Structural Deficits Research Articles

The role of the brainstem in sleep disturbances and chronic pain of Gulf War and Iraq/Afghanistan veterans.

Gulf War Illness is a type of chronic multisymptom illness, that affects about 30% of veterans deployed to the 1990-91 Persian Gulf War. Veterans deployed to Iraq/Afghanistan after 2000 are reported to have a similar prevalence of chronic multisymptom illness. More than 30 years after the Persian Gulf War, Gulf War Illness still has an unexplained symptom complex, unknown etiology and lacks definitive diagnostic criteria and effective treatments. Our recent studies have found that substantially smaller brainstem volumes and lower fiber integrity are associated with increased sleep difficulty and pain intensity in 1990-91 Persian Gulf War veterans. This study was conducted to investigate whether veterans deployed to Iraq/Afghanistan present similar brainstem damage, and whether such brainstem structural differences are associated with major symptoms as in Gulf War Illness. Here, we used structural magnetic resonance imaging and diffusion tensor imaging to measure the volumes of subcortices, brainstem subregions and white matter integrity of brainstem fiber tracts in 188 veterans including 98 Persian Gulf War veterans and 90 Iraq/Afghanistan veterans. We found that compared to healthy controls, veterans of both campaigns presented with substantially smaller volumes in brainstem subregions, accompanied by greater periaqueductal gray matter volumes. We also found that all veterans had reduced integrity in the brainstem-spinal cord tracts and the brainstem-subcortical tracts. In veterans deployed during the 1990-91 Persian Gulf War, we found that brainstem structural deficits significantly correlated with increased sleep difficulties and pain intensities, but in veterans deployed to Iraq/Afghanistan, no such effect was observed. These structural differences in the brainstem neurons and tracts may reflect autonomic dysregulation corresponding to the symptom constellation, which is characteristic of Gulf War Illness. Understanding these neuroimaging and neuropathological relationships in Gulf War and Iraq/Afghanistan veterans may improve clinical management and treatment strategies for modern war related chronic multisymptom illness.

Diffusion tensor imaging of the brain in children with sensory processing disorder: A review.

Sensory processing disorder (SPD) is a clinical condition characterized by difficulties in the neurological processes of registering, discriminating, organizing, and responding to various sensory sensations. This study aimed to review the association between impaired white matter (WM) tract structure and neurofunctional deficits in children with SPD using diffusion tensor imaging (DTI). A comprehensive literature search was conducted using the online databases Google Scholar and PubMed (from 2010 to July 2023), resulting in the selection of nine relevant studies. Findings revealed that the splenium of the corpus callosum (SCC), superior longitudinal fasciculus (SLF), posterior corona radiata (PCR), and posterior thalamic radiation (PTR) exhibited reduced microstructural integrity, strongly associated with SPD. Specifically, auditory over-responsivity, a subtype of SPD, was linked to impaired integrity of the PCR, PTR, anterior corona radiata, and SLF. Tactile over-responsivity (TOR) was correlated with markers of decreased integrity in the SCC, superior corona radiata, and left PTR. Among the DTI parameters, decreased fractional anisotropy (FA) emerged as the most reliable factor for identifying SPD, followed by increased radial diffusivity (RD) and mean diffusivity (MD). Notably, significant correlations were observed between with auditory over-responsivity and TOR with the DTI parameters (positive for FA and negative for RD and MD). Overall, this review confirms the impaired integrity of specific WM tracts in children with SPD and establishes correlations between DTI parameters and neurobehavioral deficits associated with the disorder. The insights gained from this review contribute to a better understanding of SPD and hold clinical implications for its diagnosis and treatment.

CHONDROCYTE-SPECIFIC KNOCKOUT OF PIEZO ION CHANNELS PROTECTS AGAINST POST-TRAUMATIC OSTEOARTHRITIS

Osteoarthritis (OA) is the leading cause of pain and disability worldwide and is characterized by the degenerative changes of articular cartilage. Joint loading is required for cartilage maintenance; however, hyper-physiologic loading is a risk factor for OA. Mechanosensitive ion channels Piezo1 and Piezo2 synergistically transduce hyper-physiologic compression of chondrocytes, leading to chondrocyte death and onset of OA. This injury response is inhibited by Piezo channel loss of function, however the mechanistic role of Piezo channels in vivo is unknown. We examined the hypothesis that deletion of Piezo in chondrocytes will protect mice from joint damage and pain-related behaviors following a surgical destabilization of the medial meniscus (DMM), investigating a key mechanistic and mechanobiological role of these channels in the pathogenesis of OA.Aggrecan-Cre Piezo1 and Piezo1/2 knockout mice ((Agc)1-CREERT2;Piezo1fl/flPiezo2fl/fl) were generated and given a 5-day Tamoxifen regimen at 12-weeks of age (n=6–12/group/sex). Cre-negative mice served as controls. At 16-weeks, mice received DMM surgery on the left knee. 12-weeks following DMM prior to sacrifice, activity and hyperalgesia were measured using spontaneous running wheels and a small animal algometer. Structural changes in bone, cartilage, and synovium were characterized using microCT, histology, and Modified Mankin Score criteria.Knockout of Piezo1/2 channels was chondroprotective in both sexes following DMM surgery as demonstrated by reduced Modified Mankin Score compared to control animals. Piezo1 KO was chondroprotective in only female mice, indicating a sexually dimorphic response. Piezo1 and Piezo1/2 KO was protective against pain in male mice, while females displayed no differences compared to controls. No changes were observed in bone morphology.Chondrocyte-specific Piezo1/2 knockout protects the knee joint from structural damage, hyperalgesia and functional deficits in a surgical model of PTOA in male and female mice, illustrating the importance of Piezo channels in response to injury in vivo. Future work aims to interrogate potential sexually dimorphic responses to cartilage damage and investigating Piezo2 KO mice.

The double connection: towards a bi-directional notion of participation

Self-organised initiatives are increasingly recognised as an alternative to the structural deficit of participatory planning approaches, both in theory and in practice. Nevertheless, public governance is struggling to find ways to deal with such initiatives. This article identifies four prominent categories of self-organised practice, analysing the main motivation to engage in and with these practices, from the perspective of government as well as the self-organised actors. This is in turn linked to three prominent theoretical answers on how governments might deal with self-organisation. Lastly, we reflect on the complexities of a possible double connection between policymakers and self-organisations.

Growth hormone releasing peptide-6 (GHRP-6) prevents doxorubicin-induced myocardial and extra-myocardial damages by activating prosurvival mechanisms.

Introduction: Dilated cardiomyopathy (DCM) is a fatal myocardial condition with ventricular structural changes and functional deficits, leading to systolic dysfunction and heart failure (HF). DCM is a frequent complication in oncologic patients receiving Doxorubicin (Dox). Dox is a highly cardiotoxic drug, whereas its damaging spectrum affects most of the organs by multiple pathogenic cascades. Experimentally reproduced DCM/HF through Dox administrations has shed light on the pathogenic drivers of cardiotoxicity. Growth hormone (GH) releasing peptide 6 (GHRP-6) is a GH secretagogue with expanding and promising cardioprotective pharmacological properties. Here we examined whether GHRP-6 administration concomitant to Dox prevented the onset of DCM/HF and multiple organs damages in otherwise healthy rats. Methods: Myocardial changes were sequentially evaluated by transthoracic echocardiography. Autopsy was conducted at the end of the administration period when ventricular dilation was established. Semiquantitative histopathologic study included heart and other internal organs samples. Myocardial tissue fragments were also addressed for electron microscopy study, and characterization of the transcriptional expression ratio between Bcl-2 and Bax. Serum samples were destined for REDOX system balance assessment. Results and discussion: GHRP-6 administration in parallel to Dox prevented myocardial fibers consumption and ventricular dilation, accounting for an effective preservation of the LV systolic function. GHRP-6 also attenuated extracardiac toxicity preserving epithelial organs integrity, inhibiting interstitial fibrosis, and ultimately reducing morbidity and mortality. Mechanistically, GHRP-6 proved to sustain cellular antioxidant defense, upregulate prosurvival gene Bcl-2, and preserve cardiomyocyte mitochondrial integrity. These evidences contribute to pave potential avenues for the clinical use of GHRP-6 in Dox-treated subjects.

Large supratentorial intraventricular meningiomas: post-operative analysis and results of structural and functional visual field deficits following a lateral anatomically-based trajectory

Large supratentorial intraventricular meningiomas: post-operative analysis and results of structural and functional visual field deficits following a lateral anatomically-based trajectory

The role of an emergency basic income: Lessons from the Latin American experience to confront the COVID‐19 pandemic

AbstractThe article provides a brief overview of the social impacts of the COVID‐19 crisis in Latin America and the Caribbean, presenting how these are intertwined with a structural deficit of social protection systems. It also describes the main features of the emergency social protection responses adopted by Latin American countries that are relevant to the ongoing debate on an emergency basic income. Finally, it discusses the role, implications, and challenges in implementing an emergency basic income as a sustainable entitlement, embedded in the social protection system, to be activated in times of crisis.

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks.

Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses a severe burden on the patients and caregivers, yet relatively little is known about its pathobiology. Cognitive deficits are evident throughout the course of PD, with around 25% of subtle cognitive decline and mild CI (MCI) at the time of diagnosis and up to 83% of patients developing dementia after 20 years. The heterogeneity of cognitive phenotypes suggests that a common neuropathological process, characterized by progressive degeneration of the dopaminergic striatonigral system and of many other neuronal systems, results not only in structural deficits but also extensive changes of functional neuronal network activities and neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical and subcortical atrophies and alterations in intrinsic neuronal connectivities. The decreased functional connectivity (FC) of the default mode network (DMN) in the bilateral prefrontal cortex is affected already before the development of clinical CI and in the absence of structural changes. Longitudinal cognitive decline is associated with frontostriatal and limbic affections, white matter microlesions and changes between multiple functional neuronal networks, including thalamo-insular, frontoparietal and attention networks, the cholinergic forebrain and the noradrenergic system. Superimposed Alzheimer-related (and other concomitant) pathologies due to interactions between α-synuclein, tau-protein and β-amyloid contribute to dementia pathogenesis in both PD and dementia with Lewy bodies (DLB). To further elucidate the interaction of the pathomechanisms responsible for CI in PD, well-designed longitudinal clinico-pathological studies are warranted that are supported by fluid and sophisticated imaging biomarkers as a basis for better early diagnosis and future disease-modifying therapies.

Significant loss of retinal nerve fibre layer and contrast sensitivity in people with well controlled HIV disease: implications for aging with HIV.

Antiretroviral therapy has decreased the prevalence of retinal opportunistic infections in people living with HIV (PLWH). However, abnormalities in visual function are evident and may be associated with an early onset of aging in PLWH. In this study, we examined the Retinal Nerve Fibre Layer (RNFL) thickness and visual function in PLWH and HIV non-infected controls in Malaysia. Cross-sectional study. Two hundred and two (202) PLWH without retinal opportunistic infection and 182 age-matched, HIV seronegative individuals were enrolled. PLWH were recruited from the Infectious Disease clinic at the University Malaya Medical Centre. Controls were recruited among the hospital staff and community volunteers. RNFL thickness was measured with spectral domain optical coherence tomography (SDOCT). Visual functions include visual acuity using LogMAR chart and contrast sensitivity using Pelli- Robson Chart. All PLWH (mean age 46.1 years ± 9.9 years) in the study were on ART and 61.2% had a CD4+ T-cell count more than 500 cell/μl. The mean visual acuity was similar between the two groups (LogMAR 0.05 vs. 0.07, p = 0.115). Contrast sensitivity was lower in PLWH compared to HIV seronegative individuals (1.90 vs 1.93, p = 0.032). RNFL thickness was significantly thinner in the temporal quadrant for PLWH compared to controls (68.89 μm vs 74.08 μm, p = 0.001). Changes in RNFL thickness and contrast sensitivity were seen in PLWH despite their relatively young age and well controlled HIV disease. The changes reflect structural and functional deficits, and could have long-term implications on their health trajectory.

The Effectiveness of Financial Sustainability in Targeting Inflation, Nigeria as a Model for the Period 2004-2040

Creating a sovereign fund financed by Nigeria's oil surpluses is a significant objective. Rentier countries tend to see their current operating expenditures increase in tandem with oil revenue growth, surpassing the growth of the gross domestic product. This points to a structural deficit resulting from excessive spending. The government controls the money supply by managing the monetary base, which, in turn, is influenced by foreign reserves. Therefore, the study focused on assessing the effectiveness of fiscal policy tools and financial sustainability in addressing inflation. The goal is to predict these financial variables accurately until 2040 to safeguard monetary stability against fluctuations in oil prices. Utilizing the autoregressive model and moving averages (ARIMA), the study aims to address government spending growth, primarily driven by the monetization of oil revenues. This has led to a structural deficit within the Nigerian economy, which needs to be curbed by the effectiveness of the sovereign fund. This effectiveness is reflected in the concept of financial sustainability, with a focus on targeting inflation through what is known as nominal financial wealth. This translation of economic sustainability into tangible financial wealth does not adequately clarify the increase in non-oil output achieved through investment spending. The latter, in turn, results in actual growth in non-oil revenues, which is essential for addressing inflation through fiscal policy tools. In a rentier economy reliant on oil, achieving economic stability isn't assured solely by a balanced budget. It's crucial that public spending is managed with a level of independence from fluctuations in oil prices. The study's findings demonstrate the relative effectiveness of the financial sustainability forecasting model in influencing inflation targeting in the Nigerian economy.

Morphine aggravates inflammatory, behavioral, and hippocampal structural deficits in septic rats

Although pain and sepsis are comorbidities of intensive care units, reported data on whether pain control by opioid analgesics could alter inflammatory and end-organ damage caused by sepsis remain inconclusive. Here, we tested the hypothesis that morphine, the gold standard narcotic analgesic, modifies behavioral and hippocampal structural defects induced by sepsis in male rats. Sepsis was induced with cecal ligation and puncture (CLP) and behavioral studies were undertaken 24 h later in septic and/or morphine-treated animals. The induction of sepsis or exposure to morphine (7 mg/kg) elicited similar: (i) falls in systolic blood pressure, (ii) alterations in spatial memory and learning tested by the Morris water maze, and (iii) depression of exploratory behavior measured by the new object recognition test. These hemodynamic and cognitive defects were significantly exaggerated in septic rats treated with morphine compared with individual interventions. Similar patterns of amplified inflammatory (IL-1β) and histopathological signs of hippocampal damage were noted in morphine-treated septic rats. Additionally, the presence of intact opioid receptors is mandatory for the induction of behavioral and hemodynamic effects of morphine because no such effects were observed when the receptors were blocked by naloxone. That said, our findings suggest that morphine provokes sepsis manifestations of inflammation and interrelated hemodynamic, behavioral, and hippocampal deficits.

Thrombotic Thrombocytopenic Purpura (TTP) Survivors Exhibit Impaired Stress Perfusion on Cardiac MRI

Introduction: Thrombotic thrombocytopenic purpura (TTP) survivors have increased rates of cardiovascular morbidity and mortality when compared with the general population. In this prospective pilot study, we sought to further characterize the long-term cardiovascular sequelae of TTP survivors through pharmacologic stress cardiac magnetic resonance imaging (CMR). Stress CMR has been increasingly utilized to detect clinical and subclinical structural and functional changes. A CMR biomarker of myocardial remodeling is extracellular volume (ECV); an increase in ECV may indicate the development of interstitial myocardial fibrosis. ECV was chosen for structural assessment as it has been implicated with diastolic dysfunction and other cardiac issues in other hematologic diseases, like sickle cell anemia. Methods: Adult patients (age ≥18 years of age) with TTP (immune-mediated or congenital) in the Ohio State University (OSU) TTP registry were prospectively consented and enrolled from March 2023 through July 2023 to undergo adenosine stress CMR at standard clinical dosing. All patients in the TTP cohort had confirmed diagnosis based on ADAMTS13 activity <15% during an acute episode and were in clinical remission at the time of CMR testing. Standard baseline and stress CMR parameters were obtained and compared with an age and sex matched control population, selected from patients without TTP who underwent identical stress CMR protocol for other indications and demonstrated normal stress perfusion. Patients in the control cohort predominantly had diagnoses of arrhythmia, stable angina, or heart failure. We collected data on patient demographics, details of TTP history, and underlying comorbidities. On CMR standard structural measurements were evaluated, and ECV was calculated (normal range 25.3 ± 3.5%). Perfusion was measured per standard protocols via global myocardial blood flow (MBF) as ml/min/g. Differences between the TTP and control populations were tested using the Fischer's exact test for categorical variables and Mann-Whitney U test for continuous variables. Results: A total of 10 TTP patients (9 immune-mediated, 1 congenital) were enrolled between March and July 2023. Median age at enrollment was 44.5 years (IQR 40.8-49.5) and 80% (8/10) were female. Patients were in documented clinical and ADAMTS13 activity remission with median ADAMTS13 activity of 68% (64.0-84.5), excluding the activity level of the congenital patient. Median time from initial diagnosis was 15 years (range 0.5 - 41 years) and median number of acute TTP episodes was 2 (IQR 1.0-4.5). Characteristics of the study (n= 10) and control cohort (n = 13) are summarized in Table 1. There were no significant differences in the TTP and control cohorts with respect to age, sex, race, and presence of hypertension or diabetes. Patients in the TTP cohort had significantly higher BMI (median 34.5 mg/m 2 vs 26.5 mg/m 2, p = .012), diastolic blood pressure (94 mmHg vs 82 mmHg, p = .003), and a lower rate of known cardiac disease (10% vs 85%, p<.001). Stress CMR showed reduced myocardial perfusion in TTP survivors: Nine out of 10 (90%) TTP survivors had evidence of structural or perfusion deficits on CMR. The median ECV in the TTP cohort (28.5%, 24.8 - 31.5) was increased compared with controls (26%, 23.5 - 27.5) though it did not reach significance (p = .08). There were no significant differences in median global MBF at rest in the TTP group (1.30, 1.16 - 1.37) compared with controls (1.18, 1.07 - 1.31, p = .210). However, TTP survivors had significantly reduced stress MBF (3.28, 2.21 - 3.53) vs controls (4.1, 3.88 - 4.22, p <.001) with adenosine. Reductions in quantitative stress perfusion in the TTP cohort was primarily noted in the subendocardium as shown in Figure 2. Conclusion: Asymptomatic structural changes and reduction in quantitative perfusion are common in TTP survivors. The study is ongoing to recruit more patients to ensure clinical significance and generalizability of these preliminary findings. Stress CMR may detect subclinical myocardial damage in TTP survivors who otherwise do not exhibit overt cardiovascular symptoms until a later time and may provide the basis to understand increased cardiovascular morbidity and mortality in this population.

Role of the Glycine Receptor β Subunit in Synaptic Localization and Pathogenicity in Severe Startle Disease.

Startle disease is due to the disruption of recurrent inhibition in the spinal cord. Most common causes are genetic variants in genes (GLRA1, GLRB) encoding inhibitory glycine receptor (GlyR) subunits. The adult GlyR is a heteropentameric complex composed of α1 and β subunits that localizes at postsynaptic sites and replaces embryonically expressed GlyRα2 homomers. The human GlyR variants of GLRA1 and GLRB, dominant and recessive, have been intensively studied in vitro. However, the role of unaffected GlyRβ, essential for synaptic GlyR localization, in the presence of mutated GlyRα1 in vivo is not fully understood. Here, we used knock-in mice expressing endogenous mEos4b-tagged GlyRβ that were crossed with mouse Glra1 startle disease mutants. We explored the role of GlyRβ under disease conditions in mice carrying a missense mutation (shaky) or resulting from the loss of GlyRα1 (oscillator). Interestingly, synaptic targeting of GlyRβ was largely unaffected in both mouse mutants. While synaptic morphology appears unaltered in shaky animals, synapses were notably smaller in homozygous oscillator animals. Hence, GlyRβ enables transport of functionally impaired GlyRα1 missense variants to synaptic sites in shaky animals, which has an impact on the efficacy of possible compensatory mechanisms. The observed enhanced GlyRα2 expression in oscillator animals points to a compensation by other GlyRα subunits. However, trafficking of GlyRα2β complexes to synaptic sites remains functionally insufficient, and homozygous oscillator mice still die at 3 weeks after birth. Thus, both functional and structural deficits can affect glycinergic neurotransmission in severe startle disease, eliciting different compensatory mechanisms in vivo.

Cerebrovascular Function is Altered in Hemodialysis Patients.

Hemodialysis (HD) patients have declines in cerebral blood flow (CBF) and cerebral oxygenation during HD that may lead to ischemic brain injury. Cerebrovascular reactivity (CVR) may indicate which individuals are more susceptible to intradialytic hypoperfusion and ischemia. We hypothesized that HD patients would have decreased CVR and increased CBF relative to controls and deficits in CVR would be related to brain structural deficits. We measured cortical thickness and white matter hyperintensity (WMH) volume from T1 and T2 FLAIR images respectively, CVR from a breath hold BOLD CVR fMRI and arterial transit time (ATT) and CBF from ASL. Cerebrovascular and structural deficits in gray and white matter (GM and WM) were tested by averaging across the tissue and with a pothole analysis. Finally, we correlated cortical thickness and WMH volume with GM and WM cerebrovascular variables to assess the relationship between brain structure and cerebrovascular health. In ten HD patients, cortical thickness was found to be decreased (p= 0.002), WMH volume increased (p=0.004), and WM CBF increased (p=0.02) relative to ten controls. Pothole analysis indicated a higher number of increased GM and WM CBF voxels (p=0.03, p=0.02) and a higher number of decreased GM and WM CVR voxels (p=0.02, p=0.01). This pilot study demonstrates that HD patients have decreased CVR and increased CBF relative to controls, along with reduced brain integrity. Further investigation is required to fully understand if these cerebrovascular deficits may lead to structural changes.

Cigarette smoking and structural brain deficits in patients with atrial fibrillation

Abstract Background Brain lesions are common in patients with atrial fibrillation (AF). Whether cigarette smoking is associated with an increased risk of brain lesions and reduced brain volume in patients with AF is currently unknown. Purpose In this analysis, we aimed to investigate the association of cigarette smoking habits with cerebral small vessel disease and overall brain volume. Methods For this cross-sectional analysis, we included AF patients from a multicentre cohort study. Smoking habits were defined by smoking status categories (never, former, current), duration (tertiles of years), cigarettes per day (CPD as obtained at baseline), packyears (PKY, tertiles) and time since smoking cessation (≤5 years, 6-10 years, 11-15 and ≥16 years). A standardized brain magnetic resonance imaging was done to assess the prevalence of small vessel disease white matter lesions (WML, graded according to the Fazekas scale) and small non-cortical infarcts (SNCI). Additionally, MRI was used to quantify the volumes of WML and SNCI; as well as to measure grey matter (GM) and white matter (WM) brain volumes. Multivariable adjusted logistic and linear regression analyses were applied. Results 1746 patients were enrolled (mean age 72.6 years, 27.5% females). 131 (7.5%) were current smokers, 846 (48.5%) former and 769 (44%) never smokers. Patients with a longer smoking duration, higher amount of CPD and PKY had reduced GM brain volume (p for linear trend 0.05, 0.005 and 0.02, respectively). Patient with higher CPD also had a reduced WM brain volume (p for linear trend 0.04). Compared to patients with a smoking duration in the lowest tertile (≤18 years), patients who had smoked for 19-34 years (second tertile) and more than 35 years (third tertile) had a higher risk for WML Fazekas ≥2 with an OR (95% CI) of 1.85 (1.29; 2.66, p=0.001) and 1.46 (1.01; 2.09, p=0.04) (Figure 1). Additionally, increasing smoking duration tertiles exhibited larger WML volumes, with a significant linear trend (p=0.05). AF patients who quit smoking ≥16 years ago had a lower odds for SNCI (OR 0.47 (0.24; 0.94, p= 0.03), less WML volume (β: -0.451 (-0.8; -0.11, p=0.01), and a higher WM brain volume (β: 16.9 (0.3; 33.6, p= 0.05) compared to patients who quit 5 years prior to the study enrolment (Figure 2). We found no significant difference in any structural brain deficit between current and former smokers compared to never smokers. Conclusion In a large AF population, we found that smoking duration and amount were associated with the loss of brain volumes. Smoking duration and time since smoking cessation were associated with small vessel disease.

Real-world drug prescription patterns and mortality risk in patients hospitalized with acute heart hailure: impact of multimorbidity and heart failure phenotype

Abstract Background Real-world data on the impact of multimorbidity and of heart failure (HF) phenotype on longitudinal drug prescription patterns and dosing of guideline-recommended HF drugs and on mortality risk following acute HF (AHF) is sparse. Purpose We studied prescription rates (PR) and dosing of renin-angiotensin-system inhibitors (RASi), betablockers (BB), and mineralocorticoid-receptor antagonists (MRA) in patients hospitalized with AHF by comorbidity burden (CB) and HF phenotype on admission, at discharge, and at 6-month follow-up (6MFUP), and determined 12-month mortality risk. Methods Consecutive AHF patients enrolled on a 24/7 basis in a single-center prospective cohort study from 8/2014 to 2/2020, who had their left ventricular ejection fraction (LVEF) measured while in hospital, were eligible. Proportions of patients taking each HF drug class on admission, at discharge and at 6MFUP were determined in subgroups according to LVEF (<50% versus ≥50%) and CB (number present of: hypertension, chronic kidney disease, diabetes, anemia, chronic lung disease, psychiatric disorder, malignancy, atrial fibrillation, coronary disease, peripheral vascular disease, hypercholesterolemia). Results Of 943 patients, 47% had a LVEF <50%, and 53% had a LVEF of ≥50% (Table). CB was similar in both groups (p = 0.197), but patients with LVEF ≥50% were older and more often female (Table). Average PR of the 3 HF drug classes were higher in patients with LVEF <50% compared with ≥50% (mean count 2.2±0.8 vs. 1.7±0.8, respectively, p<0.001), but PR trajectories were similar: In patients with fewer comorbidities, PR were lower on admission but showed the greatest increase during the hospital stay (in particular for BB and RASi). PR improved in all patients irrespective of CB and reached a maximum at discharge (Figure). Still, many patients remained on suboptimal drug doses (irrespective of CB), and PR tended to decrease again at 6MFUP, except for MRA, which were often not prescribed at all even in patients with LVEF <50%. Absolute 12-month mortality risk was similar in the patients with LVEF <50% and ≥50%, but CB and number of HF drugs prescribed at discharge impacted significantly on 12-month mortality risk only in patients with LVEF <50% (Table). Conclusion In this study, PR of HF drugs increased during the in-hospital period, irrespective of HF phenotype. Neither PR, nor daily doses improved further after discharge. Prescription patterns were similar across spectra of LVEF and CB, but only in patients with LVEF <50% the number of comorbidities and of prescribed HF drug classes impacted mortality risk significantly. Given that timely implementation of foundational HF therapies (which today include also SGLT2 inhibitors) may improve outcomes, reasons for underprescription (e.g., suspected intolerability of individual drug classes or structural deficits of post-discharge HF management) in real world warrant further study and better control.TableFigure

Experimental Models of Synaptopathies Based on Zebrafish

Synaptopathies include a heterogeneous group of severely debilitating neurological diseases characterized by structural and functional deficits of neuronal synapses. Common synaptopathies include epilepsy, schizophrenia, prion diseases, autism spectrum disorders, various autoimmune diseases and cochlear synaptopathies. Their pathogenesis is caused by both genetic and environmental factors. However, the relationship between the cause and clinical manifestations of each particular synaptopathy, and their therapy, remain poorly understood. Here, we discuss animal models of synaptopathies, with a specific emphasis on zebrafish (Danio rerio), as well as outline several lines of future research in this field. Overall, zebrafish emerge as a promising organism to mimic a wide range of synaptopahies, paralleling and complementing their existing models in rodents.

Intermediate gray matter interneurons in the lumbar spinal cord play a critical and necessary role in coordinated locomotion.

Locomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of individual spinal interneuron (SpIN) subtypes, the phenotype of combined SpIN loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VIII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system that strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VIII in spinal L2-L4 correlates with hindlimb dysfunction. White matter alterations and lower motoneuron loss were not observed with this KA lesion. Animals did not regain lost sensorimotor function three months after injury, indicating that natural recovery mechanisms of the spinal cord cannot compensate for loss of laminae V-VIII neurons. As gray matter damage accounts for neurological/walking dysfunction in instances of spinal cord injury affecting the cervical or lumbar enlargement, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function.

Decreased grey matter volume in dorsolateral prefrontal cortex and thalamus accompanied by compensatory increases in middle cingulate gyrus of premature ejaculation patients.

The prefrontal-cingulate-thalamic areas are associated with ejaculation control. Functionalabnormalities of these areas and decreased grey matter volume (GMV) in the subcortical areas have been confirmed in premature ejaculation (PE) patients. However, no study has explored the corresponding GMVchanges in the prefrontal-cingulate-thalamic areas, which are considered as the important basis for functionalabnormalities. This study aimed to investigated whether PE patients exhibited impaired GMV in the brain, especially the prefrontal-cingulate-thalamic areas, and whether these structural deficits were associated with declined ejaculatory control. T1-weighted structural magnetic resonance imaging (MRI) data were acquired from 50 lifelong PE patients and 50 age-, and education-matched healthy controls (HCs). The PE diagnostic tool (PEDT) was applied to assess the subjective symptoms of PE. Based on the method of voxel-based morphometry (VBM), GMV were measured and compared between groups. In addition, the correlations between GMV of brain regions showed differences between groups and PEDT scores were evaluated in the patient group. PE patients showed decreased GMV in the right dorsolateral superior frontal gyrus (clusters=13, peak T-values=-4.30) and left thalamus (clusters=47, T=-4.33), and increased GMV in the left middle cingulate gyrus (clusters=12, T=4.02) when compared with HCs. In the patient group, GMV of the left thalamus were negatively associated with PEDT scores (r=-0.35; P=0.01). Receiver operating characteristic (ROC) analysis showed that GMV of the right dorsolateral superior frontal gyrus (AUC=0.71, P<0.01, sensitivity=60%, specificity=78%), left thalamus (AUC=0.72, P<0.01, sensitivity=92%, specificity=46%) and middle cingulate gyrus (AUC=0.69, P<0.01, sensitivity=50%, specificity=90%), and the combined model (AUC=0.84, P<0.01, sensitivity=78%, specificity=80%) all had theability to distinguish PE patients from HCs. Disturbances in GMV were revealed in the prefrontal-cingulate-thalamic areas of PE patients. The findings implied that decreased GMV in the dorsolateral prefrontal cortex and thalamus might be associated with the central pathological neural mechanism underlying the declined ejaculatory control while increased GMV in the middle cingulate gyrus might be the compensatory mechanism underlying PE.

Structural and Functional Brain Changes After Glucocorticoid Therapy in Thyroid-Associated Ophthalmopathy.

To investigate the brain structural and functional alterations in patients with thyroid-associated ophthalmopathy (TAO) before and after glucocorticoid therapy, using voxel-based morphometry (VBM) as well as resting-state functional magnetic resonance imaging (MRI) with amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo). Between 2019 and 2022, 32 patients with TAO and 23 healthy controls underwent pre-therapy MRI in Nanjing, China. Intravenous glucocorticoid therapy was administered to all patients. At 3 months after end of therapy, 26 patients were available for rescanned MRI. VBM, ALFF, and ReHo were used to evaluate the brain structural and functional differences. Before therapy, TAO patients showed significantly decreased gray matter volume (GMV) in the left orbital part of superior frontal gyrus (ORBsup) and medial superior frontal gyrus (SFGmed) than healthy controls. Patients had higher ALFF values in bilateral gyrus rectus and olfactory cortex and lower values in bilateral cuneus. Patients also showed decreased ReHo values in bilateral lingual gyrus. After therapy, increased GMV in the left anterior cingulate gyrus and SFGmed, increased ALFF values in bilateral cuneus and superior occipital gyrus, and increased ReHo values in bilateral SFGmed were found in TAO patients compared to the pre-therapy cohort. Compared to controls, decreased GMV in left ORBsup was observed in post-therapy TAO patients. Our results indicated that TAO might cause functional and structural deficits in the visual and emotional regions of the brain, with recovery in the former and partial restoration in the latter after effective glucocorticoid therapy. These findings may lead to deeper understanding of the pathophysiological mechanism behind TAO.