La primera epístola de Alfonso de Valladolid

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La «Carta de Léntulo al Senado de Roma»: Fortuna de un retrato de Cristo en la Baja Edad Media castellana

La «Carta de Léntulo al Senado de Roma» es un breve texto pseudohistórico y piadoso incluido por el cartujo Ludolfo de Sajonia al comienzo de su Vita Christi (ca. 1450). Este artículo se ocupa de su difusión hispánica en el siglo XV y presenta algunos testimonios, tanto manuscritos como impresos. The «Lentulus Letter to the Román Senate» is a brief pseudohistorical andpious text included by the chartusian Ludolph ofSaxony at the beginning ófhis Vita Christi (ca. 1450). Our article deals with its Hispanic diffusion in the XVth. century and presents some manuscript and printed examples of it

Antidote use in a pediatric emergency department

INTRODUCTION: Poisoning is an infrequent cause of consultation in a pediatric emergency department (PED), but it can be potentially serious. Pediatricians should know how to use the available antidotes properly. OBJECTIVES: To analyze the use of antidotes in a PED and to assess the suitability of their indications. MATERIALS AND METHODS: A retrospective review of antidote use in a PED between January 2008 and June 2012. Inclusion criteria were age younger than 18 years and consultation for suspicious poisoning by a substance that could be treated with an antidote. The adequacy of antidote indication was based on the recommendations of the Spanish Society of Pediatric Emergencies (SSPE). RESULTS: A total of 1728 consultations for suspicious poisoning (0.4% of the total visits in the PED) were recorded. In 353 cases (20.4%) the involved poison could be treated with an antidote. Sixty-seven patients received an antidote (3.9% of consultations for suspicious poisoning), and a total of 69 administrations of an antidote were made: 100% oxygen (46), N-acetylcysteine (10), flumazenil (4), naloxone (3), deferoxamine (2), vitamin K (2), bicarbonate (1), and carnitine (1). In 3 cases there was no indication for administration: flumazenil without respiratory depression, and vitamin K following coumarin exposure. As side effects, agitation was noted after the use of flumazenil, and a decrease in the prothrombin time during infusion of N-acetylcysteine. CONCLUSIONS: The administration of antidotes in this PED is uncommon and, mainly, in accordance with the SSPE recommendations, and without serious side effects. The use of flumazenil needs to be limited to the cases with a clear indication and without any contraindication

Efficacy and safety of 0.1% ciclosporin A cationic emulsion in dry eye disease: a pooled analysis of two double-masked, randomised, vehicle-controlled phase III clinical studies

Background/aim To assess the treatment effect of 0.1% ciclosporin A cationic emulsion (CsA CE) versus vehicle on signs/symptoms of dry eye disease (DED) in various subgroups (moderate-to-severe DED/severe DED/ Sjogren's syndrome (SS)/SS with severe DED). Methods Pooled data were analysed from two similar phase III studies: SICCANOVE (moderate-to-severe DED) and SANSIKA (severe DED with severe keratitis). In both studies, patients aged >= 18 years received CsA CE 0.1% (n=395) or vehicle (n=339) once daily for 6 months. A composite responder efficacy endpoint (corneal fluorescein staining-Ocular Surface Disease Index (CFSOSDI) at month 6) was used to evaluate the efficacy of CsA CE in alleviating signs/symptoms of DED (response defined as improvement of >= 2 grades in CFS and >= 30% in OSDI (baseline to month 6)). Human leucocyte antigen-DR (HLA-DR) conjunctival expression was used as a biomarker of ocular surface inflammation. Results CsA CE-treated patients were significantly more likely to be CFS-OSDI responders than vehicletreated patients in the overall (OR 1.66, 95% CI 1.11 to 2.50;P=0.015), severe DED (1.80, 1.04 to 3.19;P=0.038) and SS with severe DED (3.37, 1.20 to 11.19;P=0.030) populations. The difference was not significant for CsA CE versus vehicle for the overall Sjogren's population (OR 1.77, CI 0.89 to 3.66;P=0.109). CsA CE also significantly reduced median HLA-DR expression versus vehicle at 6 months (P=0.002). Conclusion Pooled phase III data indicate CsA CE produced significant improvement in signs/symptoms versus vehicle in patients with moderate-to-severe DED (especially in those with severe keratitis), including patients with SS with severe DED

Effectiveness of TNF-α blockade in the treatment of refractory non-infectious scleritis: a multicentre study

OBJECTIVES: To evaluate the efficacy of tumour necrosis factor (TNF)-α inhibitors in refractory non-infectious scleritis. METHODS: We carried out a retrospective study assessing the efficacy of TNF-α inhibitors in the treatment of scleritis, scleritis relapses, glucocorticoid (GC)-sparing effect, impact on best-corrected visual acuity (BCVA) and safety profile. RESULTS: Nineteen patients (28 eyes) were eligible for analysis. Scleritis inflammatory grading significantly improved from baseline to the last follow-up (median ± IQR 2±4 and 0±0 respectively, p=0.0006). Scleritis relapses significantly decreased between the 12 months preceding and following biologic therapy (p=0.001). Mean GC dosage decreased from baseline (19.00±13.56 mg) to the last follow-up (7.59±5.56 mg) (p=0.003). No significant differences regarding BCVA were observed. Two AEs were recorded (1 severe urticaria and 1 case of pneumonia and paradoxical psoriasis). CONCLUSIONS: TNF-α inhibitors are effective in the treatment of scleritis while allowing a GC-sparing effect and preserving BCVA

Baseline Inflammatory Status Reveals Dichotomic Immune Mechanisms Involved In Primary-Progressive Multiple Sclerosis Pathology

To ascertain the role of inflammation in the response to ocrelizumab in primary-progressive multiple sclerosis (PPMS).Multicenter prospective study including 69 patients with PPMS who initiated ocrelizumab treatment, classified according to baseline presence [Gd+, n=16] or absence [Gd-, n=53] of gadolinium-enhancing lesions in brain MRI. Ten Gd+ (62.5%) and 41 Gd- patients (77.4%) showed non-evidence of disease activity (NEDA) defined as no disability progression or new MRI lesions after 1 year of treatment. Blood immune cell subsets were characterized by flow cytometry, serum immunoglobulins by nephelometry, and serum neurofilament light-chains (sNfL) by SIMOA. Statistical analyses were corrected with the Bonferroni formula.More than 60% of patients reached NEDA after a year of treatment, regardless of their baseline characteristics. In Gd+ patients, it associated with a low repopulation rate of inflammatory B cells accompanied by a reduction of sNfL values 6 months after their first ocrelizumab dose. Patients in Gd- group also had low B cell numbers and sNfL values 6 months after initiating treatment, independent of their treatment response. In these patients, NEDA status was associated with a tolerogenic remodeling of the T and innate immune cell compartments, and with a clear increase of serum IgA levels.Baseline inflammation influences which immunological pathways predominate in patients with PPMS. Inflammatory B cells played a pivotal role in the Gd+ group and inflammatory T and innate immune cells in Gd- patients. B cell depletion can modulate both mechanisms.Copyright © 2022 Fernández-Velasco, Monreal, Kuhle, Meca-Lallana, Meca-Lallana, Izquierdo, Oreja-Guevara, Gascón-Giménez, Sainz de la Maza, Walo-Delgado, Lapuente-Suanzes, Maceski, Rodríguez-Martín, Roldán, Villarrubia, Saiz, Blanco, Diaz-Pérez, Valero-López, Diaz-Diaz, Aladro, Brieva, Íñiguez, González-Suárez, Rodríguez de Antonio, García-Domínguez, Sabin, Llufriu, Masjuan, Costa-Frossard and Villar

Lateral wedge insoles for reducing biomechanical risk factors for medial knee osteoarthritis progression : a systematic review and meta-analysis

Objective Lateral wedge insoles are intended to reduce biomechanical risk factors of medial knee osteoarthritis (OA) progression, such as increased knee joint load; however, there has been no definitive consensus on this topic. The aim of this systematic review and meta-analysis was to establish the within-subject effects of lateral wedge insoles on knee joint load in people with medial knee OA during walking. Methods Six databases were searched from inception until February 13th 2015. Included studies reported on the acute biomechanical effects of lateral wedge insoles in people with medial knee osteoarthritis during walking. Primary outcomes of interest relating to the biomechanical risk of disease progression were the 1st and 2nd peak external knee adduction moment (EKAM) and knee adduction angular impulse (KAAI). Eligible studies were pooled using random-effects meta-analysis. Results Eighteen studies were included with a total of 534 participants. Lateral wedge insoles resulted in a small but statistically significant reduction in the 1st peak EKAM (SMD: -0.19; 95% CI -0.23 − -0.15) and 2nd peak EKAM (SMD: -0.25; 95% CI -0.32 − -0.19) with a low level of heterogeneity (I2 = 5% and 30%, respectively). There was a favourable but small reduction in the KAAI with lateral wedge insoles (SMD: -0.14; 95% CI -0.21 − -0.07, I2 =31%). Risk of methodological bias scores (Quality Index) ranged from 8 to 13 out of 16. Conclusions Lateral wedge insoles cause small reductions in the EKAM and KAAI in people with medial knee OA during walking. At present, they appear ineffective at attenuating structural changes in people with medial knee OA as a whole and may be better suited to targeted use in biomechanical phenotypes associated with larger reductions in knee load

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.This work was supported by grants FIS-PI15/00513, FIS-PI18/00572 and RD16/0015/0001 from the Instituto de Salud Carlos III. Ministerio de Ciencia e Innovación, Spain and FEDER: "Una manera de hacer Europa"

Phase II Randomized, Double-Masked, Vehicle-Controlled Trial of Recombinant Human Nerve Growth Factor for Neurotrophic Keratitis

Purpose: To evaluate the safety and efficacy of topical recombinant human nerve growth factor (rhNGF) for treating moderate-to-severe neurotrophic keratitis (NK), a rare degenerative corneal disease resulting from impaired corneal innervation. Design: Phase II multicenter, randomized, double-masked, vehicle-controlled trial. Participants: Patients with stage 2 (moderate) or stage 3 (severe) NK in 1 eye. Methods: The REPARO phase II study assessed safety and efficacy in 156 patients randomized 1:1:1 to rhNGF 10 \u3bcg/ml, 20 \u3bcg/ml, or vehicle. Treatment was administered 6 drops per day for 8 weeks. Patients then entered a 48- or 56-week follow-up period. Safety was assessed in all patients who received study treatment, whereas efficacy was by intention to treat. Main Outcome Measures: Corneal healing (defined as <0.5-mm maximum diameter of fluorescein staining in the lesion area) was assessed by masked central readers at week 4 (primary efficacy end point) and week 8 (key secondary end point) of controlled treatment. Corneal healing was reassessed post hoc by masked central readers using a more conservative measure (0-mm staining in the lesion area and no other persistent staining). Results: At week 4 (primary end point), 19.6% of vehicle-treated patients achieved corneal healing (<0.5-mm lesion staining) versus 54.9% receiving rhNGF 10 \u3bcg/ml (+35.3%; 97.06% confidence interval [CI], 15.88\u201354.71; P < 0.001) and 58.0% receiving rhNGF 20 \u3bcg/ml (+38.4%; 97.06% CI, 18.96\u201357.83; P < 0.001). At week 8 (key secondary end point), 43.1% of vehicle-treated patients achieved less than 0.5-mm lesion staining versus 74.5% receiving rhNGF 10 \u3bcg/ml (+31.4%; 97.06% CI, 11.25\u201351.49; P = 0.001) and 74.0% receiving rhNGF 20 \u3bcg/ml (+30.9%; 97.06% CI, 10.60\u201351.13; P = 0.002). Post hoc analysis of corneal healing by the more conservative measure (0-mm lesion staining and no other persistent staining) maintained statistically significant differences between rhNGF and vehicle at weeks 4 and 8. More than 96% of patients who healed after controlled rhNGF treatment remained recurrence free during follow-up. Treatment with rhNGF was well tolerated; adverse effects were mostly local, mild, and transient. Conclusions: Topical rhNGF is safe and more effective than vehicle in promoting healing of moderate-to-severe NK