In the past few decades vitamin K has emerged from a single‐function “haemostasis vitamin” to a “multi‐function vitamin.” The use of vitamin K antagonists (VKA) inevitably showed that the inhibition ...was not restricted to vitamin K dependent coagulation factors but also synthesis of functional extrahepatic vitamin K dependent proteins (VKDPs), thereby eliciting undesired side effects. Vascular calcification is one of the recently revealed detrimental effects of VKA. The discovery that VKDPs are involved in vascular calcification has propelled our mechanistic understanding of this process and has opened novel avenues for diagnosis and treatment. This review addresses mechanisms of VKDPs and their significance for physiological and pathological calcification.
Patients with chronic kidney disease (CKD) are more likely to experience falls and fractures due to renal osteodystrophy and the high prevalence of risk factors for falls. However, it is not well ...established how great the risk is for falls and fractures for the different stages of CKD compared to the general population. The objective of this systematic review and meta-analysis was to assess whether, and in which degree, CKD was associated with falls and fractures in adults. A systematic search in PubMed, Embase, CINAHL, and The Cochrane Library was performed on 7 September 2018. All retrospective, cross-sectional, and longitudinal studies of adults (18 years of older) that studied the association between CKD, fractures, and falls were included. Additional studies were identified by cross-referencing. A total of 39 publications were included, of which two publications assessed three types of outcome and four publications assessed two types of outcome. Ten studies focused on accidental falling; seventeen studies focused on hip, femur, and pelvis fractures; seven studies focused on vertebral fractures; and thirteen studies focused on any type of fracture without further specification. Generally, the risk of fractures increased when kidney function worsened, with the highest risks in the patients with stage 5 CKD or dialysis. This effect was most pronounced for hip fractures and any type of fractures. Furthermore, results on the association between CKD and accidental falling were contradictory. Compared to the general population, fractures are highly prevalent in patients with CKD. Besides more awareness of timely fracture risk assessment, there also should be more focus on fall prevention.
Chorioamnionitis can induce pulmonary inflammation and promote bronchopulmonary dysplasia development, distinguished by alveolar simplification and impaired vascular growth. Chorioamnionitis is more ...common during the extremely preterm canalicular lung stage (crucial for vascular development); and increases the risk for subsequent sepsis. We hypothesized that single/combined exposure to chronic and/or acute inflammation induces pulmonary inflammatory responses and vascular changes.
Ovine fetuses were intra-amniotically exposed to chronic Ureaplasma parvum (UP) at 24 days (d) before extreme preterm delivery at 94d (term 147d) and/or to lipopolysaccharide (LPS) 7 or 2d before delivery. Pulmonary inflammation, vascular remodeling and angiogenic factors were assessed.
LPS exposure increased CD3-positive and myeloperoxidase-positive cells. Combined UP-LPS exposure increased pulmonary inflammation compared with 2d LPS or UP groups. The UP+2d LPS group had an increased adventitial fibrosis score when compared with UP-treated animals. A reduced wall-to-lumen ratio was found in the 7d LPS animals when compared to the 2d LPS-treated animals. Exposure to UP+2d LPS reduced VEGF and VEGFR-2 levels compared with 2d LPS-treated animals. Angiopoietin-1 (Ang1) and tunica interna endothelial cell kinase 2 (Tie-2) levels were decreased after UP+7d LPS as well as after 7d LPS, but not with UP alone.
Chronic UP and subsequent LPS exposure increased pulmonary inflammation and decreased expression of angiogenic growth factors and receptors when compared to single hit-exposed animals.
To investigate therapeutic effects of annexin A1 (anxA1) on atherogenesis in LDLR-/- mice.
Human recombinant annexin A1 (hr-anxA1) was produced by a prokaryotic expression system, purified and ...analysed on phosphatidylserine (PS) binding and formyl peptide receptor (FPR) activation. Biodistribution of 99mTechnetium-hr-anxA1 was determined in C57Bl/6J mice. 12 Weeks old LDLR-/- mice were fed a Western Type Diet (WTD) during 6 weeks (Group I) or 12 weeks (Group P). Mice received hr-anxA1 (1 mg/kg) or vehicle by intraperitoneal injection 3 times per week for a period of 6 weeks starting at start of WTD (Group I) or 6 weeks after start of WTD (Group P). Total aortic plaque burden and phenotype were analyzed using immunohistochemistry.
Hr-anxA1 bound PS in Ca2+-dependent manner and activated FPR2/ALX. It inhibited rolling and adherence of neutrophils but not monocytes on activated endothelial cells. Half lives of circulating 99mTc-hr-anxA1 were <10 minutes and approximately 6 hours for intravenously (IV) and intraperitoneally (IP) administered hr-anxA1, respectively. Pharmacological treatment with hr-anxA1 had no significant effect on initiation of plaque formation (-33%; P = 0.21)(Group I) but significantly attenuated progression of existing plaques of aortic arch and subclavian artery (plaque size -50%, P = 0.005; necrotic core size -76% P = 0.015, hr-anxA1 vs vehicle) (Group P).
Hr-anxA1 may offer pharmacological means to treat chronic atherogenesis by reducing FPR-2 dependent neutrophil rolling and adhesion to activated endothelial cells and by reducing total plaque inflammation.
Vascular and valvular calcifications are pathological processes regulated by resident cells, and depending on a complex interplay between calcification promoters and inhibitors, resembling skeletal ...metabolism. Here, we study the role of the vitamin K-dependent Gla-rich protein (GRP) in vascular and valvular calcification processes.
Immunohistochemistry and quantitative polymerase chain reaction showed that GRP expression and accumulation are upregulated with calcification simultaneously with osteocalcin and matrix Gla protein (MGP). Using conformation-specific antibodies, both γ-carboxylated GRP and undercarboxylated GRP species were found accumulated at the sites of mineral deposits, whereas undercarboxylated GRP was predominant in calcified aortic valve disease valvular interstitial cells. Mineral-bound GRP, MGP, and fetuin-A were identified by mass spectrometry. Using an ex vivo model of vascular calcification, γ-carboxylated GRP but not undercarboxylated GRP was shown to inhibit calcification and osteochondrogenic differentiation through α-smooth muscle actin upregulation and osteopontin downregulation. Immunoprecipitation assays showed that GRP is part of an MGP-fetuin-A complex at the sites of valvular calcification. Moreover, extracellular vesicles released from normal vascular smooth muscle cells are loaded with GRP, MGP, and fetuin-A, whereas under calcifying conditions, released extracellular vesicles show increased calcium loading and GRP and MGP depletion.
GRP is an inhibitor of vascular and valvular calcification involved in calcium homeostasis. Its function might be associated with prevention of calcium-induced signaling pathways and direct mineral binding to inhibit crystal formation/maturation. Our data show that GRP is a new player in mineralization competence of extracellular vesicles possibly associated with the fetuin-A-MGP calcification inhibitory system. GRP activity was found to be dependent on its γ-carboxylation status, with potential clinical relevance.
Background
Interactions with professional caregivers affect the quality of support and life of people with intellectual disabilities and contribute to the occurrence of challenging behaviour. The ...present literature review provides an overview of factors facilitating or hindering meaningful staff–client interactions in people with borderline to profound intellectual disabilities and challenging behaviour.
Method
Database searches, reference list and citation screening, and expert consultations were undertaken. A thematic synthesis of 28 studies was performed.
Results
Factors were identified at the client (i.e. behaviour, emotions and (dis)abilities), staff (i.e. interactive principles, knowledge, psychological resources, attributions, attitudes and (coping with) emotions) and context levels (i.e. group size, team and organization).
Conclusions
The present overview provides insights into factors that facilitate or hinder meaningful staff–client interactions with people with intellectual disabilities and challenging behaviour. The results support the need to combine client, staff and contextual factors when considering staff–client interactions in research and practice.
Objective
The aim of this retrospective analysis was to evaluate, in adult patients treated for periodontitis, the periodontal stability during supportive periodontal therapy (SPT).
Methods
Data were ...collected and analyzed retrospectively for periodontitis patients aged ≥36 years who underwent active periodontal therapy (APT) and were following an SPT programme. The stability of the APT success, defined as a probing pocket depth (PPD) of ≤5 mm, was the main outcome parameter. Analyses were performed in which PPD, tooth loss (TL), bleeding on probing (BOP), periodontal epithelium surface area (PESA), and the effects of age, gender, smoking status, and the number of years in SPT were evaluated. The annual TL and BOP of <10% in addition to a PPD of ≤5 mm were considered to be secondary outcome variables.
Results
In total, 993 patients were included, in 36% of whom a PPD ≤5 mm was found at the evaluation of APT. If the outcome was defined as a BOP of <10% in addition to a PPD of ≤5 mm, this was present in only 16% of the patients. During SPT, a small overall increase in clinical parameters for the total population and an annual average TL of 0.15 per patient was observed. Patients of male gender and smokers negatively affected the success of SPT.
Conclusion
The periodontal clinical status remained ‘fairly’ stable during SPT in chronic periodontitis patients aged ≥36 years. Smoking negatively affects the outcome of APT and periodontal stability during SPT.
To identify possible technological solutions that can contribute to stroke patients' participation at home.
In this qualitative case study, data on factors that negatively influenced participation at ...home were collected
semi-structured interviews with stroke patients (
= 6). Additionally, data on possible technologies to improve this participation were collected
a group interview with experts (
= 4). The domains "cognition, mobility, self-care, and getting along" (International Classification of Functioning, Disability and Health) guided the data collection and interpretation; open, axial and selective coding was part of the analysis.
Patients reported 21 factors negatively influencing participation at home, including psychological, cognitive, and physical factors. Experts suggested technological solutions regarding these factors to increase participation of stroke patients; digital assistants, apps, and virtual reality were frequently mentioned. To facilitate the use of these technologies, experts indicated the importance of involving patients in their design. They also suggested that rehabilitation specialists and family members could support the uptake and use of technologies.
Various technologies were identified by experts as having the potential to improve the participation of stroke patients in their homes. Future research may study the influence of these technologies on the actual participation of stroke patients at home.Implications for rehabilitationThe identified technological solutions can support rehabilitation specialists in guiding stroke patients towards technologies that can support a patient's participation at home.Rehabilitation specialists can be champions in introducing, recommending and promoting technologies to stroke patients and their families, as well as in training them to use technologies.Virtual reality as a technology can be part of rehabilitation, not only to train stroke patients in daily life activities but also to increase empathy and understanding in caregivers and carers on stroke impairments.Rehabilitation specialists can recommend technologies integrated in daily life and presented as general consumer goods; stroke patients are more likely to adopt these kind of technologies.
Intra-amniotic exposure to proinflammatory agonists causes chorioamnionitis and fetal gut inflammation. Fetal gut inflammation is associated with mucosal injury and impaired gut development. We ...tested whether this detrimental inflammatory response of the fetal gut results from a direct local (gut derived) or an indirect inflammatory response mediated by the chorioamnion/skin or lung, since these organs are also in direct contact with the amniotic fluid. The gastrointestinal tract was isolated from the respiratory tract and the amnion/skin epithelia by fetal surgery in time-mated ewes. Lipopolysaccharide (LPS) or saline (controls) was selectively infused in the gastrointestinal tract, trachea, or amniotic compartment at 2 or 6 days before preterm delivery at 124 days gestation (term 150 days). Gastrointestinal and intratracheal LPS exposure caused distinct inflammatory responses in the fetal gut. Inflammatory responses could be distinguished by the influx of leukocytes (MPO(+), CD3(+), and FoxP3(+) cells), tumor necrosis factor-α, and interferon-γ expression and differential upregulation of mRNA levels for Toll-like receptor 1, 2, 4, and 6. Fetal gut inflammation after direct intestinal LPS exposure resulted in severe loss of the tight junctional protein zonula occludens protein 1 (ZO-1) and increased mitosis of intestinal epithelial cells. Inflammation of the fetal gut after selective LPS instillation in the lungs caused only mild disruption of ZO-1, loss in epithelial cell integrity, and impaired epithelial differentiation. LPS exposure of the amnion/skin epithelia did not result in gut inflammation or morphological, structural, and functional changes. Our results indicate that the detrimental consequences of chorioamnionitis on fetal gut development are the combined result of local gut and lung-mediated inflammatory responses.
Abstract
Background
The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes ...(LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients.
Methods
This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life.
Discussion
This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis.
Trial registration
Clinicaltrials.gov:
NCT04838496
, registered on 02–04-2021 Netherlands Trial Register: NL9790.
Protocol version
Version 3 dd 11–4-2022.
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