings highlight the impact of specific host SNPs on the composition and diversity of the oral bacterial community. Importantly, our results indicate an intricate interplay between host genetics, the oral microbiota, and metabolic health. We emphasize the need for integrative approaches considering genetic, microbial, and metabolic factors.
Topics: Humans; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Female; Microbiota; Male; Middle Aged; Mouth; Adult; RNA, Ribosomal, 16S; Diabetes Mellitus, Type 2; Saliva; Aged
PubMed: 38926497
DOI: 10.1038/s41598-024-65538-8 -
BMJ Open Jun 2024Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage heart failure. Compared with the best medical therapy,...
BACKGROUND
Left ventricular assist devices (LVADs) have emerged as a successful treatment option for patients with end-stage heart failure. Compared with the best medical therapy, LVADs improve survival and enhance functional capacity and quality of life. However, two major complications compromise this patient population's outcomes: thrombosis and bleeding. Despite technological innovations and better hemocompatibility, these devices alter the rheology, triggering the coagulation cascade and, therefore, require antithrombotic therapy. Anticoagulation and antiplatelet therapies represent the current standard of care. Still, inconsistency in the literature exists, especially whether antiplatelet therapy is required, whether direct oral anticoagulants can replace vitamin K antagonists and even whether phosphodiesterase type 5 inhibitors with their antithrombotic effects could be added to the regimen of anticoagulation.
METHODS AND ANALYSIS
We will perform a living systematic review with network meta-analysis and indirect comparison between current antithrombotic therapies, which have and have not been directly compared within clinical trials and observational studies. We will systematically search the following electronic sources: Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica Database (EMBASE). We will exclusively examine studies published in English from 2016 to the present. Studies conducted before 2016 will be omitted since our primary focus is evaluating continuous flow devices. Two independent reviewers will assess the articles by title, abstract and full text; any disagreement will be resolved through discussion, and a third reviewer will be involved if necessary. The Cochrane Risk of Bias tool will be used to assess the risk of bias. We will then conduct a pairwise meta-analysis; if the assumption of transitivity is satisfied, we will proceed with network meta-analysis using Bayesian methodology.
ETHICS AND DISSEMINATION
Formal ethical approval is not required as no primary data are collected. This systematic review and network meta-analysis will delineate the risks of stroke, thromboembolic events, pump thrombosis, gastrointestinal bleeding and mortality in patients equipped with LVADs who are subjected to various antithrombotic regimens. The findings will be disseminated via a peer-reviewed publication and presented at conference meetings. This will enhance clinical practice and guide future research on anticoagulation strategies within this distinct patient cohort.
PROSPERO REGISTRATION NUMBER
CRD42023465288.
Topics: Humans; Heart-Assist Devices; Systematic Reviews as Topic; Network Meta-Analysis; Fibrinolytic Agents; Anticoagulants; Thrombosis; Heart Failure; Platelet Aggregation Inhibitors; Research Design; Hemorrhage
PubMed: 38925683
DOI: 10.1136/bmjopen-2023-080110 -
American Journal of Kidney Diseases :... Jun 2024Sex differences in cardiovascular disease (CVD) are well-established, but whether chronic kidney disease (CKD) modifies these risk differences, and whether they differ...
RATIONALE & OBJECTIVE
Sex differences in cardiovascular disease (CVD) are well-established, but whether chronic kidney disease (CKD) modifies these risk differences, and whether they differ between atheromatous (ACVD) and non-atheromatous (N-ACVD) CVD is unknown. Assessing this interaction was the principal goal of this study.
STUDY DESIGN
Prospective cohort study.
SETTING & PARTICIPANTS
Adults enrolled in the CKD-Renal Epidemiology and Information Network (CKD-REIN) cohort from from 2013 to 2020, a nationally representative sample of 40 nephrology clinics in France.
EXPOSURE
Sex.
OUTCOMES
Fatal and non-fatal composite ACVD events (ischaemic coronary, cerebral, and peripheral artery disease) and composite N-ACVD events (heart failure, haemorrhagic stroke, and arrhythmias).
ANALYTICAL APPROACH
Multivariable cause-specific Cox proportional hazards models.
RESULTS
1,044 women and 1,976 men with moderate to severe CKD (median age, 67 vs. 69; mean estimated glomerular filtration rate [eGFR], 32±12 vs. 33±12 mL/min/1.73m) were studied. Over a median follow-up of 5.0 (interquartile range, 4.8;5.2) years, the ACVD rate (per 100 patient-years) was significantly lower in women than men: 2.1 (95% confidence interval: 1.6-2.5) vs 3.6 (3.2-4.0) (P<0.01), while the N-ACVD rate was not: 5.7 (5.0-6.5) vs 6.4 (5.8-7.0) (P=0.55). N-ACVD had a steeper relationship with eGFR than did ACVD. There was an interaction (P<0.01) between sex and baseline eGFR and the ACVD hazard: the adjusted hazard ratio for women compared to men was 0.42 (0.25;0.71) at 45 mL/min/1.73m and gradually attenuated at lower levels of eGFR, reaching 1.00 (0.62;1.63) at 16 mL/min/1.73m. In contrast, the N-ACVD hazard did not differ between the sexes across the eGFR range studied.
LIMITATIONS
Cardiovascular biomarkers and sex hormones were not assessed.
CONCLUSION
This study shows how the lower risk of ACVD among women compared to men attenuates fully with kidney disease progression. The equal risk of N-ACVD between sexes across CKD stages and its steeper association with eGFR suggest an important contribution of CKD to the development of this CVD type.
PubMed: 38925506
DOI: 10.1053/j.ajkd.2024.04.013 -
European Journal of Cardio-thoracic... Jun 2024Gender difference in the outcome after type A aortic dissection surgery remains an issue of ongoing debate. In this study we aimed to evaluate the impact of gender on...
OBJECTIVES
Gender difference in the outcome after type A aortic dissection surgery remains an issue of ongoing debate. In this study we aimed to evaluate the impact of gender on the short- and long-term outcome after surgery for type A aortic dissection.
METHODS
A multicentre European registry retrospectively included all consecutive type A aortic dissection surgery patients between 2005 and 2021 from 18 hospitals across eight European countries. Early and late mortality, and cumulative incidence of aortic reoperation were compared between genders.
RESULTS
A total of 3902 patients underwent type A aortic dissection surgery, with 1185 (30.4%) being females. After propensity score matching, 766 pairs of males and females were compared. No statistical differences were detected in the early postoperative outcome between genders. Ten-year survival was comparable between genders (47.8% vs 47.1%; Log-rank test, p = 0.679), as well as cumulative incidences of distal or proximal aortic reoperations. Ten-year relative survival compared to country-, year-, age-, and sex-matched general population was higher among males (0.65) compared to females (0.58). The time-period subanalysis revealed advancements in surgical techniques in both genders over the years. However, an increase of stroke was observed over time for both populations, particularly among females.
CONCLUSIONS
The past sixteen years have witnessed marked advancements in surgical techniques for TAAD in both males and females, achieving comparable early and late mortality rates. Despite these findings, late relative survival was still in favour of males.
PubMed: 38924518
DOI: 10.1093/ejcts/ezae242 -
European Journal of Clinical... Jun 2024Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a novel class of drugs with cardioprotective effects through their lipid-lowering... (Review)
Review
BACKGROUND
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a novel class of drugs with cardioprotective effects through their lipid-lowering effects.
OBJECTIVE
This review aims to discuss existing and novel strategies of PCSK9 inhibition, providing an overview of established randomized controlled trials and ongoing outcome trials that assess the efficacy and long-term safety of PCSK9 inhibitors. It also explores the evolving role of PCSK9 beyond lipid metabolism and outlines the pleiotropic actions of PCSK9 inhibition in various disorders and future directions including novel strategies to target PCSK9.
CONCLUSION
PCSK9 inhibition shows promise not only in lipid metabolism but also in other disease processes, including atherosclerotic plaque remodeling, acute coronary syndrome, stroke, inflammation, and immune response.
PubMed: 38924090
DOI: 10.1111/eci.14272 -
Journal of Clinical Pharmacology Jun 2024Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are...
Subarachnoid hemorrhage (SAH) is a devastating type of stroke, leading to high mortality and morbidity rates. Cerebral vasospasm and delayed cerebral ischemia (DCI) are common complications following SAH that contribute significantly to the poor outcomes observed in these patients. Intrathecal (IT) nicardipine delivered via an existing external ventricular drain is an off-label intervention that has been shown to be correlated with reduced DCI and improved patient outcomes. The current study aims to characterize the population pharmacokinetic (popPK) properties of intermittent IT nicardipine. Following informed consent, serial cerebrospinal fluid (CSF) samples were obtained from 16 SAH patients (50.4 ± 9.3 years old; 13 females) treated with IT nicardipine every 6 h (q6h, n = 8) or every 8 h (q8h, n = 8) for an average of 72 ± 21 doses. High-performance liquid chromatography was used to quantify CSF concentration from each sample. Our popPK analysis showed that the CSF pharmacokinetics of IT nicardipine in the cohort was adequately described by a two-compartment model with a lag time. Model parameter estimates were reliable (relative standard error <50%). Intracranial pressure influenced both the total clearance and the central volume of nicardipine (i.e., negative correlation, P <-.001). Calculated PK parameters were similar between q6h and q8h dosing regimens. Despite a small cohort of SAH patients, we successfully developed a popPK model to describe the nicardipine disposition kinetics in the CSF following IT administration. These findings may help inform future clinical trials designed to examine the optimal dosing of IT nicardipine.
PubMed: 38923537
DOI: 10.1002/jcph.2488