bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors associated with development of stroke long‐term after myocardial infarction: experiences from the LoWASA trial
Authors: HERLITZ J. , HOLM J. , PETERSON M. , KARLSON B. W. , EVANDER M. HAGLID , ERHARDT L. ,   FOR THE LOWASA STUDY GROUP
Published: January 2005

Abstract.Objective.  To describe factors associated with the development of stroke during long‐term follow‐up after acute myocardial infarction (AMI) in the LoWASA trial.Patients.  Patients who had been hospitalized for AMI were randomized within 42 days to receive either warfarin 1.25 mg plus aspirin 75 mg daily or aspirin 75 mg alone.Design.  The study was performed according to the probe design, that is open treatment and blinded end‐point evaluation.Setting.  The study was performed in 31 hospitals in Sweden. The mean follow‐up time was 5.0 years with a range of 1.7–6.7 years.Results.  In all, 3300 patients were randomized in the trial, of which 194 (5.9%) developed stroke (4.2% nonhaemorrhagic, 0.5% haemorrhagic and 1.3% uncertain. The following factors appeared as independent predictors for an increased risk of stroke: age, hazard ratio and 95% confidence interval (1.07; 1.05–1.08), a history of diabetes mellitus (2.4; 1.8–3.4), a history of stroke (2.3; 1.5–3.5), a history of hypertension (2.0; 1.5–2.7) and a history of smoking (1.5;1.1–2.0). Most of these factors were also predictors of a nonhaemorrhagic stroke whereas no predictor of haemorrhagic stroke was found.Conclusion.  Risk indicators for stroke long‐term after AMI were increasing age, a history of either diabetes mellitus, stroke, hypertension or smoking.
Effects of long‐term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover
Authors: REJNMARK L. , VESTERGAARD P. , HEICKENDORFF L. , ANDREASEN F. , MOSEKILDE L. 
Published: January 2005

Abstract.Background.  Loop diuretics (LD) are widely used in the treatment of cardiovascular diseases and disorders with fluid accumulation. LD are known to increase renal calcium losses and may thereby affect calcium homeostasis and bone metabolism.Objective.  We studied to what extent long‐term treatment with LD affects calcium homeostasis and bone metabolism.Design and subjects.  In a cross‐sectional design we compared 140 postmenopausal women treated with a LD for more than 2 years with 140 age‐matched women not in diuretic therapy.Results.  Treatment with LD was associated with significantly increased urinary calcium, plasma parathyroid hormone (PTH) and 1,25‐dihydroxyvitamin D levels. Per 40 mg day−1 of furosemide, urinary calcium was increased by 17% (P < 0.05) and plasma PTH levels were increased by 28% (P = 0.04). Users of LD had a 17% higher body weight (P < 0.001) compared with nonusers. This was due to a 32% higher fat mass (P < 0.001) and a 6% higher lean tissue mass (P < 0.001). Moreover, users of LD had a higher bone mineral density (BMD) at the spine (+7.5%, P < 0.001), hip (+4.8%, P = 0.004), forearm (+3.7%, P = 0.01) and whole body (+2.5%, P = 0.06). However, after adjustment for body weight differences, BMD did not differ between groups. Nevertheless, duration of LD treatment was positively associated with BMD at the spine (P = 0.03) and whole body (P < 0.05). BMD at the spine increases by 0.3% per 1 year of treatment.Conclusions.  The increased renal calcium losses in users of LD are compensated for by a PTH‐dependent increase in 1,25(OH)2D levels. Thereby calcium balance remains neutral without major effects on bone metabolism.
The G‐250A substitution in the promoter region of the hepatic lipase gene is associated with the conversion from impaired glucose tolerance to type 2 diabetes: the STOP‐NIDDM trial
Authors: ZACHAROVA J. , TODOROVA B. R. , CHIASSON J.‐L. , LAAKSO M. ,   FOR THE STOP‐NIDDM STUDY GROUP
Published: January 2005

Abstract.Objectives.  Dyslipidaemia that includes high levels of triglycerides and low high‐density lipoprotein cholesterol is a risk factor for type 2 diabetes. Hepatic lipase gene encoding a lipolytic enzyme participating in remodelling of plasma lipoproteins and formation of serum lipid profile is a promising candidate gene for type 2 diabetes. The purpose of the study was to investigate whether the G‐250A promoter polymorphism of the LIPC gene predicts the conversion from impaired glucose tolerance (IGT) to type 2 diabetes.Subjects and design.  Study population comprised of subjects who participated in the STOP‐NIDDM trial aiming to investigate the effect of acarbose compared with placebo on the prevention of type 2 diabetes in subjects with IGT.Results.  Compared with subjects carrying the G‐250G genotype, subjects with the A‐250A genotype of the LIPC gene had a 2.35‐fold [95% confidence interval (CI) 1.27–4.33, P = 0.006] higher risk of developing type 2 diabetes. Subjects in the placebo group and all women carrying the A‐250A genotype had an especially high risk for the conversion to type 2 diabetes [odds ratio (OR) 2.74, 95% CI 1.14–6.61, P = 0.024 and OR 3.70, 95% CI 1.35–10.1, P = 0.011 respectively].Conclusion.  The G‐250A promoter polymorphism of the LIPC gene is associated with an increased risk of development of type 2 diabetes in high‐risk subjects with IGT. Therefore, genes regulating atherogenic dyslipidaemia are promising candidate genes for type 2 diabetes.
The inflammatory reflex – Introduction
Authors: ANDERSSON J. 
Published: January 2005

Abstract.Sepsis is the third leading cause of death in the developed world. Despite recent advances in intensive care treatment and the discovery of antibiotics, sepsis remains associated with a high mortality rate. The pathogenesis of sepsis is characterized by an overwhelming systemic inflammatory response that is central to the development of lethal multiple organ failure. This volume of the Journal of Internal Medicine contains three reviews addressing novel aspects of a system we are only beginning to understand – the interactions between the immune and the nervous systems, the ‘neuro‐immune axis’. Tracey (Nature 2002; 420: 853) recently discovered that the nervous system, through the vagus nerve, can modulate circulating TNF‐α levels induced by microbial invasion or tissue injury. This cholinergic anti‐inflammatory pathway is mediated primarily by nicotinic acetylcholine receptors on tissue macrophages – the pathway leads to decreased production of proinflammatory cytokines. The author reports that treatment with the acetylcholine receptor agonist, nicotine, modulates this system and reduces mortality in ‘established’ sepsis. Watkins and Maier (J Intern Med 2005; 257: 139) illustrate that pathological pain (induced by inflammation) is not simply a strict neuronal phenomenon, but is a component of the immune response, and is modulated by peripheral immune cells and spinal cord glia cells. This may be of importance for future development of novel drugs for neuropathic pain as well as our understanding of increased risks for infections in anaesthetic skin areas. Blalock (J Immunol 1984; 132: 1067) elucidates the possibility that the immune system actually functions as the sixth sense, sensing microbes and microbial toxins that we cannot see, hear, taste, touch or smell. Activation of the sympathetic nervous system also has predominantly anti‐inflammatory effects that are mediated through direct nerve to immune cell interaction or through the adrenal neuro‐endocrine axis.
The immune system as the sixth sense
Authors: BLALOCK J. E. 
Published: January 2005

Abstract.One of the truly remarkable discoveries in modern biology is the finding that the nervous system and immune system use a common chemical language for intra‐ and inter‐system communication. This review will discuss some of the pivotal results that deciphered this chemical language. Specifically the nervous and immune systems produce a common set of peptide and nonpeptide neurotransmitters and cytokines that act on a common repertoire of receptors in the two systems. The paper will also review more recent studies that have delineated hardwired and humoral pathways for such bidirectional communication. This is discussed in the context of the idea that the sharing of ligands and receptors allows the immune system to serve as the sixth sense that notifies the nervous system of the presence of entities, such as viruses and bacteria, that are imperceptible to the classic senses. Lastly, this review will suggest ways to apply the newfound knowledge of the sixth sense to understand a placebo effect and to treate human disease.
Autonomic neural regulation of immunity
Authors: CZURA C. J. , TRACEY K. J. 
Published: January 2005

Abstract.The ‘cytokine theory of disease’ states that an overproduction of cytokines can cause the clinical manifestations of disease. Much effort has been expended to determine how cytokines are regulated in normal health. Transcriptional, translational and other molecular control mechanisms protect the host from excessive cytokine production. A recent discovery revealed an unexpected pathway that inhibits macrophage cytokine production. The inflammatory reflex is a physiological pathway in which the autonomic nervous system detects the presence of inflammatory stimuli and modulates cytokine production. Afferent signals to the brain are transmitted via the vagus nerve, which activates a reflex response that culminates in efferent vagus nerve signalling. Termed the ‘cholinergic anti‐inflammatory pathway’, efferent activity in the vagus nerve releases acetylcholine (ACh) in the vicinity of macrophages within the reticuloendothelial system. ACh can interact specifically with macrophage α7 subunits of nicotinic ACh receptors, leading to cellular deactivation and inhibition of cytokine release. This ‘hard‐wired’ connection between the nervous and immune systems can be harnessed therapeutically in animal models of inflammatory disease, via direct electrical stimulation of the vagus nerve, or through the use of cholinergic agonists that specifically activate the macrophage α7 subunit of the ACh receptor. Autonomic dysfunction has been associated with human inflammatory diseases including rheumatoid arthritis, diabetes and sepsis; whether this dysfunction results from the inflammatory component of these diseases, or is actually an underlying cause, is now less clear. The description of the cholinergic anti‐inflammatory now brings to the fore several new therapeutic strategies for inflammatory disease, and suggests that many of these diseases may actually be diseases of autonomic dysfunction.
Immune regulation of central nervous system functions: from sickness responses to pathological pain
Authors: WATKINS L. R. , MAIER S. F. 
Published: January 2005

Abstract.Classically, the central nervous system (CNS) and the immune system are thought to operate independently of each other. This simplistic view has been corrected in recent years, first with the recognition that the brain dynamically modulates the immune system, and later with the reverse; that is, that the immune system modulates the CNS as well. The evidence that the immune system regulates CNS functions is first reviewed. This immune‐to‐brain communication pathway triggers the production of a constellation of CNS‐mediated phenomena, collectively referred to as ‘sickness responses’. These sickness responses are created by immune‐to‐brain signals activating CNS glia to release glial proinflammatory cytokines. The most recently recognized member of this constellation of changes is enhanced pain responsivity. The hypothesis is then developed that pathological, chronic pain may result from ‘tapping into’ this ancient survival‐oriented circuitry, including the activation of immune and glial cells and the release of immune/glial proinflammatory cytokines. This can occur at the level of peripheral nerves, dorsal root ganglia, spinal cord, and likely at higher brain areas. The implications of this model for human chronic pain syndromes and clinical resolution of these chronic pain states are then discussed.
Seroepidemiology of hepatitis A in patients with chronic liver disease
Authors: Saab S. , Lee C. , Shpaner A. , Ibrahim A. B. 
Published: January 2005

Summary.  Hepatitis A virus (HAV) rarely causes fulminant hepatic failure in the general population. Yet it is a cause of significant morbidity and mortality in patients with chronic liver disease (CLD), in whom routine HAV vaccination is recommended. However, studies of HAV seroprevalence and exposure predictors in populations with CLD are scarce. We have studied a cohort of 473 patients with various causes of CLD between July 2000 and June 2002. Patients were stratified on the basis of age, gender, ethnicity and aetiology of liver disease. The HAV seroprevalence in patients with CLD was compared with that in the general population. We used a logistic regression analysis to identify independent predictors of HAV exposure. Of the 473 patients studied, HAV seroprevalence was available for 454 individuals. HCV, HBV, alcohol, and HCV and alcohol were the causes of CLD in 337, 72, 37 and eight patients, respectively. The overall HAV seroprevalence was 55% in the studied cohort. The age‐stratified HAV prevalence for ages 21–30, 31–40, 41–50, 51–60, 61–70 and greater than 70 years was 44, 51, 44, 63, 65 and 64%, respectively. Hispanic ethnicity, Asian ethnicity, alcohol use and ages of 51–70 years were found to be independent predictive variables of prior exposure to HAV. HAV infection in patients with CLD causes considerable morbidity and mortality. We demonstrated that age‐stratified seroprevalence of HAV in patients with CLD of various aetiologies is significantly higher than that of the general population, and identified several independent predictors of HAV prior exposure.
Effects of selective dopamine receptor subtype agonists on cardiac contractility and regional haemodynamics in rats
Authors: Polakowski James S , Segreti Jason A , Cox Bryan F , Hsieh Gin C , Kolasa Teodozyj , Moreland Robert B , Brioni Jorge D 
Published: January 2005

SUMMARY1. Activation of dopamine (DA) receptors produces cardiovascular responses such as vasodilation and hypotension. However, knowledge of the role of specific dopamine receptor subtypes (especially D3 and D4) in the cardiovascular system is limited. The objective of the present study was to characterize the haemodynamic and cardiac responses to agonists with selectivity for D1, D2, D3 and D4 receptor subtypes.2. Inactin‐anaesthetized rats were instrumented to measure regional haemodynamic and cardiac contractility responses with slow intravenous infusion of agonists.3. Fenoldopam (a D1 receptor agonist) decreased (P < 0.05) renal vascular resistance beginning at a dose of 3 µmol/kg. Infusion of PNU‐95666E (a D2 receptor agonist) produced dose‐dependent decreases (P < 0.05) in mean arterial pressure (MAP), heart rate (HR) and hindquarter vascular resistance (HQVR). Administration of BP897 (a partial D3 receptor agonist) decreased (P < 0.05) MAP and HQVR at 3 µmol/kg. PD168077 (a D4 receptor agonist) caused significant increases in HQVR at 1 µmol/kg. None of the compounds tested elicited significant changes in cardiac contractility.4. Using selective agonists of dopamine receptor subtypes, the present studies characterize distinct cardiovascular effects in anaesthetized rats. Consistent with its well‐defined effects as a D1 receptor agonist, fenoldopam administration resulted in renal vasodilation. Similar to earlier studies using the non‐selective D2‐like receptor agonist quinpirole, selective agonism at the D2 receptor using PNU‐95666E resulted in bradycardia, hindquarter vasodilation and decreases in arterial pressure. Partial agonism at the D3 receptor with BP897 had no effect on heart rate, but did produce depressor responses driven by decreases in HQVR. Conversely, agonism of the D4 receptor using PD168077 resulted in modest hindquarter vasoconstriction that was not dose dependent. Hence, by comparison, agonism of the D4 receptor has little effect in the cardiovascular system of the rat relative to the other dopamine receptor subtype agonists tested.
Inhibition of inducible nitric oxide synthase reduces lipopolysaccharide‐induced renal injury in the rat
Authors: Kadkhodaee M , Qasemi A 
Published: January 2005

SUMMARY1. Gram‐negative bacterial lipopolysaccharide (LPS) release and subsequent septic shock is a major cause of death in intensive care units. Lipopolysaccharide has been reported to increase the production of nitric oxide (NO) and the formation of oxygen‐derived free radicals (OFR) in different organs. The aim of the present study was to evaluate the role of an inducible form of NO synthase (iNOS) and OFR production in LPS‐induced renal impairment.2. Measurement of vitamin E as the most important fat‐soluble anti‐oxidant was used as a marker of tissue oxidative stress. Lipopolysaccharide (10 mg/kg), l‐iminoethyl lysine (L‐Nil; 3 mg/kg, i.p.; a specific inhibitor of iNOS activity) and dimethyl thiourea (DMTU; 500 mg/kg i.p.; a well‐known OFR scavenger) were used. Four groups of eight rats were studied. One group received LPS, whereas a second group received LPS + L‐Nil. A third group received LPS + DMTU and the fourth group, receiving saline, acted as a control group. To evaluate renal function, plasma creatinine and blood urea nitrogen (BUN) were measured. High‐pressure liquid chromatography and ultraviolet detection were used to measure plasma and tissue vitamin E levels. Light microscopy was used to examine histopathological changes in the four groups.3. Lipopolysaccharide markedly decreased the vitamin E content of renal plasma and tissue (P < 0.05). Administration of L‐Nil attenuated renal dysfunction and preserved vitamin E levels. However, DMTU failed to prevent renal injury, as indicated by plasma BUN levels and renal histology, despite the fact that it maintained renal vitamin E levels and increased plasma vitamin E levels. Thus, the overproduction of NO by iNOS may have a role in this model of LPS‐induced renal impairment.
Development of low‐affinity, membrane‐targeted Ca2+ sensors suitable for measuring presynaptic Ca2+
Authors: Monif M , Smart ML , Reid CA , Williams DA 
Published: January 2005

SUMMARY1. Our aim is to measure near‐membrane Ca2+ flux within the presynaptic terminals of central neurons by modifying new genetically encoded Ca2+ sensors to develop tools capable of measuring localized Ca2+ signals.2. We used standard recombinant DNA technologies to generate the DNA coding for a fusion construct of a modified fluorescent ‘pericam’ Ca2+ biosensor with a presynaptic P2X7 receptor (P2X7R). The Ca2+ sensitivity of the biosensor was modified by rational site‐directed mutagenesis of the calmodulin portion of the pericam.3. Biosensor–receptor fusions were transfected into expression systems for evaluation. Expression studies in HEK‐293 cells showed that biosensor–receptor fusion construct‐delivered protein was localized exclusively to the plasma membrane, confirming that fusion did not affect the ability of the receptor to undergo normal protein synthesis and trafficking.4. The Ca2+‐dependent fluorescence of the pericam portion of the fusion protein was also retained. Site‐direct mutagenesis within the calmodulin moiety of the pericam significantly reduced the Ca2+ affinity of the complex. The dynamic range of the sensor following this modification is better matched to the higher Ca2+ levels expected within presynaptic Ca2+ microdomains.
Functional imaging: New views on lens structure and function
Authors: Donaldson Paul J , Grey Angus C , Merriman‐Smith B Rachelle , Sisley Aran MG , Soeller Christian , Cannell Mark B , Jacobs Marc D 
Published: January 2005

SUMMARY1. We have developed an experimental imaging approach that allows the distribution of lens membrane proteins to be mapped with subcellular resolution over large distances as a function of fibre cell differentiation.2. Using this approach in the rat lens, we have localized precisely histological sites of connexin 46 cleavage, quantitatively mapped changes in gap junction distribution and fibre cell morphology and correlated these changes to differences in intercellular dye transfer.3. Profiling of glucose transporter isoform expression showed that lens epithelial cells express GLUT1, whereas deeper cortical fibre cells express the higher‐affinity GLUT3 isoform. Near the lens periphery, GLUT3 was located in the cytoplasm of fibre cells, but it underwent a differentiation‐dependent membrane insertion.4. Similarly, the putative adhesion protein membrane protein 20 is inserted into fibre cell membranes at the stage when the cells lose their nuclei. This redistribution is strikingly rapid in terms of fibre cell differentiation and correlates with a barrier to extracellular diffusion.5. Our imaging‐orientated approach has facilitated new insights into the relationships between fibre cell differentiation and lens function. Taken together, our results indicate that a number of strategies are used by the lens during the course of normal differentiation to change the subcellular distribution, gross spatial location and functional properties of key membrane transport proteins.
Quantitative phase microscopy: A new tool for investigating the structure and function of unstained live cells
Authors: Curl Claire L , Bellair Catherine J , Harris Peter J , Allman Brendan E , Roberts Ann , Nugent Keith A , Delbridge Lea MD 
Published: January 2005

SUMMARY1. The optical transparency of unstained live cell specimens limits the extent to which information can be recovered from bright‐field microscopic images because these specimens generally lack visible amplitude‐modulating components. However, visualization of the phase modulation that occurs when light traverses these specimens can provide additional information.2. Optical phase microscopy and derivatives of this technique, such as differential interference contrast (DIC) and Hoffman modulation contrast (HMC), have been used widely in the study of cellular materials. With these techniques, enhanced contrast is achieved, which is useful in viewing specimens, but does not allow quantitative information to be extracted from the phase content available in the images.3. An innovative computational approach to phase microscopy, which provides mathematically derived information about specimen phase‐modulating characteristics, has been described recently. Known as quantitative phase microscopy (QPM), this method derives quantitative phase measurements from images captured using a bright‐field microscope without phase‐ or interference‐contrast optics.4. The phase map generated from the bright‐field images by the QPM method can be used to emulate other contrast image modes (including DIC and HMC) for qualitative viewing. Quantitative phase microscopy achieves improved discrimination of cellular detail, which permits more rigorous image analysis procedures to be undertaken compared with conventional optical methods.5. The phase map contains information about cell thickness and refractive index and can allow quantification of cellular morphology under experimental conditions. As an example, the proliferative properties of smooth muscle cells have been evaluated using QPM to track growth and confluency of cell cultures. Quantitative phase microscopy has also been used to investigate erythrocyte cell volume and morphology in different osmotic environments.6. Quantitative phase microscopy is a valuable, new, non‐destructive, non‐interventional experimental tool for structural and functional cellular investigations.