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The importance of proper skin wound healing becomes evident when our body's repair mechanisms fail, leading to either non-healing (chronic) wounds or excessive repair (fibrosis). Chronic wounds are a tremendous burden for patients and global healthcare systems and are on the rise due to their increasing incidence with age and diabetes. Curiously, these same risk factors also sign responsible for the development of hypertrophic scarring and organ fibrosis. Activated repair cells – myofibroblasts – are the main producers and organizers of extracellular matrix which is needed to restore tissue integrity after injury. Too many myofibroblasts working for too long cause tissue contractures that ultimately obstruct organ function. Insufficient myofibroblast activation and activities, in turn, prevents normal wound healing. This short review puts a spotlight on the myofibroblast for those who seek therapeutic targets in the context of dysregulated tissue repair. “Keep your myofibroblasts in balance” is the message. [ABSTRACT FROM AUTHOR]

After spinal surgery, patients often want to know whether driving a car or using public transportation can be dangerous for their spine. In order to answer this question, a clinically proven vertebral body replacement (VBR) has been modified. Six load sensors and a telemetry unit were integrated into the inductively powered implant. The modified implant allows the measurement of six load components. Telemeterized devices were implanted in five patients; four of them agreed to exposure themselves to whole-body vibration. During the measurements, the patients sat on a driver seat fixed to a hexapod. They were exposed to random single-axis vibrations in X, Y, and Z directions as well as in multi-axis XYZ directions with frequencies between 0.3 and 30 Hz. Three intensity levels (unweighted root mean square values of 0.25, 0.5 and 1.0 m/s(2)) were applied. Three postures were studied: sitting freely, using a vertical backrest, and a backrest declined by an angle of 25 degrees . The patients held their hands on their thighs. As expected, the maximum force on the VBR increased with increasing intensity and the number of axes. For the highest intensity level and multi-axis vibration, the maximum forces increased by 89% compared to sitting relaxed. Leaning at the backrest as well as lower intensity levels markedly decreased the implant loads. Driving a car or using public transportation systems-when the patient leans towards the backrest-leads to lower implant loads than walking, and can therefore be allowed already shortly after surgery. [ABSTRACT FROM AUTHOR]

The enzyme cyclooxygenase (COX) was shown to exist as two distinct isoforms about a decade ago. COX-1 is constitutively expressed as a 'housekeeping' enzyme in nearly all tissues, and mediates physiological responses (e.g. cytoprotection of the stomach, and platelet aggregation). On the other hand, COX-2, expressed by cells involved in inflammation (e.g. macrophages, monocytes, synoviocytes), has emerged as the isoform that is primarily responsible for the synthesis of prostanoids involved in acute and chronic inflammatory states. Consequently, the hypothesis that selective inhibition of COX-2 might have therapeutic actions similar to those of non-steroidal anti-inflammatory drugs, but without causing gastrointestinal side effects, was the rationale for the development of selective inhibitors of the COX-2 isoenzyme. Selective COX-2 inhibitors currently used in the clinic are the sulphonamides celecoxib and valdecoxib (parecoxib is a prodrug of valdecoxib), as well as the methylsulphones rofecoxib and etoricoxib. Furthermore, the phenylacetic acid derivative lumiracoxib has gained permission recently to be marketed in Europe. This review discusses the clinically relevant similarities and differences of these substances, with particular emphasis on their diverse pharmacokinetic characteristics. [ABSTRACT FROM AUTHOR]

WBV-exposures are often linked with forced postures as prolonged sitting, bent forward sitting, or sitting without a backrest. No quantitative data are available to describe the exposure–effect relationships for different conditions of seating, posture, and the biological variability of workers. Experiments and subsequent predictions of forces acting within the spine during WBV can help to improve the assessment of the health risk. An experimental study was performed with 39 male subjects sitting on a suspension seat with or with no backrest contact. They were exposed to random whole-body vibration with a weighted r.m.s. value of 0·6 m/s2 at a relaxed or a forward bending posture. A two-dimensional finite element model was used for the calculation of the internal spinal load. The model simulates the human response on a suspension driver seat. Individual exposure conditions were considered by including the transfer functions between the seat cushion and the seat base as well as between the backrest and the seat base for the calculation of the vibration input to the buttocks and to the back respectively. The average peak seat transmissibility was higher for the seat with the backrest, but the peak seat-to-head transmissibility was higher for the seat without the backrest for both postures. The peak transmissibilities between the accelerations at the seat base and the compressive forces at L5/S1 were highest for the seat without the backrest during the bending posture. Various biological effects can result from identical exposures combined with different backrest contact and postures. The backrest contact and posture conditions should not be neglected in the assessment of health risk caused by whole-body vibration. [Copyright &y& Elsevier]

The role of cyclooxygenase-2 (COX-2) in cancer remains controversial. Using cervical carcinoma cells (HeLa), the present study investigates the involvement of COX-2 in apoptosis elicited by the chemotherapeutics paclitaxel, cisplatin and 5-fluorouracil. Each compound led to a profound induction of COX-2 expression and prostaglandin (PG) synthesis, accompanied by a substantial decrease of viability and enhanced apoptosis. Cells were significantly less sensitive to apoptotic death when either COX-2 expression or its activity was suppressed by small-interfering RNA (siRNA) and by the selective COX-2 inhibitor NS-398, respectively. Experiments performed to clarify how COX-2 leads to apoptosis revealed a profound proapoptotic action of PGD2 and its dehydration product, 15-deoxy-Δ12,14 PGJ2 (15d-PGJ2). In line with these findings, chemotherapeutics-induced apoptosis was prevented by siRNA targeting lipocalin-type PGD synthase (L-PGDS), which catalyses the isomerization of PGH2 to PGD2. Moreover, apoptosis by chemotherapeutics, PGD2 and 15d-PGJ2 was suppressed by the peroxisome proliferator-activated receptor γ (PPARγ) antagonist, GW-9662 or PPARγ siRNA. Finally, a COX-2-dependent apoptotic mechanism of all investigated chemotherapeutics was confirmed in human lung cancer cells (A549) as well as in another cervical carcinoma cell line (C33A). Collectively, this study suggests COX-2 induction and synthesis of L-PGDS-derived, PPARγ-activating PGs as a decisive target by which several chemotherapeutics induce apoptosis. COX-2 is therefore suspected to sensitize cancer cells to apoptotic death under certain circumstances, suggesting that COX-2 inhibition during cancer therapy could diminish its efficacy.Oncogene (2008) 27, 3032–3044; doi:10.1038/sj.onc.1210962; published online 10 December 2007 [ABSTRACT FROM AUTHOR]

Cancer cell invasion is one of the crucial events in local spreading, growth and metastasis of tumors. The present study investigates the mechanism underlying the anti-invasive action of the chemotherapeutic cisplatin. In human cervical carcinoma cells (HeLa), cisplatin caused a time- and concentration-dependent suppression of cell invasion through Matrigel. Inhibition of invasion was accompanied by upregulation of tissue inhibitor of matrix metalloproteinases-1 (TIMP-1), whereas levels of matrix metalloproteinase-2 (MMP-2), MMP-9 and TIMP-2 remained unchanged. Cisplatin's effects on TIMP-1 expression and invasion were associated with phosphorylations of p38 and p42/44 mitogen-activated protein kinases and were abrogated by specific inhibitors of both pathways. The impact of TIMP-1 in the anti-invasive action of cisplatin was proven by transfecting cells with small interfering RNA targeting TIMP-1, which completely reversed suppression of invasion by cisplatin. A functional relevance of TIMP-1 upregulation was substantiated by findings showing a concentration-dependent inhibition of Matrigel invasion by recombinant TIMP-1. The essential role of TIMP-1 in the anti-invasive action of cisplatin was confirmed using another human cervical carcinoma cell line (C33A) and human lung carcinoma cells (A549). Altogether, our data demonstrate a hitherto unknown mechanism by which cisplatin exerts its antimetastatic properties on highly invasive cancer cells.Oncogene (2007) 26, 5822–5827; doi:10.1038/sj.onc.1210358; published online 19 March 2007 [ABSTRACT FROM AUTHOR]

Synaptophysin interacts with synaptobrevin in membranes of adult small synaptic vesicles. The synaptophysin/synaptobrevin complex promotes synaptobrevin to built up functional SNARE complexes thereby modulating synaptic efficiency. Synaptophysin in addition is a cholesterol-binding protein. Depleting the membranous cholesterol content by filipin or β-methylcyclodextrin (β-MCD) decreased the solubility of synaptophysin in Triton X-100 with less effects on synaptobrevin. In small synaptic vesicles from rat brain the synaptophysin/synaptobrevin complex was diminished upon β-MCD treatment as revealed by chemical cross-linking. Mice with a genetic mutation in the Niemann–Pick C1 gene developing a defect in cholesterol sorting showed significantly reduced amounts of the synaptophysin/synaptobrevin complex compared to their homo- or heterozygous littermates. Finally when using primary cultures of mouse hippocampus the synaptophysin/synaptobrevin complex was down-regulated after depleting the endogenous cholesterol content by the HMG-CoA-reductase inhibitor lovastatin. Alternatively, treatment with cholesterol up-regulated the synaptophysin/synaptobrevin interaction in these cultures. These data indicate that the synaptophysin/synaptobrevin interaction critically depends on a high cholesterol content in the membrane of synaptic vesicles. Variations in the availability of cholesterol may promote or impair synaptic efficiency by interfering with this complex. [ABSTRACT FROM AUTHOR]

Back muscle forces contribute essentially to the whole-body vibration-induced spinal load. The electromyogram (EMG) can help to estimate these forces during whole-body vibration (WBV). Thirty-eight subjects were exposed to identical random low-frequency WBV (0·7, 1·0 and 1·4 m/s-2 r.m.s. weighted acceleration) at a relaxed, erect and bent forward postures. The acceleration of the seat and the force between the seat and the buttocks were measured. Six EMGs were derived from the right side of the m. trapezius pars descendens, m. ileocostalis lumborum pars thoracis, m. ileocostalis lumborum pars lumborum; m. longissimus thoracis pars thoracis, m. longissimus thoracis pars lumborum, and lumbar multifidus muscle. All data were filtered for anti-aliasing and sampled with 1000 Hz. Artefacts caused by the ECG in the EMG were identified and eliminated in the time domain using wavelets. The individually rectified and normalized EMGs were averaged across subjects. The EMGs without WBV exhibited characteristic patterns for the three postures examined. The coherence and transfer functions indicated characteristic myoelectric responses to random WBV with several effects of posture and WBV magnitude. A comprehensive set of transfer functions from the seat acceleration or the mean normalized input force to the mean processed EMG was presented.The results can be used for the development of more sophisticated models with a separate control of various back muscle groups. However, the EMG–force relationship under dynamic conditions needs to be examined in more detail before the results can be implemented. Since different reflex mechanisms depending on the frequency of WBV are linked with different types of active muscle fibres, various time delays between the EMG and muscle force may be necessary. [Copyright &y& Elsevier]

Chronic lung allograft dysfunction (CLAD) continues to be the primary cause of mortality in lung transplant recipients. Macrophages (MΦ) are an abundant population of immune cells in the lung and serve homeostatic and immunoregulatory functions, but their contribution to CLAD is not clear. Our single cell RNA sequencing (scRNAseq) data suggested that a distinct MΦ subsets expressing osteopontin (SPP1) and other pro-fibrotic genes is present in CLAD lungs. We hypothesized that SPP1 MΦ have important pro-fibrotic properties in CLAD. Here, we isolated SPP1 MΦ by fluorescence-activated cell sorting (FACS) to assess their in vitro function. scRNAseq data from 9 CLAD lungs obtained at re-transplantation or autopsy were analysed for surface proteins-coding genes in SPP1 MΦ, allowing us to develop antibody panels to FACS sort SPP1 MΦ and verify protein expression of SPP1. qRT-PCR was performed to confirm expression of fibrosis-associated MPP9 gene. Sorted SPP1 MΦ were put into culture. Analysis of cell surface protein-coding genes through scRNAseq revealed that SPP1 MΦ co-express SDC2 and LILRB4 transcripts, which show minimal expression in non-SPP1 MΦ clusters (Fig A). Flow cytometry showed co-expression of surface SDC2 protein with intracellular SPP1 protein in CLAD lung MΦ (Fig B) and FACS was used to isolate SDC2+ and SDC2- MΦ. qRT-PCR showed that SDC2+ MΦ expressed more MMP9 transcripts than SDC2- MΦ (Fig C). Sorted SDC2+ and SDC2- MΦ were then cultured (Fig D). We have shown that we are able to: 1) sort the SPP1 MΦ from human CLAD lungs based on SDC2 expression, 2) that sorted SDC2+ MΦ express SPP1 protein and MMP9 transcripts, and that sorted SDC2+ MΦ can be maintained in culture. In future work, the effect of SDC2 MΦ culture supernatant on lung fibroblast function will be assessed in wound-healing and collagen gel contraction assays as measures of fibroblast migration and contractility, characteristics of fibrosis. [ABSTRACT FROM AUTHOR]

Epidermolytic hyperkeratosis (bullous congenital ichthyosiform erythroderma), characterized by ichthyotic, rippled hyperkeratosis, erythroderma and skin blistering, is a rare autosomal dominant disease caused by mutations in keratin 1 or keratin 10 (K10) genes. A severe phenotype is caused by a missense mutation in a highly conserved arginine residue at position 156 (R156) in K10. To analyse molecular pathomechanisms of hyperproliferation and hyperkeratosis, we investigated the defects in mechanosensation and mechanotransduction in keratinocytes carrying the K10 mutation. Differentiated primary human keratinocytes infected with lentiviral vectors carrying wild-type K10 (K10) or mutated K10 were subjected to 20% isoaxial stretch. Cellular fragility and mechanosensation were studied by analysis of mitogen-activated protein kinase activation and cytokine release. Cultured keratinocytes expressing K10 showed keratin aggregate formation at the cell periphery, whereas the filament network in K10 cells was normal. Under stretching conditions K10 keratinocytes exhibited about a twofold higher level of filament collapse compared with steady state. In stretched K10 cells, higher p38 activation, higher release of tumour necrosis factor-α and RANTES but reduced interleukin-1β secretion compared with K10 cells was observed. These results demonstrate that the R156H mutation in K10 destabilizes the keratin intermediate filament network and affects stress signalling and inflammatory responses to mechanical stretch in differentiated cultured keratinocytes. [ABSTRACT FROM AUTHOR]

Aims Individuals with diabetic retinopathy (DR) represent a high-risk group who would benefit from intensive metabolic control and risk factor management. This brief report examines quality of care among diabetic patients attending a tertiary retinal clinic. Methods A cross-sectional survey, notes review, and slit-lamp examination was conducted in 139 diabetic patients attending a specialist retinal clinic to assess the quality of comprehensive diabetes care. DR was graded according to the Early Treatment Diabetic Retinopathy Study scale. Results The prevalence of non-proliferative DR (NPDR) and proliferative DR (PDR) was 39.6 and 35.2%, respectively. The prevalence of microalbuminuria in patients with no DR, NPDR and PDR was 32, 54.1 and 68.8%, respectively. Glycaemic control was suboptimal (mean HbA1c 8.0 ± 1.8%) and 15.8% were current smokers. Drugs affecting the renin–angiotensin system were used by only 61.9% of patients with both DR and microalbuminuria, and aspirin by only 35.3%. Conclusions These data suggest that diabetes care in this high-risk population with established microvascular complications was suboptimal. Specialist clinics dealing with diabetic complications may be a setting where quality improvement strategies to reduce morbidity and mortality should be focused. [ABSTRACT FROM AUTHOR]

The durability of prosthetic arteriovenous (AV) grafts for hemodialysis access is low, predominantly due to stenotic lesions in the venous outflow tract and infectious complications. Tissue engineered blood vessels (TEBVs) might offer a tailor-made autologous alternative for prosthetic grafts. We have designed a method in which TEBVs are grown in vivo , by utilizing the foreign body response to subcutaneously implanted polymeric rods in goats, resulting in the formation of an autologous fibrocellular tissue capsule (TC). One month after implantation, the polymeric rod is extracted, whereupon TCs (length 6 cm, diameter 6.8 mm) were grafted as arteriovenous conduit between the carotid artery and jugular vein of the same goats. At time of grafting, the TCs were shown to have sufficient mechanical strength in terms of bursting pressure (2382 ± 129 mmHg), and suture retention strength (SRS: 1.97 ± 0.49 N). The AV grafts were harvested at 1 or 2 months after grafting. In an ex vivo whole blood perfusion system, the lumen of the vascular grafts was shown to be less thrombogenic compared to the initial TCs and ePTFE grafts. At 8 weeks after grafting, the entire graft was covered with an endothelial layer and abundant elastin expression was present throughout the graft. Patency at 1 and 2 months was comparable with ePTFE AV-grafts. In conclusion, we demonstrate the remodeling capacity of cellularized in vivo engineered TEBVs, and their potential as autologous alternative for prosthetic vascular grafts. Image 1 [ABSTRACT FROM AUTHOR]