RESUMO
BACKGROUND: Adult studies have demonstrated within-season declines in influenza vaccine effectiveness (VE); data in children are limited. METHODS: We conducted a prospective, test-negative study of children 6 months through 17 years hospitalized with acute respiratory illness at 7 pediatric medical centers during the 2015-2016 through 2019-2020 influenza seasons. Case-patients were children with an influenza-positive molecular test matched by illness onset to influenza-negative control-patients. We estimated VE [100% × (1 - odds ratio)] by comparing the odds of receipt of ≥1 dose of influenza vaccine ≥14 days before illness onset among influenza-positive children to influenza-negative children. Changes in VE over time between vaccination date and illness onset date were estimated using multivariable logistic regression. RESULTS: Of 8430 children, 4653 (55%) received ≥1 dose of influenza vaccine. On average, 48% were vaccinated through October and 85% through December each season. Influenza vaccine receipt was lower in case-patients than control-patients (39% vs 57%, P < .001); overall VE against hospitalization was 53% (95% confidence interval [CI]: 46, 60%). Pooling data across 5 seasons, the odds of influenza-associated hospitalization increased 4.2% (-3.2%, 12.2%) per month since vaccination, with an average VE decrease of 1.9% per month (n = 4000, P = .275). Odds of hospitalization increased 2.9% (95% CI: -5.4%, 11.8%) and 9.6% (95% CI: -7.0%, 29.1%) per month in children ≤8 years (n = 3084) and 9-17 years (n = 916), respectively. These findings were not statistically significant. CONCLUSIONS: We observed minimal, not statistically significant within-season declines in VE. Vaccination following current Advisory Committee on Immunization Practices (ACIP) guidelines for timing of vaccine receipt remains the best strategy for preventing influenza-associated hospitalizations in children.
Assuntos
Vacinas contra Influenza , Influenza Humana , Adulto , Criança , Humanos , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Estações do Ano , Estudos Prospectivos , Eficácia de Vacinas , Estudos de Casos e Controles , Vacinação , Hospitalização , Vírus da Influenza A Subtipo H3N2RESUMO
Aberrant activation of matrix metalloproteinases (MMPs) is a common feature of pathological cascades observed in diverse disorders, such as cancer, fibrosis, immune dysregulation, and neurodegenerative diseases. MMP-9, in particular, is highly dynamically regulated in several pathological processes. Development of MMP inhibitors has therefore been an attractive strategy for therapeutic intervention. However, a long history of failed clinical trials has demonstrated that broad-spectrum MMP inhibitors have limited clinical utility, which has spurred the development of inhibitors selective for individual MMPs. Attaining selectivity has been technically challenging because of sequence and structural conservation across the various MMPs. Here, through a biochemical and structural screening paradigm, we have identified JNJ0966, a highly selective compound that inhibited activation of MMP-9 zymogen and subsequent generation of catalytically active enzyme. JNJ0966 had no effect on MMP-1, MMP-2, MMP-3, MMP-9, or MMP-14 catalytic activity and did not inhibit activation of the highly related MMP-2 zymogen. The molecular basis for this activity was characterized as an interaction of JNJ0966 with a structural pocket in proximity to the MMP-9 zymogen cleavage site near Arg-106, which is distinct from the catalytic domain. JNJ0966 was efficacious in reducing disease severity in a mouse experimental autoimmune encephalomyelitis model, demonstrating the viability of this therapeutic approach. This discovery reveals an unprecedented pharmacological approach to MMP inhibition, providing an opportunity to improve selectivity of future clinical drug candidates. Targeting zymogen activation in this manner may also allow for pharmaceutical exploration of other enzymes previously viewed as intractable drug targets.
Assuntos
Precursores Enzimáticos/antagonistas & inibidores , Precursores Enzimáticos/química , Metaloproteinase 9 da Matriz/química , Inibidores de Metaloproteinases de Matriz/química , Regulação Alostérica , Animais , Células COS , Domínio Catalítico , Chlorocebus aethiops , Precursores Enzimáticos/genética , Precursores Enzimáticos/metabolismo , Humanos , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Domínios ProteicosRESUMO
Psoriasis is a T-cell-mediated autoimmune disease involving the skin. Two cytokines, interleukin-12 (IL-12) and IL-23 have been shown to play a pivotal role in the pathogenesis of the disease. Ustekinumab (Stelara) is a therapeutic monoclonal antibody (mAb) targeted against the p40 shared subunit of IL-12 and IL-23. Recently the ability of therapeutic proteins (TP) including mAbs that target either cytokines directly (e.g., Pegasys; peginterferon α-2a) or their respective cell surface receptors [e.g., tocilizumab (Actemra); anti IL-6R] to desuppress cytochrome P450 (P450) enzymes in vitro and in the clinic, has been demonstrated. In the present study the ability of IL-12 and IL-23 to suppress multiple P450 enzymes was investigated in vitro using six separate lots of cultured human hepatocytes. Following exposure of 10 ng/ml IL-12 and IL-23 for 48 hours, either alone or in combination, no change in CYP2B6, 2C9, 2C19, or 3A4 gene expression or functional activity was observed. None of the untreated hepatocyte donors showed appreciable expression of the IL-12 or IL-23 receptors. Similar results were seen with whole human liver samples. Exposure of hepatocytes to IL-12 and/or IL-23, known P450 suppressors (IL-6 and tumor necrosis factor-α) or known P450 inducers (ß-naphthoflavone, phenobarbital, and rifampicin) did not appreciably alter the expression of the IL-12 and IL-23 receptors either. Finally, in contrast to the positive control IL-6, expression of the acute phase C-reactive protein was unaltered following IL-12 and/or IL-23 treatment. Together, these data suggest a negligible propensity for IL-12 or IL-23 to directly alter P450 enzymes in human hepatocytes.
Assuntos
Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hepatócitos/enzimologia , Interleucina-12/farmacologia , Interleucina-23/farmacologia , Fígado/efeitos dos fármacos , Proteína C-Reativa/biossíntese , Células Cultivadas , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Hepatócitos/efeitos dos fármacos , Humanos , Interleucina-6/farmacologia , Fígado/enzimologia , Fenobarbital/farmacologia , Receptores de Interleucina/biossíntese , Receptores de Interleucina/efeitos dos fármacos , Receptores de Interleucina-12/biossíntese , Receptores de Interleucina-12/efeitos dos fármacos , Rifampina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , beta-Naftoflavona/farmacologiaRESUMO
The detection of drug-induced hepatotoxicity remains an important safety issue in drug development. A liver-specific microRNA species, microRNA-122 (miR-122), has recently shown potential for predicting liver injury in addition to the standard hepatic injury biomarkers. The objective of this study was to measure miR-122 together with several other liver markers in distinct settings of acute liver toxicity in rats to determine the value of miR-122 as a biomarker for liver injury in this species. Rats were exposed to 3 well-established liver toxicants (acetaminophen, allyl alcohol, and α-naphthyl isothiocyanate), a liver-enzyme inducer (phenobarbital), or a cardiotoxicant (doxorubicin). There was a clear increase in plasma miR-122 following administration of acetaminophen, allyl alcohol, and α-naphthyl isothiocyanate. The response of miR-122 paralleled that of other markers and was consistent with liver injury as indicated by histopathological evaluation. Furthermore, the changes in miR-122 were detected earlier than standard liver injury markers and exhibited a wide dynamic range. In contrast, miR-122 responses to phenobarbital and doxorubicin were low. Based on these findings, miR-122 shows significant promise and may provide added value for assessing liver toxicity in drug development.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/sangue , MicroRNAs/sangue , Acetaminofen/toxicidade , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Isocianatos/toxicidade , Fígado/química , Fígado/patologia , Masculino , Naftalenos/toxicidade , Propanóis/toxicidade , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade AgudaRESUMO
BACKGROUND: A cross-laboratory analytic evaluation of a commercially available human inhibin B ELISA for measuring inhibin B in rat serum and plasma has been undertaken. METHODS: Dilution linearity, spiked recovery, intra- and inter-assay precision, functional sensitivity, matrix effects, and frozen stability were assessed across five laboratories. Reference ranges were generated for male Sprague Dawley and Han Wistar rats. RESULTS: Acceptable performance was defined as an overall assay coefficient of variation ≤ 20% with an intraday LLOQ ≤ 20 pg/ml. Intra- and inter-assay precision and functional sensitivity (≤6.4 pg/ml) generally met these criteria, but with occasional evidence of greater variability, particularly at lower concentrations. Dilution linearity was acceptable with occasional low recovery. Acceptable recovery of kit calibrators from rat serum confirmed the absence of matrix effects. Matched serum and plasma samples gave comparable results. The signal increased on freezing, remained constant for ≥3 freeze-thaw cycles and was generally stable for at least 8 weeks. Mean inhibin B ranged from 33.5 to 140.6 pg/ml in adult rats across laboratories, with some evidence for a decline from 6 to 9 weeks of age. Power calculations using preliminary reference range data indicated 10 animals/group would generally detect a 40% decrease in inhibin B at AstraZeneca, but laboratories with lower control values would require larger groups. CONCLUSIONS: The assay meets the analytical performance criteria; however, precision at the low end of the standard curve, biological variability, and low control values observed in some laboratories indicate that the utility of the assay may be limited in some laboratories.
Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Inibinas/sangue , Animais , Bioensaio , Congelamento , Humanos , Masculino , Controle de Qualidade , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Valores de Referência , Soro/metabolismoRESUMO
BACKGROUND: Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children. METHODS: Hospitalized children <18 years of age with acute respiratory illness (ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment. RESULTS: Of the 2299 hospitalized children with ARI enrolled during one influenza season, 51% (n = 1183) were tested clinically for influenza. Clinicians provided antiviral treatment for 61 of 117 (52%) patients with a positive influenza test versus 66 of 1066 (6%) with a negative or unknown test result. In multivariable analyses, factors associated with testing included neuromuscular disease (aOR = 5.35, 95% CI [3.58-8.01]), immunocompromised status (aOR = 2.88, 95% CI [1.66-5.01]), age (aOR = 0.93, 95% CI [0.91-0.96]), private only versus public only insurance (aOR = 0.78, 95% CI [0.63-0.98]), and chronic lung disease (aOR = 0.64, 95% CI [0.51-0.81]). Factors associated with antiviral treatment included neuromuscular disease (aOR = 1.86, 95% CI [1.04, 3.31]), immunocompromised state (aOR = 2.63, 95% CI [1.38, 4.99]), duration of illness (aOR = 0.92, 95% CI [0.84, 0.99]), and chronic lung disease (aOR = 0.60, 95% CI [0.38, 0.95]). CONCLUSION: Approximately half of children hospitalized with influenza during the 2015-2016 influenza season were treated with antivirals. Because antiviral treatment for influenza is associated with better health outcomes, further studies of subsequent seasons would help evaluate current use of antivirals among children and better understand barriers for treatment.
Assuntos
Influenza Humana , Pneumopatias , Antivirais/uso terapêutico , Criança , Criança Hospitalizada , Hospitalização , Humanos , Influenza Humana/diagnóstico , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Oseltamivir/uso terapêuticoRESUMO
At nine US hospitals that enrolled children hospitalized with acute respiratory illness (ARI) during 2015-2016 through 2017-2018 influenza seasons, 50% of children with ARI received clinician-initiated testing for influenza and 35% of cases went undiagnosed due to lack of clinician-initiated testing. Marked heterogeneity in testing practice was observed across sites.
Assuntos
Influenza Humana , Infecções Respiratórias , Criança , Criança Hospitalizada , Hospitais , Humanos , Lactente , Influenza Humana/diagnóstico , Estações do Ano , Estados UnidosRESUMO
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG.
Assuntos
Azetidinas/farmacologia , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Hipuratos/farmacologia , Receptores CCR2/antagonistas & inibidores , Azetidinas/síntese química , Azetidinas/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Hipuratos/síntese química , Hipuratos/química , Humanos , Estrutura Molecular , Receptores CCR2/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.
Assuntos
Amidas/química , Anti-Inflamatórios/química , Receptores CCR2/antagonistas & inibidores , Doença Aguda , Administração Oral , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Camundongos , Camundongos Transgênicos , Ratos , Receptores CCR2/metabolismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Annual United States (US) estimates of influenza vaccine effectiveness (VE) in children typically measure protection against outpatient medically attended influenza illness, with limited data evaluating VE against influenza hospitalizations. We estimated VE for preventing laboratory-confirmed influenza hospitalization among US children. METHODS: We included children aged 6 months-17 years with acute respiratory illness enrolled in the New Vaccine Surveillance Network during the 2015-2016 influenza season. Documented influenza vaccination status was obtained from state immunization information systems, the electronic medical record, and/or provider records. Midturbinate nasal and throat swabs were tested for influenza using molecular assays. We estimated VE as 100% × (1 - odds ratio), comparing the odds of vaccination among subjects testing influenza positive with subjects testing negative, using multivariable logistic regression. RESULTS: Of 1653 participants, 36 of 707 (5%) of those fully vaccinated, 18 of 226 (8%) of those partially vaccinated, and 85 of 720 (12%) of unvaccinated children tested positive for influenza. Of those vaccinated, almost 90% were documented to have received inactivated vaccine. The majority (81%) of influenza cases were in children ≤ 8 years of age. Of the 139 influenza-positive cases, 42% were A(H1N1)pdm09, 42% were B viruses, and 14% were A(H3N2). Overall, adjusted VE for fully vaccinated children was 56% (95% confidence interval [CI], 34%-71%) against any influenza-associated hospitalization, 68% (95% CI, 36%-84%) for A(H1N1)pdm09, and 44% (95% CI, -1% to 69%) for B viruses. CONCLUSIONS: These findings demonstrate the importance of annual influenza vaccination in prevention of severe influenza disease and of reducing the number of children who remain unvaccinated or partially vaccinated against influenza.
Assuntos
Vírus da Influenza A Subtipo H1N1 , Vacinas contra Influenza , Influenza Humana , Estudos de Casos e Controles , Criança , Hospitalização , Humanos , Vírus da Influenza A Subtipo H3N2 , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Estações do Ano , Estados Unidos/epidemiologia , VacinaçãoRESUMO
BACKGROUND: Parent-reported influenza vaccination history may be valuable clinically and in influenza vaccine effectiveness (VE) studies. Few studies have assessed the validity of parental report among hospitalized children. METHODS: Parents of 2597 hospitalized children 6 months-17 years old were interviewed from November 1, 2015 to June 30, 2016, regarding their child's sociodemographic and influenza vaccination history. Parent-reported 2015-2016 influenza vaccination history was compared with documented vaccination records (considered the gold standard for analysis) obtained from medical records, immunization information systems, and providers. Multivariable logistic regression analyses were conducted to determine potential factors associated with discordance between the 2 sources of vaccination history. Using a test-negative design, we estimated VE using vaccination history obtained through parental report and documented records. RESULTS: According to parental report, 1718 (66%) children received the 2015-2016 influenza vaccine, and of those, 1432 (83%) had documentation of vaccine receipt. Percent agreement was 87%, with a sensitivity of 96% (95% confidence interval [CI], 95%-97%) and a specificity of 74% (95% CI, 72%-77%). In the multivariable logistic regression, study site and child's age 5-8 years were significant predictors of discordance. Adjusted VE among children who received ≥1 dose of the 2015-2016 influenza vaccine per parental report was 61% (95% CI, 43%-74%), whereas VE using documented records was 55% (95% CI, 33%-69%). CONCLUSIONS: Parental report of influenza vaccination was sensitive but not as specific compared with documented records. However, VE against influenza-associated hospitalizations using either source of vaccination history did not differ substantially. Parental report is valuable for timely influenza VE studies.
Assuntos
Vacinas contra Influenza , Influenza Humana , Criança , Pré-Escolar , Humanos , Imunização , Lactente , Influenza Humana/prevenção & controle , Pais , VacinaçãoRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of hospitalized acute respiratory illness (ARI) among young children. With RSV vaccines and immunoprophylaxis agents in clinical development, we sought to update estimates of US pediatric RSV hospitalization burden. METHODS: Children <5 years old hospitalized for ARI were enrolled through active, prospective, population-based surveillance from November 1, 2015, to June 30, 2016, at 7 US pediatric hospital sites. Clinical information was obtained from parent interviews and medical records. Midturbinate nasal and throat flocked swabs were collected and tested for RSV by using molecular diagnostic assays at each site. We conducted descriptive analyses and calculated population-based rates of RSV-associated hospitalizations. RESULTS: Among 2969 hospitalized children included in analyses, 1043 (35%) tested RSV-positive; 903 (87%) children who were RSV-positive were <2 years old, and 526 (50%) were <6 months old. RSV-associated hospitalization rates were 2.9 per 1000 children <5 years old and 14.7 per 1000 children <6 months old; the highest age-specific rate was observed in 1-month-old infants (25.1 per 1000). Most children who were infected with RSV (67%) had no underlying comorbid conditions and no history of preterm birth. CONCLUSIONS: During the 2015-2016 season, RSV infection was associated with one-third of ARI hospitalizations in our study population of young children. Hospitalization rates were highest in infants <6 months. Most children who were RSV-positive had no history of prematurity or underlying medical conditions, suggesting that all young children could benefit from targeted interventions against RSV.
Assuntos
Hospitalização/estatística & dados numéricos , Infecções por Vírus Respiratório Sincicial/epidemiologia , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos , Fatores de TempoRESUMO
Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Dispositivos Lab-On-A-Chip , Fígado/patologia , Animais , Biomarcadores/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Cães , Humanos , Células de Kupffer/metabolismo , Fígado/lesões , Hepatopatias/patologia , Fenótipo , Ratos , Reprodutibilidade dos Testes , Fatores de Risco , Especificidade da EspécieRESUMO
The synthesis and biological evaluation of a series of substituted dipiperidine alcohols are described. Structure-activity relationship studies led to the discovery of potent CCR2 antagonists displaying IC(50) values in the nanomolar or subnanomolar range. The cinnamoyl compounds had higher binding affinities than the corresponding urea analogs.
Assuntos
Álcoois/farmacologia , Piperidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Álcoois/síntese química , Álcoois/química , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationship of a series of 7-azaindole piperidine derivatives are described. SAR studies led to the discovery of the potent CCR2 antagonists displaying IC(50) values in the nanomolar range. The representative compound 15 showed reasonable P450 and pharmacokinetics profile.
Assuntos
Química Farmacêutica/métodos , Quimiocina CCL2/química , Indóis/química , Piperidinas/química , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Álcoois/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
This paper examines the role of the history of medicine in case of congenital isolated hemihyperplasia. Isolated hemihyperplasia is a genetic disorder in which one side of the body grows more than the other, causing visible lateral asymmetry of the human body. The date of the occurrence of the genetic mutation that leads to hemihyperplasia is not known yet. The aim of the current research was to confirm or to disprove the fact that isolated hemihyperplasia was first described in the first half of the 19th century. Using the case of hemihyperplasia we aimed to demonstrate how historical analysis may assist medical genetics in cases when estimating a mutation date is necessary. Medical literature from 1573 onwards was searched for any mention of hemihypertrophy, hemihyperplasia, hemi-gigantism, partial gigantism, hemi-macrosomia and other possible descriptions for pathological lateral body overgrowth. Historical analysis suggests that the mutation in question occurred in the first half of the 19th century, approximately 200â¯years ago. This led to the appearance of hemihyperplasia and subsequent hemihyperplasia-including syndromes. An additional genetic research is needed for investigation of the development of the involved chromosomal region instability since this period. Such research may use the timeline orientation provided by the history of medicine.
Assuntos
Hiperplasia , Antropologia Médica , Feminino , Genética Médica , História do Século XVI , História do Século XX , Humanos , Hiperplasia/história , Hiperplasia/patologia , Hipertricose , Masculino , Mutação/genética , Gêmeos UnidosRESUMO
Streptococcus pneumoniae (SP) is a leading cause of child mortality globally, killing around half a million children aged 5 years and less per year. Nasopharyngeal carriage of SP is a prerequisite to disease, and the prevalence of colonization reaches 100% within the first few years of life. Serotype prevalence varies geographically, impacting the serotype coverage of pneumococcal vaccines, and serotype prevalence data are limited from large regions of the world, including sub-Saharan Africa. We enrolled 323 unvaccinated children, aged 4-7 years from coastal Kenya and obtained nasopharyngeal swab samples before and after vaccination with the 10-valent pneumococcal vaccine. Vaccination did not reduce the overall prevalence of pneumococcal carriage in our cohort, with 65 (20%) children colonized before vaccination and 63 (19.4%) colonized postvaccination. However, the prevalence of vaccine-included serotypes (vaccine strains) declined from 43% to 19% of positive swabs, whereas non-vaccine serotypes increased from 46% to 73%. This study contributes to the few data available regarding pneumococcal carriage and serotype prevalence in Kenya and is in concordance with reports of dynamic serotype replacement, driven by vaccine pressure.
Assuntos
Infecções Pneumocócicas/epidemiologia , Vacinas Pneumocócicas/administração & dosagem , Streptococcus pneumoniae/imunologia , Vacinação , Portador Sadio/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Humanos , Quênia/epidemiologia , Nasofaringe/microbiologia , Infecções Pneumocócicas/microbiologia , Infecções Pneumocócicas/prevenção & controle , Prevalência , Sorogrupo , Streptococcus pneumoniae/genéticaRESUMO
A series of substituted dipiperidine compounds have been synthesized and identified as selective CCR2 antagonists. Combining the most favorable substituents led to the discovery of remarkably potent CCR2 antagonists displaying IC50 values in the nanomolar range. Compound 7a had outstanding selectivity over CCR1, CCR3, CCR4, CCR5, CCR6, CCR7, and CCR8 and showed excellent efficacy in adjuvant-induced arthritis model, collagen-induced arthritis model, and allergic asthma model.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Piperidinas/síntese química , Receptores CCR2/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Asma/tratamento farmacológico , Linhagem Celular , Quimiotaxia/efeitos dos fármacos , Cristalografia por Raios X , Humanos , Masculino , Camundongos , Piperidinas/química , Piperidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Receptores CCR2/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
BACKGROUND AND OBJECTIVE: Streptococcus pneumoniae is a leading cause of mortality before age 5, but few studies examine details of childhood response to pneumococcal vaccine in less-developed settings. Although malnutrition, HIV, and concurrent infections can impair response, evidence suggests that chronic parasitic infections can also contribute to poor vaccination results. The objective of this study was to determine whether response to pneumococcal vaccine varied among children either exposed to parasitic infections in utero, previously infected in infancy, or infected at the time of immunization. METHODS: Children from a 2006 to 2010 maternal-infant cohort were eligible for the current study. Children were screened for malaria, schistosomiasis, filariasis, intestinal helminths, and protozoa. Data on in utero exposure and early life infections were linked, and baseline antipneumococcal immunoglobulin G levels and nasopharyngeal carrier status were determined. Participants received decavalent pneumococcal vaccine, and 4 weeks later, serology was repeated to assess vaccine response. RESULTS: A total of 281 children were included. Preimmunity was associated with greater postvaccination increments in anti-pneumococcal polysaccharide immunoglobulin G, especially serotypes 4, 7, 9, 18C, and 19. Present-day growth stunting was independently associated with weaker responses to 1, 4, 6B, 7, 9V, and 19. Previous exposure to Trichuris was associated with stronger responses to 1, 5, 6B, 7, 18C, and 23, but other parasite exposures were not consistently associated with response. CONCLUSIONS: In our cohort, hyporesponsiveness to pneumococcal conjugate vaccine was associated with growth stunting but not parasite exposure. Parasite-related vaccine response deficits identified before age 3 do not persist into later childhood.
Assuntos
Doenças Parasitárias/imunologia , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Vacinas Conjugadas/imunologia , Animais , Anticorpos Antibacterianos/sangue , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Masculino , Parasitos , Infecções Pneumocócicas/prevenção & controleRESUMO
BACKGROUND: Parasitic infections, which are among the most common infections worldwide, disproportionately affect children; however, little is known about the impact of parasitic disease on growth in very early childhood. Our objective was to document the prevalence of parasitic infections and examine their association with growth during the first three years of life among children in coastal Kenya. METHODOLOGY/PRINCIPAL FINDINGS: Children enrolled in a maternal-child cohort were tested for soil transmitted helminths (STHs: Ascaris, Trichuris, hookworm, Strongyloides), protozoa (malaria, Entamoeba histolytica and Giardia lamblia), filaria, and Schistosoma infection every six months from birth until age three years. Anthropometrics were measured at each visit. We used generalized estimating equation (GEE) models to examine the relationship between parasitic infections experienced in the first three years of life and growth outcomes (weight, length and head circumference). Of 545 children, STHs were the most common infection with 106 infections (19%) by age three years. Malaria followed in period prevalence with 68 infections (12%) by three years of age. Filaria and Schistosoma infection occurred in 26 (4.8%) and 16 (2.9%) children, respectively. Seven percent were infected with multiple parasites by three years of age. Each infection type (when all STHs were combined) was documented by six months of age. Decreases in growth of weight, length and head circumference during the first 36 months of life were associated with hookworm, Ascaris, E. histolytica, malaria and Schistosoma infection. In a subset analysis of 180 children who followed up at every visit through 24 months, infection with any parasite was associated with decelerations in weight, length and head circumference growth velocity. Multiple infections were associated with greater impairment of linear growth. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate an under-recognized burden of parasitism in the first three years of childhood in rural Kenya. Parasitic infection and polyparasitism were common, and were associated with a range of significant growth impairment in terms of weight, length and/or head circumference.