bluuebunny/crossref_metadata_2025 huggingface dataset:
MUTYH-Null Mice Are Susceptible to Spontaneous and Oxidative Stress–Induced Intestinal Tumorigenesis
Authors: Sakamoto Katsumi , Tominaga Yohei , Yamauchi Kazumi , Nakatsu Yoshimichi , Sakumi Kunihiko , Yoshiyama Kaoru , Egashira Akinori , Kura Shinobu , Yao Takashi , Tsuneyoshi Masazumi , Maki Hisaji , Nakabeppu Yusaku , Tsuzuki Teruhisa
Published: July 2007

MUTYH is a mammalian DNA glycosylase that initiates base excision repair by excising adenine opposite 8-oxoguanine and 2-hydroxyadenine opposite guanine, thereby preventing G:C to T:A transversion caused by oxidative stress. Recently, biallelic germ-line mutations of MUTYH have been found in patients predisposed to a recessive form of hereditary multiple colorectal adenoma and carcinoma with an increased incidence of G:C to T:A somatic mutations in the APC gene. In the present study, a systematic histologic examination revealed that more spontaneous tumors had developed in MUTYH-null mice (72 of 121; 59.5%) than in the wild type (38 of 109; 34.9%). The increased incidence of intestinal tumors in MUTYH-null mice (11 tumors in 10 of 121 mice) was statistically significant compared with the wild type (no intestinal tumors in 109 mice). Two adenomas and seven adenocarcinomas were observed in the small intestines, and two adenomas but no carcinomas were found in the colons. In MUTYH-null mice treated with KBrO3, the occurrence of small intestinal tumors dramatically increased. The mean number of polyps induced in the small intestines of these mice was 61.88 (males, 72.75; females, 51.00), whereas it was 0.85 (males, 0.50; females, 1.00) in wild-type mice. The tumors developed predominantly in the duodenum and in the upper region of the (jejunum) small intestines. We conclude that MUTYH suppresses spontaneous tumorigenesis in mammals, thus providing experimental evidence for the association between biallelic germ-line MUTYH mutations and a recessive form of human hereditary colorectal adenoma and carcinoma. [Cancer Res 2007;67(14):6599–604]
Matrix Metalloproteinase 7 Mediates Mammary Epithelial Cell Tumorigenesis through the ErbB4 Receptor
Authors: Lynch Conor C. , Vargo-Gogola Tracy , Martin Michelle D. , Fingleton Barbara , Crawford Howard C. , Matrisian Lynn M.
Published: July 2007

To delineate the role of matrix metalloproteinase 7 (MMP7) in mammary tumorigenesis, MMP7 was expressed in the normal murine mammary gland cell line, c57MG. MMP7 markedly enhanced the growth rate of the c57MG cells in three-dimensional culture and promoted tumor formation in vivo. Subsequent investigation showed that MMP7 (a) up-regulated ErbB4 receptor levels, (b) solubilized the ErbB4 receptor cognate ligand heparin-bound epidermal growth factor, and (c) mediated the proteolytic processing of ErbB4 to yield a soluble intracellular domain (ICD) that localized to the cytoplasm and the nucleus. Furthermore, overexpression of the ErbB4 ICD in the c57MG cell line recapitulated the proliferative effects of MMP7 in vitro and in vivo. These data indicate a novel mechanism for mammary epithelial cell transformation by MMP7. [Cancer Res 2007;67(14):6760–7
Structural Analysis Identifies Imidazo[1,2-b]Pyridazines as PIM Kinase Inhibitors with In vitro Antileukemic Activity
Authors: Pogacic Vanda , Bullock Alex N. , Fedorov Oleg , Filippakopoulos Panagis , Gasser Christelle , Biondi Andrea , Meyer-Monard Sandrine , Knapp Stefan , Schwaller Juerg
Published: July 2007

Much attention has recently been focused on PIM kinases as potential targets for the treatment of hematopoietic malignancies and some solid cancers. Using protein stability shift assays, we identified a family of imidazo[1,2-b]pyridazines to specifically interact with and inhibit PIM kinases with low nanomolar potency. The high-resolution crystal structure of a PIM1 inhibitor complex revealed that imidazo[1,2-b]pyridazines surprisingly interact with the NH2-terminal lobe helix αC rather than with the kinase hinge region. Thus, the identified inhibitors are ATP competitive but not ATP mimetic compounds, explaining their enhanced selectivity with respect to conventional type I kinase inhibitors. One of the identified imidazo[1,2-b]pyridazines (K00135) was further tested in several hematopoietic cellular systems. First, K00135 dose-dependently impaired survival of murine Ba/F3 cells that have been rendered cytokine independent by overexpression of human PIMs. Second, K00135 impaired survival and clonogenic growth of a panel of human acute leukemia cells. Third, exposure of K00135 significantly suppressed in vitro growth of leukemic blasts from five acute myelogenous leukemia patients but not of normal umbilical cord blood mononuclear cells. In vitro kinase assays and immunoblotting using lysates from human MV4;11 leukemic cells showed inhibition of phosphorylation of known PIM downstream targets, such as BAD and eukaryotic translation initiation factor 4E–binding protein 1, by K00135. Taken together, we report a family of small molecules that selectively interact and block PIM kinases and could serve as a lead to develop new targeted antileukemic therapeutics. [Cancer Res 2007;67(14):6916–24]
Induction of Sonic Hedgehog Mediators by Transforming Growth Factor-β: Smad3-Dependent Activation of Gli2 and Gli1 Expression In vitro and In vivo
Authors: Dennler Sylviane , André Jocelyne , Alexaki Ismini , Li Allen , Magnaldo Thierry , ten Dijke Peter , Wang Xiao-Jing , Verrecchia Franck , Mauviel Alain
Published: July 2007

Hedgehog (Hh) and transforming growth factor-β (TGF-β) family members are involved in numerous overlapping processes during embryonic development, hair cycle, and cancer. Herein, we show that TGF-β induces the expression of the Hh signaling molecules Gli1 and Gli2 in various human cell types, including normal fibroblasts and keratinocytes, as well as various cancer cell lines. Gli2 induction by TGF-β is rapid, independent from Hh receptor signaling, and requires a functional Smad pathway. Gli1 expression is subsequently activated in a Gli2-dependent manner. In transgenic mice overexpressing TGF-β1 in the skin, Gli1 and Gli2 expression is also elevated and depends on Smad3. In pancreatic adenocarcinoma cell lines resistant to Hh inhibition, pharmacologic blockade of TGF-β signaling leads to repression of cell proliferation accompanied with a reduction in Gli2 expression. We thus identify TGF-β as a potent transcriptional inducer of Gli transcription factors. Targeting the cooperation of Hh and TGF-β signaling may provide new therapeutic opportunities for cancer treatment. [Cancer Res 2007;67(14):6981–6]
Cyclin-Dependent Kinase 2–Dependent Phosphorylation of ATRIP Regulates the G2-M Checkpoint Response to DNA Damage
Authors: Myers Jeremy S. , Zhao Runxiang , Xu Xin , Ham Amy-Joan L. , Cortez David
Published: July 2007

The ATR-ATRIP kinase complex regulates cellular responses to DNA damage and replication stress. Mass spectrometry was used to identify phosphorylation sites on ATR and ATRIP to understand how the kinase complex is regulated by post-translational modifications. Two novel phosphorylation sites on ATRIP were identified, S224 and S239. Phosphopeptide-specific antibodies to S224 indicate that it is phosphorylated in a cell cycle–dependent manner. S224 matches a consensus site for cyclin-dependent kinase (CDK) phosphorylation and is phosphorylated by CDK2-cyclin A in vitro. S224 phosphorylation in cells is sensitive to CDK2 inhibitors. Mutation of S224 to alanine causes a defect in the ATR-ATRIP–dependent maintenance of the G2-M checkpoint to ionizing and UV radiation. Thus, ATRIP is a CDK2 substrate, and CDK2-dependent phosphorylation of S224 regulates the ability of ATR-ATRIP to promote cell cycle arrest in response to DNA damage. [Cancer Res 2007;67(14):6685–90]
Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose
Authors: Brown Karen , Tompkins Elaine M. , Boocock David J. , Martin Elizabeth A. , Farmer Peter B. , Turteltaub Kenneth W. , Ubick Esther , Hemingway David , Horner-Glister Emma , White Ian N.H.
Published: July 2007

Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14C]-labeled therapeutic (20 mg) dose, ∼18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N2-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/109 nucleotides. No [14C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to α-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifen-induced damage displayed a degree of interindividual variability, when present, it was ∼10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo[4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women. [Cancer Res 2007;67(14):6995–7002]
Body Mass Index and Prognosis in Patients With Chronic Heart Failure
Authors: Kenchaiah Satish , Pocock Stuart J. , Wang Duolao , Finn Peter V. , Zornoff Leonardo A.M. , Skali Hicham , Pfeffer Marc A. , Yusuf Salim , Swedberg Karl , Michelson Eric L. , Granger Christopher B. , McMurray John J.V. , Solomon Scott D.
Published: July 2007

Background—

In individuals without known cardiovascular disease, elevated body mass index (BMI) (weight/height
2
) is associated with an increased risk of death. However, in patients with certain specific chronic diseases, including heart failure, low BMI has been associated with increased mortality.

Methods and Results—

We examined the influence of BMI on prognosis using Cox proportional hazards models in 7599 patients (mean age, 65 years; 35% women) with symptomatic heart failure (New York Heart Association class II to IV) and a broad spectrum of left ventricular ejection fractions (mean, 39%) in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. During a median follow-up of 37.7 months, 1831 patients died. After adjustment for potential confounders, compared with patients with BMI between 30 and 34.9, patients in lower BMI categories had a graded increase in the risk of death. The hazard ratios (95% confidence intervals) were 1.22 (1.06 to 1.41), 1.46 (1.24 to 1.71), and 1.69 (1.43 to 2.01) among those with BMI of 25 to 29.9, 22.5 to 24.9, and <22.5, respectively. The increase in risk of death among patients with BMI ≥35 was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43). The association between BMI and mortality was not altered by age, smoking status, or left ventricular ejection fraction (
P
for interaction >0.20). However, lower BMI was associated with a greater risk of all-cause death in patients without edema but not in patients with edema (
P
for interaction <0.0001). Lower BMI was associated with a greater risk of cardiovascular death and noncardiovascular death. Baseline BMI did not influence the risk of hospitalization for worsening heart failure or due to all causes.

Conclusions—

In patients with symptomatic heart failure and either reduced or preserved left ventricular systolic function, underweight or low BMI was associated with increased mortality, primarily in patients without evidence of fluid overload (edema).
Resistance Exercise in Individuals With and Without Cardiovascular Disease: 2007 Update
Authors: Williams Mark A. , Haskell William L. , Ades Philip A. , Amsterdam Ezra A. , Bittner Vera , Franklin Barry A. , Gulanick Meg , Laing Susan T. , Stewart Kerry J.
Published: July 2007

Prescribed and supervised resistance training (RT) enhances muscular strength and endurance, functional capacity and independence, and quality of life while reducing disability in persons with and without cardiovascular disease. These benefits have made RT an accepted component of programs for health and fitness. The American Heart Association recommendations describing the rationale for participation in and considerations for prescribing RT were published in 2000. This update provides current information regarding the (1) health benefits of RT, (2) impact of RT on the cardiovascular system structure and function, (3) role of RT in modifying cardiovascular disease risk factors, (4) benefits in selected populations, (5) process of medical evaluation for participation in RT, and (6) prescriptive methods. The purpose of this update is to provide clinicians with recommendations to facilitate the use of this valuable modality.
Residential Exposure to Traffic Is Associated With Coronary Atherosclerosis
Authors: Hoffmann B. , Moebus S. , Möhlenkamp S. , Stang A. , Lehmann N. , Dragano N. , Schmermund A. , Memmesheimer M. , Mann K. , Erbel R. , Jöckel K.-H.
Published: July 2007

Background—

Long-term exposure to fine-particulate-matter (PM
2.5
) air pollution may accelerate the development and progression of atherosclerosis. We investigated the associations of long-term residential exposure to traffic and fine particulate matter with the degree of coronary atherosclerosis.

Methods and Results—

We used baseline data on 4494 participants (age 45 to 74 years) from the German Heinz Nixdorf Recall Study, a population-based, prospective cohort study that started in 2000. To assess exposure differences, distances between residences and major roads were calculated, and annual fine particulate matter concentrations, derived from a small-scale dispersion model, were assigned to each address. The main outcome was coronary artery calcification (CAC) assessed by electron-beam computed tomography. We evaluated the association between air pollution and CAC with logistic and linear regression analyses, controlling for individual level risk factors of coronary atherosclerosis. Compared with participants living >200 m away from a major road, participants living within 50, 51 to 100, and 101 to 200 m had odds ratios of 1.63 (95% CI, 1.14 to 2.33), 1.34 (95% CI, 1.00 to 1.79), and 1.08 (95% CI, 0.85 to 1.39), respectively, for a high CAC (CAC above the age- and gender-specific 75th percentile). A reduction in the distance between the residence and a major road by half was associated with a 7.0% (95% CI, 0.1 to 14.4) higher CAC. Fine particulate matter exposure was associated with CAC only in subjects who had not been working full-time for at least 5 years.

Conclusions—

Long-term residential exposure to high traffic is associated with the degree of coronary atherosclerosis.
Prostaglandin E2Induces Vascular Relaxation by E-Prostanoid 4 Receptor-Mediated Activation of Endothelial Nitric Oxide Synthase
Authors: Hristovska Ana-Marija , Rasmussen Lasse E. , Hansen Pernille B.L. , Nielsen Susan S. , Nüsing Rolf M. , Narumiya Shuh , Vanhoutte Paul , Skøtt Ole , Jensen Boye L.
Published: July 2007

The present experiments were designed to test the hypothesis that prostaglandin (PG) E2causes vasodilatation through activation of endothelial NO synthase (eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE2were measured in conscious mice. Single doses of PGE2caused concentration-dependent relaxations during contractions to phenylephrine (EC50=5*10−8mol/L). Relaxation after PGE2was absent in rings without endothelium and in rings from eNOS−/−mice and was abolished byNG-nitro-l-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H1,2,4-oxadiazolo-[4,3-a]quinoxalin-1-one. In PGE2-relaxed aortic rings, the cGMP content increased significantly. PGE2-induced relaxations were abolished by the EP4 receptor antagonist AE3–208 (10−8mol/L) and mimicked by an EP4 agonist (AE1–329, 10−7mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4−/−mice but normal in EP2−/−. Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10−8mol/L), abolished the PGE2-mediated relaxation. In aortic rings, PGE2dephosphorylated eNOS at Thr495. Chronically catheterized eNOS−/−mice were hypertensive (137±3.6 mm Hg, n=13, versus 101±3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE2compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE2elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr495resulting in guanylyl cyclase–dependent vasorelaxation and accumulation of cGMP in aortic rings.
Genome-Wide Scans Meta-Analysis for Pulse Pressure
Authors: Zintzaras Elias , Kitsios Georgios , Kent David , Camp Nicola J. , Atwood Larry , Hopkins Paul N. , Hunt Steven C.
Published: July 2007

Genome scans for identifying susceptibility loci for pulse pressure have produced inconclusive results. A heterogeneity-based genome search meta-analysis was applied to available genome-scan data on pulse pressure. A genome search meta-analysis divides the whole genome into 120 bins and identifies bins that rank high on average in terms of linkage statistics across genome scans unweighted or weighted by study size. The significance of each bin’s average rank (right-sided test) and heterogeneity among studies (left-sided test) was calculated using a Monte Carlo test. The meta-analysis involved 7 genome scans, 3 consisting of subjects of European descent. Of the 120 bins, 5 bins had significant average rank (
P
rank
≤0.05) by either unweighted or weighted analyses, 4 of which (bins 21.2: 21q22.11 to 21q22.3, 18.3: 18q12.2 to 18q21.33, 18.4: 18q21.33 to 18q23, and 6.2: 6p22.3 to 6p21.1) were significant by both. In subjects of European descent, 3 bins (22.1: 22q11.1 to 22q12.3, 22.2: 22q12.3 to 22q13.3, 10.4: 10q22.1 to 10q23.32) had
P
rank
≤0.05 with both unweighted and weighted analyses. Bin 10.4 showed low heterogeneity (
P
Q
=0.04). None of the bins showed low heterogeneity (
P
Q
>0.05), indicating variation in the strength of association. Further investigation of these regions may help to direct the identification of candidate genes for pulse pressure variation.
Relation of Left Ventricular Hypertrophy With Systemic Inflammation and Endothelial Damage in Resistant Hypertension
Authors: Salles Gil F. , Fiszman Roberto , Cardoso Claudia R.L. , Muxfeldt Elizabeth S.
Published: July 2007

The relation between left ventricular hypertrophy (LVH) and unfavorable cardiovascular prognosis may involve systemic inflammation and endothelial dysfunction/damage. The aim of this study was to investigate in a cross-sectional design the relationships of LVH with C-reactive protein (CRP) levels (a marker of systemic low-grade inflammation) and with microalbuminuria (a marker of glomerular endothelial damage) in 705 patients with resistant hypertension. At baseline, all were submitted to a laboratory evaluation including 24-hour urinary albumin excretion, 2D echocardiogram, and 24-hour ambulatory blood pressure monitoring. A total of 463 patients also had high-sensitivity CRP levels determined. LVH was defined as an indexed left ventricular mass >110 g/m
2
in women and >125 g/m
2
in men. Microalbuminuria was evaluated in 3 categories: low normal (<15 mg/24 hours), high normal (between 15 and 29 mg/24 hours), and abnormal (between 30 and 299 mg/24 hours). CRP was dichotomized at the median value (3.7 mg/L). Associations with LVH were examined after adjustment for all of the potential confounders by multivariate logistic regression. A total of 534 patients (75.7%) had LVH. After full adjustment, both abnormal microalbuminuria (odds ratio: 1.97; 95% CI: 1.04 to 3.73) and high CRP (OR: 1.76; 95% CI: 1.06 to 2.93) were independently associated with LVH occurrence. The high-normal albuminuria was associated with a borderline significant 46% increased chance of having LVH. Furthermore, the association between high CRP and LVH was observed exclusively in the subgroup with normal albuminuria. In conclusion, both systemic inflammation and endothelial damage were associated with LVH occurrence. These relationships offer insight into the pathophysiological mechanisms linking LVH to atherosclerosis and to increased cardiovascular morbidity and mortality.
Nerve Regeneration after Radiofrequency Application
Authors: Ochiai Nobuyasu , Tasto James P. , Ohtori Seiji , Takahashi Norimasa , Moriya Hideshige , Amiel David
Published: July 2007

Background

Many patients with chronic tendinosis have experienced early pain relief after application of bipolar radiofrequency treatment. It is hypothesized that the mechanism of action may be the acute degeneration and/or ablation of sensory nerve fibers.

Hypothesis

After ablation or degeneration by bipolar radiofrequency, nerve fibers will have the ability to regenerate with time.

Study Design

Controlled laboratory study.

Methods

Eighteen Sprague-Dawley rats were used in this study. These rats were divided into 3 groups (30, 60, and 90 days after bipolar radiofrequency). These rats were treated with 2 points of bipolar radiofrequency applications to the left hindpaws with the Topaz microdebrider device. Right hindpaws were used as the contralateral control. Tissues were processed for neural class III β-tubulin or calcitonin gene-related peptide immunohistochemistry by using the free-floating avidin biotin complex technique. The numbers of neural class III β-tubulin—immunoreactive and calcitonin gene-related peptide-immunoreactive nerve fibers in the epidermis were counted and compared with those in the contralateral control.

Results

Although the numbers of nerve fibers demonstrated by both the antibodies of neural class III β-tubulin and calcitonin gene-related peptide were significantly decreased (P < .0001) until 60 days after bipolar radiofrequency treatment, regeneration of the epidermal nerve fibers occurred 90 days after treatment.

Conclusion

Bipolar radiofrequency treatment induced degeneration of sensory nerve fibers immediately after treatment, but by 90 days posttreatment, there was evidence of complete regeneration.

Clinical Relevance

Early degeneration followed by later regeneration of nerve fibers after bipolar radiofrequency treatment may explain long-term postoperative pain relief after microtenotomy for tendinosis.
Square Pegs in Round Holes
Authors: Phaneuf Marie-Rose , Lomas Jonathan , McCutcheon Chris , Church John , Wilson Douglas
Published: July 2007

In May 2003 all university faculties of medicine, health sciences, nursing, business, and public administration in Canada were surveyed to document whether their promotion practices gave equal treatment to researchers with traditional disciplinary-based scholarly outputs versus those with nontraditional outputs flowing from an applied interest in interdisciplinary research, collaboration with nonacademics, and knowledge transfer. Forty-seven deans (response rate = 67 percent) and thirty-two promotion committee members (response rate = 51 percent) consistently rated research as more important than teaching and community service in promotion proceedings. Furthermore, in their considerations of research they accorded significantly more value in promotion to traditional than to nontraditional scholarly outputs. Among the deans, for example, the top ten ranked activities included seven traditional research outputs, two teaching-related outputs, and only one nontraditional research output. Scholars with nontraditional outputs were slightly less disadvantaged in health-related faculties compared to the nonhealth faculties. Despite broader acceptance of an evolving research landscape in Canadian universities, current reward structures may create barriers for academics interested in conducting nontraditional research characteristic of the emerging paradigm of applied scholarship.
Telling the Columbia Story
Authors: Sumpter Randall S. , Garner Johny T.
Published: July 2007

This content analysis of newspaper stories seeks to answer three questions about the Columbia space shuttle disaster: What sources did journalists cite in telling the Columbia story? What did those sources say? Which sources were heard most often? Stories analyzed were published by the New York Times, Washington Post, and Houston Chronicle in the 217-day period following the accident. News reporters most frequently used elected and appointed government leaders and NASA administrators, engineers, and other agency employees as sources. Those sources most often communicated “neutral” facts and observations while not placing blame for the accident or evaluating the shuttle program's progress. Astronauts and their relatives, NASA contractors who built and maintained the shuttle fleet, and government accident investigators from agencies other than NASA or the Columbia Accident Investigation Board rarely appeared in the stories. Journalistic routines call for reporters to balance their story narratives with sources representing different viewpoints. In the Columbia story, however, this was not necessarily the case.
The Impact of Risk Communication on the Acceptance of Irradiated Food
Authors: Rodriguez Lulu
Published: July 2007

This study uses a quasi-experimental design to assess the impact of pro- and anti-food irradiation messages on consumer opinions. The data came from a panel study of 223 adults in Minneapolis, Minnesota, who completed three successive questionnaires. One group received a packet of information materials; another did not. Packet recipients perceived irradiation to be less safe and held less favorable opinions about the protagonists in the irradiation debate. Opinions changed over three months, although the changes were not statistically significant. Those who did not receive the packet showed significantly more favorable opinions of food irradiation opponents.
Evaluation of Off-Label Recombinant Activated Factor VII for Multiple Indications in Children
Authors: Reiter Pamela D. , Valuck Robert J. , Taylor Ruston S.
Published: July 2007

Despite a paucity of safety and efficacy data, the use of recombinant activated factor VII in children for off-label indications has now surpassed its use in hemophilia. A retrospective chart review was conducted of 46 subjects (age, 6.7 ± 6 years; weight, 26 ± 20 kg) who received recombinant activated factor VII for nonhemophiliac indications between January 1, 2004, and September 1, 2005. Indications for use included prevention (n = 6) or treatment (n = 40) of bleeding due to general surgery, hepatic failure, gastrointestinal bleeding, severe traumatic brain injury, bone marrow transplant, cardiac, acetaminophen overdose, and multiorgan system failure. Decreases in prothrombin time, partial thromboplastin time, and international normalized ratio were observed. No inappropriate thrombotic events were noted. Administration of recombinant activated factor VII was associated with a reduction in coagulation markers without obvious adverse thrombotic events at cost of $4189 per dose. These findings should be confirmed in a prospective trial.
Singlet Oxygen Potentiates Thrombolysis
Authors: Stief Thomas W.
Published: July 2007

Activated polymorphonuclear neutrophils (PMN) participate in physiologic thrombolysis. PMN produce large amounts of urokinase (u-PA) and oxidants of the hypochlorite/chloramine-type that generate nonradical excited singlet oxygen (1O2). The u-PA/1O2—mediated thrombolysis was imitated in vitro. One hundred microliters microclots of normal human plasma were oxidized with 25 μL 0 to 5.0 μmoles of chloramine-T in physiol. NaCl in the absence or presence of 100 μL 6% bovine serum albumin or 100 μL normal plasma. Twenty-five microliters 0 to 167 IU/mL (related to 150 μL added supernatant) u-PA or 0 to 2.08 μg/mL t-PA were added. The absorbance at 405 nm was determined after 0 to 27 hours (37°C). The specific clot turbidity was calculated, subtracting the 100% lysis absorbance from the respective measured absorbance. The chloramine-effective dose 50% (ED50) after 27 hours was determined in the presence of 2.6 IU/mL u-PA. The plasminogen activator-ED25 was determined after 2 hours (37°C), and the ET25; i.e., the time needed to lyse a microclot by 25%, was determined for each respective clot-oxidation. The ED25 of u-PA depends on the oxidation of the microclots: 1.25 μmoles chloramine/100 μL clot enhances thrombolysis approximately 20-fold; here, 25% of clot lysis is achieved within 50 minutes (using approximately 20 IU/mL u-PA), whereas approximately 5 hours are needed to lyse an unoxidized microclot by 25%. The present global assay technique imitates the u-PA/1O2 aspects of physiologic thrombolysis by PMN.
Preliminary Study Showing the Relationship Between Platelet Fibronectin, Sialic Acid, and ADP-induced Aggregation Levels in Coronary Heart Disease
Authors: Bütün Ilknur I. , Ekmekçi Hakan , Sönmez Hüseyin , Gürel Çiğdem , Çiftçi Özlem , Ulutin Turgut , Kökoğlu Emine , Domaniç Nergiz , Dirican Ahmet
Published: July 2007

Several studies indicate that thrombosis plays an important role in the pathogenesis of coronary heart disease (CHD). Fibronectin is a multifunctional protein in plasma, other body fluids, and cell surface and plays an important role in platelet functions, including mediation of cell-cell and cell-surface interactions. Sialic acid is a regular constituent of glycoproteins and gangliozides in the outer cell membrane of mammalian cells. Therefore, the sialic acid content of platelets, which are characterized by their ability to aggregate with each other, can be important in leading to thrombus formation. In this study, platelet fibronectin, sialic acid-, and adenosine diphosphate (ADP)-induced platelet aggregation levels were determined in patients with CHD. Platelet sialic acid concentrations were determined by Warren's method. Platelet aggregation tests with ADP in platelet-rich plasma (PRP) were analyzed by use of an aggregometer. Platelet homogenate fibronectin levels were determined by ELISA. Total protein levels were determined by Lowry method. Our results indicate that, in patients with no vessel disease (patients with no obstructed vessel but suffering from chest pain, like angina pectoris) platelet fibronectin levels were significantly lower than the total of the other patients (patients with 1, 2, or 3 obstructed coronary vessels) (p<0.05). Sialic acid levels in patients with no vessel disease were significantly lower than the total of the patient group (p<0.05). There was significant (+) correlation between platelet aggregation, platelet fibronectin, platelet sialic acid, and severity of disease (p<0.05). Our preliminary findings suggest that, especially platelet fibronectin levels potentially represent a pathogenic factor for CHD.
Disseminated Intravascular Coagulation in Acute Leukemia at Presentation and During Induction Therapy
Authors: Dixit Ashish , Chatterjee Tathagat , Mishra Pravas , Kannan Meganathan , Choudhry Dharma R. , Mahapatra Manoranjan , Choudhry V.P. , Saxena Renu
Published: July 2007

Between January 2001 and December 2003, 67 patients with acute leukemia were evaluated prospectively for hemostatic abnormality at presentation, of which 43 (64.2%) had acute lymphoblastic leukemia and 24 (35.8%) had acute myelogenous leukemia. At presentation, 27 patients (40.3%) had bleeding manifestations. Thrombocytopenia was present in 57 patients (85%), and 33(49.3%) had some abnormality of global coagulation markers. Disseminated intravascular coagulation was defined by International Society of Thrombosis and Hemostasis criteria. Disseminated intravascular coagulation was more often associated with bleeding manifestations in acute myelogenous leukemia cases than in acute lymphoblastic leukemia cases. Two patients presented disseminated intravascular coagulation on day 7 of chemotherapy, without any bleeding manifestations. Four of 15 evaluated cases who had a bleeding or infection complication after day 7 of induction therapy also had disseminated intravascular coagulation. It is recommended that all patients with leukemia be investigated for disseminated intravascular coagulation at presentation.
Ximelagatran for Treatment and Prophylaxis of Recurrent Events in Deep Vein Thrombosis
Authors: Koscielny J. , Kiesewetter H. , Jörg I. , Harenberg J.
Published: July 2007

The treatment of acute venous thromboembolism and prophylaxis of recurrent events with heparin/low molecular weight heparin followed by vitamin K antagonists is limited by several factors. Oral direct thrombin inhibitors (ODTIs) showed a better pharmacological activity and might be an alternative in the treatment of venous thromboembolism. The Thrombin Inhibition in Venous Thromboembolism (THRIVE) program performed some studies developing the ODTI ximelagatran for this indication, and it is presented in the overview. The aim of the THRIVE I study was the dose finding, and that of the THRIVE IV study the applicability in hemodynamic stabile pulmonary embolism. A prospective, randomized, double blind trial was performed to compare oral ximelagatran with enoxaparin/warfarin for a 6-month treatment of acute venous thrombosis (THRIVE II and V). A second double blind study compared ximelagatran with placebo over 18 months after a 6-month anticoagulant therapy of acute deep vein thrombosis. The efficacy and safety of treatment of patients with acute deep venous thrombosis who received 2 ∞ 36 mg ximelagatran was not inferior to that of patients who received a conventional anticoagulant for prophylaxis of recurrent events over 6 months. Ximelagatran 2 ∞ 24 mg significantly reduced recurrent thromboembolic events compared to placebo without increasing the risk for hemorrhage. A reversible symptomless increase of alanine aminotransferase occurs in 6% to 9.6% of patients between months 2 and 4. The results of the follow-up studies suggest that thromboembolic events may recur in patients with acute venous thromboembolism after termination of treatment with both vitamin K antagonists and ximelagatran.
Administration of Recombinant Activated Factor VII (NovoSeven) in Three Cases of Uncontrolled Bleeding Caused by Disseminated Intravascular Coagulopathy
Authors: Schmid Stefan , Friesenecker Barbara , Lorenz Ingo , Innerhofer Petra , Koscielny Jürgen , Velik-Salchner Corinna , Mutz Norbert , Fries Dietmar
Published: July 2007

Recombinant activated factor VII has been used successfully in many cases of traumatic and surgical bleeding complications that were unresponsive to standard treatment. However, because disseminated intravascular coagulation can develop from a thrombin burst as a side effect of recombinant activated factor VII, it is not yet established for bleeding complications induced by disseminated intravascular coagulation. This article presents 3 patients with severe sepsis and fulminant disseminated intravascular coagulation. Excessive microvascular bleeding persisted despite conventional therapy, and surgical intervention and radiologic embolization did not control bleeding. After administration of recombinant activated factor VII, bleeding ceased in all patients, and no overt thromboembolic events occurred. One patient survived to be discharged from the hospital. The other 2 patients died from refractory multiorgan failure and overall poor prognosis. Recombinant factor VIIa might be an option for the treatment of severe bleeding complications in the case of DIC refractory to the conventional therapy.
Prophylaxis of Venous Thromboembolism in Minor Orthopedic Surgery With Parnaparin
Authors: Montebugnoli Milena , Bugamelli Stefano , Calo Piero , Zangheri Elena , Ferrari Patrizio
Published: July 2007

This study analyzed the efficacy of venous thromboembolism prophylaxis in knee arthroscopy in 509 patients who received Parnaparin (Alfa Wassermann, Bologna, Italy), 3200 IU to 4250 IU daily, after minor arthroscopic knee surgery. No proximal deep venous thrombosis or other thromboembolic events occurred. Adverse events related to the treatment with Parnaparin were observed in 2 of 172 patients treated with 3200 IU/d and in 6 of 337 patients treated with 4250 IU/d, without any evidence of dose-proportionality in the incidence. Prophylaxis with a low-molecular-weight heparin such as Parnaparin should be considered in all patients who will be undergoing a procedure in which a tourniquet is used. If Parnaparin is used, it should be started immediately after knee arthroscopy at doses of 3200 to 4250 IU/d, according to the characteristics of the patients. Depending on the patient's risk factors, postoperative prophylaxis for 10 days may be appropriate.
State of the Art Reviews: Health Benefits Related to Exercise in Patients With Chronic Low-Grade Systemic Inflammation
Authors: Pedersen Bente Klarlund
Published: July 2007

Today, there is substantial evidence to suggest that regular exercise has health-promoting effects, which are beyond its effect on weight control. Regular exercise offers protection against all-cause mortality, and there is evidence from randomized intervention studies that physical training is effective as a treatment in patients with chronic heart diseases, type 2 diabetes, and symptoms related with the metabolic syndrome. Chronic diseases such as cardiovascular disease and type 2 diabetes are associated with chronic low-grade systemic inflammation. This review focuses on the anti-inflammatory effects of exercise that are mediated by muscle-derived cytokines (myokines). It is suggested that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation.
State of the Art Reviews: Effects of Obesity on Cardiac Function in Adolescent Females
Authors: Rowland Thomas W. , Dunbar Nancy S.
Published: July 2007

Cardiomyopathy of obesity in adults is characterized by augmented cardiac output but diminished myocardial performance. This study of healthy adolescent females (mean age 13.7 ± 1.9 years) with a wide range of body fat content was designed to assess evidence of cardiomyopathy in obese youth. Thirteen adolescent females with morbid obesity (body mass index >40 kg m—2) underwent evaluation of resting cardiac size and function as well as cardiac functional reserve during a maximal cycle exercise test. Data were combined with that previously published from this laboratory of nonobese and moderately obese teenage girls and then correlated with body mass index as a marker of obesity. At rest, heart size, stroke volume, and cardiac output were directly related to degree of obesity, whereas a negative correlation was observed between ventricular shortening fraction and body mass index (r = -0.47, P < .01). However, no impairment was observed in cardiac functional reserve with exercise. Maximal cardiac output and stroke volume were directly related to body mass index, but no effect of obesity was seen when values were related to body surface area. Subclinical evidence of diminished myocardial contractility was observed in obese adolescent girls, although no negative effect was seen on cardiac responses to exercise.
Behavioral Medicine Review: The Dialectic of Tradition and Progress in Osteoarthritis Management
Authors: Terre Lisa
Published: July 2007

In his state of the art review, Katz provided an evidence-based perspective on nonpharmacologic approaches to osteoarthritis. His overview prompts discussion of the tradition-progress dialectic that has punctuated this area as exemplified, on one hand, by continuing tendencies to privilege biomedical over biopsychosocial conceptualizations and persisting barriers to the widespread implementation of nonpharmacologic, best-evidence treatments in primary care. On the other hand, the field has been sparked by considerable innovation, including the bursting of traditional treatment boundaries, an expanding range of intervention strategies, and the emergence of promising trends that may unleash further advances in patient care.
Nutrition Review: Diet, Nutrition, and Osteoarthritis
Authors: Melanson Kathleen J.
Published: July 2007

Despite abundant lay claims regarding diet, nutrients, and osteoarthritis (OA), scientific study on these relationships is in its early stages. The strongest risk factor for OA, particularly of the knee, is overweight and obesity. Initial weight loss studies for the treatment of OA have shown promising results, but longer-term trials are needed. Potential roles of specific nutrients in OA prevention and treatment are under study, but to date, results are somewhat less clear. The ratio of dietary omega-6 to omega-3 fatty acids has been proposed to be related to OA because they are precursors of proinflammatory and anti-inflammatory eicosanoids and cytokines, respectively. However, human data are lacking to substantiate this relationship. Low serum levels of some vitamins, such as C and D, have been associated with OA in epidemiological research, but much more work must be conducted to understand the roles of these and other vitamins in OA prevention and treatment. Biological plausibility exists for the protective properties of antioxidants against OA, so continued research to assist in making specific dietary recommendations with respect to these is needed for OA patients. As the study of diet, nutrients, and OA evolves, it is prudent for practitioners to stay abreast of the research so that they can address patients' questions and recommend diets with adequate omega-3 fatty acids, vitamins, minerals, and antioxidants while avoiding megadoses.
Pharmacy Review: Osteoarthritis: The Pharmacist's Perspective
Authors: Prevost Rebecca
Published: July 2007

A wide variety of treatment options are available for osteoarthritis pain relief. The pharmacist can serve as a source of information within his or her area of expertise, addressing controversies such as nonsteroidal antiinflammatory drugs versus acetaminophen, glucosamine-chondroitin, topical therapies, and herbals. Patients should be encouraged to use pain scales and diaries as they try different therapies.
Signaling through CD43 regulates CD4 T-cell trafficking
Authors: Mody Purvi D. , Cannon Judy L. , Bandukwala Hozefa S. , Blaine Kelly M. , Schilling Alexander B. , Swier Kevin , Sperling Anne I.
Published: July 2007

The mucin-like protein CD43 is excluded from the immune synapse, and regulates T-cell proliferation as well as T-cell migration. While the CD43 cytoplasmic domain is necessary for regulation of T-cell activation and proliferation, the mechanism via which CD43 regulates trafficking is not well defined. To investigate whether CD43 phosphorylation regulates its function in T cells, we used tandem mass spectrometry and identified Ser76 in murine CD43 as a previously unidentified site of basal phosphorylation. Interestingly, mutation of this single serine to alanine greatly diminishes T-cell trafficking to the lymph node, while CD43 exclusion and CD43-mediated regulation of T-cell proliferation remain intact. Furthermore, the CD43 extracellular domain was also required for T-cell trafficking, providing a hitherto unknown function for the extracellular domain, and suggesting that the extracellular domain may be required to transduce signals via the cytoplasmic domain. These data reveal a novel mechanism by which CD43 regulates T-cell function, and suggest that CD43 functions as a signaling molecule, sensing extracellular cues and transducing intracellular signals that modulate T-cell function.
Pbx homeodomain proteins pattern both the zebrafish retina and tectum
Authors: French Curtis R , Erickson Timothy , Callander Davon , Berry Karyn M , Koss Ron , Hagey Daniel W , Stout Jennifer , Wuennenberg-Stapleton Katrin , Ngai John , Moens Cecilia B , Waskiewicz Andrew J
Published: July 2007

Background

Pbx genes encode TALE class homeodomain transcription factors that pattern the developing neural tube, pancreas, and blood. Within the hindbrain, Pbx cooperates with Hox proteins to regulate rhombomere segment identity. Pbx cooperates with Eng to regulate midbrain-hindbrain boundary maintenance, and with MyoD to control fast muscle cell differentiation. Although previous results have demonstrated that Pbx is required for proper eye size, functions in regulating retinal cell identity and patterning have not yet been examined.

Results

Analysis of retinal ganglion cell axon pathfinding and outgrowth in pbx2/4 null embryos demonstrated a key role for pbx genes in regulating neural cell behavior. To identify Pbx-dependent genes involved in regulating retino-tectal pathfinding, we conducted a microarray screen for Pbx-dependent transcripts in zebrafish, and detected genes that are specifically expressed in the eye and tectum. A subset of Pbx-dependent retinal transcripts delineate specific domains in the dorso-temporal lobe of the developing retina. Furthermore, we determined that some Pbx-dependent transcripts also require Meis1 and Gdf6a function. Since gdf6a expression is also dependent on Pbx, we propose a model in which Pbx proteins regulate expression of the growth factor gdf6a, which in turn regulates patterning of the dorso-temporal lobe of the retina. This, in concert with aberrant tectal patterning in pbx2/4 null embryos, may lead to the observed defects in RGC outgrowth.

Conclusion

These data define a novel role for Pbx in patterning the vertebrate retina and tectum in a manner required for proper retinal ganglion cell axon outgrowth.
Genotypic variation in genome-wide transcription profiles induced by insect feeding: Brassica oleracea – Pieris rapae interactions
Authors: Broekgaarden Colette , Poelman Erik H , Steenhuis Greet , Voorrips Roeland E , Dicke Marcel , Vosman Ben
Published: July 2007

Background

Transcriptional profiling after herbivore attack reveals, at the molecular level, how plants respond to this type of biotic stress. Comparing herbivore-induced transcriptional responses of plants with different phenotypes provides insight into plant defense mechanisms. Here, we compare the global gene expression patterns induced by Pieris rapae caterpillar attack in two white cabbage (Brassica oleracea var. capitata) cultivars. The two cultivars are shown to differ in their level of direct defense against caterpillar feeding. Because Brassica full genome microarrays are not yet available, 70-mer oligonucleotide microarrays based on the Arabidopsis thaliana genome were used for this non-model plant.

Results

The transcriptional responses of the two cultivars differed in timing as characterized by changes in their expression pattern after 24, 48 and 72 hours of caterpillar feeding. In addition, they also differed qualitatively. Surprisingly, of all genes induced at any time point, only one third was induced in both cultivars. Analyses of transcriptional responses after jasmonate treatment revealed that the difference in timing did not hold for the response to this phytohormone. Additionally, comparisons between Pieris rapae- and jasmonate-induced transcriptional responses showed that Pieris rapae induced more jasmonate-independent than jasmonate-dependent genes.

Conclusion

The present study clearly shows that global transcriptional responses in two cultivars of the same plant species in response to insect feeding can differ dramatically. Several of these differences involve genes that are known to have an impact on Pieris rapae performance and probably underlie different mechanisms of direct defense, present in the cultivars.