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There are a diverse range of haematological malignancies with varying clinical presentations and prognoses. Patients with haematological malignancy may require admission to critical care at the time of diagnosis or due to treatment related effects and complications. Although the prognosis for such patients requiring critical care has improved, there remain uncertainties in optimal clinical management. Identification of patients who will benefit from critical care admission is challenging and selective involvement of palliative care may help to reduce unnecessary and non-beneficial treatments. While patients with haematological malignancy can present a challenge to critical care physicians, good outcomes can be achieved. In this narrative review, we provide a brief overview of relevant haematological malignancies for the critical care physician and a summary of recent treatment advances. Subsequently, we focus on critical care management for the patient with haematological malignancy including sepsis; acute respiratory failure; prevention and treatment of tumour lysis syndrome; thrombocytopaenia; and venous thromboembolism. We also discuss immunotherapeutic-specific related complications and their management, including cytokine release syndrome and immune effector cell associated neurotoxicity syndrome associated with chimeric antigen receptor T-cell therapy. While the management of haematological malignancies is highly specialised and increasingly centralised, acutely unwell patients often present to their local hospital with complications requiring critical care expertise. The aim of this review is to provide a contemporary overview of disease and management principles for non-specialist critical care teams.
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Neoplasias Hematológicas , Humanos , Adulto , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/tratamiento farmacológico , Pronóstico , Cuidados Críticos , Hospitalización , HospitalesRESUMEN
Increases in youth psychiatric presentations to out-patient and emergency department settings during COVID-19 have been reported. This study, using data from five hospitals in Ireland, examines changes in the number and type of paediatric admissions during COVID-19 (March 2020 - February 2021) compared to the previous two years. ICD-10 classification was used to establish admissions with mental, behavioural, neuro-developmental disorders and psychosocial reasons (MBN-PS). Overall hospital admissions fell by 25.3%, while MBN-PS fell by only 2.6%, mostly during an initial lockdown. Admissions for MBN-PS increased in July-August (9.2%), increased further in September-December (28.3%), returning to pre-COVID-19 levels in January-February 2021. Significant increases were observed among youths with anorexia nervosa (47.8%), other eating disorders (42.9%), and admissions for anxiety (29.6%), with these effects relating to females only. Although admissions for self-harm increased (3%) and rates of ASD admissions reduced (17%), these were not statistically significant. The disproportionate increase in admissions for MBN-PS compared to medical admissions suggests an adverse effect of COVID-19 on youth mental health, for females in particular, and supports previous reports of a pandemic specific increase in eating psychopathology. Combined community and acute service delivery and capacity planning are urgently needed given the prior underfunding of services pre-pandemic.
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COVID-19 , Adolescente , COVID-19/epidemiología , Niño , Control de Enfermedades Transmisibles , Femenino , Hospitales Pediátricos , Humanos , Pandemias , Admisión del PacienteRESUMEN
BACKGROUND: Health disparities for children with intellectual disabilities can be challenging to measure due to many other factors that can impact health and healthcare use. The aim of the current study was to use longitudinal cohort data to compare children with intellectual disability (ID) in Ireland between 2006 and 2014 on healthcare utilisation and unmet need, at ages 9 and 13, using a propensity score matching (PSM) approach. METHODS: Using data from the Growing up in Ireland study, PSM was used to identify an appropriate control sample to compare with a sample of children with ID (n = 124). Participants were matched on variables that are known to influence healthcare utilisation to reduce the impact of confounding variables between groups so that differences between the groups can be estimated. Logistic regression was used to estimate effects at ages 9 and 13. RESULTS: Children with ID were no more likely to have visited a general practitioner or emergency department in the past 12 months than children without ID. They did have a greater likelihood of visiting a doctor in a hospital in the past 12 months and of having an overnight stay in hospital by age 9. Primary caregivers of children with ID were more likely to report unmet health needs at ages 9 and 13. CONCLUSIONS: This approach is a novel means of comparing healthcare use in this population by balancing the impact of other factors that may result in inequities, to which children with ID may be more vulnerable.
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Discapacidad Intelectual , Adolescente , Niño , Estudios de Cohortes , Servicio de Urgencia en Hospital , Humanos , Discapacidad Intelectual/epidemiología , Discapacidad Intelectual/terapia , Aceptación de la Atención de Salud , Puntaje de PropensiónRESUMEN
INTRODUCTION: Health systems offer access to unscheduled care through numerous routes; however, it is typically provided by general practitioners (GPs), by emergency medicine doctors in in emergency departments (EDs) and by GPs in out-of-hours GP services such as practitioner cooperatives. Unscheduled healthcare constitutes a substantial portion of healthcare delivery. A systematic review was conducted to establish the factors that influence parents' decision making when seeking unscheduled healthcare for their children. The systematic review question was "What are the factors that influence the decision making of parents and families seeking unscheduled paediatric healthcare?" METHOD: Five databases (CINAHL, PubMed, SCOPUS, PsycInfo, EconLit) and four grey literature databases (Proquest, Lenus, OpenGrey, Google Scholar) were searched. The titles and abstracts of 3746 articles were screened and full-text screening was performed on 177 of these articles. Fifty-six papers were selected for inclusion in the review. Data relating to different types of unscheduled health services (namely primary care, the emergency department and out-of-hours services) were extracted from these articles. A narrative approach was used to synthesise the extracted data. RESULTS: Several factors were identified as influencing parental preferences and decision making when seeking unscheduled healthcare for their children. A number of the included studies identified pre-disposing factors such as race, ethnicity and socioeconomic status (SES) as impacting the healthcare-seeking behaviour of parents. Unscheduled healthcare use was often initiated by the parent's perception that the child's condition was urgent and their need for reassurance. The choice of unscheduled service was influenced by a myriad of factors such as: waiting times, availability of GP appointments, location of the ED, and the relationship that the parent or caregiver had with their GP. CONCLUSION: Policy and planning initiatives do not always reflect how patients negotiate the health system as a single entity with numerous entry points. Altering patients' behaviour through public health initiatives that seek to improve, for instance, health literacy or reducing emergency hospital admissions through preventative primary care requires an understanding of the relative importance of factors that influence behaviour and decision making, and the interactions between these factors.
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Atención Posterior , Toma de Decisiones , Padres , Aceptación de la Atención de Salud , Niño , Servicio de Urgencia en Hospital , Femenino , Medicina General , Humanos , Masculino , Pediatría , Atención Primaria de SaludRESUMEN
BACKGROUND: We assessed whether a near-infrared spectroscopy (NIRS)-based algorithm for the personalized optimization of cerebral oxygenation during cardiopulmonary bypass combined with a restrictive red cell transfusion threshold would reduce perioperative injury to the brain, heart, and kidneys. METHODS: In a randomized controlled trial, participants in three UK centres were randomized with concealed allocation to a NIRS (INVOS 5100; Medtronic Inc., Minneapolis, MN, USA)-based 'patient-specific' algorithm that included a restrictive red cell transfusion threshold (haematocrit 18%) or to a 'generic' non-NIRS-based algorithm (standard care). The NIRS algorithm aimed to maintain cerebral oxygenation at an absolute value of > 50% or at > 70% of baseline values. The primary outcome for the trial was cognitive function measured up to 3 months postsurgery. RESULTS: The analysis population comprised eligible randomized patients who underwent valve or combined valve surgery and coronary artery bypass grafts using cardiopulmonary bypass between December 2009 and January 2014 ( n =98 patient-specific algorithm; n =106 generic algorithm). There was no difference between the groups for the three core cognitive domains (attention, verbal memory, and motor coordination) or for the non-core domains psychomotor speed and visuo-spatial skills. The NIRS group had higher scores for verbal fluency; mean difference 3.73 (95% confidence interval 1.50, 5.96). Red cell transfusions, biomarkers of brain, kidney, and myocardial injury, adverse events, and health-care costs were similar between the groups. CONCLUSIONS: These results do not support the use of NIRS-based algorithms for the personalized optimization of cerebral oxygenation in adult cardiac surgery. CLINICAL TRIAL REGISTRATION: http://www.controlled-trials.com , ISRCTN 23557269.
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Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Procedimientos Quirúrgicos Cardíacos , Circulación Cerebrovascular/fisiología , Trastornos del Conocimiento/prevención & control , Complicaciones Posoperatorias/prevención & control , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Puente Cardiopulmonar , Transfusión de Eritrocitos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Espectroscopía Infrarroja Corta/métodos , Reino Unido , Adulto JovenRESUMEN
Scrapie is a naturally occurring transmissible spongiform encephalopathy of sheep and goats. There are different strains of sheep scrapie that are associated with unique molecular, transmission, and phenotype characteristics. However, in the United States, very little is known about the potential presence of scrapie strains. Scrapie strain and PRNP genotype could both affect susceptibility, potential for transmission, incubation period (IP), and control measures required for eliminating scrapie from a flock. The investigators evaluated 2 US scrapie isolates, No. 13-7 and x124, after intranasal inoculation to compare clinical signs, IPs, spongiform lesions, and patterns of PrPSc deposition in sheep with scrapie-susceptible PRNP genotypes (QQ171). After inoculation with x124, susceptibility and IP were associated with valine at codon 136 (V136) of the prion protein: VV136 sheep had short IPs (6.9 months), those in AV136 sheep were 11.9 months, and AA136 sheep did not develop scrapie. All No. 13-7 inoculated sheep developed scrapie, with IPs of 20.1 months for AA136 sheep, 22.8 months for AV136 sheep, and 26.7 months for VV136 sheep. Patterns of immunoreactivity in the brain were influenced by inoculum isolate and host genotype. Differences in PrPSc profiles versus isolate were most striking when examining brains from sheep with the VV136 genotype. Inoculation into C57BL/6 mice resulted in markedly different attack rates (90.5% for x124 and 5.9% for No. 13-7). Taken together, these data demonstrate that No. 13-7 and x124 represent 2 distinct strains of scrapie with different IPs, genotype susceptibilities, and PrPSc deposition profiles.
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Priones/genética , Scrapie/epidemiología , Animales , Encéfalo/patología , Genotipo , Ratones , Ratones Endogámicos C57BL , Proteínas PrPSc/genética , Priones/clasificación , Priones/aislamiento & purificación , Priones/patogenicidad , Scrapie/patología , Ovinos , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Early implementation of programmatic colorectal cancer (crc) screening for average-risk individuals 50-74 years of age in Canada has used fecal occult blood tests [fts (guaiac or immunochemical)] and colonoscopy for follow-up of abnormal fts. This paper presents results of an evaluation of this crc screening. METHODS: Five Canadian provincial programs provided aggregated data for individuals with a first-round ft processed between January 1, 2009, and December 31, 2011. RESULTS: The 104,750 people who successfully completed a first round of screening represented 16.1% of those who had access to the programs between January 1, 2009, and December 31, 2011 (mean age: 61.2 years; men: 61.4 years; women: 61.1 years). Of those participants, 4661 had an abnormal ft (4.4%). Uptake of colonoscopy within 180 days after an abnormal ft was 80.5%, ranging from 67.8% to 89.5% by program. The positive predictive value (ppv) for adenoma was 35.9% for guaiac ft and 50.6% for immunochemical ft. Adenoma and crc detection rates were, respectively, 16.9 and 1.8 per 1000 screened. Of invasive crcs detected, 64.6% were stage i or ii. CONCLUSIONS: Considering the variation in characteristics and stage of implementation of each provincial program, the collaboration of the provinces leading to this report on the early performance of crc screening in Canada is a major milestone. Targets are met or nearly met for significant indicators such as ppv for adenoma and cancer detection rate. Participation is expected to increase as programs are fully implemented in the provinces. Additional effort may be needed to improve timely access to follow-up colonoscopy.
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Despite evidence linking obesity with increased mortality, older adults with excessive adiposity seem protected, resulting in a so-called obesity paradox. Obesity is characterized by leptin resistance, which contributes to increased risk of all-cause mortality. Therefore, lifestyle factors, such as physical fitness, that lower leptin independent of adiposity may be confounding the obesity paradox. To investigate this, we evaluated whether physical fitness moderated the relationship between leptin and adiposity. We found older adults with higher fitness had lower body mass (r(39) = -0.43, p < 0.01), leptin (r(39) = -0.29, p = 0.03) and inflammation (IL-1ß: (r(39) = -0.69, p < 0.01); TNF-α: (r(39) = -0.30, p = 0.03)). Fitness moderated the relationship between leptin and adiposity (F(5, 37) = 3.73, p < 0.01, R2 = 0.33) to reveal the obesity paradox in moderately and high fit individuals (b = 216.24, t(37) = 1.46, p = 0.15; b= -88.10, t(37) = -0.49, p = 0.63) but not in low fit individuals. These results show the link between obesity and mortality may not be dependent on total adiposity, but rather on endocrine function and adipocyte leptin secretion. These results have important implications for older adults struggling to maintain healthy body composition and suggest that fitness may promote overall wellbeing.
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Tejido Adiposo , Envejecimiento/fisiología , Capacidad Cardiovascular/fisiología , Leptina , Obesidad , Aptitud Física/fisiología , Tejido Adiposo/inmunología , Tejido Adiposo/metabolismo , Adiposidad/fisiología , Anciano , Biomarcadores/sangre , Índice de Masa Corporal , Canadá/epidemiología , Factores de Riesgo Cardiometabólico , Estudios Transversales , Modificador del Efecto Epidemiológico , Femenino , Humanos , Inflamación/sangre , Leptina/sangre , Leptina/metabolismo , Masculino , Obesidad/diagnóstico , Obesidad/metabolismo , Obesidad/mortalidad , Obesidad/fisiopatología , Factores ProtectoresRESUMEN
BACKGROUND: Dissociated primary neuronal cultures are widely used as a model system to investigate the cellular and molecular properties of diverse neuronal populations and mechanisms of action potential generation and synaptic transmission. Typically, rodent primary neuronal cultures are obtained from freshly-dissociated embryonic or postnatal brain tissue, which often requires intense animal husbandry. This can strain resources when working with genetically modified mice. NEW METHOD: Here we describe an experimental protocol for frozen storage of mouse hippocampi, which allows fully functional dissociated primary neuronal cultures to be prepared from cryopreserved tissue. RESULTS: We show that thawed hippocampal neurons have functional properties similar to those of freshly dissociated neurons, including neuronal morphology, excitability, action potential waveform and synaptic neurotransmitter release, even after cryopreservation for several years. COMPARISON TO THE EXISTING METHODS: In contrast to the existing methods, the protocol described here allows for efficient long-term storage of samples, allowing researchers to perform functional experiments on neuronal cultures from brain tissue collected in other laboratories. CONCLUSIONS: We anticipate that this method will facilitate collaborations among laboratories based at distant locations and will thus optimise the use of genetically modified mouse models, in line with the 3Rs (Replacement, Reduction and Refinement) recommended for scientific use of animals in research.
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Potenciales de Acción/fisiología , Hipocampo/fisiología , Neuronas/fisiología , Transmisión Sináptica/fisiología , Animales , Técnicas de Cultivo de Célula , Células Cultivadas , Criopreservación , Hipocampo/citología , Ratones , Ratones Endogámicos C57BL , Neuronas/citologíaRESUMEN
The western pond turtle (WPT), recently separated into two paripatrically distributed species (Emys pallida and Emys marmorata), is experiencing significant reductions in its range and population size. In addition to habitat loss, two potential causes of decline are female-biased road mortality and high juvenile mortality from non-native predatory bullfrogs (Rana catesbeiana). However, quantitative analyses of these threats have never been conducted for either species of WPT. We used a combination of historical museum samples and published and unpublished field studies shared with us through personal communications with WPT field researchers (B. Shaffer, P. Scott, R. Fisher, C. Brown, R. Dagit, L. Patterson, T. Engstrom, 2019, personal communications) to quantify the effect of roads and bullfrogs on WPT populations along the west coast of the United States. Both species of WPT shift toward increasingly male biased museum collections over the last century, a trend consistent with increasing, female-biased road mortality. Recent WPT population studies revealed that road density and proximity were significantly associated with increasingly male-biased sex ratios, further suggesting female-biased road mortality. The mean body size of museum collections of E. marmorata, but not E. pallida, has increased over the last 100 years, consistent with reduced recruitment and aging populations that could be driven by invasive predators. Contemporary WPT population sites that co-occur with bullfrogs had significantly greater average body sizes than population sites without bullfrogs, suggesting strong bullfrog predation on small WPT hatchlings and juveniles. Overall, our findings indicate that both species of WPT face demographic challenges which would have been difficult to document without the use of both historical data from natural history collections and contemporary demographic field data. Although correlational, our analyses suggest that female-biased road mortality and predation on small turtles by non-native bullfrogs are occurring, and that conservation strategies reducing both may be important for WPT recovery.
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Background: The human papillomavirus (hpv) is a common sexually transmitted infection and a primary cause of cervical cancer. The Government of Canada has set a target of reaching 90% hpv vaccine coverage among adolescents by 2025. Here, we examine hpv vaccine uptake in school-based immunization programs across Canada and explore how achieving the 90% target could affect the future incidence of cervical cancer, mortality, and health system expenditures in a cohort of Canadian women. Methods: Data for hpv vaccine uptake in the most recent reported school year available in each jurisdiction were provided in 2017 by jurisdictional school-based immunization programs and were used to estimate a national weighted average of 67%. The OncoSim microsimulation model (version 2.5) was used to compare 3 different levels of hpv vaccine uptake (0%, 67%, 90%) on health and economic outcomes for a hypothetical cohort of all 5- to 10-year-old girls in Canada in 2015. Results: Vaccine uptake for girls in school-based programs varied from 55.0% to 92.0% in the jurisdictions reviewed. The OncoSim model projects that increasing uptake to 90% from 67% would result in a 23% reduction in cervical cancer incidence rates (to 3.1 cases from 4.0 cases per 100,000, averaged across the lifetime of the cohort) and a 23% decline in the average annual mortality rate (to 1.0 deaths from 1.3 deaths per 100,000). Finally, the model projects that the health system will incur a cost of $9 million (1% increase) during the lifetime of the cohort if uptake is increased to 90% from 67%. Costs are discounted (1.5%) and expressed in 2016 Canadian dollars. Costs reflect the payer perspective. Conclusions: Our model shows that increasing hpv vaccine uptake to 90% from current levels for girls in school-based immunization programs could result in substantial reductions in the future incidence and mortality rates for cervical cancer in Canada.
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Vacunación Masiva/economía , Modelos Teóricos , Vacunas contra Papillomavirus/uso terapéutico , Neoplasias del Cuello Uterino/prevención & control , Adulto , Anciano , Canadá , Análisis Costo-Beneficio , Femenino , Humanos , Vacunación Masiva/estadística & datos numéricos , Persona de Mediana Edad , Vacunas contra Papillomavirus/economía , Neoplasias del Cuello Uterino/economía , Adulto JovenRESUMEN
Bovine spongiform encephalopathy (BSE) is a neurodegenerative disease of cattle caused by abnormally folded prion proteins. Two regulatory region polymorphisms in the bovine prion gene are associated with resistance to classical BSE disease: a 23-bp region in the promoter that contains a binding site for the repressor protein RP58, and a 12-bp region in intron 1 that has a binding site for the transcription factor SP1. The presence of these binding sites enhances BSE resistance in cattle, whereas cattle that lack these regions are more susceptible to the disease. The present study examined the allele, genotype, and haplotype frequencies for the 23-bp and 12-bp polymorphisms in Holstein cattle from 9 different US states, and these frequencies were compared with data previously established for Holstein cattle from the United Kingdom, Germany, and Japan. Additionally, the coding region of the prion gene was sequenced from the US samples. Finally, archival samples from US Holstein sires born between 1953 and 1957 were analyzed. We found that the resistant allele and genotype frequencies for the US Holstein cattle were as high, or higher, relative to that observed in other countries. Furthermore, the current US frequencies were comparable to those determined in the archival samples from the 1950s. Based on the frequencies of these regulatory region polymorphisms, the US Holstein population is not at a greater risk for BSE than Holsteins worldwide.
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Bovinos/genética , Encefalopatía Espongiforme Bovina/genética , Priones/genética , Alelos , Animales , Secuencia de Bases , ADN/química , ADN/genética , Femenino , Haplotipos , Masculino , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/veterinaria , Polimorfismo de Nucleótido Simple , Estados UnidosRESUMEN
To determine the transmissibility of chronic wasting disease (CWD) to fallow deer (Dama dama) and to provide information about clinical course, lesions and suitability of currently used diagnostic procedures for detection of CWD in this species, 13 fawns were inoculated intracerebrally with CWD brain suspension from elk (n=6) or white-tailed deer (n=7). Three other fawns were kept as uninfected controls. Three CWD-inoculated deer were killed 7.6 months post-inoculation (mpi). None had abnormal prion protein (PrPd) in their tissues. One sick deer died at 24 mpi and one deer without clinical signs was killed at 26 mpi. Both animals had a small focal accumulation of PrPd in the midbrain. Between 29 and 37 mpi, three other deer became sick and were killed. All had shown gradual decrease in appetite and some loss of body weight. Microscopical lesions of spongiform encephalopathy were not observed, but PrPd was detected in tissues of the central nervous system (CNS) by immunohistochemistry, western blot and by two commercially available rapid diagnostic tests. This study demonstrates that intracerebrally inoculated fallow deer amplified CWD PrPd from white-tailed deer and elk in the absence of lesions of spongiform encephalopathy. Four years after CWD inoculation, the remaining five inoculated and two control deer are alive and apparently healthy.
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Encéfalo/metabolismo , Ciervos , Médula Espinal/metabolismo , Enfermedad Debilitante Crónica/transmisión , Animales , Western Blotting , Encéfalo/patología , ADN Viral/análisis , Susceptibilidad a Enfermedades , Transmisión de Enfermedad Infecciosa , Femenino , Inmunohistoquímica , Masculino , Reacción en Cadena de la Polimerasa , Priones/genética , Priones/metabolismo , Priones/patogenicidad , Pase Seriado , Médula Espinal/patología , Enfermedad Debilitante Crónica/metabolismo , Enfermedad Debilitante Crónica/patologíaRESUMEN
OBJECTIVE: Determine the association between key dental outcomes and added sugar intake using a survey instrument to assess added sugars, which was specifically tailored to immigrant and US-born adults of Mexican origin. METHODS: Hispanic adults of Mexican origin (n = 326; 36.2 ± 12.1 years) completed a self-administered survey to gather acculturation, self-reported dental experiences and self-care practices (eg brushing, flossing, pain, bleeding gums), and socio-demographic information. The survey included a culturally tailored 22-item Added Sugar Intake Estimate (ASIE) that assessed added sugar intake from processed foods and sugar-sweetened beverages in a semiquantitative food frequency questionnaire format. Linear regression, 2-sample t test, and ANOVA were used to evaluate associations of demographic and dental outcomes with daily added sugar intake. RESULTS: Of the mean total daily added sugar intake (99.6 ± 94.6 g), 36.5 ± 44.4 g was derived from sugar-containing foods and snacks, and 63.1 ± 68.2 g from beverages. Participants who reported greater added sugar intake were more likely to have reported the presence of a toothache in the preceding 12 months, having been prescribed antibiotics for dental reasons, being less likely to floss daily, have reported eating or drinking within 1 hour before bed and have lower psychological acculturation (P < .05 for all). Results were comparable when assessing intake from sugar-containing foods/snacks and sugar-sweetened beverages. CONCLUSIONS: This study confirmed the association between added sugar intake and self-reported dental outcomes among adults of Mexican origin and points to an urgent need to improve dietary behaviours in this population.
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Caries Dental/etnología , Azúcares de la Dieta/efectos adversos , Americanos Mexicanos , Aculturación , Adolescente , Adulto , Anciano , Bebidas Gaseosas/efectos adversos , Caries Dental/epidemiología , Caries Dental/etiología , Femenino , Humanos , Masculino , Americanos Mexicanos/estadística & datos numéricos , Persona de Mediana Edad , Salud Bucal , Higiene Bucal , Encuestas y Cuestionarios , Estados Unidos/epidemiología , Adulto JovenRESUMEN
It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.
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Maleato de Dizocilpina , Interneuronas/metabolismo , Parvalbúminas/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/fisiopatología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Ratones Noqueados , Esquizofrenia/inducido químicamenteRESUMEN
In an effort to quantify the importance of hydrogen bonding and alpha-helix formation to protein stability, a capping box motif was introduced into the small phosphocarrier protein HPr. Previous studies had confirmed that Ser46, at the N-cap position of the short helix-B in HPr, serves as an N-cap in solution. Thus, only a single-site mutation was required to produce a canonical S-X-X-E capping box: Lys49 at the N3 position was substituted with a glutamic acid residue. Thermal and chemical denaturation studies on the resulting K49E HPr show that the designed variant is approximately 2 kcal mol-1 more stable than the wild-type protein. However, NMR studies indicate that the side-chain of Glu49 does not participate in the expected capping H-bond interaction, but instead forms a new tertiary H-bond that links helix-B to the four-stranded beta-sheet of HPr. Here, we demonstrate that a strategy in which new non-native H-bonds are introduced can generate proteins with increased stability. We discuss why the original capping box design failed, and compare the energetic consequences of the new tertiary side-chain to main-chain H-bond with a local (helix-capping) side-chain to main-chain H-bond on the protein's global stability.
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Escherichia coli/química , Mutación , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/química , Ingeniería de Proteínas , Sustitución de Aminoácidos , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Enlace de Hidrógeno , Cinética , Modelos Moleculares , Resonancia Magnética Nuclear Biomolecular , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/genética , Sistema de Fosfotransferasa de Azúcar del Fosfoenolpiruvato/metabolismo , Conformación Proteica , Desnaturalización Proteica , Pliegue de Proteína , Estructura Secundaria de Proteína , Protones , Serina/genética , Serina/metabolismo , Solventes , Temperatura , Termodinámica , UreaRESUMEN
Children aged 1-10 in five villages were contacted fortnightly. Their axillary temperatures, reports of fevers and blood slides were taken. Following the introduction of permethrin impregnated nets into two estate villages the slide positivity for falciparum malaria declined markedly. In traditional villages the introduction of impregnated nets had less convincing effects than in the estate villages and DDT spraying had no perceptible effect on malaria. Over all villages there was a clear relationship between axillary temperature greater than 37.4 degrees C, reports of fever and high parasitaemia. We defined malaria fever in this way, and found in some cases significant reductions in occurrence of such fever following some time after introduction of permethrin impregnated nets. No such effects were found with lambdacyhalothrin nets or with DDT spraying.
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Ropa de Cama y Ropa Blanca , Fiebre , Insecticidas , Malaria/epidemiología , Piretrinas , Sangre/parasitología , Niño , Preescolar , DDT , Vivienda , Humanos , Lactante , Malaria/prevención & control , Control de Mosquitos/métodos , Nitrilos , Permetrina , Prevalencia , Tanzanía/epidemiologíaRESUMEN
The plasma, in addition to the liver, is a major site of hydrolysis of aspirin. Human plasma and liver aspirin esterase activities in samples from a group of patients varied over a two fold range and there was a significant correlation between individual plasma and liver activities. Human liver aspirin esterase was present in the cytosolic and microsomal fractions. Cytosolic and microsomal enzymes had different activities and apparent affinities for aspirin.
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Hidrolasas de Éster Carboxílico/metabolismo , Hígado/enzimología , Anciano , Hidrolasas de Éster Carboxílico/sangre , Cromatografía Líquida de Alta Presión , Citosol/enzimología , Femenino , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/enzimología , Persona de Mediana Edad , Fracciones Subcelulares/enzimologíaRESUMEN
The authors describe a placebo controlled trial of a slow-release form of aminophylline in a total of twenty asthmatic patients. The data resulting from this work confirmed the fact that the aminophylline is a bronchodilator which improves mean peak flow rate and reduces the intake of beta-agonist drugs in the majority of asthmatic patients.
Asunto(s)
Aminofilina/uso terapéutico , Asma/tratamiento farmacológico , Aminofilina/administración & dosificación , Asma/fisiopatología , Niño , Ensayos Clínicos como Asunto , Preparaciones de Acción Retardada , Femenino , Humanos , Masculino , PlacebosRESUMEN
Twenty-three infants who had positive cord blood VDRL test results are described. Fourteen had clinical signs of congenital syphilis. All but one of the affected, and only one of the unaffected infants had high immunoglobulin M (IgM) levels. Several affected infants had low immunoglobulin G (IgG) levels suggesting poor placental transfer. Total protein, albumin and colloid osmotic pressure (COP) levels were generally within the normal range in the whole group, so these are unlikely to be responsible for the neonatal edema found in many of the affected infants.