RESUMEN
Neuronal nicotinic acetylcholine receptors (nAChRs) are widely distributed in both the peripheral and the central nervous systems. nAChRs exert a crucial modulatory influence on several brain biological processes; they are involved in a variety of neuronal diseases including Parkinson's disease, Alzheimer's disease, epilepsy, and nicotine addiction. The influence of nAChRs on brain function depends on the activity of other neurotransmitter receptors that co-exist with nAChRs on neurons. In fact, the crosstalk between receptors is an important mechanism of neurotransmission modulation and plasticity. This may be due to converging intracellular pathways but also occurs at the membrane level, because of direct physical interactions between receptors. In this line, this review is dedicated to summarizing how nAChRs and other ionotropic and metabotropic receptors interact and the relevance of nAChRs cross-talks in modulating various neuronal processes ranging from the classical modulation of neurotransmitter release to neuron plasticity and neuroprotection.
Asunto(s)
Receptores Nicotínicos , Receptores Nicotínicos/metabolismo , Sistema Nervioso Central/metabolismo , Neuronas/metabolismo , Transmisión Sináptica/fisiología , Encéfalo/metabolismoRESUMEN
Establishing a common language that allows univocal and objective communication in describing wounds and their healing is of utmost importance in defining the diagnostic hypothesis and proper wound management. To measure the level of agreement on the description of wounds, an international study was performed among experts of different professional backgrounds on several common terms used to describe ulcerative lesions. A panel of 27 wound care experts anonymously completed a multiple-choice questionnaire on 100 images of 50 ulcerative lesions. The participants were asked to describe each image using a set of pre-defined terms. An expert data analyst interpreted the questionnaires to map the level of agreement on the used terminology. Our findings show a very low level of agreement among experts in using the proposed terminology to describe the wound bed, the wound edge, and the surrounding skin conditions. Efforts should be planned to find a consensus on the correct use of terminology for wound description. To this aim, partnership, consensus, and agreement with educators in medicine and nursing are necessary.
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Cicatrización de Heridas , Humanos , ConsensoRESUMEN
Parapoxvirus (PPV) infections are considered neglected zoonoses because their incidence is often unknown or greatly underestimated despite being endemic globally. Here, we report the comprehensive diagnostic workflow that led to the identification of two cases of persistent PPV infections. The results obtained underline the importance of adopting a "One Health" approach and cross-sectoral collaboration between human and veterinary medicine for precise aetiological diagnosis and correct management of patients affected by zoonotic diseases.
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Parapoxvirus , Infecciones por Poxviridae , Animales , Humanos , Zoonosis/epidemiología , Infecciones por Poxviridae/epidemiología , Infecciones por Poxviridae/veterinariaRESUMEN
The progressive neuropathological damage seen in Parkinson's disease (PD) is thought to be related to the spreading of aggregated forms of α-synuclein. Clearance of extracellular α-synuclein released by degenerating neurons may be therefore a key mechanism to control the concentration of α-synuclein in the extracellular space. Several molecular chaperones control misfolded protein accumulation in the extracellular compartment. Among these, clusterin, a glycoprotein associated with Alzheimer's disease, binds α-synuclein aggregated species and is present in Lewy bodies, intraneuronal aggregates mainly composed by fibrillary α-synuclein. In this study, using murine primary astrocytes with clusterin genetic deletion, human-induced pluripotent stem cell (iPSC)-derived astrocytes with clusterin silencing and two animal models relevant for PD we explore how clusterin affects the clearance of α-synuclein aggregates by astrocytes. Our findings showed that astrocytes take up α-synuclein preformed fibrils (pffs) through dynamin-dependent endocytosis and that clusterin levels are modulated in the culture media of cells upon α-synuclein pffs exposure. Specifically, we found that clusterin interacts with α-synuclein pffs in the extracellular compartment and the clusterin/α-synuclein complex can be internalized by astrocytes. Mechanistically, using clusterin knock-out primary astrocytes and clusterin knock-down hiPSC-derived astrocytes we observed that clusterin limits the uptake of α-synuclein pffs by cells. Interestingly, we detected increased levels of clusterin in the adeno-associated virus- and the α-synuclein pffs- injected mouse model, suggesting a crucial role of this chaperone in the pathogenesis of PD. Overall, our observations indicate that clusterin can limit the uptake of extracellular α-synuclein aggregates by astrocytes and, hence, contribute to the spreading of Parkinson pathology.
Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Animales , Astrocitos , Clusterina/genética , Humanos , Cuerpos de Lewy , Ratones , alfa-Sinucleína/genéticaRESUMEN
Deficits in social cognition and communication, the processes associated with human social behavior and interaction, have been described in individuals with eating disorder psychopathology. The current study examined whether social communication characteristics present in middle childhood (ages 8-14) were associated with eating disorder behaviors, cognitions, and diagnoses across adolescence (ages 14-18) in a large, population-based sample. Participants (N = 4864) were children enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based, prospective study of women and their children. Regression methods tested prospective associations between social functioning using a facial emotion recognition task and parentally reported social communication symptoms (or difficulties), measured by the Social Communication Disorder Checklist (SCDC), with eating disorder symptoms and diagnoses. Misattribution of faces as sad or angry at age 8.5 was associated with purging and anorexia nervosa diagnosis at age 14, respectively, among girls. Furthermore, autistic-like social communication difficulties during middle childhood were associated with bulimia nervosa symptoms during adolescence among both girls and boys. Results did not support global associations between measured social communication deficits and eating disorder risk in this sample, but specific difficulties with facial emotion recognition and social communication may enhance the risk for disordered eating behaviors.
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Anorexia Nerviosa , Bulimia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Adolescente , Niño , Comunicación , Trastornos de Alimentación y de la Ingestión de Alimentos/diagnóstico , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Estudios ProspectivosRESUMEN
Perioperative antibiotic treatment duration in skin reconstruction with dermal substitutes is not well established. This study compares the incidence of infective complications after two different durations of perioperative antibiotic treatment in patients undergoing surgical reconstruction with skin dermal substitutes (SDS) after excision of skin cancer. Infective complications at the site of SDS were compared in subjects undergoing surgical reconstruction who received either a > 24-hour (extended protocol) or a ≤ 24-hour (short protocol) perioperative antibiotic treatment. Of 116 patients undergoing SDS surgical reconstruction, 62 (53.4%) received an extended schedule, and 54 (46.6%) received a short schedule. The two groups were similar for gender, age, comorbidities, American Society of Anesthesiologists score, and type of skin cancer. Overall incidence rate of infection was 20.7% (24/116). No differences in terms of risk of infection were observed between the two groups (OR: 1.04, 95% CI: 0.42-2.55; P = .937). Patients undergoing SDS reconstruction in the limb/foot had a higher risk of infection in comparison with those undergoing SDS reconstruction in the chest/head (OR: 2.69, 95% CI: 1.06-6.86; P = .038). The short protocol was demonstrated to be beneficial to patients undergoing surgical reconstruction with SDS. A ≤ 24-hour perioperative antibiotic schedule did not increase the infection rate, potentially allowing a reduction of antibiotic exposure.
Asunto(s)
Antibacterianos/uso terapéutico , Profilaxis Antibiótica/métodos , Atención Perioperativa/métodos , Procedimientos de Cirugía Plástica/métodos , Neoplasias Cutáneas/cirugía , Trasplante de Piel/métodos , Infección de la Herida Quirúrgica/prevención & control , Dermis Acelular/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Profilaxis Antibiótica/estadística & datos numéricos , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Atención Perioperativa/estadística & datos numéricos , Procedimientos de Cirugía Plástica/estadística & datos numéricos , Neoplasias Cutáneas/epidemiología , Trasplante de Piel/estadística & datos numéricosRESUMEN
We recently found that in mouse dopaminergic neurons, the heteromer formed by the dopamine D3 receptor (D3R) and the ß2 subunit of acetylcholine nicotinic receptor (nAChR) exerts neurotrophic effects when activated by nicotine, leading to neurons with enlarged cell bodies and increased dendrite arborization. Beside this action, we now show that nicotine, by activating the D3R-nAChR heteromer, protects dopaminergic neurons against neuronal injury. In primary cultures of mouse dopaminergic neurons, in fact, the ability of nicotine to inhibit both the pathological accumulation of alpha-synuclein induced by glucose deprivation and the consequent morphological defects were strongly prevented by disrupting the D3R-nAChR heteromer with specific interfering TAT-peptides; the relevance of the phosphoinositide 3-kinase (PI3K) intracellular signaling in mediating nicotine prevention of alpha-synuclein aggregation has been also demonstrated. Moreover, the ability of nicotine in restoring the ubiquitin-proteasome system has been found as a mechanism contributing to the neuroprotective properties of nicotine. By using the proximity ligation assay, we have shown that the D3R-nAChR heteromer is also expressed in human dopaminergic neurons derived from induced pluripotent stem cells. In this human cell model, nicotine exerts neuroprotective effects specifically acting through the D3R-nAChR complex thus indicating that this heteromer is a relevant molecular effector involved in the protection of human dopaminergic neurons.
Asunto(s)
Neuronas Dopaminérgicas/metabolismo , Nicotina/farmacología , Receptores de Dopamina D3/metabolismo , Receptores Nicotínicos/metabolismo , alfa-Sinucleína/efectos de los fármacos , Animales , Células Cultivadas , Neuronas Dopaminérgicas/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/efectos de los fármacos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fármacos Neuroprotectores/farmacología , Receptores de Dopamina D3/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacosRESUMEN
The reconstruction of complex wounds in patients with comorbidities in the lower extremities is a challenging problem for surgeons. Skin grafting is frequently used to cover large skin defects, but it has several limits, including unwanted outcomes resulting from scars, poor elasticity and limitations in joint movement due to contractures. Locoregional flaps, particularly in the lower limbs, have limited application due to the size of the defect. Tissue engineering of the skin has offered major improvements in the coverage of large defects. Dermal matrix can be applied in order to generate a new dermis that allows good re-epithelialisation or skin grafting at a later stage. The reconstruction of large lower limb defects is more complicated in the case of chronic wounds showing no tendency to heal due to chronic infection. For all surgeons, it is very important to prevent the formation of a biofilm or manage it when it is already established before undertaking surgical procedures that involve a dermal matrix. We report our reconstruction strategy of chronic infected neoplastic ulcers of the lower extremities with a dermal matrix and our postoperative dressing protocol.
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Complicaciones Posoperatorias/cirugía , Trasplante de Piel/métodos , Traumatismos de los Tejidos Blandos/cirugía , Colgajos Quirúrgicos/trasplante , Muslo/cirugía , Ingeniería de Tejidos/métodos , Cicatrización de Heridas/fisiología , Anciano , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised by painful, necrotic ulcerations. PG is described as a rare disease: the world-wide incidence is estimated to be around 3 to 10 cases per million population per year. These estimations are based mostly on case reports and retrospective case series; there are no prospective, multicentre studies on the matter. The apparent rarity of PG is in contrast with our clinical perception as dermatologists: in our opinion, PG is not so uncommon. Therefore, we decide to investigate the epidemiology of PG in the Italian population and confirm our clinical suspicions that it is not an orphan disease. We enrolled all patients diagnosed with PG in 8 Italian Dermatological Departments from 1st October 2014 to 1st November 2015, and we recorded their features. Our data, collected from 64 patients, are in accordance with those of the published literature regarding the epidemiology and features of PG. In an Italian population of roughly 8 million inhabitants of 7 provinces, we found an incidence of 5.17 new cases per million population per year. Unlike our predictions before the study, we confirmed the world-wide incidence of PG. To our knowledge, this is the first observational, multicentre study on PG. We hope that it provides a stimulus for further researches on PG and for the creation of an Italian register.
Asunto(s)
Mediciones Epidemiológicas , Piodermia Gangrenosa/epidemiología , Femenino , Humanos , Incidencia , Italia/epidemiología , Masculino , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Glycaemic index (GI) and glycaemic load (GL) are indicators of dietary carbohydrate quantity and quality and have been associated with increased risk of certain cancers and type 2 diabetes. Insulin resistance has been associated with increased melanoma risk. However, GI and GL have not been investigated for melanoma. We present the first study to examine the possible association of GI and GL with melanoma risk. We carried out a population-based, case-control study involving 380 incident cases of cutaneous melanoma and 719 age- and sex-matched controls in a northern Italian region. Dietary GI and GL were computed for each subject using data from a self-administered, semi-quantitative food frequency questionnaire. We computed the odds ratio (OR) for melanoma according to quintiles of distribution of GL and GL among controls. A direct association between melanoma risk and GL emerged in females (OR 2·38; 95 % CI 1·25, 4·52 for the highest v. the lowest quintile of GL score, P for trend 0·070) but not in males. The association in females persisted in the multivariable analysis after adjusting for several potential confounders. There was no evidence of an association between GI and melanoma risk. GL might be associated with melanoma risk in females.
Asunto(s)
Glucemia/metabolismo , Carbohidratos de la Dieta/efectos adversos , Índice Glucémico , Carga Glucémica , Melanoma/etiología , Adulto , Anciano , Estudios de Casos y Controles , Encuestas sobre Dietas , Carbohidratos de la Dieta/sangre , Femenino , Humanos , Resistencia a la Insulina , Masculino , Melanoma/sangre , Persona de Mediana Edad , Oportunidad Relativa , Autoinforme , Factores Sexuales , Neoplasias Cutáneas , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Certain features of the social environment could maintain and even improve not only psychological well-being, but also health and cognition of the elderly. AIMS: We tested the association between social network characteristics and the number of chronic diseases in the elderly. METHODS: A randomized sample of the elderly population of Brescia, Italy, was evaluated (N = 200, age ≥65 years). We performed a comprehensive geriatric assessment, including information on socio-demographic variables (family, friendships, and acquaintance contacts). We measured each person's social network, i.e., degree, efficiency, and variety. RESULTS: The sample included 118 women and 82 men, mean age 77.7 years. The mean number of chronic diseases was 3.5. A higher social network degree, i.e., more social connections, was associated with fewer diseases. We also found that having more contacts with people similar to each other or intense relationships with people who do not know each other were associated with fewer diseases. CONCLUSION: More healthy people tend to share certain characteristics of social networks. Our study indicates that it is important to look at diseases and health as complex phenomena, which requires integrating different levels of analysis.
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Evaluación Geriátrica/métodos , Estado de Salud , Apoyo Social , Anciano , Anciano de 80 o más Años , Enfermedad Crónica/epidemiología , Enfermedad Crónica/psicología , Estudios Transversales , Femenino , Humanos , Italia/epidemiología , Masculino , Estudios ProspectivosRESUMEN
BACKGROUND: Dyskinesia, the major side effect of l-dopa therapy in PD, is mainly associated with nonphysiological stimulation of denervated receptors in the striatum. In particular, DA D1 receptor-mediated aberrant extracellular signal-regulated protein kinases 1 and 2 activation have been associated with striatal changes leading to dyskinesia. We recently identified the tyrosine phosphatase Shp-2 as a crucial effector transmitting D1 receptor signaling to extracellular signal-regulated protein kinases 1 and 2 activation and reported the involvement of the D1 receptor/Shp-2/extracellular signal-regulated protein kinases 1 and 2 pathway in the development of l-dopa-induced dyskinesia. OBJECTIVES: In this study, the role of Shp-2 in l-dopa-induced dyskinesia development was investigated by in vivo silencing of Shp-2 in the striatum of the 6-hydroxy-dopamine rat model of PD. METHODS: Lentiviral particles delivering short hairpin RNA were used to obtain long-term striatal Shp-2 downregulation. Rats were then treated with l-dopa and analyzed for both the improvement of akinesia and the development of l-dopa-induced dyskinesia. RESULTS: The results show that Shp-2 knockdown remarkably decreased extracellular signal-regulated protein kinases 1 and 2 phosphorylation and attenuated the severity of l-dopa-induced dyskinesia likely without compromising the therapeutic efficacy of l-dopa. CONCLUSION: These data suggest that the striatal D1 receptor/Shp-2 complex may represent a promising novel target for the development of antidyskinetic drugs.
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Antiparkinsonianos/efectos adversos , Conducta Animal/efectos de los fármacos , Discinesia Inducida por Medicamentos/metabolismo , Levodopa/efectos adversos , Neostriado/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo , Discinesia Inducida por Medicamentos/prevención & control , Masculino , Neostriado/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The current study investigated the role of congruent visual context information in the recognition of facial emotional expression in 190 participants from 5 to 15years of age. Children performed a matching task that presented pictures with different facial emotional expressions (anger, disgust, happiness, fear, and sadness) in two conditions: with and without a visual context. The results showed that emotions presented with visual context information were recognized more accurately than those presented in the absence of visual context. The context effect remained steady with age but varied according to the emotion presented and the gender of participants. The findings demonstrated for the first time that children from the age of 5years are able to integrate facial expression and visual context information, and this integration improves facial emotion recognition.
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Emociones/fisiología , Expresión Facial , Reconocimiento Facial/fisiología , Adolescente , Ira/fisiología , Niño , Preescolar , Miedo/fisiología , Femenino , Felicidad , Humanos , Masculino , Estimulación Luminosa , Reconocimiento en Psicología/fisiología , Percepción Visual/fisiologíaRESUMEN
BACKGROUND: Some results from laboratory and epidemiologic studies suggest that diet may influence the risk of melanoma, but convincing evidence for a role of single nutrients or food items is lacking. Diet quality, which considers the combined effect of multiple food items, may be superior for examining this relation. OBJECTIVE: We sought to assess whether diet quality, evaluated with the use of 4 different dietary indexes, is associated with melanoma risk. METHODS: In this population-based case-control study, we analyzed the relation between 4 diet quality indexes, the Healthy Eating Index 2010 (HEI-2010), Dietary Approaches to Stop Hypertension (DASH) index, Greek Mediterranean Index (GMI), and Italian Mediterranean Index (IMI), and melanoma risk in a northern Italian community, with the use of data from 380 cases and 719 matched controls who completed a semiquantitative food frequency questionnaire. RESULTS: In the overall sample, we found an inverse association between disease risk and the HEI-2010 and DASH index, but not the Mediterranean indexes, adjusting for potential confounders (skin phototype, body mass index, energy intake, sunburn history, skin sun reaction, and education). However, in sex stratified analyses, the association appeared only in women (P-trend: 0.10 and 0.04 for the HEI-2010 and DASH index, respectively). The inverse relations were stronger in women younger than age 50 y than in older women, for whom the GMI and IMI scores also showed an inverse association with disease risk (P-trend: 0.05 and 0.02, respectively). CONCLUSIONS: These results suggest that diet quality may play a role in cutaneous melanoma etiology among women.
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Dieta/normas , Melanoma/epidemiología , Melanoma/etiología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Recolección de Datos , Encuestas sobre Dietas , Conducta Alimentaria , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Factores de Riesgo , Encuestas y CuestionariosRESUMEN
Adenosine-to-inosine RNA editing is a post-transcriptional process, catalyzed by ADAR enzymes, with an important role in diversifying the number of proteins derived from a single gene. In neurons, editing of ionotropic AMPA glutamate receptors has been shown to be altered under several experimental conditions, including severe pathologies, thus highlighting the potential significance of its modulation. In this study, we treated rat primary cortical cell cultures with a sub-lethal dose of glutamate (10 µM), focusing on RNA editing and ADAR activity. We found that chronic glutamate treatment down-regulates RNA editing levels at the R/G site of GluA2-4 subunits of AMPA receptors and at the K/E site of CYFIP2. These changes are site-specific since they were not observed either for the GluA2 Q/R site or for other non-glutamatergic sites. Glutamate treatment also down-regulates the protein expression levels of both ADAR1 and ADAR2 enzymes, through a pathway that is Ca(2+)- and calpain-dependent. Given that AMPA receptors containing unedited subunits show a slower recovery rate from desensitization compared to those containing edited forms, the reduced editing at the R/G site may, at least in part, compensate for glutamate over-stimulation, perhaps through the reduced activation of postsynaptic receptors. In summary, our data provide direct evidence of the involvement of ADAR1 and ADAR2 activity as a possible compensatory mechanism for neuronal protection following glutamate over-stimulation.
Asunto(s)
Adenosina Desaminasa/metabolismo , Ácido Glutámico/farmacología , Neuronas/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores AMPA/genética , Receptores AMPA/metabolismo , Animales , Calcio/metabolismo , Calpaína/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Cultivo Primario de Células , ARN Mensajero/química , Ratas Sprague-DawleyRESUMEN
Non-metastatic glycoprotein melanoma protein B (GPNMB), also known as osteoactivin (OA) is expressed in a wide array of tumors and represents an emerging target for drug development. In this study, we investigated the role of GPNMB/OA in the progression of human metastatic DU145 and PC3 prostate cancer cells. GPNMB/OA contribution in PCa malignant phenotype has been analyzed by small interfering RNA-induced GPNMB/OA silencing. We found that following GPNMB/OA silencing the migration capability of both DU145 and PC3 cells, evaluated by using in vitro invasivity assay, as well as the metalloproteinases MMP-2 and MMP-9 activity were equally strongly inhibited. By contrast knocking down GPNMB/OA weakly attenuated cell proliferation rate of DU145, an effect that paralleled with an increase number of apoptotic cells. However, PC3 cell growth seems to be not affected by GPNMB/OA. Together, these data reveal that GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines.
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Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias de la Próstata/patología , Apoptosis/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Expresión Génica , Humanos , Masculino , Glicoproteínas de Membrana/genética , Invasividad Neoplásica , Metástasis de la Neoplasia , Fosforilación , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño , Inhibidor Tisular de Metaloproteinasa-1/biosíntesis , Inhibidor Tisular de Metaloproteinasa-2/biosíntesisAsunto(s)
Vendajes , Carcinoma de Células Escamosas/cirugía , Epidermólisis Ampollosa/complicaciones , Neoplasias Cutáneas/cirugía , Cicatrización de Heridas/fisiología , Adulto , Carcinoma de Células Escamosas/etiología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Cutáneas/etiología , Resultado del TratamientoRESUMEN
Dopaminergic neurons express a heteromer composed of the dopamine D3 receptor and the α4ß2 nicotinic acetylcholine receptor, the D3R-nAChR heteromer, activated by both nicotine and dopamine D2 and D3 receptors agonists, such as quinpirole, and crucial for dopaminergic neuron homeostasis. We now report that D3R-nAChR heteromer activity is potentiated by 17-ß-estradiol which acts as a positive allosteric modulator by binding a specific domain on the α4 subunit of the nicotinic receptor protomer. In mouse dopaminergic neurons, in fact, 17-ß-estradiol significantly increased the ability of nicotine and quinpirole in promoting neuron dendritic remodeling and in protecting neurons against the accumulation of α-synuclein induced by deprivation of glucose, with a mechanism that does not involve the classical estrogen receptors. The potentiation induced by 17-ß-estradiol required the D3R-nAChR heteromer since either nicotinic receptor or dopamine D3 receptor antagonists and interfering TAT-peptides, but not the estrogen receptor antagonist fulvestrant, specifically prevented 17-ß-estradiol effects. Evidence of estrogens neuroprotection, mainly mediated by genomic mechanisms, have been provided, which is in line with epidemiological data reporting that females are less likely to develop Parkinson's Disease than males. Therefore, potentiation of D3R-nAChR heteromer activity may represent a further mechanism by which 17-ß-estradiol reduces dopaminergic neuron vulnerability.
Asunto(s)
Neuronas Dopaminérgicas , Estradiol , Fármacos Neuroprotectores , Receptores de Dopamina D3 , Receptores Nicotínicos , Receptores de Dopamina D3/metabolismo , Receptores de Dopamina D3/agonistas , Estradiol/farmacología , Animales , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Receptores Nicotínicos/metabolismo , Ratones , Fármacos Neuroprotectores/farmacología , Femenino , MasculinoRESUMEN
We have established Noonan syndrome (NS)-derived induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) of a family cohort carrying the heterozygous PTPN11 c.188 A > G (p.Y63C) mutation. The new iPSC lines were validated by confirming the normal karyotype and targeted mutation, the pluripotent gene expression, and the differentiation capacity into three germ layers.
Asunto(s)
Células Madre Pluripotentes Inducidas , Síndrome de Noonan , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Leucocitos Mononucleares , Mutación/genética , Heterocigoto , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
BACKGROUND: The delayed diagnosis of skin tumors is associated with a worsened prognosis. The impact of the interruption of clinical and surgical health services during the COVID-19 pandemic lockdowns has been documented among many pathologies. The impact of delayed diagnoses on patients with cutaneous squamous cell carcinomas (cSCCs) is poorly defined. OBJECTIVE: To compare patient and lesion characteristics and the surgical management of excised cSCCs prior to the pandemic shutdown of services (2018-2019) with the phase following the pandemic's second wave (2021-2022). METHODS: An observational, single-center, cross-sectional study of 416 surgically excised cSCCs over the course of two years was performed. Only patients with histologically confirmed cSCC were enrolled. Data collection included patient demographics and lesion characteristics, time to surgery, surgical approach, and histological data. RESULTS: More cSCC lesions were excised prior to the interruption of services (n = 312 vs. n = 186). Lesions were significantly larger (1.7 ± 1.2 vs. 2.1 ± 1.5 cm; p = 0.006) and more invasive (52% vs. 89%; p < 0.001), in the period 2021-2022. Surgical reconstructive techniques were significantly different (p = 0.001). Metastatic involvement was confirmed in three subjects (one in 2018-2019 and two in 2021-2022). There were no significant differences in the time to surgery or patient characteristics. Multivariable regression analysis identified a 4.7-times higher risk of tumor invasion (OR 4.69, 95%CI 2.55-8.16, p < 0.001), a two-times higher chance of dermo-epidermal grafts (OR 2.06, 95%CI 1.09-3.88, p = 0.025), and a 3.2-times higher risk of positive surgical margins (OR 3.21, 95%CI 1.44-7.17, p = 0.004). CONCLUSIONS: Diagnostic delays of cutaneous SCCs associated with reduced patient access to clinical and diagnostic services are associated with a 4.7-times increased risk of more severe invasion, a three-times increased risk of positive surgical margins, and a significant impact on surgical management, compared to the pre-pandemic period. Comparable patient cohort characteristics and time to surgery remained unchanged.