Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats

Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10 +/- 1 x 10(3) to 17 +/- 2 x 10(3) mu m(2); 6 weeks: 13 +/- 2 x 10(3) to 24 +/- 3 x 10(3) mu m(2)). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (empty set: 385 +/- 13 to 463 +/- 14 mu m). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 x 10(3) +/- 1 x 10(3) mu m(2)). The diameter of the HF arteries of normotensive rats increased (empty set: 463 +/- 22 mu m) but no expansion occurred in the HF arteries of hypertensive rats (empty set: 471 +/- 16 mu m). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (empty set: 419 +/- 13 to 475 +/- 16 mu m). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean empty set between 235 and 290 mu m), and infiltration of monocyte/ macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/ macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition. Hypertension Research (2012) 35, 1093-1101; doi:10.1038/hr.2012.94; published online 12 July 201

Study protocol subacromial impingement syndrome: the identification of pathophysiologic mechanisms (SISTIM)

<p>Abstract</p> <p>Background</p> <p>The Subacromial Impingement Syndrome (SIS) is the most common diagnosed disorder of the shoulder in primary health care, but its aetiology is unclear. Conservative treatment regimes focus at reduction of subacromial inflammatory reactions or pathologic scapulohumeral motion patterns (<it>intrinsic </it>aetiology). Long-lasting symptoms are often treated with surgery, which is focused at enlarging the subacromial space by resection of the anterior part of the acromion (based on <it>extrinsic </it>aetiology). Despite that acromionplasty is in the top-10 of orthopaedic surgical procedures, there is no consensus on its indications and reported results are variable (successful in 48-90%). We hypothesize that the aetiology of SIS, i.e. an increase in subacromial pressure or decrease of subacromial space, is multi-factorial. SIS can be the consequence of pathologic scapulohumeral motion patterns leading to humerus cranialisation, anatomical variations of the scapula and the humerus (e.g. hooked acromion), a subacromial inflammatory reaction (e.g. due to overuse or micro-trauma), or adjoining pathology (e.g. osteoarthritis in the acromion-clavicular-joint with subacromial osteophytes).</p> <p>We believe patients should be treated according to their predominant etiological mechanism(s). Therefore, the objective of our study is to identify and discriminate etiological mechanisms occurring in SIS patients, in order to develop tailored diagnostic and therapeutic strategies.</p> <p>Methods</p> <p>In this cross-sectional descriptive study, applied clinical and experimental methods to identify intrinsic and extrinsic etiologic mechanisms comprise: MRI-arthrography (eligibility criteria, cuff status, 3D-segmented bony contours); 3D-motion tracking (scapulohumeral rhythm, arm range of motion, dynamic subacromial volume assessment by combining the 3D bony contours and 3D-kinematics); EMG (adductor co-activation) and dynamometry instrumented shoulder radiographs during arm tasks (force and muscle activation controlled acromiohumeral translation assessments); Clinical phenotyping (Constant Score, DASH, WORC, and SF-36 scores).</p> <p>Discussion</p> <p>By relating anatomic properties, kinematics and muscle dynamics to subacromial volume, we expect to identify one or more predominant pathophysiological mechanisms in every SIS patient. These differences in underlying mechanisms are a reflection of the variations in symptoms, clinical scores and outcomes reported in literature. More insight in these mechanisms is necessary in order to optimize future diagnostic and treatment strategies for patients with SIS symptoms.</p> <p>Trial registration</p> <p>Dutch Trial Registry (Nederlands Trial Register) <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2283">NTR2283</a>.</p

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Cost of Robustness of Independent WCRT Analysis for CBS of Ethernet AVB Using Eligible Intervals

The existing worst-case response time (WCRT) analysis for individual priority classes under credit-based shaping (CBS) in Ethernet AVB based on so-called eligible intervals is both independent and tight. This WCRT analysis does not rely on any assumptions on interfering inter-priority streams other than those enforced by the Ethernet standard. A major advantage of this independent analysis is that CBS may be viewed as resource reservation, where allocated bandwidth is both guaranteed and enforced. Although independent analysis provides inter-priority class robustness, it comes at a cost of over-provisioning bandwidth. We illustrate this cost of inter-priority class robustness by means of an example that requires 7.8 times the amount of bandwidth reservation for a given set of streams compared to a different analysis that takes knowledge of inter-priority streams into account.</p

Retrobulbar steatitis and meningitis/empyema secondary to right otitis media, right otitis interna and an inflammatory polyp in a cat

The purpose was to describe a case of retrobulbar steatitis and meningitis in a cat caused by otitis media, otitis interna and an inflammatory polyp in the middle ear. Investigations included ophthalmic and neurological examinations, haematology and biochemistry, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and aerobic, anaerobic bacterial and fungal culture of material from the middle ear. A 6-year-old female neutered domestic-short-haired cat presented with right-sided exophthalmos and resistance to retropulsion. Anisocoria, reduced corneal sensation and oculocephalic movements and low Schirmer tear test (STT1) were found. An MRI revealed the right external ear canal and tympanic bulla to be fluid filled with presence of a thickened contrast-enhancing mucosa. Contrast enhancement extended into the calvarium, as marked thickening and contrast enhancement of the pachymeninges, and further rostrally through the right orbital fissure into the orbit. The retrobulbar tissues were swollen, resulting in mild exophthalmos. Enrichment culture of material from the middle ear revealed Klebsiella pneumonia susceptible to marbofloxacin. The cat underwent a total ear canal ablation with removal of the cartilaginous cuff at the external auditory meatus and local debridement and curettage. A polypoid structure was removed from the middle ear No bulla osteotomy was performed. Horner’s syndrome was present immediately following surgery. The cat received a course of systemic dexamethasone (1mg/cat SID/3 weeks) tapered off and marbofloxacin (2mg/kg SID/2 weeks). Follow up at 120 days showed no recurrence of the symptoms. The Horner’s syndrome and low STT1 had resolved and returned to normal values respectively. This case highlights the importance of MRI in the investigation of retrobulbar diseases. MRI is a useful tool for the evaluation of the extent of the lesion and the appearance of adjacent structures in which additional potentially life-threatening abnormalities, such as meningitis, can be seen

Expert-driven trace clustering with instance-level constraints

Within the field of process mining, several different trace clustering approaches exist for partitioning traces or process instances into similar groups. Typically, this partitioning is based on certain patterns or similarity between the traces, or driven by the discovery of a process model for each cluster. The main drawback of these techniques, however, is that their solutions are usually hard to evaluate or justify by domain experts. In this paper, we present two constrained trace clustering techniques that are capable to leverage expert knowledge in the form of instance-level constraints. In an extensive experimental evaluation using two real-life datasets, we show that our novel techniques are indeed capable of producing clustering solutions that are more justifiable without a substantial negative impact on their quality.</p

An approach for incorporating expert knowledge in trace clustering

Trace clustering techniques are a set of approaches for partitioning traces or process instances into similar groups. Typically, this partitioning is based on certain patterns or similarity between the traces, or done by discovering a process model for each cluster of traces. In general, however, it is likely that clustering solutions obtained by these approaches will be hard to understand or difficult to validate given an expert’s domain knowledge. Therefore, we propose a novel semi-supervised trace clustering technique based on expert knowledge. Our approach is validated using a case in tablet reading behaviour, but widely applicable in other contexts. In an experimental evaluation, the technique is shown to provide a beneficial trade-off between performance and understandability.status: publishe