Human adult cardiac autonomic innervation : controversies in anatomical knowledge and relevance for cardiac neuromodulation

Background: Cardiac sympathetic blockade is a therapeutic approach for arrhythmias and heart failure and may be a beneficial effect of high thoracic epidural anesthesia. These treatments require detailed knowledge of the spatial location and distribution of cardiac autonomic nerves, however, there are controversies on this subject in humans. Objective: To provide a systematic overview of current knowledge on human anatomy of the cardiac autonomic nervous system. Results: In contrast to the often claimed assumption that human preganglionic sympathetic cardiac neurons originate mainly from thoracic spinal segments T1-T4 or T5, there is ample evidence indicating involvement of cervical spinal segment C8 and thoracic spinal segments below T5. Whether cervical ganglia besides the stellate ganglion play a role in transmission of cardiac sympathetic signals is unclear. Similarly, there is debate on the origin of cardiac nerves from different thoracic ganglia. Most human studies report thoracic cardiac nerves emerging from the first to fourth thoracic paravertebral ganglia; others report contributions from the fifth, sixth and even the seventh thoracic ganglia. There is no agreement on the precise composition of nerve plexuses at the cardiac level. After years of debate, it is generally accepted that the vagal nerve contributes to ventricular innervation. Vagal distribution appears higher in atria, whereas adrenergic fibers exceed the number of vagal fibers in the ventricles. Conclusion: Anatomy of the human cardiac autonomic nervous system is highly variable and likely extends beyond generally assumed boundaries. This information is relevant for thoracic epidural anesthesia and procedures targeting neuronal modulation of cardiac sympathetic innervation

Paediatric aortic valve replacement:a meta-analysis and microsimulation study

AIMS: To support decision-making in children undergoing aortic valve replacement (AVR), by providing a comprehensive overview of published outcomes after paediatric AVR, and microsimulation-based age-specific estimates of outcome with different valve substitutes. METHODS AND RESULTS: A systematic review of published literature reporting clinical outcome after paediatric AVR (mean age &lt;18 years) published between 1/1/1990 and 11/08/2021 was conducted. Publications reporting outcome after paediatric Ross procedure, mechanical AVR (mAVR), homograft AVR (hAVR), and/or bioprosthetic AVR were considered for inclusion. Early risks (&lt;30d), late event rates (&gt;30d) and time-to-event data were pooled and entered into a microsimulation model. Sixty-eight studies, of which one prospective and 67 retrospective cohort studies, were included, encompassing a total of 5259 patients (37 435 patient-years; median follow-up: 5.9 years; range 1-21 years). Pooled mean age for the Ross procedure, mAVR, and hAVR was 9.2 ± 5.6, 13.0 ± 3.4, and 8.4 ± 5.4 years, respectively. Pooled early mortality for the Ross procedure, mAVR, and hAVR was 3.7% (95% CI, 3.0%-4.7%), 7.0% (5.1%-9.6%), and 10.6% (6.6%-17.0%), respectively, and late mortality rate was 0.5%/year (0.4%-0.7%/year), 1.0%/year (0.6%-1.5%/year), and 1.4%/year (0.8%-2.5%/year), respectively. Microsimulation-based mean life-expectancy in the first 20 years was 18.9 years (18.6-19.1 years) after Ross (relative life-expectancy: 94.8%) and 17.0 years (16.5-17.6 years) after mAVR (relative life-expectancy: 86.3%). Microsimulation-based 20-year risk of aortic valve reintervention was 42.0% (95% CI: 39.6%-44.6%) after Ross and 17.8% (95% CI: 17.0%-19.4%) after mAVR. CONCLUSION: Results of paediatric AVR are currently suboptimal with substantial mortality especially in the very young with considerable reintervention hazards for all valve substitutes, but the Ross procedure provides a survival benefit over mAVR. Pros and cons of substitutes should be carefully weighed during paediatric valve selection.</p

De consequenties van de Europese bodemrichtlijn voor het Nederlandse beleid

Deze publicatie beoogt het Nederlandse Kabinet, Parlement, belangengroepen en andere EU-landen te informeren over drie vragen: 1. Wat zijn de bodemproblemen in Nederland? 2. Wat doet het bestaande Nederlandse bodembeleid daaraan? 3. Hoe sluit de voorgestelde Kaderrichtlijn Bodem (KRB) aan op dat bestaande beleid

Exploring pelvic floor muscle activity in men with lower urinary tract symptoms

Aim We aimed to explore the utility of the Multiple Array Probe Leiden (MAPLe) device to assess pelvic floor muscle activity in men with lower urinary tract symptoms (LUTS). Methods This was an observational cohort study performed at the urology outpatient department of a large teaching hospital in the Netherlands between April and October 2018. We recruited male patients referred for the assessment of LUTS, without a history of prostate surgery, if they had an International Prostate Symptom Score greater than or equal to 8. The MAPLe device was then used to assess the puborectalis, pubococcygeus, iliococcygeus, urogenital diaphragm, and the internal and external anal sphincters during three tasks: a rest period (1 minute), five maximum voluntary contractions (held for 3 seconds each), and three maximal endurance contractions (held for 15 seconds each). Results In total, 57 patients were included, 5 of which had diabetes mellitus. Muscle activity at rest was significantly lower than during either contraction task and did not differ between the muscle groups. By contrast, the external anal sphincter had significantly less activity than any other muscle group during the endurance task, and the internal anal sphincter and puborectalis had significantly less activity during the maximum voluntary contraction task. No association was found between pelvic floor muscle activity and LUTS severity during any task. Conclusion Pelvic floor muscle activity and LUTS severity appear to be unrelated, but this does not completely exclude the possibility of muscle involvement in the development or experience of symptoms. Further research is needed

Impact of medicine shortages on patients - a framework and application in the Netherlands

Background: Medicine shortages are often described in plain numbers, suggesting all shortages have a uniform impact. However, some shortages have a direct and serious effect on patients and need a prompt reaction from stakeholders. This study aims to create a broad framework to assess the impact of a shortage. Method: We identified high impact shortages and selected exemplary shortages which we considered our learning cases. From five learning cases, we identified elements that had a potentially profound impact on one or more of these cases. We tested data saturation on the elements with another five test cases. Based on these elements, we created a framework to assess impact of shortages on patients and presented practical examples how to rate these different elements. Subsequently, we visualised the impact of these five learning cases on patients in radar charts. Results: The five elements which we identified as potentially having a large impact were 1) alternative product, 2) disease, 3) susceptibility, 4) costs and 5) number of patients affected. The five learning cases rated high on different elements, leading to diverse and sometimes even opposite patterns of impact. Conclusion: We created a framework for assessing the impact of a medicine shortage on patients by means of five key elements. By rating these elements, an indication of the impact can be obtained

Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia

Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar–Hannover rats were injected with lipopolysaccharide (LPS+) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS−). After LPS+, proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS− group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS+, a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney

Asymmetry and heterogeneity: part and parcel in cardiac autonomic innervation and function

The cardiac autonomic nervous system (cANS) regulates cardiac adaptation to different demands. The heart is an asymmetrical organ, and in the selection of adequate treatment of cardiac diseases it may be relevant to take into account that the cANS also has sidedness as well as regional differences in anatomical, functional, and molecular characteristics. The left and right ventricles respond differently to adrenergic stimulation. Isoforms of nitric oxide synthase, which plays an important role in parasympathetic function, are also distributed asymmetrically across the heart. Treatment of cardiac disease heavily relies on affecting left-sided heart targets which are thought to apply to the right ventricle as well. Functional studies of the right ventricle have often been neglected. In addition, many principles have only been investigated in animals and not in humans. Anatomical and functional heterogeneity of the cANS in human tissue or subjects is highly valuable for understanding left- and right-sided cardiac pathology and for identifying novel treatment targets and modalities. Within this perspective, we aim to provide an overview and synthesis of anatomical and functional heterogeneity of the cANS in tissue or subjects, focusing on the human heart.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

RAD18-mediated ubiquitination of PCNA activates the Fanconi anemia DNA repair network

The DNA damage–activated E3 ubiquitin ligase RAD18 promotes repair of interstrand DNA cross-links by ubiquitylating PCNA and recruiting FANCL to chromatin