bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors
Authors: Zelcer Noam , Khanlou Negar , Clare Ryan , Jiang Qingguang , Reed-Geaghan Erin G. , Landreth Gary E. , Vinters Harry V. , Tontonoz Peter
Published: June 2007

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either
Lxr
α or
Lxr
β in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid β peptide (fAβ) in a receptor-dependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fAβ-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.
The effect of geographic range on extinction risk during background and mass extinction
Authors: Payne Jonathan L. , Finnegan Seth
Published: June 2007

Wide geographic range is generally thought to buffer taxa against extinction, but the strength of this effect has not been investigated for the great majority of the fossil record. Although the majority of genus extinctions have occurred between major mass extinctions, little is known about extinction selectivity regimes during these “background” intervals. Consequently, the question of whether selectivity regimes differ between background and mass extinctions is largely unresolved. Using logistic regression, we evaluated the selectivity of genus survivorship with respect to geographic range by using a global database of fossil benthic marine invertebrates spanning the Cambrian through the Neogene periods, an interval of ≈500 My. Our results show that wide geographic range has been significantly and positively associated with survivorship for the great majority of Phanerozoic time. Moreover, the significant association between geographic range and survivorship remains after controlling for differences in species richness and abundance among genera. However, mass extinctions and several second-order extinction events exhibit less geographic range selectivity than predicted by range alone. Widespread environmental disturbance can explain the reduced association between geographic range and extinction risk by simultaneously affecting genera with similar ecological and physiological characteristics on global scales. Although factors other than geographic range have certainly affected extinction risk during many intervals, geographic range is likely the most consistently significant predictor of extinction risk in the marine fossil record.
Proteome-wide identification of
in vivo
targets of DNA damage checkpoint kinases
Authors: Smolka Marcus B. , Albuquerque Claudio P. , Chen Sheng-hong , Zhou Huilin
Published: June 2007

Understanding the role of DNA damage checkpoint kinases in the cellular response to genotoxic stress requires the knowledge of their substrates. Here, we report the use of quantitative phosphoproteomics to identify
in vivo
kinase substrates of the yeast DNA damage checkpoint kinases Mec1, Tel1, and Rad53 (orthologs of human ATR, ATM, and CHK2, respectively). By analyzing 2,689 phosphorylation sites in wild-type and various kinase-null cells, 62 phosphorylation sites from 55 proteins were found to be controlled by the DNA damage checkpoint. Examination of the dependency of each phosphorylation on Mec1 and Tel1 or Rad53, combined with sequence and biochemical analysis, revealed that many of the identified targets are likely direct substrates of these kinases. In addition to several known targets, 50 previously undescribed targets of the DNA damage checkpoint were identified, suggesting that a wide range of cellular processes is likely regulated by Mec1, Tel1, and Rad53.
Werner syndrome protein interacts functionally with translesion DNA polymerases
Authors: Kamath-Loeb Ashwini S. , Lan Li , Nakajima Satoshi , Yasui Akira , Loeb Lawrence A.
Published: June 2007

Werner syndrome (WS) is characterized by premature onset of age-associated disorders and predisposition to cancer. The WS protein, WRN, encodes 3′ → 5′ DNA helicase and 3′ → 5′ DNA exonuclease activities, and is implicated in the maintenance of genomic stability. Translesion (TLS) DNA polymerases (Pols) insert nucleotides opposite replication-blocking DNA lesions and presumably prevent replication fork stalling/collapse. Here, we present
in vitro
and
in vivo
data that demonstrate functional interaction between WRN and the TLS Pols, Polη, Polκ, and Polι.
In vitro
, WRN stimulates the extension activity of TLS Pols on lesion-free and lesion-containing DNA templates, and alleviates pausing at stalling lesions. Stimulation is mediated through an increase in the apparent
V
max
of the polymerization reaction. Notably, by accelerating the rate of nucleotide incorporation, WRN increases mutagenesis by Polη.
In vivo
, WRN and Polη colocalize at replication-dependent foci in response to UVC irradiation. The functional interaction between WRN and TLS Pols may promote replication fork progression, at the expense of increased mutagenesis, and obviate the need to resolve stalled/collapsed forks by processes involving chromosomal rearrangements.
Control of hypothalamic orexin neurons by acid and CO
2
Authors: Williams Rhîannan H. , Jensen Lise T. , Verkhratsky Alex , Fugger Lars , Burdakov Denis
Published: June 2007

Hypothalamic orexin/hypocretin neurons recently emerged as key orchestrators of brain states and adaptive behaviors. They are critical for normal stimulation of wakefulness and breathing: Orexin loss causes narcolepsy and compromises vital ventilatory adaptations. However, it is unclear how orexin neurons generate appropriate adjustments in their activity during changes in physiological circumstances. Extracellular levels of acid and CO
2
are fundamental physicochemical signals controlling wakefulness and breathing, but their effects on the firing of orexin neurons are unknown. Here we show that the spontaneous firing rate of identified orexin neurons is profoundly affected by physiological fluctuations in ambient levels of H
+
and CO
2
. These responses resemble those of known chemosensory neurons both qualitatively (acidification is excitatory, alkalinization is inhibitory) and quantitatively (≈100% change in firing rate per 0.1 unit change in pH
e
). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pH
e
: Acidification increases intrinsic excitability, whereas alkalinization depresses it. The effects of pH
e
involve acid-induced closure of leak-like K
+
channels in the orexin cell membrane. These results suggest a new mechanism of how orexin/hypocretin networks generate homeostatically appropriate firing patterns.
Impaired dopamine release and synaptic plasticity in the striatum of
PINK1
-deficient mice
Authors: Kitada Tohru , Pisani Antonio , Porter Douglas R. , Yamaguchi Hiroo , Tscherter Anne , Martella Giuseppina , Bonsi Paola , Zhang Chen , Pothos Emmanuel N. , Shen Jie
Published: June 2007

Parkinson's disease (PD) is characterized by the selective vulnerability of the nigrostriatal dopaminergic circuit. Recently, loss-of-function mutations in the
PTEN-induced kinase 1
(
PINK1
) gene have been linked to early-onset PD. How PINK1 deficiency causes dopaminergic dysfunction and degeneration in PD patients is unknown. Here, we investigate the physiological role of PINK1 in the nigrostriatal dopaminergic circuit through the generation and multidisciplinary analysis of
PINK1
−/−
mutant mice. We found that numbers of dopaminergic neurons and levels of striatal dopamine (DA) and DA receptors are unchanged in
PINK1
−/−
mice. Amperometric recordings, however, revealed decreases in evoked DA release in striatal slices and reductions in the quantal size and release frequency of catecholamine in dissociated chromaffin cells. Intracellular recordings of striatal medium spiny neurons, the major dopaminergic target, showed specific impairments of corticostriatal long-term potentiation and long-term depression in
PINK1
−/−
mice. Consistent with a decrease in evoked DA release, these striatal plasticity impairments could be rescued by either DA receptor agonists or agents that increase DA release, such as amphetamine or
l
-dopa. These results reveal a critical role for PINK1 in DA release and striatal synaptic plasticity in the nigrostriatal circuit and suggest that altered dopaminergic physiology may be a pathogenic precursor to nigrostriatal degeneration.
Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor
Authors: Tansky Morris F. , Pothoulakis Charalabos , Leeman Susan E.
Published: June 2007

The neurokinin 1 receptor (NK1R), a G protein-coupled receptor involved in diverse functions including pain and inflammation, has two putative N-linked glycosylation sites, Asn-14 and Asn-18. We studied the role of N-linked glycosylation in the functioning of the NK1R by constructing three receptor mutants: two single mutants (Asn → Gln-14 and Asn → Gln-18) and a double mutant, lacking both glycosylation sites. Using a lentiviral transfection system, the mutants were stably transfected into NCM 460 cells, a nontransformed human colonic epithelial cell line. We observed that the magnitude of glycosylation as estimated by changes in gel migration depends on the number of glycosylation sites available, with the wild-type receptor containing the greatest amount of glycosylation. All mutant receptors were able to bind to substance P and neurokinin A ligand with similar affinities; however, the double mutant, nonglycosylated NK1R showed only half the
B
max
of the wild-type NK1R. In terms of receptor function, the ablation of both N-linked glycosylation sites did not have a profound effect on the receptors' abilities to activate the MAP kinase families (p42/p44, JNK, and p38), but did affect SP-induced IL-8 secretion. All mutants were able to internalize, but the kinetics of internalization of the double mutant receptor was more rapid, when compared with wild-type NK1R. Therefore, glycosylation of NK1R may stabilize the receptor in the plasma membrane. These results contribute to the ongoing elucidation of the role of glycosylation in G protein-coupled receptors and the study of the neurokinin receptors in particular.
Structure of CD84 provides insight into SLAM family function
Authors: Yan Qingrong , Malashkevich Vladimir N. , Fedorov Alexander , Fedorov Elena , Cao Erhu , Lary Jeffrey W. , Cole James L. , Nathenson Stanley G. , Almo Steven C.
Published: June 2007

The signaling lymphocyte activation molecule (SLAM) family includes homophilic and heterophilic receptors that modulate both adaptive and innate immune responses. These receptors share a common ectodomain organization: a membrane-proximal immunoglobulin constant domain and a membrane-distal immunoglobulin variable domain that is responsible for ligand recognition. CD84 is a homophilic family member that enhances IFN-γ secretion in activated T cells. Our solution studies revealed that CD84 strongly self-associates with aKdin the submicromolar range. These data, in combination with previous reports, demonstrate that the SLAM family homophilic affinities span at least three orders of magnitude and suggest that differences in the affinities may contribute to the distinct signaling behavior exhibited by the individual family members. The 2.0 Å crystal structure of the human CD84 immunoglobulin variable domain revealed an orthogonal homophilic dimer with high similarity to the recently reported homophilic dimer of the SLAM family member NTB-A. Structural and chemical differences in the homophilic interfaces provide a mechanism to prevent the formation of undesired heterodimers among the SLAM family homophilic receptors. These structural data also suggest that, like NTB-A, all SLAM family homophilic dimers adopt a highly kinked organization spanning an end-to-end distance of ≈140 Å. This common molecular dimension provides an opportunity for all two-domain SLAM family receptors to colocalize within the immunological synapse and bridge the T cell and antigen-presenting cell.
Life cycle transcriptome of the malaria mosquito
Anopheles gambiae
and comparison with the fruitfly
Drosophila melanogaster
Authors: Koutsos Anastasios C. , Blass Claudia , Meister Stephan , Schmidt Sabine , MacCallum Robert M. , Soares Marcelo B. , Collins Frank H. , Benes Vladimir , Zdobnov Evgeny , Kafatos Fotis C. , Christophides George K.
Published: June 2007

The African mosquito
Anopheles gambiae
is the major vector of human malaria. We report a genome-wide survey of mosquito gene expression profiles clustered temporally into developmental programs and spatially into adult tissue-specific patterns. Global expression analysis shows that genes that belong to related functional categories or that encode the same or functionally linked protein domains are associated with characteristic developmental programs or tissue patterns. Comparative analysis of our data together with data published from
Drosophila melanogaster
reveal an overall strong and positive correlation of developmental expression between orthologous genes. The degree of correlation varies, depending on association of orthologs with certain developmental programs or functional groups. Interestingly, the similarity of gene expression is not correlated with the coding sequence similarity of orthologs, indicating that expression profiles and coding sequences evolve independently. In addition to providing a comprehensive view of temporal and spatial gene expression during the
A. gambiae
life cycle, this large-scale comparative transcriptomic analysis has detected important evolutionary features of insect transcriptomes.
Hypogonadotropic hypogonadism in mice lacking a functional
Kiss1
gene
Authors: d'Anglemont de Tassigny Xavier , Fagg Lisa A. , Dixon John P. C. , Day Kate , Leitch Harry G. , Hendrick Alan G. , Zahn Dirk , Franceschini Isabelle , Caraty Alain , Carlton Mark B. L. , Aparicio Samuel A. J. R. , Colledge William H.
Published: June 2007

The G protein-coupled receptor GPR54 (AXOR12, OT7T175) is central to acquisition of reproductive competency in mammals. Peptide ligands (kisspeptins) for this receptor are encoded by the
Kiss1
gene, and administration of exogenous kisspeptins stimulates hypothalamic gonadotropin-releasing hormone (GnRH) release in several species, including humans. To establish that kisspeptins are the authentic agonists of GPR54
in vivo
and to determine whether these ligands have additional physiological functions we have generated mice with a targeted disruption of the
Kiss1
gene.
Kiss1
-null mice are viable and healthy with no apparent abnormalities but fail to undergo sexual maturation. Mutant female mice do not progress through the estrous cycle, have thread-like uteri and small ovaries, and do not produce mature Graffian follicles. Mutant males have small testes, and spermatogenesis arrests mainly at the early haploid spermatid stage. Both sexes have low circulating gonadotropin (luteinizing hormone and follicle-stimulating hormone) and sex steroid (β-estradiol or testosterone) hormone levels. Migration of GnRH neurons into the hypothalamus appears normal with appropriate axonal connections to the median eminence and total GnRH content. The hypothalamic–pituitary axis is functional in these mice as shown by robust luteinizing hormone secretion after peripheral administration of kisspeptin. The virtually identical phenotype of
Gpr54
- and
Kiss1
-null mice provides direct proof that kisspeptins are the true physiological ligand for the GPR54 receptor
in vivo. Kiss1
also does not seem to play a vital role in any other physiological processes other than activation of the hypothalamic–pituitary–gonadal axis, and loss of
Kiss1
cannot be overcome by compensatory mechanisms.
Automated comparative sequence analysis by base-specific cleavage and mass spectrometry for nucleic acid-based microbial typing
Authors: Honisch Christiane , Chen Yong , Mortimer Chloe , Arnold Catherine , Schmidt Oliver , van den Boom Dirk , Cantor Charles R. , Shah Haroun N. , Gharbia Saheer E.
Published: June 2007

Traditional microbial typing technologies for the characterization of pathogenic microorganisms and monitoring of their global spread are often difficult to standardize and poorly portable, and they lack sufficient ease of use, throughput, and automation. To overcome these problems, we introduce the use of comparative sequencing by MALDI-TOF MS for automated high-throughput microbial DNA sequence analysis. Data derived from the public multilocus sequence typing (MLST) database (
http://pubmlst.org/neisseria
) established a reference set of expected peak patterns. A model pathogen,
Neisseria meningitidis
, was used to validate the technology and explore its applicability as an alternative to dideoxy sequencing. One hundred
N. meningitidis
samples were typed by comparing MALDI-TOF MS fingerprints of the standard MLST loci to reference sequences available in the public MLST database. Identification results can be obtained in 2 working days. Results were in concordance with classical dideoxy sequencing with 98% correct automatic identification. Sequence types (STs) of 89 samples were represented in the database, seven samples revealed new STs, including three new alleles, and four samples contained mixed populations of multiple STs. The approach shows interlaboratory reproducibility and allows for the exchange of mass spectrometric fingerprints to study the geographic spread of epidemic
N. meningitidis
strains or other microbes of clinical importance.
P-cluster maturation on nitrogenase MoFe protein
Authors: Hu Yilin , Fay Aaron W. , Lee Chi Chung , Ribbe Markus W.
Published: June 2007

Biosynthesis of nitrogenase P-cluster has attracted considerable attention because it is biologically important and chemically unprecedented. Previous studies suggest that P-cluster is formed from a precursor consisting of paired [4Fe–4S]-like clusters and that P-cluster is assembled stepwise on MoFe protein, i.e., one cluster is assembled before the other. Here, we specifically tackle the assembly of the second P-cluster by combined biochemical and spectroscopic approaches. By using a P-cluster maturation assay that is based on purified components, we show that the maturation of the second P-cluster requires the concerted action of NifZ, Fe protein, and MgATP and that the action of NifZ is required before that of Fe protein/MgATP, suggesting that NifZ may act as a chaperone that facilitates the subsequent action of Fe protein/MgATP. Furthermore, we provide spectroscopic evidence that the [4Fe–4S] cluster-like fragments can be converted to P-clusters, thereby firmly establishing the physiological relevance of the previously identified P-cluster precursor.
Clinicopathological and Tissue Indicators of Para-Aminophenol Nephrotoxicity in Sprague–Dawley Rats
Authors: Yang Amy , Trajkovic Dusko , Illanes Oscar , Ramiro-Ibáñez Fernando
Published: June 2007

A model of para-aminophenol (PAP) nephrotoxicity in Sprague–Dawley rats was utilized to characterize potential indicators of toxicity in the kidney and in biofluids, and to chronicle the progression of acute renal injury. Rats were administered PAP at a low or high dose and examined terminally at 6, 24 and 48 hours (4 animals/group with matching controls). Acute tubular necrosis was observed in the medullary rays (low and high doses) and the outer stripe of outer medulla (high dose only) as early as 6 hours postdosing. Starting at 24 hours, regeneration of the tubular epithelium was evident in both low and high dose studies. Associated with the tubular lesions, we observed elevation of urinary α-glutathione S-transferase levels, an indicator of proximal tubular injury. By immunohistochemistry of the kidney, decreased γ-glutamylcysteine synthetase expression correlated with tubular injury, especially at high dose, whereas elevation of vimentin, osteopontin, and Ki-67 expression was concurrent with tubular regeneration. Clusterin and kidney injury molecule-1 displayed expression patterns characteristic of both renal injury and regeneration. Taken together, this study provided insight into the progression of nephrotoxicity, and allowed the evaluation of potential urinary and tissue protein biomarkers that could complement the early detection of acute tubular injury.
α2u-Globulin Nephropathy and Renal Tumors in National Toxicology Program Studies
Authors: Doi Adriana M. , Hill Georgette , Seely John , Hailey James R. , Kissling Grace , Bucher John R.
Published: June 2007

Chemically induced renal neoplasms in male rats, developed coincident with α2u-globulin nephropathy, are not considered predictive of risk to humans by the International Agency for Research on Cancer (IARC) and the U.S. Environmental Protection Agency. Criteria have been defined to establish the role of α2u-globulin nephropathy in renal carcinogenesis, based on a proposed mode of action involving sustained tubular cell proliferation resulting from α2u-induced nephropathy, with consequent development of neoplastic lesions. Recent NTP studies demonstrated inconsistencies with this proposed mechanism, including in some cases, far weaker kidney tumor responses than expected based on the extent of α2u-globulin nephropathy. NTP studies with decalin, propylene glycol mono-t-butyl ether and Stoddard solvent IIC included extended evaluations of α2u-related nephropathy, and were thus used in assessing the linkage between key events in 90-day studies with renal tumors in 2-year studies. This review revealed no or at best weak associations of tumor responses with renal α2u-globulin concentrations, indices of cell turnover, or microscopic evidence of α2u-associated nephropathy in prechronic studies. While tumor responses corresponded somewhat with a measure of cumulative α2u-associated nephropathy (linear mineralization of the papilla) at the end of the 2-year studies, the severity of chronic nephropathy was generally in best agreement with the pattern of tumor response. These results suggest that while α2u-globulin nephropathy may contribute to the renal tumor response, the critical component(s) of the nephropathy most closely associated with the development of tumors could not be clearly identified in this review.
Chemopreventive and Bioenergetic Signaling Effects of PDK1/Akt Pathway Inhibition in a Transgenic Mouse Model of Prostate Cancer
Authors: Sargeant Aaron M. , Klein Russell D. , Rengel Robert C. , Clinton Steven K. , Kulp Samuel K. , Kashida Yoko , Yamaguchi Mamoru , Wang Xingya , Chen Ching-Shih
Published: June 2007

The phosphoinositide-dependent kinase 1 (PDK1)/Akt pathway is an important regulator of multiple biological processes including cell growth, survival, and glucose metabolism. In light of the mechanistic link between Akt signaling and prostate tumorigenesis, we evaluated the chemopreventive relevance of inhibiting this pathway in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model with OSU03012, a celecoxib-derived, but COX-2-inactive, PDK1 inhibitor. Beginning at ten weeks of age when prostatic intraepithelial neoplasia (PIN) lesions are well developed, TRAMP mice received OSU03012 via daily oral gavage for 8 weeks. The drug treatment significantly decreased the weight of all 4 prostate lobes as well as the grade of epithelial proliferation in the dorsal and lateral lobes compared to vehicle-treated control mice. The incidences of carcinoma and metastasis were decreased, although not to statistically significant levels. Treated mice lost body fat and failed to gain weight independent of food intake. This change and periportal hepatocellular atrophy can be linked to sustained PDK1 inhibition through downstream inactivation of glycogen synthase. Centrilobular hepatocellular hypertrophy and necrosis of Type II skeletal myofibers were also compound-related effects. We conclude that targeting of the PDK1/Akt pathway has chemopreventive relevance in prostate cancer and causes other in vivo effects mediated in part by an alteration of bioenergetic signaling.
Carcinogenicity Evaluation: Comparison of Tumor Data from Dual Control Groups in the CD–1 Mouse
Authors: Baldrick Paul , Reeve Lesley
Published: June 2007

Current regulatory thinking allows for the use of single control groups for rodent carcinogenicity testing although there has been a trend until recently to use dual control groups. To date, virtually nothing has been published on whether a shift from dual to single control groups will affect the identification of tumorigenic risk potential in these studies. A recent evaluation of dual control carcinogenicity data in the rat (Baldrick, Toxicol Pathol 2005, 33: 283–291) showed that although no major differences in tumor incidences between the control groups were found, some interstudy variation occurred and in cases were a notable difference was seen, the use of 2 control groups, as well as robust, contemporary background data, allowed an easier interpretation of findings in drug-treated groups. In this paper, the results of 10 mouse carcinogenicity studies, performed between 1991 and 2004, with 2 control groups, are presented. As in the rat, interstudy variation was seen and in some cases, the use of dual control groups assisted in the tumor risk assessment. Thus, the continued use of 2 control groups can have a vital role in mouse carcinogenicity studies. The paper also presents an update on survival, on the range and extent of background spontaneous neoplasms and comments on genetic drift in this commonly used mouse strain.
Interleukin 25 promotes the initiation of proallergic type 2 responses
Authors: Angkasekwinai Pornpimon , Park Heon , Wang Yui-Hsi , Wang Yi-Hong , Chang Seon Hee , Corry David B. , Liu Yong-Jun , Zhu Zhou , Dong Chen
Published: June 2007

The molecular mechanisms underlying the initiation of innate and adaptive proallergic type 2 responses are not understood. Interleukin (IL) 25, a member of the IL-17 cytokine family, was recently reported (Owyang, A.M., C. Zaph, E.H. Wilson, K.J. Guild, T. McClanahan, H.R. Miller, D.J. Cua, M. Goldschmidt, C.A. Hunter, R.A. Kastelein, and D. Artis. 2006. J. Exp. Med. 203:843–849; Fallon, P.G., S.J. Ballantyne, N.E. Mangan, J.L. Barlow, A. Dasvarma, D.R. Hewett, A. McIlgorm, H.E. Jolin, and A.N. McKenzie. 2006. J. Exp. Med. 203:1105–1116) to be important in Th2 cell–mediated immunity to parasitic infection. However, the cellular source and targets of IL-25 are not well understood. We show that mouse IL-25 is expressed by lung epithelial cells as a result of innate immune responses to allergens. Transgenic overexpression of IL-25 by these cells leads to mucus production and airway infiltration of macrophages and eosinophils, whereas blockade of IL-25 conversely reduces the airway inflammation and Th2 cytokine production in an allergen-induced asthma model. In addition, IL-25, with a receptor more highly expressed in Th2 than other effector T cells, promotes Th2 cell differentiation in an IL-4– and signal transducer and activator of transcription 6–dependent manner. During early T cell activation, IL-25 potentiates expression of the nuclear factor of activated T cells c1 and JunB transcription factors, which possibly results in increased levels of initial IL-4 production, up-regulation of GATA-3 expression, and enhanced Th2 cell differentiation. Thus, IL-25 is a critical factor regulating the initiation of innate and adaptive proallergic responses.
Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis
Authors: Anthoni Christoph , Russell Janice , Wood Katherine C. , Stokes Karen Y. , Vowinkel Thorsten , Kirchhofer Daniel , Granger D. Neil
Published: June 2007

There is growing evidence for an interplay between inflammatory and coagulation pathways in acute and chronic inflammatory diseases. However, it remains unclear whether components of the coagulation pathway, such as tissue factor (TF), contribute to intestinal inflammation, and whether targeting TF will blunt the inflammatory cell recruitment, tissue injury, and enhanced thrombus formation that occur in experimental colitis. Mice were fed 3% dextran sodium sulfate (DSS) to induce colonic inflammation, with some mice receiving a mouse TF-blocking antibody (muTF-Ab). The adhesion of leukocytes and platelets in colonic venules, light/dye-induced thrombus formation in cremaster muscle microvessels, as well as disease activity index, thrombin–antithrombin (TAT) complexes in plasma, and histopathologic changes in the colonic mucosa were monitored in untreated and muTF-Ab–treated colitic mice. In untreated mice, DSS elicited the recruitment of adherent leukocytes and platelets in colonic venules, caused gross and histologic injury, increased plasma TAT complexes, and enhanced thrombus formation in muscle arterioles. muTF-Ab prevented elevation in TAT complexes, reduced blood cell recruitment and tissue injury, and blunted thrombus formation in DSS colitic mice. These findings implicate TF in intestinal inflammation and support an interaction between inflammation and coagulation in experimental colitis.
Antioxidant Activity of 45 Chinese Herbs and the Relationship with their TCM Characteristics
Authors: Liao Hui , Banbury Linda K. , Leach David N.
Published: June 2007

Here, 45 Chinese herbs that regulate blood circulation were analyzed for antioxidant activity using the oxygen radical absorbance capacity (ORAC) assay. A recent publication by Ou et al. identified a close relationship between in vitro antioxidant activity and classification of Chinese herbs as yin or yang. The 45 Chinese herbs in this study could be assigned the traditional characteristics of natures (cold, cool, hot and warm), flavors (pungent, sweet, sour, bitter and salty) and functions (arresting bleeding, promoting blood flow to relieve stasis, nourishing blood and clearing away heat from blood). These characteristics are generalized according to the theory of yin and yang. We identified a broad range, 40–1990 µmol Trolox Equivalent/g herbs, of antioxidant activity in water extracts. There was no significant correlation between ORAC values and natures or functions of the herbs. There was a significant relationship between flavors and ORAC values. Bitter and/or sour herbs had the highest ORAC values, pungent and/or sweet herbs the lowest. Other flavors had intermediate values. Flavors also correspond with the yin/yang relationship and our results are supportive of the earlier publication. We reported for the first time antioxidant properties of many Chinese herbs. High antioxidant herbs were identified as Spatholobus suberectus vine (1990 µmol TE/g), Sanguisorba officinalis root (1940 µmol TE/g), Agrimonia pilosa herb (1440 µmol TE/g), Artemisia anomala herb (1400 µmol TE/g), Salvia miltiorrhiza root (1320 µmol TE/g) and Nelembo nucifera leaf (1300 µmol TE/g). Antioxidant capacity appears to correlate with the flavors of herbs identified within the formal TCM classification system and may be a useful guide in describing their utility and biochemical mechanism of action.
Regulation of Cellular Metabolism and Cytokines by the Medicinal Herb Feverfew in the Human Monocytic THP‐1 Cells
Authors: Chen Chin-Fu , Cheng Chun-Huai
Published: June 2007

The herb feverfew is a folk remedy for various symptoms including inflammation. Inflammation has recently been implicated in the genesis of many diseases including cancers, atherosclerosis and rheumatoid arthritis. The mechanisms of action of feverfew in the human body are largely unknown. To determine the cellular targets of feverfew extracts, we have utilized oligo microarrays to study the gene expression profiles elicited by feverfew extracts in human monocytic THP‐1 cells. We have identified 400 genes that are consistently regulated by feverfew extracts. Most of the genes are involved in cellular metabolism. However, the genes undergoing the highest degree of change by feverfew treatment are involved in other pathways including chemokine function, water homeostasis and heme‐mediated signaling. Our results also suggest that feverfew extracts effectively reduce Lipopolysaccharides (LPS)‐mediated TNF‐α and CCL2 (MCP‐1) releases by THP‐1 cells. We hypothesize that feverfew components mediate metabolism, cell migration and cytokine production in human monocytes/macrophages.
Linearized dynamics equations for the balance and steer of a bicycle: a benchmark and review
Authors: Meijaard J.P , Papadopoulos Jim M , Ruina Andy , Schwab A.L
Published: June 2007

We present canonical linearized equations of motion for the Whipple bicycle model consisting of four rigid laterally symmetric ideally hinged parts: two wheels, a frame and a front assembly. The wheels are also axisymmetric and make ideal knife-edge rolling point contact with the ground level. The mass distribution and geometry are otherwise arbitrary. This conservative non-holonomic system has a seven-dimensional accessible configuration space and three velocity degrees of freedom parametrized by rates of frame lean, steer angle and rear wheel rotation. We construct the terms in the governing equations methodically for easy implementation. The equations are suitable for e.g. the study of bicycle self-stability. We derived these equations by hand in two ways and also checked them against two nonlinear dynamics simulations. In the century-old literature, several sets of equations fully agree with those here and several do not. Two benchmarks provide test cases for checking alternative formulations of the equations of motion or alternative numerical solutions. Further, the results here can also serve as a check for general purpose dynamic programs. For the benchmark bicycles, we accurately calculate the eigenvalues (the roots of the characteristic equation) and the speeds at which bicycle lean and steer are self-stable, confirming the century-old result that this conservative system can have asymptotic stability.
They saw a movie: Long-term memory for an extended audiovisual narrative
Authors: Furman Orit , Dorfman Nimrod , Hasson Uri , Davachi Lila , Dudai Yadin
Published: June 2007

We measured long-term memory for a narrative film. During the study session, participants watched a 27-min movie episode, without instructions to remember it. During the test session, administered at a delay ranging from 3 h to 9 mo after the study session, long-term memory for the movie was probed using a computerized questionnaire that assessed cued recall, recognition, and metamemory of movie events sampled ∼20 sec apart. The performance of each group of participants was measured at a single time point only. The participants remembered many events in the movie even months after watching it. Analysis of performance, using multiple measures, indicates differences between recent (weeks) and remote (months) memory. While high-confidence recognition performance was a reliable index of memory throughout the measured time span, cued recall accuracy was higher for relatively recent information. Analysis of different content elements in the movie revealed differential memory performance profiles according to time since encoding. We also used the data to propose lower limits on the capacity of long-term memory. This experimental paradigm is useful not only for the analysis of behavioral performance that results from encoding episodes in a continuous real-life-like situation, but is also suitable for studying brain substrates and processes of real-life memory using functional brain imaging.
Warfarin for Stroke Prevention in Octogenarians with Atrial Fibrillation
Authors: Howard Patricia A. , Ellerbeck Edward F. , Engelman Kimberly K. , Dunn Marvin I.
Published: June 2007

The authors examined warfarin use in elderly patients with atrial fibrillation. Medical records were abstracted from a random sample of Medicare beneficiaries with atrial fibrillation who were discharged from Kansas hospitals. Data were analyzed for warfarin and aspirin use and risk factors for stroke or bleeding in patients 65–79 years of age or 80 years and older. Stroke risk factors other than age and atrial fibrillation were seen in 98% of 142 patients less than 80 years of age and 100% of 141 octogenarians. Warfarin use was similar in the younger and older age groups (50% vs. 45%, respectively; p=ns) and was not associated with the number of stroke or bleeding risk factors. Compared to patients less than 80 years of age, octogenarians were less likely to receive aspirin (38% vs. 27%, respectively; p<0.05). Anticoagulation rates for high‐risk patients with atrial fibrillation were low and poorly explained by stroke or bleeding risks.
Ischemic Preconditioning: Implications for the Geriatric Heart
Authors: Kloner Robert A. , Shook Thomas , Cannon Christopher P. , Przyklenk Karin
Published: June 2007

Ischemic preconditioning is among the most consistent and powerful modes of reducing myocardial infarct size. Although several clinical studies have suggested that the human heart can be preconditioned, controversy exists in both the experimental and clinical literature as to whether the senescent heart can be preconditioned. The authors recently reported that older patients (≥60 years of age) in the Thrombolysis in Myocardial Infarction‐4 study appeared to benefit from a history of angina prior to acute myocardial infarction. This observation may lead to a clinical counterpart to successful preconditioning in the older heart.
Cardiac Tamponade Complicating Myocardial Infarction in the Era of Thrombolytics and Platelet IIb/IIIa: Case Report and Literature Review
Authors: Mixon Timothy A. , Tak Tahir , Lawrence Mark E.
Published: June 2007

Pericardial tamponade is a rare complication of acute myocardial infarction. The authors present the case of a patient with a large anterior myocardial infarction administered thrombolytics who developed postinfarction pericarditis. Because of a stuttering course with concomitant postinfarction angina, urgent angiography, leading to percutaneous transluminal coronary angioplasty and stent implantation, was performed. Administration of abciximab prior to percutaneous transluminal coronary angioplasty appears to have precipitated pericardial tamponade. The authors review the literature concerning numerous commonly utilized therapeutic options that could have contributed to the development of pericardial tamponade.
Ethical Issues in the Management of Geriatric Cardiac Patients
Authors: Basta Lofty L.
Published: June 2007

Ethical Issue: A patient explicitly wanting to avoid a harsh death ends up with a horrific one.
Mitral Annulus Calcification with a Mobile Component as a Possible Source of Embolism
Authors: Shohat‐Zabarski Ronit , Paz Rami , Adler Yehuda , Vaturi Mordechai , Jortner Ruth , Sagie Alex
Published: June 2007

Mitral annulus calcification has been associated with embolic events, but the precise pathophysiology has not been elucidated. The authors describe four patients who experienced embolic events whose transesophageal echocardiograms showed a mitral annulus calcification, with a mobile component that exhibited the same echogenicity as the calcification. Three patients had no other conditions known to be associated with embolism. On follow‐up transesophageal echocardiography, the mobile component of the mitral annulus calcification had disappeared in three patients. These findings support the hypothesis that mitral annulus calcification not only is associated with but also is possibly a direct cause of embolic events in some patients.
Treating Hypertension in the Elderly
Authors: Schrier Robert W.
Published: June 2007

Hypertension is highly prevalent in elderly individuals, the most rapidly growing segment of the US population. Epidemiologic studies have established that increased risk of cardiovascular disease is associated with elevated blood pressure. Treatment of hypertension in elderly patients significantly reduces their cardiovascular morbidity and mortality. However, antihypertensive therapy is often challenging in this patient population because of potential metabolic and physiologic alterations, multiple comorbidities, polypharmacy, and biologic variability. Drugs with a convenient dosing schedule, minimal side effects, and the ability to impact comorbid conditions are important considerations in the treatment of hypertension in the elderly.
Ethical Issues in the Management of Geriatric Cardiac Patients
Authors: Morrow Michael F. , Plunkitt Kenneth , Basta Lofty L.
Published: June 2007

Ethical Issue: After the death of his appointed surrogate, a demented, senile patient is caught in a whirlwind of medical decision‐making.
Ethical Issues in the Management of Geriatric Cardiac Patients
Authors: Basta Lofty L.
Published: June 2007

Ethical Issue: A nonterminally ill cardiac patient opts for a high‐risk revascularization procedure but insists on not receiving cardiopulmonary resuscitation in the event of an iatrogenic cardiac arrest.
What I Tell Medical House Staff About Old Hearts
Authors: Hurst J. Willis
Published: June 2007

House officers tend to view elderly patients with heart disease in the same way they view middle‐aged patients. This essay discusses the difference between old hearts and middle‐aged hearts. The teaching setting, as well as the common cardiovascular problems seen in the elderly, are described in this essay. In addition, an explanation is given as to why the clinical picture of the same disease is different in elderly patients than in middle‐aged patients.
Benefits of Cardiac Rehabilitation and Exercise Training Programs in Elderly Coronary Patients
Authors: Lavie Carl J. , Milani Richard V.
Published: June 2007

The authors review several studies from the Ochsner Heart and Vascular Institute showing the benefits of formal phase II cardiac rehabilitation and exercise training programs in elderly patients with coronary artery disease, including benefits on plasma lipids, obesity indices, exercise capacity, peak oxygen consumption, behavioral characteristics (especially depression), and quality of life. Marked benefits were noted in elderly women and all elderly patients over the age of 75 years. The authors conclude that the therapy has proved to be safe and effective for elderly coronary patients, and that these individuals should be routinely referred to, and vigorously encouraged to attend, cardiac rehabilitation programs following major coronary events.
Diagnosis and Management of Myocardial Ischemia (Angina) in the Elderly Patient
Authors: Tresch Donald D. , Alla Haritha R.
Published: June 2007

Coronary artery disease is a major problem in the elderly population. Approximately 60% of all acute myocardial infarctions in the United States occur in people 65 years or older, and 30% occur in persons older than 75 years. Morbidity and mortality are high in elderly patients who sustain a myocardial infarction. Due to the atypical presentation of myocardial ischemia and absence of classic symptoms, coronary artery disease may not be diagnosed in many of these patients until an acute myocardial infarction occurs. Early diagnosis of coronary artery disease and reduction of all coronary risk factors are beneficial in reducing future coronary events in older as well as in younger patients. Many studies have shown that anti‐ischemic and acute myocardial infarction therapies have been underutilized in the elderly population. The principles of drug therapy for myocardial ischemia are the same as those for younger patients. Aggressive therapy, including early coronary angiography and revascularization, has been found to be as beneficial in high‐risk, unstable older patients as in younger patients. Therapy should be individualized according to the patient's clinical condition. On the basis of current knowledge, elderly, high‐risk patients with acute coronary syndromes may be treated with a combination of intensive medical therapy and early coronary angiography with revascularization.
Exercise Therapy for Older Persons With Cardiovascular Disease
Authors: Aronow Wilbert S.
Published: June 2007

Cardiac rehabilitation with exercise training after myocardial infarction in persons younger than 70 years has been found to cause a significant decrease in all‐cause mortality, cardiovascular mortality, and fatal reinfarction, but no significant difference in nonfatal reinfarction. After myocardial infarction or coronary revascularization in older individuals, such programs significantly improve physical work capacity, body mass index, percent body fat, serum lipids, behavioral characteristics, and quality of life. Exercise modalities should include aerobic, resistance, and flexibility exercises. Less intense exercise of longer duration should be performed by older persons with coronary artery disease. Exercise training programs in patients with congestive heart failure produce significant improvement in peak oxygen consumption, exercise duration, and power output. The benefits of exercise training in patients with congestive heart failure may be due to an increase in cardiac output, an improvement in skeletal muscle metabolism, and an increase in peak blood flow to the exercising limb caused by a reduction in vascular resistance.
Outpatient Cardiac Infusion Units: Impact in Elderly Patients with Refractory Heart Failure
Authors: LÓpez‐Candales Angel , Carron Christine , Graham Susan , Schwartz Jeffrey
Published: June 2007

Background. The use of intermittent intravenous infusions of inotropic drugs is under evaluation in the management of patients with refractory heart failure. Objectives. We investigated the impact of intermittent outpatient infusions of inotropes on hospital admissions, emergency room visits, functional class, and symptom‐free interval after administration of inotropes to elderly patients with advanced heart failure symptoms. Methods. This retrospective analysis involved 24 elderly outpatients with a New York Heart Association class of III or IV and refractory heart failure symptoms. Results. Seven patients with class III heart failure (age 74±4 years; left ventricular ejection fraction 27±9%) and 17 patients of class IV (age 73±4 years; LVEF 21±10%) were included. Twenty patients were males. A total of 365 outpatient treatment sessions were administered, with 15±9 sessions per patient (range, 6–43). Eleven patients improved and were discharged; seven patients died; three discontinued treatment; two patients remain on therapy; and one patient required continuous infusion. During this treatment, there were only three emergency room visits and six hospital admissions due solely to heart failure. Fourteen patients required no emergency room visits or hospitalization. Of the patients discharged from the program, the interval without heart failure symptoms ranged from 60–356 days, with an improvement in NYHA class from 3.5±0.6 to 1.4±0.5 and no emergency room visits or hospital admissions. Conclusions. This type of therapy is well tolerated among elderly patients with refractory heart failure symptoms and its use deserves further investigation.