bluuebunny/crossref_metadata_2025 huggingface dataset:
Syncope in patients with pulmonary embolism: comparison between patients with syncope as the presenting symptom of pulmonary embolism and patients with pulmonary embolism without syncope
Authors: Castelli R , Tarsia P , Tantardini C , Pantaleo G , Porro A Guariglia F
Published: April 2004

Syncope as an initial presentation of pulmonary embolism occurs in 10% of patients. We compared clinical and instrumental parameters in patients with syncope as the presenting symptom of pulmonary embolism and in patients with documented pulmonary embolism without syncope. Seventy patients with the diagnosis of pulmonary embolism and apparently stable clinical conditions were evaluated. They were divided in two groups: 10 patients with syncope as the presenting symptom of pulmonary embolism (group 1) and 60 patients without syncope (group 2). Patients with syncope showed a more pronounced tendency to present with main pulmonary artery embolus than patients without syncope (contingency coefficient = 0.301, p < 0.04; one-tailed). However, despite the evidence that patients with syncope have significant reductions in systolic and=or diastolic blood pressure, shock was not observed in any patient. In no case was thrombolytic treatment given and all patients received standard anticoagulation with unfractioned heparin and oral anticoagulant. We suggest that syncope in the setting of non-massive pulmonary embolism may be due to vaso-vagal mechanism that can lead to a reduction of arterial blood pressure when central artery thrombosis is involved.
Vascular viewpoint
Authors: Anand Sonia S
Published: April 2004

Question: To determine by how much statins reduce serum concentrations of low density lipo-protein (LDL) cholesterol according to drug, dose, and duration of treatment.

Population: Patients included in randomized, placebo-controlled trials of six statins (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin).

Design and methods: Meta analysis of 164 short-term, randomized trials including 24 000 drug-treated and 14000 placebo-treated patients. Studies were found by searching Medline, the Cochrane Collaboration, Web of Science databases, and BMJ.com. All double-blind, placebo-controlled trials were considered eligible. Excluded trials were those with no placebo group, any which lasted less than 2 weeks, those that used titrated doses, those that used combination drugs to lower cholesterol, crossover trials, or those with chronic renal failure patients. The efficacy of each statin was defined as the reduction of LDL for a given dose of a statin expressed as the change in the treated group minus that in the placebo group.

Results: The doses of atorvastatin, lovastatin, rosuvastatin and simvastatin used to lower LDL by an absolute amount of 1.8 mmol=l or 40% are shown in the table. Pravastatin and fluvastatin were a less effective treatment, with maximum doses (80 mg=day) lowering LDL by 1.58 mmol=l and 1.60 mmol=l, respectively. Statins increased high density lipoprotein cholesterol by 0.07 mmol=l on average with no dose effects observed. For safety outcomes, 1063=14 197 statin patients compared with 923=10 568 control patients reported one or more symptoms possibly associated with the drug. Rhabdomyolysis was observed in eight statin patients compared with five placebo patients.

[Table: see text]

Conclusion: Statins can lower the LDL cholesterol concentration by an average of 1.8 mmol=l, and the LDL lowering effect varies across statin type and dose: simvastatin, lovastatin, atorvastatin and rosuvastatin appearing more effective, and fluvastatin and pravastatin appearing less effective.
Monteggia fractures in adults
Authors: Ramisetty NM , Revell M , Porter KM , Greaves I
Published: April 2004

Monteggia fractures are part of a spectrum of forearm injuries and commonly result either from a fall on the outstretched arm with forced pronation or from a direct injury. An understanding of the mechanism of injury and an appropriate clinical examination followed by operative intervention is the basis of present day good practice. This paper reviews the literature and presents a contemporary overview of the Monteggia fracture in adults.
Review of the biomechanics and patterns of limb fractures
Authors: McGee AM , Qureshi AA , Porter KM
Published: April 2004

The pattern of a limb fracture can be determined by the material property of the bone and the characteristics of the deforming force. In this review we outline the composition and material properties of cortical and cancellous bone, and articular cartilage. We defi ne the biomechanics of fractures and describe the various fracture patterns that are seen clinically.
Galeazzi fractures in adults
Authors: Ramisetty NM , Revell M , Porter KM
Published: April 2004

Galeazzi fractures are not uncommon. They frequently result from falls with forced hyperpronation of the forearm. They are potentially unstable because of certain destabilizing factors at the wrist. Early recognition is essential, as is early operative xation of the radius in adults. This paper reviews the English language literature and current knowledge of Galeazzi fractures in adults.
Commonly missed injuries in the accident and emergency department
Authors: Lee Caroline , Bleetman Anthony
Published: April 2004

Accident and emergency (A&E) medicine is a high-risk speciality in which the majority of patients are managed by junior doctors with limited clinical experience. A review of the literature identified that the rate of missed injury ranges from 0.4 to 65%. Missed injuries are by definition preventable and have multiple implications for patients and health-care workers. This article reviews the types of injury that are commonly missed in A&E departments and identifies the errors that have been made in the past, with recommendations for management strategies to reduce the incidence of missed injury.
Presentation, examination, investigation and early treatment of acute knee injuries
Authors: Hunt PA , Greaves Ian
Published: April 2004

Acute knee injuries are common presentations that frequently occur during sporting activities and can result in permanent disability. However, they often result in a single visit, seldom receive surgical intervention and, in the main, are cared for entirely by General Practitioners or Emergency Department physicians. Thorough clinical assessment and appropriate early treatment at the primary presentation is vital in order to offer the best chance of maximal functional recovery and to minimize long-term disability. This requires a sound knowledge of basic knee anatomy, careful assessment of the mechanism of injury, detection and consideration of physical ndings and the results of adjunctive investigations. This article aims to give a comprehensive review of the examination, investigation and early treatment of acute knee injuries at the primary presentation. In addition, comments on important epidemiological and aetiological factors and a brief description of basic knee anatomy are also provided.
Trauma and critical care II: abdominal trauma
Authors: Thavasothy M
Published: April 2004

The Intensivist is involved in the management of patients with abdominal trauma from their original presentation in the Emergency Department, where assessment of haemodynamic stability will influence the decision to opt for surgical, as opposed to conservative, treatment. Subsequently a large percentage of these patients, particularly those with blunt abdominal injuries, may require level 2 (HDU) or level 3 (ITU) care to monitor progress, correct any coagulopathy, maintain organ support and allow for early recognition of the major sequelae of such injuries. These include severe sepsis, trauma-related pancreatitis and the abdominal compartment syndrome. All are associated with significant morbidity and mortality, usually many days or weeks after admission. This article, in addition to reviewing some of the contributory factors involved in trauma-related coagulopathy, will discuss these sequelae and some of the concepts and strategies currently used in their management. It also includes an overview of therapies used in a critical care setting to maintain nutrition and renal homeostasis in the event of sequential organ failure.
WB Cannon: a trauma pioneer
Authors: Horne ST
Published: April 2004

Many papers on hypovolaemia refer to ‘The Preventive Treatment of Wound Shock’ (Cannon WB, Fraser J, Cowell E. 1918. The preventive treatment of wound shock. JAMA 70: 618- 21). It is a practical paper dealing with the sequelae of blood loss, and how to minimize their impact in injured soldiers. Despite constant reference to this work, Cannon is not a name that is often heard in British medical circles, and many of his achievements are not well remembered. He was, however, a key researcher into many aspects of the physiology upon which our medical practice depends today. This brief paper aims to introduce this important gure to a wider circle.
Current concepts in the diagnosis and management of trauma-related sepsis
Authors: Easby Jason , Greaves Ian
Published: April 2004

Traumatic injury is common, and accounts for a large health care burden. Trauma and in particular haemorrhagic shock are closely related to the onset of multiple organ failure, the systemic inflammatory response and sepsis. Despite overall improvements in the care of septic critically ill patients there has been little impact on morbidity and mortality. In recent years our understanding of sepsis both as an illness and at a molecular level has led to the development of a number of therapeutic interventions. This article outlines the current evidence for such interventions and points to possible future research that is required in the diagnosis and management of trauma-related sepsis.
Place and the art of belonging
Authors: Mackenzie A. Fiona D.
Published: April 2004

This paper explores the connections among place, identity and visual art with reference to the Harris Tapestry, created to mark the beginning of a new Millennium on the Isle of Harris, Outer Hebrides, Scotland. I focus on the material practices through which the Tapestry was created and the historical and cultural metaphors evoked through its embroidered motifs with a view to considering what it means to belong on the island. As a site where people’s stories of the past and present are translated into the visual field, the Tapestry is a deeply politicized aesthetics, making visible social relations through which both island and aesthetic spaces are constituted. Centrally, these concern rights to land, the Tapestry exposing tensions through which metaphors of belonging have been challenged and resisted through time. In this sense, the Tapestry is iconic of a ‘culture of resistance’ (Said, 1994) whose geography is island-centred rather than globally peripheral.
The nature of protest: constructing the spaces of British Columbia’s rainforests
Authors: Rossiter David
Published: April 2004

This paper examines the representations of nature circulating in a Greenpeace anti-logging campaign in British Columbia, Canada. The effort to stop industrial logging in a region of the central coast named ‘the Great Bear Rainforest’ is presented as a case study through which nature’s social production can be glimpsed. Part of the larger ‘war in the woods’ that gripped British Columbia throughout the 1990s, the campaign considered here pitted Greenpeace and other environmental non-governmental organizations and their grassroots supporters against the forestry industry and many members of resource-producing communities. Through an analysis of campaign literature, newspaper coverage and ‘letters to the editor’, it is argued that the preservationist position advanced by Greenpeace visually and discursively constructs a concept of pristine nature which appeals to urban populations, employs a neocolonial representation of First Nations peoples and the nature within which they are situated, and finds authority and legitimacy in ecosystem discourse. Drawing both on work by Matthew Sparke concerning mapping and the narration of the nation and on Haripriya Rangan’s identification of regionality as a key concept in understanding nature’s production, it is suggested that the construction of nature considered in this case study needs to be understood as part of an articulation of a particular west coast metropolitan identity.
Monsters of modernity: Frankenstein and modern environmentalism
Authors: Hammond Kim
Published: April 2004

The story of Frankenstein is often interpreted and mobilized as a powerful and popular symbol of concerns over the risks and dangers of science, progressive modernity and its ensuing technological creations, and - as in the recent GM ‘Frankenstein food’ debate - the dangers of ‘messing with nature’ or ‘playing God’. Shelley’s narrative is seen to symbolize Romantic fears, offering a dystopic tale of certain demise, one that demonizes technology in the form of Frankenstein’s ‘monster’. Such interpretations and mobilizations align the myth of Frankenstein with the neo-Romantic, conservative, nostalgic and counter-modern currents of elements of deep green, ecobiocentric ideology. In contrast, and in the context of contemporary environmental discourses, this paper offers a reading of Frankenstein as a critical questioning of both anti-Enlightenment Romanticism and anti-Enlightenment science that provides a framework for evaluating contemporary ecobiocentric ideals. Frankenstein is not an outdated tale. Shelley’s novel is characterized and punctuated by a subtle and sophisticated appreciation of the vital role of social relations in determining the nature, direction, products and consequences of science and technology. The tale of Frankenstein presents a challenge to the usual anti-modernist, anti-science, pro-nature alignments of the Frankenstein myth, drawing our attention instead to important questions about what kind of socio-nature we want produced, by whom, for what purposes and under what conditions.
Impact of BRCA1/BRCA2 Counseling and Testing on Newly Diagnosed Breast Cancer Patients
Authors: Schwartz Marc D. , Lerman Caryn , Brogan Barbara , Peshkin Beth N. , Hughes Halbert Chanita , DeMarco Tiffani , Lawrence William , Main David , Finch Clinton , Magnant Colette , Pennanen Marie , Tsangaris Theodore , Willey Shawna , Isaacs Claudine
Published: April 2004

Purpose

Approximately 5% to 10% of newly diagnosed breast cancer patients carry a BRCA1 or BRCA2 mutation. Given these patients' high risk for contralateral breast cancer, bilateral mastectomy is increasingly considered a treatment option for newly diagnosed BRCA1/2 carriers. In the present study, we prospectively evaluated the impact on surgical decision-making of pretreatment genetic counseling and BRCA1/BRCA2 testing among breast cancer patients at high-risk for carrying a mutation.

Patients and Methods

Participants were 194 newly diagnosed breast cancer patients who had not yet received definitive surgical treatment and who had at least a 10% prior probability of carrying a BRCA1/2 mutation. Participants were offered free genetic counseling and rapid BRCA1/2 testing. Primary analyses focused on the impact of BRCA1/2 test result on subsequent breast cancer surgical treatment.

Results

Forty-eight percent of patients who were found to carry a BRCA1/2 mutation chose bilateral mastectomy as their definitive breast cancer surgery. In contrast, 24% of patients in whom no mutation was detected and 4% of test decliners opted for bilateral mastectomy. Additional predictors of bilateral mastectomy included patients' self-reports of physician recommendations for BRCA1/2 testing and bilateral mastectomy.

Conclusion

This study highlights patient interest in and the technical feasibility of offering presurgery BRCA1/2 testing to high-risk patients. Most importantly, these results demonstrate that BRCA1/2 test results significantly affect patients' surgical decision-making. The availability of genetic counseling and testing could serve as a valuable aid to patient decision-making for newly diagnosed breast cancer patients at high-risk for carrying a mutation.
Pooled Analysis of Fluorouracil-Based Adjuvant Therapy for Stage II and III Colon Cancer: Who Benefits and by How Much?
Authors: Gill Sharlene , Loprinzi Charles L. , Sargent Daniel J. , Thomé Stephan D. , Alberts Steven R. , Haller Daniel G. , Benedetti Jacqueline , Francini Guido , Shepherd Lois E. , Francois Seitz Jean , Labianca Roberto , Chen Wei , Cha Stephen S. , Heldebrant Michael P. , Goldberg Richard M.
Published: April 2004

Purpose

Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain.

Patients and Methods

Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets.

Results

Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients.

Conclusion

Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs . This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.
Eplerenone, But Not Steroid Withdrawal, Reverses Cardiac Fibrosis in Deoxycorticosterone/ Salt-Treated Rats
Authors: Young Morag , Funder John W.
Published: April 2004

Aldosterone has been thought to act primarily on epithelia to regulate fluid and electrolyte homeostasis. Mineralocorticoid receptors (MR), however, are also expressed in nonepithelial tissues, such as the heart and vascular smooth muscle. Recently, pathophysiological effects of nonepithelial MR activation by aldosterone have been demonstrated in the context of inappropriate mineralocorticoid levels for salt status, including coronary vascular inflammation and cardiac fibrosis. These effects are mostly prevented by the concomitant administration of MR antagonists, but to date, no equivalent studies have determined whether MR blockade can reverse established inflammation and fibrosis. Uninephrectomized rats maintained on 0.9% NaCl solution to drink were treated as follows: group 1 served as controls; group 2 received deoxycorticosterone (DOC; 20 mg/wk) for 4 wk until death, and group 3 received DOC for 8 wk. Group 4 received DOC for 4 wk and no steroid from wk 5–8; group 5 received DOC for 8 wk and eplerenone in their chow during wk 5–8. DOC progressively raised cardiac collagen accumulation at 4 and 8 wk. Rats given DOC for 4 wk and killed at 8 wk showed levels of fibrosis identical to those in animals killed at 4 wk, i.e. persistently elevated above control values. Rats given DOC for 8 wk and eplerenone for the second half of the period showed cardiac collagen levels indistinguishable from control values. Values for inflammatory marker and NAD(P)H oxidase subunit expression in coronary vessels showed a similar pattern of response, with minor variation. Thus, MR antagonists do not only prevent cardiac fibrosis, but also reverse cardiac fibrosis once it is established. In addition, the continuing vascular inflammatory response and fibrosis after DOC withdrawal (group 4) support a role for activation of vascular MR by endogenous glucocorticoids in the context of tissue damage and generation of reactive oxygen species.
Thyroid Hormone Affects Secretory Activity and Uncoupling Protein-3 Expression in Rat Harderian Gland
Authors: Chieffi Baccari Gabriella , Monteforte Rossella , de Lange Pieter , Raucci Franca , Farina Paola , Lanni Antonia
Published: April 2004

The effects of T3 administration on the rat Harderian gland were examined at morphological, biochemical, and molecular levels. T3 induced hypertrophy of the two cell types (A and B) present in the glandular epithelium. In type A cells, the hypertrophy was mainly due to an increase in the size of the lipid compartment. The acinar lumina were filled with lipoproteic substances, and the cells often showed an olocrine secretory pattern. In type B cells, the hypertrophy largely consisted of a marked proliferation of mitochondria endowed with tightly packed cristae, the mitochondrial number being nearly doubled (from 62 to 101/100 μm2). Although the average area of individual mitochondria decreased by about 50%, the total area of the mitochondrial compartment increased by about 80% (from 11 to 19/100 μm2). This could be ascribed to T3-induced mitochondrial proliferation. The morphological and morphometric data correlated well with our biochemical results, which indicated that mitochondrial respiratory activity is increased in hyperthyroid rats. T3, by influencing the metabolic function of the mitochondrial compartment, induces lipogenesis and the release of secretory product by type A cells. Mitochondrial uncoupling proteins 2 and 3 were expressed at both mRNA and protein levels in the euthyroid rat Harderian gland. T3 treatment increased the mRNA levels of both uncoupling protein 2 (UCP2) and UCP3, but the protein level only of UCP3. A possible role for these proteins in the Harderian gland is discussed.
Extrahypothalamic Expression of the Glucagon-Like Peptide-2 Receptor Is Coupled to Reduction of Glutamate-Induced Cell Death in Cultured Hippocampal Cells
Authors: Lovshin J. A. , Huang Q. , Seaberg R. , Brubaker P. L. , Drucker D. J.
Published: April 2004

Proglucagon-derived glucagon-like peptide-2 (GLP-2) is liberated in enteroendocrine cells and neurons. GLP-2 regulates energy absorption and epithelial integrity in the gastrointestinal tract, whereas GLP-2 action in the central nervous system remains poorly defined. We identified proglucagon and GLP-2 receptor (GLP-2R) mRNA transcripts by RT-PCR in multiple regions of the developing and adult rat central nervous system. GLP-2R mRNA transcripts were localized by in situ hybridization to the hippocampus, hypothalamus, nucleus of the solitary tract, parabrachial nucleus, supramammillary nucleus, and substantia nigra. The bioactive form of GLP-2, GLP-2-(1–33) was detected by RIA and HPLC analysis in the fetal and adult brainstem and hypothalamus. GLP-2 stimulated increases in cAMP accumulation in postnatal d 8, but not embryonic d 14, dispersed neonatal rat brainstem tissues. The actions of GLP-2 were independent of the GLP-1R antagonist exendin-(9–39), and GLP-2 stimulated cAMP accumulation in hippocampal cell cultures from both wild-type and GLP-1R−/− mice. GLP-2 significantly reduced glutamate-induced excitotoxic injury in hippocampal cells via a protein kinase A-dependent pathway, but had no effect on the rate of cell proliferation. These findings establish the presence of a functional GLP-2-GLP-2R axis in the developing rodent brain and demonstrate that GLP-2 exerts cytoprotective actions in cells derived from the central nervous system.
Penile Development Is Initiated in the Tammar Wallaby Pouch Young during the Period when 5α-Androstane-3α,17β-Diol Is Secreted by the Testes
Authors: Leihy Michael W. , Shaw Geoffrey , Wilson Jean D. , Renfree Marilyn B.
Published: April 2004

Virilization of the urogenital tract is under the control of testicular androgens in all mammals. In tammar young, prostate differentiation begins between d 20 and d 40 under the control of the testicular androgen 5α-androstane-3α,17β-diol (5α-adiol), but uncertainties exist about the control of penile development. We performed longitudinal studies up to d 150 of pouch life to define normal penile development and the effects of androgen administration and castration. In control animals the male phallus was longer than the female phallus by d 48. Closure of the urethra in males begins around d 60 and continues to at least d 150. Administration of supraphysiological doses of testosterone to females caused penile development equivalent to that of the male and also induced partial closure of the urethral groove by d 150. Castration of male pouch young at d 25 prevented penile development, whereas the penis in males castrated at d 40, 80, or 120 had partial closure of the urethral groove. Administration of 5α-adiol to females from d 20–40 also caused partial closure of the urethral groove and some growth of the phallus at d 150, whereas 5α-adiol treatment from d 40–80 or 80–120 caused some penile growth but had little effect on urethral development. These findings, together with the fact that we found no sex differences in plasma levels of testosterone, dihydrotestosterone, 5α-adiol, dehydroepiandrosterone, or androstenedione from d 51–227, clearly indicate that the action of 5α-adiol between d 20 and 40 imprints later differentiation of the male penis.
Genetic Background (C57BL/6J Versus FVB/N) Strongly Influences the Severity of Diabetes and Insulin Resistance in ob/ob Mice
Authors: Haluzik Martin , Colombo Carlo , Gavrilova Oksana , Chua Streamson , Wolf Nicole , Chen Min , Stannard Bethel , Dietz Kelly R. , Le Roith Derek , Reitman Marc L.
Published: April 2004

We studied the effects of genetic background on the phenotype of ob/ob mice, a model of severe obesity, insulin resistance, and diabetes caused by leptin deficiency. Despite a comparable degree of obesity and hyperinsulinemia, C57BL/6J ob/ob mice had much milder hyperglycemia and, surprisingly, normal circulating adiponectin levels despite still-prominent signs of insulin resistance. Hyperinsulinemic-euglycemic clamp revealed relatively less whole-body and muscle insulin resistance in C57BL/6J ob/ob mice, whereas liver insulin resistance tended to be more severe than in FVB/N ob/ob mice. C57BL/6J ob/ob mice had also more rapid clearance of circulating triglycerides and more severe hepatic steatosis. We suggest that strain-related distinction in lipid handling is the most important player in the differences in diabetic phenotype and insulin sensitivity, whereas the impact of circulating adiponectin levels on the overall phenotype of ob/ob mice is less important.
Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar
Authors: Hegarty Bronwyn D. , Furler Stuart M. , Oakes Nicholas D. , Kraegen Edward W. , Cooney Gregory J.
Published: April 2004

Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.
Thyroid Hormone Causes Mitogen-Activated Protein Kinase-Dependent Phosphorylation of the Nuclear Estrogen Receptor
Authors: Tang Heng-Yuan , Lin Hung-Yun , Zhang Shenli , Davis Faith B. , Davis Paul J.
Published: April 2004

Activated by thyroid hormone, the MAPK (ERK1/2) signaling pathway causes serine phosphorylation by MAPK of several nucleoproteins, including the nuclear thyroid hormone receptor β1. Because estrogen can activate MAPK and cause MAPK-dependent serine phosphorylation of nuclear estrogen receptor (ER)α, we studied whether thyroid hormone also promoted MAPK-mediated ERα phosphorylation. Human breast cancer (MCF-7) cells were incubated with physiological concentrations of l-T4 or 17β-estradiol (E2) for 15 min to 24 h, and nuclear ERα and serine-118-phosphorylated ERα were identified by Western blotting. Serine-118-phosphorylated ERα was recovered at 15 min in nuclei of MCF-7 cells exposed to either T4 or E2. The T4 effect was apparent at 15 min and peaked at 2 h, whereas the E2 effect was maximal at 4–6 h. T4-agarose was as effective as T4 in causing phosphorylation of ERα. T4 action on ERα was inhibited by PD 98059, an inhibitor of ERK1/2 phosphorylation, and by tetraiodothyroacetic acid, a T4 analog that blocks cell surface-initiated actions of T4 but is not itself an agonist. Electrophoretic mobility shift assay of nuclear extracts from T4-treated and E2-treated cells showed similar specific protein-DNA-binding. Indexed by [3H]thymidine incorporation and nuclear proliferating cell nuclear antigen, MCF-7 cell proliferation was stimulated by T4 and T4-agarose to an extent comparable with the effect of E2. This T4 effect was blocked by either PD 98059 or ICI 182,780, an ER antagonist. Thus, T4, like E2, causes phosphorylation by MAPK of nuclear ERα at serine-118 in MCF-7 cells and promotes cell proliferation through the ER by a MAPK-dependent pathway.
Dissolution media simulating the intralumenal composition of the small intestine: physiological issues and practical aspects
Authors: Vertzoni Maria , Fotaki Nikoletta , Nicolaides Eleftheria , Reppas Christos , Kostewicz Edmund , Stippler Erika , Leuner Christian , Dressman Jennifer
Published: April 2004

The objective of this study was to test various aspects of dissolution media simulating the intralumenal composition of the small intestine, including the suitability of the osmolality-adjusting agents and of the buffers, the substitution of crude sodium taurocholate (from ox bile) for pure sodium taurocholate and the substitution of partially hydrolysed soybean phosphatidylcholine for egg phosphatidylcholine. It was concluded that biorelevant media should contain sodium as the major cation species to better reflect the physiology. However, the use of non-physiologically relevant buffers is inevitable, especially for simulation of the fed state in the small intestine. The buffers used may affect the solubility product of weakly basic compounds with pKa(s) higher than about 5, the solubility of extremely highly lipophilic compounds due to salting in/out properties of the anion of the buffer and the stability of the dissolving compound. It is prudent in relevant situations to run an additional dissolution test in a modified fed state simulated intestinal fluid (FeSSIF) (or fasted state simulated intestinal fluid (FaSSIF), where applicable) containing alternative buffer species. Although a mixture of bile salts is physiologically more relevant than pure sodium taurocholate, this issue seems to be of practical importance in only a few cases. Adequate simulations in these cases will probably require the use of a number of pure substances and could substantially increase the cost of the test. Finally, unless the drug is extremely lipophilic (ca. logP > 5), egg phosphatidylcholine can be substituted by partially hydrolysed soybean phosphatidylcholine.
A gallic acid derivative and polysaccharides with antioxidative activity from rose (Rosa rugosa) flowers
Authors: Ng T B , He J S , Niu S M , Pi Z F , Shao W , Liu F , Zhao L
Published: April 2004

In this study, the major antioxidant components of rose flower were identified. An aqueous extract of rose flowers was chromatographed on CM-cellulose in ammonium acetate buffer (10 mm, pH 4.5) to yield three un-adsorbed peaks F1, F2 and F3. Each of these peaks was subjected to gel filtration on Sephadex G75. F1 yielded two peaks, whereas both F2 and F3 gave rise to only a single peak. Spectroscopic studies using NMR and FTIR revealed that F3 is a gallic acid derivative. It exhibited the highest antioxidative potency. F1-a derived from F1 by gel filtration is mainly a polysaccharide-peptide complex with less potent antioxidative activity. F2 is a polysaccharide also with reduced antioxidant activity. This study demonstrates, for the first time, the presence of both gallic acid derivatives and polysaccharides as major antioxidant principles of the aqueous extract of rose flowers.
Coptidis Rhizoma: protective effects against peroxynitrite-induced oxidative damage and elucidation of its active components
Authors: Yokozawa Takako , Ishida Ai , Cho Eun Ju , Kim Hyun Young , Kashiwada Yoshiki , Ikeshiro Yasumasa
Published: April 2004

We have investigated the protective effects of Coptidis Rhizoma against peroxynitrite (ONOO−)-induced oxidative damage and have elucidated the active components of this preparation. In an invitro system, Coptidis Rhizoma extract scavenged ONOO− and its precursors, nitric oxide (NO) and superoxide anion (O2−). This scavenging activity was more marked for ONOO− than its precursors. In addition, against 3-morpholinosydnonimine-induced cellular damage, this extract significantly reduced cellular ONOO− formation and increased cell viability. In an in-vivo lipopolysaccharide plus ischaemia-reperfusion system that generated ONOO−, the administration of Coptidis Rhizoma extract at 50 and 100 mg kg−1/day for 30 days exerted greater inhibition of ONOO− than NO and O2−. This suggested that it acted as a direct scavenger of ONOO− rather than as a scavenger of its precursors. Moreover, the suppression of the activities of the antioxidative enzymes superoxide dismutase, catalase and glutathione peroxidase was significantly attenuated by the administration of Coptidis Rhizoma extract. Furthermore, the extract ameliorated renal dysfunction judged by decreasing serum urea nitrogen and creatinine levels. To elucidate the active components of Coptidis Rhizoma extract, we evaluated and compared the effects of the phenol plus alkaloid and alkaloid fractions on ONOO−-induced damage. We found that the alkaloid fraction consisting of berberine, palmatine and coptisine was the most effective at protecting against ONOO−. We confirmed that berberine (10 and 20 mg kg−1/day for 10 days), the main and most active alkaloid in Coptidis Rhizoma extract, was also protective, exerting NO-, O2−- and ONOO−-scavenging activities. This study suggested that Coptidis Rhizoma could protect against ONOO−-induced oxidative damage and that this effect was mainly attributable to the constituent alkaloids, especially berberine. This study is the first to demonstrate an antioxidative effect of alkaloids, including berberine, against ONOO−-induced damage.
Astilbin prevents concanavalin A-induced liver injury by reducing TNF-α production and T lymphocyte adhesion
Authors: Wang Jun , Zhao Ying , Xu Qiang
Published: April 2004

The aim of this study was to evaluate the effect of astilbin on concanavalin A (Con A)-induced hepatitis, a T cell-dependent model of liver injury. Con A administration resulted in a severe liver injury in mice, with a strong increment in spleen cell adhesion and liver infiltration of T cells, as well as in tumour necrosis factor (TNF)-α production. Against this liver injury, astilbin significantly inhibited the elevation in transaminase activity, reduced the TNF-α production, and improved the histological changes, including inflammatory infiltration, hepatocyte necrosis and degeneration and Kupffer cell hyperplasia. In addition, astilbin inhibited the adhesion of spleen cells and purified T lymphocytes isolated from the liver-injured mice to fibronectin, laminin and type IV collagen. Moreover, the adhesion of human Jurkat T cells to endothelial cell line ECV-304 was also inhibited by astilbin. These results suggest that the improvement of the T cell-mediated liver injury by astilbin may be related to the reduction in TNF-α production and in T cell adhesion to extracellular matrices and endothelial cells.
Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy volunteers
Authors: Antonijoan R M , Barbanoj M J , Cordero J A , Peraire C , Obach R , Vallès J , CheZérif-Cheikh R , Torres M-L , Bismuth F , Montes M
Published: April 2004

The pharmacokinetics/tolerability of lanreotide Autogel have been evaluated. Healthy volunteers (n = 24) first received immediate-release lanreotide as a single subcutaneous (s.c.) injection. After two days, 40 or 60 mg lanreotide Autogel was injected subcutaneously. Blood was sampled at various intervals for 56 days. Systemic/local adverse events and changes in biological profile/vital signs were recorded. Lanreotide Autogel produced a prolonged-release pharmacokinetic profile: mean area under the serum concentration-time curve from time 0 to infinity (AUC) was 53.73 + 8.99 and 79.48 + 13.06 ng mL−1 day for 40 and 60 mg, respectively, mean peak serum concentration (Cmax) was 4.38 + 2.91 and 5.71 + 3.52 ng mL−1, respectively, median time to reach Cmax (minimum-maximum) was 0.50 (0.083–18.0) and 0.38 (0.083–9.01) days, respectively, mean apparent elimination half-life was 21.63 + 9.42 and 22.01 + 9.87 days, respectively, and relative bioavailability was 0.93 + 0.12 and 0.82 + 0.15, respectively. Thus, lanreotide Autogel exhibited linear pharmacokinetics for the doses studied. Pharmacokinetic profiles were similar in both genders, apart from statistically significant differences in Cmax and Cmax/AUC. The Autogel formulation of lanreotide was well tolerated, with systemic adverse events being mild/moderate. Erythema and a painless subcutaneous induration were the most common local adverse events. Lanreotide Autogel provided a prolonged dosing interval and good tolerability for treating acromegaly and carcinoid syndrome.
Absorption, distribution and excretion of 14C-levofloxacin after single oral administration in albino and pigmented rats: binding characteristics of levofloxacin-related radioactivity to melanin in vivo
Authors: Tanaka Makoto , Ono Chiho , Yamada Masayoshi
Published: April 2004

After single oral administration of 14C-levofloxacin at a dose of 20 mg kg−1 under non-fasting conditions, the absorption, distribution and excretion of radioactivity were studied in albino and pigmented rats. Good penetration of radioactivity into tissues was indicated by higher concentrations in most tissues compared with serum and there were no quantitative differences in the distribution of radioactivity between albino and pigmented rats except for melanin-containing tissues such as the uveal tract of eyes and hair follicles. There was selective and strong binding of drug-related radioactivity to these tissues in pigmented rats. The uveal tract concentrations reached the maximum value (Cmax) of 26.33 + 0.75 μg eq.g−1 at 24 h after dosing and declined slowly with a terminal half-life of 468.1 h (19.5 days). The uveal tract concentration at 12 weeks was 0.73 + 0.12 μg eq.g−1, which is c. 1/36 of Cmax. The AUC0-∞ for the uveal tract was 12.58 mg h−1 g−1. The uveal tracts separated from one eye of each rat were extracted with 0.067 m phosphate buffer (pH 7.4) and 1m HCl/EtOH (30:70), successively. In pigmented rats, approximately 85–48% of radioactivity bound to the uveal tract was released from the tissue by the washing procedures. Most of the eluted radioactivity was released with 1m HCl/EtOH (30:70), indicating that the binding to melanin is reversible, and hydrophobic and electrostatic interactions play an important role in the binding of levofloxacin and/or its metabolites with melanin-containing ocular tissues. Only unchanged drug was detected in the extracts of the uveal tracts. The concentrations and half-life of radioactivity in the uveal tract after dosing of 14C-levofloxacin were found to be much lower and shorter than those after dosing of 14C-chloroquine. It is unlikely that levofloxacin causes toxicity because of its much lower affinity to melanin-containing ocular tissues and shorter duration of therapy compared to chloroquine.
Design, synthesis and properties of novel iron(III)-specific fluorescent probes
Authors: Luo Wei , Ma Yong M , Quinn Peter J , Hider Robert C , Liu Zu D
Published: April 2004

Bidentate chelators such as hydroxypyridinones and hydroxypyranones are highly iron selective. The synthesis of two novel fluorescent probes N-[2-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)ethyl]-2-(7-methoxy-2-oxo-2H-chromen-4-yl)acetamide (CP600) and N-[(3-hydroxy-6-methyl-4-oxo-4H-pyran-2-yl)methyl]-2-(7-methoxy-2-oxo-2H-chromen-4-yl)acetamide (CP610) is reported. The method involves coupling the bidentate ligands, 3-hydroxypyridin-4-one and 3-hydroxypyran-4-one, with the well-characterised fluorescent probe methoxycoumarin. Fluorescence emission of both probes at 380 nm is readily quenched by Fe3+. The fluorescence was quenched to a greater extent by Fe3+ than by Mn2+, Co2+, Zn2+, Ca2+, Mg2+, Na+ and K+ and to approximately the same extent as Cu2+. Comparison of the fluorescence-quenching ability by a range of metal ions on CP600 and CP610 and the hexadentate chelator, calcein, under in-vitro conditions, demonstrated advantages of the two novel fluorescent probes with respect to both iron(III) sensitivity and selectivity. Chelation of iron(III) by CP600 and CP610 leads to the formation of a complex with a metal-to-ligand ratio of 1:3. Fluorescence is quenched on formation of such complexes. These probes possess a molecular weight less than 400 and thus they are predicted to permeate biological membranes by passive diffusion, and have potential for reporting intracellular organelle labile iron levels.
Delivery systems for bone growth factors — the new players in skeletal regeneration
Authors: Rose Felicity R A J , Hou Qingpu , Oreffo Richard O C
Published: April 2004

Given the challenge of an increasing elderly population, the ability to repair and regenerate traumatised or lost tissue is a major clinical and socio-economic need. Pivotal in this process will be the ability to deliver appropriate growth factors in the repair cascade in a temporal and tightly regulated sequence using appropriately designed matrices and release technologies within a tissue engineering strategy. This review outlines the current concepts and challenges in growth factor delivery for skeletal regeneration and the potential of novel delivery matrices and biotechnologies to influence the healthcare of an increasing ageing population.
A genomic analysis ofDrosophilasomatic sexual differentiation and its regulation
Authors: Arbeitman Michelle N. , Fleming Alice A. , Siegal Mark L. , Null Brian H. , Baker Bruce S.
Published: April 2004

In virtually all animals, males and females are morphologically,physiologically and behaviorally distinct. Using cDNA microarrays representing one-third of Drosophila genes to identify genes expressed sex-differentially in somatic tissues, we performed an expression analysis on adult males and females that: (1) were wild type; (2) lacked a germline; or(3) were mutant for sex-determination regulatory genes. Statistical analysis identified 63 genes sex-differentially expressed in the soma, 20 of which have been confirmed by RNA blots thus far. In situ hybridization experiments with 11 of these genes showed they were sex-differentially expressed only in internal genital organs. The nature of the products these genes encode provides insight into the molecular physiology of these reproductive tissues. Analysis of the regulation of these genes revealed that their adult expression patterns are specified by the sex hierarchy during development, and that doublesex probably functions in diverse ways to set their activities.
General transcriptional silencing by a Polycomb response element inDrosophila
Authors: Sengupta Aditya K. , Kuhrs Antje , Müller Jürg
Published: April 2004

Polycomb response elements (PREs) are cis-regulatory sequences required for Polycomb repression of Hox genes in Drosophila. PREs function as potent silencers in the context of Hox reporter genes and they have been shown to partially repress a linked miniwhite reporter gene. The silencing capacity of PREs has not been systematically tested and, therefore, it has remained unclear whether only specific enhancers and promoters can respond to Polycomb silencing. Here, using a reporter gene assay in imaginal discs, we show that a PRE from the Drosophila Hox gene Ultrabithoraxpotently silences different heterologous enhancers and promoters that are normally not subject to Polycomb repression. Silencing of these reporter genes is abolished in PcG mutants and excision of the PRE from the reporter gene during development results in loss of silencing within one cell generation. Together, these results suggest that PREs function as general silencer elements through which PcG proteins mediate transcriptional repression.