Endothelial dysfunction of peripheral arteries in patients with immunohistologically confirmed myocardial inflammation correlates with endothelial expression of human leukocyte antigens and adhesion molecules in myocardial biopsies

OBJECTIVES: The aim of this study was to investigate whether myocardial inflammation (MC) and endothelial activation are associated with clinically detectable endothelial dysfunction. BACKGROUND: In patients with MC, immunohistologic evaluation of myocardial biopsies demonstrates a cellular infiltrate of lymphocytes in the myocardium and endothelial activation, as indicated by enhanced expression of human leukocyte antigen (HLA)-1, HLA-DR and intercellular adhesion molecule (ICAM)-1. This chronic inflammatory process may be associated with endothelial dysfunction. METHODS: In 65 patients with suspected MC, endothelial function of the radial artery was noninvasively assessed. By means of high-resolution ultrasound, diameter changes in response to reactive hyperemia (endothelium-dependent), as compared with glyceroltrinitrate (endothelium-independent), were analyzed. In the myocardial biopsies, MC was confirmed by immunohistology in 53 patients; 12 patients with normal myocardial biopsies served as controls. Endothelial expression of HLA-1, HLA-DR and ICAM-1 was semiquantitatively evaluated by immunohistology. To minimize other factors influencing endothelial function, patients with coronary artery disease, diabetes, severely impaired left ventricular function or more than one arteriosclerotic risk factor were excluded from this study. RESULTS: Endothelial function, as determined by flow-mediated vasodilation (FMD), in patients with MC was impaired (FMD(MC) 4.28%), as compared with controls (FMD(Co) 10.10%). The severity of endothelial dysfunction in patients with MC correlated significantly with the extent of endothelial expression of HLA-1, HLA-DR and ICAM-1 in myocardial biopsies. Endothelium-independent vasodilation was not affected by MC or endothelial activation. CONCLUSIONS: Myocardial inflammation is associated with endothelial dysfunction of peripheral arteries. The severity of endothelial dysfunction correlates with the extent of endothelial activation.     

Orodispersible films as a personalized dosage form for nursing home residents,an exploratory study

International Journal of Clinical Pharmacy - Background A frequent problem in ageing patients, and thus in nursing home residents, is dysphagia, affecting the ability to swallow solid dosage forms....     

Solid‐phase extraction–liquid chromatography–tandem mass spectrometry method for the qualitative analysis of 61 synthetic cannabinoid metabolites in urine

This article comprises the development and validation of a protocol for the qualitative analysis of 61 phase I synthetic cannabinoid metabolites in urine originating from 29 synthetic cannabinoids, combining solid‐phase extraction (SPE) utilizing a reversed phase silica‐based sorbent (phenyl) with liquid chromatography–tandem mass spectrometry (LC?MS/MS). Validation was performed according to the guidelines of the German Society of Toxicological and Forensic Chemistry. Sufficient chromatographic separation was achieved within a total runtime of 12.3 minutes. Validation included specificity and selectivity, limit of detection (LOD), recovery and matrix effects, as well as auto‐sampler stability of processed urine samples. LOD ranged between 0.025 ng/mL and 0.5 ng/mL in urine. Recovery ranged between 43% and 97%, with only two analytes exhibiting recoveries below 50%. However, for those two analytes, the LODs were 0.05 ng/mL in urine. In addition, matrix effects between 81% and 185% were determined, whereby matrix effects over 125% were observed for 10 non‐first‐generation synthetic cannabinoid metabolites. The developed method enables the rapid and sensitive detection of synthetic cannabinoid metabolites in urine, complementing the spectrum of existing analytical tools in forensic case work. Finally, application to 61 urine samples from both routine and autopsy case work yielded one urine sample that tested positive for ADB‐PINACA N‐pentanoic acid.     

Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability

Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca²⁺ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca²⁺ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca²⁺ entry and coupling to Ca²⁺ release microdomains at the intercalated disc, resulting in enhanced Ca²⁺ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca²⁺ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure.     

ERCC1 mutations impede DNA damage repair and cause liver and kidney dysfunction in patients

ERCC1-XPF is a multifunctional endonuclease involved in nucleotide excision repair (NER), interstrand cross-link (ICL) repair, and DNA double-strand break (DSB) repair. Only two patients with bi-allelic ERCC1 mutations have been reported, both of whom had features of Cockayne syndrome and died in infancy. Here, we describe two siblings with bi-allelic ERCC1 mutations in their teenage years. Genomic sequencing identified a deletion and a missense variant (R156W) within ERCC1 that disrupts a salt bridge below the XPA-binding pocket. Patient-derived fibroblasts and knock-in epithelial cells carrying the R156W substitution show dramatically reduced protein levels of ERCC1 and XPF. Moreover, mutant ERCC1 weakly interacts with NER and ICL repair proteins, resulting in diminished recruitment to DNA damage. Consequently, patient cells show strongly reduced NER activity and increased chromosome breakage induced by DNA cross-linkers, while DSB repair was relatively normal. We report a new case of ERCC1 deficiency that severely affects NER and considerably impacts ICL repair, which together result in a unique phenotype combining short stature, photosensitivity, and progressive liver and kidney dysfunction.     

Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles

In hair follicle development, a placode-derived signal is believed to induce formation of the dermal condensation, an essential component of ectodermal organs. However, the identity of this signal is unknown. Furthermore, although induction and patterning of hair follicles are intimately linked, it is not known whether the mesenchymal condensation is necessary for inducing the initial epithelial pattern. Here, we show that fibroblast growth factor 20 (Fgf20) is expressed in hair placodes and is induced by and functions downstream from epithelial ectodysplasin (Eda)/Edar and Wnt/β-Catenin signaling to initiate formation of the underlying dermal condensation. Fgf20 governs formation of primary and secondary dermal condensations in developing hair follicles and subsequent formation of guard, awl, and auchene hairs. Although primary dermal condensations are absent in Fgf20 mutant mice, a regular array of hair placodes is formed, demonstrating that the epithelial patterning process is independent of known histological and molecular markers of underlying mesenchymal patterns during the initial stages of hair follicle development.     

Do cognitive interventions for preschoolers improve executive functions and reduce ADHD and externalizing symptoms? A meta-analysis of randomized controlled trials

Many interventions targeting executive function (EF) development in the preschool period, where malleability might be particularly high, have been created and evaluated. We conducted a meta-analysis of randomized controlled trials (RCTs) on the effects of these interventions on (a) EFs in preschool children from the general population as well as preschool children with (symptoms of) attention-deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), and (b) ADHD and ODD symptoms in preschool children with ADHD/ODD (symptoms). Literature search yielded 35 RCTs. Risk of bias of the individual studies was assessed. A random-effects model was used. Moderator effects were tested using mixed model analyses. The overall effects on EFs were: d = 0.46 (95% CI 0.30–0.61) for working memory (WM), d = 0.30 (95% CI 0.21–0.38) for inhibitory control (IC), d = 0.33 (95% CI − 0.04 to 0.71) for reward-related IC, and d = 0.47 (95% CI 0.28–0.66) for flexibility. In children with ADHD/ODD, mean effects were d = 0.64 (95% CI 0.31–0.96) for WM and d = 0.46 (95% CI 0.07–0.84) for IC. Studies on reward-related IC and FL were lacking. Effects on ODD and ADHD symptoms were d = 0.40 (95% CI − 0.23 to 1.03) and d = 0.28 (95% CI − 0.08 to 0.64), respectively. Interventions targeting multiple EFs and using interpersonal cognitive scaffolding approaches showed large and statistically significant effects on ADHD and ODD symptoms. In preschool children of the general population and in those with ADHD/ODD (symptoms), interventions led to an improvement of EF performance. In children with ADHD and ODD, cognitive scaffolding interventions were most effective in terms of reducing ADHD and ODD symptoms. However, more well-controlled studies need to be conducted before any firm conclusions can be drawn.

     

Clinical and Radiological Characteristics Associated with Respiratory Failure in Unilateral Lateral Medullary Infarction

BackgroundThe prognosis for unilateral lateral medullary infarction (ULMI) is generally good but may be aggravated by respiratory failure with fatal outcome. Respiratory failure has been reported in patients with severe bulbar dysfunction and large rostral medullary lesions, but its associated factors have not been systematically studied. We aimed to assess clinical and radiological characteristics associated with respiratory failure in patients with pure acute ULMI.Materials and MethodsSeventy-one patients (median age 55 years, 59 males) with MRI-confirmed acute pure ULMI were studied retrospectively. Clinical characteristics were assessed and bulbar symptoms were scored using a scale developed for this study. MRI lesions were classified into 4 groups based on their vertical extent (localized/extensive) and the involvement of the open and/or closed medulla. Clinical characteristics, bulbar scores and MRI lesion characteristics were compared between patients with and without respiratory failure.ResultsRespiratory failure occurred in 8(11%) patients. All patients with respiratory failure were male (p = 0.336), had extensive lesions involving the open medulla (p = 0.061), progression of bulbar symptoms (p=0.002) and aspiration pneumonia (p < 0.001). Peak bulbar score (OR, 7.9 [95% CI, 2.3–160.0]; p < 0.001) and older age (OR, 1.2 [95%CI, 1.0-1.6]; p=0.006) were independently associated with respiratory failure.ConclusionsExtensive damage involving the open/rostral medulla, clinically presenting with severe bulbar dysfunction, in conjunction with factors such as aspiration pneumonia and older age appears to be crucial for the development of respiratory failure in pure ULMI. Further prospective studies are needed to identify other potential risk factors, pathophysiology, and effective preventive measures for respiratory failure in these patients.