αv integrins play an important role in myofibroblast differentiation

Transforming growth factor-beta1 is a potent mediator of the differentiation of fibroblasts into myofibroblasts, which is characterized by the appearance of the cytoskeletal protein alpha-smooth muscle actin. The aim of this study was to investigate the role of integrin extracellular matrix receptors in transforming growth factor-beta1-induced myofibroblast differentiation. We show that blockade of the alphav and/or beta1 integrins prevents the transforming growth factor-beta1-induced myofibroblast differentiation, seen by the increased expression of alpha-smooth muscle actin and enhanced collagen gel contraction in three human fibroblast cell lines (from the mouth, skin, and kidney). Further, blockade of alphav specific integrins alphavbeta5 and alphavbeta3 suppressed myofibroblast differentiation in fibroblasts from the mouth and skin; however, in the kidney cells, the prevention of differentiation was seen only with blockade of alphavbeta5 integrin but not alphavbeta3. A possible reason for this result may be different degrees of responsiveness to transforming growth factor-beta1 treatment seen from different anatomical origins of the cell lines. These data indicate a novel role for alphav integrins in the differentiation of human fibroblasts from the mouth, skin, and kidney into myofibroblasts and suggest that there is a common differentiation pathway.     

Brain‐derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells

We used cultured adult mouse retinae as a model system to follow and quantify the retraction of dendrites using diolistic labelling of retinal ganglion cells (RGCs) following explantation. Cell death was monitored in parallel by nuclear staining as ‘labelling’ with RGC and apoptotic markers was inconsistent and exceedingly difficult to quantify reliably. Nuclear staining allowed us to delineate a lengthy time window during which dendrite retraction can be monitored in the absence of RGC death. The addition of brain‐derived neurotrophic factor (BDNF) produced a marked reduction in dendritic degeneration, even when application was delayed for 3 days after retinal explantation. These results suggest that the delayed addition of trophic factors may be functionally beneficial before the loss of cell bodies in the course of conditions such as glaucoma.     

Age‐related changes in amygdala–frontal connectivity during emotional face processing from childhood into young adulthood

The ability to process and respond to emotional facial expressions is a critical skill for healthy social and emotional development. There has been growing interest in understanding the neural circuitry underlying development of emotional processing, with previous research implicating functional connectivity between amygdala and frontal regions. However, existing work has focused on threatening emotional faces, raising questions regarding the extent to which these developmental patterns are specific to threat or to emotional face processing more broadly. In the current study, we examined age‐related changes in brain activity and amygdala functional connectivity during an fMRI emotional face matching task (including angry, fearful, and happy faces) in 61 healthy subjects aged 7–25 years. We found age‐related decreases in ventral medial prefrontal cortex activity in response to happy faces but not to angry or fearful faces, and an age‐related change (shifting from positive to negative correlation) in amygdala–anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) functional connectivity to all emotional faces. Specifically, positive correlations between amygdala and ACC/mPFC in children changed to negative correlations in adults, which may suggest early emergence of bottom‐up amygdala excitatory signaling to ACC/mPFC in children and later development of top‐down inhibitory control of ACC/mPFC over amygdala in adults. Age‐related changes in amygdala–ACC/mPFC connectivity did not vary for processing of different facial emotions, suggesting changes in amygdala–ACC/mPFC connectivity may underlie development of broad emotional processing, rather than threat‐specific processing. Hum Brain Mapp 37:1684–1695, 2016. © 2016 Wiley Periodicals, Inc .     

Efficacy and safety of emergency non-invasive pelvic ring stabilisation

BackgroundUrgent non-invasive pelvic ring stabilisation (pelvic binding, PB) in shocked patients is recommended by state and institutional guidelines regardless of the fracture pattern. The purpose of this study was to determine the adherence to the guidelines, efficacy of the technique and identification of potential adverse effects associated with PB.Patients and methodsA 41-month retrospective analysis of the prospective pelvic fracture database was undertaken at a level 1 trauma centre. High-energy pelvic fractures were included in the analysis with exclusion of the A type injuries (AO/OTA classification) and patients who were dead on arrival. Collected data included patient demographics, injury severity score, fracture classification, application and timing of PB, associated injuries, physiological parameters, resuscitation fluids and outcomes. Pre and post-PB radiographs were reviewed. The potential effects of the PB on soft tissue (femoral vessel, bladder and rectal injury) complications were assessed by independent experts.Results115 patients with high-energy B and C type pelvic ring injuries were included. Thirty-six (31%) patients presented in haemorrhagic shock on arrival. A total of 43 pelvic bindings were performed, 18 of them on shocked patients. The adherence to the guidelines was 50% (18/36) overall. Analysing fracture types of shocked patients the adherence was: B1 80%, B2 20%, B3 20%, C1 66%, C2 86%, C3 33%. The alignment of the pelvis was improved or perfect on post-PB radiographs in 68% and had not changed in 21%. In some cases of B2 and B3 type injuries the PB increased the deformity after application (11%). There were 10 deaths (8.7%) in the study group, with 4 deaths attributed to acute pelvic bleeding. Two of these had PB applied and two were identified as potential for improvement. One femoral artery injury, four bladder injuries and three rectum injuries were identified in patients who had PB applied. Association between the PB and these injuries is unlikely.ConclusionThe adherence to the guidelines should be improved with further education and system development. The good effect of the technique was evident on radiographs. Although in some lateral compression fracture patterns the deformity increased, no hazards were associated with the use of PB.     

A murine model of neurofibromatosis type 1 tibial pseudarthrosis featuring proliferative fibrous tissue and osteoclast‐like cells

Neurofibromatosis type 1 (NF1) is a common genetic condition caused by mutations in the NF1 gene. Patients often suffer from tissue‐specific lesions associated with local double‐inactivation of NF1. In this study, we generated a novel fracture model to investigate the mechanism underlying congenital pseudarthrosis of the tibia (CPT) associated with NF1. We used a Cre‐expressing adenovirus (AdCre) to inactivate Nf1 in vitro in cultured osteoprogenitors and osteoblasts, and in vivo in the fracture callus of Nf1^flox/flox and Nf1^flox/? mice. The effects of the presence of Nf1^null cells were extensively examined. Cultured Nf1^null‐committed osteoprogenitors from neonatal calvaria failed to differentiate and express mature osteoblastic markers, even with recombinant bone morphogenetic protein‐2 (rhBMP‐2) treatment. Similarly, Nf1^null‐inducible osteoprogenitors obtained from Nf1 mouse muscle were also unresponsive to rhBMP‐2. In both closed and open fracture models in Nf1^flox/flox and Nf1^flox/? mice, local AdCre injection significantly impaired bone healing, with fracture union being <50% that of wild type controls. No significant difference was seen between Nf1^flox/flox and Nf1^flox/? mice. Histological analyses showed invasion of the Nf1^null fractures by fibrous and highly proliferative tissue. Mean amounts of fibrous tissue were increased upward of 10‐fold in Nf1^null fractures and bromodeoxyuridine (BrdU) staining in closed fractures showed increased numbers of proliferating cells. In Nf1^null fractures, tartrate‐resistant acid phosphatase–positive (TRAP+) cells were frequently observed within the fibrous tissue, not lining a bone surface. In summary, we report that local Nf1 deletion in a fracture callus is sufficient to impair bony union and recapitulate histological features of clinical CPT. Cell culture findings support the concept that Nf1 double inactivation impairs early osteoblastic differentiation. This model provides valuable insight into the pathobiology of the disease, and will be helpful for trialing therapeutic compounds. © 2012 American Society for Bone and Mineral Research     

Demography of paediatric renal care in Europe: organization and delivery.

BACKGROUND: Members of the European Society of Paediatric Nephrology (ESPN) initiated a study of the demography and policy of paediatric renal care among European countries at the end of the 20th century. METHODS: A questionnaire was mailed to the presidents of each of 43 national renal paediatric societies or working groups in Europe. Data on each country's population, income as reflected by its gross national product and infant mortality rate, were obtained from the United Nations. The paediatric health care systems were previously divided into three types: general practitioner care system, paediatric care system and combined care system (CCS). RESULTS: In 1998, 842 specialized paediatric nephrologists worked in hospitals in 42 European countries. The median number of paediatric nephrologists per million child population (pmcp) was 4.9 (range 0-15). The median number of children served per paediatric nephrologist was significantly higher in countries with the general practitioner care system than in those with the paediatric or combined care system (CCS), namely 370 747 vs 169 456 and 191 788, respectively. In addition to specially trained paediatric nephrologists, there were 1087 paediatricians with a part-time interest/activity in paediatric nephrology in hospitals in 34 European countries. Eastern European countries had significantly more general paediatricians with part-time nephrological activities than countries belonging to the European Union (EU), 16.7 vs 6.6 pmcp. In 1998, 92% of 42 European countries offered paediatric dialysis facilities for acute renal failure and 90% for chronic renal failure and 55% offered paediatric renal transplantation (RTx). Only 30% of Eastern European countries (central omitted) offered paediatric RTx vs 87% of EU countries. The availability of paediatric RTx was associated significantly with the countries' gross national product (r = 0.53, P<0.001). The median number of paediatric hospitals offering dialysis for childhood chronic renal failure was 1.5 pmcp (range 0-5.0) and the median number of paediatric hospitals offering paediatric RTx was 0.4 pmcp (range 0-3.5). Fewer children were on dialysis or were transplanted in Eastern European countries than in the EU. CONCLUSIONS: At the end of the 20th century, there was a marked variation in delivery of paediatric renal care within Europe. This was related to factors such as size of the population, geographical and political situation, the type of primary paediatric care system and economic situation. European countries were far from equal with regard to access of renal replacement therapy for children. Improvement of the economic situation is beyond the capabilities of paediatric nephrologists. However, in these days of world-wide globalization paediatricians in greater Europe should be able to achieve better cooperation and exchange of ideas and information which would be the first step towards equality of renal care for children.     

Lip reconstruction

The lip presents a unique challenge to the facial plastic surgeon because of its prominent location, elegant form, and important functions. The anatomy and pathology relevant to the lip are considered herein, along with general concepts to guide lip surgery. The more common approaches to reconstructing lip defects are outlined, illustrated, and discussed.     

Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery

BACKGROUND: Morphine-6-glucuronide (M6G) has promising preclinical characteristics and encouraging pharmacokinetic features for acute nociceptive pain. Early studies have produced a good safety profile when compared to morphine sulfate, although in surrogate pain models studies, a mixed picture emerged. A study to evaluate the efficacy and safety profile in a clinical setting was designed. METHODS: The authors conducted a double-blind, randomized, dose-finding study of patients scheduled to undergo major joint replacement. One hundred patients of both sexes were included, with 50 patients in each group. A loading dose of 10 mg of study medication was given intravenously at induction of anesthesia, and two further doses were allowed during surgery if required. Bolus doses via a patient-controlled analgesia system were given subcutaneously at 2 mg/dose and set at a 10-min lockout. Assessments of pain intensity and relief were recorded during the 24-h period. RESULTS: There were no statistically significant differences between the treatments for 24-h mean pain intensity. However, pain intensity was significantly higher in the M6G group than in the morphine group at 30 min and 1 h. There was no statistical difference in 24-h mean pain relief or retrospective pain scores at any time point during the 24-h period. The severity of sedation was significantly greater in the morphine group than in the M6G group at 30 min, 1 h, 2 h, and 24 h. Respiratory depression was greater in the morphine group than in the M6G group, and more patients in the morphine group withdrew from the study because of respiratory depression. CONCLUSIONS: Overall, M6G has an analgesic effect similar to that of morphine over the first 24 h postoperatively. However, M6G may be slower onset initially than morphine; therefore, a larger initial dose may be required.