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Endogenous time of day-dependent modulation of brain activity and visual perception in humans
(2023)
Earth’s rotation and the resulting day-night cycle of solar irradiance causes rhythmic changes in environmental conditions. The circadian system anticipates these predictable challenges and the brain integrates this information with homeostatic cues in order to time behavior accordingly. Humans highly depend on the visual system, which is most drastically affected by planetary rotation, with the most pronounced changes occurring during twilight. Yet, it is still unclear how visual perception and its underlying neural processes are modulated according to the time of day. We thus investigated human brain activity in constant dim light via the fMRI BOLD-signal during resting-state and a close-to-threshold visual detection task over 6 times of the day.
BOLD-variability decreased endogenously at times of twilight in sensory cortices during resting-state and, even more, in the visual cortex during visual perception at these times. Furthermore, the visual cortex BOLD-variability reductions were associated with improved visual detection performance. In contrast, mean BOLD-activations related to visual perception were not significantly modulated by the time of day.
In conclusion, these results imply that the visual cortex BOLD-variability reductions at times of twilight constitute a predictive mechanism facilitating visual perception to compensate for the degraded visual signal quality at these times. Individual chronotype and homeostatic sleep pressure explained part of the BOLD-variability modulation, suggesting a combined circadian and homeostatic regulation. Human activity usually extends into times of twilight, even in preindustrial societies. Therefore, anticipatory optimization of the visual system at twilight may have been crucial for survival and may still be relevant today whenever electric light is not available at these times. Moreover, the findings suggest that endogenous BOLD-variability reductions in sensory cortices constitute a novel general mechanism underlying enhanced close-to-threshold perception, further supporting the biological significance of BOLD-variability.
Objectives: Patients with open pulmonary tuberculosis (opTB) are subject to strict isolation rules. Sputum smear microscopy is used to determine infectivity, but sensitivity is lower than for culture. This study aimed to investigate the clinical relevance of this mismatch in contemporary settings.
Methods: Differential results between microscopy and culture were determined at the time of microscopic sputum conversion, from all patients with opTB between 01/2013 and 12/2017. In addition, data on HIV, multi/extensive drug-resistant TB status, time to smear- and cultural-negativity conversion were analyzed; and a Kaplan-Meier curve was developed.
Results: Of 118 patients with opTB, 58 had demographic data available for microbiological and clinical follow-up analysis; among these, 26 (44.8%) had still at least one positive culture result. Median time from opTB-treatment initiation to full microscopic sputum- or culture conversion, was 16.5 days (range 2-105), and 20 days (1-105), respectively (median difference: +3.5 days). Sixteen days after de-isolation, >90% had converted culturally. HIV- or multi/extensive drug-resistant TB status did not impact conversion time.
Conclusion: When patients with opTB were de-isolated after 3 negative sputum smear microscopy tests, a substantial part still revealed cultural growth of Mycobacterium tuberculosis complex, but it remains unclear, whether smear-negative and culturally-positive individuals on therapy are really infective. Thus, the clinical relevance of this finding warrants further investigation.
In this case report, we present a rare case of a female patient who developed pain and swelling after a total knee arthroplasty. An extensive diagnostic workup including serum and synovial testing to rule out infection was performed in addition to advanced imaging including an MRI of the knee, but it was only after an arthroscopic synovectomy that the diagnosis of secondary synovial chondromatosis was confirmed. The purpose of this case report is to highlight the occurrence of secondary synovial chondromatosis as a rare cause of pain and swelling after total knee arthroplasty, thereby assisting clinicians in providing prompt diagnosis, surgical treatment, and efficient recovery in the setting of secondary synovial chondromatosis after total knee arthroplasty.
Of mice and men: a semiquantitative analysis of Kv4.3 expression in mouse and human midbrains
(2024)
Idiopathic Parkinson syndrome is one of the most common neurodegenerative diseases and plays a major role in clinical neurological practice. However, the exact pathogenesis has not yet been fully elucidated. It is assumed that a combination of genetic and environmental factors fuels a neurodegenerative process during aging, which result in a selective loss of dopaminergic neurons in the substantia nigra. In rare instances, Parkinson disease (PD) is caused by single toxic-gain of function mutations for instance a single amino acid exchange (A53T) in the gene coding for a-synuclein (SNCA). A central event in idiopathic and mono-genetic PD is the formation of intracytoplasmic accumulation of α-synuclein in so-called Lewy bodies. On this basis, a mouse model was developed that overexpresses human α-synuclein through an A53T mutation in the SNCA gene. In previous work, this mutation was found to lead to both oxidative dysfunction and enhanced expression of Kv4.3 channels in middle-aged mice. Given the central role of aging in the pathogenesis of neurodegeneration, this study analyzed Kv4.3 protein expression in dopamine midbrain neurons using immunohistochemical methods in aged male transgenic A53T SNCA and wildtype mice.
Using semi-quantitative analysis of confocal images of fluorescent Kv4.3 immunosignals, I found significantly reduced Kv4.3 protein expression in old A53T SNCA animals compared to those in age-matched WT mice.
To improve comparison between mouse models and human brain tissue, I also developed a protocol for identical histological processing of human and murine brain sections and Kv4.3 immunohistochemistry. This protocol will be useful to study Kv4.3 expression in DA neurons of human control brains and in various stages of PD.
Highlights
• Pediatric patients with RASopathies exhibit an increased heart mass.
• Cardiomyocyte size and volume are reduced in pediatric patients with RASopathies.
• Cardiomyocyte numbers per heart are increased in pediatric RASopathy patients.
• Cardiomyocytes in juvenile RASopathy have an immature state.
• Elevated LV mass in RASopathy patients is mainly due to cardiomyocyte hyperplasia.
Abstract
Aims: RASopathies are caused by mutations in genes that alter the MAP kinase pathway and are marked by several malformations with cardiovascular disorders as the predominant cause of mortality. Mechanistic insights in the underlying pathogenesis in affected cardiac tissue are rare. The aim of the study was to assess the impact of RASopathy causing mutations on the human heart.
Methods and results: Using single cell approaches and histopathology we analyzed cardiac tissue from children with different RASopathy-associated mutations compared to age-matched dilated cardiomyopathy (DCM) and control hearts. The volume of cardiomyocytes was reduced in RASopathy conditions compared to controls and DCM patients, and the estimated number of cardiomyocytes per heart was ∼4–10 times higher. Single nuclei RNA sequencing of a 13-year-old RASopathy patient (carrying a PTPN11 c.1528C > G mutation) revealed that myocardial cell composition and transcriptional patterns were similar to <1 year old DCM hearts. Additionally, immaturity of cardiomyocytes is shown by an increased MYH6/MYH7 expression ratio and reduced expression of genes associated with fatty acid metabolism. In the patient with the PTPN11 mutation activation of the MAP kinase pathway was not evident in cardiomyocytes, whereas increased phosphorylation of PDK1 and its downstream kinase Akt was detected.
Conclusion: In conclusion, an immature cardiomyocyte differentiation status appears to be preserved in juvenile RASopathy patients. The increased mass of the heart in such patients is due to an increase in cardiomyocyte number (hyperplasia) but not an enlargement of individual cardiomyocytes (hypertrophy).
Objective: This study presents data from the admission trial to show the feasibility, safety and effectiveness of the Nit-Occlud® Lê VSD in the treatment of perimembranous ventricular septal defects with an aneurysmal configuration and a diameter up to 8 mm.
Background: The majority of ventricular septal defects (VSD) are still closed surgically, while a less invasive transcatheter treatment by closure devices is available. Device-based closure is reported to be associated with the risk of complete atrio-ventricular block, especially with double-disc devices in perimembranous defects.
Methods: In six tertiary centers in Germany and Israel, an interventional closure of a periembranous VSD was attempted in 88 patients using the Nit-Occlud® Lê VSD.
Results: The interventional VSD closure was performed in 85 patients. Patients had a median age of 8.0 (2–65) years and a median body weight of 26.7 (10–109) kg. A complete closure of the defects was achieved in 85.4% 2 weeks after device implantation, in 88.9% after three months and in 98.6% at the 5-year follow-up. There was no incidence of death during the study nor did any patient suffer of permanent atrio-ventricular block of higher degree. Serious adverse events, by definition, are potentially life-threatening or require surgery to correct, while major serious events require medical or transcatheter intervention to correct. The study results exhibit a serious adverse event rate of 3.5% (3/85 patients) and a major adverse event rate of 5.9% (5/85 patients).
Conclusion: The Nit-Occlud® Lê VSD coil offers the possibility of an effective and safe approach in patients with aneurysmal perimembranous ventricular septal defects.
Background: Newborns with hypoplastic left heart (HLH) are usually palliated with the Norwood procedure or a hybrid stage I procedure. Hybrid is our preferred approach. Given the critical relationship between stage I, interstage, and comprehensive stage II or advanced biventricular repair, we hypothesized that appropriate drug treatment is a significant therapeutic cornerstone, especially for the management of the high-risk interstage.
Methods: We report a single-center observational study addressing the cardiovascular effects of, in particular, oral β-blockers and the additional use of angiotensin-converting enzyme (ACE) and mineralocorticoid inhibitors.
Results: In total, 51 newborns—30 with HLH syndrome (HLHS) and 21 with HLH complex (HLHC)—with a median bodyweight of 3.0 kg (range 1.9–4.4; nine with bodyweight ≤ 2500 g) underwent an uneventful “Giessen hybrid approach” using a newly approved duct stent. All patients were discharged home with a single, double or triple therapy consisting of ß-blockers, ACE and mineralocorticoid inhibitors; 90% of the patients received bisoprolol, 10% received propranolol, 72% received lisinopril, and 78% received spironolactone. Resting heart rate decreased from 138 bpm (range 112–172; n = 51) at admission to 123 bpm (range 99–139; n = 51) at discharge and 110 bpm before stage II/biventricular repair/heart transplantation (range 90–140; n = 37) accompanied by favorable bodyweight gain. No side effects were evident.
Conclusion: In view of drug risk/benefit profiles, as well as the variable morphology and hemodynamics, the highly selective β1-adrenoceptor blocker bisoprolol is our preferred drug for treatment of HLHS/HLHC in the interstage. We avoid using ACE inhibitor monotherapy and exclude potential risks for coronary and cerebral perfusion pressure beforehand.
Arterial duct stenting, pioneered in the early 1990s for newborns with a duct-dependent pulmonary and systemic circulation, has evolved significantly over the past decades. This progressive technique has led to the development of novel therapeutic strategies, including the Hybrid approach introduced three decades ago, and more recently, a complete transcatheter approach for treating newborns with hypoplastic left heart syndrome (HLHS). Subsequently, the transcatheter method has been extended to bi-ventricular lesions and patients with pulmonary hypertension, establishing a reverse Potts-shunt pathophysiology. Considering current experiences, this review aims to assess the strengths, weaknesses, and complications associated with ductal stenting, which represents a critical component of these complex treatment strategies. Despite advancements, the mortality rate of Norwood and Hybrid stage-1 procedures has plateaued, underscoring the importance of enhancing the quality of life of affected patients as the primary therapeutic goal. The prerequisite is a gentle, almost atraumatic medicine, particularly during the newborn period. It is essential to recognize that both the Hybrid and total transcatheter approaches demand comparable experience to Norwood surgery. Successful outcomes hinge on much more than merely inserting a stent into the duct; they require meticulous attention to detail and comprehensive management strategies.