Hsp27 inhibits release of mitochondrial protein Smac in multiple myeloma cells and confers dexamethasone resistance

Smac, second mitochondria-derived activator of caspases, promotes apoptosis via activation of caspases. Heat shock protein 27 (Hsp27) negatively regulates another mitochondrial protein, cytochrome c, during apoptosis; however, the role of Hsp27 in modulating Smac release is unknown. Here we show that Hsp27 is overexpressed in both dexamethasone (Dex)-resistant multiple myeloma (MM) cell lines (MM.1R, U266, RPMI-8226) and primary patient cells. Blocking Hsp27 by an antisense (AS) strategy restores the apoptotic response to Dex in Dex-resistant MM cells by triggering the release of mitochondrial protein Smac, followed by activation of caspase-9 and caspase-3. Moreover, AS-Hsp27 overcomes interleukin-6 (IL-6)-mediated protection against Dex-induced apoptosis. These data demonstrate that Hsp27 inhibits the release of Smac, and thereby confers Dex resistance in MM cells.     

When and where perceptual load interacts with voluntary visuospatial attention: an event-related potential and dipole modeling study

Perceptual load is recognized to affect visual selective attention, but at an unknown spatiotemporal locus in the brain. To examine this issue, event-related potentials (ERPs) were recorded while participants performed an orientation discrimination task, under conditions of low or high perceptual load. Participants were required to respond to targets (10% of trials) presented in the attended visual field while ignoring all stimuli in the unattended visual field. The interaction between voluntary attention and perceptual load was significant for the posterior N1 component (190 ms) but not for the earlier C1 (84 ms) or P1 (100 ms) components. This load by attention interaction for N1 was localized to the temporoparietal-occipital (TPO) gyrus by dipole modeling analysis. Dipole modeling also showed that a reversed attentional effect in the C1 time range was due to ERP overlap from the subsequent attention-sensitive P1 component. Results suggest that perceptual load affects voluntary visuospatial attention at an early (but not the earliest) processing stage and that the TPO gyrus mediates target selection at the discrimination stage.     

ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

Closure of ATP-regulated K⁺ channels (K_ATP channels) plays a central role in glucose-stimulated insulin secretion in beta cells. K_ATP channels are also highly expressed in glucagon-producing alpha cells, where their function remains unresolved. Under hypoglycaemic conditions, K_ATP channels are open in alpha cells but their activity is low and only ~1% of that in beta cells. Like beta cells, alpha cells respond to hyperglycaemia with K_ATP channel closure, membrane depolarisation and stimulation of action potential firing. Yet, hyperglycaemia reciprocally regulates glucagon (inhibition) and insulin secretion (stimulation). Here we discuss how this conundrum can be resolved and how reduced K_ATP channel activity, via membrane depolarisation, paradoxically reduces alpha cell Ca²⁺ entry and glucagon exocytosis. Finally, we consider whether the glucagon secretory defects associated with diabetes can be attributed to impaired K_ATP channel regulation and discuss the potential for remedial pharmacological intervention using sulfonylureas.     

Vitamin D and bone health in adults with cystic fibrosis

Background  Cystic fibrosis (CF) patients have chronic pancreatic insufficiency leading to malabsorption of fat-soluble vitamins, including vitamin D which can contribute to poor skeletal health and respiratory function.
Objective  This study evaluated the prevalence of vitamin D insufficiency and its impact on bone and respiratory health in adults with CF.
Design and measurements  This was a retrospective study in which data were collected from medical records over a 2-year period. Data included patient demographics, lung function, biochemical data, bone mineral densities, X-rays and ascertainment of use of vitamin supplements. Data were collected from medical records at a single accredited CF Center. Serum 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density studies were also collected.
Patients  A total of 185 adults with CF were identified with a mean age of 29 ± 9 years.
Results  The prevalence of vitamin D insufficiency [25(OH)D < 75 nmol/l] was 76%. Mean serum 25(OH)D concentrations were 58·8 ± 30 nmol/l. Use of specific vitamin D supplementation was protective against vitamin D insufficiency whereas use of multivitamins was not. There was a small, but significant, positive association between serum 25(OH)D and FEV₁ per cent predicted after controlling for age, gender, BMI and race ( R ² = 0·30, P  < 0·001). A high prevalence (27%) of vertebral fractures was detected on lateral chest X-ray.
Conclusions  The prevalence of vitamin D insufficiency and poor skeletal health is high in the US CF population. Vitamin D status appears to be positively associated with lung function. Prospective studies to examine the impact of correction of vitamin D insufficiency on skeletal and lung health in adult CF are warranted.     

Presentation and treatment of monozygotic twins with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation during sleep secondary to a blunted response to hypercapnia and hypoxia. The current case report describes developmentally normal four-year-old monozygotic twin boys who presented in infancy with variable presentations and clinical severity of congenital central hypoventilation syndrome. Both were managed with noninvasive positive pressure ventilation.     

Impact of accelerated progression to AIDS on public health monitoring of late HIV diagnosis

Some patients develop AIDS within a year of HIV infection ("accelerated progression"). Classifying such cases as late HIV diagnosis may lead to inaccurate evaluation of HIV testing efforts. We sought to determine this group's contribution to overall late diagnosis rates. To identify cases of accelerated progression (development of AIDS within 12 months of a negative HIV test), we reviewed published HIV seroconverter cohort studies and used New York City's (NYC) HIV/AIDS surveillance registry. From the literature review, three seroconverter cohort studies revealed that 1.0-3.6% of participants had accelerated progression to AIDS. Applying this frequency estimate to the number of new infections in NYC (4762) for 2006 calculated by the Centers for Diseases Control and Prevention's incidence formula, we estimated that 3.6-13.0% of 1317 NYC HIV cases who are diagnosed with AIDS within 12 months of HIV diagnosis are accelerated progressors, not persons HIV infected for many years who did not test and present with AIDS (i.e., delayed diagnosis). In addition, our analysis of the 2006 NYC surveillance registry confirmed the occurrence of accelerated progression in a population-based setting; 67 accelerated progressors were reported and 9 (13%) could be confirmed through follow-up medical record review. With increased HIV testing initiatives, the irreducible proportion of AIDS cases with accelerated progression must be considered when interpreting late diagnosis data.     

Diaminothiazoles inhibit angiogenesis efficiently by suppressing Akt phosphorylation

The prevention of neovessel formation or angiogenesis is a recent popular strategy for limiting and curing cancer. Diaminothiazoles are a class of compounds that have been reported to show promise in the treatment of cancer by inhibiting cancer cell proliferation and inducing apoptosis, because of their effects on microtubules and as inhibitors of cyclin-dependent kinases. Many microtubule-targeting agents are being studied for their antiangiogenic activity, and a few have shown promising activity in the treatment of cancer. Here, we report that diaminothiazoles can be highly effective as antiangiogenic agents, as observed in the chick membrane assay. The lead compound, 4-amino-5-benzoyl-2-(4-methoxyphenylamino)thiazole (DAT1), inhibits endothelial cell processes such as invasion, migration, and tubule formation, which require a functional cytoskeleton. DAT1 also decreases the expression of cell adhesion markers. The antiangiogenic activities of DAT1 occur at concentrations that are not cytotoxic to the normal endothelium. Analysis of intracellular signaling pathways shows that DAT1 inhibits Akt phosphorylation, which is actively involved in the angiogenic process. The antiangiogenic properties of diaminothiazoles, in addition to their promising antimitotic and cytotoxic properties in cancer cell lines, give them an extra advantage in the treatment of cancer.     

GW654652, the pan-inhibitor of VEGF receptors, blocks the growth and migration of multiple myeloma cells in the bone marrow microenvironment

Previous studies have shown that the multiple myeloma (MM) cell line and MM patient cells express high-affinity vascular endothelial growth factor (VEGF) receptor-1 or Fms-like tyrosine kinase-1 (Flt-1) but not VEGF receptor-2 or Flk-1/kinase insert domain-containing receptor (Flk-1/KDR) and that VEGF triggers MM cell proliferation through a mitogen-activated protein kinase (MAPK)-dependent pathway and migration through a protein kinase C (PKC)-dependent pathway. The present study evaluates the efficacy of the small molecule tyrosine-kinase inhibitor GW654652, which inhibits all 3 VEGF receptors with similar potency. We show that GW654652 acts directly on MM cells and in the bone marrow microenvironment. Specifically, GW654652 (1-10 microg/mL) inhibits, in a dose-dependent fashion, VEGF-triggered migrational activity and cell proliferation of MM cell lines that are sensitive and resistant to conventional therapy. As expected from our previous studies of VEGF-induced signaling and sequelae in MM cells, GW654652 blocked VEGF-induced Flt-1 phosphorylation and downstream activation of AKT-1 and MAPK-signaling cascades. Importantly, GW654652 also inhibits interleukin-6 and VEGF secretion and proliferation of MM cells induced by tumor cell binding to bone marrow (BM) stromal cells. The activity of a pan-VEGF receptor inhibitor against MM cells in the BM milieu, coupled with its lack of major toxicity in preclinical mouse models, provides the framework for clinical trials of this drug class to improve patient outcome in MM.     

Gender significance of ST-segment deviation detected by ambulatory (Holter) monitoring

OBJECTIVE: To evaluate the gender influence in diagnostic and prognostic value of Holter-detected ST-segment deviation. METHODS: Two-hundred seventy-seven consecutive patients (196 men) who underwent coronary angiography for evaluation of chest pain were studied with 24-h Holter monitoring within 72 h of coronary angiography, and were followed up for 65+/-21 months. RESULTS: Men had a higher prevalence of coronary artery disease (169 of 196, 86%) compared to that of women (54 of 81, 67%), p<0.00025. Thirty-three (17%) men and 15 (19%) women had ST-segment deviation during 24-h recording. The sensitivity, specificity and positive predictive values of ST-segment deviation (elevation, depression, or both) for the detection of significant coronary artery disease were similar in men and women. The negative predictive values were significantly higher in women than men for ST-segment deviation (36% vs. 15%, p<0.001), ST-segment elevation (35% vs. 14%, p<0.001), and ST-segment depression (34% vs. 15%, p<0.001). Similarly, the diagnostic accuracies were significantly higher in women than men for ST-segment deviation (44% vs. 29%, p<0.025), ST-segment elevation (38% vs. 19%, p<0.001), and ST-segment depression (40% vs. 24%, p<0.025). There was no significant difference in composite end-point of events (mortality, nonfatal myocardial infarction, unstable angina, and coronary revascularization) in men versus women with ST-segment deviation (elevation, depression, or both). CONCLUSION: Holter-detected ST-segment deviation has a higher negative predictive value and diagnostic accuracy for detection of significant coronary artery disease in women than in men, although the prognostic values are not significantly different between men and women.