Efficacy of Omalizumab for the treatment of Bullous Pemphigoid. Spanish multicenter real-world experience.

BACKGROUND: Bullous Pemphigoid (BP) is the most common autoimmune blistering disease. Most patients are elderly and associate multiple comorbidities. Topical and systemic corticosteroids are considered as the first-line treatment for BP and immunosuppressors are used as steroid-sparing treatments but both have side effects and contraindications which are even more common in this elderly population. New treatments targeting interleukins and receptors related to BP pathogenesis have been proposed to decrease this side effects while achieving equal or better effectiveness response rates.Omalizumab is a monoclonal antibody that targets IgE that has been proposed for the treatment of BP due to the evidence that IgE autoantibodies play an essential role in BP pathogenesis. OBJECTIVES AND METHODOLOGY: To assess the efficacy and security of Omalizumab for the treatment of BP, we carried out a multicenter, retrospective, observational study including patients diagnosed of BP who received omalizumab for at least 3 months from 15 tertiary hospitals in Spain. IgE levels prior to treatment was measured and we evaluate the possible correlation with clinical response. We excluded patients treated with Omalizumab for less than 3 months as we consider this duration is insufficient for a comprehensive assessment of its efficacy. To evaluate the effectiveness of the treatment we used the percentage of BSA improvement. RESULTS: We included 36 patients. The vast majority associate multiple comorbidities and all patients had used other systemic therapies apart from corticoids before Omalizumab.83% experienced some kind of treatment response and 42% of all patient treated achieved complete response.We did not find any correlation between higher levels and a better response (p=0,1791).All patients tolerated Omalizumab without reported side-effects. CONCLUSIONS: Omalizumab is a good therapeutic alternative for BP as it obtained clinical response in most patients and nearly half of the cases achieving complete response. It showed no side effects which is crucial in elderly patients suffering from BP.

Type V aplasia cutis congenita in a preterm newborn successfully resolved.

Aplasia cutis congenita (ACC) associated with fetus papyraceus is a rare subtype of aplasia cutis categorized as type V in Frieden's classification. It is characterized by stellate lesions in a symmetrical distribution over the trunk and proximal extremities. Conservative treatment is recommended, but there is not a well-defined therapeutic protocol. We report the case of a type V ACC in a preterm male newborn with lesions on the trunk and scalp successfully treated with topical 1% silver sulfadiazine and petrolatum gauze with an excellent evolution. This case associates a severe affectation of the scalp which represents a rare variant of type V ACC.

Anti-IL17 treatment ameliorates Down syndrome phenotypes in mice.

Down syndrome (DS) is characterized by structural and functional anomalies that are present prenatally and that lead to intellectual disabilities. Later in life, the cognitive abilities of DS individuals progressively deteriorate due to the development of Alzheimer's disease (AD)-associated neuropathology (i.e., ß-amyloid (Aß) plaques, neurofibrillary tangles (NFTs), neurodegeneration, synaptic pathology, neuroinflammation and increased oxidative stress). Increasing evidence has shown that among these pathological processes, neuroinflammation plays a predominant role in AD etiopathology. In AD mouse models, increased neuroinflammation appears earlier than Aß plaques and NFTs, and in DS and AD models, neuroinflammation exacerbates the levels of soluble and insoluble Aß species, favoring neurodegeneration. The Ts65Dn (TS) mouse, the most commonly used murine model of DS, recapitulates many alterations present in both DS and AD individuals, including enhanced neuroinflammation. In this study, we observed an altered neuroinflammatory milieu in the hippocampus of the TS mouse model. Pro-inflammatory mediators that were elevated in the hippocampus of this model included pro-inflammatory cytokine IL17A, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Here, we analyzed the ability of an anti-IL17A antibody to reduce the neuropathological alterations that are present in TS mice during early neurodevelopmental stages (i.e., hippocampal neurogenesis and hypocellularity) or that are aggravated in later-life stages (i.e., cognitive abilities, cholinergic neuronal loss and increased cellular senescence, APP expression, Aß peptide expression and neuroinflammation). Administration of anti-IL17 for 5 months, starting at the age of 7 months, partially improved the cognitive abilities of the TS mice, reduced the expression of several pro-inflammatory cytokines and the density of activated microglia and normalized the APP and Aß1-42 levels in the hippocampi of the TS mice. These results suggest that IL17-mediated neuroinflammation is involved in several AD phenotypes in TS mice and provide a new therapeutic target to reduce these pathological characteristics.

Reducing GABAA α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome.

Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) α5 NAMs to treat cognitive dysfunction in DS.

Chronic melatonin treatment rescues electrophysiological and neuromorphological deficits in a mouse model of Down syndrome.

The Ts65Dn mouse (TS), the most commonly used model of Down syndrome (DS), exhibits several key phenotypic characteristics of this condition. In particular, these animals present hypocellularity in different areas of their CNS due to impaired neurogenesis and have alterations in synaptic plasticity that compromise their cognitive performance. In addition, increases in oxidative stress during adulthood contribute to the age-related progression of cognitive and neuronal deterioration. We have previously demonstrated that chronic melatonin treatment improves learning and memory and reduces cholinergic neurodegeneration in TS mice. However, the molecular and physiological mechanisms that mediate these beneficial cognitive effects are not yet fully understood. In this study, we analyzed the effects of chronic melatonin treatment on different mechanisms that have been proposed to underlie the cognitive impairments observed in TS mice: reduced neurogenesis, altered synaptic plasticity, enhanced synaptic inhibition and oxidative damage. Chronic melatonin treatment rescued both impaired adult neurogenesis and the decreased density of hippocampal granule cells in trisomic mice. In addition, melatonin administration reduced synaptic inhibition in TS mice by increasing the density and/or activity of glutamatergic synapses in the hippocampus. These effects were accompanied by a full recovery of hippocampal LTP in trisomic animals. Finally, melatonin treatment decreased the levels of lipid peroxidation in the hippocampus of TS mice. These results indicate that the cognitive-enhancing effects of melatonin in adult TS mice could be mediated by the normalization of their electrophysiological and neuromorphological abnormalities and suggest that melatonin represents an effective treatment in retarding the progression of DS neuropathology.

Long-term oral administration of melatonin improves spatial learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome.

Ts65Dn mice (TS), the most commonly used model of Down syndrome (DS), exhibit phenotypic characteristics of this condition. Both TS mice and DS individuals present cognitive disturbances, age-related cholinergic degeneration, and increased brain expression of ß-amyloid precursor protein (AßPP). These neurodegenerative processes may contribute to the progressive cognitive decline observed in DS. Melatonin is a pineal indoleamine that has been reported to reduce neurodegenerative processes and improve cognitive deficits in various animal models. In this study, we evaluated the potentially beneficial effects of long-term melatonin treatment on the cognitive deficits, cholinergic degeneration, and enhanced AßPP and ß-amyloid levels of TS mice. Melatonin was administered for 5 months to 5- to 6-month-old TS and control (CO) mice. Melatonin treatment improved spatial learning and memory and increased the number of choline acetyltransferase (ChAT)-positive cells in the medial septum of both TS and CO mice. However, melatonin treatment did not significantly reduce AßPP or ß-amyloid levels in the cortex or the hippocampus of TS mice. Melatonin administration did reduce anxiety in TS mice without inducing sensorimotor alterations, indicating that prolonged treatment with this indoleamine is devoid of noncognitive behavioral side effects (e.g., motor coordination, sensorimotor abilities, or spontaneous activity). Our results suggest that melatonin administration might improve the cognitive abilities of both TS and CO mice, at least partially, by reducing the age-related degeneration of basal forebrain cholinergic neurons. Thus, chronic melatonin supplementation may be an effective treatment for delaying the age-related progression of cognitive deterioration found in DS.

Decreasing the Expression of GABAA α5 Subunit-Containing Receptors Partially Improves Cognitive, Electrophysiological, and Morphological Hippocampal Defects in the Ts65Dn Model of Down Syndrome.

Trisomy 21 or Down syndrome (DS) is the most common cause of intellectual disability of a genetic origin. The Ts65Dn (TS) mouse, which is the most commonly used and best-characterized mouse model of DS, displays many of the cognitive, neuromorphological, and biochemical anomalies that are found in the human condition. One of the mechanisms that have been proposed to be responsible for the cognitive deficits in this mouse model is impaired GABA-mediated inhibition. Because of the well-known modulatory role of GABAA α5 subunit-containing receptors in cognitive processes, these receptors are considered to be potential targets for improving the intellectual disability in DS. The chronic administration of GABAA α5-negative allosteric modulators has been shown to be procognitive without anxiogenic or proconvulsant side effects. In the present study, we use a genetic approach to evaluate the contribution of GABAA α5 subunit-containing receptors to the cognitive, electrophysiological, and neuromorphological deficits in TS mice. We show that reducing the expression of GABAA α5 receptors by deleting one or two copies of the Gabra5 gene in TS mice partially ameliorated the cognitive impairments, improved long-term potentiation, enhanced neural differentiation and maturation, and normalized the density of the GABAergic synapse markers. Reducing the gene dosage of Gabra5 in TS mice did not induce motor alterations and anxiety or affect the viability of the mice. Our results provide further evidence of the role of GABAA α5 receptor-mediated inhibition in cognitive impairment in the TS mouse model of DS.

Pre- and post-natal melatonin administration partially regulates brain oxidative stress but does not improve cognitive or histological alterations in the Ts65Dn mouse model of Down syndrome.

Melatonin administered during adulthood induces beneficial effects on cognition and neuroprotection in the Ts65Dn (TS) mouse model of Down syndrome. Here, we investigated the effects of pre- and post-natal melatonin treatment on behavioral and cognitive abnormalities and on several neuromorphological alterations (hypocellularity, neurogenesis impairment and increased oxidative stress) that appear during the early developmental stages in TS mice. Pregnant TS females were orally treated with melatonin or vehicle from the time of conception until the weaning of the offspring, and the pups continued to receive the treatment from weaning until the age of 5 months. Melatonin administered during the pre- and post-natal periods did not improve the cognitive impairment of TS mice as measured by the Morris Water maze or fear conditioning tests. Histological alterations, such as decreased proliferation (Ki67+ cells) and hippocampal hypocellularity (DAPI+ cells), which are typical in TS mice, were not prevented by melatonin. However, melatonin partially regulated brain oxidative stress by modulating the activity of the primary antioxidant enzymes (superoxide dismutase in the cortex and catalase in the cortex and hippocampus) and slightly decreasing the levels of lipid peroxidation in the hippocampus of TS mice. These results show the inability of melatonin to prevent cognitive impairment in TS mice when it is administered at pre- and post-natal stages. Additionally, our findings suggest that to induce pro-cognitive effects in TS mice during the early stages of development, in addition to attenuating oxidative stress, therapies should aim to improve other altered processes, such as hippocampal neurogenesis and/or hypocellularity.

Leishmaniasis mucocutánea labial, las apariencias pueden engañar / Mucocutaneous lip leishmaniasis, a diagnonstic challenge

La leishmaniasis es una infección endémica en nuestro medio. Dentro de sus presentaciones, la forma mucocutánea es la menos frecuente. A pesar de ello se ha de tener en cuenta incluso en casos clínicamente sugestivos de patología tumoral, como el que presentamos

Leishmaniasis is an endemic disease in the mediterranean region. Although mucocutaneous presentation is not frequent, we should considerate it in the differential diagnosis of tumoral pathology

The use of 1.5-anhydroglucitol for monitoring glycemic control in islet transplant recipients.

We evaluated whether 1,5-anhydroglucitol (1,5-AG) (GlycoMark(®)), a test for measuring postprandial glucose and glucose variability, could be a tool for assessing short-term glycemic control in islet cell transplant (ICT) subjects. Data of 21 subjects, with type 1 DM and allogenic islet transplantation, who had concomitant fructosamine, HbA1c, 1,5-AG (n = 85 samples), and capillary glucose self-monitoring measurements (n = 2,979) were analyzed retrospectively at different time points after ICT. A significant negative association was observed between 1,5-AG and HbA1c (p = 0.02), but not with fructosamine. When HbA1c was divided in quartiles as <5.6, 5.6-5.9, 5.9-6.2, and >6.2, a decrease of an estimated 0.70 ± 0.30 µg/ml in 1,5-AG was associated with each quartile of increase in HbA1c (p < 0.0001). There was a significant decline of 1.64 ± 0.3mg/dl in postprandial glucose values for each 1 unit increase in 1,5-AG (p < 0.0001). For those with HbA1c ≥ 6.0% when 1,5-AG was ≥8.15 µg/ml, the mean estimated glucose level was 103.71 ± 3.66 mg/dl, whereas it was 132.12 ± 3.71 mg/dl when 1,5-AG was <8.15 µg/ml. The glucose variability (Glumax - Glumin) in subjects with 1,5-AG <8.15 µg/ml was 46.23 mg/dl greater than the subjects with 1,5-AG ≥8.15 µg/ml (HbA1c ≥ 6.0%). There was no significant association between GlycoMark and glucose variability where HbA1c < 6%. 1,5-AG significantly associated with postprandial glucose levels and glucose variability in ICT recipients with near-normal HbA1c (6.0-6.5%) levels. These findings suggest that 1,5-AG can be used to differentiate those ICT subjects with higher glucose variability despite having near-normal HbA1c. However, prospective studies are needed to evaluate the association between GlycoMark levels and the parameters of graft dysfunction/failure.

Liver fat accumulation after islet transplantation and graft survival.

Our objective is to evaluate if there is an association between liver fat accumulation after islet transplantation (ITx) and graft survival. A cohort study was conducted in 34 subjects with type 1 diabetes postallogeneic ITx. Liver fat content was evaluated by magnetic resonance imaging (MRI) (change in liver signal intensity on in-phase and opposed-phase images). Kaplan-Meier curves and Cox regression analysis were performed with islet dysfunction duration as the dependent variable and fat liver content as an independent one. Values of p < 0.05 were significant (SSPS(®)18.0 and MedCalc(®)12.5). Patients' mean age was 40 ± 8 years (diabetes duration: 31 ± 12 years; male: 41%). Islet survival did not differ in patients without (51 months, 95% CI 40-62 months) or with steatosis (48 months, 95% CI 38-58 months; p = 0.55) during islet dysfunction period. Nevertheless, survival curves appear to separate late in the follow-up, and after 40 months steatosis was associated with shorter graft survival (p log rank = 0.049). This association remained (RR 23.5, 95% CI 1.1-516.0; p = 0.045) after adjustments for possible confounding factors. In this sample of subjects with type 1 diabetes submitted to ITx, steatosis was not associated with islet failure in the whole cohort. However, in subjects with functional islets after 40 months, a shorter graft survival was observed in those with steatosis during the islet dysfunction period, even after adjustments to variables known to be associated with islet failure.

Overexpression of Dyrk1A is implicated in several cognitive, electrophysiological and neuromorphological alterations found in a mouse model of Down syndrome.

Down syndrome (DS) phenotypes result from the overexpression of several dosage-sensitive genes. The DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A) gene, which has been implicated in the behavioral and neuronal alterations that are characteristic of DS, plays a role in neuronal progenitor proliferation, neuronal differentiation and long-term potentiation (LTP) mechanisms that contribute to the cognitive deficits found in DS. The purpose of this study was to evaluate the effect of Dyrk1A overexpression on the behavioral and cognitive alterations in the Ts65Dn (TS) mouse model, which is the most commonly utilized mouse model of DS, as well as on several neuromorphological and electrophysiological properties proposed to underlie these deficits. In this study, we analyzed the phenotypic differences in the progeny obtained from crosses of TS females and heterozygous Dyrk1A (+/-) male mice. Our results revealed that normalization of the Dyrk1A copy number in TS mice improved working and reference memory based on the Morris water maze and contextual conditioning based on the fear conditioning test and rescued hippocampal LTP. Concomitant with these functional improvements, normalization of the Dyrk1A expression level in TS mice restored the proliferation and differentiation of hippocampal cells in the adult dentate gyrus (DG) and the density of GABAergic and glutamatergic synapse markers in the molecular layer of the hippocampus. However, normalization of the Dyrk1A gene dosage did not affect other structural (e.g., the density of mature hippocampal granule cells, the DG volume and the subgranular zone area) or behavioral (i.e., hyperactivity/attention) alterations found in the TS mouse. These results suggest that Dyrk1A overexpression is involved in some of the cognitive, electrophysiological and neuromorphological alterations, but not in the structural alterations found in DS, and suggest that pharmacological strategies targeting this gene may improve the treatment of DS-associated learning disabilities.