bluuebunny/crossref_metadata_2025 huggingface dataset:
Magnetic resonance imaging findings in pulmonary Kaposi's sarcoma: a series of 10 cases
Authors: Khalil AM , Carette MF , Cadranel JL , Mayaud CM , Akoun GM , Bigot JM
Published: July 2004

Since chest X-ray and CT scan features of Kaposi's sarcoma (KS) are nonspecific, we wanted to test the hypothesis that the histological components of this tumour and/or the associated haemorrhagic component, may result in a characteristic signal pattern on magnetic resonance imaging (MRI). Thoracic MRI was performed in a prospective manner in ten patients with acquired immune deficiency syndrome (AIDS) and pulmonary KS. MRI examinations (1.5 Tesla) included Spin-echo T1 (SE-T1), before and after gadolinium injection, as well as T2-weighted sequences (SE-T2). For each sequence the signal intensity of lesions was measured and compared with each other as well as with the signal intensity of muscle. Results were compared to the hemosiderin content of macrophages in the bronchoalveolar lavage (BAL) in all patients and with histological findings in three. The results were compared to values obtained in a control group of seven patients with pneumocystis carinii pneumonia. SE-T1 showed focally increased signal intensity in the pulmonary parenchyma (n = 5). Signal enhancement in parenchymal lesions (n = 10) and along peribronchovascular trees (n = 5) was observed after gadolinium injection. The second echo of SE-T2 showed a markedly reduced signal intensity in pathologic areas (n = 10). This last finding was not observed in the control group. In conclusion, we have identified a pattern of MRI signal abnormalities suggestive of Kaposi's sarcoma. The MRI signal intensity of KS lesions may be related to the angiomatous and fibrous components of the tumour.(ABSTRACT TRUNCATED AT 250 WORDS)
Central bronchiectasis in allergic bronchopulmonary aspergillosis: comparative evaluation of computed tomography of the thorax with bronchography
Authors: Panchal N , Pant C , Bhagat R , Shah A
Published: July 2004

Demonstration of central bronchiectasis (CB) with normal peripheral bronchi is an essential requirement for the diagnosis of allergic bronchopulmonary aspergillosis (ABPA). Although the results of bronchography remain the gold standard for demonstration of central bronchiectasis they are not always diagnostic. Moreover, it is an unpleasant invasive procedure which may be difficult to perform in a patient of allergic bronchopulmonary aspergillosis with acute severe asthma. In an attempt to find a safe and effective alternative to demonstrate central bronchiectasis computed tomography (CT) of the thorax was evaluated against bronchography. Twenty one patients with allergic bronchopulmonary aspergillosis underwent computed tomography of the thorax followed by bronchography. Of the 378 bronchopulmonary segments available for analysis, 42 had to be excluded because of consolidation or non-filling of the contrast dye, leaving 336 segments for evaluation. CB was identified on CT in all 21 patients. Detailed analysis of the visualized segments revealed that computed tomography (using 8 mm contiguous scans) identified 146 of the 212 segments showing central bronchiectasis on bronchography (sensitivity 70%) and 114 of the 124, read as normal on bronchography (specificity 92%). Supplemental 4 mm scans, used in 8 out of 21 patients improved the overall sensitivity of computed tomography to 83%, whilst the specificity remained unchanged at 92%. Thus, computed tomography of the thorax, being more acceptable to the patient, has the potential of being the investigation of choice for the demonstration of central bronchiectasis in patients with allergic bronchopulmonary aspergillosis.
Pulmonary haemodynamics in awake rats following treatment with endotracheal pancreatic elastase
Authors: Sato S , Kato S , Arisaka Y , Takahashi H , Tomoike H
Published: July 2004

The purpose of this paper was to study pulmonary haemodynamics in an elastase-induced emphysema model in awake rats (Group-EL, n = 9) in comparison with saline-treated controls (Group-C, n = 12). Four weeks before haemodynamic study, porcine pancreatic elastase and normal saline were intratracheally instilled in Group-EL and Group-C, respectively. Indwelling pulmonary artery and abdominal aortic catheters were positioned two days before the haemodynamic study. Breathing room air, mean pulmonary artery pressure (Ppa) tended to be higher in Group-EL than in Group-C, although the difference was not statistically significant. Systemic pressure, total systemic vascular resistance and cardiac index did not differ between groups. When exposed to 10% O2, Ppa and pulmonary vascular resistance (PVR) of both groups rose significantly. The increase of Ppa, (but not PVR) in Group-EL during hypoxia was significantly higher than that in Group-C. The magnitude of hypoxic pulmonary vasoconstriction (HPV) tended to be larger in Group-EL than in Group-C. Right ventricles of Group-EL were more hypertrophic than those of Group-C, suggesting a period of higher pulmonary artery pressure than for Group-C. The present results imply that the pressor response of pulmonary vasculature to acute alveolar hypoxia is possibly enhanced in awake rats upon examination four weeks after elastase treatment.
Airway blood flow and bronchovascular congestion in sheep
Authors: Baile EM , Sotres-Vega A , Pare PD
Published: July 2004

Vascular congestion could play an important role in causing airway narrowing in asthma. However, the effects of altered bronchial vascular volume and blood flow on airway morphology and pulmonary resistance have not been studied. The aim of this study was to measure airway calibre and vascular volume during inhalation of reputed dilators and constrictors of the airway vasculature in sheep. After baseline measurements of pulmonary resistance (RL) and airway blood flow (Qaw), anaesthetized sheep inhaled an aerosol of either: 0.9% saline (n = 6); histamine 16 mg.ml-1 (n = 5); phenylephrine 0.1-10 mg.ml-1 (n = 6), or methoxamine 1 mg.ml-1 (n = 5). RL and Qaw were measured at the time of peak bronchoconstriction, and the sheep were rapidly killed and lung blood loss prevented. Right lung Qaw was calculated and left lung processed for histology; measurements of cartilaginous airway size, wall thickness and fraction of the wall occupied by blood were made using morphometric techniques. Results showed that 20-30% of the airway wall was occupied by blood vessels. Inhalation of histamine caused an increase in Qaw and RL, and a 50% increase in the vascular volume fraction of the airway wall, whereas inhaled alpha-agonists did not reduce Qaw or vascular volume fraction. We conclude that the major cause of airway narrowing after inhalation of histamine is contraction of the smooth muscle, and the bronchovascular congestion contributes little to airway narrowing in cartilaginous airways of sheep. In addition inhaled alpha-agonists do not constrict the bronchial microvasculature under baseline conditions. Therefore, our results do not support the hypothesis that protection against bronchoconstriction provided by alpha-agonists is due to vasoconstriction.
Pulmonary immune cells in health and disease: mast cells and basophils
Authors: Warner JA , Kroegel C
Published: July 2004

Mast cells and basophils are multifunctional immune cells and have been implicated in the pathogenesis of asthma and other pulmonary diseases. Although they are derived from distinct lineages, they share a number of important features which justifies discussing them collectively. This review covers the cellular characteristics and biological properties of both cell types, including origin, maturation and differentiation, morphological and phenotypical properties, as well as their capacity to secrete preformed and newly generated mediators of inflammation. In addition, the mechanisms of cell activation and priming of mast cells and basophils will be outlined, as well as the putative mechanisms through which both cell types communicate with other inflammatory cells. The final section of the review focuses on the possible pathogenetic role of mast cells and basophils in several pulmonary diseases, such as parasitic infections, allergic diseases, pulmonary fibrosis and malignant disorders.
Chronic lung diseases and the perception of breathlessness: a clinical perspective
Authors: Burdon JG , Pain MC , Rubinfeld AR , Nana A
Published: July 2004

Breathlessness is an extremely common symptom. Its genesis is incompletely understood but is known to be largely determined by many of the mechanical factors associated with the act of breathing. As with all subjective sensations various other factors including volition, behavioural style and other cortical and subcortical factors play a part in its genesis. The relief of breathlessness is primarily directed at the underlying disorder. In those conditions and situations where specific therapy has little to offer or little impact it is reasonable to consider ways of reducing the perception of breathlessness by pharmacological means. However, to date there is no convincing evidence that use of drugs in the pursuit of the relief of breathlessness has any specific effect in modifying the perception of this often distressing symptom. Any reduction in breathlessness achieved in this way can be adequately explained in terms of a reduction in ventilation and other indices of respiratory mechanics.
The upper limit of alveolar capillary recruitment in a young man with lung growth impairment
Authors: Donnelly PM , Daxini BV , Bye PT
Published: July 2004

In order to obtain further insight into the adaptive mechanisms relating to gas exchange in anatomically small lungs, tests of mechanical lung function and gas exchange were made in an active young man, whose lung growth had been severely impaired due to pectus excavatum developed in childhood. We found our patient to have small (total lung capacity, 59% of predicted) but mechanically normal lungs. He had a normal cardiac output, a normal single-breath diffusing capacity (100% pred), and a high diffusion coefficient (148% pred) associated with a high pulmonary capillary blood volume (131% pred) at rest. Pulmonary distensibility (K) and elastic recoil were normal. During steady-state exercise he was unable to recruit further reserves of pulmonary capillaries, but this was not reflected in a plateau for oxygen consumption, which was presumably the result of an increased pulmonary capillary blood flow rather than volume. The recruitment of pulmonary capillary reserves in this young man has enabled him to maintain a normal maximum exercise capacity. In addition, the high stroke volume and a haemoglobin level in the high normal range (176 g.l-1) may have maintained his maximal exercise function, despite fewer alveolar units. This study suggests that, contrary to previous findings, loss of a major proportion of lung tissue need not impair exercise capacity. Patients with either small lungs or following pneumonectomy may benefit from physical training sufficient to optimize both an increase in cardiac output and recruitment of their existing alveolar capillary reserves.
Altered immune parameters in chronic alcoholic patients at the onset of infection and of septic shock
Authors: von Dossow Vera , Schilling Corinna , Beller Stefan , Hein Ortrud Vargas , von Heymann Christian , Kox Wolfgang J , Spies Claudia D
Published: July 2004

Introduction

Chronic alcoholic patients have a threefold to fourfold increased risk for developing a severe infection or septic shock after surgery, which might be due to altered immune response. The aim of this outcome matched study was to investigate proinflammatory and anti-inflammatory immune parameters during the course of infection and subsequent septic shock in chronic alcoholic patients, and to compare these parameters with those in nonalcoholic patients.

Methods

Twenty-eight patients from a cohort of fifty-six with either pneumonia or peritonitis and subsequent septic shock were selected. Fourteen patients were chronic alcoholics whereas fourteen were nonalcoholic patients. Chronic alcoholic patients met criteria (Diagnostic and Statistical Manual of Mental Disorders IV, of the American Psychiatric Association) for alcohol abuse or dependence. Measurements were performed during the onset of infection (within 24 hours after the onset of infection), in early septic shock (within 12 hours after onset of septic shock) and in late septic shock (72 hours after the onset). Blood measurements included proinflammatory and anti-inflammatory cytokines.

Results

Chronic alcoholic patients exhibited significantly lower plasma levels of IL-8 (P < 0.010) during the onset of infection than did matched nonalcoholic patients. In early septic shock, chronic alcoholic patients had significantly decreased levels of IL-1β (P < 0.015), IL-6 (P < 0.016) and IL-8 (P < 0.010). The anti-inflammatory parameters IL-10 and tumour necrosis factor receptors I and II did not differ between alcoholic and nonalcoholic patients.

Conclusion

At the onset of infection and during early septic shock, chronic alcoholic patients had lower levels of proinflammatory immune parameters than did nonalcoholic patients. Therefore, immunomodulatory therapy administered early may be considered in chronic alcoholic patients at the onset of an infection because of their altered proinflammatory immune response.
R5 HIV gp120-mediated cellular contacts induce the death of single CCR5-expressing CD4 T cells by a gp41-dependent mechanism
Authors: Blanco Julià , Barretina Jordi , Clotet Bonaventura , Esté José A
Published: July 2004

The use of CXC chemokine receptor 4 (CXCR4) and CC chemokine receptor 5 (CCR5) by X4 and R5 human immunodeficiency virus (HIV) envelopes (Env) influences HIV cytopathicity. Here, we have evaluated the role of CCR5 and gp41 in Env-induced cell death occurring during the contacts of uninfected, primary cells with MOLT cells infected with different R5 and X4 HIV isolates. As reported for X4-Env, R5 HIV-infected cells destroyed CD4 T cells expressing the appropriate coreceptor by inducing the formation of syncytia and the death of single target cells. Therefore, only the small (<10%) CCR5+ subset of primary CD4 T cells was sensitive to cellular presentation of R5-Env, and CCR5–CD4 T cells showed complete resistance to R5-Env-mediated cell death. X4- and R5-infected cells killed single primary cells by a common mechanism that was dependent on gp41 function and induced a rapid loss of mitochondrial membrane potential and plasma membrane integrity in target cells. Single-cell death was not affected by the blockade of HIV replication in target cells or G-protein signaling through CXCR4/CCR5. In contrast, caspase inhibition (Z-Val-Ala-Asp-fluoromethylketone) profoundly changed the outcome of cell-to-cell contacts by reducing the number of single dead CD4 T cells and increasing the rate of syncytium formation. In conclusion, X4 and R5 HIV Env share a common gp41-dependent mechanism to kill CD4 T cells during cellular contacts. Env tropism and coreceptor expression but not differential killing mechanisms seem to govern the extent of cytopathic effects induced by HIV infection.
The THC-induced suppression of Th1 polarization in response toLegionella pneumophilainfection is not mediated by increases in corticosterone and PGE2
Authors: Newton Catherine A , Lu Tangying , Nazian Stanley J , Perkins Izabella , Friedman Herman , Klein Thomas W
Published: July 2004

T helper cell type 1 (Th1)-polarizing cytokines are induced by Legionella pneumophila infection and are suppressed by pretreatment with marijuana cannabinoids (CB). Glucocorticoids and prostaglandin E2(PGE2) are also reported to suppress Th1 polarization and are induced by Δ9-tetrahydrocannabinol (THC), so their role in the suppression of polarizing cytokines was examined. Injection of L. pneumophila or THC alone into BALB/c mice induced a rapid and transient rise in serum corticosterone (CS), and the injection of both agents significantly augmented the CS response, demonstrating that THC increased CS in Legionella-infected mice. Pretreatment with the CB receptor 1 (CB1) antagonist SR141716A had no effect on the THC-induced CS response, but CB2 antagonist (SR144528) treatment increased the CS response. To see if increased CS contributed to the down-regulation of Th1 cytokines, mice were pretreated with the steroid antagonist RU486 before THC injection and Legionella infection. The results showed that RU486 did not attenuate the THC-induced suppression of serum interleukin (IL)-12 or interferon-γ (IFN-γ). In addition to CS, THC injection increased urinary PGE2 metabolites, and the CB1 antagonist attenuated this increase. Although L. pneumophila infection increased urinary PGE2, THC pretreatment did not enhance this response; in addition, treatment with the cyclooxygenase inhibitor, indomethacin, did not block the THC-induced suppression of IL-12 and IFN-γ. These results suggest that the elevation of CS and PGE2 does not account for the THC-induced attenuation of the Th1 cytokine response, and it is concluded that other suppressive mediators are induced by THC or that the drug acts directly on immune cells to suppress cytokine production.
Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein
Authors: Hatao Fumihiko , Muroi Masashi , Hiki Naoki , Ogawa Toshihisa , Mimura Yoshikazu , Kaminishi Michio , Tanamoto Ken-ichi
Published: July 2004

Interleukin-1 receptor-associated kinase (IRAK)-4 is a key mediator in the Toll-like receptor (TLR) signaling. We found that stimulation of TLR2, TLR4, or TLR9, but not TLR3, caused a decrease in IRAK-4 protein without affecting its mRNA level in a mouse macrophage cell line, RAW 264. The decrease in IRAK-4 was accompanied by the appearance of a smaller molecular weight protein (32 kD), which was recognized by an anti-IRAK-4 antibody raised against the C-terminal region. The decrease in IRAK-4 and the appearance of the 32-kD protein occurred with slower kinetics than the activation of IRAK-1 and were suppressed by inhibitors of the proteasome, inducible inhibitor of κBα phosphorylation or protein synthesis, but not by caspase inhibitors. These results indicate that prolonged stimulation of TLR2, TLR4, or TLR9 causes a down-regulation of IRAK-4 protein, which may be mediated through cleavage of IRAK-4 by a protease induced by the activation of nuclear factor-κB.
Counteracting corneal immunoinflammatory lesion with interleukin-1 receptor antagonist protein
Authors: Biswas Partha Sarathi , Banerjee Kaustuv , Zheng Mei , Rouse Barry T
Published: July 2004

Herpetic stromal keratitis (HSK) is a T cell-orchestrated, immunoinflammatory lesion that results from corneal Herpes simplex virus infection. Previous reports indicate an essential role for proinflammatory cytokine interleukin (IL)-1 in HSK pathogenesis. The present study evaluates the efficacy of IL-1 receptor antagonist (IL-1 ra) protein in the management of HSK. Mice receiving IL-1 ra had diminished disease severity. The administration of IL-1 ra was shown to reduce the influx into the cornea of cells of the innate and adaptive immune response. In addition, the treatment diminished corneal vascular endothelial growth factor levels, resulting in reduced angiogenic response. Our results show the importance of targeting early proinflammatory molecules such as IL-1 to counteract HSK and advocate IL-1 ra as an effective agent to achieve this.
Genoprotective role of vitamin E and selenium in rabbits anaesthetized with sevoflurane
Authors: Kaymak Cetin , Kadioglu Ela , Basar Hulya , Sardas Semra
Published: July 2004

In this study, genotoxic effects of repeated sevoflurane anaesthesia were investigated in rabbits with or without antioxidant supplementation. Twenty-one New Zealand male rabbits were included in the study and randomized into three groups as: placebo treated (Group I), vitamin E supplemented (Group II) and selenium supplemented (Group III). Vitamin E and selenium were given intraperitoneally for 15 days before anaesthesia treatment. Anaesthesia was administered using 3% sevoflurane in 4 L/min oxygen for a 3-hour period and continued for 3 days. Blood samples were collected before anaesthesia (Sample 1), after the first, second and third days of sevoflurane administration (Sample 2, Sample 3 and Sample 4 respectively) and the last samples were taken 5 days after the last sevoflurane administration (Sample 5). Genotoxic damage was examined using the comet assay. The degree of damage is assessed by grading the cells into three categories of no migration (NM), low migration (LM) and high migration (HM) depending on the fraction of DNA pulled out into the tail under the influence of the electric field. The number of comets in each sample was calculated (1 × number of comets in category NM + 2 × number of comets in category LM + 3 ×number of comets in category HM) and expressed as the total comet score (TCS), which summarizes the damage frequencies. In Group I, a significant increase in the mean TCSs was observed for Samples 3 and 4 as compared with Sample 1. However, there were no significant differences between Samples 1, 2 and 5. The mean TCS of Sample 4 was significantly higher than Sample 1, 2 and 3 in Group II. Group III demonstrated no significant mean TCSs for any experimental conditions. Statistical differences were also observed between the groups with significant P values. This experimental study points out the presence of DNA damage with repeated sevoflurane anaesthesia and the genoprotective role of antioxidant supplementation on DNA damage in mononuclear leukocytes of rabbits by highly sensitive comet assay.
Copper treatment alters the barrier functions of human intestinal Caco-2 cells: involving tight junctions and P-glycoprotein
Authors: Liu Zhiwei , Chen Bingheng
Published: July 2004

This study investigated the effects of copper on paracellular permeability and P-glycoprotein (P-gp) in Caco-2 cells. Apical treatment with 100–300,μM CuS04 in Hanks' balanced salt solution (HBSS, up to 3 hours) induced a time-and concentration-dependent increase in permeability of Caco-2 cell monolayers monitored by transepithelial electrical resistance (TEER). Copper treatment also induced a concentration-dependent reduction of F-actin stain, but not of tight junctional protein ZO-1. In addition, without any adverse effects on TEER, apical treatment with 300 μM CuS04 in complete medium (for 24 hours) could reduce basolateral-to-apical transport, and increase apical-to-basolateral transport of rhodamine-123 (Rho-123) and accumulation of Rho-123 in Caco-2 cells. Treatment with 10-100 μM CuS04 in HBSS (up to 3 hours) also induced a time-and concentration-dependent increase in accumulation of Rho-123 in Caco-2 cells. The results indicated that copper treatment increased the paracellular perme-ability probably by perturbing F-actin skeleton, and inhibited P-gp, thus altering the barrier functions of Caco-2 cells.
Statistical evaluation of an acute dermal toxicity test using the dermal fixed dose procedure
Authors: Stallard Nigel , Whitehead Anne , Indans Ian
Published: July 2004

The conventional method for the assessment of acute dermal toxicity (OECD Test Guideline 402, 1987) uses death of animals as an endpoint to identify the median lethal dose (LD50). A new OECD Testing Guideline called the dermal fixed dose procedure (dermal FDP) is being prepared to provide an alternative to Test Guideline 402. In contrast to Test Guideline 402, the dermal FDP does not provide a point estimate of the LD50, but aims to identify that dose of the substance under investigation that causes clear signs of nonlethal toxicity. This is then used to assign classification according to the new Globally Harmonised System of Classification and Labelling scheme (GHS). The dermal FDP has been validated using statistical modelling rather than by in vivo testing. The statistical modelling approach enables calculation of the probability of each GHS classification and the expected numbers of deaths and animals used in the test for imaginary substances with a range of LD50 values and dose-response curve slopes. This paper describes the dermal FDP and reports the results from the statistical evaluation. It is shown that the procedure will be completed with considerably less death and suffering than guideline 402, and will classify substances either in the same or a more stringent GHS class than that assigned on the basis of the LD50 value.
Aniline: early indicators of toxicity in male rats and their relevance to spleen carcinogenicity
Authors: Mellert W , Deckardt K , Gembardt C , Zwirner-Baier I , Jäckh R , van Ravenzwaay B
Published: July 2004

Early indicators of aniline hydrochloride (AH) toxicity were investigated in male Fisher 344 rats for 1 or 4 weeks at dietary dose levels of 10, 30 or 100 mg/kg body weight (bw)/day (actual intake at least 6, 17 and 57 mg/kg). The doses were based on earlier studies that had shown spleen toxicity and carcinogenicity in male rats at 100 mg/kg/day but not at 10 mg/12/kg/day. In the present study a dose-related formation of haemoglobin adducts and Heinz bodies was found from 10 and 30 mg/kg bw/day, respectively, onwards. Signs of anaemia (decreased red blood cell counts and increased reticulocytes) were recorded from 30 mg/kg onwards. At 100 mg/kg, an overt haemolytic anaemia was associated with increases in serum transferrin concentration and total iron binding capacity in the blood reflecting major perturbations in iron metabolism. At this dose there was an increase in peripheral neutrophil leucocytosis in the blood, indicating an inflammatory process in the spleen. Histopathologic evaluation showed a focal perisplenitis and haemosiderin deposition in sinusoidal Kupffer cells of the liver at 100 mg/kg. These results corroborate the contention that carcinogenic doses of aniline cause early effects on haematological parameters, inflammatory reaction in the spleen and perturbations in iron metabolism as a result of haemolytic anaemia. Accordingly, the carcinogenicity of aniline may be linked to definable threshold-related processes.
Male reproductive toxicity of sodium arsenite in mice
Authors: Pant Niraj , Murthy R C , Srivastava S P
Published: July 2004

The effect of chronic oral exposure to arsenic on male mouse testicular and accessory sex organ weights, sperm parameters and testicular marker enzymes was studied. In addition, the distribution of arsenic in reproductive organs was measured using atomic absorption spectrophotometry. Sodium arsenite administered to mice (Mus musculus) via drinking water at a dose of 53.39 βmol/L (4 ppm As) for 365 days caused a decrease in the absolute and relative testicular weight. However, epididymal and accessory sex organ weight was similar to control. The activities of marker testicular enzymes such as sorbitol dehydrogenase, acid phosphatase and 17β-hydroxysteroid dehydrogenase (17β-HSD) were significantly decreased, but those of lactate dehydrogenase and γ-glutamyl transpeptidase (γ-GT) were significantly increased. A decrease in sperm count and sperm motility, along with an increase in abnormal sperm, was observed in arsenite-exposed mice. A significant accumulation of arsenic in testes, epididymis, seminal vesicle and prostate gland was observed in treated animals. Thus long term exposure (365 days) at the dose level of 53.39 μmol/L sodium arsenite (4 ppm As), to which human beings are likely to be exposed via drinking water, may cause testicular and spermatotoxic effect.
Systemic Inflammation‐Associated Glucocorticoid Resistance and Outcome of ARDS
Authors: MEDURI G UMBERTO , YATES CHARLES R.
Published: July 2004

Abstract: Dysregulated systemic inflammation with excess activation of pro‐inflammatory transcription factor nuclear factor‐κB (NF‐κB)—activated by inflammatory signals—compared to the anti‐inflammatory transcription factor glucocorticoid receptor‐α (GRα)—activated by endogenous or exogenous glucocorticoids (GCs)—is an important pathogenetic mechanism for pulmonary and extrapulmonary organ dysfunction in patients with acute respiratory distress syndrome (ARDS). Activation of one transcription factor in excess of the binding (inhibitory) capacity of the other shifts cellular responses toward increased (dysregulated) or decreased (regulated) transcription of inflammatory mediators over time. Recent data indicate that failure to improve in ARDS (unresolving ARDS) is frequently associated with failure of the activated GRs to downregulate the transcription of inflammatory cytokines despite elevated levels of circulating cortisol, a condition defined as systemic inflammation‐associated acquired GC resistance; it is potentially reversible with prolonged GC supplementation.

In the first part of this paper, after a brief description of inflammation in ARDS and our model of translational research, we review the two cellular signaling pathways that are central to the regulation of inflammation—the stimulatory NF‐αB and the inhibitory GRα. In the second part, we review findings of recent studies indicating that excessive inflammatory activity in patients with unresolving ARDS may induce noncompensated GC resistance in target organs. In the third part, we review factors affecting cellular response to GC and potential mechanisms involved in inflammation‐associated GC resistance.
Physiological and Pathological Consequences of the Interactions of the p53 Tumor Suppressor with the Glucocorticoid, Androgen, and Estrogen Receptors
Authors: SENGUPTA SAGAR , WASYLYK BOHDAN
Published: July 2004

Abstract: The p53 tumor suppressor plays a key role in protection from the effects of different physiological stresses (DNA damage, hypoxia, transcriptional defects, etc.), and loss of its activity has dire consequences, such as cancer. Its activity is finely tuned through interactions with other important regulatory circuits in the cell. Recently, striking evidence has emerged for crosstalk with another class of important regulators, the steroid hormone receptors, and in particular the glucocorticoid (GR), androgen (AR), and estrogen (ER) receptors. These receptors are important in maintaining homeostasis in response to internal and external stresses (GR) and in the development, growth, and maintenance of the male and female reproductive systems (AR and ER, respectively). We review how p53 interacts closely with these receptors, to the extent that they share the same E3 ubiquitin ligase, the MDM2 oncoprotein. We discuss the different physiological contexts in which such interactions occur, and also how these interactions have been undermined in various pathological situations. We will describe future areas for research, with special emphasis on GR, and how certain common features, such as cytoplasmic anchoring of p53 by the receptors, may become targets for the development of therapeutic interventions. Given the importance of GR in inflammation, erythropoiesis, and autoimmune diseases, and the importance of AR and ER in prostate and breast cancer (respectively), the studies on p53 interactions with the steroid receptors will be an important domain in the near future.
Modulation of Glucocorticoid Receptor Function via Phosphorylation
Authors: ISMAILI NAIMA , GARABEDIAN MICHAEL J.
Published: July 2004

Abstract: The glucocorticoid receptor (GR) is phosphorylated at multiple serine residues in a hormone‐dependent manner. It has been suggested that GR phosphorylation affects turnover, subcellular trafficking, or the transcriptional regulatory functions of the receptor, yet the contribution of individual GR phosphorylation sites to the modulation of GR activity remains enigmatic. This review critically evaluates the literature on GR phosphorylation and presents more recent work on the mechanism of GR phosphorylation from studies using antibodies that recognize GR only when it is phosphorylated. In addition, we present support for the notion that GR phosphorylation modifies protein‐protein interactions, which can stabilize the hypophosphorylated form of the receptor in the absence of ligand, as well as facilitate transcriptional activation by the hyperphosphorylation of GR via cofactor recruitment upon ligand binding. Finally, we propose that GR phosphorylation also participates in the nongenomic activation of cytoplasmic signaling pathways evoked by GR. Thus, GR phosphorylation is a versatile mechanism for modulating and integrating multiple receptor functions.
l‐Carnitine Is a Modulator of the Glucocorticoid Receptor Alpha
Authors: ALESCI SALVATORE , DE MARTINO MASSIMO U. , KINO TOMOSHIGE , ILIAS IOANNIS
Published: July 2004

Abstract: l‐Carnitine (LC) is a nutrient with an essential role in cellular energy production. At high doses, LC can mimic some of the biological activities of glucocorticoids, particularly immunomodulation. To explore the molecular bases of this property, we tested the influence of LC on glucocorticoid receptor‐a (GRα) functions. LC reduced the binding capacity of GRα, induced its nuclear translocation, and stimulated its transcriptional activity. Moreover, LC suppressed TNFα and IL‐12 release from human monocytes in glucocorticoid‐like fashion. We conclude that pharmacologic doses of LC can activate GRα and, via this mechanism, regulate glucocorticoid‐responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.
Human Immunodeficiency Virus Type‐1 Accessory Protein Vpr: A Causative Agent of the AIDS‐Related Insulin Resistance/Lipodystrophy Syndrome?
Authors: KINO TOMOSHIGE , CHROUSOS GEORGE P.
Published: July 2004

Abstract: Recent advances in the development of three different types of antiviral drugs, the nucleotide and non‐nucleotide analogues acting as reverse transcriptase inhibitors (NRTIs) and the nonpeptidic viral protease inhibitors (PI), and their introduction in the management of patients with AIDS, either alone or in combination, have dramatically improved the clinical course of the disease and prolonged life expectancy in patients with AIDS. The increase in life expectancy in association with the long‐term use of the above antiviral agents, however, have generated novel morbidities and complications. Central among them is the quite common AIDS‐related insulin resistance and lipodystrophy syndrome, which is characterized by a striking phenotype and marked metabolic disturbances. To look for the pathologic causes of this particular syndrome, we focused on one of the HIV‐1 accessory proteins, Vpr, which has multiple functions, such as virion incorporation, nuclear translocation of the HIV‐1 preintegration complex, nucleo‐cytoplasmic shuttling, transcriptional activation, and induction of apoptosis. Vpr may also act like a hormone, which is secreted into the extracellular space and affects the function of distant organs. Vpr functions as a coactivator of the glucocorticoid receptor and potentiates the action of glucocorticoid hormones, thereby inducing tissue glucocorticoid hypersensitivity. Vpr also arrests host cells at the G2/M phase of the cell cycle by interacting with novel 14‐3‐3 proteins. Vpr facilitates the interaction of 14‐3‐3 and its partner protein Cdc25C, which is critical for the transition of G2/M checkpoint in the cell cycle, and suppresses its activity by segregating it into the cytoplasm. The same Vpr protein also suppresses the association of 14‐3‐3 with other partner molecules, the Foxo transcription factors. Since the Foxo proteins function as negative transcription factors for insulin, Vpr may cause resistance of tissues to insulin. Through these two newly identified functions of Vpr, namely, coactivation of glucocorticoid receptor activity and inhibition of insulin effects on Foxo proteins, Vpr may participate in the development of AIDS‐related insulin resistance/lipodystrophy syndrome.
Familial/Sporadic Glucocorticoid Resistance: Clinical Phenotype and Molecular Mechanisms
Authors: CHARMANDARI EVANGELIA , KINO TOMOSHIGE , CHROUSOS GEORGE P.
Published: July 2004

Abstract: Glucocorticoids regulate a variety of biologic processes and exert profound influences on many physiologic functions. Their actions are mediated by the glucocorticoid receptor (GR), which belongs to the nuclear receptor family of ligand‐dependent transcription factors. Alterations in tissue sensitivity to glucocorticoids may manifest as states of resistance or hypersensitivity. Glucocorticoid resistance is a rare, familial or sporadic, condition characterized by generalized, partial target‐tissue resistance to glucocorticoids. Compensatory elevations in circulating adrenocorticotropic hormone (ACTH) concentrations lead to increased production of adrenal steroids with mineralocorticoid and/or androgenic activity and their corresponding clinical manifestations, as well as increased urinary free‐cortisol excretion in the absence of symptomatology suggestive of hypercortisolism. The molecular basis of the condition has been ascribed to mutations in the GR gene, which impair normal glucocorticoid signal transduction, altering tissue sensitivity to glucocorticoids. The present review focuses on the mechanisms of GR action and the clinical manifestations and molecular mechanisms of familial/sporadic glucocorticoid resistance.
Frontal‐wave development by interaction between a front and a cyclone: Application to FASTEX IOP 17
Authors: Arbogast Philippe
Published: July 2004

The way new cyclones appear along a baroclinic zone is central to the problem of the prediction of mid‐latitude cyclones. A new barotropic mechanism for frontal‐wave development is proposed in the present paper. The ingredients are a frontal environment characterized by horizontal wind shear and a finite‐amplitude initial wind perturbation orthogonal to the main deformation axis associated with the front. It is found that the initial wind perturbation can be provided by a low‐level vortex maximum located north‐westward with respect to the position of the new cyclone. Interactions between these synoptic features are documented using local energetics. The theory is only valid at the very early stage of development. After a few hours the main growing phase, which is mostly baroclinic, will take place.

A wide set of experiments is performed in order to find the preferred location of the vortex at the initial time in the frame of the barotropic vorticity equation. The result is found to be consistent with the Fronts and Atlantic Storm‐Track Experiment case studied in this paper. Frontogenetic forcing provided by a deformation field does not inhibit the perturbation amplification. It is also found that the impact of the vortex is significantly larger than potential instabilities developing along the front where the unstable feature is defined as the most unstable singular vector. Copyright © 2004 Royal Meteorological Society.
Perturbation growth in terms of baroclinic alignment properties
Authors: Rivière G. , Hua B. L. , Klein P.
Published: July 2004

Mechanisms leading to perturbation growth in complex time‐dependent quasi‐geostrophic (QG) flows are addressed in this paper. The dynamics of small three‐dimensional (3D) perturbations are studied for the complete set of the linearized local QG equations. An analytical diagnostic of these equations shows that, at each spatial location, the preferred 3D structures of the perturbations are related to the eigenvector directions of a matrix, denoted Ā, which is the 3D generalization of the basic‐state strain‐rate tensor. The matrix Ā has a degenerate form and depends on both the horizontal deformation and the vertical shear of the unperturbed reference flow. By using a nonlinear Monte‐Carlo technique, the 3D structures related to Ā's eigenvectors are shown to be the most probable ones for perturbation growth. We also provide simple analytical expressions for quantifying the barotropic and baroclinic energy extraction from the reference flow by the perturbations. In particular, our analytical expression for baroclinic energy extraction is found to be more relevant than the Eady index widely used in the literature. An interesting outcome of the Monte‐Carlo simulations is that the maxima of the total‐energy error field are found to be localized in regions where the norm of Ā is large. Copyright © 2004 Royal Meteorological Society.
Sensitivity of tropospheric forecasts to stratospheric initial conditions
Authors: Charlton A. J. , O'neill A. , Lahoz W. A. , Massacand A. C.
Published: July 2004

A number of recent papers in the atmospheric science literature have suggested that a dynamical link exists between the stratosphere and troposphere. Numerical modelling studies have shown that the troposphere has a time‐mean response to changes to the stratospheric climatological state. In this study the response of the troposphere to an imposed transient stratospheric change is examined.

The study uses a high horizontal and vertical resolution numerical weather‐prediction model. Experiments compare the tropospheric forecasts of two medium‐range forecast ensembles which have identical tropospheric initial conditions and different stratospheric initial conditions. In three case studies described here, stratospheric initial conditions have a statistically significant impact on the tropospheric flow. The mechanism for this change involves, in its most basic step, a change to tropospheric synoptic‐scale systems. A consistent change to the tropospheric synoptic‐scale systems occurs in response to the stratospheric initial conditions. The aggregated impact of changes to individual synoptic systems maps strongly onto the structure of the Arctic Oscillation, particularly over the North Atlantic storm track. The relationship between the stratosphere and troposphere, while apparent in Arctic Oscillation diagnostics, does not occur on coherent, hemispheric scales. Copyright © 2004 Royal Meteorological Society.
Significance testing for variational assimilation
Authors: Muccino Julia C. , Hubele Norma F. , Bennett Andrew F.
Published: July 2004

The hypothesis test associated with a variational data‐assimilation algorithm is examined in detail. It can be shown that the test statistic, Ĵ, should have a$\chi^{2}_{M}$distribution, whereMis the number of scalar data assimilated,ifthe hypothesis regarding the model and data residuals is consistent with the true physical system. The skill of the Kolmogorov–Smirnov (KS) test in identifying whether the hypothesis used in the assimilation is ‘true’ (that is, the hypothesis correctly reflects the residuals in the model and the data) or not (that is, the hypothesis has either incorrect parameters in the covariance or an incorrect bias) is evaluated. It is shown that the KS test does indeed have some skill in identifying a false hypothesis. However, as one might expect, the skill is limited to cases where the particular component of the hypothesis that is incorrect has an impact on the test statistic and therefore on its distribution. Copyright © 2004 Royal Meteorological Society.
Inversion effects on mountain lee waves
Authors: Vosper S. B.
Published: July 2004

The effect of a sharp low‐level temperature inversion on flow over a mountain is investigated via a series of two‐dimensional idealized numerical model simulations. The main focus of the study is the effect of the inversion on the formation of lee waves, lee‐wave rotors, low‐level hydraulic jumps and the occurrence of wave breaking aloft. The idealized problem considered consists of an upwind velocity profile that is independent of height (above the boundary layer) and directed normal to an isolated two‐dimensional ridge. The upstream stratification consists of a neutral layer immediately above the ground capped by a sharp temperature inversion. Above this, the atmosphere is stably stratified and the Brunt–Väisälä frequency is independent of height. Simulations were conducted for a range of inversion strengths (measured by the difference in potential temperature across the inversion) and inversion heights. The effect of both a free‐slip and a no‐slip lower boundary condition is investigated. Results show that, when the upwind Froude number (defined in the usual way for two‐layer shallow‐water flow) falls below a critical value, a short‐wavelength resonant lee wave forms downwind of the mountain on the inversion. It is shown that both the critical Froude‐number value and the wavelength of the lee wave are accurately predicted by linear theory. The lee‐wave amplitude, however, can be significantly underestimated by linear theory if the wavelength is less than the hill length scale. In the case of a no‐slip boundary condition, if the wave amplitude is sufficiently large, boundary‐layer separation occurs underneath the wave crests and closed rotor circulations occur. In general, flow separation (and rotors) do not occur in the free‐slip case. In both the free‐slip and no‐slip flows, as the Froude number decreases the lee wave is eventually replaced by a stationary hydraulic jump above the lee slope of the mountain. Copyright © 2004 Royal Meteorological Society.
Telerehabilitation — a new model for community-based stroke rehabilitation
Authors: Lai Jerry CK , Woo Jean , Hui Elsie , Chan WM
Published: July 2004

Community resources for stroke clients are underdeveloped in Hong Kong and stroke survivors often face difficulties in community reintegration. We have examined the feasibility of using videoconferencing for community-based stroke rehabilitation. The sample comprised 21 stroke patients living at home. All the subjects participated in an eight-week intervention programme at a community centre for seniors. The intervention, which comprised educational talks, exercise and psychosocial support, was conducted by a physiotherapist via a videoconference link. The Berg Balance Scale (BBS), State Self-Esteem Scale (SSES), Medical Outcomes Study 36-item Short Form (SF-36) and a stroke knowledge test were administered at the start and end of the programme. In addition, at the start of the study the Geriatric Depression Scale 15-item Short Form, the Elderly Mobility Scale and the Lawton Instrumental Activities of Daily Living Scale were used to assess subjects' baseline status, and a focus group was also held at the end of the programme to gather qualitative findings. Nineteen subjects completed the eight-week intervention. The baseline functional status was high, although 52% had symptoms of depression. After the intervention, there were significant improvements in BBS, SSES and knowledge test scores and scores on all subscales of the SF-36. All the subjects accepted the use of videoconferencing for delivery of the intervention. The pilot study demonstrated the feasibility, efficacy and high level of acceptance of telerehabilitation for community-dwelling stroke clients.
Intercontinental videoconferences between US and Hungarian obstetricians: a 30-month study
Authors: Török Miklós , Pasternak Alfred , Hobel Calvin , Korányi Lajos , Doszpod József
Published: July 2004

Over 30 months, 19 videoconferences were held between the Department of Obstetrics and Gynecology of the Cedars-Sinai Medical Center in Los Angeles and the Department of Obstetrics and Gynecology at the Semmelweis University in Budapest. Videoconferences used ISDN transmission at 384 kbit/s. In the main part of each videoconference a US expert presented various clinical topics. Every videoconference was recorded and later evaluated by two independent Hungarian researchers. The novelty of the information was scored on a Likert scale from 0 (low) to 10 (high). The novelty scores ranged from 0 to 8, with a tendency to low scores. There was a significant negative correlation between the novelty scores and the number of questions discussed during the videoconferences ( r = -0.63). There was also a significant negative correlation between novelty scores and the length of discussions ( r = -0.84). Medical expertise and practice were quite similar in the two institutions. The presentations on matters that were more familiar to the audience generated longer discussions and led to the sharing of experiences.