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Background: Although communication is strongly emphasized in palliative care, not much research has focused on communication between patients and their loved ones. The purpose was to increase understanding of communication around severe illness between patients with a life-threatening disease, receiving palliative care, and their loved ones. Secondary intention was to identify strategies making easier for patients to talk about their condition with loved ones. The article is based on in-depth interviews with 15 patients and 8 loved ones. Interviews were analysed using qualitative content analysis. Communication about patient's illness was often described as balancing between wanting to inform or know and wanting to protect. Both patients and loved ones deliberately talk in a way that reflects their relationship. They act, negotiate and communicate aiming at not wanting to create situations that are perceived as uncomfortable, either for themselves or for others. Patients also take everyday practicalities into account. In these interactions, some people become the patients' inner circle - people with whom information is shared and co-owned. Other people find themselves outside the circle and patients may use them as test-subjects - speaking to them about things they might not dare reveal to their inner circle. These considerations are reflected in the themes: What is communicated, How communication is performed, and When it takes place. Our findings show that acting on the ideals of an "open and honest" form of communication is not always to be recommended. Professionals must instead strive to understand and respect the intentions of those involved.
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Enfermería de Cuidados Paliativos al Final de la Vida , Cuidados Paliativos , Humanos , Pacientes , ComunicaciónAsunto(s)
Diabetes Mellitus Tipo 1 , Hipoglucemia , Humanos , Adulto , Diabetes Mellitus Tipo 1/complicaciones , Hipoglucemia/inducido químicamente , Hipoglucemia/prevención & control , Hipoglucemia/complicaciones , Hipoglucemiantes/efectos adversos , Miedo , Automonitorización de la Glucosa Sanguínea , Glucemia , InsulinaRESUMEN
Arginase 1 (Arg1) is a ubiquitous enzyme belonging to the urea cycle that catalyzes the conversion of l-arginine into l-ornithine and urea. In endothelial cells (ECs), Arg1 was proposed to limit the availability of l-arginine for the endothelial nitric oxide synthase (eNOS) and thereby reduce nitric oxide (NO) production, thus promoting endothelial dysfunction and vascular disease. The role of EC Arg1 under homeostatic conditions is in vivo less understood. The aim of this study was to investigate the role of EC Arg1 on the regulation of eNOS, vascular tone, and endothelial function under normal homeostatic conditions in vivo and ex vivo. By using a tamoxifen-inducible EC-specific gene-targeting approach, we generated EC Arg1 KO mice. Efficiency and specificity of the gene targeting strategy was demonstrated by DNA recombination and loss of Arg1 expression measured after tamoxifen treatment in EC only. In EC Arg1 KO mice we found a significant decrease in Arg1 expression in heart and lung ECs and in the aorta, however, vascular enzymatic activity was preserved likely due to the presence of high levels of Arg1 in smooth muscle cells. Moreover, we found a downregulation of eNOS expression in the aorta, and a fully preserved systemic l-arginine and NO bioavailability, as demonstrated by the levels of l-arginine, l-ornithine, and l-citrulline as well as nitrite, nitrate, and nitroso-species. Lung and liver tissues from EC Arg1 KO mice showed respectively increase or decrease in nitrosyl-heme species, indicating that the lack of endothelial Arg1 affects NO bioavailability in these organs. In addition, EC Arg1 KO mice showed fully preserved acetylcholine-mediated vascular relaxation in both conductance and resistant vessels but increased phenylephrine-induced vasoconstriction. Systolic, diastolic, and mean arterial pressure and cardiac performance in EC Arg1 KO mice were not different from the wild-type littermate controls. In conclusion, under normal homeostatic conditions, lack of EC Arg1 expression is associated with a down-regulation of eNOS expression but a preserved NO bioavailability and vascular endothelial function. These results suggest that a cross-talk exists between Arg1 and eNOS to control NO production in ECs, which depends on both L-Arg availability and EC Arg1-dependent eNOS expression.
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Arginasa , Óxido Nítrico Sintasa de Tipo III , Animales , Arginasa/genética , Arginasa/metabolismo , Arginina/metabolismo , Regulación hacia Abajo , Células Endoteliales/metabolismo , Ratones , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Ornitina , Tamoxifeno/metabolismo , Urea/metabolismoRESUMEN
Nitric oxide (NO) contributes to maintaining normal cardiovascular and renal function. This bioactive signalling molecule is generally formed enzymatically by NO synthase in the vascular endothelium. NO bioactivity can also be attributed to dietary intake of inorganic nitrate, which is abundant in our diet, especially in green leafy vegetables and beets. Ingested nitrate is reduced to nitrite by oral commensal bacteria and further to NO systemically. Previous studies have shown that dialysis, by means of removing nitrate and nitrite from the body, can reduce NO bioactivity. Hence, dietary intervention approaches aimed to boost the nitrate-nitrite-NO pathway may be of benefit in dialysis patients. The purpose of this study was to examine the kinetics of plasma nitrate and nitrite after a single intake of nitrate-rich concentrated beetroot juice (BJ) in adult hemodialysis (HD) patients and in age-matched healthy volunteers (HV). Eight HD patients and seven HV participated in this single center, randomized, single-blind, placebo-controlled, crossover study. Each participant received a sequential single administration of active BJ (70 mL, 400 mg nitrate) and placebo BJ (70 mL, 0 mg nitrate) in a random order separated by a washout period of seven days. For the kinetic analysis, blood samples were collected at different time-points before and up to 44 h after BJ intake. Compared with placebo, active BJ significantly increased plasma nitrate and nitrite levels both in HD patients and HV. The area under the curve and the maximal concentration of plasma nitrate, but not of nitrite, were significantly higher in HD patients as compared with HV. In both groups, active BJ ingestion did not affect blood pressure or plasma potassium levels. Both BJs were well tolerated in all participants with no adverse events reported. Our data provide useful information in planning dietary nitrate supplementation efficacy studies in patients with reduced NO bioactivity.
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Beta vulgaris , Nitritos , Adulto , Antioxidantes/análisis , Presión Sanguínea , Estudios Cruzados , Suplementos Dietéticos , Jugos de Frutas y Vegetales/análisis , Humanos , Cinética , Nitratos , Óxido Nítrico/metabolismo , Diálisis Renal , Método Simple CiegoRESUMEN
BACKGROUND: the ageing global population is living longer with complex health conditions addressed by multiple medications. Little is known about how older people manage these medications and associated packaging at home. OBJECTIVES: to explore how older people manage the use of multiple medication and associated packaging in their process of self-care. METHODS: fifteen older, home-dwelling participants (mean age = 76.2 years) participated in this study. All participants used three or more daily medications and resided in Southern Sweden. Data were collected using photographs and written diaries completed by each participant over seven consecutive days, complemented by researcher-led interviews. Interviews and diary data were analysed using thematic analysis. RESULTS: six major themes emerged and are discussed: systematic organisation of medication, design of medication packaging, design of tablets, ease of package opening, emotional response to the need for medication, and environmental waste. CONCLUSION: packaging plays an important role in protecting products and enabling easy storage, product longevity and transportation. Medication packaging is no exception. However, the design of medication packaging poses challenges for older people managing medications for their chronic health conditions at home. There is a need to facilitate the systematic management of multiple medications, especially for new medication regimes or changes in treatment. Design of both packaging and medication should be consistent for older users to avoid potential errors; difficulties opening packaging can potentially hinder adherence to treatment. This study highlights the need for patient-centred solutions and involvement of older people in a co-design process for medication and packaging design.
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Embalaje de Medicamentos , Autocuidado , Anciano , Estado de Salud , Humanos , Cumplimiento de la Medicación , SueciaRESUMEN
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant of concern (VOC) has destabilized global efforts to control the impact of coronavirus disease 2019 (COVID-19). Recent data have suggested that B.1.1.529 can readily infect people with naturally acquired or vaccine-induced immunity, facilitated in some cases by viral escape from antibodies that neutralize ancestral SARS-CoV-2. However, severe disease appears to be relatively uncommon in such individuals, highlighting a potential role for other components of the adaptive immune system. We report here that SARS-CoV-2 spike-specific CD4+ and CD8+ T cells induced by prior infection or BNT162b2 vaccination provide extensive immune coverage against B.1.1.529. The median relative frequencies of SARS-CoV-2 spike-specific CD4+ T cells that cross-recognized B.1.1.529 in previously infected or BNT162b2-vaccinated individuals were 84% and 91%, respectively, and the corresponding median relative frequencies for SARS-CoV-2 spike-specific CD8+ T cells were 70% and 92%, respectively. Pairwise comparisons across groups further revealed that SARS-CoV-2 spike-reactive CD4+ and CD8+ T cells were functionally and phenotypically similar in response to the ancestral strain or B.1.1.529. Collectively, our data indicate that established SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses, especially after BNT162b2 vaccination, remain largely intact against B.1.1.529.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19 , Protección Cruzada , SARS-CoV-2 , Anticuerpos Antivirales , Vacuna BNT162 , Humanos , Glicoproteína de la Espiga del CoronavirusRESUMEN
BACKGROUND: Patient centricity has gained attention ranging from regulatory authorities to patient advocacy groups, calling for pharmaceutical companies to revise their traditional business approach to drug development by including the development of solutions that are meaningful in patients' lives. Medication packaging is one area where empirical evidence is lacking about the incorporation of patient centricity. This study aimed to explore patient centricity applied to pharmaceutical companies' packaging, and to identify the specific challenges faced and lessons learned when developing patient-centered packaging. METHODS: The study followed a multiple-case study research approach based on five cases of patient-centered packaging development in mid- and large-sized pharmaceutical companies. RESULTS: Patient-centered packaging is often associated with the intuitive and self-explanatory use of the medication by patients. Patient-centered packaging comes with challenges, but also offers opportunities for the creation of better solutions for patients and learning for the teams involved. To overcome these challenges, it is essential to build a business case that justifies such development, one where patient needs are present from the start and aligned with other imperative deadlines of drug development, with stakeholders onboard. CONCLUSION: Patient-centered packaging is the exception rather than the norm in packaging development due to a conventional approach where packaging plays an ancillary role to drug protection. The cases presented here challenge this approach and can inspire other companies to carry out patient-centered packaging development. The cases are also relevant to other actors who are interested in continuously promoting the dialogue about patient centricity in healthcare.
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Comercio , Industria Farmacéutica , Embalaje de Medicamentos , Humanos , Atención Dirigida al Paciente , Preparaciones FarmacéuticasRESUMEN
BACKGROUND: Declining humoral immunity in coronavirus disease 2019 (COVID-19) patients and possible reinfection have raised concern. Mucosal immunity, particularly salivary antibodies, may be short lived although long-term studies are lacking. METHODS: Using a multiplex bead-based array platform, we investigated antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins in 256 saliva samples from convalescent patients 1-9 months after symptomatic COVID-19 (nâ =â 74, cohort 1), undiagnosed individuals with self-reported questionnaires (nâ =â 147, cohort 2), and individuals sampled prepandemic (nâ =â 35, cohort 3). RESULTS: Salivary IgG antibody responses in cohort 1 (mainly mild COVID-19) were detectable up to 9 months postrecovery, with high correlations between spike and nucleocapsid specificity. At 9 months, IgG remained in blood and saliva in most patients. Salivary IgA was rarely detected at this time point. In cohort 2, salivary IgG and IgA responses were significantly associated with recent history of COVID-19-like symptoms. Salivary IgG tolerated temperature and detergent pretreatments. CONCLUSIONS: Unlike SARS-CoV-2 salivary IgA that appeared short lived, specific saliva IgG appeared stable even after mild COVID-19, as for blood serology. This noninvasive saliva-based SARS-CoV-2 antibody test with home self-collection may be a complementary alternative to conventional blood serology.
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Anticuerpos Antivirales/inmunología , COVID-19/inmunología , Inmunoglobulina G/inmunología , SARS-CoV-2/inmunología , Saliva/inmunología , Adulto , Anciano , Anticuerpos Antivirales/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19.
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Convalecencia , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Linfocitos T/inmunología , Adulto , Anticuerpos Antivirales/inmunología , Infecciones Asintomáticas , Betacoronavirus/inmunología , COVID-19 , Infecciones por Coronavirus/patología , Femenino , Humanos , Memoria Inmunológica , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , SARS-CoV-2RESUMEN
Objectives: Anti-TNF treatment is established for patients with severe inflammatory bowel disease (IBD) refractory to conventional medication. However, long-term real-life observations are limited. We have monitored 200 patients with primary response to infliximab (Remicade®).Methods: Patients with either Crohn's disease (CD) or ulcerative colitis (UC) who started IFX and had clinical response at 1 year were prospectively followed. C-reactive protein (CRP), albumin, fecal calprotectin (FCP), Harvey Bradshaw index (HBI) in CD cases, and Quality of Life index were monitored. Concomitant medications, surgery and hospitalisation were assessed.Results: Out of the 200 patients, 164 suffered from CD. Median disease duration was 5.0 (0.2-44.0) years and the observation time was 3.4 (1.0-13.9) years. Steroid use was reduced from 51% to 10%. HBI in CD patients decreased from 8.0 ± 0.40 to 2.7 ± 0.26. Disease activity in UC patients was only assessed by biochemical markers. CRP decreased from 29.0 ± 6.2 to 8.0 ± 7.1 mg/L. FCP showed a decrease from 1918 (1837) to 191 (646) mg/kg. Hospitalization showed similar tendency and quality of life was improved. Twenty-seven percent had been operated before IFX introduction compared to 11% during the observation period. Loss of response was seen in 42 patients, of which 20 patients needed intestinal surgery.Conclusion: Two-thirds of the patients demonstrated stable clinical benefit from maintenance IFX. The results show steroid-sparing efficacy as well as improved quality of life and reduced need for surgery.
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Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Infliximab/uso terapéutico , Calidad de Vida , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adolescente , Adulto , Biomarcadores/análisis , Proteína C-Reactiva/metabolismo , Niño , Preescolar , Procedimientos Quirúrgicos del Sistema Digestivo , Heces/química , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Enfermedades Inflamatorias del Intestino/cirugía , Complejo de Antígeno L1 de Leucocito/metabolismo , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Regresión , Inducción de Remisión , Suecia , Resultado del Tratamiento , Adulto JovenRESUMEN
Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
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Homeostasis , Nitrato-Reductasa/fisiología , Nitratos , Óxido Nítrico/metabolismo , Nitritos/metabolismo , Adulto , Alopurinol/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Homeostasis/efectos de los fármacos , Homeostasis/fisiología , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Nitrato-Reductasa/metabolismo , Nitratos/sangre , Nitratos/farmacología , Nitratos/uso terapéutico , Óxido Nítrico Sintasa/metabolismo , Nitritos/sangre , Especificidad de Órganos , Oxidación-Reducción , Ratas , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/enzimología , Daño por Reperfusión/metabolismo , Xantina Deshidrogenasa/metabolismoRESUMEN
Enterovirus infections, in particular those with Coxsackieviruses, have been linked to the development of type 1 diabetes (T1D). Although animal models have demonstrated that interferons (IFNs) regulate virus-induced T1D by acting directly on the beta cell, little is known on the human pancreatic islet response to IFNs. Here we show that human islet cells respond to IFNs by expressing signature genes of antiviral defense. We also demonstrate that they express three intracellular sensors for viral RNA, the toll like receptor 3 (TLR3) gene, the retinoic acid-inducible gene I (RIG-I) and the melanoma differentiation-associated gene-5 (MDA-5), which induce type I IFN production in infected cells. Finally, we show for the first time that the IFN-induced antiviral state provides human islets with a powerful protection from the replication of Coxsackievirus. This may be critical for beta cell survival and protection from virus-induced T1D in humans.
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Antivirales/farmacología , Interferón-alfa/farmacología , Interferón gamma/farmacología , Islotes Pancreáticos/inmunología , Adulto , Anciano , Infecciones por Coxsackievirus/inmunología , Infecciones por Coxsackievirus/virología , Enterovirus Humano B/fisiología , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inmunidad Innata , Islotes Pancreáticos/virología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas/genética , Proteínas/metabolismo , Replicación Viral/inmunologíaRESUMEN
Enterovirus infections of the pancreatic islets are believed to trigger or precipitate the near total destruction of beta-cells that constitutes type 1 diabetes (T1D). This study investigated the ability of an anti-picornaviral compound, pleconaril, to block the replication of two beta-cell tropic Coxsackie B4 virus (CBV-4) strains in isolated human islets. The two strains, VD2921 and V89 4557, with demonstrated abilities to cause non-lytic persistence or lytic infection, respectively, in islets, represented two different potential mechanisms behind virus-induced T1D. The virus replication in the islets was studied with and without addition of pleconaril. In addition, islet morphology was studied every day. To test the effects of pleconaril and/or DMSO on the beta-cells' insulin secretion, glucose perifusions were performed on treated and untreated islets. Virus titrations showed a clear reduction of the replication of both strains after pleconaril treatment. The VD2921 strain was inhibited to undetectable levels. The V89 4557 strain, however, showed an initial reduction of titers but virus titers then increased despite the addition of a second dose of pleconaril. This incomplete inhibition of viral replication suggested the existence of a resistant subtype within this strain. Pleconaril treatment reduced the beta-cells' insulin secretion in response to glucose stimulation in some experiments and induced slight morphological changes to the islets compared to untreated controls. In summary, pleconaril reduced the replication of the two beta-cell tropic CBV-4 strains in human islets. However, genetic differences between these strains influenced the effectiveness of pleconaril treatment. This stresses the importance of using multiple viral strains in antiviral tests.
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Antivirales/farmacología , Infecciones por Coxsackievirus/tratamiento farmacológico , Enterovirus Humano B/efectos de los fármacos , Oxadiazoles/farmacología , Células Cultivadas , Infecciones por Coxsackievirus/patología , Infecciones por Coxsackievirus/virología , Efecto Citopatogénico Viral/efectos de los fármacos , Diabetes Mellitus Tipo 1/virología , Enterovirus Humano B/fisiología , Humanos , Insulina/análisis , Insulina/metabolismo , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Islotes Pancreáticos/virología , OxazolesRESUMEN
Enterovirus (EV) infections have been associated with the pathogenesis of type 1 diabetes (T1D). They may cause beta-cell destruction either by cytolytic infection of the cells or indirectly by triggering the autoimmune response. Evidence for EV involvement have been presented in several studies, EV-IgM antibodies have been reported in T1D patients, EV-RNA has been found in the blood from T1D patients at onset, and EV have been isolated from newly diagnosed T1D. Our aim was to study infections with EV isolates from newly diagnosed T1D patients in human pancreatic islets in vitro. Two of them (T1 and T2) originated from a mother and her son diagnosed with T1D on the same day, the other two (A and E) were isolated from a pair of twins at the time of diagnosis of T1D in one of them. Isolated human pancreatic islets were infected and viral replication, viability and degree of cytolysis as well as insulin release in response to high glucose were measured. All four EV isolates replicated in the islet cells and virus particles and virus-induced vesicles were seen in the cytoplasm of the beta-cells. The isolates varied in their ability to induce cytolysis and to cause destruction of the islets and infection with two of the isolates (T1 and A) caused more pronounced destruction of the islets. Infection with the isolate from the healthy twin boy (E) was the least cytolytic. The ability to secrete insulin in response to high glucose was reduced in all infected islets as early as 3 days post infection, before any difference in viability was observed. To conclude, strains of EV isolated from T1D patients at clinical presentation of T1D revealed beta-cell tropism, and clearly affected the function of the beta-cell. In addition, the infection caused a clear increase in the number of dead cells.
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Diabetes Mellitus Tipo 1/virología , Infecciones por Enterovirus/virología , Enterovirus/crecimiento & desarrollo , Enterovirus/aislamiento & purificación , Islotes Pancreáticos/patología , Islotes Pancreáticos/virología , Adulto , Supervivencia Celular , Células Cultivadas , Niño , Citoplasma/virología , Vesículas Citoplasmáticas/ultraestructura , Femenino , Humanos , Inmunohistoquímica , Insulina/biosíntesis , Masculino , Microscopía Electrónica de Transmisión , Virión/ultraestructura , Replicación ViralRESUMEN
BACKGROUND: Total tau (T-tau) and beta-amyloid((1-42)) (Abeta(1-42)) levels in cerebrospinal fluid (CSF) can differentiate Alzheimer's disease (AD) from normal aging or depressive pseudo-dementia. Differential diagnosis from dementia with Lewy bodies (DLB) in clinical settings is difficult. METHODS: The analytical performance of the INNOTEST PHOSPHO-TAU(181P) assay was validated in terms of selectivity, sensitivity, specificity, precision, robustness, and stability. Clinical utility of the assay alone, or combined with T-tau and Abeta(1-42), for discrimination of AD (n=94) from patients suffering from DLB (n=60) or from age-matched control subjects (CS) (n=60) was assessed in a multicenter study. RESULTS: CSF concentrations of tau phosphorylated at threonine 181 (P-tau(181P)) in AD was significantly higher than in DLB and CS. Discriminant analysis, a classification tree, and logistic regression showed that P-tau(181P) was the most statistically significant single variable of the three biomarkers for discrimination between AD and DLB. CONCLUSIONS: P-tau(181P) quantification is a robust and reliable assay that may be useful in discriminating AD from DLB.
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Enfermedad de Alzheimer/diagnóstico , Enfermedad por Cuerpos de Lewy/diagnóstico , Juego de Reactivos para Diagnóstico/normas , Proteínas tau/líquido cefalorraquídeo , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Diagnóstico Diferencial , Análisis Discriminante , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fosfotreonina/metabolismo , Curva ROC , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Proteínas tau/metabolismoRESUMEN
We show that genital infection with neurotropic HSV type 2 (HSV-2) induced a significant increase of the neuropeptide substance P (SP) within the genital tract of mice. SP was shown to weakly interfere with the HSV-2 replication. Furthermore, lack of SP signaling through the use of mice deficient in the SP receptor, neurokinin 1 receptor (NK1R), revealed an important role for SP in the innate defense against HSV-2. NK1R-deficient mice had significantly enhanced levels of HSV-2 in the genital tract and in the CNS following infection and a significantly accelerated disease progression, which was associated with an impaired NK cell activity locally in the vagina. Lack of NK1R signaling did, however, not impair the animals' ability to mount a protective immune response to HSV-2 following vaccination with an attenuated virus. Both NK1R+/+ and NK1R-/- mice developed strong HSV-2-specific Th1 T cell responses following vaccination. No genital viral replication was observed in either vaccinated NK1R-deficient or NK1R+/+ control animals following a genital HSV-2 challenge, and all of these animals survived without any symptoms of disease. In conclusion, the present results indicate that SP and NK1R signaling contributes to the innate resistance against HSV-2 infection in mice.
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Herpes Genital/inmunología , Receptores de Neuroquinina-1/inmunología , Animales , Sistema Nervioso Central/patología , Sistema Nervioso Central/virología , Femenino , Herpes Genital/metabolismo , Herpes Genital/prevención & control , Herpes Genital/virología , Vacunas contra el Virus del Herpes Simple/farmacología , Herpesvirus Humano 2/efectos de los fármacos , Herpesvirus Humano 2/inmunología , Herpesvirus Humano 2/fisiología , Inmunidad Innata , Técnicas In Vitro , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Neuroquinina-1/deficiencia , Receptores de Neuroquinina-1/genética , Transducción de Señal , Sustancia P/metabolismo , Sustancia P/farmacología , Vacunas Atenuadas/farmacología , Vagina/inmunología , Vagina/metabolismo , Vagina/virología , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Early identification of patients with mild cognitive impairment (MCI) progressing to Alzheimer disease (MCI-AD) by use of biomarkers in cerebrospinal fluid (CSF) is an essential step toward improving clinical diagnosis and drug development. We evaluated whether different beta-amyloid(42) (Abeta42) peptides can add further information to the combined use of tau and Abeta1-42 for predicting risk of progression of MCI to AD. METHODS: We used xMAP technology to simultaneously quantify different Abeta42 peptides modified at the amino terminus, tau, and phosphorylated tau (P-tau181P) in CSF. Abeta42 peptide concentrations were measured by use of immunoreactivity toward Abeta monoclonal antibodies [3D6 (Abeta42-3D6), WO2 (Abeta42-WO2), 6E10 (Abeta42-6E10), and 4G8 (Abeta42-4G8)]. The discriminant ability of the markers was evaluated by ROC curve analysis. RESULTS: The areas under the curves for the separation of MCI-AD from nonprogressing MCI (MCI-N) were significantly higher when we used Abeta42-3D6/Abeta42-WO2, Abeta42-3D6/Abeta42-6E10, or Abeta42-3D6/Abeta42-4G8 compared with Abeta42-3D6. In addition, differentiation of MCI-N from MCI-AD was improved by quantification of full-length Abeta1-42 (Abeta42-3D6) compared with Abeta42-WO2, Abeta42-6E10, or Abeta42-4G8. Several Abeta42 peptides truncated at the amino terminus (Abeta11-42 and Abeta8-42) were identified in CSF by surface-enhanced laser desorption/ionization time-of-flight technology. CONCLUSION: The CSF markers tau, Abeta42 forms, and P-tau181P, when used as adjuncts to clinical diagnosis, have the potential to help identify AD pathology and could be a valuable asset for early AD diagnosis.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Trastornos del Conocimiento/diagnóstico , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Trastornos del Conocimiento/patología , Progresión de la Enfermedad , Femenino , Humanos , Inmunoensayo , Masculino , Proteínas del Tejido Nervioso/líquido cefalorraquídeo , Fosforilación , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Proteínas tauRESUMEN
We have investigated to what extent microinjected beta-endorphin could migrate from the rat brain parenchyma into the CSF compartment. Exogenous rat beta-endorphin (0.1 nmol) was microinjected into the left striatum 1 mm from the lateral ventricle in anesthetized male rats. CSF samples were collected at different time points up to 2 h post-injection from a catheter affixed to the atlanto-occipital membrane of the cisterna magna. Radioimmunoassay and mass spectrometry were performed on the CSF samples, and brain sections were immunostained for beta-endorphin and mu-opioid receptors. The beta-endorphin injected rats showed a marked increase in beta-endorphin immunoreactive (IR) material in the CSF, with a peak at 30-45 min post-injection, and this beta-endorphin-IR material existed mainly as the intact beta-endorphin peptide. The immunohistochemistry results revealed the appearance of distinct beta-endorphin-IR cell bodies in the globus pallidus and the bed nucleus of stria terminalis supracapsular part, regions distant from the injection site, at 2 h post-injection of exogenous beta-endorphin. The beta-endorphin-IR in several of the globus pallidus cell bodies colocalized with the mu-opioid receptor-IR at the cell surface. These findings show that upon delivery of synthetic beta-endorphin, there is a significant intracerebral spread of the injected peptide, reaching regions far from the site of injection via diffusion in the extracellular space and flow in the cerebrospinal fluid. This may be of relevance when interpreting studies based on intracerebral injections of peptides, and advances our knowledge regarding the migration of compounds within the brain.
Asunto(s)
Líquido Cefalorraquídeo/química , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Espacio Extracelular/efectos de los fármacos , betaendorfina/líquido cefalorraquídeo , betaendorfina/farmacocinética , Animales , Líquido Cefalorraquídeo/fisiología , Difusión , Espacio Extracelular/metabolismo , Globo Pálido/citología , Globo Pálido/efectos de los fármacos , Globo Pálido/metabolismo , Inmunohistoquímica , Ventrículos Laterales/fisiología , Masculino , Espectrometría de Masas , Microinyecciones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismo , Núcleos Septales/citología , Núcleos Septales/efectos de los fármacos , Núcleos Septales/metabolismo , Factores de Tiempo , betaendorfina/administración & dosificaciónRESUMEN
The event that triggers the autoimmune destruction of insulin-producing beta-cells in type 1 diabetes mellitus (T1DM) is still unknown. Enterovirus, especially Coxsackievirus, infections have long been associated with this disease. Cytokines and chemokines induced by an enterovirus infection may act to trigger the autoimmune reactions that produce T1DM. Gene expression was examined in isolated human islets infected with a Coxsackievirus-B4 (CBV-4) strain causing lytic infection (V89-4557) and in islets infected with a CBV-4 strain establishing persistent infection (VD2921). Microarray analysis indicated that infection with the CBV-4 strains resulted in specific induction of a number of inflammatory genes, including IL-1beta, IL-6, IL-8, MCP-1, and RANTES. Importantly, the inflammatory genes induced by the CBV-4 infections differed in the two strains, with more cytokines being induced by the non-lytic CBV-4 strain than by the lytic strain. These cytokines and chemokines have the potential to rapidly induce inflammatory reactions when expressed in vivo and could contribute to the autoimmune reactions associated with the development of T1DM.