bluuebunny/crossref_metadata_2025 huggingface dataset:
Research and the organisation of complex provision: conceptualising health visiting services and early years programmes
Authors: Cowley Sarah , Kemp Lynn , Day Crispin , Appleton Jane
Published: March 2012

This paper developed from discussions about the possible implementation and trial of an Australian maternal and early childhood sustained home visiting programme (MECSH), into a United Kingdom (UK) context. There are many similarities in services in the two countries, but some differences. To summarise and illustrate the complex and interconnected way that early years and preventive health services are specified, a diagram was developed, which provides a framework for this paper. The paper describes a health visiting service that encompasses universal, indicated and selective forms of prevention, with some embedded evidence-based programmes, forming part of a proactive and preventive service that is, itself, embedded within a wider resource system. Policy-driven terms derived from the English Health Visitor Implementation Plan have been used, but translated into the generic language of prevention (universal, indicated and selective), as a basis for future research. The place for different types of practitioner and needs of families with different levels of personal capacity or resource are also considered.

Increased understanding about how social determinants affect the whole population across a gradient has drawn attention to the need for more universal prevention, to tackle health inequalities. The components of successful early intervention programmes are well established, but more information is needed to support universal preventive services, which are delivered in a way that is proportionate to need. This paper, including the diagram that summarises its contents, is presented to stimulate discussion as well as guide future research and service development.
The challenges of establishing and researching a sustained nurse home visiting programme within the universal child and family health service system
Authors: Kemp Lynn , Harris Elizabeth
Published: March 2012

This paper reflects on the challenges and strategies used to conduct a sustained nurse home visiting randomised trial within the universal child and family health service system in Australia. The Maternal Early Childhood Sustained Home-visiting (MECSH) programme is a complex multilevel intervention acting in parallel at the individual and organisational levels, addressing change in individuals and families, as well as the structural and social factors that affect the individuals, particularly families’ access to support and services. MECSH is targeted towards 20–25% of the population who are at risk of poorer maternal and child health and development outcomes. Establishing the intervention within the service system and conducting the research trial simultaneously presented many challenges. The researchers encountered both technical and ethical problems. The role of researchers as disinterested, objective scientists was constantly challenged. We argue that the MECSH trial was a hybrid research model, testing both efficacy and effectiveness, in a participatory framework. Hybrid research can help to generate evidence of the effectiveness of multilevel interventions in more timely ways, but requires greater investment in the time and resources to conduct the research. We see that such investment would pay dividends in the simultaneous development, testing and embedding of effective interventions for families and sustainable capacity for services.
Targeted approaches to the treatment of pulmonary hypertension
Authors: Fares Wassim H. , Trow Terence K.
Published: March 2012

Pulmonary arterial hypertension is a progressive and incurable disease. Over the past two decades, significant advances have been made in understanding and thus managing this disease. Multiple therapeutic options are currently available and optimizing the treatment of pulmonary arterial hypertension has become complex. Patients who meet the American College of Chest Physicians criteria for vasoresponsiveness can be safely and effectively treated with high-dose calcium channel blockers but require close follow up to assure durability of response. Patients with World Health Organization (WHO) functional class IV status and those with determinants of high risk for progression and death should be treated with an infused prostanoid agent without delay. These patients should also be referred early after stabilization for transplant evaluation. Patients with WHO functional class II status benefit from early initiation of oral therapies. Those with WHO functional class III status and lower determinants of risk for progression may receive treatment with one or more oral or inhaled agents, though many experts would advise early use of infused prostanoids for these patients as well.
Post-docetaxel therapy in castration resistant prostate cancer – the forest is growing in the desert
Authors: Altavilla Amelia , Iacovelli Roberto , Procopio Giuseppe , Cortesi Enrico
Published: March 2012

In Europe, prostate cancer is the most common cancer among men with 382.000 new cases and 89.000 deaths annually. Historically, androgen deprivation therapy and docetaxel based chemotherapy were the only treatments able to improve survival. Two studies have been published during last few months regarding the management of castration resistant prostate cancer (CRPC) progressed after docetaxel: for the first time second line therapies have been demonstrated to improve prognosis of these patients. The relevance of these trials is the reintroduction of chemotherapy and hormonal therapy in a disease once considered chemotherapy and castration resistant. All these data may change the traditional approach to CRPC but no evidences have came out from recently closed or ongoing clinical trials about the therapeutic algorithm. How to get oriented in this forest? We propose that patient’s conditions, response and toxicities reported with previous treatments and, above all, dynamics and evolution of disease may influence the choice of subsequent therapies in docetaxel progressed CRPC.
Chemotherapy in penile cancer
Authors: Hakenberg Oliver W. , Protzel Chris
Published: March 2012

Penile cancer is an aggressive disease and after systemic progression it is virtually incurable. While this squamous cell cancer responds to chemotherapy, successful treatment of lymphatic metastases can only be achieved with aggressive surgical treatment in combination with chemotherapy. However, because penile carcinoma is relatively rare there is a paucity of clinical data on the chemotherapy for this aggressive disease. Recent advances have included the establishment of less toxic regimens incorporating taxanes, while cisplatinum remains central to all regimens. Multi-institutional studies are urgently needed to advance the multimodal care for patients with penile cancer.
Bilateral Osteonecrosis of the Navicular and Medial Cuneiform in a Patient with Systemic Lupus Erythematosus
Authors: Greenhagen Robert M. , Crim Brandon E. , Shinabarger Andrew B. , Burns Patrick R.
Published: March 2012

Introduction. Atraumatic avascular necrosis (AVN) is an unusual pathology to the foot. Risk factors include the use of corticosteroids, smoking, alcohol, rheumatologic disorders, hematologic disorders, and metabolic disorders. To the authors’ knowledge, this study presents the first case of bilateral atraumatic AVN to the navicular and medial cuneiform in a patient with systemic lupus erythamatosus (SLE). Case description. A 40-year-old man presented with a past medical history of SLE in which he developed AVN of the tarsal navicular and medial cuneiform. This occurred first on the subject’s right foot and then while recovering from surgical intervention, on his left foot. Talonaviculocuneiform arthrodesis was performed with the use of distal tibial autograft on both extremities. The subject’s American Orthopaedic Foot and Ankle Society midfoot score improved from 34 to 80 at 21 months on the right and 37 to 90 at 15 months to the left. Discussion. Patients with SLE carry a significant risk of developing AVN. Comorbidities such as vasculitis, corticosteroid use, cytotoxic medication, and peripheral neuropathy are known risk factors in the development of AVN. Unusual features such as multifocal AVN and unusual anatomic locations can occur with SLE. AVN of the foot is generally treated with surgical intervention. Treatments such as core decompression, open reduction and internal fixation, and arthrodesis have been recommended based on the symptoms and presentation. Conclusion. The authors present a very rare presentation of bilateral osteonecrosis of the tarsal navicular and first cuneiform in a patient with SLE. The patient was treated with bilateral talonaviculocuneiform arthrodesis. The patient demonstrated considerable improvement to both extremities.

Levels of Evidence: Therapeutic, Level IV
Accuracy of Magnetic Resonance Imaging of the Knee in the Community Setting
Authors: Hardy Jolene C. , Evangelista Gregory T. , Grana William A. , Hunter Robert E.
Published: March 2012

Background: Magnetic resonance imaging (MRI) is routinely used in the diagnosis of sports-related knee injuries.

Purpose: To determine the accuracy, sensitivity, and specificity of MRI compared with clinical evaluation in the diagnosis of meniscal pathology when the MRI facility and the radiologist are not preselected.

Methods: A total of 288 knee arthroscopies were retrospectively compared. Patients were divided into 3 groups: those who had MRI performed and interpreted at a single institution, MRI performed and interpreted at community facilities, or a clinical evaluation by a senior orthopaedic surgeon.

Results: The sensitivity, specificity, and accuracy of the diagnosis of medial meniscal pathology at a single institution were 90%, 59%, 76%; in community facilities, 73%, 68%, 70%; and by a clinical evaluation, 93%, 55%, 73%, respectively. For lateral meniscal pathology, the results were as follows: single institution, 75%, 76%, 81%; community facilities, 60%, 88%, 79%; and clinical evaluation, 45%, 90%, 79%, respectively. Sensitivity for medial meniscus was greater than for lateral meniscus, but specificity of diagnosis was better for lateral meniscus by MRI and clinical evaluation. While not statistically significant, there was increased sensitivity in the diagnosis of medial meniscus and lateral meniscus at SIs, but they have less specificity than at community facilities. The number of false-positive diagnoses (ie, no intra-articular pathology) that resulted in surgery was 4 of 288 (1.39%). The overall accuracy for medial meniscus by MRI was 73% vs 73% for clinical evaluation. The overall accuracy for MRI for lateral meniscus was 78% vs 79% for clinical evaluation.

Conclusion: Routine MRI may not be more beneficial than clinical evaluation when there is no preselection of MRI facility and interpreting radiologist.

Clinical Relevance: The use of MRI for diagnosing meniscal pathology should be reserved for those cases where the orthopaedic clinical examination is ambiguous.
Opioids and endocrine dysfunction
Authors: Seyfried Oliver , Hester Joan
Published: March 2012

The endocrine effects of opioids used for the management of persistent pain are poorly understood by clinicians and patients, and hormone levels are rarely measured. It is recognized that opioids exert this effect via the hypothalamic-pituitary-gonadal axis. Additional effects on adrenal hormones, weight, blood pressure and bone density may also occur. Symptoms and signs of sex hormone deficiency occur in both men and women but are under-reported and are often clinically unrecognized.

The potential effects of long term opioid therapy on the endocrine system should be explained to patients before opioid therapy is commenced. Monitoring of sex hormones is recommended; if there are deficiencies opioids should be tapered and withdrawn, if this is clinically acceptable.

If opioid therapy has to continue, hormone replacement therapy should be initiated and monitored by an endocrinologist.
Neuraxial (epidural and intrathecal) opioids for intractable pain
Authors: Farquhar-Smith Paul , Chapman Suzanne
Published: March 2012

Summary Points

1. Neuraxial opioids are considered for use in patients who have resistant intractable pain that fails to respond to other treatment options or pain that responds to analgesia but for which the doses required result in unacceptable side-effects.

2. Neuraxial opiods can be considered for both chronic non-malignant pain and chronic cancer-related pain.

3. Effectiveness in chronic non-malignant pain and cancer pain is exerted through the use of either single-agent drugs (opioids) or a combination of drugs: opioids, local anaesthetics and other drugs such as clonodine and ziconotide.

4. Complications of long-term continuous infusion therapy are related to the insertion process (haematoma), the mechanical device (both pump and catheter) and the long-term effects of the drugs.

5. Patients will require ongoing ambulatory monitoring and supportive care.
A Novel N of 1 Trial Design and Proposed Utility in Complementary and Alternative Medicine Research
Authors: Goldenberg Joshua Z. , Wenner Cynthia A.
Published: March 2012

An N of 1 trial is a multiple crossover study in a single participant. N of 1trials can combine the benefits of individualized patient practice and evidence-based medicine and are amenable to complementary and alternative medicine practice and research. This article will review the basic structure of N of 1trials, discuss how they are commonly used, and review their limitations and statistical considerations. The authors also propose a novel use of the N of 1 trial in the form of mixed-methodology add-on N of 1 trials targeted to a parent trial’s responders. This design can help uncover evidence of subgroup effects in small trials, address issues surrounding the small study effect, and explore the role of interparticipant variability and random chance in the parent trial.
Treating Type 2 Diabetes: A Cross-sectional Audit of Naturopathic Standards of Care Using the Naturopathic Patient Database
Authors: Habib Christopher , Gowan Matthew , Podgrabinski Stefan , Grodski Tom , Leung Brenda , Shapoval Maria , Seely Dugald , Cooley Kieran
Published: March 2012

The Naturopathic Patient Database is a data management tool developed by the Canadian College of Naturopathic Medicine to collect patient data from its teaching clinic, the Robert Schad Naturopathic Clinic. This study investigated how type 2 diabetes mellitus was managed at the Robert Schad Naturopathic Clinic from May 2009 to February 2011. Cases of type 2 diabetes mellitus from the Robert Schad Naturopathic Clinic reported in the Naturopathic Patient Database were extracted based on an International Classification of Diseases, 10th revision code assessment of E11 (non-insulin-dependent diabetes mellitus) and files were audited. The American Diabetes Association 2010 standards of medical care in diabetes were used as guidelines for the audit. Multiple categories in diagnosis, physical exam, laboratory tests, and management were graded on a 0 to 2 scale. The average audit score was 55.5/90. The most common interventions being used are diet and aerobic exercise, followed by supplements (omega-3 fatty acids) and botanicals. These data suggest that the American Diabetes Association standards of care for type 2 diabetes mellitus are not followed stringently. Education and creation of a naturopathic standard of care may improve audit performance and patient outcomes.
Inhibition of factor XI activation attenuates inflammation and coagulopathy while improving the survival of mouse polymicrobial sepsis
Authors: Tucker Erik I. , Verbout Norah G. , Leung Philberta Y. , Hurst Sawan , McCarty Owen J. T. , Gailani David , Gruber András
Published: March 2012

Severe bacterial sepsis often leads to a systemic procoagulant and proinflammatory condition that can manifest as disseminated intravascular coagulation, septic shock, and multiple organ failure. Because activation of the contact proteases factor XII (FXII), prekallikrein, and factor XI (FXI) can trigger coagulation and inflammatory responses, the contact factors have been considered potential targets for the treatment of sepsis. However, the pathogenic role of contact activation in severe infections has not been well defined. We therefore investigated whether an anticoagulant antibody (14E11) that selectively inhibits prothrombotic FXI activation by activated FXII (FXIIa) modifies the course of bowel perforation-induced peritoneal sepsis in mice. Early anticoagulation with 14E11 suppressed systemic thrombin- antithrombin complex formation, IL-6, and TNF-α levels, and reduced platelet consumption in the circulation and deposition in the blood vessels. Treatment with 14E11 within 12 hours after bowel perforation significantly improved survival compared with vehicle treatment, and the saturating dose did not increase tail bleeding. These data suggest that severe polymicrobial abdominal infection induces prothrombotic FXI activation, to the detriment of the host. Systemic anticoagulation by inhibiting FXI activation or FXIIa procoagulant activity during sepsis may therefore limit the development of disseminated intravascular coagulation without increasing bleeding risks.
Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection
Authors: Elahi Shokrollah , Niki Toshiro , Hirashima Mitsuomi , Horton Helen
Published: March 2012

Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4+ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4+ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4+ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection.
MHC I–associated peptides preferentially derive from transcripts bearing miRNA response elements
Authors: Granados Diana Paola , Yahyaoui Wafaa , Laumont Céline M. , Daouda Tariq , Muratore-Schroeder Tara L. , Côté Caroline , Laverdure Jean-Philippe , Lemieux Sébastien , Thibault Pierre , Perreault Claude
Published: March 2012

MHC I–associated peptides (MIPs) play an essential role in normal homeostasis and diverse pathologic conditions. MIPs derive mainly from defective ribosomal products (DRiPs), a subset of nascent proteins that fail to achieve a proper conformation and the physical nature of which remains elusive. In the present study, we used high-throughput proteomic and transcriptomic methods to unravel the structure and biogenesis of MIPs presented by HLA-A and HLA-B molecules on human EBV-infected B lymphocytes from 4 patients. We found that although HLA-different subjects present distinctive MIPs derived from different proteins, these MIPs originate from proteins that are functionally interconnected and implicated in similar biologic pathways. Secondly, the MIP repertoire of human B cells showed no bias toward conserved versus polymorphic genomic sequences, were derived preferentially from abundant transcripts, and conveyed to the cell surface a cell-type–specific signature. Finally, we discovered that MIPs derive preferentially from transcripts bearing miRNA response elements. Furthermore, whereas MIPs of HLA-disparate subjects are coded by different sets of transcripts, these transcripts are regulated by mostly similar miRNAs. Our data support an emerging model in which the generation of MIPs by a transcript depends on its abundance and DRiP rate, which is regulated to a large extent by miRNAs.
Sarcoidosis-associated fatigue
Authors: Drent Marjolein , Lower Elyse E. , De Vries Jolanda
Published: March 2012

Sarcoidosis-associated fatigue is globally recognised as a disabling symptom. Fatigue has been reported in up to 50–70% of sarcoidosis patients, causing impaired quality of life. The aetiology of this troublesome problem remains elusive and is usually multifactorial. Fatigue can be a consequence of treatment itself, including as a complication of corticosteroid therapy. The diagnosis of sarcoidosis-associated fatigue requires an extensive evaluation to identify and treat potentially reversible causes. Granuloma formation and cytokine release may be involved in its aetiology. However, despite adequate sarcoidosis treatment, many patients continue to experience fatigue. Comorbidities associated with sarcoidosis, including depression, anxiety, hypothyroidism and altered sleep patterns, may all contribute to fatigue. Despite an exhaustive search for treatable clinical causes of fatigue, most patients’ complaints of fatigue are not correlated with clinical parameters of disease activity. Recent studies have demonstrated the effectiveness of various neurostimulants, including methylphenidate, for the treatment of sarcoidosis-associated fatigue. These and other agents may be useful adjuncts for the treatment of sarcoidosis-associated fatigue. Obviously, there is a need for studies evaluating the causes and new therapeutic options of sarcoidosis-associated fatigue. Psychological interventions should also be examined.
A role for 12R-lipoxygenase in MUC5AC expression by respiratory epithelial cells
Authors: Garcia-Verdugo Ignacio , BenMohamed Fatima , Tattermusch Sonja , Leduc Dominique , Charpigny Gilles , Chignard Michel , Ollero Mario , Touqui Lhousseine
Published: March 2012

Eicosanoids are metabolites of arachidonic acid produced by cyclooxygenases (COXs) or lipoxygenases (LOXs). They mediate inflammation and mucus secretion in chronic pulmonary inflammatory diseases. The gel-forming mucin MUC5AC is over-expressed in the airways of patients with these diseases. MUC5AC expression is mediated by an extracellular signal-regulated kinase (ERK)/Sp1 dependent mechanism.

Our aim was to study the role of eicosanoids and their signalling pathways in MUC5AC expression.

Inhibitors of 12-LOX, but not those of COX, 5-LOX or 15-LOX, reduce MUC5AC expression induced by phorbol myristate acetate (PMA) in the bronchial epithelial cell line NCI-H292. These inhibitors also abrogate the production of whole mucus by cell monolayers. Two forms of 12-LOX (R and S) exist in mammals. Using siRNAs we show that 12R-LOX but not 12S-LOX is involved in MUC5AC expression induced by PMA, lipopolysaccharide or transforming growth factor-α. 12R-LOX also participates in MUC2 and MUC5B expression, although to a lesser extent than for MUC5AC. Contrarily, 12R-LOX silencing does not modify interleukin-8 production. 12-LOX inhibitors reduce ERK activation and Sp1 translocation induced by PMA. Moreover, the 12R-LOX product 12(R)-hydroxyeicosatetraenoic acid, induces MUC5AC expression, ERK activation and Sp1 translocation.

12R-LOX is involved in MUC5AC expression. This occursviaERK- and Sp1-signalling pathways.
Reduced nuclear factor-κB repressing factor: a link toward systemic inflammation in COPD
Authors: Lee Kang-Yun , Ho Shu-Chuan , Chan Yao-Fei , Wang Chun-Hua , Huang Chien-Da , Liu Wen-Te , Lin Shu-Min , Lo Yu-Lun , Chang Ya-Ling , Kuo Lu-Wei , Kuo Han-Pin
Published: March 2012

Chronic systemic inflammation is implicated in the systemic manifestations and, probably, the excess mortality risk of chronic obstructive pulmonary disease (COPD). The role of nuclear factor (NF)-κB repressing factor (NRF), a DNA-binding, protein-inhibiting NF-κB response gene, in human diseases has not been explored. We hypothesised that the NRF-negative regulatory mechanism is impaired in COPD peripheral blood mononuclear cells (PBMCs) leading to excessive interleukin (IL)-8/CXCL8 production.

NRF expression, NF-κB activation, IL-8/CXCL8 release and intracellular oxidative stress were assessed in PBMCs of normal subjects and stable COPD patients. Primary PBMCs with NRF overexpression, NRF knockdown and exposure to H2O2were used to elucidate the mechanisms.

Stable COPD patients, especially those with severe COPD, showed decreased NRF expression, enhanced NF-κB activation and increased IL-8/CXCL8 release in PBMCs compared with normal subjects. This was associated with reduced NRF and increased RNA polymerase II occupancy at theIL-8/CXCL8promoter. NRF knockdown enhanced IL-8/CXCL8 production in normal PBMCs, whilst NRF overexpression attenuated IL-8/CXCL8 production. Intracellular oxidative stress was increased in COPD PBMCs. H2O2-decreased NRF expression and -enhanced IL-8/CXCL8 production was augmented in COPD PBMCs.

NRF expression is reduced in PBMCs of stable COPD patients, probably through oxidative stress, leading to increased production of IL-8/CXCL8 and potentially chronic systemic inflammation.
CHRNA3genotype, nicotine dependence, lung function and disease in the general population
Authors: Kaur-Knudsen Diljit , Nordestgaard Børge G. , Bojesen Stig E.
Published: March 2012

TheCHRNA3rs1051730 polymorphism has been associated to chronic obstructive pulmonary disease (COPD), lung cancer and nicotine dependence in case–control studies with high smoking exposure; however, its influence on lung function and COPD severity in the general population is largely unknown.

We genotyped 57,657 adult individuals from the Copenhagen General Population Study, of whom 34,592 were ever-smokers. Information on spirometry, hospital admissions, smoking behaviour and use of nicotinic replacement therapy was recorded.

In homozygous (11%), heterozygous (44%) and noncarrier (45%) ever-smokers, forced expiratory volume in 1 s (FEV1) was 94.1% predicted, 95.3% pred and 96.5% pred, forced vital capacity (FVC) was 97.1% pred, 97.5% pred and 98.3% pred, and FEV1/FVC was 0.770, 0.773 and 0.777, respectively (all p<0.001 for trend). Smoking interacted with genotype on FEV1% pred and FEV1/FVC (both p<0.001). When adjusted for cumulative tobacco consumption, these associations remained significant. In ever-smokers, odds ratios for COPD in homozygotesversusnoncarriers were 1.3 (95% CI 1.2–1.4) for Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages I–IV, 1.4 (95% CI 1.2–1.6) for GOLD II–IV and 1.7 (95% CI 1.3–2.1) for GOLD III–IV. The corresponding value for lung cancer was 1.8 (95% CI 1.2–2.6). Genotype was also associated with daily and cumulative tobacco consumption and with use of nicotinic replacement therapy in former smokers.

In ever-smokers, theCHRNA3rs1051730 genotype associated with reduced lung function and increased COPD severity.
Streptococcus pneumoniae-induced regulation of cyclooxygenase-2 in human lung tissue
Authors: Szymanski Kolja V. , Toennies Mario , Becher Anne , Fatykhova Diana , N'Guessan Philippe D. , Gutbier Birgitt , Klauschen Frederick , Neuschaefer-Rube Frank , Schneider Paul , Rueckert Jens , Neudecker Jens , Bauer Torsten T. , Dalhoff Klaus , Drömann Daniel , Gruber Achim D. , Kershaw Olivia , Temmesfeld-Wollbrueck Bettina , Suttorp Norbert , Hippenstiel Stefan , Hocke Andreas C.
Published: March 2012

The majority of cases of community-acquired pneumonia are caused byStreptococcus pneumoniaeand most studies on pneumococcal host interaction are based on cell culture or animal experiments. Thus, little is known about infections in human lung tissue.

Cyclooxygenase-2 and its metabolites play an important regulatory role in lung inflammation. Therefore, we established a pneumococcal infection model on human lung tissue demonstrating mitogen-activated protein kinase (MAPK)-dependent induction of cyclooxygenase-2 and its related metabolites.

In addition to alveolar macrophages and the vascular endothelium, cyclooxygenase-2 was upregulated in alveolar type II but not type I epithelial cells, which was confirmed in lungs of patients suffering from acute pneumonia. Moreover, we demonstrated the expression profile of all four E prostanoid receptors at the mRNA level and showed functionality of the E prostanoid4receptor by cyclic adenosine monophosphate production. Additionally, in comparison to previous studies, cyclooxygenase-2/prostaglandin E2related pro- and anti-inflammatory mediator regulation was partly confirmed in human lung tissue after pneumococcal infection.

Overall, cell type-specific and MAPK-dependent cyclooxygenase-2 expression and prostaglandin E2formation in human lung tissue may play an important role in the early phase of pneumococcal infections.
What shall we do with the damaged proteins in lung disease? Ask the proteasome!
Authors: Meiners Silke , Eickelberg Oliver
Published: March 2012

The proteasome constitutes the main protein waste disposal and recycling system of the cell. Together with endoplasmic reticulum stress and the autophagosome pathway, it takes centre stage in cellular protein quality control.

In lung research, the proteasome is, first of all, a promising therapeutic target to intervene in the malignant growth of lung cancer cells. Therapeutic targeting of the proteasome has also been extended to pulmonary fibrosis and asthma using animal models. Moreover, the proteasome is involved in lung pathogenesis. In cystic fibrosis, rapid proteasomal degradation of mutant cystic fibrosis transmembrane conductance regulator contributes to loss of function of lung epithelial cells. In chronic obstructive pulmonary disease (COPD), pulmonary proteasome expression and activity are downregulated and inversely correlate with lung function. In addition, as the proteasome degrades signalling mediators that have been oxidatively modified in COPD, it contributes to further compromise cellular function.

The consequences of proteasomal dysfunction are loss of protein quality control, accumulation of misfolded proteins and exacerbation of cellular stress, which are also hallmarks of protein quality diseases and premature ageing. This suggests that proteasome dysfunction can be regarded as a new pathomechanism for chronic lung diseases, awaiting further therapeutic exploration in the future.
Serial computed tomography and lung function testing in pulmonary Langerhans’ cell histiocytosis
Authors: Tazi Abdellatif , Marc Karima , Dominique Stéphane , de Bazelaire Cédric , Crestani Bruno , Chinet Thierry , Israel-Biet Dominique , Cadranel Jacques , Frija Jacques , Lorillon Gwenael , Valeyre Dominique , Chevret Sylvie
Published: March 2012

Little is known about longitudinal lung function variation in patients with pulmonary Langerhans’ cell histiocytosis (LCH). The contribution of serial lung computed tomography (CT) to managing these patients has not been evaluated.

This long-term retrospective study included 49 patients who were serially evaluated by lung CT and pulmonary function tests. The lung function variation was categorised as improvement or deterioration. The extent of the CT lesions was correlated with lung function.

Lung function deteriorated in ∼60% of the patients. Forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lung for carbon monoxide (DL,CO) were the parameters that most frequently deteriorated. A subgroup of patients experienced a dramatic decline in FEV1within 2 yrs of diagnosis. Airway obstruction was the major functional pattern observed. In a multivariate analysis, % predicted FEV1at diagnosis was the only factor associated with the incidence of airway obstruction. The increase in cystic lesions on the lung CTs was associated with impaired lung function but did not anticipate the decline in FEV1orDL,CO.

Serial lung function tests are essential for following patients with pulmonary LCH, who frequently develop airway obstruction. A lung CT at diagnosis is informative, but routine sequential CTs seem less useful. A prospective study is needed to characterise those patients with early progressive disease.
Increased frequencies of pulmonary regulatory T-cells in latentMycobacterium tuberculosisinfection
Authors: Herzmann Christian , Ernst Martin , Ehlers Stefan , Stenger Steffen , Maertzdorf Jeroen , Sotgiu Giovanni , Lange Christoph
Published: March 2012

Regulation of specific immune responses following exposure toMycobacterium tuberculosisin humans and the role of regulatory T (Treg) cells in the immune control of latent infection withM. tuberculosisare incompletely understood.

Latent infection was assayed by an interferon-γ release assay (IGRA) in healthcare workers regularly exposed to tuberculosis (TB) patients and in household TB contacts in Germany. Immunophenotypes of bronchoalveolar lavage (BAL) mononuclear cells and peripheral blood mononuclear cells (PBMCs) were analysed by fluorescence-activated cell sorting.

All TB contacts with latent infection (n=15) had increased (p<0.0001) frequencies of CD4+ CD25+ CD127- Treg cells (median 2.12%, interquartile range (IQR) 1.63–3.01%) among BAL mononuclear cells compared with contacts (n=25) with negative IGRA results (median 0.68%, IQR 0.32–0.96%) No differences were seen when PBMC immunophenotypes of IGRA+ and IGRA- TB contacts were compared (IGRA+ median 9.6%, IQR 5.9–10.1%; IGRA- median 7.7%, IQR 4.6–11.3%; p=0.47). Five out of 25 contacts with negative blood IGRAs showed a positive IGRA from BAL cells, possibly indicating a limited local immune response.

In Germany, latent infection withM. tuberculosis, as defined by a positiveM. tuberculosis-specific IGRA response on cells from the peripheral blood, is characterised by an increased frequency of Treg cells in the BAL.
Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study
Authors: Jones Paul W. , Singh Dave , Bateman Eric D. , Agusti Alvar , Lamarca Rosa , de Miquel Gonzalo , Segarra Rosa , Caracta Cynthia , Garcia Gil Esther
Published: March 2012

The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

In this 24-week, double-blind trial, patients were randomised to twice-daily aclidinium (200 μg or 400 μg) or placebo. The primary efficacy end-point was change in trough forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included peak FEV1, health status (St George's Respiratory Questionnaire; SGRQ) and dyspnoea (Transitional Dyspnoea Index; TDI).

Overall, 828 patients were randomised. At week 24, significant improvements from baseline were observed with aclidinium 200 μg and 400 μgversusplacebo for trough FEV1(99 and 128 mL; both p<0.0001) and peak FEV1(185 and 209 mL; both p<0.0001). Peak FEV1improvements on day 1 were comparable with week 24. Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score (-3.8 and -4.6 units; p<0.001 and p<0.0001) and TDI focal score (0.6 and 1.0 units; p<0.05 and p<0.001) at week 24. With both aclidinium doses, the incidence of anticholinergic adverse events was low, and similar to placebo.

Twice-daily aclidinium significantly improved bronchodilation, health status and dyspnoea, and was well tolerated in patients with COPD.
Prediction of a deletion copy number variant by a dense SNP panel
Authors: Kadri Naveen K , Koks Patrick D , Meuwissen Theo H E
Published: March 2012

Background

A newly recognized type of genetic variation, Copy Number Variation (CNV), is detected in mammalian genomes, e.g. the cattle genome. This form of variation can potentially cause phenotypic variation. Our objective was to determine whether dense SNP (single nucleotide polymorphisms) panels can capture the genetic variation due to a simple bi-allelic CNV, with the prospect of including the effect of such structural variations into genomic predictions.

Methods

A deletion type CNV on bovine chromosome 6 was predicted from its neighboring SNP with a multiple regression model. Our dataset consisted of CNV genotypes of 1,682 cows, along with 100 surrounding SNP genotypes. A prediction model was fitted considering 10 to 100 surrounding SNP and the accuracy obtained directly from the model was confirmed by cross-validation.

Results and conclusions

The accuracy of prediction increased with an increasing number of SNP in the model and the predicted accuracies were similar to those obtained by cross-validation. A substantial increase in accuracy was observed when the number of SNP increased from 10 to 50 but thereafter the increase was smaller, reaching the highest accuracy (0.94) with 100 surrounding SNP. Thus, we conclude that the genotype of a deletion type CNV and its putative QTL effect can be predicted with a maximum accuracy of 0.94 from surrounding SNP. This high prediction accuracy suggests that genetic variation due to simple deletion CNV is well captured by dense SNP panels. Since genomic selection relies on the availability of a dense marker panel with markers in close linkage disequilibrium to the QTL in order to predict their genetic values, we also discuss opportunities for genomic selection to predict the effects of CNV by dense SNP panels, when CNV cause variation in quantitative traits.
Strategies of exploitation of mammalian reservoirs by Bartonella species
Authors: Deng Hongkuan , Le Rhun Danielle , Buffet Jean-Philippe R , Cotté Violaine , Read Amanda , Birtles Richard J , Vayssier-Taussat Muriel
Published: March 2012

Numerous mammal species, including domestic and wild animals such as ruminants, dogs, cats and rodents, as well as humans, serve as reservoir hosts for variousBartonellaspecies. Some of those species that exploit non-human mammals as reservoir hosts have zoonotic potential. Our understanding of interactions between bartonellae and reservoir hosts has been greatly improved by the development of animal models for infection and the use of molecular tools allowing large scale mutagenesis ofBartonellaspecies. By reviewing and combining the results of these and other approaches we can obtain a comprehensive insight into the molecular interactions that underlie the exploitation of reservoir hosts byBartonellaspecies, particularly the well-studied interactions with vascular endothelial cells and erythrocytes.
Correlation set analysis: detecting active regulators in disease populations using prior causal knowledge
Authors: Huang Chia-Ling , Lamb John , Chindelevitch Leonid , Kostrowicki Jarek , Guinney Justin , DeLisi Charles , Ziemek Daniel
Published: March 2012

Background

Identification of active causal regulators is a crucial problem in understanding mechanism of diseases or finding drug targets. Methods that infer causal regulators directly from primary data have been proposed and successfully validated in some cases. These methods necessarily require very large sample sizes or a mix of different data types. Recent studies have shown that prior biological knowledge can successfully boost a method's ability to find regulators.

Results

We present a simple data-driven method, Correlation Set Analysis (CSA), for comprehensively detecting active regulators in disease populations by integrating co-expression analysis and a specific type of literature-derived causal relationships. Instead of investigating the co-expression level between regulators and their regulatees, we focus on coherence of regulatees of a regulator. Using simulated datasets we show that our method performs very well at recovering even weak regulatory relationships with a low false discovery rate. Using three separate real biological datasets we were able to recover well known and as yet undescribed, active regulators for each disease population. The results are represented as a rank-ordered list of regulators, and reveals both single and higher-order regulatory relationships.

Conclusions

CSA is an intuitive data-driven way of selecting directed perturbation experiments that are relevant to a disease population of interest and represent a starting point for further investigation. Our findings demonstrate that combining co-expression analysis on regulatee sets with a literature-derived network can successfully identify causal regulators and help develop possible hypothesis to explain disease progression.
Rab11-FIP3 is a cell cycle-regulated phosphoprotein
Authors: Collins Louise L , Simon Glenn , Matheson Johanne , Wu Christine , Miller M Clare , Otani Tetsuhisa , Yu Xinzi , Hayashi Shigeo , Prekeris Rytis , Gould Gwyn W
Published: March 2012

Background

Rab11 and its effector molecule, Rab11-FIP3 (FIP3), associate with recycling endosomes and traffic into the furrow and midbody of cells during cytokinesis. FIP3 also controls recycling endosome distribution during interphase. Here, we examine whether phosphorylation of FIP3 is involved in these activities.

Results

We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. Over-expression of FIP3-S102D increased the frequency of binucleate cells consistent with a role for this phospho-acceptor site in cytokinesis. Mutation of S-280, S-347 or S-450 or other previously identified phospho-acceptor sites (S-488, S-538, S-647 and S-648) was without effect on binucleate cell formation and did not modulate the distribution of FIP3 during the cell cycle. In an attempt to identify a functional role for FIP3 phosphorylation, we report that the change in FIP3 distribution from cytosolic to membrane-associated observed during progression from anaphase to telophase is accompanied by a concomitant dephosphorylation of FIP3. However, the phospho-acceptor sites identified here did not control this change in distribution.

Conclusions

Our data thus identify FIP3 as a cell cycle regulated phosphoprotein and suggest dephosphorylation of FIP3 accompanies its translocation from the cytosol to membranes during telophase. S102 is dephosphorylated during telophase; mutation of S102 exerts a modest effect on cytokinesis. Finally, we show that de/phosphorylation of the phospho-acceptor sites identified here (S-102, S-280, S-347 and S-450) is not required for the spatial control of recycling endosome distribution or function.
Antistaphylococcal activity of bacteriophage derived chimeric protein P128
Authors: Vipra Aradhana A , Desai Srividya Narayanamurthy , Roy Panchali , Patil Raghu , Raj Juliet Mohan , Narasimhaswamy Nagalakshmi , Paul Vivek Daniel , Chikkamadaiah Ravisha , Sriram Bharathi
Published: March 2012

Background

Bacterial drug resistance is one of the most significant challenges to human health today. In particular, effective antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA) are urgently needed. A causal relationship between nasal commensal S. aureus and infection has been reported. Accordingly, elimination of nasal S. aureus reduces the risk of infection. Enzymes that degrade bacterial cell walls show promise as antibacterial agents. Bacteriophage-encoded bacterial cell wall-degrading enzymes exhibit intrinsic bactericidal activity. P128 is a chimeric protein that combines the lethal activity of the phage tail-associated muralytic enzyme of Phage K and the staphylococcal cell wall targeting-domain (SH3b) of lysostaphin.

Here we report results of in vitro studies evaluating the susceptibility of staphylococcal strains to this novel protein.

Results

Using the broth microdilution method adapted for lysostaphin, we found that P128 is effective against S. aureus clinical strains including MRSA, methicillin-sensitive S. aureus (MSSA), and a mupirocin-resistant S. aureus. Minimum bactericidal concentrations and minimum inhibitory concentrations of P128 (1-64 μg/mL) were similar across the 32 S. aureus strains tested, demonstrating its bactericidal nature.

In time-kill assays, P128 reduced colony-forming units by 99.99% within 1 h and inhibited growth up to 24 h.

In an assay simulating topical application of P128 to skin or other biological surfaces, P128 hydrogel was efficacious when layered on cells seeded on solid media. P128 hydrogel was lethal to Staphylococci recovered from nares of healthy people and treated without any processing or culturing steps, indicating its in situ efficacy. This methodology used for in vitro assessment of P128 as an agent for eradicating nasal carriage is unique.

Conclusions

The novel chimeric protein P128 is a staphylococcal cell wall-degrading enzyme under development for clearance of S. aureus nasal colonization and MRSA infection. The protein is active against globally prevalent antibiotic-resistant clinical isolates and other clinically significant staphylococcal species including S. epidermidis. The P128 hydrogel formulation was bactericidal against Staphylococci including S. aureus recovered from the nares of 31 healthy people, demonstrating its in situ efficacy.
Genomes-based phylogeny of the genus Xanthomonas
Authors: Rodriguez-R Luis M , Grajales Alejandro , Arrieta-Ortiz Mario L , Salazar Camilo , Restrepo Silvia , Bernal Adriana
Published: March 2012

Background

The genusXanthomonascomprises several plant pathogenic bacteria affecting a wide range of hosts. Despite the economic, industrial and biological importance ofXanthomonas, the classification and phylogenetic relationships within the genus are still under active debate. Some of the relationships between pathovars and species have not been thoroughly clarified, with old pathovars becoming new species. A change in the genus name has been recently suggested forXanthomonas albilineans, an early branching species currently located in this genus, but a thorough phylogenomic reconstruction would aid in solving these and other discrepancies in this genus.

Results

Here we report the results of the genome-wide analysis of DNA sequences from 989 orthologous groups from 17Xanthomonasspp. genomes available to date, representing all major lineages within the genus. The phylogenetic and computational analyses used in this study have been automated in a Perl package designated Unus, which provides a framework for phylogenomic analyses which can be applied to other datasets at the genomic level. Unus can also be easily incorporated into other phylogenomic pipelines.

Conclusions

Our phylogeny agrees with previous phylogenetic topologies on the genus, but revealed that the genomes ofXanthomonas citriandXanthomonas fuscansbelong to the same species, and that ofXanthomonas albilineansis basal to the joint clade ofXanthomonasandXylella fastidiosa. Genome reduction was identified in the speciesXanthomonas vasicolain addition to the previously identified reduction inXanthomonas albilineans. Lateral gene transfer was also observed in two gene clusters.