RESUMEN
BACKGROUND AND PURPOSE: Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. METHODS: In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). CONCLUSIONS: This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Herpesvirus Humano 6 , Esclerosis Múltiple , Adolescente , Estudios de Casos y Controles , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/epidemiología , Herpesvirus Humano 4 , Humanos , Esclerosis Múltiple/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown. PATIENTS AND METHODS: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay). RESULTS: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis. CONCLUSIONS: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades.
Asunto(s)
Anticuerpos Antivirales/sangre , Papillomavirus Humano 16/inmunología , Neoplasias Orofaríngeas/diagnóstico , Infecciones por Papillomavirus/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Adulto , Anciano , Carcinogénesis/inmunología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Papillomavirus Humano 16/aislamiento & purificación , Humanos , Masculino , Persona de Mediana Edad , Proteínas Oncogénicas Virales/inmunología , Neoplasias Orofaríngeas/sangre , Neoplasias Orofaríngeas/inmunología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/sangre , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Estudios Prospectivos , Proteínas Represoras/inmunología , Seroconversión , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Factores de TiempoRESUMEN
We show that Fano resonances created by two ð« ð¯ -symmetric nonlinear micro-resonators coupled to a waveguide, have line-shape and resonance position that depends on the direction of the incident light. We utilize these features in order to induce asymmetric transport, up to 47 dBs, in the optical C-window. Our theoretical proposal requires low input power and does not compromise the power or frequency characteristics of the output signal.
RESUMEN
A mechanism for asymmetric transport which is based on parity-time-symmetric nonlinearities is presented. We show that in contrast to the case of conservative nonlinearities, an increase of the complementary conductance strength leads to a simultaneous increase of asymmetry and transmittance intensity. We experimentally demonstrate the phenomenon using a pair of coupled Van der Pol oscillators as a reference system, each with complementary anharmonic gain and loss conductances, connected to transmission lines. An equivalent optical setup is also proposed.
RESUMEN
INTRODUCTION: The omega-3 long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are important for brain development and cognitive performance. Because they are semi-essential fatty acids, they must be obtained from food. However, the dietary reference intakes of DHA and EPA have not yet been established. In women, a low DHA and/or EPA serum level during pregnancy or breastfeeding might negatively affect their children. For this study, we conducted a systematic review and meta-analysis of randomized control trials on the association between the consumption of fish oil supplements in pregnant and/or breastfeeding women and the cognitive performance of their children. METHODS: The PubMed, Embase, and Central literature databases were systematically searched. We included and extracted relevant studies in duplicate and assessed study quality. Cognitive outcomes were grouped according to published criteria and according to time elapsed after the intervention. We performed fixed-effects meta-analyses for each cognitive outcome and for birth weight. We assessed potential confounding with meta-regressions and sensitivity analyses. RESULTS: A total of 11 trials were included. No significant association was found between DHA/EPA supplementation and any of the assessed cognitive parameters or birth weight. DISCUSSION: Our results confirm previous reviews on the studied topic. Reasons for inconclusive results may be small sample sizes for each assessed category, questionable quality of included studies, and the difficulty of reliably measuring cognitive performance in small children. Blood levels of omega-3 long-chain polyunsaturated fatty acids were mostly not comparable. Furthermore, the influence of genetic and environmental factors could not be assessed. Studies in this field should address such shortcomings.
Asunto(s)
Cognición/efectos de los fármacos , Suplementos Dietéticos , Ácidos Docosahexaenoicos/administración & dosificación , Ácido Eicosapentaenoico/administración & dosificación , Niño , Preescolar , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Femenino , Humanos , Lactante , EmbarazoRESUMEN
Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.
RESUMEN
INTRODUCTION: How the long-chain fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in the diet permitted human brain evolution, and how much our brains need today to function optimally are still hot topics for debate. DHA and EPA are considered as semi-essential because only insufficient amounts can be produced from other nutrients, such that they must be ingested with the diet. However, the Dietary Reference Intake of DHA and EPA, or of fish containing these fatty acids, has not yet been established. Eating fish is often recommended and generally considered beneficial for health and cognitive development in children and adolescents. For this study, data from a large cohort study were analysed to assess the association between fish consumption and cognitive school performance in children and adolescents. METHODS: Data from the German cohort of children and adolescent health KiGGS, which was conducted 2003-06 and included more than 17 000 children, were analysed. Ordered logistic regressions were performed to test for associations between fish intake and school performance. Potential confounders were included in the models. RESULTS: A statistically significant association was found between an intake of 8 g of fish per day and the probability of increasing the final grade in German [odds ratio (OR) 1.193, 95% confidence interval (CI) 1.049-1.358] and mathematics (OR 1.16, 95% CI 1.022-1.317) by one point, compared to no or very limited fish consumption. For the outcome German, higher levels of fish intake also showed a positive effect. These relationships were not linear but tended to decrease again at higher doses of fish. DISCUSSION: Our result confirms previous reports of a positive association between fish intake and school performance. Interestingly, this relationship was not linear but tended to decrease again in the highest categories of fish intake. We hypothesize that mercury or other pollutants in the fish could be detrimental at high levels. As only half of all children met the minimal fish intake recommendations, fish consumption should be promoted more strongly in children to meet the minimal requirements of long-chain polyunsaturated fatty acids. LAY SUMMARY: Polyunsaturated fatty acids like DHA and EPA that are present in fish are essential for a healthy human brain development. We found a U-shaped association between fish intake and school performance in children. We hypothesize that mercury or other pollutants in the fish could be detrimental at high intake levels.
RESUMEN
In epidemiologic studies, patients with head and neck squamous cell carcinoma (HNSCC) are classified mainly by the International Classification of Diseases (ICD) codes. However, some patients are of an unclear subsite, the "gray zone" cases, which could reflect ICD coding error, absence of primary subsite, or extensive primary tumors that cross over multiple subsites of the oral cavity and oropharynx. Patients with gray zone squamous cell carcinomas were compared with patients with oral cavity squamous cell carcinoma (OSCC) or oropharyngeal squamous cell carcinoma (OPSCC) and stratified by human papillomavirus (HPV) status that was determined by p16 immunostaining or HPV serology. Comparisons consisted of clinicodemographic features and prognostic outcomes presented by Kaplan-Meier curves and Cox proportional hazards regression models, reported as hazard ratios. There were 158 consecutive patients with gray zone HNSCC diagnosed at the Princess Margaret Cancer Center between 2006 and 2017: 66 had subsite coding discrepancies against the clinician's documentation ("discrepant" cases; e.g., the diagnosis by the clinician was OSCC, while the classification by ICD coding was OPSCC), while 92 were squamous cell carcinoma of unknown primary of the head and neck (SCCUPHN) after complete diagnostic workup. Comparators included 721 consecutive OSCC and 938 OPSCC adult cases. All HPV-positive cohorts (OPSCC, discrepant, and SCCUPHN) had similar clinicodemographic characteristics and better 3- and 5-y overall survival and disease-free survival than their HPV-negative counterparts. In contrast, HPV-negative discrepant cases had prognostic outcomes most similar to HPV-negative OPSCC cases, while HPV-negative SCCUPHN had survival outcomes most similar to those of patients with OSCC in this study. HPV-positive status can improve the classification of patients with unclear or discrepant oral/oropharyngeal subsite, an improvement over classification systems that are solely clinician defined or conducted through ICD coding. However, due to clinical practice, we could not make definitive reclassification for patients with HPV-negative gray zone HNSCC.
Asunto(s)
Carcinoma de Células Escamosas/clasificación , Neoplasias de Cabeza y Cuello/clasificación , Neoplasias Orofaríngeas/clasificación , Papillomaviridae , Infecciones por Papillomavirus , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/virología , Codificación Clínica , Femenino , Neoplasias de Cabeza y Cuello/virología , Humanos , Clasificación Internacional de Enfermedades , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/virología , Adulto JovenRESUMEN
OBJECTIVE: To identify appropriate dosages of ramipril and hydrochlorothiazide (HCT) when given in combination once a day for the treatment of essential hypertension. DESIGN: A 2- or 4-week placebo run-in followed by 6-week, double-blind, parallel-group phase: 4 x 3 factorial (2.5, 5 and 10 mg ramipril; 12.5 and 25 mg HCT; all six combinations; placebo). SETTING: Office practice (21 centres). PATIENTS AND PARTICIPANTS: Patients with mild-to-moderate essential hypertension (World Health Organization stage I-II; supine diastolic blood pressure 100-115 mmHg in last 2 weeks of run-in): 581 enrolled, 534 randomly assigned to double-blind therapy and 517 completed. MAIN OUTCOME MEASURES: Reduction in supine and standing blood pressure. RESULTS: In pairwise comparisons, the combinations of 5 mg ramipril with 12.5 and 25 mg HCT and 10 mg ramipril with 12.5 mg HCT consistently produced significantly greater blood pressure reductions than their respective components. Response surface analyses were performed, and a stairstep model was constructed to characterize the shape of the dose-response surface. The combinations involving 5 and 10 mg ramipril with 12.5 and 25 mg HCT were again more effective than their components. Withdrawals and adverse effects were minimal for all treatments. A large drop in serum potassium was observed on 25 mg HCT, but not on combination therapy. Addition of ramipril appeared to reduce the hyperuricaemic effect of HCT. CONCLUSIONS: Several dosage combinations of ramipril plus HCT produced significantly greater blood pressure reductions than the monotherapies at the same dosages. Overall, the combination of 5 mg ramipril and 25 mg HCT gave the best mean reduction. Combination therapy with ramipril plus HCT was safe and effective for patients with mild-to-moderate essential hypertension.
Asunto(s)
Hidroclorotiazida/administración & dosificación , Hipertensión/tratamiento farmacológico , Ramipril/administración & dosificación , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Hidroclorotiazida/uso terapéutico , Masculino , Persona de Mediana Edad , Ramipril/uso terapéutico , Proyectos de InvestigaciónRESUMEN
In order to evaluate the pharmacokinetics and excretion of ramipril in man, 8 cholecystectomy patients aged between 53 and 68 years received 5 mg ramipril orally as a single dose. All patients had a T-drain inserted to permit bile collection; all gave their informed consent to participate in the trial. Serum samples were collected half-hourly until 2 hours, then hourly until 6 hours, then at 8, 10, 24 and 25 hours after intake. Urine was collected in 2-hour fractions until 8 hours, followed by a 4- and a 12-hour fraction. Bile was collected hourly until 6 hours, followed by a 6- and a 12-hour collecting fraction. Concentrations of ramipril and ramiprilat in serum, and determinations in urine and bile of ramipril, ramiprilat, ramipril glucuronide, ramiprilat glucuronide, diketopiperazine and diketopiperazine acid were made; total amounts excreted were calculated. Peak concentrations of ramiprilat in plasma (8.7 +/- 1.6 ng/ml) were reached after about 8 hours. AUC0-8 and AUC0-24-values were 36.5 and 111.9 ng.h/ml, respectively. Ramiprilat Cmax-concentrations were about 300-fold higher in bile than in plasma, the corresponding difference for ramipril between bile and plasma was about 4-fold. The main fractions excreted in the urine were diketopiperazine acid and ramiprilat amounting to 13.2 +/- 5.6 and 4.4 +/- 2.4%, respectively, of the dose administered. Only a very small fraction of the dose was excreted with urine as unchanged ramipril, on average 0.9 +/- 1.0%. The main fractions excreted in the bile were diketopiperazine acid, ramiprilat glucuronide and diketopiperazine, 9.0 +/- 5.3, 3.4 +/- 4.2 and 2.0 +/- 1.2% in 24 hours, respectively, of the dose administered. Only a negligible fraction of the dose (average 0.1 +/- 0.1%) was excreted with bile as unchanged ramipril. In conclusion, there is strong evidence that circulating ramipril and ramiprilat are eliminated by both the liver and the kidneys. For the patients studied it can be estimated from late collection periods that some 2/3 of circulating ramipril and ramiprilat are eliminated by the kidneys and 1/3 eliminated by the liver.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/metabolismo , Bilis/metabolismo , Ramipril/análogos & derivados , Ramipril/metabolismo , Administración Oral , Anciano , Inhibidores de la Enzima Convertidora de Angiotensina/farmacocinética , Biotransformación , Colecistectomía , Cromatografía de Gases , Femenino , Humanos , Riñón/metabolismo , Análisis de los Mínimos Cuadrados , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Radioinmunoensayo , Ramipril/farmacocinética , Factores de TiempoRESUMEN
The spatial resolution and contrast resolution required of a multiformat camera (MFC) for medical imaging are discussed. A typical cathode-ray tube (CRT) MFC and a prototype laser MFC are compared based on the following measured quantities: line spread function and associated contrast transfer function, noise characteristics, intensity transfer function (dynamic range), large-area contrast, and film irradiance. The laser MFC is found to provide significantly better performance than the CRT MFC in all of these areas.
Asunto(s)
Rayos Láser , Análisis de Fourier , Humanos , Fotograbar/instrumentación , Fotograbar/métodos , Enfermedades Torácicas/diagnósticoRESUMEN
Research into drug therapy for the acute treatment of ischemic stroke is now booming, and a number of promising drugs with very different mechanisms of action are at an advanced stage of development. Ideally, use of single agents or combinations of agents will result in favorable neurologic and functional outcomes for the majority of stroke patients. Given the current focus within our society on controlling health care costs, pharmacoeconomic tools will be important in determining which of these agents should achieve formulary acceptance. Cost-minimization analysis, cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis are all likely to be valuable methodologies to aid in decision making. More complex situations may require the use of decision-tree analysis.
Asunto(s)
Trastornos Cerebrovasculares/tratamiento farmacológico , Árboles de Decisión , Quimioterapia Combinada , Economía Farmacéutica , Humanos , Fármacos Neuroprotectores/uso terapéuticoRESUMEN
In a parallel-group multicenter study, the efficacy and safety of combination therapy with ramipril 5 mg plus hydrochlorothiazide 25 mg were compared double-blind with those of 5 mg and 10 mg ramipril monotherapy in patients with mild to moderate hypertension who had not responded adequately to ramipril 5 mg alone. Patients were initially treated single-blind for 1 week with ramipril 2.5 mg and 3 weeks with ramipril 5 mg. Of 240 patients enrolled, 165 were subsequently classed as nonresponders (diastolic blood pressure > 90 mmHg) and were randomized to one of the three double-blind treatments for a further 4 weeks. In the double-blind phase, the mean reductions in supine systolic and diastolic blood pressures at end point were significantly greater in the 5 mg plus 25 mg combination group (11.6/10.6 mmHg) than in the groups receiving ramipril 5 mg (6.2/5.9 mmHg; both p < 0.01) and ramipril 10 mg (7.4/7.1 mmHg; both p < 0.05). The proportion of responders at end point was also higher for combination therapy (72%) than for monotherapy (48% for ramipril 5 mg and 62% for ramipril 10 mg). All three treatments were well tolerated. Analysis of laboratory values revealed no clinically important changes.
Asunto(s)
Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Ramipril/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Método Doble Ciego , Combinación de Medicamentos , Tolerancia a Medicamentos , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/efectos adversos , Masculino , Persona de Mediana Edad , Placebos , Ramipril/administración & dosificación , Ramipril/efectos adversos , Seguridad , Método Simple CiegoRESUMEN
In an open, multicenter extension of a short-term study, 159 patients with mild to moderate hypertension were treated with either ramipril monotherapy or a combination of ramipril and hydrochlorothiazide for up to 1 year. Patients started with either 5 mg ramipril once daily (responders in the short-term study) or a combination of ramipril 5 mg plus hydrochlorothiazide 25 mg once daily. The dose could be adjusted and nonresponders to ramipril monotherapy could have hydrochlorothiazide added. In the 38 patients treated with ramipril monotherapy, the largest drop in mean blood pressure (BP) had already occurred in the previous short-term study; from Week 2 in the long-term study, the BP remained stable with means below 150/90 mmHg. In the 83 patients treated with the combination for 50 weeks or more, mean BP continued to decrease until around Week 10 in the long-term study while therapy was being adjusted. Thereafter, it also remained stable with means below 150/85 mmHg. Both treatment groups showed good mean reductions at end point, as did the group of 38 patients treated with the combination for less than 50 weeks. High response rates (84-95%) were seen in all groups at end point. The combination was well tolerated and the efficacy of ramipril in combination with hydrochlorothiazide was maintained over the 1-year period of investigation.
Asunto(s)
Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Ramipril/uso terapéutico , Adulto , Anciano , Presión Sanguínea/efectos de los fármacos , Quimioterapia Combinada , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/efectos adversos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Ramipril/administración & dosificación , Ramipril/efectos adversosRESUMEN
Gene therapy is a new therapeutic approach which is tested in numerous diseases connected with either non or only limited therapeutic effects. This paper aims at discussing the actual state of the clinical development of gene-therapy which targets an approval by either the FDA or EMEA. Basis of all the figures and tables presented is a BioMedNet/Medline search reviewing all titles found under the keywords gene therapy and/or clinical development. The review period begins in the year 1992 and ends in 2002. Publications identified were sorted into the following categories: therapeutic areas with gene therapy activities; indications and diseases with gene-therapy activities; vectors used in gene therapy and clinical studies using gene therapy. Only in some indications like breast cancer, colorectal cancer, HIV, and cystic fibrosis a variety of clinical studies had been published indicating a serious attempt to develop the indication for approval. But most developments are still in phase I/II. In all other therapeutic areas no systematic continuous approach was identified. Clinical activities in cardiovascular diseases and in peripheral vascular diseases increased during the preceding five years compared other therapeutic areas.
Asunto(s)
Terapia Genética/tendencias , Ensayos Clínicos como Asunto , Terapia Genética/economía , Humanos , MEDLINE , Apoyo a la Investigación como AsuntoRESUMEN
Obesity is a major public health issue and an important contributor to the global burden of chronic disease and disability. Studies indicate that fish and omega-3 polyunsaturated fatty acids (n3-PUFA) supplements may help prevent cardiovascular and metabolic diseases. However, the effect of fish oil on body composition is still uncertain, so we performed a systematic review of randomized controlled trials and the first meta-analysis on the association between fish or fish oil intake and body composition measures. We found evidence that participants taking fish or fish oil lost 0.59 kg more body weight than controls (95% confidence interval [CI]: -0.96 to -0.21). Treatment groups lost 0.24 kg m(-2) (body mass index) more than controls (-0.40 to -0.08), and 0.49 % more body fat than controls (-0.97 to -0.01). Fish or fish oil reduced waist circumference by 0.81 cm (-1.34 to -0.28) compared with control. There was no difference for fat mass and lean body mass. Further research is needed to confirm or refute our findings and to reveal possible mechanisms by which n3-PUFAs might reduce weight.