Psychosocial issues in patients with congestive heart failure

Psychosocial issues are important variables that need to be addressed in patients with congestive heart failure (CHF). Unfortunately, these issues are often overlooked. Depression and lack of social support have been shown to have a negative impact on patients with CHF. Patients with CHF who are depressed or who lack social support have been shown to have increased morbidity and hospital readmission rates, to be less adherent to their medical regimen, and to have an overall increase in cost of care. The variables are often interrelated, as high levels of social support may lessen the impact of depression on mortality. In addition, certain biologic factors may influence the impact of psychosocial factors in patients with CHF. This review addresses the effects of depression, treatment adherence, and social support in patients with CHF and suggests interventions targeted to these problems. Health care professionals must assess these issues in all patients with CHF, address their specific needs, and intervene appropriately when warranted.     

Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling

OBJECTIVE: To determine whether hydralazine might decrease DNA methyltransferase (DNMT) expression and induce autoimmunity by inhibiting extracellular signal-regulated kinase (ERK) pathway signaling. METHODS: The effect of hydralazine on DNMT was tested in vitro using enzyme inhibition studies, and in vivo by measuring messenger RNA (mRNA) levels and enzyme activity. Effects on ERK, c-Jun N-terminal kinase, and p38 pathway signaling were tested using immunoblotting. Murine T cells treated with hydralazine or an ERK pathway inhibitor were injected into mice and anti-DNA antibodies were measured by enzyme-linked immunosorbent assay. RESULTS: In vitro, hydralazine did not inhibit DNMT activity. Instead, hydralazine inhibited ERK pathway signaling, thereby decreasing DNMT1 and DNMT3a mRNA expression and DNMT enzyme activity similar to mitogen-activated protein kinase kinase (MEK) inhibitors. Inhibiting T cell ERK pathway signaling with an MEK inhibitor was sufficient to induce anti-double-stranded DNA antibodies in a murine model of drug-induced lupus, similar to the effect of hydralazine. CONCLUSION: Hydralazine reproduces the lupus ERK pathway signaling abnormality and its effects on DNMT expression, and inhibiting this pathway induces autoimmunity. Hydralazine-induced lupus could be caused in part by inducing the same ERK pathway signaling defect that occurs in idiopathic lupus.     

Genome-wide copy number imbalances identified in familial and sporadic medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) is a malignant tumor of the calcitonin-secreting parafollicular C cells of the thyroid occurring sporadically and as a component of the multiple endocrine neoplasia type 2/familial medullary thyroid carcinoma syndrome. The primary genetic cause of multiple endocrine neoplasia type 2 is germline mutation of the RET protooncogene. Somatic point mutations in RET also occur in sporadic MTC. Although RET mutation is likely sufficient to cause C-cell hyperplasia, the precursor lesion to MTC, tumor progression is thought to be due to clonal expansion caused by the accumulation of somatic events. Using the genome-scanning technique comparative genomic hybridization, we identified chromosomal imbalances that occur in MTC including deletions of chromosomes 1p, 3q26.3-q27, 4, 9q13-q22, 13q, and 22q and amplifications of chromosome 19. These regions house known tumor suppressor genes as well as genes encoding subunits of the multicomponent complex of glycosylphosphatidylinositol-linked proteins (glial cell line-derived neurotrophic factor family receptors alpha-2-4) and their ligands glial cell line-derived neurotrophic factor, neurturin, persephin, and artemin that facilitate RET dimerization and downstream signaling. Chromosomal imbalances in the MTC cell line TT were largely identical to those identified in primary MTC tumors, consolidating its use as a model for studying MTC.     

Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications

Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappa B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappa B activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM.     

Prevalence of hypotensive disorders in older patients with a pacemaker in situ who attend the Accident and Emergency Department because of falls or syncope.

AIMS: To ascertain the proportion of adults with a pacemaker in situ attending the Accident and Emergency Department because of syncope or unexplained falls and the cause of index symptoms in these patients, including the prevalence of hypotensive syndromes. METHODS AND RESULTS: Patients presenting to the Accident and Emergency Department with unexplained syncope or non-accidental falls, who had a pacemaker in situ, were studied. Eligible patients had cardiovascular assessment (morning orthostatic blood pressure measurement, heart rate and BP measurements during carotid sinus stimulation (supine and upright), head-up tilt at 70 degrees for 40 min), assessment of haemodynamics during fixed mode pacing and gait and balance assessment. Of 5863 patients screened, 13.5% had unexplained syncope or a non-accidental fall; of these only 3% (26 patients) had pacemakers in situ. Of 18 study patients (82 +/- 8 years), 10 were female. Sixteen had a hypotensive diagnosis. Seven had more than one attributable hypotensive diagnosis. Five of 13 with vasodepressor carotid sinus syndrome had no previous diagnosis of carotid sinus hypersensitivity. No patients had vasovagal syncope induced during passive head-up tilt testing. CONCLUSION: It is rare for patients who attend the Accident and Emergency Department because of syncope or unexplained falls to have a pacemaker in situ. In those who do, hypotensive disorders are a common finding.     

2-Methoxyestradiol overcomes drug resistance in multiple myeloma cells

2-Methoxyestradiol (2ME2) an estrogen derivative, induces growth arrest and apoptosis in leukemic cells and is also antiangiogenic. In this study, we demonstrate that 2ME2 inhibits growth and induces apoptosis in multiple myeloma (MM) cell lines and patient cells. Significantly, 2ME2 also inhibits growth and induces apoptosis in MM cells resistant to conventional therapies including melphalan (LR-5), doxorubicin (Dox-40 and Dox-6), and dexamethasone (MM.1R). In contrast to its effects on MM cells, 2ME2 does not reduce the survival of normal peripheral blood lymphocytes. Moreover, 2ME2 enhances Dex-induced apoptosis, and its effect is not blocked by interleukin-6 (IL-6). We next examined the effect of 2ME2 on MM cells in the bone marrow (BM) milieu. 2ME2 decreases survival of BM stromal cells (BMSCs), as well as secretion of vascular endothelial growth factor (VEGF), and IL-6 triggered by the adhesion of MM cells to BMSCs. We show that apoptosis induced by 2ME2 is mediated by the release of mitochondrial cytochrome-c (cyto-c) and Smac, followed by the activation of caspases-8, -9, and -3. Finally, 2ME2 inhibits MM cell growth, prolongs survival, and decreases angiogenesis in a murine model. These studies, therefore, demonstrate that 2ME2 mediates anti-MM activity directly on MM cells and in the BM microenvironment. They provide a framework for the use of 2ME2, either alone or in combination with Dex, to overcome drug resistance and to improve outcome in MM.     

How reproducible is the cardioinhibitory response to carotid sinus massage in fallers?

AIMS: To ascertain the reproducibility of the cardioinhibitory subtype of carotid sinus hypersensitivity (CICSH) in fallers. METHODS AND RESULTS: One hundred and seventy-five subjects with CICSH and unexplained or recurrent falls were randomized to pacemaker implantation or control. Sixty-four control subjects (61% female, mean age 71.8 years, median 2 falls in the previous year) completed one-year follow-up and had carotid sinus massage (CSM) performed on 4 occasions (twice before randomization, at 6 months and 1 year following randomization). CSM was performed sequentially on the right and then left sides, initially supine and then upright at 70 degrees head-up tilt by the same investigator. On each occasion CSM was discontinued once CICSH was demonstrated. CICSH was demonstrated on 82% of occasions, 75% on right CSM and 77% whilst the subject was supine. Before randomization, and at 6 months and 1 year, 91%, 67%, and 70% of subjects had reproducible CICSH respectively. Half had CICSH on all 4 occasions. Only 17% had a consistent response on the same side in the same position. CONCLUSIONS: In the majority of subjects CICSH is reproducible and this is more likely shortly after the initial response. However the cardioinhibitory response to CSM is inconsistent both in side elicited and subject position.     

Assessing the burden of respiratory disease in the UK

This review explores the health and social burden of some of the main respiratory diseases (asthma, chronic obstructive pulmonary disease, cryptogenic fibrosing alveolitis, cystic fibrosis, lung cancer, mesothelioma, obstructive sleep apnoea and tuberculosis) in order to increase awareness of these diseases and highlight areas where improvements in care are required. The overall impact of respiratory diseases in the U.K. in terms of prevalence, mortality, morbidity and economic costs, with particular reference to secondary care has been considered and comparisons made with the rest of Europe where data are available. Respiratory diseases are responsible for a significant proportion of serious morbidity and premature death among the population of the U.K. and they will continue to present a growing challenge; special support is needed to tackle this burden.