bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of a quantitative real-time PCR for the detection of respiratory syncytial virus in pulmonary diseases
Authors: Borg I. , Rohde G. , Löseke S. , Bittscheidt J. , Schultze-Werninghaus G. , Stephan V. , Bufe A.
Published: September 2008

Respiratory syncytial virus (RSV) is known to cause acute lower respiratory tract infections (ARI) in young children and is involved in exacerbation of chronic obstructive pulmonary disease (COPD) in adults. The role of RSV in stable COPD and the viral load in different respiratory diseases has not been investigated to date.

The present authors established and evaluated a quantitative TaqMan® real-time polymerase chain reaction assay specific for RSV subgroup A. Absolute quantification for the determination of viral load input was achieved using a control plasmid. The assay allowed for a quantification over a >6-log range and a detection limit of <10 RSV copies per reaction mixture.

The assay was 30 times more sensitive than conventional nested polymerase chain reaction assays. Interassay sd was 1.3 and coefficient of variation 4.7% on average. Clinical specimens from infants with ARI (n=62) and elderly adults with COPD (n=125) were compared for viral loads. A total of 47% RSV-positive samples were found in the ARI study group and 28% in the COPD study group. The viral load of both study groups was found to differ significantly. In the ARI study group the viral load was increased almost 2000-fold, suggesting acute infection in this group and former or latent infection in the COPD group.

Respiratory syncytial virus-A specific TaqMan® real-time polymerase chain reaction assay is a sensitive and rapid method for the determination of viral load in clinical samples. It enables differential statements concerning the involvement of respiratory syncytial virus in acute lower respiratory tract infections and chronic obstructive pulmonary disease to be achieved.
Possible anti-inflammatory effect of salmeterol against interleukin-8 and neutrophil activation in asthmain vivo
Authors: Reid D.W. , Ward C. , Wang N. , Zheng L. , Bish R. , Orsida B. , Walters E.H.
Published: September 2008

In-vitrodata suggest that long-acting β2-agonists may have a neutrophil-stabilising effect. A reduction in airway wall eosinophil number following introduction of salmeterol in persistent asthma has previously been described. There is currently interest in the “neutrophil system” in asthma, and thus the aim of the present study was to investigate the effect of salmeterol on interleukin (IL)-8, neutrophils and myeloperoxidase (MPO) in persistent asthma.

In the same 12-week double-blind parallel-group placebo-controlled study as described previously, the effects on bronchoalveolar lavage fluid (BALF) IL-8, neutrophils and MPO of introducing salmeterol (50 µgb.i.d.) or giving additional inhaled corticosteroid (fluticasone 100 µgb.i.d.) in 45 subjects with persistent asthma already on low/moderate doses of inhaled corticosteroids were further investigated.

At baseline, BALF IL-8 but not neutrophil or MPO levels were significantly raised in the asthmatic subjects compared to normal controls. MPO levels correlated strongly with IL-8 levels, and weakly with BALF neutrophil numbers in the asthmatics. Fluticasone treatment resulted in significantly elevated neutrophil numbers, but not MPO or IL-8 levels. In contrast, introducing salmeterol significantly reduced IL-8 and MPO levels, but did not affect BALF neutrophil numbers. Interestingly, salmeterol and fluticasone showed significantly contrasting effects on MPO and neutrophils, and there was a divergent effect on IL-8 levels that almost reached significance.

Excessive interleukin-8 levels may be relevant to asthma pathogenesis, even in the setting of moderate-dose inhaled corticosteroid therapy. Reduction in interleukin-8 production and possibly stabilisation of airway neutrophil numbers may explain the greater clinical benefit of adding a long-acting β2-agonist rather than merely increasing inhaled corticosteroid doses. Indeed, high-dose inhaled corticosteroid therapy alone may promote airway neutrophilia.
Definitions and types of work-related asthma: a nosological approach
Authors: Vandenplas O. , Malo J-L.
Published: September 2008

The workplace can trigger or induce asthma and cause the onset of different types of work-related asthma. Analysis of previous definitions of occupational asthma (OA) led to the conclusion that evidence of a direct causal relationship between workplace exposure and the development of asthma remains the key element for defining OA.

Based on clinical features and pathophysiological mechanisms, the following conditions should be distinguished in the spectrum of work-related asthma: 1) immunological OA characterised by a latency period necessary to acquire immunologically induced sensitisation; 2) nonimmunological OA characterised by the rapid onset of asthma following single or multiple exposures to high concentrations of irritant compounds; 3) work-related asthma defined by exacerbation of symptoms in workers with pre-existing or coincident asthma; and 4) variant syndromes including eosinophilic bronchitis, potroom asthma, and asthma-like disorders caused by organic dusts.

The issues and controversies relating to this approach are critically reviewed in order to stimulate the consensus development of operational definitions of work-related asthma.
Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome
Authors: Moloney E.D. , Evans T.W.
Published: September 2008

Pulmonary hypertension (PH) is a characteristic feature of the acute respiratory distress syndrome (ARDS). The magnitude of PH has been shown to correlate with the severity of lung injury in patients with ARDS independently of the severity of associated hypoxaemia and has an adverse prognostic significance.

Early in the histopathological evolution of ARDS, pulmonary vasoconstriction, thromboembolism and interstitial oedema contribute to the development of PH, although pulmonary vascular remodelling probably occurs eventually. Intravenous vasodilator agents lead to an increase in intrapulmonary shunting and systemic hypotension, which can limit their therapeutic use, and have not been shown to improve survival. By contrast, rapidly metabolised vasodilators administered by inhalation induce selective pulmonary vasodilatation and decrease shunting, but again do not appear to confer a survival benefit.

Research aimed at further understanding the mechanisms that underlie pulmonary hypertension, a characteristic feature of the acute respiratory distress syndrome, are expected to provide improvements in pharmacological interventions for the treatment of pulmonary hypertension in the acute respiratory distress syndrome.
Immunological mechanisms in pleural disease
Authors: Antony V.B.
Published: September 2008

The pleural membrane consisting of pleural mesothelial cells and its underlying connective tissue layers play a critical role in immunological responses in both local and systemic diseases. The pleura, because of its intimate proximity to the lung, is positioned to respond to inflammatory changes in the lung parenchyma. Importantly, several systemic diseases have a predilection for expression on the pleural surface.

Immunological responses in the pleura include the development of pleural permeability and pleural effusion formation as well as the development of pleural fibrosis and scarring. Under either circumstance, the normal functioning of the pleura is impaired and has multiple consequences leading to increased morbidity and even mortality for the patient.

During infections in the pleural space, the pleural mesothelium responds by actively recruiting inflammatory phagocytic cells and allowing the movement of proteins from the vascular compartment into the pleural space. The release of chemokines by the pleural mesothelium allows for directed migration of phagocytic cells from the basilar surface of the pleura towards the apical surface.

In malignant disease, the pleura may be the site of primary tumours such as mesothelioma and also the site for malignant metastatic deposits. Certain cancers such as cancers of the breast, ovary, lung, and stomach have a predilection for the pleural mesothelium. The process whereby malignant cells attach to the pleural mesothelium and develop autocrine mechanisms for survival in the pleural space are elucidated in this review. The pleura functions not only as a mechanical barrier, but also as an immunologically and metabolically responsive membrane that is involved in maintaining a dynamic homeostasis in the pleural space.
Single-breath transfer factor in young healthy adults: 21% or 17.5% inspired oxygen?
Authors: Normand H. , Marie C. , Mouadil A.
Published: September 2008

For the measurement of the single-breath transfer factor of the lung for carbon monoxide (TL,CO,sb), the American Thoracic Society (ATS) recommends using a test gas with a 21% inspired fraction of oxygen (FI,O2) whereas the European Respiratory Society (ERS) expressly recommends 17–18%FI,O2. The ERS committee argues that with a higher concentration (e.g.21%) the alveolar fraction of oxygen (and accordinglyTL,CO,sb) “varies with the volume of the test gas which is inspired”, that is, presumably, in proportion to the volume of the test gas that is diluted in the alveolar volume.

The current study measuredTL,CO,sband the transfer coefficient (KCO,sb) in duplicate in 67 healthy adults (age 17–23 yrs) using, in random order, an inspired gas containing either 17.5% or 21% oxygen. A correction was applied for carboxyhaemoglobin, in line with ATS recommendations.

As expected,TL,CO,sbwas higher with 17.5%FI,O2test gas compared with 21%FI,O2test gas (11.98±2.68versus11.38±2.56 mmol·min−1·kPa−1, respectively) as well asKCO,sb(1.98±0.24versus1.90±0.23 mmol·min−1·kPa−1, respectively). The ratio ofTL,CO,sbmeasurements was strictly independent of the residual volume/total lung capacity ratio measured with plethysmography.

Hence, the rationale used by the European Respiratory Society, which utilises a 17–18% inspired fraction of oxygen test gas for single-breath transfer of the lung for carbon monoxide measurements, would appear to be unwarranted in young healthy adults.
“Cyst-like” structures within the ciliary shafts in children with bronchiectasis
Authors: Pifferi M. , Cangiotti A.M. , Caramella D. , Pietrobelli A. , Ragazzo V. , De Marco E. , Macchia P. , Cinti S. , Boner A.L.
Published: September 2008

“Cyst-like” structures within the ciliary shafts were considered in four adults as a primary defect involved in the development of bronchiectasis. In this study, the presence and the primary or secondary nature of this abnormality were assessed in children with bronchiectasis.

High resolution computed tomography (HRCT) and nasal biopsies for motion analysis and transmission electron microscopy (TEM) evaluation of cilia were obtained in 45 children with recurrent lower airway infections and abnormal chest radiography.

HRCT disclosed bronchiectasis in 35 out of 45 (77.8%) children and cyst-like structures were demonstrated with TEM in 29 out of 45 (64.4%) patients. Cyst-like structures were constantly associated with other ultrastructural abnormalities commonly observed in chronic inflammation, and were found both in subjects with primary and with secondary ciliary dyskinesia. When considering only patients with bronchiectasis, a significant correlation between prevalence of cyst-like structures and the severity of bronchiectasis was demonstrated. Follow-up (2–22 months) of seven patients demonstrated that in the five children with secondary dyskinesia, the ultrastructural defect completely disappeared and there was a small reduction in the abnormality in the two patients with primary dyskinesia.

In contrast to one previous report, the reversibility of the defect suggests its secondary origin, which is most likely related to chronic airway inflammation.
Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD
Authors: McNicholas W.T. , Calverley P.M.A. , Lee A. , Edwards J.C.
Published: September 2008

Oxygen desaturation occurs during sleep in severe chronic obstructive pulmonary disease (COPD), especially during rapid eye movement (REM) sleep, due to hypoventilation and ventilation-perfusion mismatching, but the possible contribution of airflow limitation is unclear.

In a randomised, placebo-controlled, double-blind study of severe, stable COPD patients, the authors compared 4 weeks treatment with a long-acting inhaled anticholinergic agent (tiotropium), taken in the morning (tiotropium-AM), or in the evening (tiotropium-PM), on sleeping arterial oxygen saturation (Sa,O2) and sleep quality. Overnight polysomnography was performed at baseline and after 4 weeks treatment. A total of 95 patients with awake resting arterial oxygen tension ≤9.98 kPa (75 mmHg) were randomised, with a mean age of 66.4 yrs and mean forced expiratory volume in one second (FEV1) of 32% predicted.

A total of 80 patients completed the study, of which 56 fulfilled the polysomnographic criterion of at least 2 h sleep in both sleep study nights and represent the group analysed. Tiotropium significantly improved spirometry compared with placebo. Both tiotropium-AM and tiotropium-PM groups had higherSa,O2during REM than placebo (+2.41% and +2.42%, respectively, and both pooled and tiotropium-PM groups had higherSa,O2during total sleep time (+2.49% and +3.06%, respectively). End-of-treatment FEV1correlated withSa,O2during REM sleep, however, tiotropium did not change sleep quality.

Sustained anticholinergic blockade improves sleeping arterial oxygen saturation without affecting sleep quality.
Inversion of allosteric effect of arginine on N-acetylglutamate synthase, a molecular marker for evolution of tetrapods
Authors: Haskins Nantaporn , Panglao Maria , Qu Qiuhao , Majumdar Himani , Cabrera-Luque Juan , Morizono Hiroki , Tuchman Mendel , Caldovic Ljubica
Published: September 2008

Background

The efficient conversion of ammonia, a potent neurotoxin, into non-toxic metabolites was an essential adaptation that allowed animals to move from the aquatic to terrestrial biosphere. The urea cycle converts ammonia into urea in mammals, amphibians, turtles, snails, worms and many aquatic animals and requires N-acetylglutamate (NAG), an essential allosteric activator of carbamylphosphate synthetase I (CPSI) in mammals and amphibians, and carbamylphosphate synthetase III (CPSIII) in fish and invertebrates. NAG-dependent CPSI and CPSIII catalyze the formation of carbamylphosphate in the first and rate limiting step of ureagenesis. NAG is produced enzymatically by N-acetylglutamate synthase (NAGS), which is also found in bacteria and plants as the first enzyme of arginine biosynthesis. Arginine is an allosteric inhibitor of microbial and plant NAGS, and allosteric activator of mammalian NAGS.

Results

Information from mutagenesis studies of E. coli and P. aeruginosa NAGS was combined with structural information from the related bacterial N-acetylglutamate kinases to identify four residues in mammalian NAGS that interact with arginine. Substitutions of these four residues were engineered in mouse NAGS and into the vertebrate-like N-acetylglutamate synthase-kinase (NAGS-K) of Xanthomonas campestris, which is inhibited by arginine. All mutations resulted in arginine losing the ability to activate mouse NAGS, and inhibit X. campestris NAGS-K. To examine at what point in evolution inversion of arginine effect on NAGS occur, we cloned NAGS from fish and frogs and examined the arginine response of their corresponding proteins. Fish NAGS were partially inhibited by arginine and frog NAGS were activated by arginine.

Conclusion

Difference in arginine effect on bacterial and mammalian NAGS most likely stems from the difference in the type of conformational change triggered by arginine binding to these proteins. The change from arginine inhibition of NAGS to activation was gradual, from complete inhibition of bacterial NAGS, to partial inhibition of fish NAGS, to activation of frog and mammalian NAGS. This change also coincided with the conquest of land by amphibians and mammals.
Expression study of cadherin7 and cadherin20 in the embryonic and adult rat central nervous system
Authors: Takahashi Masanori , Osumi Noriko
Published: September 2008

Background

Vertebrate classic cadherins are divided into type I and type II subtypes, which are individually expressed in brain subdivisions (e.g., prosomeres, rhombomeres, and progenitor domains) and in specific neuronal circuits in region-specific manners. We reported previously the expression of cadherin19 (cad19) in Schwann cell precursors. Cad19 is a type II classic cadherin closely clustered on a chromosome with cad7 and cad20. The expression patterns of cad7 and cad20 have been reported previously in chick embryo but not in the developing and adult central nervous system of mammals. In this study, we identified rat cad7 and cad20 and analyzed their expression patterns in embryonic and adult rat brains.

Results

Rat cad7 protein showed 92% similarity to chick cad7, while rat cad20 protein had 76% similarity to Xenopus F-cadherin. Rat cad7 mRNA was initially expressed in the anterior neural plate including presumptive forebrain and midbrain regions, and then accumulated in cells of the dorsal neural tube and in rhombomere boundary cells of the hindbrain. Expression of rat cad20 mRNA was specifically localized in the anterior neural region and rhombomere 2 in the early neural plate, and later in longitudinally defined ventral cells of the hindbrain. The expression boundaries of cad7 and cad20 corresponded to those of region-specific transcription factors such as Six3, Irx3 and Otx2 in the neural plate, and Dbx2 and Gsh1 in the hindbrain. At later stages, the expression of cad7 and cad20 disappeared from neuroepithelial cells in the hindbrain, and was almost restricted to postmitotic cells, e.g. somatic motor neurons and precerebellar neurons. These results emphasized the diversity of cad7 and cad20 expression patterns in different vertebrate species, i.e. birds and rodents.

Conclusion

Taken together, our findings suggest that the expression of cad7 and cad20 demarcates the compartments, boundaries, progenitor domains, specific nuclei and specific neural circuits during mammalian brain development.
Role of IFN-gamma and IL-6 in a protective immune response to Yersinia enterocoliticain mice
Authors: Matteoli Gianluca , Fahl Edda , Warnke Philipp , Müller Steffen , Bonin Michael , Autenrieth Ingo B , Bohn Erwin
Published: September 2008

Background

Yersinia outer protein (Yop) H is a secreted virulence factor of Yersinia enterocolitica (Ye), which inhibits phagocytosis of Ye and contributes to the virulence of Ye in mice. The aim of this study was to address whether and how YopH affects the innate immune response to Ye in mice.

Results

For this purpose, mice were infected with wild type Ye (pYV+) or a YopH-deficient Ye mutant strain (ΔyopH). CD11b+ cells were isolated from the infected spleen and subjected to gene expression analysis using microarrays. Despite the attenuation of ΔyopH in vivo, by variation of infection doses we were able to achieve conditions that allow comparison of gene expression in pYV+ and ΔyopH infection, using either comparable infection courses or splenic bacterial burden. Gene expression analysis provided evidence that expression levels of several immune response genes, including IFN-γ and IL-6, are high after pYV+ infection but low after sublethal ΔyopH infection. In line with these findings, infection of IFN-γR-/- and IL-6-/- mice with pYV+ or ΔyopH revealed that these cytokines are not necessarily required for control of ΔyopH, but are essential for defense against infection with the more virulent pYV+. Consistently, IFN-γ pretreatment of bone marrow derived macrophages (BMDM) strongly enhanced their ability in killing intracellular Ye bacteria.

Conclusion

In conclusion, this data suggests that IFN-γ-mediated effector mechanisms can partially compensate virulence exerted by YopH. These results shed new light on the protective role of IFN-γ in Ye wild type infections.
Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues
Authors: Kilpinen Sami , Autio Reija , Ojala Kalle , Iljin Kristiina , Bucher Elmar , Sara Henri , Pisto Tommi , Saarela Matti , Skotheim Rolf I , Björkman Mari , Mpindi John-Patrick , Haapa-Paananen Saija , Vainio Paula , Edgren Henrik , Wolf Maija , Astola Jaakko , Nees Matthias , Hautaniemi Sampsa , Kallioniemi Olli
Published: September 2008

Our knowledge on tissue- and disease-specific functions of human genes is rather limited and highly context-specific. Here, we have developed a method for the comparison of mRNA expression levels of most human genes across 9,783 Affymetrix gene expression array experiments representing 43 normal human tissue types, 68 cancer types, and 64 other diseases. This database of gene expression patterns in normal human tissues and pathological conditions covers 113 million datapoints and is available from the GeneSapiens website.
Tissue-Specific Difference in the Molecular Mechanisms for the Development of Acute Insulin Resistance after Injury
Authors: Li Li , Thompson LaWanda H. , Zhao Ling , Messina Joseph L.
Published: September 2008

Acute insulin resistance occurs after injury, hemorrhage, infection, and critical illness. However, little is known about the development of this acute insulin-resistant state. In the current study, we found that insulin resistance develops rapidly in skeletal muscle, with the earliest insulin signaling defects at 60 min. However, defects in insulin signaling were measurable even earlier in liver, by as soon as 15 min after hemorrhage. To begin to understand the mechanisms for the development of acute insulin resistance, serine phosphorylation of insulin receptor substrate (IRS)-1 and c-Jun N-terminal kinase phosphorylation/activation was investigated. These markers (and possible contributors) of insulin resistance were increased in the liver after hemorrhage but not measurable in skeletal muscle. Because glucocorticoids are important counterregulatory hormones responsible for glucose homeostasis, a glucocorticoid synthesis inhibitor, metyrapone, and a glucocorticoid receptor antagonist, RU486, were administered to adult rats prior to hemorrhage. In the liver, the defects of insulin signaling after hemorrhage, including reduced tyrosine phosphorylation of the insulin receptor and IRS-1, association between IRS-1 and phosphatidylinositol 3-kinase and serine phosphorylation of Akt in response to insulin were not altered by pretreatment of rats with metyrapone or RU486. In contrast, hemorrhage-induced defects in insulin signaling were dramatically reversed in skeletal muscle, indicating a prevention of insulin resistance in muscle. These results suggest that distinct mechanisms for hemorrhage-induced acute insulin resistance are present in these two tissues and that glucocorticoids are involved in the rapid development of insulin resistance in skeletal muscle, but not in the liver, after hemorrhage.

Glucocorticoids play a major role in the development of acute insulin resistance following hemorrhage in skeletal muscle, but not in the liver.
Down-Regulation of Akt/Mammalian Target of Rapamycin Signaling Pathway in Response to Myostatin Overexpression in Skeletal Muscle
Authors: Amirouche Adel , Durieux Anne-Cécile , Banzet Sébastien , Koulmann Nathalie , Bonnefoy Régis , Mouret Catherine , Bigard Xavier , Peinnequin André , Freyssenet Damien
Published: September 2008

Myostatin, a member of the TGF-β family, has been identified as a master regulator of embryonic myogenesis and early postnatal skeletal muscle growth. However, cumulative evidence also suggests that alterations in skeletal muscle mass are associated with dysregulation in myostatin expression and that myostatin may contribute to muscle mass loss in adulthood. Two major branches of the Akt pathway are relevant for the regulation of skeletal muscle mass, the Akt/mammalian target of rapamycin (mTOR) pathway, which controls protein synthesis, and the Akt/forkhead box O (FOXO) pathway, which controls protein degradation. Here, we provide further insights into the mechanisms by which myostatin regulates skeletal muscle mass by showing that myostatin negatively regulates Akt/mTOR signaling pathway. Electrotransfer of a myostatin expression vector into the tibialis anterior muscle of Sprague Dawley male rats increased myostatin protein level and decreased skeletal muscle mass 7 d after gene electrotransfer. Using RT-PCR and immunoblot analyses, we showed that myostatin overexpression was ineffective to alter the ubiquitin-proteasome pathway. By contrast, myostatin acted as a negative regulator of Akt/mTOR pathway. This was supported by data showing that the phosphorylation of Akt on Thr308, tuberous sclerosis complex 2 on Thr1462, ribosomal protein S6 on Ser235/236, and 4E-BP1 on Thr37/46 was attenuated 7 d after myostatin gene electrotransfer. The data support the conclusion that Akt/mTOR signaling is a key target that accounts for myostatin function during muscle atrophy, uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle.

Myostatin down-regulates Akt/mammalian target of rapamycin (mTOR) signaling pathway uncovering a novel role for myostatin in protein metabolism and more specifically in the regulation of translation in skeletal muscle.
Early Postnatal Nutrition Determines Somatotropic Function in Mice
Authors: Kappeler Laurent , De Magalhaes Filho Carlos , Leneuve Patricia , Xu Jie , Brunel Nadège , Chatziantoniou Christos , Le Bouc Yves , Holzenberger Martin
Published: September 2008

Increasing evidence suggests a developmental origin for a number of human diseases, notably after intrauterine or postnatal nutrient deprivation. Nutritional changes readily translate into alterations of somatic growth. However, whereas intrauterine growth retardation often shows postnatal catch-up growth, recovery from food restriction immediately after birth is limited. Therefore, we investigated whether early postnatal nutrition (undernutrition and overfeeding) modifies plasticity of growth through developmental control of the somatotropic hormone axis. We used cross-fostering in mice to induce changes in early nutrition, and examined endocrine growth regulation and the development of specific disease phenotypes in adults. We showed that underfeeding during the early postnatal period delayed growth, whereas overfeeding accelerated it. In both cases, final body size was permanently altered. We found coordinated alterations in pituitary GH, plasma IGF-I and acid labile subunit, and gene expression of hypothalamic GHRH during postnatal development. These changes were consistent with the observed phenotypes. Alterations in the somatotropic axis persisted throughout adulthood. Although limited to the early postnatal period, both underfeeding and overfeeding led to reduced glucose tolerance later in life. These metabolic abnormalities were in line with defective insulin secretion in restricted mice and insulin resistance in overfed mice. Moreover, both restricted and overfed mice had increased arterial blood pressure, suggestive of vascular impairment. Our findings indicate a significant link between early postnatal diet, somatotropic development, and specific late onset diseases in mice. We suggest that, together with other hormones like leptin, IGF-I may play a role in modulating hypothalamic stimulation of the developing somatotropic function.

Early postnatal nutrition determines adult activity of the GH axis through an early modulation of hypothalamic GHRH stimulation, probably via hormones like leptin or IGF-I.
Tissue- and Context-Dependent Modulation of Hormonal Sensitivity of Glucocorticoid-Responsive Genes by Hexamethylene Bisacetamide-Inducible Protein 1
Authors: Shimizu Noriaki , Yoshikawa Noritada , Wada Tadashi , Handa Hiroshi , Sano Motoaki , Fukuda Keiichi , Suematsu Makoto , Sawai Takashi , Morimoto Chikao , Hirotoshi Hirotoshi
Published: September 2008

Physiological and pharmacological processes mediated by glucocorticoids involve tissue- and context-specific regulation of glucocorticoid-responsive gene expression via glucocorticoid receptor (GR). However, the molecular mechanisms underlying such highly coordinated regulation of glucocorticoid actions remain to be studied. We here addressed this issue using atp1a1 and scnn1a, both of which are up-regulated in response to corticosteroids in human embryonic kidney-derived 293 cells, but resistant in liver-derived HepG2 cells. Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) represses gene expression via, at least, two distinct mechanisms, i.e. positive transcription elongation factor b sequestration and direct interaction with GR, and is relatively high in HepG2 cells compared with 293 cells. Given this, we focused on the role of HEXIM1 in transcriptional regulation of these GR target genes. In HepG2 cells, hormone resistance of atp1a1 and scnn1a was diminished by either knockdown of HEXIM1 or overexpression of GR. Such a positive effect of exogenous expression of GR was counteracted by concomitant overexpression of HEXIM1, indicating the balance between GR and HEXIM1 modulates hormonal sensitivity of these genes. In support of this, the hormone-dependent recruitment of RNA polymerase II onto atp1a1 promoter was in parallel with that of GR. Moreover, we revealed that not positive transcription elongation factor b-suppressing activity but direct interaction with GR of HEXIM1 plays a major role in suppression of promoter recruitment of the receptor and subsequent atp1a1 and scnn1a gene activation. Collectively, we may conclude that HEXIM1 may participate in tissue-selective determination of glucocorticoid sensitivity via direct interaction with GR at least in certain gene sets including atp1a1 and scnn1a.
Professionalism and Nonprofit Organizations
Authors: Majone Giandomenico
Published: September 2008

Many professionals prefer to work in nonprofit organizations, rather than in either for-profit or bureaucratic organizations. This preference suggests that nonprofits may be successful in reducing the tension between professional principles and institutional requirements. Professionals in for-profit organizations must submit to the control of a manager who is motivated to overrule them whenever their decisions come into conflict with the goal of profit maximization. Bureaucratic organizations stress predictability of results and adherence to rules as the overriding criteria of evaluation and control. This paper argues that nonprofits are on the whole superior from the point of view of professional ideology and practice. Thus, given a commitment to the values of professionalism, the preference for the nonprofit form becomes understandable, even without the usual assumptions about income-maximizing behavior.
Hospital Rate Regulation: American and Foreign Comparisons
Authors: Glaser William A.
Published: September 2008

Rate regulation in the United States usually is inspired by widespread indignant pressures to protect the public against venal exploitation. Rate regulation of American hospitals does not ride such a wave of outrage but is motivated by the need to restrain Medicaid spending and insurance premium increases in some states. Hospital rate regulation in America lacks strong political support, makes many politically prudent concessions to hospitals, and is often threatened by repeal. Since Americans distrust regulators and since individual scrutiny of so many hospitals is burdensome and contentious, they often seek automatic formulae that will produce equitable results by rational calculation.

In contrast, rate regulation in Europe is a method of refereeing between hospitals and alert third parties. Hospitals' prospective budgets are always scrutinized by regulators. Guidelines are transmitted by government to link public policy to hospital payment, and the regulators apply the guidelines to each hospital's individual situation. The system results in less contention and more stability in European than in American regulation. Certain features of European hospital practice have kept hospital costs high, but the regulators are now reducing annual increases in costs below America's. In order to reduce cost increases further, Europe is moving toward global budgeting and public grants of hospitals' operating costs, instead of regulation of unit rates. However, regulators may still be essential to scrutinize hospital prospective budgets and to investigate the merits of the claims by individual establishments.
Organized Dentistry and the Pursuit of Entry Control
Authors: Fraundorf Kenneth C.
Published: September 2008

Organized dentistry spent nearly a century laboring to obtain control over entry into the profession. The first attempt, the American Society of Dental Surgeons, failed because the issue of using amalgam so split the Society that collective action became impossible. The second attempt, state licensing during 1870–1900. gave preferential treatment (automatic licensing) to dental school graduates and appeared at first to be the solution to the entry problem, given the small number of schools in operation. However, dental school entrepreneurs recognized a profitable opportunity, and the supply of dental schools expanded rapidly. Thus, in the third and final attempt at obtaining entry control, organized dentistry attacked the for-profit schools. The dental practice acts were amended to require all candidates to pass a licensing examination, provided first that they were graduates of a school considered “reputable” by the state board of dental examiners. Moreover, rising costs generated by increased school standards took the profit out of for-profit operation, and by 1930 such schools ceased to exist. However, the competitive nature of the 1930s made altogether clear that entry control was a necessary, but not sufficient, condition for the maximization of dentist profits, and thus organized dentistry began its turn inward, focusing on the competitive behavior of existing dentists.
Public Attitudes toward Health Planning Under the Health Systems Agencies
Authors: Mick Stephen S. , Thompson John D.
Published: September 2008

The demise of the National Health Planning and Resources Development Act of 1974 (PL 93-641) raises questions about the degree of public support it had for planning goals. The results of a 1978 nationwide public opinion poll reveal (1) low confidence in and recognition of the Act's institutional arms, the Health Systems Agencies; (2) little support for hospital cost containment strategies and their consequences; and (3) less than average support for these goals and consequences among those groups traditionally under-represented in health planning activities. The results suggest that the Act did not reconcile centralized federal goal formation with democratic local health planning.
The Diseased Body in Premodern Europe: Ideology and Representation
Authors: Zimmerman Susan
Published: September 2008

The phenomenon of disease played an important role in the development of premodern European culture, and in the reciprocal exchanges between Europe and the New World. Its understanding and regulation involved all sectors of society–religion, politics, science, law, commerce–and affected the welfare of individuals in every social class. Disease is, in fact, a singularly useful subject for examining the interdependence of these social sectors as well as their competing interests, and for interrogating the divide between hegemonic and popular cultures. The essays in this special issue analyze a number of issues of particular importance to the current study of premodern medicine. These include the uses and misrepresentations of long-standing paradigms for the interpretation of disease, such as the theory of humoralism, as well as the Hippocratic Airs, Waters, and Places tradition; the neglect of nonacademic sources such as the written records of patients or the recorded comments of ordinary citizens; the relationship of disease to the constitution of civic communities; the function of disease in the defining of national identities; the representation of disease in nonmedical literature such as travel treatises; and concepts of disease in pan-European myth-making. The volume concludes with a description of a major archive for the study of medical history, the Duke University History of Medicine Collections. In a sense, each essay encapsulates both the promise of the field–the interdisciplinary richness of the possible topics, the new voices to be uncovered in archival research–and the problems of interpretation that must be taken up in mining these prospects.
“There's the Rub”: Searching for Sexual Remedies in the New World
Authors: Finucci Valeria
Published: September 2008

In his late forties, Duke Vincenzo Gonzaga of Mantua (1562–1612) decided he needed a new biostimulator to cure his legendary restlessness, for he was experiencing senior amatory difficulties. Thus he sent a young apothecary on a journey from Mantua to Spain, and then to Panama and Peru, to find an animal Viagra-equivalent in that expanse of lands where marvels were contained. The duke's discreet fantasy of resurrecting the flesh, anchored in male anxiety, narcissistic excess, and a peculiar dream of domination, occupies hardly a footnote in the multinational project of mercantile imperialism that marked the discovery of the natural beauties of the New World. Yet, within the historical moment in which it played, the halcyon cure that this aging conquistador desired serves as a miniature parable that can reconfigure what is by all means a trivial colonialist narrative into an erotics of knowledge.
The Diseased Body: Resources for Scholarly Inquiry in the Duke University History of Medicine Collections
Authors: Glaze Florence Eliza , Nance Brian K. , Porter Suzanne
Published: September 2008

This article examines the holdings of the Duke University Medical School Library's History of Medicine Collections, including the Trent Collection. It provides a generalized topical description of the collections' contents, as well as an exploration of specific resources that can be used to study the diseased body in medieval and early modern Europe. Bibliographic notations direct the nonspecialist to further readings on the subject.
αII-βV spectrin bridges the plasma membrane and cortical lattice in the lateral wall of the auditory outer hair cells
Authors: Legendre Kirian , Safieddine Saaid , Küssel-Andermann Polonca , Petit Christine , El-Amraoui Aziz
Published: September 2008

The sensitivity and frequency selectivity of the mammalian cochlea involves a mechanical amplification process called electromotility, which requires prestin-dependent length changes of the outer hair cell (OHC) lateral wall in response to changes in membrane electric potential. The cortical lattice, the highly organized cytoskeleton underlying the OHC lateral plasma membrane, is made up of F-actin and spectrin. Here, we show that αII and two of the five β-spectrin subunits, βII and βV, are present in OHCs. βII spectrin is restricted to the cuticular plate, a dense apical network of actin filaments, whereas βV spectrin is concentrated at the cortical lattice. Moreover, we show that αII-βV spectrin directly interacts with F-actin and band 4.1, two components of the OHC cortical lattice. βV spectrin is progressively recruited into the cortical lattice between postnatal day 2 (P2) and P10 in the mouse, in parallel with prestin membrane insertion, which itself parallels the maturation of cell electromotility. Although βV spectrin does not directly interact with prestin, we found that addition of lysates derived from mature auditory organs, but not from the brain or liver, enables βV spectrin–prestin interaction. Using this assay, βV spectrin, via its PH domain, indirectly interacts with the C-terminal cytodomain of prestin. We conclude that the cortical network involved in the sound-induced electromotility of OHCs contains αII-βV spectrin, and not the conventional αII-βII spectrin.
Frontal sinuses and head-butting in goats: a finite element analysis
Authors: Farke Andrew A.
Published: September 2008

Frontal sinuses in goats and other mammals have been hypothesized to function as shock absorbers, protecting the brain from blows during intraspecific combat. Furthermore, sinuses are thought to form through removal of `structurally unnecessary' bone. These hypotheses were tested using finite element modeling. Three-dimensional models of domesticated goat (Capra hircus) skulls were constructed, with variable frontal bone and frontal sinus morphology, and loaded to simulate various head-butting behaviors. In general, models with sinuses experienced higher strain energy values (a proxy for shock absorption) than did models with unvaulted frontal bones, and the latter often had higher magnitudes than models with solid vaulted frontal bones. Furthermore, vaulted frontal bones did not reduce magnitudes of principal strain on the surface of the endocranial cavity relative to models with unvaulted frontal bones under most loading conditions. Thus, these results were only partially consistent with sinuses, or the bone that walls the sinuses, acting as shock absorbers. It is hypothesized that the keratinous horn sheaths and cranial sutures are probably more important for absorbing blows to the head. Models with sinuses did exhibit a more `efficient'distribution of stresses, as visualized by histograms in which models with solid frontal bones had numerous unloaded elements. This is consistent with the hypothesis that sinuses result at least in part from the removal of mechanically unnecessary bone.
AMP-activated protein kinase activity during metabolic rate depression in the hypoxic goldfish,Carassius auratus
Authors: Jibb Lindsay A. , Richards Jeffrey G.
Published: September 2008

Cell survival during hypoxia exposure requires a metabolic reorganization to decrease ATP demands to match the reduced capacity for ATP production. We investigated whether AMP-activated protein kinase (AMPK) activity responds to 12 h exposure to severe hypoxia (∼0.3 mg O2l–1) in the anoxia-tolerant goldfish (Carassius auratus). Hypoxia exposure in goldfish was characterized by a strong activation of creatine phosphate hydrolysis and glycolysis in liver and muscle. AMPK activity increased by ∼5.5-fold in goldfish liver within 0.5 h hypoxia exposure and this increase in activity was temporally associated with an 11-fold increase in [AMPfree]/[ATP]. No changes in total AMPK protein amount were observed, suggesting that the changes in AMPK activity are due to post-translational phosphorylation of the protein. Hypoxia exposure had no effect on the expression of two identified AMPKα-subunit isoforms and caused an ∼50% decrease in the mRNA levels of AMPK β-subunit isoform. Changes in AMPK activity in the liver were associated with an increase in percentage phosphorylation of a well-characterized target of AMPK, eukaryotic elongation factor-2 (eEF2), and decreases in protein synthesis rates measured in liver cell-free extracts. No activation of AMPK was observed in muscle, brain, heart or gill during the 12 h hypoxia exposure suggesting a tissue-specific regulation of AMPK possibly related to a lack of change in cellular [AMPfree]/[ATP] as observed in muscle.
Larval anopheline mosquito recta exhibit a dramatic change in localization patterns of ion transport proteins in response to shifting salinity: a comparison between anopheline and culicine larvae
Authors: Smith Kristin E. , VanEkeris Leslie A. , Okech Bernard A. , Harvey William R. , Linser Paul J.
Published: September 2008

Mosquito larvae live in dynamic aqueous environments, which can fluctuate drastically in salinity due to environmental events such as rainfall and evaporation. Larval survival depends upon the ability to regulate hemolymph osmolarity by absorbing and excreting ions. A major organ involved in ion regulation is the rectum, the last region for modification of the primary urine before excretion. The ultrastructure and function of culicine larval recta have been studied extensively; however, very little published data exist on the recta of anopheline larvae. To gain insight into the structure and functions of this organ in anopheline species, we used immunohistochemistry to compare the localization of three proteins [carbonic anhydrase (CA9),Na+/K+ P-ATPase and H+ V-ATPase] in the recta of anopheline larvae reared in freshwater and saline water with the localization of the same proteins in culicine larvae reared under similar conditions. Based on the following key points, we concluded that anophelines differ from culicines in larval rectal structure and in regulation of protein expression: (1) despite the fact that obligate freshwater and saline-tolerant culicines have structurally distinct recta, all anophelines examined(regardless of saline-tolerance) have a structurally similar rectum consisting of distinct DAR (dorsal anterior rectal) cells and non-DAR cells; (2)anopheline larvae undergo a dramatic shift in rectal Na+/K+-ATPase localization when reared in freshwater vs saline water. This shift is not seen in any culicine larvae examined. Additionally, we use these immunohistochemical analyses to suggest possible functions for the DAR and non-DAR cells of anopheline larvae in freshwater and saline conditions.
Effects of [Ca2+]i and pH on epithelial Na+ channel activity of cultured mouse cortical collecting ducts
Authors: Gu Yuchun
Published: September 2008

[Ca2+]i and pH have been demonstrated to affect Na+ transport in epithelium mediated via the apical epithelial Na+ channel (ENaC). However, it still remains unclear whether the effects of [Ca2+]i and intracellular pH(pHi) on ENaC activity are direct. In this study, inside-out recording was employed to clarify the effects of pHi and[Ca2+]i on ENaC activity. We found that elevation of[Ca2+]i induced a significant inhibition of ENaC open probability without altering channel conductance. The inhibitory effect was due to a direct interaction between Ca2+ and ENaC, and is dependent on [Ca2+]i. pHi also directly regulated ENaC open probability. Lower pHi (<7.0) reduced the ENaC open probability as shown in shorter opening time, and higher pHi(>7.0) enhanced the ENaC open probability as shown in augmented opening time. pHi did not cause any alteration in channel conductance. The effects of pHi on ENaC open probability could be summarized as an S-shaped curve around pH 7.2.