[Sauna improves endothelial function. Let patients with heart diseases sweat?].
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Angina Pectoris↗
Biomedical subjects
M Guha
Publications and source records attributed to M Guha.
Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression.
Lipopolysaccharide (LPS) induces human monocytes to express many proinflammatory mediators, including the procoagulant molecule tissue factor (TF) and the cytokine tumor necrosis factor alpha (TNF-alpha). The TF and TNF-alpha genes are regulated by various transcription factors, including nuclear factor (NF)-kappaB/Rel proteins and Egr-1. In this study, the role of the MEK-ERK1/2 mitogen-activated protein kinase (MAPK) pathway in LPS induction of TF and TNF-alpha gene expression in human monocytic cells was investigated. The MAPK kinase (MEK)1 inhibitor PD98059 reduced LPS induction of TF and TNF-alpha expression in a dose-dependent manner. PD98059 did not affect LPS-induced nuclear translocation of NF-kappaB/Rel proteins and minimally affected LPS induction of kappaB-dependent transcription. In contrast, PD98059 and dominant-negative mutants of the Ras-Raf1-MEK-ERK (extacellular signal-regulated kinase) pathway strongly inhibited LPS induction of Egr-1 expression. In kinetic experiments LPS induction of Egr-1 expression preceded induction of TF expression. In addition, mutation of the Egr-1 sites in the TF and TNF-alpha promoters reduced expression of these proinflammatory genes. It was demonstrated that LPS induction of the Egr-1 promoter was mediated by 3 SRE sites, which bound an LPS-inducible complex containing serum response factor and Elk-1. LPS stimulation transiently induced phosphorylation of Elk-1 and increased the functional activity of a GAL4-Elk-1TA chimeric protein via the MEK-ERK1/2 pathway. The data indicate that LPS induction of Egr-1 gene expression is required for maximal induction of the TNF-alpha and TF genes in human monocytic cells.
DNA-Binding Proteins↗
LPS induction of gene expression in human monocytes.
Lipopolysaccharide (LPS [endotoxin]) is the principal component of the outer membrane of Gram-negative bacteria. Recent studies have elucidated how LPS is recognized by monocytes and macrophages of the innate immune system. Human monocytes are exquisitely sensitive to LPS and respond by expressing many inflammatory cytokines. LPS binds to LPS-binding protein (LBP) in plasma and is delivered to the cell surface receptor CD14. Next, LPS is transferred to the transmembrane signaling receptor toll-like receptor 4 (TLR4) and its accessory protein MD2. LPS stimulation of human monocytes activates several intracellular signaling pathways that include the IkappaB kinase (IKK)-NF-kappaB pathway and three mitogen-activated protein kinase (MAPK) pathways: extracellular signal-regulated kinases (ERK) 1 and 2, c-Jun N-terminal kinase (JNK) and p38. These signaling pathways in turn activate a variety of transcription factors that include NF-kappaB (p50/p65) and AP-1 (c-Fos/c-Jun), which coordinate the induction of many genes encoding inflammatory mediators.
Animals↗
Molecular mechanisms of tumor necrosis factor alpha gene expression in monocytic cells via hyperglycemia-induced oxidant stress-dependent and -independent pathways.
Increased oxidative stress has been reported in vivo in the diabetic state via the production of reactive oxygen species (ROS). Such stress is bound to play a key role on activation of circulating monocytes, leading to the accelerated atherosclerosis observed in diabetics. However the exact molecular mechanisms of monocyte activation by high glucose is currently unclear. Here, we demonstrate that chronic high glucose (CHG) causes a dramatic increase in the release of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha), at least in part through enhanced TNFalpha mRNA transcription, mediated by ROS via activation of transcription factors nuclear factor kappaB (NF-kappaB) and activating protein-1 (AP-1). TNFalpha accumulation in the conditioned media was increased 10-fold and mRNA levels were increased 11.5-fold by CHG. The following observations supported that both NF-kappaB and AP-1 mediated enhanced TNFalpha transcription by CHG: 1) A 295-base pair fragment of the proximal TNFalpha promoter containing NF-kappaB and AP-1 sites reproduced the effects of CHG on TNFalpha transcription in a luciferase reporter assay, 2) mutational analyses of both NF-kappaB and the AP-1 sites abrogated 90% of the luciferase activity, 3) gel-shift analysis using the binding sites showed activation of NF-kappaB and AP-1 in CHG nuclear extracts, and 4) Western blot analyses demonstrated elevated nuclear levels of p65 and p50 and decreased cytosolic levels of IkappaBalpha in CHG-treated monocytes. That ROS acted as a key intermediate in the CHG pathway was supported by the following evidence: 1) increased superoxide levels similar to those observed with PMA or TNFalpha, 2) increased phosphorylation of stress-responsive mitogen-activated protein kinases p38 and JNK-1, 3) counteraction of the effects of CHG on TNFalpha production, the 295TNFluc reporter activity, activation of NF-kappaB, and repression of IkappaBalpha by antioxidants and p38 mitogen-activated protein kinase inhibitors. The study suggests that ROS function as key components in the regulatory pathway progressing from elevated glucose to monocyte activation.
Acetylcysteine↗
Toll-like receptor 2-mediated NF-kappa B activation requires a Rac1-dependent pathway.
Mammalian Toll-like receptors (TLRs) are expressed on innate immune cells and respond to the membrane components of Gram-positive or Gram-negative bacteria. When activated, they convey signals to transcription factors that orchestrate the inflammatory response. However, the intracellular signaling events following TLR activation are largely unknown. Here we show that TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rac1 and Cdc42 in the human monocytic cell line THP-1 and in 293 cells expressing TLR2. Dominant-negative Rac1N17, but not dominant-negative Cdc42N17, block nuclear factor-kappa B (NF-kappa B) transactivation. S. aureus stimulation causes the recruitment of active Rac1 and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain. Tyrosine phosphorylation of TLR2 is required for assembly of a multiprotein complex that is necessary for subsequent NF-kappa B transcriptional activity. A signaling cascade composed of Rac1, PI3K and Akt targets nuclear p65 transactivation independently of I kappa B alpha degradation. Thus Rac1 controls a second, I kappa B-independent, pathway to NF-kappa B activation and is essential in innate immune cell signaling via TLR2.
Cell Line↗
Transduction of primitive human marrow and cord blood-derived hematopoietic progenitor cells with adeno-associated virus vectors.
We evaluated the capacity of adeno-associated virus (AAV) vectors to transduce primitive human myeloid progenitor cells derived from marrow and cord blood in long-term cultures and long-term culture-initiating cell (LTC-IC) assays. Single-colony analyses showed that AAV vectors transduced CD34(+) and CD34(+)38(-) clonogenic cells in long-term culture. Gene transfer was readily observed in LTC-ICs derived from 5-, 8-, and 10-week cultures. Recombinant AAV (rAAV) transduction was observed in every donor analyzed, although a wide range of gene transfer frequencies (5% to 100%) was noted. AAV transduction of LTC-ICs was stable, with week-8 and -10 LTC-ICs showing comparable or better transduction relative to week-5 LTC-ICs. Fluorescence in situ hybridization (FISH) analyses performed to determine the fate of AAV vectors in transduced cells showed that 9% to 28% of CD34(+) and CD34(+)38(-) cells showed stable vector integration as evidenced by chromosome-associated signals in metaphase spreads. Comparisons of interphase and metaphase FISH suggested that a fraction of cells also contained episomal vector at early time points after transduction. Despite the apparent loss of the episomal forms with continued culture, the number of metaphases containing integrated vector genomes remained stable long term. Transgene transcription and placental alkaline phosphatase (PLAP) expression was observed in CD34(+), CD34(+)38(-) LTC-ICs in the absence of selective pressure. These results suggest that primitive myeloid progenitors are amenable to genetic modification with AAV vectors.
Alkaline Phosphatase↗
The experience of thought-disordered individuals preceding an aggressive incident.
The purpose of this qualitative study was to increase the understanding of the experiences of individuals with thought disorders, which precede incidents of aggression. Twelve individuals, from two hospitals, who had a nursing diagnosis of thought disorder and a history of aggression were interviewed, between one and four times, to collect baseline information and information about particular aggressive incidents. The participants described in their own words their thoughts, feelings and experiences preceding the aggressive incidents. Three themes emerged. First, participants perceived themselves to be strongly affected by the external environment; their responses to aspects of the environment were influential in precipitating the aggressive incident. Second, participants perceived themselves, paradoxically, to be both powerful and powerless; the act of aggression becomes an incident of brief self-empowerment. Third, the aggressive incident occurred in spite of the participants' acknowledgement and previous use of anger-controlling strategies; the participants' perceptions of themselves as powerless in an oppressive environment may have mitigated against the success of these strategies. Nurses need to know what triggers aggressiveness in psychiatric patients, in order to intervene effectively. Mental health professionals must also reexamine the psychiatric hospital environment, to make sure they are not needlessly exacerbating their patients' powerlessness with policies that are unjustifiably controlling.
Adult↗
Time course of dimension and function of the autologous pulmonary root in the aortic position.
Although the autologous, fully vital, and compatible pulmonary root theoretically offers the prospect of an ideal aortic valve substitute, this type of replacement is performed in only a few centers. Major concern relates to the fate of root dimension and function in the systemic circulation and is largely unknown. To investigate the fate of the aortic root, we conducted echocardiographic examinations of eight freestanding pulmonary roots used for aortic valve replacement in adults. The studies were performed at discharge from the hospital and up to 21 months (mean 12.5 +/- 6.6 months) after the operation, as well as in 26 matched control subjects. There were no significant differences between the first and second postoperative studies regarding the root diameter (mean 26.6 +/- 2.1 mm and 27.6 +/- 2.6 mm, respectively), which was within control limits, the maximum transvalvular pressure gradient (mean 4.6 +/- 1.2 mm Hg and 6.6 +/- 2.1 mm Hg, respectively), the maximum leaflet separation (mean 22.1 +/- 1.4 mm and 22.1 +/- 1.8 mm, respectively), and the degree of insufficiency. At the first study, grade I aortic regurgitation was found in four patients and grade I-II in one patient. Regurgitation increased slightly in one patient with an abnormal leaflet. In three patients primary grade I regurgitation disappeared. These data suggest that the pulmonary root in the aortic position can withstand systemic circulation without changes in dimension and function for up to 21 months. Furthermore, some evidence is provided to indicate that in certain cases the viable autograft may adapt to systemic pressure, as indicated by the disappearance of primary regurgitation.
Aortic Valve Insufficiency↗
Expression in insect cells and immune reactivity of a 28K tegument protein of human cytomegalovirus.
The gene encoding the highly antigenic 28K (pp28) tegument phosphoprotein of human cytomegalovirus (HCMV) was expressed in insect cells utilizing a recombinant baculovirus. The mature intracellular form of the recombinant-derived pp28 had mobility on SDS-polyacrylamide gels similar to that of native pp28 from HCMV strain Towne-infected human foreskin fibroblasts (HFFs). In vitro labelling of recombinant Autographa california nuclear polyhedrosis virus-infected Spodoptera frugiperda cells or of HCMV-infected HFFs with [32P]orthophosphate followed by immunoprecipitation showed that both the insect cell-derived and HCMV strain Towne-infected fibroblast-derived pp28 were phosphorylated. The mobility of pp28 derived from these two sources as well as from extracellular HCMV virions indicated the existence of multiple charged forms of the protein, and a difference in the relative amounts of these forms expressed in HCMV-infected HFFs and recombinant baculovirus-infected insect cells. The recombinant pp28 expressed in insect cells was readily and specifically recognized by antibodies to native pp28, including HCMV-seropositive human serum, and was used in an ELISA to screen human sera for seropositivity.
Animals↗
Amiodarone toxicity. II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats.
The contribution of desethylamiodarone (DEA), principal metabolite of the antiarrhythmic drug amiodarone, to the major side effects of amiodarone is unclear. The effects of repeated DEA administration to rats on tissue drug accumulation, ultrastructural changes, and phospholipid concentrations were studied. Two groups (n = 8/group) of male Sprague-Dawley rats (250 g body wt) were administered a 5% aqueous solution of DEA (Dose I, 40 mg/kg/day; Dose II, 60 mg/kg/day) intraperitoneally for 21-23 days, while a third group (control, n = 8) received saline. DEA levels were significantly higher with Dose II compared to Dose I in the lung, liver, kidney, spleen, heart, and serum while the tissue to serum ratios were similar with both doses for all tissues except the heart. DEA administration caused a significant elevation in the lipid phosphorus levels of liver, lung, and alveolar macrophages compared to control levels. A strong positive correlation (p less than 0.01) was found between tissue DEA levels and lipid phosphorus for the above tissues. Electron microscopy revealed the presence of lipid inclusion bodies in liver, lung, and alveolar macrophages of DEA-treated rats. A dose-dependent increase in the percentage of vacuolar surface area was found in the lung and alveolar macrophages. The tissue ultrastructural changes after repeated DEA dosing were qualitatively similar to our previous findings with amiodarone. Increased lung and liver phospholipid levels with repeated DEA doses may result from a potent inhibitory action of DEA on tissue phospholipase A as has been observed by others in in vitro studies.
Amiodarone↗
The paediatric departmental library.
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Information Services↗
Journal costs.
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Costs and Cost Analysis↗
Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats.
Pulmonary and hepatotoxicity are the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macrophages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, monodeiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.
Amiodarone↗
Possible involvement of central cholinergic-serotonergic interaction in natural sleep.
Administration of L-5-hydroxytryptophan (L-5-HTP) (200 mg/kg, p.o.) to adult male hamsters (110-120 g) increased non-rapid-eye-movement (NREM) as well as rapid-eye-movement (REM) sleep, with an increase of total sleep time. Methysergide (10 mg/kg, i.p.) facilitated REM sleep and inhibited NREM sleep. Both REM and NREM sleep disappeared with atropine (5 mg/kg, i.p.) both in absence and in presence of L-5-HTP (200 mg/kg, p.o.). Physostigmine (0.1 mg/kg, i.p.) increased REM sleep and decreased NREM sleep without altering the total sleep time. Co-administration of physostigmine (0.1 mg/kg, i.p.) and methysergide (10 mg/kg, i.p.) increased REM but blocked completely NREM sleep. These results suggest that the serotonergic system involved in REM sleep is regulated by the interaction of cholinergic receptor activity and the involvement of the cholinergic system in NREM sleep is regulated by the interaction of serotonergic receptor activity.
5-Hydroxytryptophan↗
Does health visiting have a history?
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Community Health Nursing↗
The experience of hospitalization and restraint of women who have a history of childhood sexual abuse.
Within psychiatric settings, many female clients report experiences of childhood sexual abuse (CSA). In this paper we explore the experience of 10 women who were hospitalized in psychiatric settings, restrained, and given forced medication (FM). All the women have histories that included CSA. Some authors have suggested that the experience of psychiatric hospitalization may represent an event that reenacts the experience of trauma. The results suggest that from the perspective of these women, the experience of restraint engendered traumatic emotional reactions such as fear, anxiety, and rage, and in no way was viewed as therapeutic even years later. Women felt powerless and unheard. The women wanted nurses who were empathic and responsive to their human needs as clients, but they felt nurses did not want to hear about the abuse or their internal distress. We hope that the perspective of these women will help in the consideration of alternatives and modifications to the use of restraint in psychiatric settings.
Adult↗
Time course of lung function and exercise performance after heart transplantation.
To study the time course of exercise performance and the diffusion capacity after heart transplantation, we submitted two groups of patients to graded symptom-limited supine exercise. Patients in group 1 (n = 11) underwent operation 12.9 +/- 7.0 months before the study; those in group 2 (n = 10) underwent operation 53.9 +/- 14.8 months before the study. Respiratory and cardiovascular parameters were evaluated noninvasively at rest, at individual peak exercise, and 10 minutes later with a commercially available Sensormedics MMC 4400 metabolic measurement chart. Short-term survivors exhibited a lower maximum work capacity compared with that of long-term survivors (63.6 +/- 25.9 versus 100 +/- 50 W, p < 0.05), with a concomitant lower terminal heart rate (123 +/- 19 versus 137 +/- 17 beats/min, p < 0.05) that accounts for the lower cardiac output in this group, but statistical significance was not achieved (13.0 +/- 4.6 versus 17.5 +/- 6.3 L/min, not significant). Interestingly, significant differences were also observed for diffusion capacity before exercise (11.9 +/- 4.8 versus 19.3 +/- 7.3 ml/min/mm Hg, p < 0.05). The improvement of the diffusion capacity may be associated with a time-dependent change in the diffusion characteristics of the alveolocapillary membrane.
Azathioprine↗