bluuebunny/crossref_metadata_2025_split huggingface dataset:
Racial variations in processes of care for patients with community-acquired pneumonia
Authors: Mortensen Eric M , Cornell John , Whittle Jeff 
Published: August 2004

Abstract
Background
Patients hospitalized with community acquired pneumonia (CAP) have a substantial risk of death, but there is evidence that adherence to certain processes of care, including antibiotic administration within 8 hours, can decrease this risk. Although national mortality data shows blacks have a substantially increased odds of death due to pneumonia as compared to whites previous studies of short-term mortality have found decreased mortality for blacks. Therefore we examined pneumonia-related processes of care and short-term mortality in a population of patients hospitalized with CAP.

Methods
We reviewed the records of all identified Medicare beneficiaries hospitalized for pneumonia between 10/1/1998 and 9/30/1999 at one of 101 Pennsylvania hospitals, and randomly selected 60 patients at each hospital for inclusion. We reviewed the medical records to gather process measures of quality, pneumonia severity and demographics. We used Medicare administrative data to identify 30-day mortality. Because only a small proportion of the study population was black, we included all 240 black patients and randomly selected 720 white patients matched on age and gender. We performed a resampling of the white patients 10 times.

Results
Males were 43% of the cohort, and the median age was 76 years. After controlling for potential confounders, blacks were less likely to receive antibiotics within 8 hours (odds ratio with 95% confidence interval 0.6, 0.4–0.97), but were as likely as whites to have blood cultures obtained prior to receiving antibiotics (0.7, 0.3–1.5), to have oxygenation assessed within 24 hours of presentation (1.6, 0.9–3.0), and to receive guideline concordant antibiotics (OR 0.9, 0.6–1.7). Black patients had a trend towards decreased 30-day mortality (0.4, 0.2 to 1.0).

Conclusion
Although blacks were less likely to receive optimal care, our findings are consistent with other studies that suggest better risk-adjusted survival among blacks than among whites. Further study is needed to determine why this is the case.
Attenuation of dengue virus infection by adeno-associated virus-mediated siRNA delivery
Authors: Zhang Weidong , Singam Rajeswari , Hellermann Gary , Kong Xiaoyuan , Juan Homero San , Lockey Richard F , Wu Shuen-Ju , Porter Kevin , Mohapatra Shyam S 
Published: August 2004

Abstract
Background
The need for safe and effective treatment of dengue virus (DEN), a class A agent that causes dengue hemorrhagic fever/dengue shock syndrome, has been a critical global priority. An effective vaccine for DEN is not yet available. In this study the possibility of attenuating DEN infection using adeno-associated virus (AAV)-encoded short interfering RNAs (siRNA) was examined in Vero cells and human dendritic cells (DCs).

Methods
A cassette encoding siRNA targeted to a 3' untranslated sequence common to all DEN serotypes was designed and tested for its ability to attenuate DEN infection by use of AAV delivery.

Results
Vero cells or DCs infected with AAV-siRNA showed a significant, dose-dependent reduction in DEN infection. Treatment of DCs with AAV-siRNA also decreased the DEN-induced apoptosis of DCs and did not induce significant inflammation.

Conclusion
These results demonstrate that AAV-mediated siRNA delivery is capable of reducing DEN infection in cells and may be useful in decreasing DEN replication in humans.
Conflicts of interest in translational research
Authors: Parks Malcolm R , Disis Mary L 
Published: August 2004

AbstractTranslational research requires a team approach to scientific inquiry and product development. Translational research teams consist of basic and clinical scientists who can be members of both academic and industrial communities. The conception, pre-clinical testing, and clinical evaluation of a diagnostic or therapeutic approach demands an intense interaction between investigators with diverse backgrounds. As the barriers between industry and academia are removed, issues of potential conflict of interest become more complex. Translational researchers must become aware of the situations which constitute conflict of interest and understand how such conflicts can impact their research programs. Finally, the translational research community must participate in the dialogue ongoing in the public and private sectors and help shape the rules that will govern conflicts that arise during the evolution of their research programs.
Discovery of estrogen receptor α target genes and response elements in breast tumor cells
Authors: Lin Chin-Yo , Ström Anders , Vega Vinsensius Berlian , Li Kong Say , Li Yeo Ai , Thomsen Jane S , Chan Wan Ching , Doray Balraj , Bangarusamy Dhinoth K , Ramasamy Adaikalavan , Vergara Liza A , Tang Suisheng , Chong Allen , Bajic Vladimir B , Miller Lance D , Gustafsson Jan-Åke , Liu Edison T 
Published: August 2004

Abstract
Background
Estrogens and their receptors are important in human development, physiology and disease. In this study, we utilized an integrated genome-wide molecular and computational approach to characterize the interaction between the activated estrogen receptor (ER) and the regulatory elements of candidate target genes.

Results
Of around 19,000 genes surveyed in this study, we observed 137 ER-regulated genes in T-47D cells, of which only 89 were direct target genes. Meta-analysis of heterogeneous in vitro and in vivo datasets showed that the expression profiles in T-47D and MCF-7 cells are remarkably similar and overlap with genes differentially expressed between ER-positive and ER-negative tumors. Computational analysis revealed a significant enrichment of putative estrogen response elements (EREs) in the cis-regulatory regions of direct target genes. Chromatin immunoprecipitation confirmed ligand-dependent ER binding at the computationally predicted EREs in our highest ranked ER direct target genes, NRIP1, GREB1 and ABCA3. Wider examination of the cis-regulatory regions flanking the transcriptional start sites showed species conservation in mouse-human comparisons in only 6% of predicted EREs.

Conclusions
Only a small core set of human genes, validated across experimental systems and closely associated with ER status in breast tumors, appear to be sufficient to induce ER effects in breast cancer cells. That cis-regulatory regions of these core ER target genes are poorly conserved suggests that different evolutionary mechanisms are operative at transcriptional control elements than at coding regions. These results predict that certain biological effects of estrogen signaling will differ between mouse and human to a larger extent than previously thought.
Septopreoptic μ Opioid Receptor Mediation of Hindbrain Glucoprivic Inhibition of Reproductive Neuroendocrine Function in the Female Rat
Authors: Singh Sushma R. , Briski Karen P. 
Published: August 2004

Abstract
Central glucostasis is a critical monitored variable in neuroendocrine regulation of pituitary LH secretion. Glucoprivic signals originating within the caudal hindbrain suppress LH. Septopreoptic μ opioid receptors (μ-R) function within neural pathways maintaining basal LH levels and mediate the effects of diverse physiological stimuli on hormone release. To identify potential sites in the septopreoptic area where ligand neuromodulatory actions may occur in response to hindbrain glucoprivic signaling, the present studies evaluated the distribution of μ-R-immunoreactive (-ir) neurons in the septopreoptic area that are genomically activated in response to caudal fourth ventricular (CV4) delivery of the glucose antimetabolite, 5-thioglucose (5TG). The effects of lateral ventricular pretreatment with the selective μ-R antagonist, d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), on LH secretory and GnRH neuronal transcriptional responses to hindbrain glucoprivation were also evaluated. Estradiol benzoate- and progesterone-primed, ovariectomized female rats were treated by CV4 administration of 5TG or the vehicle, saline, at the onset of the afternoon LH surge. The inhibitory effects of hindbrain glucoprivation on mean plasma LH levels as well as colabeling of rostral preoptic GnRH neurons for Fos-ir were attenuated in animals pretreated by lateral ventricular delivery of CTOP. Dual immunocytochemical labeling for septopreoptic μ-R-ir and Fos-ir demonstrated a robust induction of Fos expression by receptor-positive neurons within discrete septopreoptic sites in response to CV4 5TG, a genomic response that was diminished by CTOP pretreatment. The current studies provide novel evidence for the transcriptional activation of neuroanatomically characterized, μ-R-expressing neurons by decreased hindbrain glucose utilization and show that the functional status of μ-R is critical for maximal induction of the Fos stimulus-transcription cascade in these cells by central glucoprivic signaling. The finding that receptor antagonist-mediated suppression of this genomic response is correlated with increased reproductive neuroendocrine output supports a role for these discrete μ-R-expressing neuron populations as substrates for ligand regulatory effects on the GnRH-pituitary LH axis during neuroglucopenia.
Identification and Characterization of the Zebrafish and Fugu Genes Encoding Tuberoinfundibular Peptide 39
Authors: Papasani Madhusudhan R. , Gensure Robert C. , Yan Yi-Lin , Gunes Yasemin , Postlethwait John H. , Ponugoti Bhaskar , John Markus R. , Jüppner Harald , Rubin David A. 
Published: August 2004

AbstractAlthough the PTH type 2 receptor (PTH2R) has been isolated from mammals and zebrafish, only its mammalian agonist, tuberoinfundibular peptide 39 (TIP39), has been characterized thus far. To determine whether zebrafish TIP39 (zTIP39) functions similarly with the zebrafish PTHR (zPTH2R) and human PTH2Rs and to determine its tissue-specific expression, fugu (Takifugu rubripes) and zebrafish (Danio rerio) genomic databases were screened with human TIP39 (hTIP39) sequences. A single TIP39 gene was identified for each fish species, which showed significant homology to mammalian TIP39. Using standard molecular techniques, we isolated cDNA sequences encoding zTIP39. The fugu TIP39 precursor was encoded by a gene comprising at least three exons. It contained a hydrophobic signal sequence and a predicted prosequence with a dibasic cleavage site, similar to that found in mammalian TIP39 ligands. Phylogenetic analyses suggested that TIP39 forms the basal group from which PTH and PTHrP have been derived. Functionally, subtle differences in potency could be discerned between hTIP39 and zTIP39. The human PTH2R and zPTH2R were stimulated slightly better by both hTIP39 and zTIP39, whereas zTIP39 had a higher potency at a previously isolated zPTH2R splice variant. Whole-mount in situ hybridization of zebrafish revealed strong zTIP39 expression in the region of the hypothalamus and in the heart of 24- and 48-h-old embryos. Similarly, zPTH2R expression was highly expressed throughout the brain of 48- and 72-h-old embryos. Because the mammalian PTH2R was also most abundantly expressed in these tissues, the TIP39-PTH2R system may serve conserved physiological roles in mammals and fishes.
Inhibition of Hepatic Gluconeogenesis and Enhanced Glucose Uptake Contribute to the Development of Hypoglycemia in Mice Bearing Interleukin-1β- Secreting Tumor
Authors: Metzger Shulamit , Nusair Samir , Planer David , Barash Varda , Pappo Orit , Shilyansky Joel , Chajek-Shaul Tova 
Published: August 2004

AbstractMice bearing IL-1β-secreting tumor were used to study the chronic effect of IL-1β on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1β gene. Serum IL-1β levels increased exponentially with time. Secretion of IL-1β from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1β caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1β. Glut-1 and Glut-4 mRNA levels in IL-1β mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1β. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1β-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.
Free Fatty Acids and Cytokines Induce Pancreatic β-Cell Apoptosis by Different Mechanisms: Role of Nuclear Factor-κB and Endoplasmic Reticulum Stress
Authors: Kharroubi Ilham , Ladrière Laurence , Cardozo Alessandra K. , Dogusan Zeynep , Cnop Miriam , Eizirik Décio L. 
Published: August 2004

AbstractApoptosis is probably the main form of β-cell death in both type 1 diabetes mellitus (T1DM) and T2DM. In T1DM, cytokines contribute to β-cell destruction through nuclear factor-κB (NF-κB) activation. Previous studies suggested that in T2DM high glucose and free fatty acids (FFAs) are β-cell toxic also via NF-κB activation. The aims of this study were to clarify whether common mechanisms are involved in FFA- and cytokine-induced β-cell apoptosis and determine whether TNFα, an adipocyte-derived cytokine, potentiates FFA toxicity through enhanced NF-κB activation. Apoptosis was induced in insulinoma (INS)-1E cells, rat islets, and fluorescence-activated cell sorting-purified β-cells by oleate, palmitate, and/or cytokines (IL-1β, interferon-γ, TNFα). Palmitate and IL-1β induced a similar percentage of apoptosis in INS-1E cells, whereas oleate was less toxic. TNFα did not potentiate FFA toxicity in primary β-cells. The NF-κB-dependent genes inducible nitric oxide synthase and monocyte chemoattractant protein-1 were induced by IL-1β but not by FFAs. Cytokines activated NF-κB in INS-1E and β-cells, but FFAs did not. Moreover, FFAs did not enhance NF-κB activation by TNFα. Palmitate and oleate induced C/EBP homologous protein, activating transcription factor-4, and immunoglobulin heavy chain binding protein mRNAs, X-box binding protein-1 alternative splicing, and activation of the activating transcription factor-6 promoter in INS-1E cells, suggesting that FFAs trigger an endoplasmic reticulum (ER) stress response. We conclude that apoptosis is the main mode of FFA- and cytokine-induced β-cell death but the mechanisms involved are different. Whereas cytokines induce NF-κB activation and ER stress (secondary to nitric oxide formation), FFAs activate an ER stress response via an NF-κB- and nitric oxide-independent mechanism. Our results argue against a unifying hypothesis for the mechanisms of β-cell death in T1DM and T2DM.
Goldfish Calmodulin: Molecular Cloning, Tissue Distribution, and Regulation of Transcript Expression in Goldfish Pituitary Cells
Authors: Huo Longfei , Lee Eric K. Y. , Leung P. C. , Wong Anderson O. L. 
Published: August 2004

AbstractCalmodulin (CaM) is a Ca2+-binding protein essential for biological functions mediated through Ca2+-dependent mechanisms. In the goldfish, CaM is involved in the signaling events mediating pituitary hormone secretion induced by hypothalamic factors. However, the structural identity of goldfish CaM has not been established, and the neuroendocrine mechanisms regulating CaM gene expression at the pituitary level are still unknown. Here we cloned the goldfish CaM and tested the hypothesis that pituitary expression of CaM transcripts can be the target of modulation by hypothalamic factors. Three goldfish CaM cDNAs, namely CaM-a, CaM-bS, and CaM-bL, were isolated by library screening. These cDNAs carry a 450-bp open reading frame encoding the same 149-amino acid CaM protein, the amino acid sequence of which is identical with that of mammals, birds, and amphibians and is highly homologous (≥90%) to that in invertebrates. In goldfish pituitary cells, activation of cAMP- or PKC-dependent pathways increased CaM mRNA levels, whereas the opposite was true for induction of Ca2+ entry. Basal levels of CaM mRNA was accentuated by GnRH and pituitary adenylate cyclase-activating polypeptide but suppressed by dopaminergic stimulation. Pharmacological studies using D1 and D2 analogs revealed that dopaminergic inhibition of CaM mRNA expression was mediated through pituitary D2 receptors. At the pituitary level, D2 activation was also effective in blocking GnRH- and pituitary adenylate cyclase-activating polypeptide-stimulated CaM mRNA expression. As a whole, the present study has confirmed that the molecular structure of CaM is highly conserved, and its mRNA expression at the pituitary level can be regulated by interactions among hypothalamic factors.
Graves’ Hyperthyroidism and the Hygiene Hypothesis in a Mouse Model
Authors: Nagayama Yuji , McLachlan Sandra M. , Rapoport Basil , Oishi Kazunori 
Published: August 2004

AbstractGraves’ hyperthyroidism is an organ-specific autoimmune disease mediated by stimulatory autoantibodies against the TSH receptor (TSHR; thyroid-stimulating antibodies), causing thyroid hyperplasia and hyperthyroidism. Development of this ailment is well known to be under polygenic and environmental control. For example, we recently demonstrated that parasite helminth Schistosoma mansoni infection suppressed a T helper cell type 1 (Th1)-type anti-TSHR immune response and prevented disease development in our mouse model of Graves’ disease using adenovirus coding for the TSHR. In the present study we examined the outcome of infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG), a Th1-promoting infectious pathogen, on Graves’ disease. Our results show that prior infection with M. bovis BCG differentiates the TSHR-specific immune response toward a Th1 phenotype, as demonstrated by enhanced secretion of a Th1 cytokine interferon-γ and impaired production of a Th2 cytokine IL-10 from splenocytes stimulated in vitro with TSHR antigen. M. bovis BCG also significantly suppressed disease induction. These data together with our recent report that coinjection of adenovirus expressing the Th1 cytokine IL-12 induced a Th1-polarized, TSHR-specific immune response without affecting disease development support the hygiene hypothesis, rather than Th1-mediated disease suppression. Thus, some infectious pathogens may influence the development of Graves’ disease regardless of their ability to modify the Th1/Th2 balance.
Adrenergic Regulation and Diurnal Rhythm of p38 Mitogen-Activated Protein Kinase Phosphorylation in the Rat Pineal Gland
Authors: Chik C. L. , Mackova M. , Price D. , Ho A. K. 
Published: August 2004

AbstractIn this study, we investigated adrenergic and photoneural regulation of p38MAPK phosphorylation in the rat pineal gland. Norepinephrine (NE), the endogenous neurotransmitter, dose-dependently increased the levels of phosphorylated MAPK kinase 3/6 (MKK3/6) and p38MAPK in rat pinealocytes. Time-course studies showed a gradual increase in MKK3/6 and p38MAPK phosphorylation that peaked between 1 and 2 h and persisted for 4 h post NE stimulation. In cells treated with NE for 2 and 4 h, the inclusion of prazosin or propranolol reduced NE-induced MKK3/6 and p38MAPK phosphorylation, indicating involvement of both α- and β-adrenergic receptors for the sustained response. Whereas treatment with dibutyryl cAMP or ionomycin mimicked the NE-induced MKK3/6 and p38MAPK phosphorylation, neither dibutyryl cGMP nor 4β-phorbol 12-myristate 13-acetate had an effect. The NE-induced increase in MKK3/6 and p38MAPK phosphorylation was blocked by KT5720 (a protein kinase A inhibitor) and KN93 (a Ca2+/calmodulin-dependent kinase inhibitor), but not by KT5823 (a protein kinase G inhibitor) or calphostin C (a protein kinase C inhibitor). In animals housed under a lighting regimen with 12 h of light, MKK3/6 and p38MAPK phosphorylation increased in the rat pineal gland at zeitgeber time 18. The nocturnal increase in p38MAPK phosphorylation was blocked by exposing the animal to constant light and reduced by treatment with propranolol, a β-adrenergic blocker. Together, our results indicate that activation of p38MAPK is under photoneural control in the rat pineal gland and that protein kinase A and intracellular Ca2+ signaling pathways are involved in NE regulation of p38MAPK.
Thyroid Hormone Treatment of Hypothyroid Rats Restores the Regenerative Capacity and the Mitochondrial Membrane Permeability Properties of the Liver after Partial Hepatectomy
Authors: Moro Loredana , Marra Ersilia , Capuano Ferdinando , Greco Margherita 
Published: August 2004

AbstractWe have investigated the effect of thyroid hormone on recovery of liver mass and on the mitochondrial membrane permeability properties during rat liver regeneration after 70% partial hepatectomy (PH). In the euthyroid state, liver weight starts to recover 24 h after PH and is completely restored 96 h after PH. Cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT) occurs 24 h after PH, and it has been suggested to act in the signaling mechanism for hepatocyte proliferation. In this study we show that hypothyroidism delays recovery of the liver mass, being only 50% of the initial weight 96 h after PH, and alters the duration and mode of MPT occurrence, first inducing a CsA-insensitive swelling 24 h after PH, followed by a CsA-sensitive swelling 96 h after PH. The occurrence of both CsA-sensitive and -insensitive swelling is shown to be associated with an increase in mitochondrial calcium content. Concurrent with mitochondrial swelling, external release of matrix proteins from mitochondria, such as aspartate aminotransferase and malate dehydrogenase, is shown to be CsA insensitive 24 h after PH and CsA sensitive 96 h after PH. After thyroid hormone administration to hypothyroid rats, the liver regenerative capacity is restored, and the duration and mode of MPT occurrence as well as changes in mitochondrial calcium content become similar to those observed in the euthyroid condition. The results of the present study suggest the involvement of a mitochondria-mediated pathway in regulation of the liver regenerative process by thyroid hormone.