The mitochondrial biogenesis regulatory program in cardiac adaptation to ischemia--a putative target for therapeutic intervention

The resurgence of mitochondrial biology research stems from the realization that the distinct regulation of mitochondria to meet diverse homeostatic demands is driven by exquisite biochemical and molecular control mechanisms. This program termed mitochondrial biogenesis is integral to orchestrating mitochondrial function and appears to exhibit adaptive remodeling following biomechanical and oxidative stress. The major bioenergetic function of mitochondria partitions the final utilization of oxygen between oxidative phosphorylation and reactive oxygen species. As disruption in oxidative phosphorylation and excessive reactive oxygen species contribute to cardiac ischemia-reperfusion injury, we hypothesize that the mitochondrial biogenesis regulatory program is an explicit target for cardiac therapeutic interventions. The objectives of this review are to (a) define the advances in understanding the mitochondrial biogenesis regulatory program integrated to its control of mitochondrial bioenergetics and oxygen utilization, (b) reveal how this program is modulated by chronic hypoxia and ischemic preconditioning, and (c) examine the therapeutic potential of modulating the regulation of mitochondrial biogenesis as a strategy to attenuate ischemia-reperfusion injury.     

The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors

In the Tropics, there is substantial temporal and spatial overlap of diseases propagated by anthropophilic mosquito vectors (such as malaria and dengue) and human helminth diseases (such as onchocerciasis and lymphatic filariasis) that are treated though mass drug administrations (MDA). This overlap will result in mosquito vectors imbibing significant quantities of these drugs when they blood feed on humans. Since many anthelmintic drugs have broad anti-invertebrate effects, the possibility of combined helminth control and mosquito-borne disease control through MDA is apparent. It has been previously shown that ivermectin can reduce mosquito survivorship when administered in a blood meal, but more detailed examinations are needed if MDA is to ever be developed into a tool for malaria or dengue control. We examined concentrations of drugs that follow human pharmacokinetics after MDA and that matched with mosquito feeding times, for effects against the anthropophilic mosquito vectors Anopheles gambiae s.s. and Aedes aegypti. Ivermectin was the only human-approved MDA drug we tested that affected mosquito survivorship, and only An. gambiae s.s. were affected at concentrations respecting human pharmacokinetics at indicated doses. Ivermectin also delayed An. gambiae s.s. re-feeding frequency and defecation rates, and two successive ivermectin-spiked blood meals following human pharmacokinetic concentrations compounded mortality effects compared to controls. These findings suggest that ivermectin MDA in Africa may be used to decrease malaria transmission if MDAs were administered more frequently. Such a strategy would broaden the current scope of polyparasitism control already afforded by MDAs, and which is needed in many African villages simultaneously burdened by many parasitic diseases.     

Reliability analysis of time series force plate data of community dwelling older adults

Frequency-based analysis of body sway has been used to distinguish between healthy young, healthy elderly adults and elderly adults with Huntingtons disease. Our aim was to assess the reliability of spectral-based outcomes of the centre of pressure (CoP) kinematics in order to determine if these outcomes could be tested for their capability to distinguish between elderly fallers and non-fallers in a future study. We have studied balance for 30 community dwelling healthy older adults 60 years or older. Four test conditions were used. Three successive trials were performed for each condition. CoP kinematics were estimated with a force platform with three strain gauges set in a triangular position. The frequency content of these signals was estimated. Intrasession correlation coefficients (ICC's) were then calculated for all test conditions. The reliability of the selected parameters varied between low and high (ICC 0.652-0.939). The ICC's for the narrow stance tests were higher compared to tests with normal standing conditions (0.771-0.94) to (0.652-0.865). The highest value was obtained in the high frequency band (0.939). These measures should be viewed with caution when screening geriatric patients because their reliability cannot always be assumed.     

Systemic lupus erythematosus in northwestern Spain: a 20-year epidemiologic study

To further investigate the epidemiology of systemic lupus erythematosus (SLE) in southern Europe, we assessed the incidence, prevalence, clinical spectrum of the disease, flares, and survival of patients diagnosed with SLE in the Lugo region of northwestern Spain. Between January 1987 and December 2006, 150 Lugo residents were diagnosed as having SLE according to the 1982 American College of Rheumatology criteria for the classification of SLE. Women outnumbered men (127 [84.7%] vs. 23 [15.3%]). The mean age at the time of disease diagnosis was 46.1 ± 19.6 years. The mean follow-up from the time of disease diagnosis was 7.8 ± 4.5 years. The age- and sex-adjusted annual incidence rate over the 20-year study period was 3.6 (95% confidence interval [CI], 3.0-4.2) per 100,000 population aged 15 years and older. The overall annual incidence rate over the 20-year study period in women (5.9/100,000 population aged ≥ 15 yr; 95% CI, 4.9-7.0) was higher than in men (1.1/100,000 population aged ≥ 15 yr; 95% CI, 0.7-1.7) (p < 0.001). By December 31, 2006, the overall age-adjusted SLE prevalence in the Lugo region for patients who fulfilled at least 4 of 1982 American College of Rheumatology criteria was 17.5 per 100,000 population aged 15 years and older (95% CI, 12.6-24.1). Prevalence in women (29.2/100,000 population aged ≥ 15 yr; 95% CI, 20.0-40.7) was higher than in men (5.8/100,000 population aged ≥ 15 yr; 95% CI, 2.0-12.0). The most frequent clinical manifestation was arthritis. As reported in population-based studies on SLE patients of European descent, renal disease was observed in only 27.3% of the patients. The rate of flares was 0.084/year. A younger age and the presence of nephritis at the time of disease diagnosis were associated with the development of flares during the follow-up of Lugo patients. Compared with the general population the probability of survival in patients with SLE was significantly reduced (p = 0.04). In conclusion, the present study establishes a baseline estimate of the incidence and clinical spectrum of SLE in northwestern Spain. According to our results, the incidence of SLE in northwestern Spain is slightly higher than that reported in most European regions. Patients with SLE from northwestern Spain have a later average age onset and a lower frequency of nephritis than in the African-American population. However, our data show a reduced probability of survival in Spanish patients with SLE.     

Combination of systemic thioacetamide (TAA) injections and ethanol feeding accelerates hepatic fibrosis in C3H/He mice and is associated with intrahepatic up regulation of MMP-2, VEGF and ICAM-1

BACKGROUND/AIMS: The induction of liver fibrosis is difficult in mice. Here, we intended to improve fibrosis induction by combination of thioacetamide (TAA) injections and ethanol (EtOH) feeding and to characterize features of liver damage in this model. Most experimental therapeutic studies are performed in mice without pre-damaged livers. METHODS: C3H mice were injected three times/week (0.15 mg/g body weight) and fed with EtOH. Tissue and serum samples were collected and analysed. RESULTS: Portal fibrosis was verified by van Gieson staining showing a mild fibrosis (score F2) in TAA-treated mice and liver fibrosis (score F4) in the combination group using TAA/EtOH. Consonant with the histological results, the fibrosis marker MMP-2 and alpha 1 procollagen (I) were elevated at week 10 and 15 after treatment initiation in the combination group, whereas tissue protective proteinase, TIMP-1, was 18.5-fold increased only at week 10 but normalized until week 15. Fibrosis development was associated with elevated ICAM-1 expression. CONCLUSIONS: Taken together, TAA/EtOH application was suitable to induce liver fibrosis characterized by typical bio-markers in C3H/He.     

A directed screen for genes involved in Drosophila blood cell activation

An attack by a parasitic wasp activates a vigorous cellular immune response in Drosophila larvae. This response is manifested by an increased number of circulating cells, the hemocytes, and by the appearance of a specialized class of hemocyte, the lamellocytes, which participate in the encapsulation and killing of the parasite. To study the molecular mechanisms of this response, we have overexpressed different genes in the hemocytes, by using the GAL4-upstream activating sequence system and a hemocyte-specific Hemese-GAL4 driver. Multiple transgenes were tested, representing several important signaling pathways. We found that the proliferation response and the activation of lamellocyte formation are independent phenomena. A drastic increase in the number of circulating hemocytes is caused by receptor tyrosine kinases, such as Egfr, Pvr, and Alk, as well as by the downstream signaling components Ras85D and pointed, supporting the notion that the Ras-mitogen-activated protein kinase pathway regulates hemocyte numbers. In the case of Pvr and Alk, this phenotype also is accompanied by lamellocyte formation. By contrast, constitutively active hopscotch and hemipterous give massive activation of lamellocyte formation with little or no increase in total hemocyte numbers. This finding indicates that both the Jak/Stat and the Jun kinase pathways affect lamellocyte formation. Still other signals, mediated by aop(ACT), Toll(10b), and Rac1 expression, cause a simultaneous increase in lamellocyte and total cell numbers, and the same effect is seen when WNT signaling is suppressed. We conclude that the activation of a cellular response is complex and affected by multiple signaling pathways.     

Low-avidity HPA-1a alloantibodies in severe neonatal alloimmune thrombocytopenia are detectable with surface plasmon resonance technology

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is mostly caused by maternal alloantibodies directed against the human platelet alloantigen (HPA)-1a. Currently, the serologic diagnosis of FNAIT is based on the characterization of the HPA alloantibodies in monoclonal antibody–based antigen-capture assays (e.g., MAIPA assay). Accumulated current evidence indicated that such assays may overlook some HPA-1a antibodies.
STUDY DESIGN AND METHODS: This study employed surface plasmon resonance (SPR) technology using immunoaffinity-purified glycoprotein IIb/IIIa isoforms immobilized on biosensor chips to study the binding kinetics of HPA-1a alloantibodies from different FNAIT cases in real time.
RESULTS: Analysis of HPA-1a alloantibodies from FNAIT cases (n = 9) in SPR showed a moderate relative response (22.2-69.7 resonance units [RU]) and slow antibody dissociation. After the dissociation phase, varying amounts of bound antibodies (41%-79%) remained on the chip. In contrast in HPA-1a alloantibodies from a patient suffering from posttransfusion purpura, a high relative response (∼490 RU) was observed at the end of the association phase and no dissociation of antibody binding was detectable. Of particular relevance, by the use of this SPR technique, HPA-1a alloantibodies were detected in two severe FNAIT cases that had determined as false negative by MAIPA assay. In SPR, these HPA-1a alloantibodies showed low-avidity nature characterized by gradual dissociation of antibody during the association phase and complete detachment of antibody binding after the dissociation phase. This high "off-rate" character of low-avidity HPA-1a alloantibodies indicates that such antibody binding is easily detachable by the extensive washing procedure of the MAIPA.
CONCLUSIONS: Our results demonstrated that the SPR method can facilitate the diagnosis of clinically relevant low-avidity HPA-1a antibodies.     

(Neo)adjuvant strategies of advanced gastric carcinoma: time for a change?

Despite surgical R0 resections, patients with gastric cancer stage UICC II-III have a high risk of recurrence and metachronic metastases. Preliminary evidence exists that adjuvant chemotherapy or neoadjuvant chemo(radio)therapy protocols may improve the prognosis of these patients undergoing surgery of gastric cancer with curative intention. As for palliative regimens, 5-fluorouracil and cisplatin are integral components of such (neo)adjuvant strategies. Upcoming cytostatic agents, i.e. irinotecan, docetaxel, oxaliplatin, and oral fluoropyridines are currently under investigation in new multimodality treatment regimens and may further increase R0 resection rates and may prolong disease-free and overall survival in the treatment of advanced localized gastric cancer.     

Reactive oxygen species-dependent hypertension in dopamine D2 receptor-deficient mice

Dysfunction of D2-like receptors has been reported in essential hypertension. Disruption of D2R in mice (D2-/-) results in high blood pressure, and several D2R polymorphisms are associated with decreased D2R expression. Because D2R agonists have antioxidant activity, we hypothesized that increased blood pressure in D2-/- is related to increased oxidative stress. D2-/- mice had increased urinary excretion of 8-isoprostane, a parameter of oxidative stress; increased activity of reduced nicotinamide-adenine dinucleotide phosphate oxidase in renal cortex; increased expression of the reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits Nox1, Nox2, and Nox4; and decreased expression of the antioxidant enzyme heme-oxygenase-2 in the kidneys, suggesting that regulation of reactive oxygen species (ROS) production by D2R involves both pro-oxidant and antioxidant systems. Apocynin, a reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor, or hemin, an inducer of heme oxigenase-1, normalized the blood pressure in D2-/- mice. Because D2Rs in the adrenal gland are implicated in aldosterone regulation, we evaluated whether alterations in aldosterone secretion contribute to ROS production in this model. Urinary aldosterone was increased in D2-/- mice and its response to a high-sodium diet was impaired. Spirolactone normalized the blood pressure in D2-/- mice and the renal expression of Nox1 and Nox4, indicating that the increased blood pressure and ROS production are, in part, mediated by impaired aldosterone regulation. However, spironolactone did not normalize the excretion of 8-isoprostane and had no effect on expression of Nox2 or heme-oxygenase-2. Our results show that the D2R is involved in the regulation of ROS production and that, by direct and indirect mechanisms, altered D2R function may result in ROS-dependent hypertension.     

Usefulness of noninvasive cardiac imaging using dual-source computed tomography in an unselected population with high prevalence of coronary artery disease

The aim of the present study was to evaluate the diagnostic accuracy of a new dual-source computed tomographic scanner generation with 83-ms temporal resolution in cardiac imaging. Fifty-one unselected consecutive patients (mean age 64 +/- 10 years) scheduled for invasive coronary angiography because of suspected or known coronary artery disease (CAD) were examined with dual-source computed tomography (DSCT). All coronary segments were analyzed regarding the presence of coronary artery lesions. The findings were compared with invasive coronary angiography. During computed tomographic examination, mean heart rate was 65 +/- 14 beats/min. Thirteen of 51 patients (25%) did not have sinus rhythm. Mean Agatston score equivalent was 779 (median 358, range 0 to 3,898). Prevalence of CAD was 75%. Based on a coronary segment model, sensitivity was 96%, specificity 87%, positive predictive value 61%, and negative predictive value 99% for the detection of significant lesions (> or =50% diameter stenosis). The main reason for false-positive results was an overestimation of mild lesions by DSCT. In conclusion, our initial data indicate that DSCT allows a high accuracy to exclude relevant coronary stenosis in unselected patients with a high prevalence of CAD and a relevant number with heart rhythm irregularities. However, overestimation of stenosis, especially in cases of calcifications, is still a limitation.