RESUMEN
The photoreceptor outer segment is a highly specialized primary cilium essential for phototransduction and vision. Biallelic pathogenic variants in the cilia-associated gene CEP290 cause non-syndromic Leber congenital amaurosis 10 (LCA10) and syndromic diseases, where the retina is also affected. While RNA antisense oligonucleotides and gene editing are potential treatment options for the common deep intronic variant c.2991+1655A>G in CEP290 , there is a need for variant-independent approaches that could be applied to a broader spectrum of ciliopathies. Here, we generated several distinct human models of CEP290 -related retinal disease and investigated the effects of the flavonoid eupatilin as a potential treatment. Eupatilin improved cilium formation and length in CEP290 LCA10 patient-derived fibroblasts, in gene-edited CEP290 knockout (CEP290 KO) RPE1 cells, and in both CEP290 LCA10 and CEP290 KO iPSCs-derived retinal organoids. Furthermore, eupatilin reduced rhodopsin retention in the outer nuclear layer of CEP290 LCA10 retinal organoids. Eupatilin altered gene transcription in retinal organoids, by modulating the expression of rhodopsin, and by targeting cilia and synaptic plasticity pathways. This work sheds light into the mechanism of action of eupatilin, and supports its potential as a variant-independent approach for CEP290 -associated ciliopathies.
RESUMEN
Gut microbiota has been suggested to affect lipid metabolism. The objective of this study was to characterize the faecal microbiota signature and both short chain fatty acids (SCFAs) and bile acids (BA) profile of hypercholesterolemic subjects. Microbiota composition, SCFAs, BA and blood lipid profile from male volunteers with hypercholesterolemia (HC) and normocholesterolemia (NC) were determined by 16S rDNA sequencing, HPLC, GC and NMR, respectively. HC subjects were characterized by having lower relative abundance of Anaeroplasma (0.002% vs 0.219%, p-value = 0.026) and Haemophilus (0.041% vs 0.078%, p-value = 0.049), and higher of Odoribacter (0.51% vs 0.16%; p-value = 0.044). Correlation analysis revealed that Anaeroplasma and Haemophilus were associated to an unfavourable lipid profile: they correlated negatively to cholesterol and triglycerides related biomarkers and the ratio total to high density lipoprotein (HDL) cholesterol, and positively to HDL size. Odoribacter displayed an opposite behaviour. Faecal SCFAs profile revealed higher abundance of isobutyric (2.76% vs 0.82%, p-value = 0.049) and isovaleric acid (1.32% vs 0.06%, p-value = 0.016) in HC. Isobutyric acid correlated positively with Odoribacter and lipid parameters indicative of an unfavourable profile. BA profile did not show differences between groups. It was concluded that HC subjects showed a particular faecal bacterial signature and SCFAs profile associated with their lipid profile.
Asunto(s)
Bacterias/metabolismo , Ácidos Grasos Volátiles/metabolismo , Heces/química , Heces/microbiología , Hipercolesterolemia/metabolismo , Bacterias/clasificación , Ácidos y Sales Biliares/metabolismo , Biomarcadores/metabolismo , Fermentación , Microbioma Gastrointestinal , Humanos , Lípidos/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: No studies have identified which patients with upper-extremity deep vein thrombosis (DVT) are at low risk for adverse events within the first week of therapy. METHODS: We used data from Registro Informatizado de la Enfermedad TromboEmbólica to explore in patients with upper-extremity DVT a prognostic score that correctly identified patients with lower limb DVT at low risk for pulmonary embolism, major bleeding, or death within the first week. RESULTS: As of December 2014, 1135 outpatients with upper-extremity DVT were recruited. Of these, 515 (45%) were treated at home. During the first week, three patients (0.26%) experienced pulmonary embolism, two (0.18%) had major bleeding, and four (0.35%) died. We assigned 1 point to patients with chronic heart failure, creatinine clearance levels 30-60 mL min(-1) , recent bleeding, abnormal platelet count, recent immobility, or cancer without metastases; 2 points to those with metastatic cancer; and 3 points to those with creatinine clearance levels < 30 mL min(-1) . Overall, 759 (67%) patients scored ≤ 1 point and were considered to be at low risk. The rate of the composite outcome within the first week was 0.26% (95% confidence interval [CI] 0.004-0.87) in patients at low risk and 1.86% (95% CI 0.81-3.68) in the remaining patients. C-statistics was 0.73 (95% CI 0.57-0.88). Net reclassification improvement was 22%, and integrated discrimination improvement was 0.0055. CONCLUSIONS: Using six easily available variables, we identified outpatients with upper-extremity DVT at low risk for adverse events within the first week. These data may help to safely treat more patients at home.
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Técnicas de Apoyo para la Decisión , Pacientes Ambulatorios , Embolia Pulmonar/etiología , Trombosis Venosa Profunda de la Extremidad Superior/etiología , Adulto , Anciano , Anticoagulantes/efectos adversos , Canadá , Europa (Continente) , Femenino , Hemorragia/inducido químicamente , Humanos , Israel , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidad , Embolia Pulmonar/prevención & control , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , América del Sur , Factores de Tiempo , Resultado del Tratamiento , Trombosis Venosa Profunda de la Extremidad Superior/diagnóstico , Trombosis Venosa Profunda de la Extremidad Superior/mortalidad , Trombosis Venosa Profunda de la Extremidad Superior/terapiaAsunto(s)
Gripe Humana/epidemiología , Trastornos Mentales/epidemiología , Estrés Psicológico/epidemiología , Comorbilidad , Susceptibilidad a Enfermedades , Femenino , Humanos , Gripe Humana/psicología , Masculino , Obesidad/epidemiología , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Factores de Riesgo , Poblaciones VulnerablesRESUMEN
PURPOSE: To determine whether macrolide-based treatment is associated with mortality in critically ill H1N1 patients with primary viral pneumonia. METHODS: Secondary analysis of a prospective, observational, multicenter study conducted across 148 Intensive Care Units (ICU) in Spain. RESULTS: Primary viral pneumonia was present in 733 ICU patients with pandemic influenza A (H1N1) virus infection with severe respiratory failure. Macrolide-based treatment was administered to 190 (25.9 %) patients. Patients who received macrolides had chronic obstructive pulmonary disease more often, lower severity on admission (APACHE II score on ICU admission (13.1 ± 6.8 vs. 14.4 ± 7.4 points, p < 0.05), and multiple organ dysfunction syndrome less often (23.4 vs. 30.1 %, p < 0.05). Length of ICU stay in survivors was not significantly different in patients who received macrolides compared to patients who did not (10 (IQR 4-20) vs. 10 (IQR 5-20), p = 0.9). ICU mortality was 24.1 % (n = 177). Patients with macrolide-based treatment had lower ICU mortality in the univariate analysis (19.2 vs. 28.1 %, p = 0.02); however, a propensity score analysis showed no effect of macrolide-based treatment on ICU mortality (OR = 0.87; 95 % CI 0.55-1.37, p = 0.5). Moreover, the sensitivity analysis revealed very similar results (OR = 0.91; 95 % CI 0.58-1.44, p = 0.7). A separate analysis of patients under mechanical ventilation yielded similar results (OR = 0.77; 95 % CI 0.44-1.35, p = 0.4). CONCLUSION: Our results suggest that macrolide-based treatment was not associated with improved survival in critically ill H1N1 patients with primary viral pneumonia.
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Mortalidad Hospitalaria , Gripe Humana/tratamiento farmacológico , Macrólidos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , APACHE , Adulto , Coinfección , Comorbilidad , Femenino , Humanos , Subtipo H1N1 del Virus de la Influenza A , Gripe Humana/mortalidad , Gripe Humana/terapia , Unidades de Cuidados Intensivos/estadística & datos numéricos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Neumonía Viral/mortalidad , Neumonía Viral/terapia , Puntaje de Propensión , Estudios Prospectivos , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/mortalidad , España/epidemiología , Resultado del TratamientoRESUMEN
OBJECTIVES: We studied SLE whose initial symptoms were related to idiopathic thrombocytopenic purpura (ITP) in order to determine if they share clinical and immunologic manifestations. METHODS: We reviewed the clinical backgrounds of 150 SLE (according to the ACR criteria) periodically followed from 1980 until 1998. We found 12 patients with both these conditions. RESULTS: All patients were female with a mean age of 32 at the time of ITP diagnosis and 36 at the time of SLE diagnosis. The most usual clinical manifestations were: arthritis (92%), cutaneous (58%) and hematologic involvement with lymphopenia (58%) and thrombocytopenia again (33%) after the initial ITP episode, always together with autoimmune hemolytic anemia (Evans syndrome). None of these patients presented with neurologic involvement and only one presented with renal involvement. 50% were positive for anti-DNA antibodies, 50% were Ro(+) and 16% were RNP (+). 66% were positive for antiphospholipid antibodies and 33% for lupus anticoagulant. Thrombocytopenia was controlled just with steroids in only 16% of the patients. Splenectomy controlled thrombocytopenia with complete remission achieved in 80% (4 from 5) of the patients and 20% (1 from 5) were refractory to this therapy after a medium follow-up time of 6.5 years. CONCLUSIONS: 1) SLE whose initial symptoms are related to ITP were characterized by joints, cutaneous and hematologic involvement without renal and neurologic manifestations. 2) Splenectomy was able to control refractory thrombocytopenia in the majority of these patients.
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Lupus Eritematoso Sistémico/diagnóstico , Púrpura Trombocitopénica Idiopática/etiología , Adulto , Autoanticuerpos/análisis , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Púrpura Trombocitopénica Idiopática/terapia , Estudios Retrospectivos , EsplenectomíaRESUMEN
AIMS: To define an unusual macular appearance found in association with nanophthalmos. METHODS: A case review. RESULTS: Seven children (aged 8 months to 17 years) with nanophthalmos were examined. They all exhibited the same clinical findings of an unusual yellow macula appearance with retinal folds and crowded optic discs. Visual electrophysiology performed in four cases was normal. CONCLUSION: A distinctive yellow macular pigmentation with associated chorioretinal folds and crowded optic discs is present in nanophthalmos. It is proposed that the retinal folds are due to a disparity between scleral and retinal growth while the macula discoloration is due to a congenital abnormality in arrangement or position of the luteal pigment and is not degenerative. Included in this case series is the second case in the literature of nanophthalmos associated with Kenny's syndrome. Inheritance of nanophthalmos appears to be autosomal recessive.
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Anomalías Múltiples/patología , Mácula Lútea , Microftalmía/complicaciones , Enfermedades de la Retina/etiología , Enfermedades de la Retina/patología , Adolescente , Niño , Preescolar , Humanos , Lactante , Masculino , SíndromeRESUMEN
The number of patients who need coronary artery surgery growth every year. Most of these surgical operations are with extracorporeal circulation (ECC). Recently in our hospital this surgery is realized without ECC in selected patients. Some studies shows that this surgery is an alternative in the treatment of coronary artery disease, especially for aged patients with associated disease and in Jehovah's witness faith. A coronary artery diameter at the anastomotic site of 2 mm or greater and satisfactory hemodynamics with the cardiac manipulation are needed to realize this surgery. Given these limitations this technique has proved useful in selected patients requiring revascularization of the left anterior descending, circumflex or right coronary artery (not for grafting the posterior descending branch). The need of mechanical ventilation, days at ICU, blood required, morbidity and mortality, in our experience as in other studies, were fewer than surgery with CEC.