Gene expression patterns and profile changes pre- and post-erlotinib treatment in patients with metastatic breast cancer.

PURPOSE: To delineate gene expression patterns and profile changes in metastatic tumor biopsies at baseline and 1 month after treatment with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib in patients with metastatic breast cancer. EXPERIMENTAL DESIGN: Patients were treated with 150 mg of oral erlotinib daily. Gene expression profiles were measured with Affymetrix U133A GeneChip and immunohistochemistry was used to validate microarray findings. RESULTS: Estrogen receptor (ER) status by immunohistochemistry is nearly coincided with the two major expression clusters determined by expression of genes using unsupervised hierarchical clustering analysis. One of 10 patients had an EGFR-positive tumor detected by both microarray and immunohistochemistry. In this tumor, tissue inhibitor of metalloproteinases-3 and collagen type 1 alpha 2, which are the EGF-down-regulated growth repressors, were significantly increased by erlotinib. Gene changes in EGFR-negative tumors are those of G-protein-linked and cell surface receptor-linked signaling. Gene ontology comparison analysis pretreatment and posttreatment in EGFR-negative tumors revealed biological process categories that have more genes differentially expressed than expected by chance. Among 495 gene ontology categories, the significant differed gene ontology groups include G-protein-coupled receptor protein signaling (34 genes, P = 0.002) and cell surface receptor-linked signal transduction (74 genes, P = 0.007). CONCLUSIONS: ER status reflects the major difference in gene expression pattern in metastatic breast cancer. Erlotinib had effects on genes of EGFR signaling pathway in the EGFR-positive tumor and on gene ontology biological process categories or genes that have function in signal transduction in EGFR-negative tumors.     

Human osteoblasts' proliferative responses to strain and 17beta-estradiol are mediated by the estrogen receptor and the receptor for insulin-like growth factor I.

The mechanism by which mechanical strain and estrogen stimulate bone cell proliferation was investigated using monolayer cultures of human osteoblastic TE85 cells and female human primary (first-passage) osteoblasts (fHOBs). Both cell types showed small but statistically significant dose-dependent increases in [3H]thymidine incorporation in response to 17beta-estradiol and to a single 10-minute period of uniaxial cyclic strain (1 Hz). In both cell types, the peak response to 17beta-estradiol occurred at 10(-8) - 10(-7) M and the peak response to strain occurred at 3500 microstrain ((mu)epsilon). Both strain-related and 17beta-estradiol-related increases in [3H]thymidine incorporation were abolished by the estrogen receptor (ER) modulator ICI 182,780 (10-8 M). Tamoxifen (10(-9) - 10(-8) M) increased [3H]thymidine incorporation in both cell types but had no effect on their response to strain. In TE85 cells, tamoxifen reduced the increase in [3H]thymidine incorporation associated with 17beta-estradiol to that of tamoxifen alone but had no such effect in fHOBs. In TE85 cells, strain increased medium concentrations of insulin-like growth factor (IGF) II but not IGF-I, whereas 17beta-estradiol increased medium concentrations of IGF-I but not IGF-II. Neutralizing monoclonal antibody (MNAb) to IGF-I (3 microg/ml) blocked the effects of 17beta-estradiol and exogenous truncated IGF-I (tIGF-I; 50 ng/ml) but not those of strain or tIGF-II (50 ng/ml). Neutralizing antibody to IGF-II (3 microg/ml) blocked the effects of strain and tIGF-II but not those of 17beta-estradiol or tIGF-I. MAb aIR-3 (100 ng/ml) to the IGF-I receptor blocked the effects on [3H]thymidine incorporation of strain, tIGF-II, 17beta-estradiol, and tIGF-I. HOBs and TE85 cells, act similarly to rat primary osteoblasts and ROS 17/2.8 cells in their dose-related proliferative responses to strain and 17beta-estradiol, both of which can be blocked by the ER modulator ICI 182,780. In TE85 cells (as in rat primaries and ROS 17/2.8 cells), the response to 17beta-estradiol is mediated by IGF-I, and the response to strain is mediated by IGF-II. Human cells differ from rat cells in that tamoxifen does not block their response to strain and reduces the response to 17beta-estradiol in TE85s but not primaries. In both human cell types (unlike rat cells) the effects of strain and IGF-II as well as estradiol and IGF-I can be blocked at the IGF-I receptor.     

Behavioural, physiological and immunological consequences of social status and aggression in chronically coexisting resident-intruder dyads of male rats

The behavioural and physiological consequences of social status and reciprocal fighting in resident-intruder dyads of Long Evans male rats were evaluated. Before a chronic cohabitation of 10 days, residents and intruders were individually housed for one month to increase their aggressiveness. Control animals included isolates, i.e., animals kept individually housed throughout the experiment and pair-housed rats, i.e., pairs of rats housed together from their rats in the laboratory. In 19 out of 20 dyads, a clear dominance relationship developed with an advantage to the resident in 68% of the cases. Dominants showed more exploratory activity than subordinates in a open-field test at the end of the cohabitation period; subordinates groomed longer than animals from other experimental groups. Dominants had lower pain thresholds than individually and pair-housed animals. Both dominants and subordinates had higher tyrosine hydroxylase enzymatic activities in the left adrenal than isolated and pair-housed rats. Subordinates lost body weight and had higher plasma corticosteroid concentrations than animals from the other experimental groups. In addition, they had smaller thymus glands and reduced spleen lymphocyte responses to mitogenic stimulation in vitro, in comparison to dominant animals. These results show that subordination in the dyadic resident-intruder paradigm leads to a complex syndrome of behavioural and physiological changes, some of which may be modulated by the intensity of aggressive interactions.     

Remission and Recovery in the Treatment for Adolescents With Depression Study (TADS): Acute and Long-Term Outcomes

ObjectiveWe examine remission rate probabilities, recovery rates, and residual symptoms across 36 weeks in the Treatment for Adolescents with Depression Study (TADS).MethodThe TADS, a multisite clinical trial, randomized 439 adolescents with major depressive disorder to 12 weeks of treatment with fluoxetine, cognitive–behavioral therapy, their combination, or pill placebo. The pill placebo group, treated openly after week 12, was not included in the subsequent analyses. Treatment differences in remission rates and probabilities of remission over time are compared. Recovery rates in remitters at weeks 12 (acute phase remitters) and 18 (continuation phase remitters) are summarized. We also examined whether residual symptoms at the end of 12 weeks of acute treatment predicted later remission.ResultsAt week 36, the estimated remission rates for intention-to-treat cases were as follows: combination, 60%; fluoxetine, 55%; cognitive–behavioral therapy, 64%; and overall, 60%. Paired comparisons reveal that, at week 24, all active treatments converge on remission outcomes. The recovery rate at week 36 was 65% for acute phase remitters and 71% for continuation phase remitters, with no significant between-treatment differences in recovery rates. Residual symptoms at the end of acute treatment predicted failure to achieve remission at weeks 18 and 36.ConclusionsMost depressed adolescents in all three treatment modalities achieved remission at the end of 9 months of treatment.     

Concomitant mitral valve surgery with aortic valve replacement: a 21-year experience with a single mechanical prosthesis

Background  

Long-term survival for combined aortic and mitral valve replacement appears to be determined by the mitral valve prosthesis from our previous studies. This 21-year retrospective study assess long-term outcome and durability of aortic valve replacement (AVR) with either concomitant mitral valve replacement (MVR) or mitral valve repair (MVrep). We consider only a single mechanical prosthesis.     

Sildenafil Prevents Cardiovascular Changes after Bone Marrow Fat Embolization in Sheep

Background: Sudden, intraoperative cardiovascular deterioration as a result of pulmonary embolization of bone marrow fat is a potentially fatal complication during total hip and knee arthroplasty, intramedullary nailing, and spine surgery. Anesthetic management is challenging in the presence of increased right ventricular afterload due to pulmonary hypertension. Selective pulmonary vasodilation may be an appropriate prophylactic or therapeutic measure. The effect of sildenafil (phosphodiesterase inhibitor) on cardiovascular deterioration after bone marrow fat embolization was therefore investigated.

Methods: Bone cement (polymethylmethacrylate) was injected into three lumbar vertebrae in 12 sheep. Invasive blood pressures and heart rate were recorded continuously until 60 min after the last injection. Cardiac output and arterial and mixed venous blood gas variables were measured at selected time points. Before the first cement injection, 6 animals received a bolus injection (0.7 mg/kg) of sildenafil, with continuous infusion (0.2 mg [middle dot] kg-1 [middle dot] h-1) thereafter. Postmortem lung and kidney biopsies were taken for semiquantitative analysis of intravascular fat.

Results: Fat embolism was associated with a transient increase (21 +/- 7mmHg) in pulmonary arterial pressure. A transient decrease in arterial blood pressure and temporary increases in central venous pressure and dead space were also observed. No significant changes in any cardiovascular variable were observed after fat embolism in the sildenafil group. There was significantly (P < 0.05) less intravascular fat in the lungs of the sildenafil (median count of 5 emboli per microscopic view) compared with the control group (median count of 1).     

Broadening the reach of cardiac rehabilitation to rural and remote Australia.

BACKGROUND: Cardiac rehabilitation (CR) has an evidence base but traditional models may not readily apply to people living in rural and remote regions. AIM:: To outline published comprehensive and non-hospital based CR models used for people discharged from hospital after a cardiac event that have potential relevance to those living in rural and remote areas in Australia. METHODS: The PubMed database was searched using Medical subject headings (MeSH) terms and the key word 'cardiac rehabilitation' limited to clinical trials. Articles were retrieved if they included at least two components of CR and were not based in an outpatient setting. RESULTS: No CR models specifically developed for rural and remote areas were identified. However, 14 studies were found that outlined 11 non-conventional comprehensive CR models. All provided CR in a home-based setting. Health professionals provided support via telephone contact or home visits, and via resources such as the Heart Manual. Reported outcomes from these CR programs varied: ranging from an increase in knowledge of risk factors, to improvements in physical activity, decreased risk factor profile, improved psychological and social functioning and reductions in health service costs and mortality. CONCLUSION: Home-based, CR models have the most substantive evidence base and, therefore the greatest potential to be developed and made accessible to eligible people living in rural and remote areas.     

Community pharmacy services to optimise the use of medications for mental illness: a systematic review

The objective of this systematic review was to evaluate the impact of pharmacist delivered community-based services to optimise the use of medications for mental illness. Twenty-two controlled (randomised and non-randomised) studies of pharmacists' interventions in community and residential aged care settings identified in international scientific literature were included for review. Papers were assessed for study design, service recipient, country of origin, intervention type, number of participating pharmacists, methodological quality and outcome measurement. Three studies showed that pharmacists' medication counselling and treatment monitoring can improve adherence to antidepressant medications among those commencing treatment when calculated using an intention-to-treat analysis. Four trials demonstrated that pharmacist conducted medication reviews may reduce the number of potentially inappropriate medications prescribed to those at high risk of medication misadventure. The results of this review provide some evidence that pharmacists can contribute to optimising the use of medications for mental illness in the community setting. However, more well designed studies are needed to assess the impact of pharmacists as members of community mental health teams and as providers of comprehensive medicines information to people with schizophrenia and bipolar disorder