Current Nuclear-medicine News Results

A New Concept Underlying Stem Cell Lineage Skewing That Explains the Detrimental Effects of Thiazolidinediones on Bone.

Stem Cells. 2010 Mar 8;
Bruedigam C, Eijken M, Koedam M, van de Peppel J, Drabek K, Chiba H, van Leeuwen JP

Bone-marrow adipogenesis is an aging-related phenomenon and correlated with osteoporosis. The latter is a prevalent bone disease in the elderly leading to increased fracture risk and mortality. It is widely hypothesized that the underlying molecular mechanism includes a shift in the commitment of mesenchymal stem cells (MSC) from the osteogenic lineage to the adipogenic lineage. Lineage skewing is at least partially a result of transcriptional changes. The nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been proposed as a major decision factor in MSC lineage commitment promoting adipogenesis at the expense of osteogenesis. Here we found that PPAR-gamma acted unexpectedly to stimulate osteoblast differentiation from human bone marrow-derived MSCs. Both rosiglitazone-mediated activation and overexpression of PPAR-gamma caused acceleration of osteoblast differentiation. Conversely, shRNAi-mediated PPAR-gamma knockdown diminished osteoblast differentiation. MSCs that were treated with rosiglitazone did not preferentially differentiate into adipocytes. However, the rosiglitazone-mediated acceleration of osteoblast differentiation was followed by increased accumulation of reactive oxygen species and apoptosis. In contrast to the osteogenic lineage, cells of the adipogenic lineage were protected from this. Our data support a new concept on bone health that adds to the explanation of the clinically observed suppressive action of activated PPAR-gamma on bone and the associated phenomenon of bone marrow adipogenesis. This concept is based on a higher susceptibility of the osteogenic than the adipogenic lineage to oxidative stress and apoptosis that is preferentially triggered in the osteoblasts by activated PPAR-gamma.

Is FDG-PET suitable for evaluating neoadjuvant therapy in non-small cell lung cancer? Evidence with systematic review of the literature.

J Surg Oncol. 2010 Mar 8;
Rebollo-Aguirre AC, Ramos-Font C, Villegas Portero R, Cook GJ, Llamas Elvira JM, Romero Tabares A

BACKGROUND: Neoadjuvant therapy response assessment is crucial in patients with non-small cell lung cancer (NSCLC). FDG-PET has emerged as a valuable tool for defining therapy response assessment in other tumours. AIM: To systematically review publications appearing in the literature describing induction therapy response assessment with FDG-PET in NSCLC. METHODS: We performed a bibliographic search and selected only prospective studies in order to include the highest levels of evidence. RESULTS: Nine of 497 potentially relevant publications were selected. The ranges of sensitivity, specificity, positive predictive value and negative predictive value for primary tumour response assessment were 80-100%, 0-100%, 42.9-100%, and 66.7-100%, respectively. Pooling data for N2 restaging after neoadjuvant response the overall sensitivity was 63.8% (95% CI, 53.3-73.7%) and overall specificity was 85.3% (95% CI, 80.4-89.4%). CONCLUSION: The results of the analysis do not support the use of FDG-PET as the only re-assessment tool for mediastinal lymph node evaluation for routine clinical use. FDG-PET seems to predict primary tumour response to induction therapy but it could not be shown by pooling analysis. J. Surg. Oncol. (c) 2010 Wiley-Liss, Inc.

Imaging assessment of osteosarcoma in childhood and adolescence: diagnosis, staging, and evaluating response to chemotherapy.

Cancer Treat Res. 2010; 152: 33-62
Eftekhari F

Osteosarcoma is an aggressive tumor of mesenchymal origin, capable of producing osteoid and immature bone. It is the most frequent primary malignant skeletal neoplasm in children and adolescents. Imaging studies play a major role in initial diagnosis, staging, and assessment of tumor response to chemotherapy. Conventional radiography is the prime imaging modality for diagnosis of bony tumors. Radionuclide bone scan is used in detection of metastatic lesions in the other bones. Computed tomography may be used as an adjunct to conventional radiography, but its main role is detection of pulmonary metastasis. The standard magnetic resonance imaging is the most specific modality for local staging and monitoring response to chemotherapy, and distinguishing postsurgical changes from residual tumor. Dynamic contrast-enhanced magnetic resonance imaging has been introduced to quantify the percentage of tumor necrosis, identify early responders, and thus predict survival. The role of (18)F fluorodeoxyglucose positron emission tomography (PET) in the staging and management of osteosarcoma is evolving. It has the advantage of total body imaging and may have an overall role in tumor staging and grading, detection of early response, and therefore, in the prognosis and detection of recurrence.

Mesenchymal-to-epithelial transition determinants as characteristics of ovarian carcinoma effusions.

Clin Exp Metastasis. 2010 Mar 7;
Elloul S, Vaksman O, Stavnes HT, Trope CG, Davidson B, Reich R

The present study investigated the intracellular regulation of E-cadherin in ovarian carcinoma. E-cadherin expression and regulation by Snail and Pak1 were studied in ES-2 and OVCAR-3 ovarian cancer cells in vitro. Twist1, Zeb1 and Vimentin mRNA expression and HIF-1alpha protein expression were analyzed in 80 and 189 clinical specimens, respectively. OVCAR-3 cells incubated with an anti-E-cadherin antibody formed smaller and looser spheroids compared to controls. Snail silencing using Small Hairpin RNA in ES-2 cells reduced invasion and MMP-2 activity, with unaltered cellular morphology. Using dominant negative (DN) and constitutively active (CA) Pak1 constructs, we found that DN Pak1 ES-2 and OVCAR-3 clones had reduced attachment to matrix proteins, invasion and MMP-2 activity compared to CA and wild-type cells. DN Pak1 ES-2 cells also bound less to LP9 mesothelial cells. DN Pak1 OVCAR-3 cells had lower Vimentin levels. Snail expression was lower in cultured effusions compared to primary carcinomas, and was cytoplasmic rather than nuclear. Twist1 (P < 0.001), Zeb1 (P = 0.003) and Vimentin (P = 0.03) mRNA expression was significantly higher in solid metastases compared to primary carcinomas and effusions. HIF-1alpha protein expression was lower in effusions compared to primary carcinomas and solid metastases (P = 0.033). Our data suggest that the previously reported E-cadherin re-expression in ovarian carcinoma effusions is regulated by Pak1. The transient nature of E-cadherin expression during ovarian carcinoma progression is probably the result of partial epithelial-to-mesenchymal transition (EMT) and the reverse process of mesenchymal-to-epithelial-like transition (MET). Expression of the EMT-related molecules Twist, Zeb1, Vimentin and HIF-1alpha is anatomic site-dependent in ovarian carcinoma.

Nuclear cardiology in the literature.

J Nucl Cardiol. 2010 Mar 6;
Brown KA

Gut microbiome-derived metabolites characterize a peculiar obese urinary metabotype.

Int J Obes (Lond). 2010 Mar 9;
Calvani R, Miccheli A, Capuani G, Tomassini Miccheli A, Puccetti C, Delfini M, Iaconelli A, Nanni G, Mingrone G

Obesity is a complex multifactorial disease involving genetic and environmental factors and influencing several different metabolic pathways. In this regard, metabonomics, that is the study of complex metabolite profiles in biological samples, may provide a systems approach to understand the global metabolic regulation of the organism in relation to this peculiar pathology. In this pilot study, we have applied a nuclear magnetic resonance (NMR)-based metabolomic approach on urinary samples of morbidly obese subjects. Urine samples of 15 morbidly obese insulin-resistant (body mass index>40; homeostasis assessment model of insulin resistance>3) male patients and 10 age-matched controls were collected, frozen and analyzed by high-resolution (1)H-NMR spectroscopy combined with partial least squares-discriminant analysis. Furthermore, two obese patients who underwent bariatric surgery (biliopancreatic diversion and gastric bypass, respectively) were monitored during the first 3 months after surgery and their urinary metabolic profiles were characterized. NMR-based metabolomic analysis allowed us to identify an obesity-associated metabolic phenotype (metabotype) that differs from that of lean controls. Gut flora-derived metabolites such as hippuric acid, trigonelline, 2-hydroxyisobutyrate and xanthine contributed most to the classification model and were responsible for the discrimination. These preliminary results confirmed that in humans the gut microflora metabolism is strongly linked to the obesity phenotype. Moreover, the typical obese metabotype is lost after weight loss induced by bariatric surgery.International Journal of Obesity advance online publication, 9 March 2010; doi:10.1038/ijo.2010.44.

Low-risk differentiated thyroid carcinoma patients still deserve I-131 remnant ablation after total thyroidectomy.

Minerva Chir. 2010 Feb; 65(1): 95-100
Verburg FA, Luster M

After total thyroidectomy for differentiated thyroid carcinoma (DTC), I-131 ablation is usually recommended in all patients but those classified as "very low risk", and mandatory for all patients classified as "high risk". For those classified as "low risk" there is some discussion as to whether I-131 ablation should still be performed. In this review various staging systems for classifying patients as "very low risk" "low risk" or "high risk" are discussed, followed by an overview of why I-131 ablation remains an eminently sensible idea in "low risk" patients.

Complement Regulator CD59 Protects Against Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice.

Circulation. 2010 Mar 8;
Wu G, Chen T, Shahsafaei A, Hu W, Bronson RT, Shi GP, Halperin JA, Aktas H, Qin X

BACKGROUND: -Complement system, an innate immunity, has been well documented to play a critical role in many inflammatory diseases. However, the role of complement in the pathogenesis of abdominal aortic aneurysm, which is considered an immune and inflammatory disease, remains obscure. Methods and Results-Here, we evaluated the pathogenic roles of complement membrane attack complex and CD59, a key regulator that inhibits the membrane attack complex, in the development of abdominal aortic aneurysm. We demonstrated that in the angiotensin II-induced abdominal aortic aneurysm model, deficiency of the membrane attack complex regulator CD59 in ApoE-null mice (mCd59ab(-/-)/ApoE(-/-)) accelerated the disease development, whereas transgenic overexpression of human CD59 (hCD59(ICAM-2+/-)/ApoE(-/-)) in this model attenuated the progression of abdominal aortic aneurysm. The severity of aneurysm among these 3 groups positively correlates with C9 deposition, and/or the activities of MMP2 and MMP9, and/or the levels of phosphorylated c-Jun, c-Fos, IKK-alpha/beta, and p65. Furthermore, we demonstrated that the membrane attack complex directly induced gene expression of matrix metalloproteinase-2 and -9 in vitro, which required activation of the activator protein-1 and nuclear factor-kappaB signaling pathways. Conclusion-Together, these results defined the protective role of CD59 and shed light on the important pathogenic role of the membrane attack complex in abdominal aortic aneurysm.

Visualization of JNK activity dynamics with a genetically encoded fluorescent biosensor.

Proc Natl Acad Sci U S A. 2010 Mar 8;
Fosbrink M, Aye-Han NN, Cheong R, Levchenko A, Zhang J

The signaling pathway mediated by JNK transduces different types of signals, such as stress stimuli and cytokines, into functional responses that mediate apoptosis, as well as proliferation, differentiation, and inflammation. To better characterize the dynamic information flow and signal processing of this pathway in the cellular context, a genetically encoded, fluorescent protein-based biosensor was engineered to detect endogenous JNK activity. This biosensor, named JNKAR1 (for JNK activity reporter), specifically detects stress- (ribotoxic and osmotic) and cytokine- (TNF-alpha) induced JNK activity in living cells with a 15 to 30% increase in the yellow-to-cyan emission ratio because of a phosphorylation-dependent increase in FRET between two fluorescent proteins. JNK activity was detected not only in the cytoplasm, but also in the nucleus, mitochondria, and plasma membrane with similar kinetics after induction of ribotoxic stress by anisomycin, suggesting relatively rapid signal propagation to the nuclear, mitochondrial, and plasma membrane compartments. Furthermore, quantitative single-cell analysis revealed that anisomycin-induced JNK activity exhibited ultrasensitivity, sustainability, and bimodality, features that are consistent with behaviors of bistable systems. The development of JNKAR1, therefore, laid a foundation for evaluating the signaling properties and behaviors of the JNK cascade in single living cells.

Increased susceptibility of Nrf2 null mice to 1-bromopropane-induced hepatotoxicity.

Toxicol Sci. 2010 Mar 8;
Liu F, Ichihara S, Valentine WM, Itoh K, Yamamoto M, Mohideen SS, Kitoh J, Ichihara G

1-Bromopropane (1-BP) was introduced as an alternative to ozone-depleting solvents. However, it was found to exhibit neurotoxicity, reproductive toxicity and hepatotoxicity in rodents and neurotoxicity in human. However, the mechanisms underlying the toxicities of 1-BP remain elusive. The present study investigated the role of oxidative stress in 1-BP-induced hepatotoxicity using nuclear factor erythroid 2-related factor 2 (Nrf2) null mice. Groups of 24 male Nrf2-null mice and 24 male wild type (WT) C57BL/6J mice were each divided into three groups of eight and exposed to 1-BP at either 0, 100 or 300 ppm for 8 hr/day for 28 days by inhalation. Liver histopathology showed significantly larger area of necrosis in Nrf2-null mice relative to WT mice at the same exposure level. Nrf2-null mice also had greater malondialdehyde (MDA) levels, higher ratio of GSSG/GSH and lower total glutathione content. The constitutional level and the increase in ratio per exposure level of glutathione S-transferase (GST) activity were lower in the liver of Nrf2-null mice than WT mice. Exposure to 1-BP at 300 ppm increased the mRNA levels of heme oxygenase-1 (HO-1), glutamate-cysteine ligase modifier subunit (GcLm), glutamate cysteine synthetase (GcLc), GR and NAD(P)H: quinone oxidoreductase 1 (NQO1) in WT mice, but not in Nrf2-null mice except for GST Yc2. Nrf2-null mice were more susceptible to 1-BP-induced hepatotoxicity. That oxidative stress plays a role in 1-BP hepatotoxicity is deduced from the low expression levels and activities of antioxidant enzymes and high MDA levels in Nrf2-null mice.

Identification of a self-association domain in the Ewing's Sarcoma (EWS) protein: a novel function for RGG-motifs?

J Biochem. 2010 Mar 7;
Shaw DJ, Morse R, Todd AG, Eggleton P, Lorson CL, Young PJ

The Ewing Sarcoma (EWS) protein is a ubiquitously expressed RNA chaperone. The EWS protein localizes predominantly to the nucleus. Previous reports have suggested that the EWS protein is capable of dimerising. However, to date this has not been confirmed. Here, using a novel panel of recombinant proteins we have performed an in vitro biomolecular interaction analysis of the EWS protein. We have demonstrated that all three RGG-motifs are capable of binding directly to the SMN protein, a Tudor domain containing EWS binding partner. We have also confirmed EWS is capable of self-associating, and we have mapped this binding domain to the RGG-motifs. We have also found that self-association may be required for EWS nuclear import. This is the first direct evidence of RGG-domains being involved in self-association and has implications on all RGG-containing proteins.

FOXO3a GOVERNS EARLY AND LATE APOPTOTIC ENDOTHELIAL PROGRAMS DURING ELEVATED GLUCOSE THROUGH MITOCHONDRIAL AND CASPASE SIGNALING.

Mol Cell Endocrinol. 2010 Mar 4;
Hou J, Chong ZZ, Shang YC, Maiese K

Mechanisms that preserve endothelial cell (EC) integrity remain elusive, but are critical for new strategies directed against endocrine disorders such as diabetes mellitus (DM). Here we demonstrate in primary cerebral ECs with a clinically relevant model of elevated D-glucose that Akt1 and the post-translational modification and subcellular trafficking of the forkhead transcription factor FoxO3a are critical for early apoptotic membrane signaling and subsequent degradation of nuclear DNA. FoxO3a also directly governs apoptotic mitochondrial signal transduction pathways, since gene knockdown of FoxO3a prevents mitochondrial membrane depolarization as well as the release of cytochrome c. Control of this apoptotic cascade extends to the rapid and progressive activation of caspases. The presence of FoxO3a is necessary for cleaved (active) caspase 1 and 3 expression, since loss of FoxO3a abrogates the induction of caspase activity. Our work identifies Akt1, FoxO3a and closely aligned pathways as key therapeutic targets during impaired glucose tolerance and DM.

Temporal trends in compliance with appropriateness criteria for stress single-photon emission computed tomography sestamibi studies in an academic medical center.

Am Heart J. 2010 Mar; 159(3): 484-489
Gibbons RJ, Askew JW, Hodge D, Miller TD

BACKGROUND: The purpose of this study was to apply published appropriateness criteria for single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) in a single academic medical center to determine if the percentage of inappropriate studies was changing over time. In a previous study, we applied the American College of Cardiology Foundation/American Society of Nuclear Cardiology (ASNC) appropriateness criteria for stress SPECT MPI and reported that 14% of stress SPECT studies were performed for inappropriate reasons. METHODS: Using similar methodology, we retrospectively examined 284 patients who underwent stress SPECT MPI in October 2006 and compared the findings to the previous cohort of 284 patients who underwent stress SPECT MPI in May 2005. RESULTS: The indications for testing in the 2 cohorts were very similar. The overall level of agreement in characterizing categories of appropriateness between 2 experienced cardiovascular nurse abstractors was good (kappa = 0.68), which represented an improvement from our previous study (kappa = 0.56). There was a significant change between May 2005 and October 2006 in the overall classification of categories for appropriateness (P = .024 by chi(2) statistic). There were modest, but insignificant, increases in the number of patients who were unclassified (15% in the current study vs 11% previously), appropriate (66% vs 64%), and uncertain (12% vs 11%). Only 7% of the studies in the current study were inappropriate, which represented a significant (P = .004) decrease from the 14% reported in the 2005 cohort. CONCLUSIONS: In the absence of any specific intervention, there was a significant change in the overall classification of SPECT appropriateness in an academic medical center over 17 months. The only significant difference in individual categories was a decrease in inappropriate studies. Additional measurements over time will be required to determine if this trend is sustainable or generalizable.

[Effects of genistein on colon cancer cells in vitro and in vivo and its mechanism of action.]

Zhonghua Zhong Liu Za Zhi. 2010 Jan; 32(1): 4-9
Fan YZ, Li GH, Wang YH, Ren QY, Shi HJ

OBJECTIVE: To study the effects of genistein on the proliferation, apoptosis induction and expression of related gene proteins of human colon cancer cells in vitro and in vivo, and its mechanisms of action. METHODS: MTT colorimetric assay was used to detect the effects of genistein on the proliferation of human colon adenocarcinoma SW480 cells. Light and transmission electron microscopy were used to study the histological and ultrastructural changes. Flow cytometry was used to determine the effects of genistein on cell cycle and apoptosis. Flow cytometry and immunohistochemistry were used to determine the effects of genistein on apoptosis induction and expression of related gene proteins of colon cancer cells. RESULTS: The MTT colorimetric assay showed that genistein inhibited the proliferation of SW480 cells in a dose-dependent and time-dependent manner, and the highest inhibition rate was 60.2% after 80 microg/ml genistein treatment for 72 h. The light microscopy revealed that many genistein-treated cancer cells were shrunken, disrupted, or showing cytoplasmic vacuolization. The electron microscopic examination showed cell shrinkage, nuclear fragmentation and pronounced chromatin condensation, sometimes formed crescent chromatin condensation attached to the nuclear membrane. The results of flow cytometry showed that: after SW480 cells were treated with 0, 20, 40, 80 microg/ml genistein for 48 h, the FI values of PCNA were 1.49 +/- 0.02, 1.28 +/- 0.04, 1.14 +/- 0.03, and 0.93 +/- 0.08; the FI values of VEGF were 1.75 +/- 0.02, 1.34 +/- 0.06, 1.32 +/- 0.04, and 1.23 +/- 0.04; the fluorescence index (FI) values of p21 were 1.26 +/- 0.05, 1.36 +/- 0.06, 1.61 +/- 0.03, and 1.73 +/- 0.03, respectively. There were statistically significant differences between the control group and each treatment group (P < 0.05 or P < 0.01). The scores of immunohistochemical staining of PCNA and VEGF proteins were decreased, while p21 increased. There were statistically significant differences between the control group and each treatment group (P < 0.05 or P < 0.01). CONCLUSION: Genistein can inhibit the growth of colon cancer cells via apoptosis induction and cell cycle arrest at G(2)/M phase. The anti-tumor mechanisms of genistein may be related with the down-regulation of expression of VEGF and PCNA, and up-regulation of the expression of p21.

In Vitro Ageing of Porcine Oocytes: Changes in Phosphorylation of the Mitogen-Activated Protein Kinase (MAPK) and Parthenogenetic Activability.

Reprod Domest Anim. 2010 Mar 2;
Ebeling S, Labudda A, Meinecke B

Contents The role of mitogen-activated protein kinase (MAPK) was investigated during ageing of porcine oocytes following in vitro maturation (IVM). Oocytes exhibiting an extruded first polar body after IVM for 46 h (79.3% metaphase II, M II) were used for the experiments. Nuclear maturation stages were not visibly altered after a further 12 h of ageing. Proportion of M II stages (42.9%) decreased significantly whereas fragmentation and degeneration of oocytes increased after an ageing time of 26 h. In vitro ageing for 12 and 26 h led to a significant reduction of MAPK phosphorylation (i.e. activation) compared to oocytes matured for 46 h. When MAPK was inhibited by U0126 in M II oocytes, 30.9% (12 h) and 39.7% (26 h) of oocytes, respectively, left metaphase II arrest and proceeded to early anaphase II. Pronuclear stages or fragmentation could be observed only sporadically (2.6-3.6%). After parthenogenetic activation of oocytes by ethanol/cycloheximide, cleavage stages were reached with rates of 51.9% (46 h IVM), 42.0% (12 h ageing) and 40.3% (26 h ageing), respectively. Furthermore, a significant higher proportion of long-term aged oocytes (26 h) showed pronuclear formation (8.6%) and fragmentation (7.9%) compared to non-aged oocytes (each 1.9%). It is concluded that both MAPK phosphorylation and cleavage rate after parthenogenetic activation decreased before alterations of nuclear stages could be detected during in vitro ageing of M II oocytes. A premature MAPK dephosphorylation of M II oocytes caused early anaphase II stages, but cleaved stages could not be achieved.

Redox Control Systems in the Nucleus: Mechanisms and Functions.

Antioxid Redox Signal. 2010 Mar 8;
Go YM, Jones DP

Abstract Proteins with oxidizable thiols are essential to many functions of cell nuclei, including transcription, chromatin stability, nuclear protein import and export, and DNA replication and repair. Control of the nuclear thiol-disulfide redox states involves both the elimination of oxidants to prevent oxidation and the reduction of oxidized thiols to restore function. These processes depend on the common thiol reductants, glutathione (GSH) and thioredoxin-1 (Trx1). Recent evidence shows that these systems are controlled independent of the cytoplasmic counterparts. In addition, the GSH and Trx1 couples are not in redox equilibrium, indicating that these reductants have nonredundant functions in their support of proteins involved in transcriptional regulation, nuclear protein trafficking, and DNA repair. Specific isoforms of glutathione peroxidases, glutathione S-transferases, and peroxiredoxins are enriched in nuclei, further supporting the interpretation that functions of the thiol-dependent systems in nuclei are at least quantitatively distinct, and probably also qualitatively distinct, from similar processes in the cytoplasm. Elucidation of the distinct nuclear functions and regulation of the thiol redox pathways in nuclei can be expected to improve understanding of nuclear processes and also to provide the basis for novel approaches to treat aging and disease processes associated with oxidative stress in the nuclei. Antioxid. Redox Signal. 13, 0000-0000.

Vitamin D deficiency and myocardial structure and function in older men and women: The Hoorn Study.

J Endocrinol Invest. 2010 Mar 5;
Pilz S, Henry RM, Snijder MB, van Dam RM, Nijpels G, Stehouwer CD, Kamp O, Tomaschitz A, Pieber TR, Dekker JM

Background: Vitamin D deficiency is frequently observed in heart failure patients and it has been shown that Vitamin D exerts various effects on the heart that may be relevant for the pathogenesis of myocardial diseases. Aims: We aimed to elucidate the largely unknown association of 25-hydroxyvitamin D (25[OH]D) serum levels with echocardiographic measures of left ventricular (LV) structure and function. Material/Subjects and Methods: We measured 25(OH)D serum levels and performed standardized LV echocardiograms in 614 persons from a population based cohort of older men and women. Echocardiographic data were used to calculate LV mass and LV geometry and for classification of systolic and diastolic dysfunction. To consider the seasonal variations of 25(OH)D levels we categorized our study participants according to season specific 25(OH)D quartiles. Results: LV systolic function, LV mass and LV geometry were not significantly associated with 25(OH)D serum levels. In binary logistic regression analyses, the prevalence of LV diastolic dysfunction was significantly higher in the first season specific 25(OH)D quartile when compared to the fourth quartile (odds ratio 2.32 [95% CI: 1.42-3.80]; p=0.001) but significance was lost after adjustments for age (odds ratio 1.51 [0.89-2.57]; p=0.123 ) and established risk factors for heart failure (odds ratio 1.47 [0.84-2.59]; p=0.178). Conclusions: Serum levels of 25(OH)D are not significantly associated with LV structure and function but a non-significant trend towards increased risk of diastolic dysfunction in persons with vitamin D deficiency warrants further studies.

Hyaluronan Inhibits Prostaglandin E(2) Production via CD44 in U937 Human Macrophages.

Tohoku J Exp Med. 2010; 220(3): 229-35
Yasuda T

Prostaglandin E(2) (PGE(2)) is one of the key mediators of inflammation in affected joints of rheumatoid arthritis (RA). Intra-articular injection of high molecular weight hyaluronan (HA) into RA knee joints relieves arthritic pain. Although HA has been shown to inhibit PGE(2) production in cytokine-stimulated synovial fibroblasts, it remains unclear how HA suppresses PGE(2) production in activated cells. Furthermore, HA effect on macrophages has rarely been investigated in spite of their contribution to RA joint pathology. This study was aimed to investigate the inhibitory mechanism of HA on lipopolysaccharide (LPS)-stimulated PGE(2) production in U937 human macrophages. Stimulation of U937 macrophages with LPS enhanced PGE(2) production in association with increased protein levels of cyclooxygenase-2 (COX-2). Pretreatment with HA of 2,700 kDa resulted in suppression of the LPS-mediated induction of COX-2, leading to a decrease in PGE(2) production. Likewise, the LPS-stimulated PGE(2) production was inhibited by the pretreatment with a specific COX2 inhibitor, NS-398, or a specific inhibitor of nuclear factor (NF)-kappaB, BAY11-7085. HA also decreased the degree of phosphorylation and nuclear translocation of NF-kappaB enhanced by LPS. Fluorescence cytochemistry demonstrated that HA bound to CD44, the principal HA receptor, on U937 macrophages. Anti-CD44 antibody reversed the inhibitory effects of HA on the LPS-mediated increase in PGE(2) production, COX-2 induction, and activation of NF-kappaB. These results indicate that HA suppresses the LPS-stimulated PGE(2) production via CD44 through down-regulation of NF-kappaB. Administration of HA into RA joints may decrease PGE(2) production by activated macrophages, which could result in improvement of arthritic pain.

Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation.

FASEB J. 2010 Mar 5;
Chinopoulos C, Gerencser AA, Mandi M, Mathe K, Töröcsik B, Doczi J, Turiak L, Kiss G, Konràd C, Vajda S, Vereczki V, Oh RJ, Adam-Vizi V

In pathological conditions, F0F1-ATPase hydrolyzes ATP in an attempt to maintain mitochondrial membrane potential. Using thermodynamic assumptions and computer modeling, we established that mitochondrial membrane potential can be more negative than the reversal potential of the adenine nucleotide translocase (ANT) but more positive than that of the F0F1-ATPase. Experiments on isolated mitochondria demonstrated that, when the electron transport chain is compromised, the F0F1-ATPase reverses, and the membrane potential is maintained as long as matrix substrate-level phosphorylation is functional, without a concomitant reversal of the ANT. Consistently, no cytosolic ATP consumption was observed using plasmalemmal KATP channels as cytosolic ATP biosensors in cultured neurons, in which their in situ mitochondria were compromised by respiratory chain inhibitors. This finding was further corroborated by quantitative measurements of mitochondrial membrane potential, oxygen consumption, and extracellular acidification rates, indicating nonreversal of ANT of compromised in situ neuronal and astrocytic mitochondria; and by bioluminescence ATP measurements in COS-7 cells transfected with cytosolic- or nuclear-targeted luciferases and treated with mitochondrial respiratory chain inhibitors in the presence of glycolytic plus mitochondrial vs. only mitochondrial substrates. Our findings imply the possibility of a rescue mechanism that is protecting against cytosolic/nuclear ATP depletion under pathological conditions involving impaired respiration. This mechanism comes into play when mitochondria respire on substrates that support matrix substrate-level phosphorylation are provided.-Chinopoulos, C., Gerencser, A. A., Mandi, M., Mathe, K., Töröcsik, B., Doczi, J., Turiak, L., Kiss, G., Konràd, C., Vajda, S., Vereczki, V., Oh, R. J., Adam-Vizi, V. Forward operation of adenine nucleotide translocase during F0F1-ATPase reversal: critical role of matrix substrate-level phosphorylation.

Diagnosis and localisation of insulinoma: the value of modern MRI in conjunction with calcium stimulation catheterization.

Eur J Endocrinol. 2010 Mar 5;
Druce M, Muthuppalaniappan V, Oleary B, Chew S, Drake W, Monson J, Akker S, Besser GM, Sahdev A, Rockall A, Vyas S, Bhattacharya S, Matson M, Berney D, Grossman A

Context: Preoperative localization of insulinoma improves cure rate and reduces complications, but may be challenging. Objective: To review diagnostic features and localisation accuracy for insulinomas. Design: Cross-sectional, retrospective analysis. Setting: A single tertiary referral center. Patients: Patients with insulinoma 1990-2009, including sporadic tumors and those in patients with multiple endocrine neoplasia (MEN) syndromes. Interventions: Patients were identified from a database, and case notes and investigation results reviewed. Tumor localization by computed tomography (CT), magnetic resonance imaging (MRI), octreotide scanning, endoscopic ultrasound (EUS) and calcium stimulation was evaluated. Main outcome measure(s): Insulinoma localisation was compared to histologically-confirmed location following surgical excision. Results: Thirty-seven instances of biochemical and/or histologically proven insulinoma were identified in 36 patients, of which 7 were managed medically. Of the 30 treated surgically, 25 had CT (83.3%) and 28 had MRI (90.3%), with successful localization in 16 (64%) by CT and 21 (75%) by MRI respectively. Considered together, such imaging correctly localised 80% of lesions. Radiolabeled octreotide scanning was positive in 10 out of 20 cases (50%); EUS correctly identified 17 lesions in 26 patients (65.3%). Twenty-seven patients had calcium stimulation testing of which 6 (22%) did not localize, 17 (63%) were correctly localized and 4 (15%) gave discordant or confusing results. Conclusions: Preoperative localization of insulinomas remains challenging. A pragmatic combination of CT and especially MRI predicts tumor localization with high accuracy. Radionuclide imaging and EUS were less helpful but may be valuable in selected cases. Calcium stimulation currently remains useful in providing an additional functional perspective.