Models to study basic and applied aspects of lysosomal storage disorders

© 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).The lack of available treatments and fatal outcome in most lysosomal storage disorders (LSDs) have spurred research on pathological mechanisms and novel therapies in recent years. In this effort, experimental methodology in cellular and animal models have been developed, with aims to address major challenges in many LSDs such as patient-to-patient variability and brain condition. These techniques and models have advanced knowledge not only of LSDs but also for other lysosomal disorders and have provided fundamental insights into the biological roles of lysosomes. They can also serve to assess the efficacy of classical therapies and modern drug delivery systems. Here, we summarize the techniques and models used in LSD research, which include both established and recently developed in vitro methods, with general utility or specifically addressing lysosomal features. We also review animal models of LSDs together with cutting-edge technology that may reduce the need for animals in the study of these devastating diseases.This work was supported by the Spanish Ministry of Science and Innovation (PID2020-112830RB-I00) (AEI/FEDER, UE) and the NextGeneration EU-CSIC funds (NeuroAging)info:eu-repo/semantics/publishedVersio

Maxillomandibular giant osteosclerotic lesions

Giant Osteosclerotic Lesions (GOLs) are a group of rarely reported intraosseous lesions. Their precise diagnosis is important since they can be confused with malignant neoplasms. Objective: This retrospective study aimed to record and analyze the clinical and radiographic Giant Osteosclerotic Lesions (GOLs) detected in the maxillomandibular area of patients attending to our institution. Materials and Methods: Informed consent from the patients was obtained and those cases of 2.5 cm or larger lesions with radiopaque or mixed (radiolucid-radiopaque) appearance located in the maxillofacial bones were selected. Assessed parameters were: age, gender, radiographic aspect, shape, borders, size, location and relations to roots. Lesions were classified as radicular, apical, interradicular, interradicular-apical, radicular-apical or located in a previous teeth extraction area. Additionally, several osseous and dental developmental alterations (DDAs) were assessed. Results: Seventeen radiopacities in 14 patients were found and were located almost exclusively in mandible and were two types: idiopathic osteosclerosis and condensing osteitis. GOLs were more frequent in females, and in the anterior and premolar zones. 94.2% of GOLs were qualified as idiopathic osteosclerosis and one case was condensing osteitis. All studied cases showed different osseous and dental developmental alterations (DDAs). The most common were: Microdontia, hypodontia, pulp stones, macrodontia and variations in the mental foramina. Conclusions: GOLs must be differentiated from other radiopaque benign and malignant tumors. Condensing osteitis, was considered an anomalous osseous response induced by a chronic low-grade inflammatory stimulus. For development of idiopathic osteosclerosis, two possible mechanisms could be related. The first is modification of the normal turnover with excessive osseous deposition. The second mechanism will prevent the normal bone resorption, arresting the osseous breakdown process

Dental developmental alterations in patients with dilacerated teeth

The aim of this study was to record and analyze all DDAs associated to dilacerated teeth in patients attending the clinics of the Postgraduate Division, Facultad de Odontología, UNAM in Mexico City. Orthopantomograms from all patients seeking for stomatological attention in our institution were reviewed and those cases of dilaceration were separated. Age, gender, diagnosis, location, involved teeth and associated DDAs were recorded and analyzed. From 6,340 patients, 99 (1.6%) harbored 125 dilacerated teeth. Of them, 45 (45.5%) showed one or more DDAs. The most frequently detected DDAs were hypodontia, enamel pearls, taurodontism and microdontia. 45.5% is a very high proportion of DDAs in patients with dilacerated roots. Findings from this study strongly suggest that patients with dilacerated teeth should be carefully screened since many of them could present other DDAs. Simultaneous occurrence of dilaceration and DDAs suggests synchronic developmental defects during dental growth

Apolipoprotein D

Apolipoprotein D (ApoD) is an extracellular glycoprotein of the lipocalin protein family, involved in different functions such as immune response, cell proliferation regulation, chemoreception, retinoid metabolism, axon growth, and proteolysis regulation. This lipocalin is expressed predominantly in the nervous system (NS), both prenatally (vascular pericytes) and postnatally (glia and neurons) and in adulthood. It is also expressed in other tissues and is carried by high-density lipoprotein (HDL) in plasma, so it could interfere in cholesterol and other lipids regulation. ApoD increases considerably in systemic apocrine gland tumors and also in some primary brain tumors. Although the specific biological role of ApoD is unknown, the presence of ApoD in tumors appears to be a prognostic factor in their evolution. Regarding the NS, increased ApoD expression observed in many neurodegenerative diseases could be used to make an early diagnosis thereof

Impacto de la pandemia por SARS-CoV2 en la actividad asistencial y en la salud del personal de hemodiálisis en las diferentes oleadas

Introducción: Además de las consecuencias del SARS-CoV-2 sobre los pacientes renales infectados, mantener la actividad durante la pandemia ha supuesto todo un reto dada la escasez de personal por las ausencias por enfermedad. Objetivo: Analizar la incidencia de contagios por Covid-19 entre los profesionales de hemodiálisis, sus características y su repercusión en bajas laborales en las diferentes oleadas. Material y Método: Estudio observacional longitudinal desde el 3/03/2020 hasta el 23/04/2022 (776 días) en una media de 406 profesionales sanitarios y no sanitarios de 18 unidades de diálisis y dos unidades administrativas de apoyo de la Fundación Renal Iñigo Álvarez de Toledo. La recogida de datos se realizó a través de la comunicación de las distintas supervisoras al departamento de recursos humanos. Resultados: 179 profesionales de un promedio de 406 (44,1%) se infectaron en el periodo de estudio, siendo el 52% enfermeras, 25% auxiliares, 11% nefrólogos y 12% otros profesionales. Un 40,2% de los casos presentaron síntomas. Un total de 160 contagiados estuvo ausente por enfermedad (89,3%), con una media de 15,9±14,3 días. En el 71,6% se detectó un contacto estrecho (todos fuera de las unidades) y esta identificación de contactos fue creciente según avanzaban las oleadas, pasando de un 6,7% en la 1ª ola a un 40% en la 6ª ola (p=0,016). Conclusiones: La sintomatología ha sido leve, al menos de dos semanas de ausencia por enfermedad; los contactos estrechos detectados han sido fundamentalmente comunitarios, sin registrarse contagios a través de los pacientes renales en las unidades

N2O and CH4 fluxes in Undisturbed and Burned Holm oak, Scots pine and Pyrenean oak forests in Central Spain

We investigated N2O and CH4 fluxes from soils of Quercus ilex, Quercus pyrenaica and Pinus sylvestris stands located in the surrounding area of Madrid (Spain). The fluxes were measured for 18 months from both mature stands and post fire stands using the static chamber technique. Simultaneously with gas fluxes, soil temperature, soil water content, soil C and soil N were measured in the stands. Nitrous oxide fluxes ranged from −11.43 to 8.34 μg N2O–N m−2 h−1 in Q.ilex, −7.74 to 13.52 μg N2O–N m−2 h−1 in Q. pyrenaica and −28.17 to 21.89 μg N2O–N m−2 h−1 in P. sylvestris. Fluxes of CH4 ranged from −8.12 to 4.11 μg CH4–C m−2 h−1 in Q.ilex, −7.74 to 3.0 μg CH4–C m−2 h−1 in Q. pyrenaica and −24.46 to 6.07 μg CH4–C m−2 h−1 in P. sylvestris. Seasonal differences were detected; N2O fluxes being higher in wet months whereas N2O fluxes declined in dry months. Net consumption of N2O was related to low N availability, high soil C contents, high soil temperatures and low moisture content. Fire decreased N2O fluxes in spring. N2O emissions were closely correlated with previous day’s rainfall and soil moisture. Our ecosystems generally were a sink for methane in the dry season and a source of CH4 during wet months. The available water in the soil influenced the observed seasonal trend. The burned sites showed higher CH4 oxidation rates in Q. ilex, and lower rates in P. sylvestris. Overall, the data suggest that fire alters both N2O and CH4 fluxes. However, the magnitude of such variation depends on the site, soil characteristics and seasonal climatic conditions

Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment

Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca (R)) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods:This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion:NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression

CHALLENGE 6: Exposing the roots of mental disorders

Mental disorders have devastating and increasing impact in our societies. CSIC researchers face the challenge of determining the biological and social causes and consequences of these disorders, and of finding efficient therapies. To these aims, the collaborative effort of neuroscientists, neurologists, psychiatrists, psychologists and human and social scientists, the use and development of state-of-the-art technologies and the contact with patient associations and pharma industry are required.Peer reviewe

SARS-CoV-2 viral load in nasopharyngeal swabs is not an independent predictor of unfavorable outcome

The aim was to assess the ability of nasopharyngeal SARS-CoV-2 viral load at frst patient’s hospital evaluation to predict unfavorable outcomes. We conducted a prospective cohort study including 321 adult patients with confrmed COVID-19 through RT-PCR in nasopharyngeal swabs. Quantitative Synthetic SARS-CoV-2 RNA cycle threshold values were used to calculate the viral load in log10 copies/mL. Disease severity at the end of follow up was categorized into mild, moderate, and severe. Primary endpoint was a composite of intensive care unit (ICU) admission and/or death (n= 85, 26.4%). Univariable and multivariable logistic regression analyses were performed. Nasopharyngeal SARS-CoV-2 viral load over the second quartile (≥7.35 log10 copies/mL, p = 0.003) and second tertile (≥ 8.27 log10 copies/mL, p = 0.01) were associated to unfavorable outcome in the unadjusted logistic regression analysis. However, in the fnal multivariable analysis, viral load was not independently associated with an unfavorable outcome. Five predictors were independently associated with increased odds of ICU admission and/or death: age≥ 70 years, SpO2, neutrophils > 7.5 × ­103 /µL, lactate dehydrogenase≥ 300 U/L, and C-reactive protein≥ 100 mg/L. In summary, nasopharyngeal SARS-CoV-2 viral load on admission is generally high in patients with COVID-19, regardless of illness severity, but it cannot be used as an independent predictor of unfavorable clinical outcome