bluuebunny/crossref_metadata_2025_split huggingface dataset:
FROM MEDICAL RATIONING TO RATIONALIZING THE USE OF HUMAN RESOURCES FOR AIDS CARE AND TREATMENT IN AFRICA: A CASE FOR TASK SHIFTING
Authors: PRICE JESSICA , BINAGWAHO AGNES 
Published: April 2010

ABSTRACTWith a global commitment to scaling up AIDS care and treatment in resource‐poor settings for some of the most HIV‐affected countries in Africa, availability of antiretroviral treatment is no longer the principal obstacle to expanding access to treatment. A shortage of trained healthcare personnel to initiate treatment and manage patients represents a more challenging barrier to offering life‐saving treatment to all patients in need. Physician‐centered treatment policies accentuate this challenge. Despite evidence that task shifting for nurse‐centered AIDS patient care is effective and can alleviate severe physician shortages that currently obstruct treatment scale‐up, political commitment and policy action to support task shifting models of care has been slow to absent. In this paper we review the evidence in support of task shifting for AIDS treatment in Africa and argue that continued policy inaction amounts to unwarranted healthcare rationing and as such is ethically untenable.
New drugs for neglected infectious diseases: Chagas' disease
Authors: Machado Fabiana S , Tanowitz Herbert B , Teixeira Mauro M 
Published: April 2010

Chagas' disease (CD) is caused by the protozoan Trypanosoma cruzi (Tc) and remains an important cause of morbidity and mortality. Most researchers in the field now agree that chronic low grade parasite persistence in tissue drives tissue damage and the autoimmune component of CD. Current therapy relies on two compounds: benznidazole and nifurtimox. Despite their long history in the treatment of CD, both compounds induce significant side‐effects. In the current issue of the BJP, two contributions demonstrate that NO‐donors are active, especially in combination with benznidazole, against Tc in vitro and in experimental models in vivo. The basic concept used by the authors to develop novel anti‐Tc compounds relied on the demonstrated ability of nitric oxide to kill the parasite. There are several issues still to be resolved but the reported studies are a clear advance to the field and should be considered for further pre‐clinical development.This article is a commentary on Silva et al., pp. 260–269 and Guedes et al., pp. 270–282 of this issue. To view these papers visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00524.x and http://dx.doi.org/10.1111/j.1476‐5381.2010.00576.x
Disruption of cellular cholesterol transport and homeostasis as a novel mechanism of action of membrane‐targeted alkylphospholipid analogues
Authors: Carrasco María P , Jiménez‐López José M , Ríos‐Marco Pablo , Segovia Josefa L , Marco Carmen 
Published: April 2010

Background and purpose:  Alkylphospholipid (APL) analogues constitute a new class of synthetic anti‐tumour agents that act directly on cell membranes. We have previously demonstrated that hexadecylphosphocholine (HePC) alters intracellular cholesterol traffic and metabolism in HepG2 cells. We now extended our studies to analyse the effects of other clinically relevant APLs, such as edelfosine, erucylphosphocholine and perifosine on intracellular cholesterol homeostasis.Experimental approach:  Using radiolabelled substrates we determined the effect of APLs on cholesterol metabolism and cholesterol traffic from the plasma membrane to the endoplasmic reticulum (ER). Protein levels and gene expression of the main proteins involved in cholesterol homeostasis were analysed by Western blot and RT‐PCR respectively. Membrane raft and non‐raft fractions were isolated from HepG2 cells by a detergent‐free method.Key results:  All APLs inhibited the transport of cholesterol from the plasma membrane to the ER, which induced a significant cholesterogenic response in HepG2 cells. This response involved an increased gene expression and higher levels of several proteins related to the biosynthesis and the receptor‐mediated uptake of cholesterol. Cell exposure to the APL‐representative HePC enhanced the content of cholesterol mainly in the membrane raft fractions, compared with the untreated cells.Conclusions and implications:  Membrane‐targeted APLs exhibited a novel and common mechanism of action, through disruption of cholesterol homeostasis, which in turn affected specific lipid microdomains of cellular membranes.
Investigating the interaction of McN‐A‐343 with the M1muscarinic receptor using its nitrogen mustard derivative and ACh mustard
Authors: Figueroa KW , Suga H , Ehlert FJ 
Published: April 2010

Background and purpose: We investigated how McN‐A‐343 inhibited the alkylation of the M1muscarinic receptor by its nitrogen mustard derivative and that of ACh to identify whether it interacts allosterically or orthosterically.Experimental approach: We incubated the M1muscarinic receptor expressed in Chinese hamster ovary cells with ACh mustard for various periods of time in the presence of McN‐A‐343 or known allosteric and orthosteric ligands. After stopping the reaction and removing unreacted ligands, unalkylated receptors were measured using [3H]N‐methylscopolamine. Analogous experiments were done using a nitrogen mustard analog of McN‐A‐343. Affinity constants, cooperativity values for allosteric interactions and rate constants for receptor alkylation were estimated using a mathematical model.Key results: The kinetics of receptor alkylation by the nitrogen mustard derivatives of ACh and McN‐A‐343 were consistent with a two‐step model in which the aziridinium ion rapidly forms a reversible receptor complex, which converts to a covalent complex at a slower rate. The inhibition of receptor alkylation by acetycholine,N‐methylscopolamine and McN‐A‐343 was consistent with competitive inhibition, whereas that caused by gallamine was consistent with allosterism. Affinity constants estimated from alkylation kinetics agreed with those measured by displacement of [3H]N‐methylscopolamine binding.Conclusions and implications: Our results suggest that McN‐A‐343 and its nitrogen mustard derivative interact competitively with ACh andN‐methylscopolamine at the orthosteric site on the M1muscarinic receptor. Measuring how drugs modulate the kinetics of receptor alkylation by an irreversible ligand is a powerful approach for distinguishing between negative allosteric modulators and competitive inhibitors.
Early growth response‐1 induction by fibroblast growth factor‐1 via increase of mitogen‐activated protein kinase and inhibition of protein kinase B in hippocampal neurons
Authors: Benz Alexander H , Shajari Mehdi , Peruzki Natalie , Dehghani Faramarz , Maronde Erik 
Published: April 2010

Background and purpose:  The transcription factor early growth response‐1 (Egr‐1) and the acidic fibroblast growth factor (FGF‐1) are involved in many regulatory processes, including hippocampus‐associated learning and memory. However, the intracellular signalling mechanisms regulating Egr‐1 in hippocampal cells are not entirely understood.Experimental approach:  We used primary mouse hippocampal neurons and the mouse hippocampal neuronal cell line HT22 to investigate how FGF‐1 transiently induces Egr‐1 protein. This was accomplished by a range of techniques including Western blotting, immunofluorescence, specific protein kinase inhibitors and transfectable constitutively active protein kinase constructs.Key results:  Protein kinase B (PKB) and mitogen‐activated protein kinase (MAPK) were both initially phosphorylated and activated by FGF‐1 treatment, but when phosphorylated MAPK reached maximal activation, phosphorylated PKB was at its lowest levels, suggesting an interaction between MAPK kinase (MEK‐1/2) and phosphatidyl inositol‐3‐kinase (PI3K) during Egr‐1 induction. Interestingly, pharmacological inhibition of MEK‐1/2 resulted in a robust increase in the phosphorylation of PKB, which was repressed in the presence of increasing doses of a PI3K inhibitor. FGF‐1‐mediated Egr‐1 induction was impaired by inhibition of MEK‐1/2, but not of PI3K. However, elevated levels of PKB, induced by transfection of constitutively active PKB (myrAkt) into hippocampal neuronal HT22 cells, led to reduced levels of Egr‐1 after FGF‐1 application.Conclusions and implications:  Our data indicate a contribution of inactive (dephosphorylated) PKB to FGF‐1‐mediated induction of Egr‐1, and strongly suggest a functionally and pharmacologically interesting cross‐talk between MEK‐1/2 and PI3K signalling in hippocampal neurons after FGF‐1 stimulation that may play a role in hippocampal synaptic plasticity.
β2‐adrenoceptor agonist clenbuterol reduces infarct size and myocardial apoptosis after myocardial ischaemia/reperfusion in anaesthetized rats
Authors: Zhang Qiufang , Xiang Jizhou , Wang Xuanbin , Liu Hui , Hu Benrong , Feng Mei , Fu Qin 
Published: April 2010

Background and purpose:  Considerable evidence indicates that the β2‐adrenoceptor agonist clenbuterol decreases apoptosis in a rodent model of ischaemic cardiomyopathy. In this study, we investigated the effects of clenbuterol on infarct size caused by myocardial ischaemia/reperfusion (I/R) in anaesthetized rats.Experimental approach:  Rats were randomly assigned to the following groups: (i) sham (ii) I/R (iii) clenbuterol + I/R (iv) ICI 118551 + clenbuterol + I/R (v) metoprolol + clenbuterol + I/R (vi) metoprolol + I/R (vii) pertussis toxin + clenbuterol + I/R. Under anaesthesia, left anterior descending coronary artery was occluded for 30 min followed by reperfusion for 2 h.Key results:  Compared with the control I/R group,the clenbuterol (0.5 mg·kg−1, i.p.) group had reduced infarct size, improved diastolic function and sarcoplasmic/endoplasmic reticulum Ca2+‐ATPase (SERCA) activity, increased superoxide dismutase activity, and decreased malondialdehyde (MDA) level and LDH, CK release. Clenbuterol increased the phosphorylation of ERK1/2, which resulted in inhibition of myocardial apoptosis as indicated by the reduction of terminal deoxynucleotidyltransferase end labelling‐positive staining, Bax/Bcl‐2 mRNA and caspase‐3 protein expression. The Gi‐protein inhibitor pertussis toxin blocked the clenbuterol‐induced improvement in cardiac function and infarct size. Pretreatment with ICI 118551(a selective β2‐adrenoceptor antagonist) inhibited the effects of clenbuterol mentioned above. The β1‐adrenoceptor agonist metoprolol had similar effects to clenbuterol but failed to reduce MDA and improve SERCA activity. When administered together, metoprolol and clenbuterol did not induce synergistic effects.Conclusions and implications:  Clenbuterol pretreatment provides significant cardioprotection against ischaemia/reperfusion injury and this is mediated by the β2‐adrenoceptor–Gi‐protein signalling. A combination of the β2‐adrenoceptor agonist clenbuterol and the β1‐antagonist metoprolol did not lead to a synergistic anti‐apoptotic effect.
Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll‐like receptor 4 responses in macrophages
Authors: Moreno L , McMaster SK , Gatheral T , Bailey LK , Harrington LS , Cartwright N , Armstrong PCJ , Warner TD , Paul‐Clark M , Mitchell JA 
Published: April 2010

Background and purpose:  Gram‐negative bacteria contain ligands for Toll‐like receptor (TLR) 4 and nucleotide oligomerization domain (NOD) 1 receptors. Lipopolysaccharide (LPS) activates TLR4, while peptidoglycan products activate NOD1. Activation of NOD1 by the specific agonist FK565 results in a profound vascular dysfunction and experimental shock in vivo.Experimental approach:  Here, we have analysed a number of pharmacological inhibitors to characterize the role of key signalling pathways in the induction of NOS2 following TLR4 or NOD1 activation.Key results:  Vascular smooth muscle (VSM) cells expressed NOD1 mRNA and protein, and, after challenge with Escherichia coli or FK565, NOS2 protein and activity were induced. Macrophages had negligible levels of NOD1 and were unaffected by FK565, but responded to E. coli and LPS by releasing increased NO and expression of NOS2 protein. Classic pharmacological inhibitors for NF‐κB (SC‐514) and mitogen‐activated protein kinase (SB203580, PD98059) signalling pathways inhibited responses in both cell types regardless of agonist. While TLR4‐mediated responses in macrophages were specifically inhibited by the pan‐caspase inhibitor z‐VAD‐fmk and the PKC inhibitor Gö6976, NOD1‐mediated responses in VSM cells were inhibited by the Rip2 inhibitor PP2.Conclusions and implications:  Our findings suggest a selective role for NOD1 in VSM cells, and highlight NOD1 as a potential novel therapeutic target for the treatment of vascular inflammation.
Molecular determinants of state‐dependent block of voltage‐gated sodium channels by pilsicainide
Authors: Desaphy J‐F , Dipalma A , Costanza T , Bruno C , Lentini G , Franchini C , George AL , Conte Camerino D 
Published: April 2010

Background and purpose: Pilsicainide, an anti‐arrhythmic drug used in Japan, is described as a pure sodium channel blocker. We examined the mechanisms by which it is able to block open channels, because these properties may be especially useful to reduce hyperexcitability in pathologies characterized by abnormal sodium channel opening.Experimental approach: The effects of pilsicainide on various heterologously expressed human sodium channel subtypes and mutants were investigated using the patch clamp technique.Key results: Pilsicainide exhibited tonic and use‐dependent effects comparable to those of mexiletine and flecainide on hNav1.4 channels. These use‐dependent effects were abolished in the mutations F1586C and Y1593C within segment 6 of domain IV, suggesting that the interaction of pilsicainide with these residues is critical for its local anaesthetic action. Its affinity constants for closed channels (KR) and channels inactivated from the closed state (KI) were high, suggesting that its use‐dependent block (UDB) requires the channel to be open for it to reach a high‐affinity blocking site. Accordingly, basic pH, which slightly increased the proportion of neutral drug, dramatically decreasedKRandKIvalues. Effects of pilsicainide were similar on skeletal muscle hNav1.4, brain hNav1.1 and heart hNav1.5 channels. The myotonic R1448C and G1306E hNav1.4 mutants were more and less sensitive to pilsicainide, respectively, due to mutation‐induced gating modifications.Conclusions and implications: Although therapeutic concentrations of pilsicainide may have little effect on resting and closed‐state inactivated channels, it induces a strong UDB due to channel opening, rendering the drug ideally suited for inhibition of high‐frequency action potential firing.
Development and responsiveness of a scale to measure clinicians’ attitudes to people with mental illness (medical student version)
Authors: Kassam A. , Glozier N. , Leese M. , Henderson C. , Thornicroft G. 
Published: April 2010

Kassam A, Glozier N, Leese M, Henderson C, Thornicroft G. Development and responsiveness of a scale to measure clinicians’ attitudes to people with mental illness (medical student version).Objective:  We report the rationale, reliability, validity and responsiveness studies of the Mental Illness: Clinicians’ Attitudes (MICA) Scale, a 16‐item scale designed to measure attitudes of health care professionals towards people with mental illness.Method:  Items were generated through focus groups with service users, carers, medical students and trainee psychiatrists. Psychometric testing was completed in a number of student samples. The responsiveness of the scale was tested after a 1.5 h mental illness stigma related intervention with medical students.Results:  The MICA scale showed good internal consistency, α = 0.79. The test–retest reliability (concordance) was 0.80 (95% CI: 0.68–0.91). The standardised response mean for the scale was 0.4 (95% CI 0.02–0.8) after a mental illness related stigma intervention.Conclusion:  The MICA scale is a responsive, reliable and valid tool, which can be used in medical education and mental health promotion settings and studies.
Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use
Authors: Van Reedt Dortland A. K. B. , Giltay E. J. , Van Veen T. , Zitman F. G. , Penninx B. W. J. H. 
Published: April 2010

van Reedt Dortland AKB, Giltay EJ, van Veen T, Zitman FG, Penninx BWJH. Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use.Objective:  The metabolic syndrome (MetSyn) predisposes to cardiovascular disease and diabetes mellitus. There might also be an association between the MetSyn and anxiety and depression, but its nature is unclear. We aimed to investigate whether diagnosis, symptom severity and antidepressant use are associated with the MetSyn.Method:  We addressed the odds for the MetSyn and its components among 1217 depressed and/or anxious subjects and 629 controls, and their associations with symptom severity and antidepressant use.Results:  Symptom severity was positively associated with prevalence of the MetSyn, [adjusted odds ratio (OR) 2.21 for very severe depression: 95% confidence interval (CI): 1.06–4.64, P = 0.04], which could be attributed to abdominal obesity and dyslipidemia. Tricyclic antidepressant (TCA) use also increased odds for the MetSyn (OR 2.30, 95% CI: 1.21–4.36, P = 0.01), independent of depression severity.Conclusion:  The most severely depressed people and TCA users more often have the MetSyn, which is driven by abdominal adiposity and dyslipidemia.
Granulomatous vasculitis in Crohn's disease: a clinicopathologic correlate of two unusual cases
Authors: Burns Ariel M. , Walsh Noreen , Green Peter J. 
Published: April 2010

Cutaneous complications occur not uncommonly in patients with Crohn's disease (CD). Gastrointestinal CD often shows non‐caseating granulomas and a rare cutaneous finding in CD is a sterile granulomatous infiltrate not contiguous with the GI tract, termed extraintestinal CD (ECD). The clinical presentation of ECD is diverse. The most common histopathological presentation is a superficial and deep granulomatous infiltrate that often accompanies a mixed perivascular infiltrate. Here we report two patients with CD and skin lesions characterized on microscopy by granulomatous vasculitis. A 29‐year‐old female presented with papules and ulcerated nodules above the ankle. The biopsy showed dermal and superficial subcutaneous involvement by a vasocentric infiltrate of mononuclear and multinucleated histiocytes as well as mural fibrin deposition. A 35‐year‐old male presented with two tender indurated erythematous plaques with punched‐out centers on the lower leg. Histopathologically, a granulomatous vasculitis of small and medium‐sized vessels in the dermis and subcutis was evident. These two cases represent the rarely described phenomenon of cutaneous granulomatous vasculitis in CD. Previously reported examples of this entity are reviewed.Burns AM, Walsh N, Green PJ. Granulomatous vasculitis in Crohn's disease: a clinicopathologic correlate of two unusual cases.
Incidence of and risk factors for neonatal morbidity after active perinatal care: extremely preterm infants study in Sweden (EXPRESS)
Authors:   The EXPRESS Group
Published: April 2010

AbstractAims:  The aim of this study was to determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors.Methods:  Population based study of infants born before 27 gestational weeks and admitted for neonatal intensive care in Sweden during 2004–2007.Results:  Of 638 admitted infants, 141 died. Among these, life support was withdrawn in 55 infants because of anticipation of poor long‐term outcome. Of 497 surviving infants, 10% developed severe intraventricular haemorrhage (IVH), 5.7% cystic periventricular leucomalacia (cPVL), 41% septicaemia and 5.8% necrotizing enterocolitis (NEC); 61% had patent ductus arteriosus (PDA) and 34% developed retinopathy of prematurity (ROP) stage ≥3. Eighty‐five per cent needed mechanical ventilation and 25% developed severe bronchopulmonary dysplasia (BPD). Forty‐seven per cent survived to one year of age without any severe IVH, cPVL, severe ROP, severe BPD or NEC. Tocolysis increased and prolonged mechanical ventilation decreased the chances of survival without these morbidities. Maternal smoking and higher gestational duration were associated with lower risk of severe ROP, whereas PDA and poor growth increased this risk.Conclusion:  Half of the infants surviving extremely preterm birth suffered from severe neonatal morbidities. Studies on how to reduce these morbidities and on the long‐term health of survivors are warranted.
Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation pattern
Authors: Schröter Juliane , Zahedi René P. , Hartmann Michael , Gaßner Birgit , Gazinski Alexandra , Waschke Jens , Sickmann Albert , Kuhn Michaela 
Published: April 2010

Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC‐A) receptor and intracellular guanosine 3′,5′‐cyclic monophosphate production, is critically involved in the regulation of blood pressure. In patients with chronic heart failure, the plasma levels of ANP are increased, but the cardiovascular actions are severely blunted, indicating a receptor or postreceptor defect. Studies on metabolically labelled GC‐A‐overexpressing cells have indicated that GC‐A is extensively phosphorylated, and that ANP‐induced homologous desensitization of GC‐A correlates with receptor dephosphorylation, a mechanism which might contribute to a loss of function in vivo. In this study, tandem MS analysis of the GC‐A receptor, expressed in the human embryonic kidney cell line HEK293, revealed unambiguously that the intracellular domain of the receptor is phosphorylated at multiple residues: Ser487, Ser497, Thr500, Ser502, Ser506, Ser510 and Thr513. MS quantification based on multiple reaction monitoring demonstrated that ANP‐provoked desensitization was accompanied by a complex pattern of receptor phosphorylation and dephosphorylation. The population of completely phosphorylated GC‐A was diminished. However, intriguingly, the phosphorylation of GC‐A at Ser487 was selectively enhanced after exposure to ANP. The functional relevance of this observation was analysed by site‐directed mutagenesis. The substitution of Ser487 by glutamate (which mimics phosphorylation) blunted the activation of the GC‐A receptor by ANP, but prevented further desensitization. Our data corroborate previous studies suggesting that the responsiveness of GC‐A to ANP is regulated by phosphorylation. However, in addition to the dephosphorylation of the previously postulated sites (Ser497, Thr500, Ser502, Ser506, Ser510), homologous desensitization seems to involve the phosphorylation of GC‐A at Ser487, a newly identified site of phosphorylation. The identification and further characterization of the specific mechanisms involved in the downregulation of GC‐A responsiveness to ANP may have important pathophysiological implications.Structured digital abstract
MINT‐7713870, MINT‐7713887: PMCA (uniprotkb:P20020) and GC‐A (uniprotkb:P18910) colocalize (MI:0403) by fluorescence microscopy (MI:0416)