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1.
Acta Psychiatr Scand ; 138(6): 558-570, 2018 12.
Artículo en Inglés | MEDLINE | ID: mdl-30203454

RESUMEN

OBJECTIVE: An evidence-base is emerging indicating detrimental and beneficial effects of social media. Little is known about the impact of social media use on people who experience psychosis. METHOD: Forty-four participants with and without psychosis completed 1084 assessments of social media use, perceived social rank, mood, self-esteem and paranoia over a 6-day period using an experience sampling method (ESM). RESULTS: Social media use predicted low mood, but did not predict self-esteem and paranoia. Posting about feelings and venting on social media predicted low mood and self-esteem and high paranoia, whilst posting about daily activities predicted increases in positive affect and self-esteem and viewing social media newsfeeds predicted reductions in negative affect and paranoia. Perceptions of low social rank when using social media predicted low mood and self-esteem and high paranoia. The impact of social media use did not differ between participants with and without psychosis; although, experiencing psychosis moderated the relationship between venting and negative affect. Social media use frequency was lower in people with psychosis. CONCLUSION: Findings show the potential detrimental impact of social media use for people with and without psychosis. Despite few between-group differences, overall negative psychological consequences highlight the need to consider use in clinical practice.


Asunto(s)
Afecto , Trastornos Paranoides/psicología , Trastornos Psicóticos/psicología , Esquizofrenia , Autoimagen , Conducta Social , Medios de Comunicación Sociales , Adulto , Evaluación Ecológica Momentánea , Femenino , Jerarquia Social , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven
2.
J Periodontal Res ; 52(3): 628-635, 2017 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-28177132

RESUMEN

BACKGROUND: Migration of gingival fibroblasts/gingival mesenchymal stem cells through macro-perforated barrier membranes may allow them to participate positively in periodontal regeneration. The optimal guided tissue membrane perforation diameter that could favor maximum cell migration into the defect area and at the same time act as an occlusive barrier for gingival epithelium and its associated gingival extracellular matrix component is not yet identified. MATERIAL AND METHODS: Cultured human gingival fibroblasts/gingival mesenchymal stem cells were placed in the upper chambers of 12-well collagen-coated polytetrafluoroethylene transwells, which were manually perforated with 0.2, 0.4 and 0.7 mm sized pores. The lower chambers of the transwells received blood clot as an attraction medium. The number of cells that have migrated to the lower chambers was calculated. Proliferation of these cells was evaluated using MTT assay. Scanning electron microscopy images were obtained for the lower surfaces of the transwell membranes. Perforated bovine collagen membranes (Tutopatch® ) were subjected to mechanical testing to determine the tensile strength and modulus of elasticity. RESULTS: Group 3 (0.7 mm) showed significantly higher values for cell migration and proliferation. All groups showed a small degree of extracellular matrix migration through membrane perforations. Scanning electron microscopy evaluation revealed variable numbers of cells in fibrin matrices located mainly around the pore edges. There were non-significant differences between groups regarding mechanical properties. CONCLUSIONS: The present study demonstrated that macro-membrane perforations of 0.2, 0.4 and 0.7 mm are suitable pore diameters that could maintain membrane stiffness and allow for cellular migration. However, these membrane perforation diameters did not allow for total gingival connective tissue isolation.


Asunto(s)
Fibroblastos/citología , Encía/citología , Regeneración Tisular Guiada Periodontal , Células Madre Mesenquimatosas/citología , Adulto , Movimiento Celular , Proliferación Celular , Células Cultivadas , Fibroblastos/fisiología , Encía/fisiología , Regeneración Tisular Guiada Periodontal/métodos , Humanos , Membranas Artificiales , Células Madre Mesenquimatosas/fisiología , Microscopía Electrónica de Rastreo , Adulto Joven
3.
BMC Public Health ; 17(1): 76, 2017 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-28086764

RESUMEN

BACKGROUND: The Internet is increasingly a source of health information for parents, who use the Internet alongside health care providers for immunisation information. Concerns have been raised about the reliability of online immunisation information, however to date there has been no audit of the quality or quantity of what is available to Australian parents. The objective of this study was to address this gap by simulating a general online search for immunisation information, and assessing the quality and quantity of the web sites returned by the search. METHODS: We used Google trends to identify the most common immunisation search terms used in Australia. The ten most common terms were entered into five search engines and the first ten non-commercial results from each search collated. A quality assessment tool was developed using the World Health Organization Global Advisory Committee on Vaccine Safety (GACVS) criteria for assessing the quality of vaccine safety web sites, and used to assess and score the quality of the sites. RESULTS: Seven hundred web pages were identified, of which 514 were duplicates, leaving 186 pages from 115 web sites which were audited. Forty sites did not include human immunisation information, or presented personal opinion about individuals, and were not scored. Of the 75 sites quality scored, 65 (87%) were supportive of immunisation, while 10 (13%) were not supportive. The overall mean quality score was 57/100 (range 14/100 to 92/100). When stratified by pro and anti-vaccination stance, the average quality score for pro-vaccine sites was 61/100, while the average score for anti-vaccine sites was 30/100. Pro-vaccine information could be divided into three content groups: generalist overview with little detail; well-articulated and understandable detail; and lengthy and highly technical explanations. The main area found to be lacking in pro-vaccine sites was lack of transparent authorship. CONCLUSION: Our findings suggest a need for information which is easily found, transparently authored, well-referenced, and written in a way that is easily understood.


Asunto(s)
Exactitud de los Datos , Promoción de la Salud/métodos , Difusión de la Información/métodos , Internet , Padres/educación , Guías de Práctica Clínica como Asunto , Vacunación/normas , Australia , Humanos , Reproducibilidad de los Resultados
4.
Intern Med J ; 46(11): 1297-1306, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-27502031

RESUMEN

BACKGROUND: Cardiotoxicity resulting in heart failure is a devastating complication of cancer therapy. A patient may survive cancer only to develop heart failure (HF), which has a higher mortality rate than some cancers. AIM: This study aimed to describe the characteristics and outcomes of HF in patients with blood or breast cancer after chemotherapy treatment. METHODS: Queensland Cancer Registry, Death Registry and Hospital Administration records were linked (1996-2009). Patients were categorised as those with an index HF admission (that occurred after cancer diagnosis) and those without an index HF admission (non-HF). RESULTS: A total of 15 987 patients was included, and 1062 (6.6%) had an index HF admission. Median age of HF patients was 67 years (interquartile range 58-75) versus 54 years (interquartile range 44-64) for non-HF patients. More men than women developed HF (48.6% vs 29.5%), and a greater proportion in the HF group had haematological cancer (83.1%) compared with breast cancer (16.9%). After covariate adjustment, HF patients had increased mortality risk compared with non-HF patients (hazard ratios 1.67 (95% confidence interval, 1.54-1.81)), and 47% of the index HF admission occurred within 1 year from cancer diagnosis and 70% within 3 years. CONCLUSION: Cancer treatment may place patients at a greater risk of developing HF. The onset of HF occurred soon after chemotherapy, and those who developed HF had a greater mortality risk.


Asunto(s)
Neoplasias de la Mama/complicaciones , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/mortalidad , Neoplasias Hematológicas/complicaciones , Adulto , Anciano , Neoplasias de la Mama/terapia , Femenino , Neoplasias Hematológicas/terapia , Mortalidad Hospitalaria , Humanos , Masculino , Persona de Mediana Edad , Admisión del Paciente , Pronóstico , Queensland , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia
5.
Nutr Metab Cardiovasc Dis ; 21(11): 851-6, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20674311

RESUMEN

BACKGROUND AND AIMS: Flow-mediated dilatation of the brachial artery (FMD) is a biomarker of endothelial function and cardiovascular health. Impaired FMD is associated with several cardiovascular risk factors including hypertension and obesity. Various food ingredients such as polyphenols have been shown to improve FMD. We investigated whether consuming resveratrol, a polyphenol found in red wine, can enhance FMD acutely and whether there is a dose-response relationship for this effect. METHODS AND RESULTS: 19 overweight/obese (BMI 25-35 kg m(-2)) men or post-menopausal women with untreated borderline hypertension (systolic BP: 130-160 mmHg or diastolic BP: 85-100 mmHg) consumed three doses of resveratrol (resVida™ 30, 90 and 270 mg) and a placebo at weekly intervals in a double-blind, randomized crossover comparison. One hour after consumption of the supplement, plasma resveratrol and FMD were measured. Data were analyzed by linear regression versus log(10) dose of resveratrol. 14 men and 5 women (age 55 ± 2 years, BMI 28.7 ± 0.5 kg m(-2), BP 141 ± 2/89 ± 1 mmHg) completed this study. There was a significant dose effect of resveratrol on plasma resveratrol concentration (P < 0.001) and on FMD (P < 0.01), which increased from 4.1 ± 0.8% (placebo) to 7.7 ± 1.5% after 270 mg resveratrol. FMD was also linearly related to log(10) plasma resveratrol concentration (P < 0.01). CONCLUSION: Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine.


Asunto(s)
Hipertensión/fisiopatología , Obesidad/fisiopatología , Sobrepeso/fisiopatología , Estilbenos/administración & dosificación , Vasodilatación/efectos de los fármacos , Arteria Braquial , Enfermedades Cardiovasculares/prevención & control , Estudios Cruzados , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Endotelio Vascular/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Placebos , Resveratrol , Factores de Riesgo , Estilbenos/sangre
6.
Euro Surveill ; 16(2)2011 Jan 13.
Artículo en Inglés | MEDLINE | ID: mdl-21251486

RESUMEN

There is uncertainty whether the 2009 seasonal influenza vaccination influences the risk of infection with the 2009 pandemic influenza A(H1N1) virus. This issue was investigated in 548 healthcare workers from Capital and Coast District Health Board, Wellington, New Zealand, presenting with influenza-like illness during the influenza pandemic between June and August 2009. All workers completed an assessment sheet and had a nasopharyngeal swab tested by real-time RT-PCR. The risk of pandemic influenza A(H1N1) infection associated with the 2009 seasonal inactivated trivalent influenza vaccine was determined by logistic regression, with adjustment for potential confounding variables. In 96 workers pandemic influenza A(H1N1) RNA was detected and 452 tested negative. The multivariate analysis did not show any effect of vaccination on PCR-confirmed influenza A(H1N1)2009 infection (odds ratio 1.2, 95% confidence interval 0.7­1.9, p=0.48). We conclude that 2009 seasonal influenza vaccination had no protective effect against influenza A(H1N1)2009 infection amongst healthcare workers. To protect against further waves of the current pandemic influenza or future pandemics in which the influenza virus is antigenically distinct from contemporary seasonal influenza viruses, it would be necessary to vaccinate with a specific pandemic influenza vaccine, or a seasonal influenza vaccine that includes the pandemic influenza serotype.


Asunto(s)
Personal de Salud , Subtipo H1N1 del Virus de la Influenza A , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/prevención & control , Pandemias , Adulto , Femenino , Humanos , Vacunas contra la Influenza/inmunología , Gripe Humana/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Nueva Zelanda/epidemiología , Oportunidad Relativa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del Tratamiento , Vacunación/estadística & datos numéricos , Adulto Joven
7.
Int Immunopharmacol ; 100: 108044, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34601202

RESUMEN

BACKGROUND: The pharmacokinetics of Ig20Gly, a 20% subcutaneous immunoglobulin (IG) therapy, is well characterized in IG-experienced patients with primary immunodeficiency diseases (PID). Data from IG-naïve patients are limited. OBJECTIVE: Simulate serum total immunoglobulin G (IgG) pharmacokinetic profiles in IG-naïve patients with PID for different Ig20Gly initiation and maintenance dosing regimens. METHODS: A population pharmacokinetic model developed with data from pivotal phase 2/3 trials of weekly Ig20Gly in PID (NCT01412385, NCT01218438) was used to simulate pharmacokinetic profiles of IgG in various scenarios with 400- or 800-mg/kg total loading doses (administered as split doses over 1-2 weeks) and corresponding 100- or 200-mg/kg weekly maintenance doses, respectively. Endogenous baseline IgG levels (1.5, 2.0, 4.0, 6.0 g/L) were evaluated for each scenario; time to putative therapeutic target IgG trough level (7 g/L) was determined. RESULTS: Serum IgG levels reached steady-state by approximately Week 12 for all scenarios and baseline endogenous IgG levels. Time to target trough level generally occurred sooner with 1-week versus 2-week loading schemes. Endogenous baseline IgG levels <4 g/L required a 1-week 800-mg/kg total loading dose to achieve target levels within 2 weeks. Both maintenance regimens sustained serum IgG above target level. CONCLUSIONS: Simulations indicated IG-naïve patients with PID can achieve protective serum IgG levels within 1-3 weeks using appropriate Ig20Gly loading regimens. Patients with low endogenous IgG may benefit most from an 800-mg/kg/month loading dose. 400- or 800-mg/kg/month Ig20Gly maintenance regimens appeared adequate to maintain stable IgG levels. Serum IgG monitoring and clinical status can guide dosing parameters.


Asunto(s)
Inmunoglobulina G/administración & dosificación , Factores Inmunológicos/farmacocinética , Modelos Biológicos , Enfermedades de Inmunodeficiencia Primaria/tratamiento farmacológico , Adolescente , Adulto , Variación Biológica Poblacional , Niño , Preescolar , Simulación por Computador , Esquema de Medicación , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/sangre , Inyecciones Subcutáneas , Masculino , Enfermedades de Inmunodeficiencia Primaria/inmunología , Adulto Joven
8.
Clin Pharmacol Drug Dev ; 10(12): 1503-1513, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34310867

RESUMEN

JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross-reactivity to Escherichia coli-derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli-derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP-458 using serum asparaginase activity (SAA) data from a phase 1, single-dose study (JZP458-101) in healthy adults. Effects of intrinsic covariates (body weight, body surface area, age, sex, and race) on JZP-458 PK were evaluated. The model included SAA data from 24 healthy adult participants from the phase 1 study who received JZP-458: intramuscular (IM) data at 12.5 mg/m2 (N = 6) and 25 mg/m2 (N = 6), and intravenous (IV) data at 25 mg/m2 (N = 6) and 37.5 mg/m2 (N = 6). Model simulations of adult and pediatric SAA profiles were performed to explore the likelihood of achieving a therapeutic target nadir SAA (NSAA) level ≥0.1 IU/mL based on different administration strategies. PopPK modeling and simulation suggest JZP-458 is expected to achieve 72-hour NSAA levels ≥0.1 IU/mL in 100% of adult or pediatric populations receiving IM administration at 25 mg/m2 , and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m2 on a Monday/Wednesday/Friday (M/W/F) dosing schedule. Based on these results, the recommended starting dose for the phase 2/3 pivotal study is 25 mg/m2 IM or 37.5 mg/m2 IV on a M/W/F dosing schedule in pediatric and adult patients.


Asunto(s)
Antineoplásicos , Erwinia , Pseudomonas fluorescens , Adulto , Asparaginasa/efectos adversos , Niño , Escherichia coli , Humanos
9.
Tissue Antigens ; 76(3): 223-9, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20403147

RESUMEN

The restricted major histocompatibilty complex of Mauritian cynomolgus macaques confers exceptional potential on this species in human immunodeficiency virus (HIV) vaccine development. However, knowledge of the effects of Mhc genetics on commonly used simian immunodeficiency virus (SIV) and simian/human immunodeficiency virus (SHIV) stocks is incomplete. We determined the effect of Mhc haplotypes on SHIVsbg replication kinetics in a cohort of 25 naïve cynomolgus macaques. Haplotype M3 was associated with a 1.58log(10) reduction in viraemia at day 28 post infection (p.i.). Haplotype M6 was associated with elevated SHIVsbg viraemia at days 28 and 56. No significant effect of Mhc class II haplotypes on viral replication was observed. These data emphasise the importance of genetic characterisation of experimental macaques and advance our understanding of host genetic effects in SIV/SHIV models of HIV infection.


Asunto(s)
Genes MHC Clase I , Haplotipos/genética , Macaca fascicularis/genética , Macaca fascicularis/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Viremia/genética , Animales , Humanos , Mauricio , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Carga Viral , Replicación Viral
10.
Reprod Toxicol ; 93: 199-210, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32126282

RESUMEN

The framework for developmental toxicity testing has remained largely unchanged for over 50 years and although it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience. Advances in omics, in silico approaches and alternative assays are providing opportunities to enhance our understanding of embryo-fetal development and the prediction of potential risks associated with the use of medicines in pregnancy. A workshop organised by the Medicines and Healthcare products Regulatory Agency (MHRA), "Predicting the Safety of Medicines in Pregnancy - a New Era?", was attended by delegates representing regulatory authorities, academia, industry, patients, funding bodies and software developers to consider how to improve the quality of and access to nonclinical developmental toxicity data and how to use this data to better predict the safety of medicines in human pregnancy. The workshop delegates concluded that based on comparative data to date alternative methodologies are currently no more predictive than conventional methods and not qualified for use in regulatory submissions. To advance the development and qualification of alternative methodologies, there is a requirement for better coordinated multidisciplinary cross-sector interactions coupled with data sharing. Furthermore, a better understanding of human developmental biology and the incorporation of this knowledge into the development of alternative methodologies is essential to enhance the prediction of adverse outcomes for human development. The output of the workshop was a series of recommendations aimed at supporting multidisciplinary efforts to develop and validate these alternative methodologies.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Intercambio Materno-Fetal , Rutas de Resultados Adversos , Alternativas a las Pruebas en Animales , Animales , Evaluación Preclínica de Medicamentos , Control de Medicamentos y Narcóticos , Femenino , Humanos , Embarazo , Relación Estructura-Actividad Cuantitativa , Pruebas de Toxicidad
11.
Int Immunopharmacol ; 71: 404-410, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30952104

RESUMEN

BACKGROUND: Immunoglobulin (IG) replacement therapy in patients with primary immunodeficiency diseases (PID) can be administered daily to every 2 weeks subcutaneously (SCIG) or every 3 or 4 weeks intravenously (IVIG). OBJECTIVES: Develop a population pharmacokinetic (PK) model simulating IG exposure with Ig20Gly, a 20% SCIG; determine the dose adjustment factor for Ig20Gly relative to IVIG. METHODS: Data from patients with PID treated with Ig20Gly and IVIG 10% were used to characterize IG population PK by nonlinear mixed-effects modeling and validated using data splitting and a visual predictive check. IG profiles were simulated for 1000 patients/interval treated with Ig20Gly (daily, every 2 days, every 3 days, twice weekly, weekly, every 2 weeks). An Ig20Gly adjustment factor of 130% was used to simulate Ig20Gly to IVIG AUC ratios for weekly or every 2 weeks Ig20Gly dosing intervals and a monthly IVIG dosing interval. RESULTS: A 1-compartment model, using weight as a covariate on clearance, derived from an index modeling dataset (n = 81) demonstrated predictability for a validation dataset (n = 21). The model estimate of bioavailability was 73.9%. Simulations for 6 dosing intervals showed similar mean profiles with overlapping prediction intervals. Mean AUC ratios of Ig20Gly to IVIG with a dose adjustment factor of 1.30:1 were 98.7% for weekly and 97.7% for twice-weekly administration demonstrating comparable exposure. CONCLUSION: Ig20Gly exposures from daily to up to every 2 weeks appeared equivalent. A 1.30 conversion factor provided coverage comparable to IVIG when Ig20Gly is administered daily to every 2 weeks.


Asunto(s)
Simulación por Computador , Inmunoglobulinas Intravenosas/farmacocinética , Síndromes de Inmunodeficiencia/tratamiento farmacológico , Administración Intravenosa , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Protocolos Clínicos , Cálculo de Dosificación de Drogas , Femenino , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Grupos de Población , Programas Informáticos , Adulto Joven
13.
Vox Sang ; 95(3): 218-25, 2008 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19121186

RESUMEN

BACKGROUND AND OBJECTIVES: An international collaborative study was undertaken to identify a replacement for the World Health Organization (WHO) 1st International Standard for human immunodeficiency virus 1 (HIV-1) RNA for use in nucleic acid-based techniques (NAT) (code 97/656). In the original study to establish the 1st International Standard, a second candidate material (code 97/650) had been shown to perform well and this was re-evaluated to establish whether it would be a suitable replacement. MATERIALS AND METHODS: Eight laboratories from six different countries participated in the collaborative study to evaluate the candidate replacement standard. A total of eight different NATs were used, five in a quantitative format and three qualitative, of which five were commercially available. RESULTS: The results showed that the estimates of RNA copies in the current study were generally in line with those of the original study and there was no evidence of any drift in overall levels expressed in International Units (IU) for the candidate standard between the two studies. Furthermore, it was shown to be stable over long-term storage at -20 degrees C. CONCLUSIONS: The candidate material code 97/650 was established by the WHO as the 2nd International Standard for HIV-1 RNA for use in NAT and assigned a unitage of 5.56 log(10) (363 078) IU/vial.


Asunto(s)
VIH-1 , Técnicas de Amplificación de Ácido Nucleico/normas , ARN Viral/sangre , Femenino , Humanos , Cooperación Internacional , Masculino , Técnicas de Amplificación de Ácido Nucleico/métodos , ARN Viral/genética , Estándares de Referencia , Organización Mundial de la Salud
14.
Phys Rev E Stat Nonlin Soft Matter Phys ; 75(3 Pt 2): 036214, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17500776

RESUMEN

A variational method is developed to describe the dynamics of a Bose-Einstein condensate (BEC) trapped in an applied external potential consisting of both a harmonic and periodic component. Using this variational method, the BEC dynamics is shown to be well approximated by four coupled nonlinear differential equations, which describe the fundamental interactions in the system arising from the interplay of amplitude (width), chirp, center position, and center frequency. The simplified analytic theory allows for an efficient and convenient method for characterizing the experimental BEC behavior when localized condensates are generated. It further gives the critical strength ratio of harmonic to periodic potential necessary to support multiple stable lattice sites for the condensate and demonstrates that there can be an underlying chaotic behavior in the condensate system.

15.
Anaesthesia ; 67(8): 927, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22775384
16.
Sci Rep ; 7(1): 15533, 2017 Nov 14.
Artículo en Inglés | MEDLINE | ID: mdl-29138501

RESUMEN

End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems.


Asunto(s)
Descubrimiento de Drogas/métodos , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/metabolismo , Mapas de Interacción de Proteínas/efectos de los fármacos , Secuencias de Aminoácidos , Sitios de Unión , Humanos , Isoleucina/química , Proteínas Asociadas a Microtúbulos/química , Prolina/química , Unión Proteica/efectos de los fármacos , Dominios y Motivos de Interacción de Proteínas , Serina/química
17.
Int Surg ; 91(5): 288-90, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17061675

RESUMEN

Among most patients attending a rectal clinic, rectal bleeding is a common presenting feature. In most patients, the cause is attributed to a benign lesion. In a small percentage, the cause is neoplastic, and for this reason, rectal bleeding merits further study. Left-sided tumors account for the majority of these tumors and are within the reach of a flexible sigmoidoscopy. This study aimed at examining the diagnostic performance of the one stop rectal clinic in Coventry. Between November 2001 and May 2002, 250 consecutive patients were seen in the one stop rectal bleeding clinic of a tertiary referral hospital. Patients were asked of the nature of rectal bleed and altered bowel habits and were examined by digital rectal examination, with a proctoscopy and rigid sigmoidoscopy before either a full colonoscopic examination or flexible sigmoidoscopy with a completion Barium enema. During the study period, colorectal cancer was detected in 4 patients (1.6%), adenomatous polyps in 36 patients (14.4%), and ulcerative colitis in 8 patients (3.2%). In 98 patients (39.2%), no abnormality was present, and in the remaining patients, diverticulosis (n = 60; 24%) and hemorrhoids were present (n = 44; 17.6%).


Asunto(s)
Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad
18.
Cancer Res ; 51(8): 1990-5, 1991 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-2009518

RESUMEN

Ricin A chain immunotoxin constructed with monoclonal antibody 791T/36, which recognizes a tumor associated glycoprotein Mr 72,000 antigen present on sarcomas and colon and ovarian cancer cells, is cytotoxic for cell lines from tumors expressing this antigen. Incubation of sarcoma 791T cells with immunotoxin for only 5 min is sufficient to produce greater than 95% inhibition of tumor cell growth. Papain treatment of these cells to remove immunotoxin from the cell surface indicated that the cell surface acts as a reservoir for continued internalization of immunotoxin over several hours, but even so, 50% inhibition of cell survival was produced over a 2- to 3-h period. Analysis of the rate of endocytosis demonstrated that 30-50% of cell bound immunotoxin was internalized over a 180-min period. This was primarily dictated by the antibody moiety, regardless of the degree of conjugation to ricin A chain. This rate is much slower than that of other cell surface ligands such as transferrin. Cell cytosol acidification experiments were performed to determine whether this immunotoxin was internalized by clathrin coated pits, which is relatively rapid, or by smooth pits, which is slower, and the results indicated the latter mechanism is almost exclusively used. Intracellular trafficking of antibody 791T/36, conjugated to human serum albumin-tetramethylrhodamine was investigated by flow cytometry. The movement of the conjugate into the lysosomal compartment was delayed so that degradation products were only detected after a lag phase of 30-60 min. The lack of potentiator dependence of 791T/36 immunotoxin is in keeping with these findings.


Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Endocitosis , Inmunotoxinas/farmacocinética , Lisosomas/metabolismo , Ricina/farmacocinética , Ensayo de Tumor de Célula Madre , Cloruro de Amonio/farmacología , Neoplasias del Colon/metabolismo , Femenino , Humanos , Monensina/farmacología , Neoplasias Ováricas/metabolismo , Sarcoma/metabolismo , Factores de Tiempo , Células Tumorales Cultivadas/metabolismo
19.
AIDS ; 9(6): 555-9, 1995 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-7662192

RESUMEN

OBJECTIVES: To characterize HIV-specific cytotoxic T-lymphocyte (CTL) activities in HIV-2-infected individuals and to relate these to HIV-2 proviral load. METHODS: Peripheral blood mononuclear cells were collected from 16 HIV-2-seropositive and four HIV-1/2 dually seropositive subjects. CTL were restimulated with autologous phytohaemagglutinin-stimulated blasts and CTL activities in 'bulk' cultures were evaluated 7 and 14 days later by a standard 51Cr-release assay using autologous B-cell lines infected with recombinant vaccinia expressing HIV-2 Gag, Pol or Nef protein. Proviral load was quantified by polymerase chain reaction (PCR) which used HIV-2 long terminal repeat primers and an external standard control made by an HIV-2CBL-22 chronically infected C8166 cell line. A biotinylated primer was used to capture the 35S dATP-incorporated secondary PCR product in a quantitative radiometric assay. RESULTS: After 14 days of culture CTL responses against Gag or Pol protein were seen in 18 (90.0%) and 14 (70.0%) out of 20 subjects, respectively, whereas a CTL response was noted against Nef protein in five (25.0%) out of 20 subjects. In 14 (70.0%) out of 20 subjects multiple HIV proteins were simultaneously recognized. The sum of specific lysis (%) against HIV-2 Gag, Pol and Nef at 30:1 effector-to-target ratio, or specific lysis of the dominant CTL response, correlated strongly with HIV-2 proviral load expressed as copies per 10(5) CD4+ cells (r = -0.625, P = 0.003 and r = -0.674, P = 0.001, respectively). CONCLUSION: HIV-2-specific CTL to multiple gene products was demonstrated in most HIV-2-infected individuals. An inverse correlation between the level of CTL activity and proviral load was found, which supports the hypothesis that CTL are important in the control of HIV-2 replication.


Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/inmunología , Antígenos VIH/inmunología , VIH-2/inmunología , Leucocitos Mononucleares/inmunología , Provirus/inmunología , Linfocitos T Citotóxicos/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Células Cultivadas , VIH-1/inmunología , Humanos , Leucocitos Mononucleares/virología
20.
AIDS ; 5(1): 69-75, 1991 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-2059363

RESUMEN

Three hundred and fifty-five prostitutes working in The Gambia were enrolled in a study of retroviral infections. Eight-seven (24.6%) were infected with HIV-2 only, two (0.6%) with HIV-1 only, four (1.1%) had sera showing double HIV-1/HIV-2 reactivity, and 37 (10.4%) were seropositive for HTLV-I. After allowing for socioeconomic and serological variables in a multivariate analysis, HIV-2 infection was associated with serological evidence of a previous episode of syphilis [a rapid plasma reagin (RPR) positive/Treponema pallidum haemagglutination assay (TPHA) positive; odds ratio (OR) = 2.18, 95% confidence interval (CI) = 1.19-3.98], with having antibodies against Haemophilus ducreyi (OR = 2.05, 95% CI = 0.89-4.70) or against HTLV-I (OR = 2.17, 95% CI = 0.91-5.19). HIV-2-seropositive prostitutes were three times more likely [17 out of 78 (22%) versus 15 out of 219 (7%), P less than 0.001] to have generalized lymphadenopathy than those who were seronegative. These data suggest that genital ulcer diseases may facilitate the transmission of HIV-2, and that HIV-2 rapidly induces the appearance of generalized lymphadenopathy in a substantial proportion of infected individuals.


Asunto(s)
Enfermedades de los Genitales Femeninos/complicaciones , Infecciones por VIH/complicaciones , VIH-2 , Trabajo Sexual , Complejo Relacionado con el SIDA/complicaciones , Adolescente , Adulto , Anciano , Chancroide/complicaciones , Estudios Transversales , Demografía , Femenino , Gambia/epidemiología , Enfermedades de los Genitales Femeninos/sangre , Infecciones por VIH/epidemiología , Infecciones por HTLV-I/complicaciones , Humanos , Persona de Mediana Edad , Análisis Multivariante , Prevalencia , Factores de Riesgo , Enfermedades de Transmisión Sexual/complicaciones , Enfermedades de Transmisión Sexual/epidemiología , Sífilis/complicaciones , Úlcera/complicaciones
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