Differences In Pathophysiology Research Articles

Sex differences in outcomes of patients with cardiogenic shock due to acute myocardial infarction: a systematic review and epidemiological meta-analysis

Abstract Background Women are at higher risk of mortality from ST-elevation myocardial infarction (1) when compared to men. There is a lack of consensus among studies examining the effect of sex on outcomes from cardiogenic shock due to acute myocardial infarction (AMI-CS) (2-5). In this systematic review and meta-analysis, we sought to assess the relationship between outcomes of AMI-CS and sex. Purpose To examine sex-related differences in mortality in patients with cardiogenic shock secondary to acute myocardial infarction (AMI-CS). Methods Cochrane Central, PubMed, MEDLINE and EMBASE were searched in February 2023 for studies reporting in-hospital or 30-day sex-specific mortality in patients with cardiogenic shock. Inclusion criteria consisted of observational or randomised controlled trials of adult patients with cardiogenic shock that reported unadjusted or adjusted (by odds or risk ratio) mortality rates by sex. In-hospital or 30-day mortality were treated as equivalent. Data were extracted for study size, number of men and women, unadjusted and adjusted mortality rates, and factors used in multivariable analysis. Studies were assessed for risk of bias and publication bias. Meta-analysis was performed using DerSimonian-Laird random effects model with inverse variant weighting, due to predicted high heterogeneity of included studies. Data are reported as odds ratios (ORs) with 95% confidence interval (CI). P values were adjusted for multiple comparison using Holm-Bonferonni correction. The primary outcomes were unadjusted and adjusted sex-specific mortality rates due to AMI-cardiogenic shock. Results 4,286 studies were identified and 37 met inclusion criteria, pooling a total of 630,890 patients. Raw 30-day/in-hospital mortality of females with AMI-cardiogenic shock was 41.2% compared to 32.3% in males. Unadjusted OR for mortality in females was 1.42 (95% CI 1.31–1.55, p <0.001, t2 = 0.02, I2 = 70.3%), and the adjusted OR was 1.11 (95% CI 1.04–1.20, p <0.001, t2 = 0.01, I2 = 76.8%). Eight studies included data on use of mechanical circulatory support (MCS), which was used in 31.2% of females compared to 39.9% of males. OR for use of MCS in females compared to males was 0.71 (95% CI 0.66–0.77, p < 0.001, t2 = 0.003, I2 = 35.2%). Conclusions Women with AMI-related cardiogenic shock are at greater risk of death compared to male patients and are less often treated with MCS. Potential explanations include residual confounding factors, differences in AMI-cardiogenic shock pathophysiology between men and women, and sex-related differences in healthcare behaviours, but we cannot exclude the effect of systemic bias on outcomes. Further research is required to address the causes of sex disparities in outcomes and ensure equitable management of AMI-cardiogenic shock in women.Unadjusted sex outcomes from AMI-CSAdjusted sex outcomes from AMI-CS

Sex differences in the substrate of atrial fibrillation and the outcome of thoracoscopic ablation

Abstract Background Women with atrial fibrillation (AF) suffer more from AF symptoms, a lower quality of life, and have an enhanced risk of stroke. The AF recurrence after ablation is higher in women than in men. We hypothesize that sex specific differences in the atrial fibrotic substrate underlie these differences in clinical outcome. Here, we sought to characterize atrial fibrosis and fibrosis formation in the left atrial appendage (LAA) of women and men undergoing thoracoscopic ablation of AF. Methods We used the excised LAA of 30 female and 30 male patients with persistent AF undergoing thoracoscopic AF ablation. Patients were matched for age. In addition propensity score matching was also conducted for adjusting intermediary variables such as AF duration, Age ≥ 75, Body mass index (BMI), and CHA2DS2-VASc score ≥ 4. LAAs were stained with picrosirius red to quantify collagen and with vimentin for fibroblasts. Images were analyzed automatically (Image J version 1.50i) using color deconvolution to identify the area fraction of collagen and fibroblast. Results Women had similar age as men (66.4±7.76 vs 66.1 ±7.57, P= 0.85) but had a trend toward more cardiovascular risk factors [CHA2DS2-VASc score ≥ 4, (23.3 vs 6.7)%, P=0.07]. The total percentage of fibroblasts was larger in women 14.98 (9.79-24.95) % than men 13 (5.85-17.46) %, P=.018. In addition, in women fibroblasts were located more in epicardially and endocardially than in the interstitium.[women 8.18 (5.06-13.36) % vs men 6.49 (2.73-9.92) % , P=0.005].There was not a remarkable differences in total amount of collagen between the groups [women 16.03 (9.67-26.98) % vs men 15.50 (9.50-20.90) %, P=0.57 ], but there was a trend towards more epicardial and endocardial collagen in women than men [11.81(5.75-22.11)% vs 10.24 (6.06-15.10) % , P=0.06]. Conclusion We demonstrate more epicardial and endocardial fibroblasts in the LAA of women compared to men with persistent AF. There was similarly a trend towards more epicardia and endocardial but not interstitial collagen deposition. These findings may –at least in part- underlie sex specific differences in AF pathophysiology and ablation outcome.

Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation.

The importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.

Nonasthmatic Eosinophilic Bronchitis: A Systematic Review of Current Treatment Options.

Nonasthmatic eosinophilic bronchitis is characterized by persistent dry or barely productive cough and bronchial eosinophilia without airway obstruction or bronchial hyperreactivity. It is primarily a chronic disease, in which some patients have clinical and pathophysiological relapses, while others progress to asthma or chronic obstructive pulmonary disease. It accounts for 5% to 30% of cases referred for chronic cough. Exposure to common inhalants and occupational sensitizers has been proposed as a possible cause of the disease, although the etiology and underlying mechanisms are uncertain. Some features are similar to those of asthma, such as airway eosinophilia, inflammatory mediator levels, and airway remodeling. Differences in airway pathophysiology, such as the location of airway inflammation and levels of IL-13 and PGE-2, have been reported. Sputum cell count is the gold standard test for diagnosis, and other biomarkers, such as exhaled nitric oxide, could support the diagnosis. A systematic review of treatments for the disease shows that while inhaled corticosteroids are the primary option, the appropriate dose, the type of corticosteroid, and the duration of treatment remain unknown. Treatment duration is inversely correlated with the relapse rate. Increased doses of inhaled corticosteroids, oral corticosteroids, and leukotriene receptor antagonists are recommended in persistent disease. Anti-IL-5 biologics could be promising in this disease. Studies that investigate biomarkers for diagnosis and prognosis are necessary, as are randomized controlled studies for second-line treatments.

Female Specific Restrictive Cardiomyopathy and Metabolic Dysregulation in transgenic mice expressing a Peptide of the Amino-Terminus of GRK2.

Cardiovascular disease and heart failure are a major health challenge, with sex differences in pathophysiology and treatment responses critically influencing patient outcomes. G protein-coupled receptor (GPCR) kinase 2 (GRK2) is a pivotal regulator of cellular signaling whose elevation is a hallmark of heart failure progression. Its complex network of protein interactions impact a wide range of physiological and pathophysiological processes including cardiac function. In this study, we examined the effects of cardiac-restricted expression of an amino-terminal peptide of GRK2 (βARKnt) in female mice subjected to acute and chronic pressure overload. Our findings reveal that that βARKnt affects hypertrophy development and cardiac function differently in female mice than in males, leading to a transition to heart failure not observed in control females or βARKnt males. Notably, the βARKnt female mice exhibited baseline hypertrophy with distinct left atrial morphology, increased fibrosis, and immune cell infiltration compared to the controls, which progressed under chronic stress, indicating adverse cardiac remodeling. Furthermore, βARKnt female mice, unlike males, exhibit impaired tissue respiration following acute pressure overload and altered glucose sensitivity and insulin tolerance, highlighting significant remodeling of cardiac and systemic metabolism.

Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds

Cerebral small vessel disease (SVD) is associated with various cerebrovascular outcomes, but data on sex differences in SVD are scarce. To investigate whether the frequency, severity, and distribution of cerebral microbleeds (CMB), other SVD markers on magnetic resonance imaging (MRI), and outcomes differ by sex. This cohort study used pooled individual patient data from the Microbleeds International Collaborative Network, including patients from 38 prospective cohort studies in 18 countries between 2000 and 2018, with clinical follow-up of at least 3 months (up to 5 years). Participants included patients with acute ischemic stroke or transient ischemic attack with available brain MRI. Data were analyzed from April to December 2023. Outcomes of interest were presence of CMB, lacunes, and severe white matter hyperintensities determined on MRI. Additionally, mortality, recurrent ischemic stroke, and intracranial hemorrhage during follow-up were assessed. Multivariable random-effects logistic regression models, Cox regression, and competing risk regression models were used to investigate sex differences in individual SVD markers, risk of recurrent cerebrovascular events, and death. A total of 20 314 patients (mean [SD] age, 70.1 [12.7] years; 11 721 [57.7%] male) were included, of whom 5649 (27.8%) had CMB. CMB were more frequent in male patients, and this was consistent throughout different age groups, locations, and in multivariable models (female vs male adjusted odds ratio [aOR], 0.86; 95% CI, 0.80-0.92; P < .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P < .001) but a higher prevalence of severe white matter hyperintensities (aOR, 1.10; 95% CI, 1.01-1.20; P = .04) compared with male patients. A total of 2419 patients (11.9%) died during a median (IQR) follow-up of 1.4 (0.7-2.5) years. CMB presence was associated with a higher risk of mortality in female patients (hazard ratio, 1.15; 95% CI, 1.02-1.31), but not male patients (hazard ratio, 0.95; 95% CI, 0.84-1.07) (P for interaction = .01). A total of 1113 patients (5.5%) had recurrent ischemic stroke, and 189 patients (0.9%) had recurrent intracranial hemorrhage, with no sex differences. This cohort study using pooled individual patient data found varying frequencies of individual SVD markers between female and male patients, indicating potential pathophysiological differences in manifestation and severity of SVD. Further research addressing differences in pathomechanisms and outcomes of SVD between female and male patients is required.

Comparative Analysis of the Protective Effect of Naringenin on Cardiovascular Parameters of Normotensive and Hypertensive Rats Subjected to the Myocardial Infarction Model.

Background: Cardiovascular diseases rank as the top global cause of mortality, particularly acute myocardial infarction (MI). MI arises from the blockage of a coronary artery, which disrupts blood flow and results in tissue death. Among therapeutic approaches, bioactives from medicinal plants emerge as promising for the development of new medicines. Objectives: This study explored the effects of naringenin (NAR 100 mg/kg), a flavonoid found in citrus fruits, in normotensive (NTR) and spontaneously hypertensive (SHR) rats, both subjected to isoproterenol (ISO 85 mg/kg)-induced MI. Results: Post-treatment assessments indicated that NAR reduced blood pressure and minimized clot formation, particularly notable in the SHR group, which helps mitigate damage related to hypertension and ISO exposure. Additionally, NAR effectively restored KCl-induced contractility in the aortas of both NTR and SHR groups. NAR treatment reduced reduced glutathione (GSH) and lipid hydroperoxides (LOOH) values and recovered the activity of the antioxidant enzymes catalase (CAT) and glutathione-s-transferase (GST) in NTR groups. Moreover, myocardial damage assessed through histological analyses was reduced in groups treated with NAR. Conclusions: The results highlight significant pathophysiological differences between the groups, suggesting that NAR has protective potential against ISO-induced cardiac damage, warranting further investigation into its protective effects and mechanisms.

Reduced resting-state periodic beta power in adults who stutter is related to sensorimotor control of speech execution

ObjectiveThe primary aim of the current study was to determine whether adults who stutter (AWS) present with anomalous periodic beta (β) rhythms when compared to typically fluent adults in the eyes-open resting state. A second aim was to determine whether lower β power in the RS is related to a measure of β event-related desynchronization (ERD) during syllable sequence execution. MethodsEEG data was collected from 128 channels in a 5 minute, eyes-open resting state condition and from a syllable sequence repetition task. Temporal independent component analysis (ICA) was used to separate volume conducted EEG sources and to find a set of component weights common to the RS and syllable repetition task. Both traditional measures of power spectral density (PSD) and parameterized spectra were computed for components showing peaks in the β band (13-30Hz). Parameterization was used to evaluate separable components adjusted for the 1/f part of the spectrum. ResultsICA revealed frontal-parietal midline and lateral sensorimotor (μ) components common to the RS and a syllable repetition task with peaks in the β band. The entire spectrum for each component was modeled using the FOOOF algorithm. Independent samples t-tests revealed significantly lower periodic β in midline central-parietal and lateral sensorimotor components in AWS. Regression analysis suggested a significant relationship between left periodic sensorimotor β power in the RS and ERD during syllable sequence execution. ConclusionsFindings suggest that periodic β peaks in the spectrum are related to hypothesized underlying pathophysiological differences in stuttering, including midline rhythms associated the default mode network (DMN) and lateral sensorimotor rhythms associated with the control of movement.

A sex-oriented analysis concerning skeletal muscle quantity and quality and associations to quality of life in hospitalized patients with cirrhosis

BackgroundThere is a paucity of data regarding sex-oriented analyses of connection between muscle quantity and quality and health-related quality of life (HRQoL), taking into account the pathophysiological differences of sarcopenia/myosteatosis in males versus females. We sought to investigate the associations between skeletal muscle index (SMI)-defined sarcopenia and intramuscular adipose tissue content (IMAC)-defined myosteatosis and EuroQol-5D (EQ-5D)-defined HRQoL in patients with decompensated cirrhosis concerning sex disparities.MethodsTotally, 382 patients were enrolled. The relationship between SMI/IMAC and HRQoL was evaluated with restricted cubic spline and Pearson correlation analyses. Furthermore, association between SMI or sarcopenia and EQ-5D utility index was determined by multiple linear regression, adjusted for age, BMI and concurrent disease severity.ResultsThe study population comprised evenly distributed male and female patients (190: 192), mean age 61.9 years. The prevalence of sarcopenia (40.5 versus 9.9%, P < 0.001) and SMI (48.8 versus 42.2 cm2/m2, P < 0.001) were significantly higher in males relative to females, with comparable myosteatosis prevalence (15.3 versus 16.7%, P = 0.708). Self-care, usual activities and pain within EQ-5D scale were more prevalent in the sarcopenia compared with non-sarcopenia groups across entire population and stratified by sex. The SMI values exhibited a significantly linear correlation with EQ-5D utility index in male but not female patients (P for non-linearity = 0.281). In multiple analysis, SMI or the presence of sarcopenia was both significantly associated with EQ-5D utility index. Subgroup analyses unveiled no discernible interactions between sarcopenia and EQ-5D utility index.ConclusionsMuscle quantity measured by SMI was associated with declined HRQoL in males rather than females, whereas no associations were found regarding muscle quality measured by IMAC in both sexes. It is tempting to manage sarcopenia by increasing SMI levels as high as possible in hopes of achieving better health consequence. Our findings represent the importance of connecting CT-demarcated body composition abnormalities to meaningful patient-centered outcomes. Future targeted studies with sizable multi-center populations are warranted to clarify this causality, and in consequence develop optimized intervention against sarcopenia/myosteatosis or key determinants concerning impaired HRQoL.

Sex-specific modulation of renal epigenetic and injury markers in aging kidney.

Sex differences in renal physiology and pathophysiology are now well established in rodent models and in humans. Epigenetic programming is known to be a critical component of renal injury, as studied mainly in male rodent models; however, not much is known about the impact of biological sex and age on the kidney epigenome. We sought to determine the influence of biological sex and age on renal epigenetic and injury markers, using male and female mice at 4 mo (4M; young), 12 mo (12M), and 24 mo (24M; aged) of age. Females had a significant increase in kidney and body weights and serum creatinine levels and a decrease in serum albumin levels from 4M to 24M of age, whereas minor changes were observed in male mice. Kidney injury molecule-1 levels in serum and renal tissue greatly enhanced from 12M to 24M in both males and females. Circulating histone 3 (H3; damage-associated molecular pattern molecules) levels extensively increased with age; however, males had higher levels than females. Overall, females had markedly high histone acetyltransferase (HAT) activity than age-matched males. Aged mice had decreased HAT activity and increased histone deacetylase activity than sex-matched 12M mice. Aged females had substantially decreased renal H3 methylation at lysine 9 and 27 and histone methyltransferase (HMT) activity than aged male mice. Antiaging protein Klotho levels were significantly higher in young males than age-matched females and decreased substantially with age in males, whereas epigenetic repressor of Klotho, trimethylated H3K27, and its HMT enzyme, enhancer of zeste homolog 2, increased consistently with age in both sexes. Moreover, nuclear translocation and activity of proinflammatory transcription factor nuclear factor-κB (p65) were significantly higher in aged mice. Taken together, our data suggest that renal aging lies in a range between normal and diseased kidneys but may differ between female and male mice, highlighting sex-related differences in the aging process.NEW & NOTEWORTHY Although there is evidence of sex-specific differences in kidney diseases, most preclinical studies have used male rodent models. The clinical data on renal injury have typically not been stratified by sex. Our findings provide convincing evidence of sex-specific differences in age-regulated epigenetic alterations and renal injury markers. This study highlights the importance of including both sexes for better realization of underlying sex differences in signaling mechanisms of aging-related renal pathophysiology.

Sex-related disparities in aortic stenosis from disease awareness to treatment: a state-of-the-art review.

This state-of-the-art review aimed to synthesize evidence from various sex-stratified studies on aortic stenosis (AS), focusing on the difference in clinical presentation, anatomical characteristics, pathophysiology, and management of AS. In comparison to men, women with AS are present at later stages, are older, more symptomatic, frailer, and exhibit higher operative risk [Society of Thoracic Surgeons (STS) score]. Women tend to have smaller aortic valve (AV) areas and left ventricular (LV) outflow tract, leading to lower stroke volumes (SVs) than men and have a higher prevalence of paradoxical, low-flow, low-gradient AS. In women, chronic pressure overload due to AS results in concentric LV remodelling and hypertrophy, characterized by reduced LV cavities, higher filling pressures, lower wall stress, and more diastolic dysfunction. Conversely, men exhibit more dilated eccentric LV remodelling and hypertrophy. AVs in women are less calcified but more fibrotic. Moreover, women are often underdiagnosed, have severity underestimated, and experience delays or receive fewer referrals for AV replacement (AVR). However, women tend to benefit from transcatheter AVR (TAVR) with a long-term survival advantage over men, although the incidence of vascular complications and bleeding events in 30 days after TAVR is higher in women. Surgical AVR (SAVR) in women has high operative risk, is technically demanding and has poorer outcomes with increased mortality at 30 days compared to men. According to the STS score and EuroSCORE, the female sex itself is considered a risk factor for SAVR. Therefore, addressing sex-related disparities in AS and increasing awareness among physicians promises improved diagnosis and treatment, facilitating equitable care and the development of sex-specific personalized medicine.

An Overview of Diabetes Types, Management of Type 1 Diabetes, and its Impact

Diabetes mellitus, a complex, and growing global health challenge, manifests in various forms, each with distinct causes, progression, and management strategies. This review provides a comprehensive overview of diabetes types, with a particular focus on the management of Type 1 Diabetes (T1D) and its profound impact on individuals’ lives. T1D, an autoimmune disorder that typically arises in childhood or adolescence, necessitates lifelong insulin therapy due to the destruction of insulin-producing beta cells in the pancreas. The review explores the classification of diabetes, highlighting the differences in etiology, pathophysiology, and management across the major types: Type 1 Diabetes, Type 2 Diabetes, Gestational Diabetes Mellitus, and other specific forms of diabetes. The management of T1D involves a multifaceted approach, including advanced insulin delivery systems, continuous glucose monitoring technologies, and lifestyle modifications. Despite advancements in diabetes care, T1D significantly impacts individuals’ physical health, psychological well-being, and social life. The relentless demands of managing T1D, coupled with the risk of acute complications such as hypoglycemia and diabetic ketoacidosis, contribute to physical and emotional strain. Additionally, the disease’s social and lifestyle implications, including the stigma associated with chronic illness, further complicate the lived experience of those with T1D. This review underscores the importance of integrated care approaches that address both the physical and psychological aspects of T1D, aiming to enhance the quality of life for affected individuals. Keywords: Diabetes, Type 1 Diabetes, Impact, Individuals’ Lives

Sex differences in sleep and sleep-disordered breathing.

There is increasing evidence for relevant sex differences in pathophysiology, symptom presentation and outcomes in obstructive sleep apnoea (OSA). However, research on sex differences and sex-specific phenotypes in sleep-disordered breathing (SDB) is still in its infancy and data on sex differences in other SDB is still very scarce. While OSA is more common in men than in premenopausal women, the prevalence of OSA doubles postmenopausally and becomes comparable to that of men. Women have a lower collapsibility of the upper airway and a lower arousal threshold. In addition, the rapid eye movement (REM)-apnoea-hypopnoea index (AHI) is typically higher in women than in men, but the non-REM-AHI and thus the total AHI is often lower. Women are often symptomatic at lower AHI and present more frequently with symptoms of sleep fragmentation and poor sleep quality. Both certain forms of OSA (e.g. REM-OSA) and certain phenotypes (e.g. COMISA) are more common in women. Men have a higher risk of high loop gain central sleep apnoea. For a better understanding of sex-typical phenotypes with the aim of a more targeted treatment approach of SDB, adequately powered studies on sex differences in SDB should be conducted.

White Matter Microstructural Changes Using Ultra-Strong Diffusion Gradient MRI in Adult-Onset Idiopathic Focal Cervical Dystonia.

Adult-onset idiopathic focal cervical dystonia (AOIFCD) involves abnormal posturing of the cervical musculature and, in some individuals, an associated head tremor. Existing neuroimaging studies have implicated key motor networks. However, measures used to date lack specificity toward underlying pathophysiologic differences. We aim to assess white matter motor pathways for localized, microstructural differences, which may aid in understanding underlying mechanisms. Individuals diagnosed with AOIFCD and an age- and sex-matched control group were prospectively recruited through the Welsh Movement Disorders Research Network. All participants underwent in-depth clinical phenotyping and MRI (structural and diffusion sequences) using ultra-strong diffusion gradients. Tractography (whole-tract median values) and tractometry (along tract profiling) were performed for key white matter motor pathways assessing diffusion kurtosis imaging (DKI), neurite orientation dispersion and density imaging (NODDI), and standard model parameters. Groups were compared using linear model analysis with Bonferroni multiple comparison correction. Fifty participants with AOIFCD and 30 healthy control participants were recruited, with 46 with AOIFCD and 30 healthy controls included for analysis (33 without head tremor, 13 with head tremor). Significant differences were observed in the anterior thalamic radiations (lower mid-tract fractional anisotropy [estimate = -0.046, p = 3.07 × 10-3], radial kurtosis [estimate = -0.165, p = 1.42 × 10-4], f-intra-axonal signal fraction [estimate = -0.044, p = 2.78 × 10-3], p2 orientation coherence [estimate = -0.043, p = 1.64 × 10-3], higher Orientation Dispersion Index [ODI, estimate = 0.023, p = 2.22 × 10-3]) and thalamopremotor tracts (higher mid-tract mean kurtosis [estimate = 0.064, p = 7.56 × 10-4], lower Neurite Density Index [estimate = 0.062, p = 2.1 × 10-3], higher distal tract ODI [estimate = 0.062, p = 3.1 × 10-3], lower f [estimate = -0.1, p = 2.3 × 10-3], and striatopremotor tracts [proximal lower f: estimate = -0.075, p = 1.06 × 10-3]). These measures correlated with clinical measures: dystonia duration (right thalamopremotor distal ODI: r = -0.9, p = 1.29 × 10-14), psychiatric symptoms (obsessive compulsive symptoms: left anterior thalamic radiation p2 r = 0.92, p = 2.797 × 10-11), sleep quality (Sleep Disorders Questionnaire Score: left anterior thalamic radiation ODI: r = -0.84, p = 4.84 × 10-11), pain (left anterior thalamic radiation ODI: r = -0.89, p = 1.4 × 10-13), and cognitive functioning (paired associated learning task p2, r = 0.94, p = 6.68 × 10-20). Overall, localized microstructural differences were identified within tracts linking the prefrontal and premotor cortices with thalamic and basal ganglia regions, suggesting pathophysiologic processes involve microstructural aberrances of motor system modulatory pathways, particularly involving intra-axonal and fiber orientation dispersion measures.

Sustained fentanyl exposure inhibits neuronal activity in dissociated striatal neuronal-glial cocultures through actions independent of opioid receptors.

Besides having high potency and efficacy at the µ-opioid (MOR) and other opioid receptor types, fentanyl has some affinity for some adrenergic receptor types, which may underlie its unique pathophysiological differences from typical opioids. To better understand the unique actions of fentanyl, we assessed the extent to which fentanyl alters striatal medium spiny neuron (MSN) activity via opioid receptors or α1-adrenoceptors in dopamine type 1 or type 2 receptor (D1 or D2)-expressing MSNs. In neuronal and mixed-glial cocultures from the striatum, acute fentanyl (100 nM) exposure decreased the frequency of spontaneous action potentials. Overnight exposure of cocultures to 100 nM fentanyl severely reduced the proportion of MSNs with spontaneous action potentials, which was unaffected by coexposure to the opioid receptor antagonist naloxone (10 µM) but fully negated by coadministering the pan-α1-adrenoceptor inverse agonist prazosin (100 nM) and partially reversed by the selective α1A-adrenoceptor antagonist RS 100329 (300 nM). Acute fentanyl (100 nM) exposure modestly reduced the frequency of action potentials and caused firing rate adaptations in D2, but not D1, MSNs. Prolonged (2-5 h) fentanyl (100 nM) application dramatically attenuated firing rates in both D1 and D2 MSNs. To identify possible cellular sites of α1-adrenoceptor action, α1-adrenoceptors were localized in subpopulations of striatal astroglia and neurons by immunocytochemistry and Adra1a mRNA by in situ hybridization in astrocytes. Thus, sustained fentanyl exposure can inhibit striatal MSN activity via a nonopioid receptor-dependent pathway, which may be modulated via complex actions in α1-adrenoceptor-expressing striatal neurons and/or glia.NEW & NOTEWORTHY Acute fentanyl exposure attenuated the activity of striatal medium spiny neurons (MSNs) in vitro and in dopamine D2, but not D1, receptor-expressing MSNs in ex vivo slices. By contrast, sustained fentanyl exposure suppressed the spontaneous activity of MSNs cocultured with glia through a nonopioid receptor-dependent mechanism modulated, in part, by α1-adrenoceptors. Fentanyl exposure can affect striatal function via a nonopioid receptor mechanism of action that appears mediated by α1-adrenoreceptor-expressing striatal neurons and/or astroglia.

Sex differences in the diagnostic algorithm of screening for heart failure by symptoms and NT-proBNP in patients with type 2 diabetes

ObjectivesThis study aimed to assess the guideline recommended diagnostic tools NT-proBNP and NYHA classification, with a focus on sex-specific differences.BackgroundPatients with Type 2 Diabetes (T2D) face a heart failure (HF) risk up to four times higher than those without T2D, particularly affecting women more than twice as much as men. Despite distinct pathophysiological differences between men and women, there are currently no sex-specific recommendations for the diagnostic algorithm of HF in diabetic patients.MethodsA total of 2083 patients with T2D were enrolled, and the primary endpoint was heart failure during hospitalization within a 5-year timeframe. The secondary endpoint was all-cause death.ResultsIn female patients, frequency of HF diagnosis prior to or during hospitalization and mortality did not differ significantly between NYHA II and III, in contrast to male patients. Additionally, there was no notable difference in mean NT-proBNP levels between NYHA stage II and III only in female patients. The multivariable regression analysis highlighted NYHA classification not to be a predictor of NT-proBNP levels in female but solely in male patients. On multivariable Cox regression NYHA score was also no significant risk factor for occurence of HF in female patients. Furthermore, there was no significant disparity in mortality between men with NT-proBNP levels between 125 and 400 pg/ml and those below 125 pg/ml, whereas in women mortality was significantly higher in the group with NT-proBNP levels between 125 and 400 pg/ml than below 125 pg/ml.ConclusionThese findings suggest that NYHA classification may not be the most suitable tool for assessing the diagnosis of HF in female patients with T2D. Moreover, the need for consideration of a more symptom-independent screening for HF in female patients with T2D and re-evaluation of current guidelines especially regarding sex-specific aspects is highlighted.

Systemic antibody responses against gut microbiota flagellins implicate shared and divergent immune reactivity in Crohn’s disease and chronic fatigue syndrome

BackgroundElevated systemic antibody responses against gut microbiota flagellins are observed in both Crohn’s disease (CD) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting potential serological biomarkers for diagnosis. However, flagellin-specific antibody repertoires and functional roles in the diseases remain incompletely understood. Bacterial flagellins can be categorized into three types depending on their interaction with toll-like receptor 5 (TLR5): (1) “stimulator” and (2) “silent” flagellins, which bind TLR5 through a conserved N-terminal motif, with only stimulators activating TLR5 (involving a C-terminal domain); (3) “evader” flagellins of pathogens, which entirely circumvent TLR5 activation via mutations in the N-terminal TLR5 binding motif.ResultsHere, we show that both CD and ME/CFS patients exhibit elevated antibody responses against distinct regions of flagellins compared to healthy individuals. N-terminal binding to Lachnospiraceae flagellins was comparable in both diseases, while C-terminal binding was more prevalent in CD. N-terminal antibody-bound flagellin sequences were similar across CD and ME/CFS, resembling “stimulator” and “silent” flagellins more than evaders. However, C-terminal antibody-bound flagellins showed a higher resemblance to the stimulator than to silent flagellins in CD, which was not observed in ME/CFS.ConclusionsThese findings suggest that antibody binding to the N-terminal domain of stimulator and silent flagellins may impact TLR5 activation in both CD and ME/CFS patients. Blocking this interaction could lead commensal bacteria to be recognized as pathogenic evaders, potentially contributing to dysregulation in both diseases. Furthermore, elevated antibody binding to the C-terminal domain of stimulator flagellins in CD may explain pathophysiological differences between the diseases. Overall, these results highlight the diagnostic potential of these antibody responses and lay a foundation for deeper mechanistic studies of flagellin/TLR5 interactions and their impact on innate/adaptive immunity balance.Graphical 3dk6-s1stA6fneys_e7fgXVideo

Comment on Utsumi et al. Differences in Pathophysiology and Treatment Efficacy Based on Heterogeneous Out-of-Hospital Cardiac Arrest. Medicina 2024, 60, 510.

We read with great interest the review article on pathophysiology and treatment based on different out-of-hospital cardiac arrest (OHCA) patients. We wish to present our comments on the threshold values for neuron-specific enolase (NSE) based on the initial rhythm and the misquoting of a few references in that article.

Sex-Related Differences in Characteristics and Therapy of Heart Failure Patients

Aim: To determine the differences in comorbidities, therapy and echocardiographic measures among patients hospitalized for heart failure relative to gender.Methods: The study included patients hospitalized for heart failure at the Department of Cardiovascular Diseases of the Clinical Hospital Center Osijek in the period from 1 January 2020 to 30 March 2021.Results: There were 200 patients included in the study, of which 100 (50%) were male and 100 (50%) were female. Female patients were older, while male patients more frequently had a history of coronary artery disease. Men had a higher dose of loop diuretic on admission to the hospital. No significant difference was found in the representation of beta blockers and ACE inhibitors in therapy with regard to gender. On the other hand, men more frequently used MRA, sacubitril/valsartan and antiplatelet medication at hospital admission. Male patients had a larger left ventricular end-diastolic diameter, left ventricular end-systolic diameter and a lower left ventricular ejection fraction (EF). Regarding the type of heart failure according to EF, 72% of men had HFrEF, 20% HFmrEF and 8% HFpEF. In women, 47% had HFrEF, 33% HFmrEF and 20% HFpEF. During hospitalization due to heart failure, 22 patients died, an equal number of men and women.Conclusion: This research confirmed the differences in risk factors and pathophysiology of heart failure between males and females. Medicine is progressing towards an individual approach to each patient, so further research will be needed to find the best therapy for both male and female patients.

Dilemmas in Elderly Diabetes and Clinical Practice Involving Traditional Chinese Medicine.

Diabetes is a widespread chronic disease that occurs mainly in the elderly population. Due to the difference in pathophysiology between elderly and young patients, the current clinical practice to treat elderly patients with anti-diabetes medications still faces some challenges and dilemmas, such as the urgent need for early diagnosis and prevention, and an imbalance between restricted dietary intake and the risk of undernutrition. Traditional Chinese medicine (TCM) offers various treatment regimens that are actively utilized in the field of diabetes management. Through multiple targets and multiple pathways, TCM formulas, medicinal herbs, and active natural products enhance the efficacy of diabetes prevention and diabetes control measures, simplify complex medication management, and improve common symptoms and common diabetic complications in elderly people. Historically, natural products have played a key role in material composition analysis of TCM and mechanism interpretation to enable drug discovery. However, there have been few conclusions on this topic. This review summarizes the development of TCM for the prevention and management of diabetes in elderly people, existing evidence-based clinical practices, and prospects for future development.