134 results on '"J. Stocks"'
Search Results
2. Ancestral SARS-CoV-2, but not Omicron, replicates less efficiently in primary pediatric nasal epithelial cells
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Yanshan Zhu, Keng Yih Chew, Melanie Wu, Anjana C. Karawita, Georgina McCallum, Lauren E. Steele, Ayaho Yamamoto, Larisa I. Labzin, Tejasri Yarlagadda, Alexander A. Khromykh, Xiaohui Wang, Julian D. J. Sng, Claudia J. Stocks, Yao Xia, Tobias R. Kollmann, David Martino, Merja Joensuu, Frédéric A. Meunier, Giuseppe Balistreri, Helle Bielefeldt-Ohmann, Asha C. Bowen, Anthony Kicic, Peter D. Sly, Kirsten M. Spann, Kirsty R. Short, Department of Virology, Helsinki Institute of Sustainability Science (HELSUS), Biosciences, Research Programs Unit, and University of Helsinki
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Adult ,General Immunology and Microbiology ,TRANSMISSION ,SARS-CoV-2 ,General Neuroscience ,COVID-19 ,CHILDREN ,Epithelial Cells ,IMMUNITY ,General Biochemistry, Genetics and Molecular Biology ,1182 Biochemistry, cell and molecular biology ,Humans ,3111 Biomedicine ,General Agricultural and Biological Sciences ,Child ,RESPONSES - Abstract
Children typically experience more mild symptoms of Coronavirus Disease 2019 (COVID-19) when compared to adults. There is a strong body of evidence that children are also less susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with the ancestral viral isolate. However, the emergence of SARS-CoV-2 variants of concern (VOCs) has been associated with an increased number of pediatric infections. Whether this is the result of widespread adult vaccination or fundamental changes in the biology of SARS-CoV-2 remain to be determined. Here, we use primary nasal epithelial cells (NECs) from children and adults, differentiated at an air–liquid interface to show that the ancestral SARS-CoV-2 replicates to significantly lower titers in the NECs of children compared to those of adults. This was associated with a heightened antiviral response to SARS-CoV-2 in the NECs of children. Importantly, the Delta variant also replicated to significantly lower titers in the NECs of children. This trend was markedly less pronounced in the case of Omicron. It is also striking to note that, at least in terms of viral RNA, Omicron replicated better in pediatric NECs compared to both Delta and the ancestral virus. Taken together, these data show that the nasal epithelium of children supports lower infection and replication of ancestral SARS-CoV-2, although this may be changing as the virus evolves.
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- 2022
3. Frontline Science: LPS-inducible SLC30A1 drives human macrophage-mediated zinc toxicity against intracellular Escherichia coli
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Kate M. Peters, Ronan Kapetanovic, Claudia J. Stocks, James E. B. Curson, Nilesh J. Bokil, Darren Foo, Minh-Duy Phan, Jessica B. von Pein, Robert G. Parton, Matthew J. Sweet, Mark A. Schembri, Taiho Kambe, and James Rae
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Lipopolysaccharides ,0301 basic medicine ,Immunology ,Cell ,chemistry.chemical_element ,Zinc ,Biology ,medicine.disease_cause ,zinc transporters ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Anti-Infective Agents ,Escherichia coli ,medicine ,Animals ,Humans ,Immunology and Allergy ,Gene silencing ,Macrophage ,Cation Transport Proteins ,Escherichia coli Infections ,Macrophages ,Intracellular parasite ,E. coli ,metal ions ,Cell Biology ,host‐pathogen ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Highlighted Article ,chemistry ,030220 oncology & carcinogenesis ,Zinc toxicity ,zinc toxicity ,Spotlight on Leading Edge Research ,antimicrobial ,Intracellular - Abstract
TLR‐inducible zinc toxicity is an antimicrobial mechanism utilized by macrophages, however knowledge of molecular mechanisms mediating this response is limited. Here, we show that E. coli exposed to zinc stress within primary human macrophages reside in membrane‐bound vesicular compartments. Since SLC30A zinc exporters can deliver zinc into the lumen of vesicles, we examined LPS‐regulated mRNA expression of Slc30a/SLC30A family members in primary mouse and human macrophages. A number of these transporters were dynamically regulated in both cell populations. In human monocyte‐derived macrophages, LPS strongly up‐regulated SLC30A1 mRNA and protein expression. In contrast, SLC30A1 was not LPS‐inducible in macrophage‐like PMA‐differentiated THP‐1 cells. We therefore ectopically expressed SLC30A1 in these cells, finding that this was sufficient to promote zinc‐containing vesicle formation. The response was similar to that observed following LPS stimulation. Ectopically expressed SLC30A1 localized to both the plasma membrane and intracellular zinc‐containing vesicles within LPS‐stimulated THP‐1 cells. Inducible overexpression of SLC30A1 in THP‐1 cells infected with the Escherichia coli K‐12 strain MG1655 augmented the zinc stress response of intracellular bacteria and promoted clearance. Furthermore, in THP‐1 cells infected with an MG1655 zinc stress reporter strain, all bacteria contained within SLC30A1‐positive compartments were subjected to zinc stress. Thus, SLC30A1 marks zinc‐containing compartments associated with TLR‐inducible zinc toxicity in human macrophages, and its ectopic over‐expression is sufficient to initiate this antimicrobial pathway in these cells. Finally, SLC30A1 silencing did not compromise E. coli clearance by primary human macrophages, suggesting that other zinc exporters may also contribute to the zinc toxicity response., Graphical Abstract The zinc transporter SLC30A1 is LPS‐inducible in human macrophages and can deliver a zinc toxicity response against intracellular Escherichia coli.
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- 2020
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4. Early Pseudomonas aeruginosa predicts poorer pulmonary function in preschool children with cystic fibrosis
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P. Aurora, Julie Anne Duncan, S. Lum, G. Davies, A. Wade, J. Stocks, L. Viviani, E. Raywood, C. Pao, G. Ruiz, and A. Bush
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Pulmonary and Respiratory Medicine ,Cystic Fibrosis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Pseudomonas aeruginosa ,Infant, Newborn ,Infant ,Humans ,Lung ,Bronchoalveolar Lavage ,Respiratory Function Tests - Abstract
We previously reported relatively normal pulmonary function (2 years of age) and computed tomography (CT, 1 year of age) in cystic fibrosis (CF) newborn screened (NBS) infants. We now report follow up of these children to preschool age.67 NBS children with CF and 41 healthy controls underwent pulmonary function tests in infancy (∼3 months, 1 year and 2 years) and at preschool (3-6 years). Broncho-alveolar lavage (BAL) and CT were undertaken in those with CF at 1 year. Primary outcomes at preschool were lung clearance index (LCI) and forced expired volume (FEVAt preschool age children with CF had poorer lung function than controls, mean(95% CI) difference in LCI z-score: 1.47(0.96;1.97) and FEVLung function deteriorates after 2 years in NBS children with CF. Isolation of Pseudomonas aeruginosa before 6 months and minor abnormalities of infant lung function tests and CT in infancy are associated with higher preschool LCI.
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- 2022
5. Modulators of CXCR4 and CXCR7/AckR3 function
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Sebastian Dekkers, Kirsten Visser, Ilze Adlere, Iwan J. P. de Esch, Michael J. Stocks, Stephen J. Briddon, Barrie Kellam, Marta Arimont, Birgit Caspar, Stephen J. Hill, Jeffrey Stuijt, Rob Leurs, Chris de Graaf, and Maikel Wijtmans
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0301 basic medicine ,Benzylamines ,Receptors, CXCR4 ,Chemokine ,Computational biology ,Cyclams ,CXCR4 ,Protein Structure, Secondary ,03 medical and health sciences ,Chemokine receptor ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Heterocyclic Compounds ,Animals ,Humans ,Amino Acid Sequence ,Receptor ,Structural motif ,G protein-coupled receptor ,Receptors, CXCR ,Pharmacology ,biology ,Drug discovery ,Chemistry ,Ligand (biochemistry) ,Protein Structure, Tertiary ,030104 developmental biology ,biology.protein ,Molecular Medicine ,030217 neurology & neurosurgery ,Protein Binding - Abstract
The two G protein-coupled receptors (GPCRs) C-X-C chemokine receptor type 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3) are part of the class A chemokine GPCR family and represent important drug targets for human immunodeficiency virus (HIV) infection, cancer, and inflammation diseases. CXCR4 is one of only three chemokine receptors with a US Food and Drug Administration approved therapeutic agent, the small-molecule modulator AMD3100. In this review, known modulators of the two receptors are discussed in detail. Initially, the structural relationship between receptors and ligands is reviewed on the basis of common structural motifs and available crystal structures. To date, no atypical chemokine receptor has been crystallized, which makes ligand design and predictions for these receptors more difficult. Next, the selectivity, receptor activation, and the resulting ligand-induced signaling output of chemokines and other peptide ligands are reviewed. Binding of pepducins, a class of lipid-peptides whose basis is the internal loop of a GPCR, to CXCR4 is also discussed. Finally, small-molecule modulators of CXCR4 and ACKR3 are reviewed. These modulators have led to the development of radio- and fluorescently labeled tool compounds, enabling the visualization of ligand binding and receptor characterization both in vitro and in vivo. SIGNIFICANCE STATEMENT To investigate the pharmacological modulation of CXCR4 and ACKR3, significant effort has been focused on the discovery and development of a range of ligands, including small-molecule modulators, pepducins, and synthetic peptides. Imaging tools, such as fluorescent probes, also play a pivotal role in the field of drug discovery. This review aims to provide an overview of the aforementioned modulators that facilitate the study of CXCR4 and ACKR3 receptors.
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- 2019
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6. Uropathogenic Escherichia coli employs both evasion and resistance to subvert innate immune-mediated zinc toxicity for dissemination
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Ronan Kapetanovic, Jayde A. Gawthorne, Minh-Duy Phan, Kate M. Peters, Nicholas D. Condon, Claudia J. Stocks, Nguyen Thi Khanh Nhu, Alastair G. McEwan, Maud E. S. Achard, Alvin W. Lo, Matthew J. Sweet, and Mark A. Schembri
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Urology ,Clone (cell biology) ,chemistry.chemical_element ,macrophage ,Zinc ,urologic and male genital diseases ,medicine.disease_cause ,Microbiology ,03 medical and health sciences ,antimicrobial responses ,medicine ,Humans ,Uropathogenic Escherichia coli ,Macrophage ,Escherichia coli ,Pathogen ,Escherichia coli Infections ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Innate immune system ,biology ,business.industry ,030306 microbiology ,Biological Sciences ,Evasion (ethics) ,biology.organism_classification ,female genital diseases and pregnancy complications ,Immunity, Innate ,3. Good health ,PNAS Plus ,chemistry ,TraDIS ,Zinc toxicity ,UPEC ,business ,Bacteria - Abstract
Significance Uropathogenic Escherichia coli (UPEC) is responsible for most urinary tract infections and is also a frequent cause of sepsis, thus necessitating an understanding of UPEC-mediated subversion of innate immunity. The role of zinc in the innate immune response against UPEC infection, and whether this pathogen counters this response, has not been examined. Here we demonstrate, both in vitro and in vivo, that UPEC both evades and resists innate immune-mediated zinc toxicity to persist and disseminate within the host. Moreover, we have defined the set of UPEC genes conferring zinc resistance and have developed highly selective E. coli reporter systems to track zinc toxicity. These innovative approaches substantially enhance our understanding of immune-mediated metal ion toxicity and bacterial pathogenesis., Toll-like receptor (TLR)-inducible zinc toxicity is a recently described macrophage antimicrobial response used against bacterial pathogens. Here we investigated deployment of this pathway against uropathogenic Escherichia coli (UPEC), the major cause of urinary tract infections. Primary human macrophages subjected EC958, a representative strain of the globally disseminated multidrug-resistant UPEC ST131 clone, to zinc stress. We therefore used transposon-directed insertion site sequencing to identify the complete set of UPEC genes conferring protection against zinc toxicity. Surprisingly, zinc-susceptible EC958 mutants were not compromised for intramacrophage survival, whereas corresponding mutants in the nonpathogenic E. coli K-12 strain MG1655 displayed significantly reduced intracellular bacterial loads within human macrophages. To investigate whether the intramacrophage zinc stress response of EC958 reflected the response of only a subpopulation of bacteria, we generated and validated reporter systems as highly specific sensors of zinc stress. Using these tools we show that, in contrast to MG1655, the majority of intramacrophage EC958 evades the zinc toxicity response, enabling survival within these cells. In addition, EC958 has a higher tolerance to zinc than MG1655, with this likely being important for survival of the minor subset of UPEC cells exposed to innate immune-mediated zinc stress. Indeed, analysis of zinc stress reporter strains and zinc-sensitive mutants in an intraperitoneal challenge model in mice revealed that EC958 employs both evasion and resistance against zinc toxicity, enabling its dissemination to the liver and spleen. We thus demonstrate that a pathogen of global significance uses multiple mechanisms to effectively subvert innate immune-mediated zinc poisoning for systemic spread.
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- 2019
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7. Development and validation of a cost‐effective and sensitive bioanalytical HPLC‐UV method for determination of lopinavir in rat and human plasma
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Pavel Gershkovich, Yeong Yeu Teo, Yen-Ju Chu, Peter Fischer, Sara Bettonte, Michael J. Stocks, Chaolong Qin, Mattia Berton, Wanshan Feng, and Jong Bong Lee
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Male ,Bioanalysis ,Calibration curve ,Cost-Benefit Analysis ,Liquid-Liquid Extraction ,Clinical Biochemistry ,Antiviral Agents ,Sensitivity and Specificity ,030226 pharmacology & pharmacy ,01 natural sciences ,Biochemistry ,Lopinavir ,Analytical Chemistry ,Rats, Sprague-Dawley ,03 medical and health sciences ,Drug Delivery Systems ,0302 clinical medicine ,Pharmacokinetics ,Limit of Detection ,Drug Discovery ,medicine ,Animals ,Humans ,Protein precipitation ,Molecular Biology ,Chromatography, High Pressure Liquid ,Pharmacology ,Chromatography ,medicine.diagnostic_test ,Chemistry ,010401 analytical chemistry ,Extraction (chemistry) ,Reproducibility of Results ,General Medicine ,Rats ,0104 chemical sciences ,Therapeutic drug monitoring ,Calibration ,Drug delivery ,Solvents ,Spectrophotometry, Ultraviolet ,Drug Monitoring ,medicine.drug - Abstract
A simple, sensitive and cost-effective HPLC-UV bioanalytical method for determination of lopinavir (LPV) in rat and human plasma was developed and validated. The plasma sample preparation procedure includes a combination of protein precipitation using cold acetonitrile and liquid-liquid extraction with n-hexane-ethyl acetate (7:3, v/v). A good chromatographic separation was achieved with a Phenomenex Gemini column (C18 , 150 mm × 2.0 mm, 5 µm) at 40°C with gradient elution, at 211 nm. Calibration curves were linear in the range 10-10,000 ng/mL, with a lower limit of quantification of 10 ng/mL using 100 µL of plasma. The accuracy and precision in all validation experiments were within the criteria range set by the guidelines of the Food and Drug Administration. This method was successfully applied to a preliminary pharmacokinetic study in rats following an intravenous bolus administration of LPV. Moreover, the method was subsequently fully validated for human plasma, allowing its use in therapeutic drug monitoring (TDM). In conclusion, this novel, simple and cost-efficient bioanalytical method for determination of LPV is useful for pharmacokinetic and drug delivery studies in rats, as well as TDM in human patients.
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- 2020
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8. An alloy of zinc and innate immunity: Galvanising host defence against infection
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Ronan Kapetanovic, Matthew J. Sweet, Mark A. Schembri, Claudia J. Stocks, and Jessica B. von Pein
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Neutrophils ,Immunology ,chemistry.chemical_element ,Zinc ,Biology ,medicine.disease_cause ,Microbiology ,Communicable Diseases ,03 medical and health sciences ,Anti-Infective Agents ,Virology ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Pathogen ,030304 developmental biology ,0303 health sciences ,Innate immune system ,030306 microbiology ,Intracellular parasite ,Macrophages ,Biological Transport ,Antimicrobial ,Immunity, Innate ,chemistry ,Gene Expression Regulation ,Infectious disease (medical specialty) ,Zinc toxicity ,Host-Pathogen Interactions - Abstract
Innate immune cells such as macrophages and neutrophils initiate protective inflammatory responses and engage antimicrobial responses to provide frontline defence against invading pathogens. These cells can both restrict the availability of certain transition metals that are essential for microbial growth and direct toxic concentrations of metals towards pathogens as antimicrobial responses. Zinc is important for the structure and function of many proteins, however excess zinc can be cytotoxic. In recent years, several studies have revealed that innate immune cells can deliver toxic concentrations of zinc to intracellular pathogens. In this review, we discuss the importance of zinc status during infectious disease and the evidence for zinc intoxication as an innate immune antimicrobial response. Evidence for pathogen subversion of this response is also examined. The likely mechanisms, including the involvement of specific zinc transporters, that facilitate delivery of zinc by innate immune cells for metal ion poisoning of pathogens are also considered. Precise mechanisms by which excess levels of zinc can be toxic to microorganisms are then discussed, particularly in the context of synergy with other antimicrobial responses. Finally, we highlight key unanswered questions in this emerging field, which may offer new opportunities for exploiting innate immune responses for anti‐infective development.
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- 2020
9. Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR
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Alaa Mashabi, Paul Williams, Fadi Soukarieh, Jonas Emsley, Ruiling Liu, Michael J. Stocks, Miguel Cámara, William Richardson, and Scott Grossman
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Virulence Factors ,Virulence ,Microbial Sensitivity Tests ,medicine.disease_cause ,Crystallography, X-Ray ,01 natural sciences ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,PqsR ,Bacterial Proteins ,Drug Discovery ,Transcriptional regulation ,medicine ,Humans ,Quinazolinone ,030304 developmental biology ,Quinazolinones ,Pharmacology ,0303 health sciences ,Molecular Structure ,010405 organic chemistry ,Pseudomonas aeruginosa ,Inhibitors ,Organic Chemistry ,Quorum Sensing ,General Medicine ,Gene Expression Regulation, Bacterial ,Pathogenicity ,X-ray crystal structure ,0104 chemical sciences ,Anti-Bacterial Agents ,Quorum sensing ,Thiazoles ,chemistry ,A549 Cells ,Drug Design ,Protein Binding ,Transcription Factors ,Research Paper - Abstract
Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50, Graphical abstract Image 1, Highlights • Pseudomonas aeruginosa – a Gram-negative pathogenic bacterium. • Quorum sensing – a cell-to-cell communication strategy used by microbes to coordinate the production of various virulence factors. • Inhibitors of PqsR – small molecules that inhibit the signal of Pseudomonas aeruginosa Quinolone Signal Receptor. • X-ray crystal structure – used to demonstrate the 3-D structural orientation of the ligand in the protein structure.
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- 2020
10. Self-Assembling Benzothiazole-Based Gelators: A Mechanistic Understanding of in Vitro Bioactivation and Gelation
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Tracey D. Bradshaw, Joel Segal, Pavel Gershkovich, Francesca Citossi, Michael J. Stocks, Jong Bong Lee, Barrie Kellam, Thomas Smith, and Maria Marlow
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Pharmaceutical Science ,Antineoplastic Agents ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,benzothiazole derivatives, low molecular weight gelators, CYP1A1 induction, in vitro antitumour activity ,Cell Line, Tumor ,Amide ,Drug Discovery ,Self assembling ,Cytochrome P-450 CYP1A1 ,medicine ,Humans ,Benzothiazoles ,Ovarian Neoplasms ,Hydrogels ,HCT116 Cells ,021001 nanoscience & nanotechnology ,Amides ,In vitro ,Nanostructures ,0104 chemical sciences ,Blot ,Physical Sciences - Materials Chemistry ,Benzothiazole ,chemistry ,Biochemistry ,Mechanism of action ,MCF-7 Cells ,Molecular Medicine ,Female ,Carbamates ,medicine.symptom ,0210 nano-technology ,Selectivity ,Linker - Abstract
Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing poly-mer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumour benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro anti-tumour activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells. In contrast, MRC-5 fibroblasts were inherently resistant to the above derivatives (GI50>10 μM), thus revealing stark selectivity against the malignant cell lines over the non-transformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its deriva-tives only in sensitive malignant cells (MCF-7), corroborating conservation of CYP1A1-mediated mechanism of action. The ability to form stable gels under relatively high strains was supported by rheological tests; in addition, their inner morphology was characterized as possessing a crossed-linked nanostructure, with formation of thick aggregates with variable widths between 1100 nm and 400 nm and lengths from 8 μm to 32 μm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 hours, therefore demonstrating its ability to act as a plat-form for localized delivery.
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- 2018
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11. Concurrent Reactive Oxygen Species Generation and Aneuploidy Induction Contribute to Thymoquinone Anticancer Activity
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Mohammed A. Alhayali, Michael J. Stocks, Aimie E. Garces, Tracey D. Bradshaw, and Hilary M. Collins
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thymoquinone ,Pharmaceutical Science ,Antineoplastic Agents ,Article ,Analytical Chemistry ,chemistry.chemical_compound ,QD241-441 ,Annexin ,Cell Line, Tumor ,Drug Discovery ,Benzoquinones ,NAD(P)H Dehydrogenase (Quinone) ,Humans ,Nigella sativa ,Physical and Theoretical Chemistry ,Clonogenic assay ,Thymoquinone ,Cell Proliferation ,chemistry.chemical_classification ,Reactive oxygen species ,GSH depletion ,Chemistry ,Organic Chemistry ,apoptosis ,Biological activity ,Glutathione ,Aneuploidy ,HCT116 Cells ,Molecular biology ,Chemistry (miscellaneous) ,Apoptosis ,Cell culture ,MCF-7 Cells ,ROS generation ,Molecular Medicine ,Reactive Oxygen Species - Abstract
Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa. Many studies have confirmed its anticancer actions. Herein, we investigated the different anticancer activities of, and considered resistance mechanisms to, TQ. MTT and clonogenic data showed TQ’s ability to suppress breast MDA-MB-468 and T-47D proliferation at lower concentrations compared to other cancer and non-transformed cell lines tested (GI50 values ≤ 1.5 µM). Flow-cytometric analyses revealed that TQ consistently induced MDA-MB-468 and T-47D cell-cycle perturbation, specifically inducing pre-G1 populations. In comparison, less sensitive breast MCF-7 and colon HCT-116 cells exhibited only transient increases in pre-G1 events. Annexin V/PI staining confirmed apoptosis induction in MDA-MB-468 and HCT-116 cells, which was continuous in the former and transient in the latter. Experiments revealed the role of reactive oxygen species (ROS) generation and aneuploidy induction in MDA-MB-468 cells within the first 24 h of treatment. The ROS-scavenger NAD(P)H dehydrogenase (quinone 1) (NQO1, DT-diaphorase) and glutathione (GSH) were implicated in resistance to TQ. Indeed, western blot analyses showed that NQO1 is expressed in all cell lines in this study, except those most sensitive to TQ-MDA-MB-468 and T-47D. Moreover, TQ treatment increased NQO1 expression in HCT-116 in a concentration-dependent fashion. Measurement of GSH activity in MDA-MB-468 and HCT-116 cells found that GSH is similarly active in both cell lines. Furthermore, GSH depletion rendered these cells more sensitive to TQ’s antiproliferative actions. Therefore, to bypass putative inactivation of the TQ semiquinone metabolite, the benzylamine analogue was designed and synthesised following modification of TQ’s carbon-3 atom. However, the structural modification negatively impacted potency against MDA-MB-468 cells. In conclusion, we disclose the following: (i) The anticancer activity of TQ may be a consequence of ROS generation and aneuploidy, (ii) Early GSH depletion could substantially enhance TQ’s anticancer activity, (iii) Benzylamine substitution at TQ’s carbon-3 failed to enhance anticancer activity.
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- 2021
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12. Uropathogenic
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Claudia J, Stocks, Minh-Duy, Phan, Maud E S, Achard, Nguyen Thi Khanh, Nhu, Nicholas D, Condon, Jayde A, Gawthorne, Alvin W, Lo, Kate M, Peters, Alastair G, McEwan, Ronan, Kapetanovic, Mark A, Schembri, and Matthew J, Sweet
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Adenosine Triphosphatases ,Male ,Escherichia coli Proteins ,Macrophages ,Gene Expression Regulation, Bacterial ,Bacterial Load ,Immunity, Innate ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Zinc ,Bacterial Proteins ,Drug Resistance, Multiple, Bacterial ,Mutation ,Urinary Tract Infections ,DNA Transposable Elements ,Animals ,Humans ,Uropathogenic Escherichia coli ,ATP-Binding Cassette Transporters ,Escherichia coli Infections ,Transcription Factors - Abstract
Toll-like receptor (TLR)-inducible zinc toxicity is a recently described macrophage antimicrobial response used against bacterial pathogens. Here we investigated deployment of this pathway against uropathogenic
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- 2019
13. Oral administration of tipranavir with long-chain triglyceride results in moderate intestinal lymph targeting but no efficient delivery to HIV-1 reservoir in mesenteric lymph nodes
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Yen-Ju Chu, Chaolong Qin, Teddy Chan, Binhua Ling, Charles Sheriston, Birgit E. Watson, Concepción Medrano-Padial, Pavel Gershkovich, Wanshan Feng, Peter Fischer, Yu Jane Khor, Michael J. Stocks, and Universidad de Sevilla. Departamento de Nutrición y Bromatología, Toxicología y Medicina Legal
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Drug ,Pyridines ,media_common.quotation_subject ,Administration, Oral ,Pharmaceutical Science ,02 engineering and technology ,Pharmacology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Intestinal lymphatic targeting ,medicine ,Animals ,Humans ,Mesenteric lymph nodes ,Tissue Distribution ,Tipranavir ,Protease inhibitor (pharmacology) ,Triglycerides ,media_common ,Sulfonamides ,business.industry ,HIV ,021001 nanoscience & nanotechnology ,Rats ,Lymphatic system ,medicine.anatomical_structure ,Protease inhibitor ,Pyrones ,HIV-1 ,Long-chain triglyceride-based formulation ,Lymph Nodes ,Lymph ,0210 nano-technology ,business ,medicine.drug ,Chylomicron - Abstract
The introduction of combination antiretroviral therapy (cART) led to substantial improvement in mortality and morbidity of HIV-1 infection. However, the poor penetration of antiretroviral agents to HIV-1 reservoirs limit the ability of the antiretroviral agents to eliminate the virus. Mesenteric lymph nodes (MLNs) are one of the main HIV-1 reservoirs in patients under suppressive cART. Intestinal lymphatic absorption pathway substantially increases the concentration of lipophilic drugs in mesenteric lymph and MLNs when they are co-administered with long-chain triglyceride (LCT). Chylomicrons (CM) play a crucial role in the intestinal lymphatic absorption as they transport drugs to the lymph lacteals rather than blood capillary by forming CM-drug complexes in the enterocytes. Thus, lipophilic antiretroviral drugs could potentially be delivered to HIV-1 reservoirs in MLNs by LCT-based formulation approach. In this study, protease inhibitors (PIs) were initially screened for their potential for intestinal lymphatic targeting using a computational model. The candidates were further assessed for their experimental affinity to CM. Tipranavir (TPV) was the only-candidate with substantial affinity to both artificial and natural CM in vitro and ex vivo. Pharmacokinetics and biodistribution studies were then performed to evaluate the oral bioavailability and intestinal lymphatic targeting of TPV in rats. The results showed similar oral bioavailability of TPV with and without co-administration of LCT vehicle. Although LCT-based formulation led to 3-fold higher concentrations of TPV in mesenteric lymph compared to plasma, the levels of the drug in MLNs were similar to plasma in both LCT-based and lipid-free formulation groups. Thus, LCT-based formulation approach alone was not sufficient for effective delivery of TPV to MLNs. Future efforts should be directed to a combined highly lipophilic prodrugs/lipid-based formulation approach to target TPV, other PIs and potentially other classes of antiretroviral agents to viral reservoirs within the mesenteric lymphatic system.
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- 2021
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14. Class 1 PI3K Clinical Candidates and Recent Inhibitor Design Strategies: A Medicinal Chemistry Perspective
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Aimie E. Garces and Michael J. Stocks
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0303 health sciences ,Molecular Structure ,Class I Phosphatidylinositol 3-Kinases ,Chemistry, Pharmaceutical ,Lipid kinases ,01 natural sciences ,Medicinal chemistry ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Drug Design ,Drug Discovery ,Molecular Medicine ,Animals ,Humans ,Idelalisib ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Copanlisib ,Phosphoinositide-3 Kinase Inhibitors ,Protein Binding - Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate the 3-OH of the inositol ring of phosphoinositides, and deregulation of this pathway has implications in many diseases. The search for novel PI3K inhibitors has been at the forefront of academic and industrial medicinal chemistry with over 600 medicinal chemistry-based publications and patents appearing to date, leading to 38 clinical candidates and the launch of two drugs, idelalisib in 2014 and copanlisib in 2017. This Perspective will discuss medicinal chemistry design approaches to novel isoform-selective inhibitors through consideration of brief case histories of compounds that have progressed into clinical development or that have revealed new structural motifs in this highly competitive area of research.
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- 2018
15. Synthesis and Evaluation of the First Fluorescent Antagonists of the Human P2Y
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Sean, Conroy, Nicholas D, Kindon, Jacqueline, Glenn, Leigh A, Stoddart, Richard J, Lewis, Stephen J, Hill, Barrie, Kellam, and Michael J, Stocks
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Microscopy, Confocal ,Dibenzocycloheptenes ,Pyrimidinones ,Astrocytoma ,Ligands ,Recombinant Proteins ,Cell Line ,Addition/Correction ,Receptors, Purinergic P2Y2 ,Structure-Activity Relationship ,Molecular Probes ,Purinergic P2 Receptor Antagonists ,Humans ,Fluorescent Dyes ,Protein Binding - Abstract
The human P2Y
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- 2018
16. The relative efficacy of topical non-steroidal anti-inflammatory drugs and capsaicin in osteoarthritis: a network meta-analysis of randomised controlled trials
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M S M, Persson, J, Stocks, D A, Walsh, M, Doherty, and W, Zhang
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Meta-analysis ,Topical ,Non-steroidal anti-inflammatory drugs (NSAIDs) ,Administration, Topical ,Anti-Inflammatory Agents, Non-Steroidal ,Network Meta-Analysis ,Osteoarthritis ,Humans ,Pain Management ,Network ,Capsaicin ,Article ,Randomized Controlled Trials as Topic - Abstract
Summary Objective To compare the efficacy of topical non-steroidal anti-inflammatory drugs (NSAIDs) with topical capsaicin for pain relief in osteoarthritis (OA). Design A systematic literature search was conducted for randomised controlled trials (RCTs) examining any topical NSAID or capsaicin in OA. Pain relief at or nearest to 4 weeks was pooled using a random-effects network meta-analysis (NMA) in a Frequentist and Bayesian setting. Analysis was conducted for all trials and for trials using drugs listed as licensed for OA in the British National Formulary (BNF). Results The trial network comprised 28 RCTs (7372 participants), of which 17 RCTs (3174 participants) were included in the as licensed analyses. No RCTs directly compared topical NSAIDs with capsaicin. Placebo was the only common comparator for topical NSAIDs and capsaicin. Frequentist and Bayesian effect size (ES) estimates were in agreement. Topical NSAIDs were statistically superior to placebo overall (ES 0.30, 95% confidence interval [CI] 0.19 to 0.41) and as licensed (ES 0.32, 95% CI 0.24 to 0.39). However, capsaicin was only statistically superior to placebo when used at licensed doses (ES 0.41, 95% CI 0.17 to 0.64). No significant differences were observed in pain relief between topical NSAIDs and capsaicin (overall: ES 0.04, 95% CI −0.26 to 0.33; as licensed: ES-0.09, 95% CI −0.34 to 0.16). Conclusions Current evidence indicates that topical NSAIDs and capsaicin in licensed doses may be equally effective for pain relief in OA. Whether the equivalence varies between individuals remains unknown.
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- 2018
17. Nucleoside-Based Self-Assembling Drugs for Localized Drug Delivery
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Michael J. Stocks, Barrie Kellam, Katherine J. Skilling, Laurence Burroughs, Tracey D. Bradshaw, Maria Marlow, and Marianne Ashford
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02 engineering and technology ,Viscoelastic Substances ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Deoxycytidine ,chemistry.chemical_compound ,Drug Delivery Systems ,Microscopy, Electron, Transmission ,Cell Line, Tumor ,Drug Discovery ,Self assembling ,medicine ,Humans ,General Pharmacology, Toxicology and Pharmaceutics ,Pharmacology ,Chemistry ,Organic Chemistry ,Lamivudine ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,Gemcitabine ,0104 chemical sciences ,Drug delivery ,Molecular Medicine ,Growth inhibition ,Drug Screening Assays, Antitumor ,0210 nano-technology ,Rheology ,Nucleoside ,Gels ,medicine.drug - Abstract
We have synthesized a range of gelators based on the nucleoside analogues gemcitabine and lamivudine, characterizing representative gels from the series using rheology and transmission electron microscopy. Growth inhibition studies of gemcitabine derivatives confirmed the feasibility of these compounds as novel treatments, indicating the potential of nucleoside-based gelators for localized drug delivery.
- Published
- 2018
18. Antitumour benzothiazoles. Part 32: DNA adducts and double strand breaks correlate with activity; synthesis of 5F203 hydrogels for local delivery
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Malcolm F. G. Stevens, Margaret Gaskell, Barrie Kellam, Tracey D. Bradshaw, Curtis Hose, Michael J. Stocks, Anne Monks, Chee-Onn Leong, Maria Marlow, Peter B. Farmer, Erica L. Stone, Balvinder Kaur, Francesca Citossi, and Rajinder Singh
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Cell Survival ,Clinical Biochemistry ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Histones ,DNA Adducts ,chemistry.chemical_compound ,Cell Line, Tumor ,Ovarian carcinoma ,Stilbenes ,Drug Discovery ,Cytochrome P-450 CYP1A1 ,Humans ,Prodrugs ,Benzothiazoles ,Molecular Biology ,Chromatography, High Pressure Liquid ,Regulation of gene expression ,Microscopy, Confocal ,biology ,Chemistry ,Organic Chemistry ,Hydrogels ,Prodrug ,In vitro ,Thiazoles ,Histone ,Gene Expression Regulation ,Drug Resistance, Neoplasm ,Resveratrol ,Cell culture ,Self-healing hydrogels ,biology.protein ,Cancer research ,Molecular Medicine ,DNA - Abstract
Potent, selective antitumour AhR ligands 5F 203 and GW 610 are bioactivated by CYPs 1A1 and 2W1. Herein we reason that DNA adducts' generation resulting in lethal DNA double strand breaks (DSBs) underlies benzothiazoles' activity. Treatment of sensitive carcinoma cell lines with GW 610 generated co-eluting DNA adducts (R(2)>0.7). Time-dependent appearance of γ-H2AX foci revealed subsequent DNA double strand breaks. Propensity for systemic toxicity of benzothiazoles steered development of prodrugs' hydrogels for localised delivery. Clinical applications of targeted therapies include prevention or treatment of recurrent disease after surgical resection of solid tumours. In vitro evaluation of 5F 203 prodrugs' activity demonstrated nanomolar potency against MCF-7 breast and IGROV-1 ovarian carcinoma cell lines.
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- 2015
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19. For when bacterial infections persist: Toll-like receptor-inducible direct antimicrobial pathways in macrophages
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Claudia J. Stocks, Ronan Kapetanovic, Matthew J. Sweet, and Mark A. Schembri
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0301 basic medicine ,Immunology ,Antigen presentation ,Antimicrobial peptides ,Biology ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Immunology and Allergy ,Animals ,Humans ,Reactive nitrogen species ,Toll-like receptor ,Innate immune system ,Macrophages ,Toll-Like Receptors ,Pattern recognition receptor ,Cell Biology ,Bacterial Infections ,Antimicrobial ,Anti-Bacterial Agents ,030104 developmental biology ,chemistry ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Macrophages are linchpins of innate immunity, responding to invading microorganisms by initiating coordinated inflammatory and antimicrobial programs. Immediate antimicrobial responses, such as NADPH-dependent reactive oxygen species (ROS), are triggered upon phagocytic receptor engagement. Macrophages also detect and respond to microbial products through pattern recognition receptors (PRRs), such as TLRs. TLR signaling influences multiple biological processes including antigen presentation, cell survival, inflammation, and direct antimicrobial responses. The latter enables macrophages to combat infectious agents that persist within the intracellular environment. In this review, we summarize our current understanding of TLR-inducible direct antimicrobial responses that macrophages employ against bacterial pathogens, with a focus on emerging evidence linking TLR signaling to reprogramming of mitochondrial functions to enable the production of direct antimicrobial agents such as ROS and itaconic acid. In addition, we describe other TLR-inducible antimicrobial pathways, including autophagy/mitophagy, modulation of nutrient availability, metal ion toxicity, reactive nitrogen species, immune GTPases (immunity-related GTPases and guanylate-binding proteins), and antimicrobial peptides. We also describe examples of mechanisms of evasion of such pathways by professional intramacrophage pathogens, with a focus on Salmonella, Mycobacteria, and Listeria. An understanding of how TLR-inducible direct antimicrobial responses are regulated, as well as how bacterial pathogens subvert such pathways, may provide new opportunities for manipulating host defence to combat infectious diseases.
- Published
- 2017
20. From UTP to AR-C118925, the discovery of a potent non nucleotide antagonist of the P2Y
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Nicholas, Kindon, Andrew, Davis, Iain, Dougall, John, Dixon, Timothy, Johnson, Iain, Walters, Steve, Thom, Kenneth, McKechnie, Premji, Meghani, and Michael J, Stocks
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Receptors, Purinergic P2Y2 ,Drug Evaluation, Preclinical ,Purinergic P2Y Receptor Antagonists ,Humans ,Uridine Triphosphate ,Dibenzocycloheptenes ,Pyrimidinones ,Protein Binding - Abstract
The G protein-coupled P2Y
- Published
- 2017
21. Ipratropium is 'luminally recycled' by an inter-play between apical uptake and efflux transporters in Calu-3 bronchial epithelial cell layers
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Vijender Panduga, Michael J. Stocks, and Cynthia Bosquillon
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Pharmaceutical Science ,Bronchi ,Pharmacology ,030226 pharmacology & pharmacy ,Cholinergic Antagonists ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Humans ,Tiotropium Bromide ,Organic cation transport proteins ,biology ,Membrane transport protein ,Ipratropium ,Transporter ,Biological Transport ,Dextrans ,Epithelial Cells ,Glycopyrrolate ,Bronchodilator Agents ,Drug Liberation ,030220 oncology & carcinogenesis ,Paracellular transport ,biology.protein ,Biophysics ,Respiratory epithelium ,Efflux ,Drug inhalation, Pulmonary drug delivery, In vitro models, Drug transporters, Carrier-mediated transport, Muscarinic M3 receptor antagonists ,Intracellular ,Fluorescein-5-isothiocyanate - Abstract
The mechanism by which quaternized anticholinergic bronchodilators permeate the airway epithelium remains controversial to date. In order to elucidate the role of drug transporters, ipratropium bidirectional transport as well as accumulation and release studies were performed in layers of the broncho-epithelial cell line Calu-3 grown at an air-liquid interface, in presence or absence of a range of transporter inhibitors. Unexpectedly, a higher transepithelial permeability was observed in the secretory direction, with an apparent efflux ratio of4. Concentration-dependent and inhibitor studies demonstrated the drug intracellular uptake was carrier-mediated. Interestingly, monitoring drug release post cell loading revealed the presence of an efficient efflux system on the apical side of the cell layers. Acting in concert, apical transporters seem to promote the 'luminal recycling' of the drug and hence, limit its transcellular transport. The data are in agreement with an apical Organic Cation Transporter (OCT) being involved in this process but also suggest the participation of unknown uptake and efflux transporters sensitive to probenecid. This study suggests the absorption of ipratropium across the pulmonary barrier is primarily governed by paracellular passive diffusion but transporters might play a significant role in controlling the drug local concentrations in the lungs.
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- 2017
22. Design and elaboration of a tractable tricyclic scaffold to synthesize druglike inhibitors of dipeptidyl peptidase-4 (DPP-4), antagonists of the C–C Chemokine Receptor Type 5 (CCR5), and highly potent and selective phosphoinositol-3 Kinase δ (PI3Kδ) inhibitors
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Leigh A. Stoddart, Nicholas Kindon, Carolin Schwehm, Aimie E. Garces, Barrie Kellam, Simon J. F. Macdonald, Michael J. Stocks, James E. Rowedder, Stephen J. Hill, Tracey D. Bradshaw, and Li Jin
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0301 basic medicine ,Scaffold ,Receptors, CCR5 ,Stereochemistry ,Chemokine receptor CCR5 ,Dipeptidyl Peptidase 4 ,01 natural sciences ,Small Molecule Libraries ,03 medical and health sciences ,Chemokine receptor ,Drug Discovery ,Humans ,Protein Kinase Inhibitors ,Dipeptidyl peptidase-4 ,Phosphoinositide-3 Kinase Inhibitors ,chemistry.chemical_classification ,Dipeptidyl-Peptidase IV Inhibitors ,biology ,010405 organic chemistry ,Drug discovery ,Chemistry ,Kinase ,Biological activity ,0104 chemical sciences ,Class Ia Phosphatidylinositol 3-Kinase ,Molecular Docking Simulation ,Protein Subunits ,030104 developmental biology ,Biochemistry ,Drug Design ,CCR5 Receptor Antagonists ,biology.protein ,Molecular Medicine ,Tricyclic - Abstract
A novel molecular scaffold has been synthesized, and its incorporation into new analogues of biologically active molecules across multiple target classes will be discussed. In these studies, we have shown use of the tricyclic scaffold to synthesize potent inhibitors of the serine peptidase DPP-4, antagonists of the CCR5 receptor, and highly potent and selective PI3K δ isoform inhibitors. We also describe the predicted physicochemical properties of the resulting inhibitors and conclude that the tractable molecular scaffold could have potential application in future drug discovery programs.
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- 2017
23. Drug-like Antagonists of P2Y Receptors-From Lead Identification to Drug Development
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Michael J. Stocks, Sean Conroy, Barrie Kellam, and Nicholas Kindon
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0301 basic medicine ,Drug ,P2Y receptor ,Molecular Structure ,Cell growth ,Receptors, Purinergic P2 ,media_common.quotation_subject ,Pharmacology ,Biology ,Small molecule ,Small Molecule Libraries ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Drug development ,030220 oncology & carcinogenesis ,Drug Discovery ,Purinergic P2 Receptor Antagonists ,Molecular Medicine ,Humans ,Identification (biology) ,Receptor ,Gene ,media_common - Abstract
P2Y receptors are expressed in virtually all cells and tissue types and mediate an astonishing array of biological functions, including platelet aggregation, smooth muscle cell proliferation, and immune regulation. The P2Y receptors belong to the G protein-coupled receptor superfamily and are composed of eight members encoded by distinct genes that can be subdivided into two groups on the basis of their coupling to specific G-proteins. Extensive research has been undertaken to find modulators of P2Y receptors, although to date only a limited number of small-molecule P2Y receptor antagonists have been approved by drug/medicines agencies. This Perspective reviews the known P2Y receptor antagonists, highlighting oral drug-like receptor antagonists, and considers future opportunities for the development of small molecules for clinical evaluation.
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- 2016
24. Wildfire Suppression Costs for Canada under a Changing Climate
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Sylvie Gauthier, Emily S. Hope, John H. Pedlar, Daniel W. McKenney, and Brian J. Stocks
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Atmospheric Science ,Time Factors ,010504 meteorology & atmospheric sciences ,Poison control ,lcsh:Medicine ,Wildfire Management ,01 natural sciences ,Geographical locations ,Trees ,Wildfires ,Mathematical and Statistical Techniques ,Environmental protection ,lcsh:Science ,Climatology ,Multidisciplinary ,Mathematical Models ,04 agricultural and veterinary sciences ,Engineering and Technology ,Seasons ,Research Article ,Canada ,Climate Change ,Climate change ,Research and Analysis Methods ,Fires ,Meteorology ,Fire protection ,Temperate climate ,Humans ,Ecosystem ,0105 earth and related environmental sciences ,040101 forestry ,Wildfire suppression ,Fire regime ,Fire Suppression Technology ,Ecology and Environmental Sciences ,lcsh:R ,Models, Theoretical ,Fire Engineering ,Boreal ,Greenhouse gas ,Firefighters ,Random Walk ,North America ,Earth Sciences ,0401 agriculture, forestry, and fisheries ,Environmental science ,lcsh:Q ,Physical geography ,People and places - Abstract
Climate-influenced changes in fire regimes in northern temperate and boreal regions will have both ecological and economic ramifications. We examine possible future wildfire area burned and suppression costs using a recently compiled historical (i.e., 1980–2009) fire management cost database for Canada and several Intergovernmental Panel on Climate Change (IPCC) climate projections. Area burned was modelled as a function of a climate moisture index (CMI), and fire suppression costs then estimated as a function of area burned. Future estimates of area burned were generated from projections of the CMI under two emissions pathways for four General Circulation Models (GCMs); these estimates were constrained to ecologically reasonable values by incorporating a minimum fire return interval of 20 years. Total average annual national fire management costs are projected to increase to just under $1 billion (a 60% real increase from the 1980–2009 period) under the low greenhouse gas emissions pathway and $1.4 billion (119% real increase from the base period) under the high emissions pathway by the end of the century. For many provinces, annual costs that are currently considered extreme (i.e., occur once every ten years) are projected to become commonplace (i.e., occur once every two years or more often) as the century progresses. It is highly likely that evaluations of current wildland fire management paradigms will be necessary to avoid drastic and untenable cost increases as the century progresses.
- Published
- 2016
25. The discovery of new spirocyclic muscarinic M3 antagonists
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David Donald, Lilian Alcaraz, Daniel J. Warner, Nicholas Kindon, Andrew Bailey, Michael J. Stocks, Garry Pairaudeau, Keith Bowers, Jill Theaker, Fraser Hunt, and Helen Edwards
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Receptor, Muscarinic M3 ,Chemistry ,High-throughput screening ,Organic Chemistry ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Antagonist ,Pharmaceutical Science ,Muscarinic acetylcholine receptor M3 ,Biochemistry ,Chemical synthesis ,Rats ,Microsomes ,Drug Discovery ,Muscarinic acetylcholine receptor ,Hepatocytes ,Animals ,Humans ,Molecular Medicine ,Potency ,Spiro Compounds ,Molecular Biology ,Acetylcholine receptor - Abstract
The optimisation of a new series of high potency muscarinic M3 antagonists, derived from high throughput screening library hit is described.
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- 2010
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26. Reference equations for specific airway resistance in children: the Asthma UK initiative
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J, Kirkby, S, Stanojevic, L, Welsh, S, Lum, M, Badier, C, Beardsmore, A, Custovic, K, Nielsen, J, Paton, W, Tomalak, J, Stocks, and C, King
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Male ,Quality Control ,Pulmonary and Respiratory Medicine ,Research design ,Spirometry ,Pediatrics ,medicine.medical_specialty ,Prospective data ,Reference Values ,Environmental health ,medicine ,Humans ,Child ,Specific Airway Resistance ,Asthma ,Data collection ,medicine.diagnostic_test ,business.industry ,Airway Resistance ,Infant ,medicine.disease ,United Kingdom ,Respiratory Function Tests ,Plethysmography ,Reference data ,Treatment Outcome ,Research Design ,Lung disease ,Child, Preschool ,Female ,business - Abstract
Plethysmographic specific airway resistance (sR(aw)) is a useful research method for discriminating lung disease in young children. Its use in clinical management has, however, been limited by lack of consensus regarding equipment, methodology and reference data. The aim of our study was to collate reference data from healthy children (3-10 yrs), document methodological differences, explore the impact of these differences and construct reference equations from the collated dataset. Centres were approached to contribute sR(aw) data as part of the Asthma UK initiative. A random selection of pressure-flow plots were assessed for quality and site visits elucidated data collection and analysis protocols. Five centres contributed 2,872 measurements. Marked variation in methodology and analysis excluded two centres. sR(aw) over-read sheets were developed for quality control. Reference equations and recommendations for recording and reporting both specific effective and total airway resistance (sR(eff) and sR(tot), respectively) were developed for White European children from 1,908 measurements made under similar conditions. Reference sR(aw) data collected from a single centre may be misleading, as methodological differences exist between centres. These preliminary reference equations can only be applied under similar measurement conditions. Given the potential clinical usefulness of sR(aw), particularly with respect to sR(eff), methodological guidelines need to be established and used in prospective data collection.
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- 2010
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27. The EPICure study: maximal exercise and physical activity in school children born extremely preterm
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Liam, Welsh, Jane, Kirkby, Sooky, Lum, Dolf, Odendaal, Neil, Marlow, Graham, Derrick, Janet, Stocks, and J, Stocks
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Male ,Pulmonary and Respiratory Medicine ,Spirometry ,Pediatrics ,medicine.medical_specialty ,Physical exercise ,Motor Activity ,Pulmonary function testing ,Oxygen Consumption ,Internal medicine ,medicine ,Humans ,Plethysmograph ,Lung volumes ,Exercise physiology ,Child ,Exercise ,Anthropometry ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,medicine.disease ,Respiratory Function Tests ,Bronchopulmonary dysplasia ,Infant, Extremely Low Birth Weight ,Exercise Test ,Respiratory Mechanics ,Breathing ,Cardiology ,Female ,business ,Infant, Premature ,Follow-Up Studies - Abstract
Rationale Evidence regarding exercise capacity and physical activity in children born extremely preterm (EP) is limited. Since survivors remain at high risk for developing bronchopulmonary dysplasia (BPD) and longterm pulmonary sequelae, reductions in exercise capacity and activity levels may be present. Objectives To compare maximal exercise ventilation characteristics and physical activity levels at 11 years of age in children born EP (
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- 2009
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28. Antagonists of the P2X7 Receptor. From Lead Identification to Drug Development
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Lilian Alcaraz, Timothy Nicholas Birkinshaw, Michael J. Stocks, Mark Ebden, Keith Bowers, Simon Guile, and Mark Furber
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Azoles ,Drug ,Chemistry ,Drug discovery ,media_common.quotation_subject ,Amidines ,Pharmacology ,Amides ,Arthritis, Rheumatoid ,Structure-Activity Relationship ,Drug development ,Drug Discovery ,Purinergic P2 Receptor Antagonists ,Animals ,Humans ,Molecular Medicine ,Identification (biology) ,Receptors, Purinergic P2X7 ,Receptor ,media_common - Published
- 2009
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29. Wireless capsule endoscopy in the investigation of intestinal Behcet's syndrome
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S. Ghosh, J. Stocks, Dorian O. Haskard, Shahir S. Hamdulay, Chandradipa Ghosh, and K. Cheent
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Adult ,Male ,medicine.medical_specialty ,Abdominal pain ,Colonoscopy ,Capsule Endoscopy ,Gastroenterology ,law.invention ,Rheumatology ,Duodenitis ,Capsule endoscopy ,law ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Ileitis ,Colitis ,Ulcer ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Behcet Syndrome ,Middle Aged ,medicine.disease ,Endoscopy ,Intestinal Diseases ,Defecation ,Female ,medicine.symptom ,business ,Immunosuppressive Agents - Abstract
Objective Intestinal Behcet's Syndrome (BS) is a difficult diagnosis to establish. We describe the use of wireless capsule endoscopy (WCE) in the investigation of 11 patients with suspected intestinal BS. Methods Out of 11 patients, 10 with suspected intestinal BS were found to have small intestinal ulcers on capsule endoscopy. Each case was retrospectively assessed for symptoms, signs, anaemia, other investigations, treatment and complications. Results All 11 patients had established diagnoses of BS as defined by the International Study Group criteria. Central abdominal pain and change in bowel habit were the predominant symptoms, both occurring in seven patients. Upper gastrointestinal (GI) endoscopy and colonoscopy identified duodenitis, ileitis and colitis in three patients. Barium studies and CT were normal in all cases. WCE revealed small intestinal ulcers throughout the ileum in five patients and ulcers located either in the proximal and/or distal ileum in five other patients. One patient had significant symptoms, signs and ulcers leading to a change in treatment to infliximab, and this resulted in resolution of symptoms and ulcers. Ten age- and sex-matched controls investigated for unexplained GI symptoms had no intestinal lesions on capsule endoscopy. Conclusion WCE is useful in the investigation of GI symptoms in BS. It is particularly helpful in those patients in whom conventional investigations have been normal or fail to account for symptoms and signs. This technique may guide treatment and provide a better understanding of intestinal pathology in BS.
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- 2008
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30. Limitations of electronic compensation for measuring plethysmographic airway resistance in infants
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Georg Hülskamp, Padmaja Subbarao, and J Stocks
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Male ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Cystic Fibrosis ,Coefficient of variation ,Cystic fibrosis ,Airway resistance ,Reference Values ,Internal medicine ,medicine ,Humans ,Plethysmograph ,Lung ,business.industry ,Airway Resistance ,Respiratory disease ,Infant ,Liter ,medicine.disease ,Surgery ,Plethysmography ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,Cardiology ,Female ,Artifacts ,Airway ,business - Abstract
Electronic compensation to overcome thermal artifacts during plethysmographic estimations of airway resistance is now used routinely in adults and school-age children, and was shown to be a valuable means of discriminating airway function between preschool children with and without lung disease. A similar system is now commercially available for infants, which could increase the applicability of this technique. However, we noted marked discrepancies in electronically calculated values of airway resistance in this age group, both with respect to absolute values displayed and marked within-subject variability on a single test occasion. The aim of this technical report is to summarize our recent findings in order to alert other users to potential problems. Airway resistance (R(aw)) was measured in 62 infants (28 with cystic fibrosis (CF); 34 healthy). Three to five epochs of quiet regular tidal breathing were collected in each infant. Marked within-subject, within-test variability was observed, with the median coefficient of variation (CV) being 9.1% (range, 1.2-52.6%) within and 8.5% (0.1-112%) between epochs. Among healthy infants, R(aw) varied from 0.1-6.4 (kPa x liter(-1) x sec), with no relationship to either body or lung size and complete overlap of results with those from infants with CF, despite abnormal lung function in the latter when assessed by other means. The marked within- and between-subject variability in healthy infants, and lack of discriminative power of R(aw) when derived from electronically compensated values, currently preclude application in either clinical or research studies.
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- 2005
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31. Effect of raised lung volume technique on subsequent measures of V?maxFRC in infants
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Sooky Lum, J Stocks, Ah-Fong Hoo, H. Ljungberg, and Georg Hülskamp
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Male ,Pulmonary and Respiratory Medicine ,Functional Residual Capacity ,Respiratory rate ,Vital Capacity ,Respiratory physiology ,Pulmonary function testing ,Functional residual capacity ,Forced Expiratory Volume ,Humans ,Medicine ,Lung volumes ,Prospective Studies ,Lung ,Tidal volume ,business.industry ,Respiratory disease ,Infant ,medicine.disease ,Respiratory Function Tests ,medicine.anatomical_structure ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Respiratory Mechanics ,Female ,Lung Volume Measurements ,business - Abstract
Partial and "full" forced expiratory maneuvers are both used to assess airway function in infants. Despite the increasing use of the raised volume technique, there is little information regarding the influence of lung inflations as are necessary for the raised volume technique on other measurements of lung function in infants. The aim of this study was to assess whether application of the raised volume technique influences subsequent tidal measurements of maximal expired flow at functional residual capacity (V'maxFRC). Paired measurements of V'maxFRC were obtained in 29 healthy infants (aged 6-65 weeks) before and after raised volume maneuvers, wherein a lung inflation pressure of 3 kPa was used. When compared with measurements prior to raising lung volume, there was a highly significant (P < 0.001) decrease in V'maxFRC by 40 ml.sec(-1) when measurements were repeated (95% CI, -59, -20 ml.sec(-1)), equivalent to a reduction of 20% or -0.6 SD scores in flows. There was no significant change in selected tidal breathing parameters, 95% CI of differences between the two sets of measurements being -1.5, 1.2 bpm for respiratory rate; -0.5, 0.2 ml.kg(-1) for weight corrected tidal volume, and -0.04, 0.01 for tidal breathing ratio (tPTEF:tE). In conclusion, although the mechanism remains unclear, raised volume maneuvers may influence subsequent measures of lung function in infants. Further research is needed to clarify the potential mechanisms. In the meantime, the potential impact of the order of lung function tests within any given study protocol should be considered carefully.
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- 2004
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32. Effect of airway inflation pressure on forced expiratory maneuvers from raised lung volume in infants
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Sooky Lum, Ah-Fong Hoo, and J Stocks
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Male ,Pulmonary and Respiratory Medicine ,Spirometry ,Vital capacity ,Vital Capacity ,Pulmonary function testing ,FEV1/FVC ratio ,Forced Expiratory Volume ,Pressure ,medicine ,Humans ,Lung volumes ,Respiratory system ,Lung ,medicine.diagnostic_test ,business.industry ,Infant, Newborn ,Infant ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Forced expiration ,Female ,Lung Volume Measurements ,Airway ,business - Abstract
The raised lung volume technique is increasingly used to measure forced expiratory maneuvers in infants. However, there is no consensus regarding the optimal airway inflation pressure (Pinf) required for such maneuvers, or the influence of small changes in Pinf within and between infants. The aim of this study was to assess the effect of small differences (0.2–0.3 kPa) in Pinf on forced vital capacity (FVC), forced expired volume in 0.5 sec (FEV0.5), and forced expired flow at 75% of vital capacity (FEF75), all derived from the raised volume rapid thoraco-abdominal compression (RVRTC) technique. Randomized paired forced expiratory maneuvers were obtained in 32 healthy infants ( 3.9–39.3 weeks old, 3.8–9.9 kg) with the safety pressure relief valve for Pinf set to 2.7 kPa or 3.0 kPa (27 or 30 cm H20). When mean (SD) Pinf was increased by 8.4 (2.8)%, there was a significant (P
- Published
- 2002
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33. Assessment of an infant whole-body plethysmograph using an infant lung function model
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B Reinmann, J Stocks, and Urs Frey
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Quality Control ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Lung ,business.industry ,Airway Resistance ,Infant, Newborn ,Infant ,Whole-body plethysmograph ,respiratory system ,Models, Biological ,Respiratory Function Tests ,Pulmonary function testing ,Airway resistance ,medicine.anatomical_structure ,Tidal Volume ,Humans ,Medicine ,Plethysmograph ,Lung volumes ,business ,Intensive care medicine ,Lung function ,Tidal volume ,Plethysmography, Whole Body - Abstract
In order to facilitate international multicentre studies and improve the quality control of infant pulmonary function measurements, the European Respiratory Society-American Thoracic Society Task Force for infant lung function testing has recently developed specifications for standardized infant lung function equipment and software. A mechanical infant lung model analogue has been developed to assess whether infant lung function equipment is able to meet these requirements. However, the practical testing of infant lung function equipment using such models is highly complex because of the need to use very small pressure and flow changes, and the numerous potentially confounding factors associated with both the design of the device and the testing procedure.The aim of this study was to determine whether the infant lung model is capable of assessing the overall function of an whole-body infant- plethysmograph, using the only infant plethysmograph that was commercially available at the time as an example.The mechanical characteristics of the model such as vibrations or noise did not disturb the delicate plethysmographic measurements and thereby allowed a reliable assessment of the system. A series of tests revealed that the plethysmograph was able to measure airway resistance 1–3.5 kPa·L−1·s with an accuracy of ±2.5% and lung volumes 75–300 mL with an accuracy of ±2.5% underin vitroconditions.To conclude, the infant lung model is a useful means of assessing the overallin vitroperformance of infant whole-body plethysmographs, but thermal, mechanical and frequency response characteristics of such a device must be taken into account when interpreting the results of such assessments.
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- 2001
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34. The infant lung function model: a mechanical analogue to test infant lung function equipment
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J Stocks, B Reinmann, and Urs Frey
- Subjects
Quality Control ,Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,Frequency response ,Models, Biological ,Pulmonary function testing ,law.invention ,Reference Values ,law ,Tidal Volume ,medicine ,Range (statistics) ,Humans ,Plethysmograph ,Lung volumes ,Lung ,business.industry ,Airway Resistance ,Infant, Newborn ,Time constant ,Infant ,Equipment Design ,Models, Theoretical ,Respiratory Function Tests ,Surgery ,medicine.anatomical_structure ,Resistor ,Pulmonary Ventilation ,business ,Biomedical engineering - Abstract
To facilitate international multicentre studies and quality control of infant pulmonary function measurements, the European Respiratory Society-American Thoracic Society (ERS-ATS) working group for infant lung function testing aims to develop specifications for standardized infant lung function equipment and software. However, a standardized test device is also needed to test whether existing infant lung function equipment is able to meet these requirements.The authors have built a “mechanical model baby” consisting of a linear pump which can reproduce prerecorded tidal flow waveforms with a precision of 0.5% (full stroke), enabling the simulation of tidal and forced flow patterns. This linear pump can be connected to a series of copper lung volumes (range 50–300 mL) with known time constants, so that lung volumes can be reproduced with a precision of ±1% at frequencies 10–120 bpm. Five airflow resistors were built using sinter material.When assessed using flows 0–300 mL·s−1all resistors showed a quasilinear pressure/flow relationship, with slopes 1.0–5.6 kPa·L−1·s. These resistances could be reproduced with a precision of ±2.5%. The infant lung model can also be used to assess frequency responses of infant lung function equipment, since the pump is capable of delivering low amplitude volumes up to 20 Hz in a pseudorandom noise manner.In summary, based on error estimations, this infant lung model is able to test whether or not infant lung function equipment meets the requirements suggested by the European Respiratory Society-American Thoracic Society standardization group, that is: flow measurements within ±2.5%, volume and resistance measurements within ±5%, frequency response: magnitude attenuation
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- 2001
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35. Influence of volume dependency and timing of airway occlusions on the Hering-Breuer reflex in infants
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J Stocks and Patricia S. Rabbette
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Male ,Time Factors ,Physiology ,Respiratory physiology ,Feedback ,Pulmonary stretch receptors ,Physiology (medical) ,Reflex ,Humans ,Medicine ,Lung volumes ,Respiratory system ,Hering–Breuer reflex ,business.industry ,Age Factors ,Infant, Newborn ,Infant ,Vagus Nerve ,Respiratory Function Tests ,Pulmonary Stretch Receptors ,Control of respiration ,Anesthesia ,Respiratory Mechanics ,Respiratory Physiological Phenomena ,Breathing ,Female ,Lung Volume Measurements ,business - Abstract
Both end-inspiratory (EIO) and end-expiratory (EEO) airway occlusions are used to calculate the strength of the Hering-Breuer inflation reflex (HBIR) in infants. However, the influence of the timing of such occlusions is unknown, as is the extent to which changes in volume within and above the tidal range affect this reflex. The purpose of this study was to compare both techniques and to evaluate the volume dependency of the HBIR in healthy, sleeping infants up to 1 yr of age. The strength of the HBIR was expressed as the ratio of expiratory or inspiratory time during EIO or EEO, respectively, to that recorded during spontaneous breathing, i.e., as the "inhibitory ratio" (IR). Paired measurements of the EIO and EEO in 26 naturally sleeping newborn and 15 lightly sedated infants at approximately 1 yr showed no statistically significant differences in the IR according to technique: mean (95% CI) of the difference (EIO - EEO) being -0.02 (-0.17, 0.13) during the first week of life and 0.04 (-0.14, 0.22) at 1 yr. During tidal breathing, a volume threshold of approximately 4 ml/kg was required to evoke the HBIR. Marked volume and age dependency were observed. In newborn infants, occlusions at approximately 10 ml/kg during sighs always resulted in an IR > 4, whereas a similar response was only evoked at 25 ml/kg in older infants. Age-related changes in the volume threshold may reflect maturational changes in the control of breathing and respiratory mechanics throughout the first year of life.
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- 1998
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36. Effect of neck rotation on the timing and pattern of infant tidal breathing
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Jenny Downs and J. Stocks
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Pulmonary and Respiratory Medicine ,Expiratory Time ,Rotation ,Respiratory rate ,business.industry ,Respiration ,Posture ,Infant ,Reproducibility of Results ,Neck rotation ,Degree (temperature) ,Anesthesia ,Pediatrics, Perinatology and Child Health ,Tidal Volume ,Humans ,Medicine ,Plethysmograph ,Lung volumes ,business ,Neck ,Tidal volume - Abstract
While neck flexion and extension are known to influence the patency of the upper airway, far less information is available regarding the effects of neck rotation. The effect of neck rotation on respiratory rate (RR), expiratory time (tE), and phase angle (phi) was assessed in 17 healthy infants aged between 1 and 4 months. An inclinometer was used to measure neck rotation and uncalibrated Respiratory inductive Plethysmography to measure the dependent variables while the infants were in natural, quiet sleep. Baseline measurements were made with the head positioned centrally (0 degree rotation); further measurement positions included 30 degrees, 60 degrees, 90 degrees rotation, and repeat measurement at 0 degree (0r degree) in randomized order. Mean RR, tE, and phi were determined for each infant in each position. Using the paired t-test, RR at 0 degree rotation was significantly higher than that at 0r degree rotation (mean difference, 5 bpm; 95% CI, 2.1, 8.1; P = 0.0023); mean tE at 0 degree rotation was significantly shorter than at 0r degree rotation (mean difference, -0.18s; 95% CI, -0.27, -0.07; P = 0.002); whereas phi remained similar (mean difference, 10 degrees; 95% CI, -2.2, 22.3; P = 0.10. These changes probably reflect the slowing of metabolism that occurs after the onset of quiet sleep, and they emphasize the importance of randomization. Measurements at 0r degree were randomized and hence were most likely to reflect the true basal condition of the infant with the head in a neutral position. Consequently, these data, rather than those collected at 0 degree at the onset of quiet sleep, were used for comparisons with all subsequent positional changes. When comparing the positions whose order was randomized, neck rotation did not significantly affect RR (P = 0.445), tE (P = 0.272), or phi (P = 0.169). However, two infants demonstrated marked changes in respiratory pattern with decreases in RR and increases in tE at 90 degrees rotation, suggesting that some infants may be susceptible to obstruction in this position.
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- 1995
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37. Respiratory function measurements in infants: symbols, abbreviations and units
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P H, Quanjer, P D, Sly, and J, Stocks
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Pulmonary and Respiratory Medicine ,International System of Units ,Humans ,Infant ,Respiratory Function Tests - Published
- 1995
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38. Respiratory function measurements in infants: symbols, abbreviations, and units. American Thoracic Society/European Respiratory Society
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Peter D. Sly, J. Stocks, and P. Quanjer
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Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,business.industry ,Infant, Newborn ,Infant ,Critical Care and Intensive Care Medicine ,United States ,Respiratory Function Tests ,Europe ,International System of Units ,medicine ,Humans ,Respiratory function ,Abbreviations as Topic ,business ,Societies, Medical - Published
- 1995
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39. Comparison of single-breath and plethysmographic measurements of resistance in infancy
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E. Jackson, J. Stocks, I. Dundas, Margaret Fletcher, and Carol Dezateux
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Pulmonary and Respiratory Medicine ,medicine.medical_specialty ,business.industry ,Airway Resistance ,Infant, Newborn ,Infant ,Single breath ,Critical Care and Intensive Care Medicine ,Gastroenterology ,Mean difference ,Respiratory Function Tests ,Surgery ,Plethysmography ,Airway resistance ,Internal medicine ,Wheeze ,medicine ,Humans ,Plethysmograph ,medicine.symptom ,Lung Volume Measurements ,business ,Lung Compliance ,Normal range ,Respiratory Sounds - Abstract
Single-breath technique (SBT) measurements of total respiratory resistance (Rrs) were compared with plethysmographic measurements of airway resistance (Raw) in healthy infantsor = 13 wk of age (Group 1; n = 49) and13 wk of age (Group 2; n = 37) and in infants13 wk of age with prior wheeze (Group 3; n = 49). A significantly higher percentage of Rrs (19%) than of Raw (2%) measurements were technically unsatisfactory, alinearity of the flow-volume curve accounting for 54% of Rrs failures. Although both Rrs and Raw were significantly higher in Group 3 infants, between-subject variability was wide in all groups. Rrs was significantly higher than initial expiratory (IE) Raw in all groups. Mean difference Rrs-IE Raw (95% CI) values were 1.98 (1.51, 2.48), 1.29 (0.96, 1.62), and 1.97 (1.56, 2.38) kPa.L-1.s for Groups 1, 2, and 3, respectively. Significant but smaller differences were seen for end-expiratory (EE) Raw in Groups 1 and 2 but not in Group 3. Mean difference Rrs-EE Raw (95% CI) values were 0.68 (0.11, 1.26), 0.55 (0.19, 0.92), and 0.31 (-0.06, 0.69) kPa.L-1.s for Groups 1, 2, and 3, respectively. Despite wide between-subject variability in Rrs and a relatively high failure rate, the SBT is simple to use, and it may be applicable to epidemiologic studies. However, clinical applications in individual infants may be limited by failure to detect the dynamic changes in resistance throughout the breath evident from plethysmographic studies.
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- 1995
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40. From libraries to candidate: the discovery of new ultra long-acting dibasic β₂-adrenoceptor agonists
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Lilian, Alcaraz, Andrew, Bailey, Elaine, Cadogan, Stephen, Connolly, Robert, Jewell, Stephen, Jordan, Nicholas, Kindon, Andrew, Lister, Mandy, Lawson, Alexander, Mullen, Ian, Dainty, David, Nicholls, Stuart, Paine, Garry, Pairaudeau, Michael J, Stocks, Phillip, Thorne, and Alan, Young
- Subjects
Time Factors ,Chemistry, Pharmaceutical ,Guinea Pigs ,Adrenergic beta-Agonists ,Asthma ,Bronchodilator Agents ,Inhibitory Concentration 50 ,Pulmonary Disease, Chronic Obstructive ,Thiazoles ,Models, Chemical ,Cell Line, Tumor ,Drug Design ,Cyclic AMP ,Animals ,Humans ,Protein Binding - Abstract
Libraries of dibasic compounds designed around the molecular scaffold of the DA(2)/β(2) dual agonist sibenadet (Viozan™) have yielded a number of promising starting points that have been further optimised into novel potent and selective target molecules with required pharmacokinetic properties. From a shortlist, 31 was discovered as a novel, high potency, and highly efficacious β(2)-agonist with high selectivity and a duration of action commensurable with once daily dosing.
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- 2011
41. Design driven HtL: The discovery and synthesis of new high efficacy β₂-agonists
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Michael J, Stocks, Lilian, Alcaraz, Andrew, Bailey, Roger, Bonnert, Elaine, Cadogan, Jadeen, Christie, Stephen, Connolly, Anthony, Cook, Adrian, Fisher, Alice, Flaherty, Stephen, Hill, Alexander, Humphries, Anthony, Ingall, Stephen, Jordan, Mandy, Lawson, Alex, Mullen, David, Nicholls, Stuart, Paine, Garry, Pairaudeau, Stephen, St-Gallay, and Alan, Young
- Subjects
Models, Molecular ,Structure-Activity Relationship ,Molecular Structure ,Drug Design ,Animals ,Humans ,Bronchi ,Crystallography, X-Ray ,Adrenergic beta-2 Receptor Agonists ,Cell Line - Abstract
The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.
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- 2011
42. Assessment of passive respiratory compliance in healthy preterm infants: A critical evaluation
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P. S. Rabbette, J. Stocks, M. Gappa, and Kate Costeloe
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Male ,Pulmonary and Respiratory Medicine ,Pediatrics ,medicine.medical_specialty ,business.industry ,Infant, Newborn ,Gestational age ,Respiratory physiology ,Pulmonary compliance ,Respiratory Function Tests ,Reference Values ,Reference values ,Intensive care ,Pediatrics, Perinatology and Child Health ,Occlusion ,Humans ,Medicine ,Female ,Respiratory system ,business ,Lung Compliance ,Infant, Premature ,Lung function - Abstract
The airway occlusion techniques for assessing passive respiratory mechanics have become well established methods in fullterm neonates and older infants. The single breath technique (SBT) is frequently used for assessing lung function in intubated infants on neonatal intensive care units. However, less is known about the reliability of these quick and noninvasive techniques in healthy preterm infants. The aim of this study was to evaluate these methods in healthy unintubated preterm infants to facilitate both establishment of reference values and more meaningful interpretation of lung function assessments in the neonatal unit. Forty-seven studies were attempted in 31 healthy preterm infants (gestational age 29–36 weeks; body weight 1.88 ± 0.28 kg; mean ± SD) during the first 2 weeks of life, using both the multiple occlusion technique (MOT) and the SBT. Whereas technically acceptable respiratory system compliance (Crs) data from either the MOT or the SBT were obtained on 37 occasions in 25 infants, satisfactory results from both techniques were achieved only on 22 occasions. In these infants mean ± SD Crs was 28.1± 5.2 mL kPa−1 when assessed by MOT and 29.1± 5 6.0 mL kPa−1 when using the SBT. The mean difference between technically satisfactory paired Crs values obtained with MOT and SBT was less than 5% (range, +28 to −18%). By contrast, in infants in whom data were invalidated as a result of expiratory airflow braking, failure to relax or instability of the end-expiratory level, gross discrepancies occurred between the techniques. In conclusion, assessment of passive respiratory compliance is feasible in healthy, unintubated preterm infants, but strict criteria for quality control should be applied to avoid gross errors in the results. Ideally, passive respiratory mechanics should be assessed using both MOT and SBT in order to increase confidence in the reported results. © 1993 Wiley-Liss, Inc.
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- 1993
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43. Changes in the FEV₁/FVC ratio during childhood and adolescence: an intercontinental study
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P H, Quanjer, S, Stanojevic, J, Stocks, G L, Hall, K V V, Prasad, T J, Cole, M, Rosenthal, R, Perez-Padilla, J L, Hankinson, E, Falaschetti, M, Golshan, B, Brunekreef, O, Al-Rawas, J, Kühr, Y, Trabelsi, M S M, Ip, and J D, Zheng
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Male ,Young Adult ,Child Development ,Adolescent ,Child, Preschool ,Forced Expiratory Volume ,Vital Capacity ,Humans ,Female ,Adolescent Development ,Child ,Lung - Abstract
In children, the ratio of forced expiratory volume in 1 s (FEV₁) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV₁/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV₁, leading to falls in FEV₁/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV₁/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV₁/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.
- Published
- 2010
44. The use of the birthing pool after a diagnosis of stillbirth
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Alexander E. P. Heazell, E. A. Martindale, J S Rowland, and L P J Stocks
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Pregnancy ,medicine.medical_specialty ,Fetal death ,business.industry ,Obstetrics ,Pain relief ,MEDLINE ,Obstetrics and Gynecology ,Baths ,Stillbirth ,medicine.disease ,Medicine ,Humans ,Female ,Analgesia ,business ,Fetal Death ,reproductive and urinary physiology - Abstract
The use of the birthing pool to provide pain relief for labour in low risk pregnancies is being increasingly provided for in UK maternity units (RCM/RCOG 2006). Reported benefits of labour in water...
- Published
- 2010
45. Respiratory compliance during sedation, anesthesia, and paralysis in infants and young children
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C. Stack, Cristyn Davies, D. J. Hatch, J. Stocks, M. Ewart, M. E. Fletcher, and S. Ridley
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Physiology ,Sedation ,medicine.medical_treatment ,Pulmonary compliance ,law.invention ,law ,Physiology (medical) ,Occlusion ,Tidal Volume ,otorhinolaryngologic diseases ,Paralysis ,medicine ,Humans ,Hypnotics and Sedatives ,Anesthesia ,Lung Compliance ,Tidal volume ,Mechanical ventilation ,business.industry ,Infant ,respiratory system ,Respiration, Artificial ,Child, Preschool ,Ventilation (architecture) ,medicine.symptom ,Halothane ,business ,medicine.drug - Abstract
Although total respiratory compliance (Crs) has been shown to fall in adults on induction of halothane anesthesia, no successful paired studies have been reported in children. The multiple occlusion technique was used to measure Crs in 17 infants and young children during sedated sleep (CrsS) and shortly after, following induction of halothane anesthesia (CrsA). Crs fell in all but one infant after induction of anesthesia, with a mean fall of 34.7% (range 0-58%). This was accompanied by a reduction in tidal volume and increase in frequency in every case. In 7 of the 17 children, who were to be paralyzed for surgical purposes, Crs was also measured in this anesthetized-paralyzed state. When tidal volume administered during manual ventilation was similar to that observed during measurement of CrsA, Crs during this low-volume ventilation was similar to CrsA. When tidal volume was increased and Crs remeasured, there was a significant increase in every case, with the high-volume Crs within 10% of CrsS in all but one child, in whom there was a 31.4% increase with respect to CrsS. Changes in tidal volume accounted for approximately 50% of the variability in each state. These results demonstrate a highly significant fall in Crs in infants and young children after induction of halothane anesthesia. In addition it appears that this reduction in Crs can be reversed by paralyzing the child and manually ventilating with tidal volumes approximating those seen during sedation.
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- 1991
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46. The EPICure study: comparison of pediatric spirometry in community and laboratory settings
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J, Kirkby, L, Welsh, S, Lum, J, Fawke, V, Rowell, S, Thomas, N, Marlow, J, Stocks, and Heather, Palmer
- Subjects
Pulmonary and Respiratory Medicine ,Spirometry ,Lung Diseases ,Male ,medicine.medical_specialty ,Pediatrics ,Pulmonary function testing ,FEV1/FVC ratio ,Epidemiology ,medicine ,Humans ,Child ,Asthma ,COPD ,medicine.diagnostic_test ,business.industry ,Repeated measures design ,Reproducibility of Results ,respiratory system ,medicine.disease ,El Niño ,Pediatrics, Perinatology and Child Health ,Physical therapy ,Female ,business - Abstract
Rationale Accuracy of spirometry testing is a prerequisite for its use as an objective outcome measure in large epidemiological studies. We compared spirometry measurements obtained by trained pediatricians in a variety of school settings with those obtained in the laboratory by respiratory physiologists. Methods Following a 3-day training course, three pediatricians carried out spirometry in children born extremely preterm (EP) and age matched controls in schools across the UK and Ireland (The EPICure study). A subgroup had repeated measurements in the laboratory. Spirometric flows and volumes were expressed as Z-scores. Bland–Altman analysis was used to calculate within-subject differences. Results Fifty children (40% boys), 37 (74%) of whom were born EP, with a mean age 10.8 years had paired spirometry results (average interval between tests: 20.3 weeks). There was no statistically significant difference between any of the outcome variables: mean (95% CI of difference) in Z-scores [school–laboratory]) being 0.0 (−0.1; 0.1) for FEV1, 0.1 (−0.1; 0.3) for FVC, −0.1 (−0.3; 0.1) for FEF25–75, and 0.0 (−0.3; 0.1) for FEV1/FVC. Within individuals, the 95% limits of agreement for repeated measures were within ± 1 Z-score for FEV1 and FVC, and within ± 1.5 Z-score for FEF25–75 and FEV1/FVC. Conclusion With appropriate training, quality control, and support, pediatric spirometry can reliably be performed outside the lung function laboratory. Pediatr. Pulmonol. 2008; 43:1233–1241. © 2008 Wiley-Liss, Inc.
- Published
- 2008
47. Unexpected diminished innervation of epidermis and dermoepidermal junction in lichen amyloidosus
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Mohammad Reza Namazi, J. Stocks, D. Maruziva, Gil Yosipovitch, L.S. Samuel, Benjamin Maddison, J. Sanchez, and R. O. Pichardo
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Aging ,Adolescent ,Nerve fiber ,Dermatology ,Biology ,Stain ,Pathogenesis ,Nerve Fibers ,medicine ,Humans ,skin and connective tissue diseases ,Dermoepidermal junction ,Aged ,Neurodermatitis ,Skin ,integumentary system ,Epidermis (botany) ,Amyloidosis ,Papillary dermis ,Middle Aged ,medicine.disease ,stomatognathic diseases ,medicine.anatomical_structure ,Immunohistochemistry ,Female ,Epidermis ,Ubiquitin Thiolesterase ,Biomarkers - Abstract
Summary Background Lichen amyloidosus is a localized, chronic, pruritic skin disease characterized by deposition of amyloid in the papillary dermis. The pathogenesis of the pruritus of lichen amyloidosus is largely unknown. Objectives To determine any change in the nerve fibre density in lichen amyloidosus lesions as an explanation for itch. Methods Using an antibody to protein gene product (PGP) 9.5, the immunohistochemical analysis of the skin biopsies of 30 Hispanic patients with clinicopathologically proven lichen amyloidosus and of 11 healthy Hispanic controls matched for age, sex and site was performed. Results Unexpectedly, the mean amount of PGP9.5 stain, a measure for nerve fibre amount, for the healthy controls was higher than the lichen amyloidosus group both in the epidermis (P
- Published
- 2008
48. Changes in metabolism induced by oral contraceptives containing desogestrel and gestodene in older women
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Walli Bounds, S. J. Machin, T Burren, John Guillebaud, J Stocks, I. J. Mackie, and GE Robinson
- Subjects
Adult ,medicine.medical_specialty ,Apolipoprotein B ,Norpregnenes ,Lipoproteins ,Antithrombin III ,Fibrinogen ,Gestodene ,chemistry.chemical_compound ,High-density lipoprotein ,Desogestrel ,Internal medicine ,medicine ,Humans ,alpha-Macroglobulins ,Fibrinolysin ,Triglycerides ,biology ,business.industry ,Cholesterol ,Antithrombin ,Obstetrics and Gynecology ,Plasminogen ,Lipid metabolism ,Factor VII ,Middle Aged ,Lipid Metabolism ,Blood Coagulation Factors ,Contraceptives, Oral, Combined ,Apolipoproteins ,Endocrinology ,Reproductive Medicine ,chemistry ,Factor X ,biology.protein ,Female ,lipids (amino acids, peptides, and proteins) ,business ,Protein C ,medicine.drug - Abstract
Forty women aged 35-45 years were investigated to determine changes in haemostasis, lipids and lipoproteins whilst taking combined contraceptive pills containing the new third generation progestogens, desogestrel and gestodene. There was no statistically significant difference between the two preparations in any of the parameters studied. Women taking the combined pill showed increases in fibrinogen and factor X and a reduction in antithrombin III when compared with their control values. There were also small but significant increases in triglycerides and triglyceride-rich lipoproteins. Total high density lipoprotein cholesterol (HDL), high density lipoprotein-2 cholesterol (HDL2), high density lipoprotein-3 cholesterol (HDL3) and apolipoprotein A-1 were all increased at some stages of the treatment cycle, whereas low density lipoprotein cholesterol (LDL) showed a reduction in the first cycle of treatment. The changes in lipids and lipoproteins would not appear to increase the risk of cardiovascular disease, however the effects of the increase in the pro-coagulant factors are uncertain.
- Published
- 1990
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49. Frequency of cervical intraepithelial neoplasia following large loop excision of the transformation zone
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Philippa J Stocks, Clive A Gie, Clive J Pickles, Reginald Dixon, Fintan M Dowling, and GeoVrey Hulman
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Adult ,medicine.medical_specialty ,Adolescent ,Biopsy ,Urology ,Uterine Cervical Neoplasms ,urologic and male genital diseases ,Cervical intraepithelial neoplasia ,Pathology and Forensic Medicine ,Humans ,Medicine ,neoplasms ,Cervix ,Aged ,Retrospective Studies ,Colposcopy ,Intraepithelial neoplasia ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,virus diseases ,Retrospective cohort study ,General Medicine ,Middle Aged ,Uterine Cervical Dysplasia ,medicine.disease ,female genital diseases and pregnancy complications ,Surgery ,surgical procedures, operative ,medicine.anatomical_structure ,Cytopathology ,Female ,Neoplasm Recurrence, Local ,business ,Research Article ,Follow-Up Studies - Abstract
AIM: To determine the frequency of cervical intraepithelial neoplasia (CIN) following large loop excision of the transformation zone of the cervix (LLETZ) according to grade and completeness of excision of CIN. METHODS: A retrospective study of 669 patients who had LLETZ biopsies showing CIN 1, 2, or 3. The patients were subdivided according to the grade and completeness of excision of CIN. The follow up period was 1.5 to 3.5 years. Risk of persistent/recurrent CIN was assessed by the frequency of histological diagnosis of CIN during the follow up period. RESULTS: Frequency of persistent/recurrent CIN increased with the grade of CIN reported: 6.7% of patients with CIN 1, 13.4% with CIN 2, and 21.7% with CIN 3 developed persistence or recurrence. The frequency of CIN persistence/recurrence was significantly lower where LLETZ showed complete excision of CIN (8.4%) than where it was incomplete (31.3%) (p < 0.0001) or equivocal (27.8%) (p < 0.0001). CONCLUSIONS: Patients with incomplete or equivocal excision of all grades of CIN merit careful, preferably colposcopic, follow up. Patients with completely excised high grade CIN require careful cervical cytologic surveillance.
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- 1998
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50. Lung function tests in neonates and infants with chronic lung disease of infancy: functional residual capacity
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J. Jane Pillow, J Stocks, Georg Hülskamp, and Jürgen Dinger
- Subjects
Pulmonary and Respiratory Medicine ,Lung Diseases ,Quality Control ,medicine.medical_specialty ,Pulmonary compliance ,Pulmonary function testing ,Functional residual capacity ,Medicine ,Humans ,Lung volumes ,Intensive care medicine ,Bronchopulmonary Dysplasia ,Plethysmography, Whole Body ,Respiratory Distress Syndrome, Newborn ,business.industry ,Airway Resistance ,Respiratory disease ,Infant, Newborn ,Infant ,respiratory system ,Airway obstruction ,medicine.disease ,Nitrogen washout ,respiratory tract diseases ,Respiratory Function Tests ,Bronchopulmonary dysplasia ,Pediatrics, Perinatology and Child Health ,Chronic Disease ,business ,Lung Volume Measurements - Abstract
This is the second paper in a review series that will summarize available data and discuss the potential role of lung function testing in infants and young children with acute neonatal respiratory disorders and chronic lung disease of infancy. The current paper addresses the expansive subject of measurements of lung volume using plethysmography and gas dilution/washout techniques. Following orientation of the reader to the subject area, we focus our comments on areas of inquiry proposed in the introductory paper to this series. The quality of the published literature is reviewed critically, and recommendations are provided to guide future investigation in this field. Measurements of lung volume are important both for assessing growth and development of lungs in health and disease, and for interpreting volume-dependent lung function parameters such as respiratory compliance, resistance, forced expiratory flows, and indices of gas-mixing efficiency. Acute neonatal lung disease is characterized by severely reduced functional residual capacity (FRC), with treatments aimed at securing optimal lung recruitment. While FRC may remain reduced in established chronic lung disease of infancy, more commonly it becomes normalized or even elevated due to hyperinflation, with or without gas-trapping, secondary to airway obstruction. Ideally, accurate and reliable bedside measurements of FRC would be feasible from birth, throughout all phases of postnatal care (including assisted ventilation), and during subsequent long-term follow-up. Although lung volume measurements in extremely preterm infants were described in a research environment, resolution of several issues is required before such investigations can be translated into routine clinical monitoring.
- Published
- 2005
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