alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.     

Virtual-reality simulation to assess performance in hip fracture surgery

Background and purpose

Internal fixation of hip fractures is a common and important procedure that orthopedic surgeons must master early in their career. Virtual-reality training could improve initial skills, and a simulation-based test would make it possible to ensure basic competency of junior surgeons before they proceed to supervised practice on patients. The aim of this study was to develop a reliable and valid test with credible pass/fail standards.

Methods

20 physicians (10 untrained novices and 10 experienced orthopedic surgeons) each performed 3 internal fixation procedures of an undisplaced femoral neck fracture: 2 hook-pins, 2 screws, and a sliding hip screw. All procedures were preformed on a trauma simulator. Performance scores for each procedure were obtained from the predefined metrics of the simulator. The inter-case reliability of the simulator metrics was explored by calculation of intra-class correlation coefficient. Validity was explored by comparison between novices’ and experts’ scores using independent-samples t-test. A pass/fail standard was set by the contrasting-groups method and the consequences were explored.

Results

The percentage of maximum combined score (PM score) showed an inter-case reliability of 0.83 (95% CI: 0.65–0.93) between the 3 procedures. The mean PM score was 30% (CI: 7–53) for the novices and 76% (CI: 68–83) for the experienced surgeons. The pass/fail standard was set at 58%, resulting in none of the novices passing the test and a single experienced surgeon failing the test.

Interpretation

The simulation-based test was reliable and valid in our setting, and the pass/fail standard could discriminate between novices and experienced surgeons. Potentially, training and testing of future junior surgeons on a virtual-reality simulator could ensure basic competency before proceeding to supervised practice on patients.Worldwide, hip fractures account for substantial healthcare costs and high mortality, morbidity, and reoperation rates. Fractures are often treated with different types of internal fixation, which is a great contributor to training of surgical skills through the principle of the master-apprentice model. This model is not without risk, though. Inexperienced trainees contribute to a higher rate of re-admissions and reoperations (Palm et al. 2007, Leblanc et al. 2013).A review of 609 studies found that virtual-reality simulation training improved operative skills (Cook et al. 2011), and simulation-based training in orthopedic surgery is starting to emerge. Most of the development is in arthroscopy, but simulation-based training in fracture fixation is also being developed (Blyth et al. 2007, 2008, Mabrey et al. 2010, Atesok et al. 2012, Rambani et al. 2013). Current papers describe the simulators and explore construct validity of the simulator metrics (Tillander et al. 2004, Froelich et al. 2011). Reliable and valid tests with credible pass/fail standards are necessary to ensure basic competency of trainees before allowing them to proceed to supervised practice on patients (Stefanidis et al. 2012a, Konge et al. 2013).The objective of this study was to develop a test, to explore the reliability of this test, and to gather validity evidence. Furthermore, we wanted to establish a credible pass/fail standard and explore the consequences of this standard. The research questions were: (1) Which simulator metrics were able to discriminate between novices and experienced orthopedic surgeons?; (2) How many procedures on the simulator must be performed to ensure sufficient reliability?; and (3) What was a credible pass/fail standard in the test?     

Functional disability and death wishes in older Europeans: results from the EURODEP concerted action

Purpose

Physical illness has been shown to be a risk factor for suicidal behaviour in older adults. The association between functional disability and suicidal behaviour in older adults is less clear. The aim of this study was to examine the relationship between functional disability and death wishes in late life.

Methods

Data from 11 population studies on depression in persons aged 65 and above were pooled, yielding a total of 15,890 respondents. Level of functional disability was trichotomised (no, intermediate, high). A person was considered to have death wishes if the death wish/suicidal ideation item of the EURO-D scale was endorsed. Odds ratios for death wishes associated with functional disability were calculated in a multilevel logistic regression model.

Results

In total, 5 % of the men and 7 % of the women reported death wishes. Both intermediate (OR 1.89, 95 % CI 1.42; 2.52) and high functional disability (OR 3.22, 95 % CI 2.34; 4.42) were associated with death wishes. No sex differences could be shown. Results remained after adding depressive symptoms to the model.

Conclusions

Functional disability was independently associated with death wishes in older adults. Results can help inform clinicians who care for older persons with functional impairment.     

PET/CT-Based Response Evaluation in Cancer—a Systematic Review of Design Issues

Molecular Imaging and Biology - Positron emission tomography/x-ray computed tomography (PET/CT) has long been discussed as a promising modality for response evaluation in cancer. When designing...     

Secular changes in the relation between social factors and depression: A study of two birth cohorts of Swedish septuagenarians followed for 5 years

Background

Rapid societal changes occurred in the Western world during the 20^th century. It is not clear whether this has changed the relation between social factors and depression in older people.

Methods

Representative samples of 70-year-olds from Gothenburg, Sweden, were examined with identical psychiatric examinations in 1971–72 (N=392; 226 women and 166 men) and 2000–01 (N=499; 270 women and 229 men). Follow-up studies were conducted after five years. Social factors were obtained by self-report and depression was diagnosed according to DSM-IV-TR.

Results

Feelings of loneliness were related to both concurrent depression at baseline and new depression at follow-up in both birth cohorts. Visits with others than children and neighbours once per month or less, compared to having more visits, and the perception of having too little contact with others, were related to both concurrent and new depression in 70-year-olds examined 1971–72, but not in those examined 30 years later.

Limitations

The response rate declined from 85.2% in 1971–72 to 65.8% in 2000–01. Participation bias may have resulted in an underestimation of depression in the later-born cohort.

Conclusions

Social contacts with others were related to depression in 70-year-olds examined in the 1970s, but not in those examined in the 2000s. This may reflect period changes in the ways of socialising, communicating and entertaining, e.g. due to technological development and expansion of mass media. Findings may be useful when developing modern and effective programs for the prevention of mental ill-health in older people.     

hace1 Influences zebrafish cardiac development via ROS‐dependent mechanisms

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Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self‐administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy–cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy–cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy–cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy–cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.     

Fluoride concentration in supragingival dental plaque after a single intake or habitual consumption of fluoridated milk

The aim of this study was to evaluate the fluoride concentration in supragingival dental plaque after single and repeated intakes of fluoridated milk. The study group consisted of 22 schoolchildren, young adults and adults of both sexes, 8-41 years of age. After a 2-week fluoride depletion period and 3 days of plaque accumulation, 200 ml of fluoridated milk (1g F) was ingested along with a standardized lunch meal. Plaque samples were collected immediately before the intake and after 30, 120 and 240 min. From the adult participants (n = 9), additional samples were colleted after 12 and 18 h. After a fluoride-free washout period of at least 2 weeks, the whole experimental procedure was repeated after 4 consecutive daily intakes of fluoridated milk. The fluoride concentration was determined after micro-diffusion with a fluoride selective electrode. The results showed a statistically significant 3-fold increase of the plaque fluoride levels up to 4 h after the intake. At 12 and 18 h after the intake, the recorded levels went gradually back to baseline. There was no significant difference between the fluoride concentrations in the supragingival plaque after the single intake compared with the repeated intakes. In conclusion, the findings support the suggestion that milk is a suitable vehicle for local fluoride administration into the oral cavity, also when consumed together with a meal.     

Mutation of the DRY motif reveals different structural requirements for the CC chemokine receptor 5-mediated signaling and receptor endocytosis

CC chemokine receptor 5 (CCR5) is a G protein-coupled receptor that governs migration of leukocytes and serves as a coreceptor for the R5 tropic strains of human immunodeficiency virus (HIV). CCR5-mediated signaling in response to CC chemokines relies on G protein activation. Desensitization, which rapidly turns off G protein-dependent signaling, involves phosphorylation of CCR5 that promotes interaction of the receptor with beta-arrestins for endocytosis. Whether coupling to G proteins, desensitization, and endocytosis of CCR5 require the same structural determinants remains a matter of investigation. Here, we show that CCR5 displayed agonist-independent coupling to G proteins. This constitutive activity of the receptor was abrogated by TAK779 (N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride), a nonpeptidic CCR5 ligand that inhibits HIV infection and was found to depend on the integrity of the Asp-Arg-Tyr (DRY) motif. Changing Arg-126 by the neutral residue Asn (R126N-CCR5 mutant) abolished CCR5-mediated activation of G proteins, either constitutively or in response to agonists. In contrast, R126N-CCR5 not only retained agonist-promoted phosphorylation and beta-arrestin-dependent endocytosis but also displayed a higher basal phosphorylation than wild-type CCR5. Expression of beta-arrestin in R126N-CCR5-expressing cells resulted in receptor down-regulation, thereby suggesting that R126N-CCR5 spontaneously interacts with beta-arrestins. However, although expression of beta-arrestin favored wild-type CCR5-mediated chemotaxis, it failed to promote migration of cells expressing R126N-CCR5. Overall, these data indicate that structural requirements for CCR5-mediated activation of G proteins, albeit not involved in receptor desensitization and internalization, are needed for beta-arrestin-mediated chemotaxis. These results have implications for how distinct biological responses of CCR5 might rely on a different set of receptor conformations.