Systemic Stimulation of TLR2 Impairs Neonatal Mouse Brain Development

Background: Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development. Methodology/Principal Findings: Mice were injected intraperitoneally (i.p.) once a day from postnatal day (PND) 3 to PND11 with endotoxin-free saline, a TLR2 agonist Pam$_{3}$CSK$_{4}$ (5 mg/kg) or Lipopolysaccharide (LPS, 0.3 mg/kg). Pups were sacrificed at PND12 or PND53 and brain, spleen and liver were collected and weighed. Brain sections were stained for brain injury markers. Long-term effects on memory function were assessed using the Trace Fear Conditioning test at PND50. After 9 days of Pam$_{3}$CSK$_{4}$ administration, we found a decreased volume of cerebral gray matter, white matter in the forebrain and cerebellar molecular layer that was accompanied by an increase in spleen and liver weight at PND12. Such effects were not observed in Pam$_{3}$CSK$_{4}$-treated TLR 2-deficient mice. Pam$_{3}$CSK$_{4}$-treated mice also displayed decreased hippocampus neuronal density, and increased cerebral microglia density, while there was no effect on caspase-3 or general cell proliferation at PND12. Significantly elevated levels of IL-1β, IL-6, KC, and MCP-1 were detected after the first Pam$_{3}$CSK$_{4}$ injection in brain homogenates of PND3 mice. Pam$_{3}$CSK$_{4}$administration did not affect long-term memory function nor the volume of gray or white matter. Conclusions/Significance: Repeated systemic exposure to the TLR2 agonist Pam$_{3}$CSK$_{4}$ can have a short-term negative impact on the neonatal mouse brain

Depressive symptoms and suicide in 56,000 older Chinese: a Hong Kong cohort study

Objective: To examine dose-response associations between depressive symptoms and suicide and modification effects of sex, age and health status in older Chinese. Methods: We used the Chinese version of the 15-item Geriatric Depression Scale (GDS) to measure depressive symptoms (GDS score ≥ 8) and Cox regression to examine association with suicide mortality in a population-based cohort of 55,946 individuals, aged 65 years or above, enrolled from July 1998 to December 2000 at one of 18 Elderly Health Centres of Hong Kong Department of Health. The cohort was followed up for suicide mortality till 31 March 2009 (mean follow-up 8.7 years). Results: Depressive symptoms were associated with suicide in men [hazard ratio (HR) 2.03, 95% confidence interval (CI) 0.96-4.29] and women (HR = 2.36, 95% CI 1.31-4.24) after adjusting for age, education, monthly expenditure, smoking, alcohol drinking, physical activity, body mass index, health status, and self-rated health. There was no threshold for GDS score and suicide in either sex. Age, sex and health status did not modify the association. Conclusions: Depressive symptoms predict higher suicide risk in older Chinese in a dose-response pattern. These associations were not attenuated by adjustment for health status, suggesting that depressive symptoms in older people are likely to be an independent causal factor for suicide. The GDS score showed no threshold in predicting suicide risk, suggesting that older people with low GDS scores deserve further attention and those with very high scores need urgent intervention. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Determination of caspase-3 activation fails to predict chemosensitivity in primary acute myeloid leukemia blasts

BACKGROUND: Ex-vivo chemosensitivity tests that measure cell death induction may predict treatment outcome and, therefore, represent a powerful instrument for clinical decision making in cancer therapy. Such tests are, however, work intensive and, in the case of the DiSC-assay, require at least four days. Induction of apoptosis is the mode of action of anticancer drugs and should, therefore, result in the induction of caspase activation in cells targeted by anticancer therapy. METHODS: To determine, whether caspase activation can predict the chemosensitivity, we investigated enzyme activation of caspase-3, a key executioner caspase and correlated these data with chemosensitivity profiles of acute myeloid leukemia (AML) blasts. RESULTS: There was, however, no correlation between the ex-vivo chemosensitivity assessed by measuring the overall rates of cell death by use of the DiSC-assay and caspase-3 activation. CONCLUSION: Thus, despite a significant reduction of duration of the assay from four to one day, induction of apoptosis evaluated by capase-3 activity does not seem to be a valid surrogate marker for chemosensitivity

Depression after low-energy fracture in older women predicts future falls: a prospective observational study

<p>Abstract</p> <p>Background</p> <p>Falls are one of the main causes of fractures in elderly people and after a recent fracture, the risk of another fall is increased, resulting in subsequent fracture. Therefore, risk factors for future falls should be determined. We prospectively investigated the relationship between depression and the incidence of falls in post-menopausal women after a low-energy fracture.</p> <p>Methods</p> <p>At baseline, 181 women aged 60 years and older who presented with a recent low-energy fracture were evaluated at the fracture and osteoporosis outpatient clinics of two hospitals. As well as clinical evaluation and bone mineral density tests, the presence of depression (measured using the Edinburgh Depression Scale, EDS, depression cut-off > 11) and risk factors for falling were assessed. During two years of follow-up, the incidence of falls was registered annually by means of detailed questionnaires and interviews.</p> <p>Results</p> <p>Seventy-nine (44%) of the women sustained at least one fall during follow-up. Of these, 28% (<it>n </it>= 22) suffered from depression at baseline compared to 10% (<it>n </it>= 10) of the 102 women who did not sustain a fall during follow-up (<it>Χ</it>²= 8.76, df = 1, <it>p </it>= .003). Multiple logistic regression showed that the presence of depression and co-morbidity at baseline were independently related to falls (OR = 4.13, 95% CI = 1.58-10.80; OR = 2.25, 95% CI = 1.11-4.56, respectively) during follow-up.</p> <p>Conclusions</p> <p>The presence of depression in women aged 60 years and older with recent low-energy fractures is an important risk factor for future falls. We propose that clinicians treating patients with recent low-energy fractures should anticipate not only on skeletal-related risk factors for fractures, but also on fall-related risk factors including depression.</p

Explaining regional variations in health care utilization between Swiss cantons using panel econometric models

<p>Abstract</p> <p>Background</p> <p>In spite of a detailed and nation-wide legislation frame, there exist large cantonal disparities in consumed quantities of health care services in Switzerland. In this study, the most important factors of influence causing these regional disparities are determined. The findings can also be productive for discussing the containment of health care consumption in other countries.</p> <p>Methods</p> <p>Based on the literature, relevant factors that cause geographic disparities of quantities and costs in western health care systems are identified. Using a selected set of these factors, individual panel econometric models are calculated to explain the variation of the utilization in each of the six largest health care service groups (general practitioners, specialist doctors, hospital inpatient, hospital outpatient, medication, and nursing homes) in Swiss mandatory health insurance (MHI). The main data source is 'Datenpool santésuisse', a database of Swiss health insurers.</p> <p>Results</p> <p>For all six health care service groups, significant factors influencing the utilization frequency over time and across cantons are found. A greater supply of service providers tends to have strong interrelations with per capita consumption of MHI services. On the demand side, older populations and higher population densities represent the clearest driving factors.</p> <p>Conclusions</p> <p>Strategies to contain consumption and costs in health care should include several elements. In the federalist Swiss system, the structure of regional health care supply seems to generate significant effects. However, the extent of driving factors on the demand side (e.g., social deprivation) or financing instruments (e.g., high deductibles) should also be considered.</p

Behavioural activation by mental health nurses for late-life depression in primary care: a randomized controlled trial

Background: Depressive symptoms are common in older adults. The effectiveness of pharmacological treatments and the availability of psychological treatments in primary care are limited. A behavioural approach to depression treatment might be beneficial to many older adults but such care is still largely unavailable. Behavioural Activation (BA) protocols are less complicated and more easy to train than other psychological therapies, making them very suitable for delivery by less specialised therapists. The recent introduction of the mental health nurse in primary care centres in the Netherlands has created major opportunities for improving the accessibility of psychological treatments for late-life depression in primary care. BA may thus address the needs of older patients while improving treatment outcome and lowering costs.The primary objective of this study is to compare the effectiveness and cost-effectiveness of BA in comparison with treatment as usual (TAU) for late-life depression in Dutch primary care. A secondary goal is to explore several potential mechanisms of change, as well as predictors and moderators of treatment outcome of BA for late-life depression. Methods/design: Cluster-randomised controlled multicentre trial with two parallel groups: a) behavioural activation, and b) treatment as usual, conducted in primary care centres with a follow-up of 52 weeks. The main inclusion criterion is a PHQ-9 score > 9. Patients are excluded from the trial in case of severe mental illness that requires specialized treatment, high suicide risk, drug and/or alcohol abuse, prior psychotherapy, change in dosage or type of prescribed antidepressants in the previous 12 weeks, or moderate to severe cognitive impairment. The intervention consists of 8 weekly 30-min BA sessions delivered by a trained mental health nurse. Discussion: We expect BA to be an effective and cost-effective treatment for late-life depression compared to TAU. BA delivered by mental health nurses could increase the availability and accessibility of non-pharmacological treatments for late-life depression in primary care. Trial registration: This study is retrospectively registered in the Dutch Clinical Trial Register NTR6013on August 25th 2016. © 2017 The Author(s)

HER2 Oncogenic Function Escapes EGFR Tyrosine Kinase Inhibitors via Activation of Alternative HER Receptors in Breast Cancer Cells

BACKGROUND: The response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. There is limited understanding of the mechanisms underlying this resistance. Furthermore, although TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses. METHODOLOGY AND PRINCIPAL FINDINGS: Here we have provided a molecular mechanism of how HER2 oncogenic function escapes TKIs' inhibition via alternative HER receptor activation as a result of autocrine ligand release. Using both Förster Resonance Energy Transfer (FRET) which monitors in situ HER receptor phosphorylation as well as classical biochemical analysis, we have shown that the specific tyrosine kinase inhibitors (TKIs) of EGFR, AG1478 and Iressa (Gefitinib) decreased EGFR and HER3 phosphorylation through the inhibition of EGFR/HER3 dimerization. Consequent to this, we demonstrate that cleavage of HER4 and dimerization of HER4/HER2 occur together with reactivation of HER3 via HER2/HER3, leading to persistent HER2 phosphorylation in the now resistant, surviving cells. These drug treatment-induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2. Whereas an anti-betacellulin antibody in combination with Iressa increased the anti-proliferative effect in resistant cells, ligands such as heregulin and betacellulin rendered sensitive SKBR3 cells resistant to Iressa. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and hence specify treatment opportunities to overcome resistance in patients