bluuebunny/crossref_metadata_2025 huggingface dataset:
Extending Worldwide Clinical Pharmacology Education Through a Pricing Approach
Authors: Ameer Barbara
Published: August 2005

Financial instruments, such as professional membership fees, are part of the science and technology policy toolkit for creating an environment conducive to developing an international health knowledge network. To minimize a hurdle to global knowledge exchange in clinical pharmacology, the American College of Clinical Pharmacology reevaluated fees for its international members. Secondary market research was conducted on salary data available from US‐based multinational firms. Salary comparisons for the same position based in the United States and in a developing economy were used to generate an index ratio. Applying this ratio, a tiered‐membership fee structure was constructed for the ∼120 countries where gross national income meets the World Bank classification of “developing economy.” The index ratio serves as a paradigm for structuring fees across a variety of programs. With the implementation of an adjusted dues structure, information and networks of colleagues are now more accessible to clinical pharmacologists in developing economies.
Practical Management of Patients With Painful Diabetic Neuropathy
Authors: Corbett Cynthia F.
Published: August 2005

Purpose

Painful diabetic neuropathy (PDN) has a significant impact on patients’ quality of life, affecting sleep, mood, mobility, ability to work, interpersonal relationships, overall self-worth, and independence. The purpose of this article is to provide diabetes educators with current and essential tools for PDN assessment and management.

Methods

Medline and CINAHL database searches identified publications on the assessment and treatment of PDN. Identified research was evaluated, and information pertinent to diabetes educators was summarized.

Results

Recent advancements in assessment of neuropathic pain include identifying characteristics that distinguish between neuropathic and nonneuropathic pain. In the absence of treatment, research demonstrates that nerve damage may progress while pain diminishes. Many disease-modifying and symptom-management treatment options are available.

Conclusion

Good glycemic control is the first priority for both prevention and management of PDN. However, even with good glycemic control, up to 20% of patients will develop PDN. PDN recognition and assessment are critical to optimize management. Although several treatment modalities are available, few patients obtain complete pain relief. Recent advances in understanding the mechanisms underlying neuropathic pain should lead to better treatment and patient outcomes. Combination therapy, including nonpharmacologic modalities, may be required. Research evaluating the efficacy of combination therapy is needed.
Choosing and Using Theories in Diabetes Education Research
Authors: Anderson Robert M. , Funnell Martha M. , Hernandez Cheri Ann
Published: August 2005

Diabetes educators use theories all the time, even if they are not aware of it. To teach, one must have some assumptions about how people learn and what constitutes effective teaching. The purpose of this article is to help diabetes educators interested in research and evaluation choose appropriate theories. The article will review the 4 purposes of theories, that is, description, explanation, prediction, and control, as well as the degree to which a theory has been articulated and elaborated. The importance of a theory’s personal resonance, its explanatory power, and its utility will also be examined. The article will also review how to use 1 or more theories at each stage of a research or evaluation project.
Participation in Novelty-Seeking Leisure Activities and Alzheimer’s Disease
Authors: Fritsch Thomas , Smyth Kathleen A. , Debanne Sara M. , Petot Grace J. , Friedland Robert P.
Published: August 2005

The objective was to study the associations between participation in different types of mentally stimulating leisure activities and status as Alzheimer’s disease (AD) case or normal control. Research suggests that participation in leisure activities, especially mentally stimulating activities, is associated with a lower risk for AD. However, no study has yet evaluated associations between AD and different types of mental leisure activities, especially those involving “novelty seeking.” The authors used a case-control design to compare participation in activities across the life span in persons with AD and normal controls. Cases (n = 264) were recruited from clinical settings and from the community. Controls were drawn from 2 populations. Control group A members (n = 364) were the friends or neighbors of the cases or members of the same organizations to which the cases belonged. Control group B members (n = 181) were randomly drawn from the community. The 2 control groups did not differ in their responses to most activity questions, so they were combined. Factor analysis of activity questions identified 3 activity factors: (1) novelty seeking; (2) exchange of ideas; and (3) social. Logistic regression analysis indicated that, adjusting for control variables, greater participation in novelty-seeking and exchange-of-ideas activities was significantly associated with decreased odds of AD. The odds of AD were lower among those who more often participated in activities involving exchange of ideas and were lower yet for those who more frequently participated in novelty-seeking activities. We conclude that participation in a variety of mental activities across the life span may lower one’s chances of developing AD.
A Review of the Biomechanics of the Diabetic Foot
Authors: van Schie C. H. M
Published: August 2005

In general, diabetic foot ulcers result from abnormal mechanical loading of the foot, such as repetitive moderate pressure applied to the plantar aspect of the foot while walking. Diabetic peripheral neuropathy causes changes in foot structure, affecting foot function and subsequently leading to increased plantar foot pressure, which is a predictive risk factor for the development of diabetic foot ulceration. Prevention of diabetic foot ulceration is possible by early identification of the insensitive foot, therefore a foot “at risk,” and by protecting the foot from abnormal biomechanical loading. Abnormal foot pressures can be reduced using several different approaches, including callus debridement, prescription of special footwear, injection of liquid silicone, Achilles tendon lengthening, and so forth. Off-loading of the diabetic wound is a key factor in successful wound healing, as it is associated with reduced inflammatory and accelerated repair processes. Pressure relief can be achieved using various off-loading modalities including accommodative dressing, walking splints, ankle-foot orthosis, total contact cast, and removable and irremovable cast walkers.
AIDS-related lymphoproliferative disease
Authors: Navarro Willis H. , Kaplan Lawrence D.
Published: August 2005

Not long after the recognition of HIV as the causative agent of AIDS, it was evident that individuals infected with HIV developed lymphoma at a greater rate than the population at large. Approximately two thirds of AIDS-related lymphoma (ARL) cases are categorized as diffuse large B-cell type, with Burkitt lymphomas comprising 25% and other histologies a much smaller proportion. Typically, these individuals have presented with advanced extranodal disease and CD4+ lymphocyte counts of less than 200/mm3. Recent clinical trials have demonstrated a better outcome with chemotherapy for ARL since the introduction of combination antiretroviral treatment, termed highly active antiretroviral therapy (HAART). For patients with relapses, solid evidence points to the safety and utility of hematopoietic-cell transplantation as a salvage modality. Coinfection with other viruses such as Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus have led to the genesis of previously rare or unrecognized lymphoma subtypes such as plasmablastic and primary effusion lymphomas. The immunosuppressive impact of treatment for patients with ARL receiving chemotherapy with HAART appears transient and opportunistic infections have become less problematic than prior to HAART. Significant progress has been made in the understanding and management of ARL but outcomes still remain inferior compared to those achieved in HIV- individuals.
Analysis of thrombocyte development in CD41-GFP transgenic zebrafish
Authors: Lin Hui-Feng , Traver David , Zhu Hao , Dooley Kimberly , Paw Barry H. , Zon Leonard I. , Handin Robert I.
Published: August 2005

Thrombocytes are the nucleated equivalent of platelets in nonmammalian vertebrates such as the zebrafish, Danio rerio. We have cloned zebrafish CD41 cDNA (αIIb, glycoprotein IIb [GPIIb]) and its promoter and have generated transgenic zebrafish lines with green fluorescent protein (GFP)–tagged thrombocytes. CD41 mRNA transcripts appeared 42 hours after fertilization (hpf) by reverse-transcriptase–polymerase chain reaction (RT-PCR) and at 48 hpf in circulating hematopoietic cells. Flow sorting of thrombocytes from the mesonephros of adult CD41-GFP zebrafish showed a GFPhigh subset, which had the morphologic appearance of mature thrombocytes, and a GFPlow subset with an immature appearance, suggesting that they may be thrombocyte precursors. Confocal laser microscopy of embryos 40 and 48 hpf also showed a nonmobile population of GFP+ cells in a discrete area between the dorsal aorta and caudal vein. Production of circulating thrombocytes was inhibited by the injection of antisense morpholinos for the stem-cell transcription factor scl and c-mpl, the receptor for thrombopoietin. The nonmobile pool of GFP+ cells was abolished by scl knockdown and partially inhibited by c-mpl knockdown. These studies have shown that it is possible to identify thrombocytes, thrombocyte precursors, and, possibly, early hematopoietic stem cells in zebrafish embryos and track their proliferation and maturation.
Oxidized β2-glycoprotein I induces human dendritic cell maturation and promotes a T helper type 1 response
Authors: Buttari Brigitta , Profumo Elisabetta , Mattei Vincenzo , Siracusano Alessandra , Ortona Elena , Margutti Paola , Salvati Bruno , Sorice Maurizio , Riganò Rachele
Published: August 2005

The human plasma protein β2-glycoprotein I (β2-GPI) is the most common target for antiphospholipid antibodies associated with thrombotic events in chronic disorders related to endothelial cell dysfunction. Crucial information is needed to clarify why this self-abundant protein is targeted by autoimmune responses. In this study, we investigated whether oxidative modification of β2-GPI, either spontaneous in culture wells or induced by treatment with H2O2, renders this self-protein able to activate immature monocyte-derived dendritic cells (DCs) from healthy human donors. Oxidized β2-GPI caused DCs to mature so that CD83 appeared and CD80, CD86, human leukocyte antigen-D region related (HLA-DR), and CD40 increased. The interaction between oxidized β2-GPI and DCs specifically stimulated these cells to secrete interleukin 12 (IL-12), IL-1β, IL-6, IL-8, tumor necrosis factor α (TNF-α), and IL-10. Oxidized β2-GPI-stimulated DCs had increased allostimulatory ability and primed naive T lymphocytes, thus inducing T helper 1 (Th1) polarization. The interaction between oxidized β2-GPI and DCs involved interleukin-1 receptor associated kinase (IRAK) phosphorylation and nuclear factor κB (NFκB) activation. Pretreatment of β2-GPI with the antioxidant α-tocopherol prevented DC maturation. These findings show that human oxidized β2-GPI, probably by interacting with a member of the Toll-like receptor (TLR) family, causes DCs to mature. Because this key β2-GPI function requires oxidative modification, in several chronic disorders related to endothelial cell dysfunction oxidative stress might trigger the “autoimmune spiral.”
Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function
Authors: Pluskota Elzbieta , Stenina Olga I. , Krukovets Irene , Szpak Dorota , Topol Eric J. , Plow Edward F.
Published: August 2005

High-throughput genomic technology identified an association between a single nucleotide polymorphism (SNP), a proline (P387) rather than the predominant alanine (A387) at position 387 in thrombospondin-4 (TSP-4) and premature myocardial infarction. The inflammatory hypothesis of atherosclerosis invokes a prominent role of leukocytes and cytokines in pathogenesis. As the expression of TSP-4 by vascular cells permits its exposure to circulating leukocytes, the interactions of human neutrophils (polymorphonuclear leukocytes [PMNs]) with both TSP-4 variants were investigated. Phorbol 12-myristate 13-acetate (PMA)–stimulated PMNs adhered and migrated well and equally on the TSP-4 variants. Integrin αMβ2 was identified as the TSP-4 receptor mediating these responses, and the 3 epidermal growth factor (EGF)–like domains of TSP-4 harboring the SNPs interacted with the αMI-domain. Despite the similarity in these responses, the P387 variant induced more robust tyrosine phosphorylation of the stress-related mitogen-activated protein kinases (MAPKs): p38MAPK and c-Jun NH2-terminal kinase (JNK), as well as signal transducer and activator of transcription-1 (STAT1) and heat shock protein 27 (HSP27) than the A387 variant. Additionally, cells adherent to P387 TSP-4 variant released 4-fold more H2O2 and secreted 2-fold more interleukin 8 (IL-8) as compared with the A387. H2O2 release and p38MAPK activation were totally inhibited by blockade of αMβ2. Thus, αMβ2 plays a central role in proinflammatory activities of TSP-4 (P387) and may contribute to the prothrombotic phenotype associated with this variant.
A role for MCP-1/CCR2 in interstitial lung disease in children
Authors: Hartl Dominik , Griese Matthias , Nicolai Thomas , Zissel Gernot , Prell Christine , Reinhardt Dietrich , Schendel Dolores J , Krauss-Etschmann Susanne
Published: August 2005

Background

Interstitial lung diseases (ILD) are chronic inflammatory disorders leading to pulmonary fibrosis. Monocyte chemotactic protein 1 (MCP-1) promotes collagen synthesis and deletion of the MCP-1 receptor CCR2 protects from pulmonary fibrosis in ILD mouse models. We hypothesized that pulmonary MCP-1 and CCR2+T cells accumulate in pediatric ILD and are related to disease severity.

Methods

Bronchoalveolar lavage fluid was obtained from 25 children with ILD and 10 healthy children. Levels of pulmonary MCP-1 and Th1/Th2-associated cytokines were quantified at the protein and the mRNA levels. Pulmonary CCR2+, CCR4+, CCR3+, CCR5+and CXCR3+T cells were quantified by flow-cytometry.

Results

CCR2+T cells and MCP-1 levels were significantly elevated in children with ILD and correlated with forced vital capacity, total lung capacity and ILD disease severity scores. Children with lung fibrosis had significantly higher MCP-1 levels and CCR2+T cells in bronchoalveolar lavage fluid compared to non-fibrotic children.

Conclusion

The results indicate that pulmonary CCR2+T cells and MCP-1 contribute to the pathogenesis of pediatric ILD and might provide a novel target for therapeutic strategies.
Low-magnesium, trans-cleavage activity by type III, tertiary stabilized hammerhead ribozymes with stem 1 discontinuities
Authors: Burke Donald H , Greathouse S Travis
Published: August 2005

Background

Low concentrations of free magnesium in the intracellular environment can present critical limitations for hammerhead ribozymes, especially for those that are designed for intermolecular (trans) cleavage of a host or pathogen RNA. Tertiary stabilizing motifs (TSM's) from natural and artificial ribozymes with a "type I" topology have been exploited to stabilize trans-cleaving hammerheads. Ribozymes with "type II" or "type III" topologies might seem incompatible with conversion to trans-cleavage designs, because opening the loop at the end of stem 1 or stem 2 to accommodate substrate binding is expected to disrupt the TSM and eliminate tertiary stabilization.

Results

Stem 1, together with single-stranded segments capping or internal to this stem, contains both the substrate-binding and tertiary stabilization functions. This stem was made discontinuous within the sTRSV hammerhead ribozyme, thereby separating the two functions into discrete structural segments. The resulting ribozyme, designated "RzC," cleaved its 13 nucleotide target substrate at MgCl2 concentrations as low as 0.2 mM at 25°C and 0.5 mM at 37°C. Under multiple-turnover conditions, nearly thirty turnovers were observed at the highest substrate:RzC ribozyme ratios. Similar stabilization was observed for several derivatives of RzC. Catalytic activity was diminished or eliminated at sub-millimolar MgCl2 concentrations for ribozymes with weakened or deleted tertiary interactions. Eadie-Hofstee analysis revealed that the stabilized and non-stabilized ribozymes bind their substrates with equivalent affinities, suggesting that differences in observed activity are not the result of diminished binding. Some of the stabilized and non-stabilized ribozymes appear to fold into a heterogeneous collection of conformers, only a subset of which are catalytically active.

Conclusion

Hammerhead ribozymes with the "type III" topology can be converted to a tertiary, trans-cleavage design. Separating the stabilization and substrate recognition functions of stem 1 increases cleavage activity at physiological concentrations of divalent magnesium while retaining recognition of exogenous targets. Trans-cleaving ribozymes that exploit the tertiary stabilizing motifs of all natural hammerhead topologies can therefore be used in intracellular applications.
Development of novel heminested PCR assays based on mitochondrial 16s rRNA gene for identification of seven pecora species
Authors: Guha Saurav , Kashyap VK
Published: August 2005

Background

Characterization of molecular markers and the development of better assays for precise and rapid detection of wildlife species are always in demand. This study describes a set of seven novel heminested PCR assays using specific primers designed based on species-specific polymorphism at the mitochondrial 16S rRNA gene for identification of Blackbuck, Goral, Nilgai, Hog deer, Chital, Sambar and Thamin deer.

Results

The designed heminested PCR assays are two consecutive amplifications of the mitochondrial 16S rRNA gene. In the first stage, ~550 bp region of the 16S rRNA gene was amplified by PCR using template DNA and universal primers. In the second stage, a species-specific internal region of the 16S rRNA gene was amplified by PCR using the amplicon of the first PCR along with one universal primer and another species-specific primer as the reverse or forward primer. The amplicon generated after two consecutive amplifications was highly unique to target species. These assays were successfully validated for sensitivity, specificity, and ruggedness under a wide range of conditions.

Conclusion

The validation experiments confirm that the designed heminested PCR assays for identification of the seven species are highly specific, sensitive, reliable and provide a reproducible method allowing analysis of low copy number DNA recovered from decomposed or highly processed tissues. The assays for identification of other species could be devised by extrapolating the principle of designed heminested PCR.
NPC1L1 haplotype is associated with inter-individual variation in plasma low-density lipoprotein response to ezetimibe
Authors: Hegele Robert A , Guy Justin , Ban Matthew R , Wang Jian
Published: August 2005

Background

NPC1L1encodes a putative intestinal sterol transporter which is the likely target for ezetimibe, a new type of lipid-lowering medication. We previously reported rare non-synonymous mutations inNPC1L1in an individual who had no plasma lipoprotein response to ezetimibe. We next hypothesized that common variants inNPC1L1would underlie less extreme inter-individual variations in the plasma LDL cholesterol response to ezetimibe.

Results

In 101 dyslipidemic subjects, we found thatNPC1L1haplotype was significantly associated with inter-individual variation in the response of plasma LDL cholesterol to treatment with ezetimibe for 12 weeks. Specifically, about one subject in eight lacked the commonNPC1L1haplotype 1735C-25342A-27677T and these subjects had a significantly greater reduction in plasma LDL cholesterol with ezetimibe than subjects with at least one copy of this haplotype (-35.9+4.0 versus -23.6+1.6 percent reduction, P = 0.0054). This was paralleled by a similar non-significant trend of between-haplotype difference in reduction of total cholesterol.

Conclusion

These preliminary pharmacogenetic results suggest thatNPC1L1variation is associated with inter-individual variation in response to ezetimibe treatment.
The fractal geometry of nutrient exchange surfaces does not provide an explanation for 3/4-power metabolic scaling
Authors: Painter Page R
Published: August 2005

Background

A prominent theoretical explanation for 3/4-power allometric scaling of metabolism proposes that the nutrient exchange surface of capillaries has properties of a space-filling fractal. The theory assumes that nutrient exchange surface area has a fractal dimension equal to or greater than 2 and less than or equal to 3 and that the volume filled by the exchange surface area has a fractal dimension equal to or greater than 3 and less than or equal to 4.

Results

It is shown that contradicting predictions can be derived from the assumptions of the model. When errors in the model are corrected, it is shown to predict that metabolic rate is proportional to body mass (proportional scaling).

Conclusion

The presence of space-filling fractal nutrient exchange surfaces does not provide a satisfactory explanation for 3/4-power metabolic rate scaling.
Improving survival rates of newborn infants in South Africa
Authors: Pattinson Robert , Woods David , Greenfield David , Velaphi Sithembiso
Published: August 2005

Background

The number, rates and causes of early neonatal deaths in South Africa were not known. Neither had modifiable factors associated with these deaths been previously documented. An audit of live born infants who died in the first week of life in the public service could help in planning strategies to reduce the early neonatal mortality rate.

Methods

The number of live born infants weighing 1000 g or more, the number of these infants who die in the first week of life, the primary and final causes of these deaths, and the modifiable factors associated with them were collected over four years from 102 sites in South Africa as part of the Perinatal Problem Identification Programme.

Results

The rate of death in the first week of life for infants weighing 1000 g or more was unacceptably high (8.7/1000), especially in rural areas (10.42/1000). Intrapartum hypoxia and preterm delivery are the main causes of death. Common modifiable factors included inadequate staffing and facilities, poor care in labour, poor neonatal resuscitation and basic care, and difficulties for patients in accessing health care.

Conclusion

Practical, affordable and effective steps can be taken to reduce the number of infants who die in the first week of life in South Africa. These could also be implemented in other under resourced countries.
Detection, quantification and genotyping of Herpes Simplex Virus in cervicovaginal secretions by real-time PCR: a cross sectional survey
Authors: Aryee Esther AN , Bailey Robin L , Natividad-Sancho Angels , Kaye Steve , Holland Martin J
Published: August 2005

Background

Herpes Simplex Virus (HSV) Genital Ulcer Disease (GUD) is an important public health problem, whose interaction with HIV results in mutually enhancing epidemics. Conventional methods for detecting HSV tend to be slow and insensitive. We designed a rapid PCR-based assay to quantify and type HSV in cervicovaginal lavage (CVL) fluid of subjects attending a Genito-Urinary Medicine (GUM) clinic. Vaginal swabs, CVL fluid and venous blood were collected. Quantitative detection of HSV was conducted using real time PCR with HSV specific primers and SYBR Green I. Fluorogenic TaqMan Minor Groove Binder (MGB) probes designed around a single base mismatch in the HSV DNA polymerase I gene were used to type HSV in a separate reaction. The Kalon test was used to detect anti-HSV-2 IgG antibodies in serum. Testing for HIV, other Sexually Transmitted Infections (STI) and related infections was based on standard clinical and laboratory methods.

Results

Seventy consecutive GUM clinic attendees were studied. Twenty-seven subjects (39%) had detectable HSV DNA in CVL fluid; HSV-2 alone was detected in 19 (70%) subjects, HSV-1 alone was detected in 4 (15%) subjects and both HSV types were detected in 4 (15%) subjects. Eleven out of 27 subjects (41%) with anti-HSV-2 IgG had detectable HSV-2 DNA in CVL fluid. Seven subjects (10%) were HIV-positive. Three of seven (43%) HIV-infected subjects and two of five subjects with GUD (40%) were secreting HSV-2. None of the subjects in whom HSV-1 was detected had GUD.

Conclusion

Quantitative real-time PCR and Taqman MGB probes specific for HSV-1 or -2 were used to develop an assay for quantification and typing of HSV. The majority of subjects in which HSV was detected had low levels of CVL fluid HSV, with no detectable HSV-2 antibodies and were asymptomatic.
Permeation of Growth Hormone across the Blood-Brain Barrier
Authors: Pan Weihong , Yu Yongmei , Cain Courtney M. , Nyberg Fred , Couraud Pierre O. , Kastin Abba J.
Published: August 2005

Exogenous GH can affect central nervous system function when given peripherally to animals and as a supplemental therapy to humans. This study tested whether GH crosses the blood-brain barrier (BBB) by a specific transport system and found that both mice and rats have small but significant uptake of GH into the brain without a species difference. Determined by multiple-time regression analysis, the blood-to-brain influx transfer constants of 125I-labeled rat GH in mice (0.23 ± 0.07 μl/g·min) and rats (0.32 ± 0.04 μl/g·min) were comparable to those of some cytokines of similar size, with a half-time disappearance of 125I-GH of 3.8–7.6 min in blood. Intact 125I-GH was present in both serum and brain homogenate 20 min after iv injection. At this time, about 26.8% of GH in brain entered the parenchyma, whereas 10% was entrapped in endothelial cells. Neither excess GH nor insulin showed acute modulation of the influx, indicating lack of a saturable transport system for GH at the BBB. Binding and cellular uptake studies in cultured cerebral microvessel endothelial cells (RBE4) further ruled out the presence of high-capacity adsorptive endocytosis. The brain influx of GH by simple diffusion adds definitive value to the long-disputed question of whether and how GH crosses the BBB. The central nervous system effects of peripheral GH can be attributed to permeation of the BBB despite the absence of a specific transport system.
Cathepsins in the Ovine Uterus: Regulation by Pregnancy, Progesterone, and Interferon Tau
Authors: Song Gwonhwa , Spencer Thomas E. , Bazer Fuller W.
Published: August 2005

Cathepsins (CTS) are peptidases that have biological roles in degrading extracellular matrix, catabolism of intracellular proteins, and processing of prohormones. Expression of CTSB, CTSD, CTSH, CTSK, CTSL, CTSS, and CTSZ genes was detected in the endometria of cyclic and early pregnant ewes with distinct temporal and spatial expression patterns. In the d 18 and 20 conceptus, expression of CTSB, CTSD, CTSL, and CTSZ mRNA was detected in the trophectoderm. Of particular note, CTSL mRNA was the most abundant CTS mRNA in the ovine endometrium and detected only in the luminal epithelium and superficial glandular epithelium of cyclic and pregnant ewes. CTSL mRNA increased 8-fold between d 10 and 18 in endometria of pregnant ewes, whereas it declined between d 14 and 16 in cyclic ewes. CTSL protein was also detected in conceptus trophectoderm, and pro-CTSL was detected in uterine flushings from ewes between d 12 and 16 of pregnancy. In ovariectomized and catheterized ewes, CTSL mRNA in the endometrium was increased by progesterone and intrauterine injections of ovine interferon (IFN)τ. Other endometrial CTS genes were also regulated by progesterone alone (CTSB, CTSK, CTSS, and CTSZ) or progesterone and IFNτ (CTSH, CTSK, CTSS, and CTSZ). These results indicate that CTS of endometrial and conceptus origin may regulate endometrial remodeling and conceptus implantation, endometrial CTS genes are regulated by ovarian and placental hormones, and CTSL is a novel IFNτ-stimulated gene expressed only in luminal epithelium and superficial glandular epithelium of the endometrium.
Overexpression of the Coactivator Bridge-1 Results in Insulin Deficiency and Diabetes
Authors: Volinic Jamie L. , Lee Jee H. , Eto Kazuhiro , Kaur Varinderpal , Thomas Melissa K.
Published: August 2005

Multiple forms of heritable diabetes are associated with mutations in transcription factors that regulate insulin gene transcription and the development and maintenance of pancreatic β-cell mass. The coactivator Bridge-1 (PSMD9) regulates the transcriptional activation of glucose-responsive enhancers in the insulin gene in a dose-dependent manner via PDZ domain-mediated interactions with E2A transcription factors. Here we report that the pancreatic overexpression of Bridge-1 in transgenic mice reduces insulin gene expression and results in insulin deficiency and severe diabetes. Dysregulation of Bridge-1 signaling increases pancreatic apoptosis with a reduction in the number of insulin-expressing pancreatic β-cells and an expansion of the complement of glucagon-expressing pancreatic α-cells in pancreatic islets. Increased expression of Bridge-1 alters pancreatic islet, acinar, and ductal architecture and disrupts the boundaries between endocrine and exocrine cellular compartments in young adult but not neonatal mice, suggesting that signals transduced through this coactivator may influence postnatal pancreatic islet morphogenesis. Signals mediated through the coactivator Bridge-1 may regulate both glucose homeostasis and pancreatic β-cell survival. We propose that coactivator dysfunction in pancreatic β-cells can limit insulin production and contribute to the pathogenesis of diabetes.
Impaired Reproductive Behavior by Lack of GluR-B Containing AMPA Receptors But Not of NMDA Receptors in Hypothalamic and Septal Neurons
Authors: Shimshek Derya R. , Bus Thorsten , Grinevich Valery , Single Frank N. , Mack Volker , Sprengel Rolf , Spergel Daniel J. , Seeburg Peter H.
Published: August 2005

The roles of ionotropic glutamate receptors in mammalian reproduction are unknown. We therefore generated mice lacking a major subtype of (S)-α-amino-3-hydroxy-5-methyl-isoxazolepropionic acid (AMPA) receptors or all N-methyl-d-aspartate (NMDA) receptors in GnRH neurons and other mainly limbic system neurons, primarily in hypothalamic and septal areas. Male mice without NMDA receptors in these neurons were not impaired in breeding and exhibited similar GnRH secretion as control littermates. However, male mice lacking GluR-B containing AMPA receptors in these neurons were poor breeders and severely impaired in reproductive behaviors such as aggression and mounting. Testis and sperm morphology, testis weight, and serum testosterone levels, as well as GnRH secretion, were unchanged. Contact with female cage bedding failed to elicit male sexual behavior in these mice, unlike in control male littermates. Their female counterparts had unchanged ovarian morphology, had bred successfully, and had normal litter sizes but exhibited pronounced impairments in maternal behaviors such as pup retrieval and maternal aggression. Our results suggest that NMDA receptors and GluR-B containing AMPA receptors are not essential for fertility, but that GluR-B containing AMPA receptors are essential for male and female reproduction-related behaviors, perhaps by mediating responses to pheromones or odorants.
Mood, dissociation and false memories using the Deese‐Roediger‐McDermott procedure
Authors: Wright Daniel B. , Startup Helen M. , Mathews Sorcha A.
Published: August 2005

Who is likely to have a false memory? Does being in a certain transient state, such as a negative mood, mean that a person is more like to have a false memory? These important questions are examined using the Deese‐Roediger‐McDermott (DRM) procedure. The amount of false memories was compared with people's score on a dissociation measure and by mood. Unlike past research, which has used different procedures to explore false memories, we found that dissociation was not associated with false memories. We argue that this is because the DRM procedure requires two processes for a false memory (the generation of the critical lure and mistaking its source), while most false memory procedures only require one process (source monitoring error) because the errant information is suggested to the participant. This pattern of results suggests that only errors with the source monitoring process are associated with dissociation. We found that mood was related to false memories, but it was dependent on the specific task demands. If participants were told to recall as many words as they could, then people in a negative mood had more false memories. However, if they were told to recall as many words as they felt like recalling, then there were more false memories for people in a positive mood. This can be explained by the mood‐as‐input hypothesis. Results are discussed in relation to both theories and applications of memory.
Analysis of Albumin-Associated Peptides and Proteins from Ovarian Cancer Patients
Authors: Lowenthal Mark S , Mehta Arpita I , Frogale Kristina , Bandle Russell W , Araujo Robyn P , Hood Brian L , Veenstra Timothy D , Conrads Thomas P , Goldsmith Paul , Fishman David , Petricoin Emanuel F , Liotta Lance A
Published: August 2005

Background: Albumin binds low–molecular-weight molecules, including proteins and peptides, which then acquire its longer half-life, thereby protecting the bound species from kidney clearance. We developed an experimental method to isolate albumin in its native state and to then identify [mass spectrometry (MS) sequencing] the corresponding bound low–molecular-weight molecules. We used this method to analyze pooled sera from a human disease study set (high-risk persons without cancer, n= 40; stage I ovarian cancer, n = 30; stage III ovarian cancer, n = 40) to demonstrate the feasibility of this approach as a discovery method.

Methods: Albumin was isolated by solid-phase affinity capture under native binding and washing conditions. Captured albumin-associated proteins and peptides were separated by gel electrophoresis and subjected to iterative MS sequencing by microcapillary reversed-phase tandem MS. Selected albumin-bound protein fragments were confirmed in human sera by Western blotting and immunocompetition.

Results: In total, 1208 individual protein sequences were predicted from all 3 pools. The predicted sequences were largely fragments derived from proteins with diverse biological functions. More than one third of these fragments were identified by multiple peptide sequences, and more than one half of the identified species were in vivo cleavage products of parent proteins. An estimated 700 serum peptides or proteins were predicted that had not been reported in previous serum databases. Several proteolytic fragments of larger molecules that may be cancer-related were confirmed immunologically in blood by Western blotting and peptide immunocompetition. BRCA2, a 390-kDa low-abundance nuclear protein linked to cancer susceptibility, was represented in sera as a series of specific fragments bound to albumin.

Conclusion: Carrier-protein harvesting provides a rich source of candidate peptides and proteins with potential diverse tissue and cellular origins that may reflect important disease-related information.
Immunoassay Interference by a Commonly Used Blood Collection Tube Additive, the Organosilicone Surfactant Silwet L-720
Authors: Bowen Raffick AR , Chan Yung , Ruddel Mark E , Hortin Glen L , Csako Gyorgy , Demosky Stephen J , Remaley Alan T
Published: August 2005

Background: A small number of immunoassays on several different types of analyzers were recently adversely affected by tube additives in Becton Dickinson (BD) Vacutainer® SST™, SST II, and Microtainer™ blood collection tubes. We examined the effect of a commonly used tube surfactant, Silwet™ L-720, on immunoassays and the mechanism for the interference.

Methods: Immunoassays were performed on serum supplemented with Silwet L-720 on the IMMULITE™ 2500 and AxSYM™ analyzers. Direct effects of the surfactant on the chemiluminescent detection step of immunoassays and on antibody immobilization on the solid phase were examined.

Results: Increasing the final surfactant concentration from 0 to 400 mg/L in serum significantly increased (∼51%) the apparent total triiodothyronine (TT3) concentrations measured on the IMMULITE 2500 but not the AxSYM analyzer. Several other competitive, but not noncompetitive, assays were also significantly affected by the surfactant on the IMMULITE 2500 analyzer. The effect was independent of serum components, and the surfactant had no direct effect on chemiluminescence reactions. The capture antibody, however, was displaced from the solid phase by incubation with solutions containing surfactant under conditions similar to the IMMULITE TT3 assay.

Conclusions: The Silwet L-720 surfactant, which is used to coat the inner surfaces of tubes, appears to account for previously reported immunoassay interference by BD Vacutainer SST blood collection tubes. One of the mechanisms for the interference is the desorption of antibodies from the solid phase by the surfactant. The results identify an important factor in the selection of suitable blood collection tube surfactants and provide an approach for solving similar tube-assay interference problems in the future.
Oxidant‐Antioxidant Status and Pulmonary Function in Welding Workers
Authors: Fidan Fatma , Ünlü Mehmet , Köken Tülay , Tetik Levent , Akgün Sema , Demirel Reha , Serteser Mustafa
Published: August 2005

Oxidant‐Antioxidant Status and Pulmonary Function in Welding Workers: Fatma Fidan, et al. Department of Pulmonary Diseases, Turkey—Welding is a process during which fumes, gases, electromagnetic radiation and noise are emitted as by‐products. Metal oxide particles are particularly hazardous components of welding fumes. Welding has been found to be associated with respiratory symptoms and our objective in the present study was to study the effects of welding on pulmonary function and serum oxidant‐antioxidant status. Fifty‐one welding workers and 31 control subjects were recruited. Face to face interviews were conducted using the respiratory illness questionnaire adapted from the American Thoracic Society with the addition of demographic characteristics, work history and working conditions. Additionally physical examinations and spirometric measurements were performed at workplaces. Thiobarbituric acid reactive substances (TBARS), protein carbonyls, protein sulfhydryls (SH) and erythrocyte reduced glutathione (GSH) levels were measured to evaluate oxidant‐antioxidant status in 34 welding workers and in 20 control subjects. No statistically significant differences were observed in age, height, weight, body mass index (BMI), smoking status and annual working durations between welding workers and controls. Coughing, sputing and wheezing were significantly higher in welding workers (p<0.05). When adjusted for age, BMI and smoking status in logistic regression, welding work showed a significant risk for chronic bronchitis (OR: 4.78, 95%CI: 1.30– 17.54). Forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) and four parameters of forced expiratory flow (FEF: FEF25, FEF50, FEF75, FEF25–75) levels measured in the welding workers were significantly lower than those in the control group (p<0.05). Serum TBARS and protein carbonyl levels were higher in welding workers than those in controls (p<0.001, p<0.05, respectively). On the other hand, total protein SH groups and GSH levels were significantly lower in welders than those in controls (p<0.05, p<0.001, respectively). Pulmonary function tests and oxidant‐antioxidant status were found to be negatively affected in welding workers chronically exposed to welding fumes and gases. Preventive measures should be taken to improve the health status of these workers.
Oral Toxicity of Bismuth in Rat: Single and 28‐Day Repeated Administration Studies
Authors: Sano Yuri , Satoh Hiroshi , Chiba Momoko , Okamoto Masahide , Serizawa Koji , Nakashima Hiroshi , Omae Kazuyuki
Published: August 2005

Oral Toxicity of Bismuth in Rat: Single and 28‐Day Repeated Administration Studies: Yuri Sano, et al. Department of Preventative Medicine and Public Health, School of Medicine, Keio University—The consumption and production of bismuth are increasing, however there is very little information about the direct toxic effect of bismuth. The present study aimed to characterize the potential toxic effects of bismuth through oral administration and observation for fourteen days following single dose of 0 and 2,000 mg/kg (acute oral toxicity study), and repeated oral administration for twenty‐eight days at dose levels of 0, 40, 200, and 1,000 mg/kg daily (28‐d repeated oral dose toxicity study) to male and female Crj:CD (SD) IGS rats (SPF). We found no deaths and no abnormalities in clinical signs, body weights, and necropsy findings for any of the animals in the acute oral toxicity study and no changes attributable to bismuth in either males or females in the dose group up to 1,000 mg/kg of the 28‐d repeated‐dose toxicity study. Therefore, we determined that the lethal dose with a 50% mortality rate (LD50) is greater than 2,000 mg/kg and the no‐observed‐adverse‐effect level (NOAEL) of bismuth is 1,000 mg/kg in both sexes. We conclude that the adverse toxic effects of bismuth as a simple metal substance are low compared to lead toxicity under the conditions tested in our studies.
Exposure Assessment to Suggest the Cause of Sinusitis Developed in Grinding Operations Utilizing Soluble Metalworking Fluids
Authors: Park Donguk , Choi Byungsoon , Kim Shinbum , Kwag Hyunseok , Joo Kuidon , Jeong Jongdeuk
Published: August 2005

Exposure Assessment to Suggest the Cause of Sinusitis Developed in Grinding Operations Utilizing Soluble Metalworking Fluids: Donguk Park et al. Korea National Open University, Korea—A worker who ground the inner parts of camshafts for automobile engines using water‐soluble metalworking fluid (MWF) for 14 yr was diagnosed with sinusitis. We postulated that the cause of sinusitis might be associated with exposure to microbes contaminating the water‐soluble MWF used in the grinding operation. To uncover responsible agents for this case of sinusitis, a quantitative exposure assessment for chemical and biological agents was made and prevalence of work‐related respiratory symptoms was investigated by questionnaire. The exposure ranges of MWF mist (0.59 mg/m3 to 2.12 mg/ m3) measured during grinding exceeded 0.5 mg/m3 of the recommended exposure limit (REL). Grinders’ exposures to bacteria, fungi and endotoxins were also generally higher than not only the proposed standards, but also those reported by several studies investigating the causes of respiratory effects. Statistical tests indicated that the prevalence rate of reported symptoms related to nasal cavities showed no significant differences among the operations. Evaluation of grinding operation characteristics and the quantitative exposure assessment indicated that repeated exposure to MWF mist, including water‐soluble MWF contaminated with microbes may cause respiratory diseases like sinusitis or at least increase susceptibility to the development of sinusitis. Further study is underway to identify environmental risk factors for sinusitis by analyzing the relationship between medical examination results and plant characteristics including exposure data.
Environmental and Biological Monitoring in a Lead Acid Battery Manufacturing Unit in India
Authors: Ravichandran B , Ravibabu K , Raghavan S , Krishnamurthy V , Rajan BK , Rajmohan HR
Published: August 2005

Environmental and Biological Monitoring in a Lead Acid Battery Manufacturing Unit in India: B Ravichandran, et al. Regional Occupational Health Centre, Bangalore Medical College Campus, India— An environmental and biological monitoring of a lead acid battery manufacturing unit was carried out to measure the respirable particulate matter, lead content in working atmosphere and blood lead levels of workers employed in different sections. The results showed high mean air lead concentration in buffing (1444.45 µg/m3), plate cutting (430.14 µg/m3) and pasting (277.48 µg/m3) sections. The mean blood lead levels of employees in these sections were also higher than the values prescribed by ACGIH.
Childhood Overweight and Maturational Timing in the Development of Adult Overweight and Fatness: The Newton Girls Study and Its Follow-up
Authors: Must Aviva , Naumova Elena N. , Phillips Sarah M. , Blum Miriam , Dawson-Hughes Bess , Rand William M.
Published: August 2005

Objective. Although several studies have suggested that early menarche is associated with the development of adult overweight, few have accounted for childhood overweight before menarche.

Study Design. A 30-year follow-up of the original participants in the Newton Girls Study, a prospective study of development in a cohort of girls followed through menarche, provided data on premenarcheal relative weight and overweight (BMI >85th percentile), prospectively obtained age at menarche, self-reported adult BMI, overweight (BMI > 25), obesity (BMI > 30) and, for a subset of participants, percentage body fat by dual-energy x-ray absorptiometry.

Results. Of the 448 women who participated in the adult follow-up at a mean age of 42.1 years (SD: 0.76 years), 307 had childhood data with which to characterize premenarcheal and menarcheal weight status and age at menarche. After a follow-up of 30.1 years (SD: 1.4 years), reported BMI was 23.4 (4.8), 28% were overweight, and 9% were obese. In multivariate linear and logistic-regression analyses, almost all of the influence on adult weight status was a result of premenarcheal weight status (model R2 = 0.199). Inclusion of a variable to reflect menarcheal timing provided very little additional information (model R2 = 0.208). Girls who were overweight before menarche were 7.7 times more likely to be overweight as adults (95% confidence interval: 2.3, 25.8), whereas early menarche (at ≤12 years of age) did not elevate risk (odds ratio: 1.3, 95% confidence interval: 0.66, 2.43). A similar pattern of results was observed when percentage body fat in adulthood was evaluated.

Conclusions. The apparent influence of early maturation on adult female overweight is largely a result of the influence of elevated relative weight on early maturation. Interventions to prevent and treat overweight should focus on girls before they begin puberty.
Effect of Solid Solution Impurities on Dislocation Nucleation During Nanoindentation
Authors: Bahr D.F. , Vasquez G.
Published: August 2005

Dislocation nucleation in solid solutions of face-centered-cubic metallic materials was studied using nanoindentation. The effects of solute impurities in the copper–nickel system on the formation of dislocations in a previously dislocation-free region were demonstrated to be minimal. The shear stress required to nucleate dislocations in copper is approximately 1.6 GPa, while in nickel a 3.9 GPa shear stress is required. Changes in shear stress for nucleation track closely with changes in elastic modulus showing the nucleation stress is approximately 1/30 to 1/20 of the shear modulus. The expected solid-solution strengthening is identified within the same experimental method, demonstrating unambiguously the fact that solid-solution impurities in this system will impact the propagation of dislocations during plastic deformation but not alter the homogeneous nucleation of dislocations in these materials.