RESUMO
Genes associated with risk for brain disease exhibit characteristic expression patterns that reflect both anatomical and cell type relationships. Brain-wide transcriptomic patterns of disease risk genes provide a molecular-based signature, based on differential co-expression, that is often unique to that disease. Brain diseases can be compared and aggregated based on the similarity of their signatures which often associates diseases from diverse phenotypic classes. Analysis of 40 common human brain diseases identifies 5 major transcriptional patterns, representing tumor-related, neurodegenerative, psychiatric and substance abuse, and 2 mixed groups of diseases affecting basal ganglia and hypothalamus. Further, for diseases with enriched expression in cortex, single-nucleus data in the middle temporal gyrus (MTG) exhibits a cell type expression gradient separating neurodegenerative, psychiatric, and substance abuse diseases, with unique excitatory cell type expression differentiating psychiatric diseases. Through mapping of homologous cell types between mouse and human, most disease risk genes are found to act in common cell types, while having species-specific expression in those types and preserving similar phenotypic classification within species. These results describe structural and cellular transcriptomic relationships of disease risk genes in the adult brain and provide a molecular-based strategy for classifying and comparing diseases, potentially identifying novel disease relationships.
Assuntos
Encefalopatias , Transcriptoma , Adulto , Animais , Humanos , Camundongos , Gânglios da Base , Encéfalo/metabolismo , Encefalopatias/genética , Encefalopatias/metabolismo , Perfilação da Expressão Gênica/métodos , Transcriptoma/genética , Transcriptoma/fisiologia , Fatores de RiscoRESUMO
Individuals living with obesity tend to have increased brain age, reflecting poorer brain health likely due to grey and white matter atrophy related to obesity. However, it is unclear if older brain age associated with obesity can be reversed following weight loss and cardiometabolic health improvement. The aim of this study was to assess the impact of weight loss and cardiometabolic improvement following bariatric surgery on brain health, as measured by change in brain age estimated based on voxel-based morphometry (VBM) measurements. We used three distinct datasets to perform this study: 1) CamCAN dataset to train the brain age prediction model, 2) Human Connectome Project (HCP) dataset to investigate whether individuals with obesity have greater brain age than individuals with normal weight, and 3) pre-surgery, as well as 4, 12, and 24 month post-surgery data from participants (n = 87, age: 44.0 ± 9.2 years, BMI: 43.9 ± 4.2 kg/m2) who underwent a bariatric surgery to investigate whether weight loss and cardiometabolic improvement as a result of bariatric surgery lowers the brain age. As expected, our results from the HCP dataset showed a higher brain age for individuals with obesity compared to individuals with normal weight (T-value = 7.08, p-value < 0.0001). We also found significant improvement in brain health, indicated by a decrease of 2.9 and 5.6 years in adjusted delta age at 12 and 24 months following bariatric surgery compared to baseline (p-value < 0.0005 for both). While the overall effect seemed to be driven by a global change across all brain regions and not from a specific region, our exploratory analysis showed lower delta age in certain brain regions (mainly in somatomotor, visual, and ventral attention networks) at 24 months. This reduced age was also associated with post-surgery improvements in BMI, systolic/diastolic blood pressure, and HOMA-IR (T-valueBMI=4.29, T-valueSBP=4.67, T-valueDBP=4.12, T-valueHOMA-IR=3.16, all p-values < 0.05). In conclusion, these results suggest that obesity-related brain health abnormalities (as measured by delta age) might be reversed by bariatric surgery-induced weight loss and widespread improvements in cardiometabolic alterations.
Assuntos
Cirurgia Bariátrica , Doenças Cardiovasculares , Adulto , Encéfalo/diagnóstico por imagem , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Obesidade/cirurgia , Redução de Peso/fisiologiaRESUMO
A 23-year-old man presenting with a 1-year history of a lesion of the right cheek. We highlight this case for awareness as this tumour may mimic other benign lesions, such as pilomatrixoma or benign cysts, as it does not have any uniquely identifying clinical or dermoscopic features. Additionally, it is of concern as malignant transformation can occur and therefore surgery should be considered as both for diagnostic and therapeutic benefit.
Assuntos
Doenças do Cabelo , Pilomatrixoma , Neoplasias Cutâneas , Adulto , Bochecha/patologia , Diagnóstico Diferencial , Doenças do Cabelo/patologia , Humanos , Masculino , Pilomatrixoma/diagnóstico , Pilomatrixoma/patologia , Pilomatrixoma/cirurgia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/cirurgia , Adulto JovemRESUMO
BACKGROUND: Metabolic disorders associated with obesity could lead to alterations in brain structure and function. Whether these changes can be reversed after weight loss is unclear. Bariatric surgery provides a unique opportunity to address these questions because it induces marked weight loss and metabolic improvements which in turn may impact the brain in a longitudinal fashion. Previous studies found widespread changes in grey matter (GM) and white matter (WM) after bariatric surgery. However, findings regarding changes in spontaneous neural activity following surgery, as assessed with the fractional amplitude of low frequency fluctuations (fALFF) and regional homogeneity of neural activity (ReHo), are scarce and heterogenous. In this study, we used a longitudinal design to examine the changes in spontaneous neural activity after bariatric surgery (comparing pre- to post-surgery), and to determine whether these changes are related to cardiometabolic variables. METHODS: The study included 57 participants with severe obesity (mean BMI=43.1 ± 4.3 kg/m2) who underwent sleeve gastrectomy (SG), biliopancreatic diversion with duodenal switch (BPD), or Roux-en-Y gastric bypass (RYGB), scanned prior to bariatric surgery and at follow-up visits of 4 months (N = 36), 12 months (N = 29), and 24 months (N = 14) after surgery. We examined fALFF and ReHo measures across 1022 cortical and subcortical regions (based on combined Schaeffer-Xiao parcellations) using a linear mixed effect model. Voxel-based morphometry (VBM) based on T1-weighted images was also used to measure GM density in the same regions. We also used an independent sample from the Human Connectome Project (HCP) to assess regional differences between individuals who had normal-weight (N = 46) or severe obesity (N = 46). RESULTS: We found a global increase in the fALFF signal with greater increase within dorsolateral prefrontal cortex, precuneus, inferior temporal gyrus, and visual cortex. This effect was more significant 4 months after surgery. The increase within dorsolateral prefrontal cortex, temporal gyrus, and visual cortex was more limited after 12 months and only present in the visual cortex after 24 months. These increases in neural activity measured by fALFF were also significantly associated with the increase in GM density following surgery. Furthermore, the increase in neural activity was significantly related to post-surgery weight loss and improvement in cardiometabolic variables, such as blood pressure. In the independent HCP sample, normal-weight participants had higher global and regional fALFF signals, mainly in dorsolateral/medial frontal cortex, precuneus and middle/inferior temporal gyrus compared to the obese participants. These BMI-related differences in fALFF were associated with the increase in fALFF 4 months post-surgery especially in regions involved in control, default mode and dorsal attention networks. CONCLUSIONS: Bariatric surgery-induced weight loss and improvement in metabolic factors are associated with widespread global and regional increases in neural activity, as measured by fALFF signal. These findings alongside the higher fALFF signal in normal-weight participants compared to participants with severe obesity in an independent dataset suggest an early recovery in the neural activity signal level after the surgery.
Assuntos
Cirurgia Bariátrica/tendências , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Imageamento por Ressonância Magnética/tendências , Obesidade/diagnóstico por imagem , Descanso/fisiologia , Adulto , Cirurgia Bariátrica/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Obesidade/cirurgia , Cuidados Pós-Operatórios/métodos , Cuidados Pré-Operatórios/métodosRESUMO
As of June 30, 2021, 33.5 million persons in the United States had received a diagnosis of COVID-19 (1). Although most patients infected with SARS-CoV-2, the virus that causes COVID-19, recover within a few weeks, some experience post-COVID-19 conditions. These range from new or returning to ongoing health problems that can continue beyond 4 weeks. Persons who were asymptomatic at the time of infection can also experience post-COVID-19 conditions. Data on post-COVID-19 conditions are emerging and information on rehabilitation needs among persons recovering from COVID-19 is limited. Using data acquired during January 2020-March 2021 from Select Medical* outpatient rehabilitation clinics, CDC compared patient-reported measures of health, physical endurance, and health care use between patients who had recovered from COVID-19 (post-COVID-19 patients) and patients needing rehabilitation because of a current or previous diagnosis of a neoplasm (cancer) who had not experienced COVID-19 (control patients). All patients had been referred to outpatient rehabilitation. Compared with control patients, post-COVID-19 patients had higher age- and sex-adjusted odds of reporting worse physical health (adjusted odds ratio [aOR] = 1.8), pain (aOR = 2.3), and difficulty with physical activities (aOR = 1.6). Post-COVID-19 patients also had worse physical endurance, measured by the 6-minute walk test (6MWT) (p<0.001) compared with control patients. Among patients referred to outpatient rehabilitation, those recovering from COVID-19 had poorer physical health and functional status than those who had cancer, or were recovering from cancer but not COVID-19. Patients recovering from COVID-19 might need additional clinical support, including tailored physical and mental health rehabilitation services.
Assuntos
Instituições de Assistência Ambulatorial , COVID-19/reabilitação , Encaminhamento e Consulta , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
The relationship between structural changes of the cerebral cortex revealed by Magnetic Resonance Imaging (MRI) and gene expression in the human fetal brain has not been explored. In this study, we aimed to test the hypothesis that relative regional thickness (a measure of cortical evolving organization) of fetal cortical compartments (cortical plate [CP] and subplate [SP]) is associated with expression levels of genes with known cortical phenotype. Mean regional SP/CP thickness ratios across age measured on in utero MRI of 25 healthy fetuses (20-33 gestational weeks [GWs]) were correlated with publicly available regional gene expression levels (23-24 GW fetuses). Larger SP/CP thickness ratios (more pronounced cortical evolving organization) was found in perisylvian regions. Furthermore, we found a significant association between SP/CP thickness ratio and expression levels of the FLNA gene (mutated in periventricular heterotopia, congenital heart disease, and vascular malformations). Further work is needed to identify early MRI biomarkers of gene expression that lead to abnormal cortical development.
Assuntos
Encéfalo/crescimento & desenvolvimento , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/embriologia , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/embriologia , Adulto , Encéfalo/diagnóstico por imagem , Córtex Cerebral/anormalidades , Feminino , Feto/diagnóstico por imagem , Feto/metabolismo , Filaminas/genética , Expressão Gênica/genética , Expressão Gênica/fisiologia , Idade Gestacional , Cabeça , Humanos , Imageamento por Ressonância Magnética , Rede Nervosa/metabolismo , Gravidez , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , TranscriptomaRESUMO
AIMS: Staging is the gold standard for predicting malignant melanoma outcome but changes in its criteria over time indicate ongoing evolution. One notable recent change from the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual was removal of mitotic count. We explore the extent to which this feature is limited by interobserver error in order to find ways to improve its fitness for use should it be revisited in future staging versions. METHODS AND RESULTS: In a cohort of 476 patients with melanoma ≤1.0 mm, a mitotic count of 0 versus 1 was significant for metastasis-free survival, but not melanoma-specific or overall survival. In 10 melanomas that were 0.9-1.0 mm thick, the mitotic count intraclass correlation coefficient for histopathologists was 0.58 (moderate agreement). Uniquely, we also assessed agreement for specific putative mitotic figures, identifying precise reasons why specific mitotic figures qualified for scoring or elimination. A kappa score was 0.54 (moderate agreement). We also gathered data on other staging features. Breslow thickness had an intraclass correlation coefficient of 0.41 (moderate agreement) and there was a systematic difference between histopathologists among cases (P = 0.04). Every case had a range that crossed the AJCC8 0.8-mm pT1a/pT1b staging boundary. Ulceration was only identified in two of the 10 cases. For ulceration, kappa agreement score was 0.31 (fair). CONCLUSION: This study supports the removal of mitotic count from staging, but shows that its scoring is substantially affected by interobserver variation, suggesting that more prescriptive guidelines might have a beneficial impact on its prognostic value.
Assuntos
Melanoma/patologia , Índice Mitótico/métodos , Estadiamento de Neoplasias/métodos , Neoplasias Cutâneas/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice Mitótico/normas , Estadiamento de Neoplasias/normas , Variações Dependentes do Observador , Prognóstico , Melanoma Maligno CutâneoRESUMO
Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin-angiotensin system (RAS) is a major physiological regulatory pathway controlling salt-water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma.
Assuntos
Proliferação de Células , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular , Sistema Renina-Angiotensina/fisiologia , Amidas/farmacologia , Amidas/uso terapêutico , Angiotensina II/farmacologia , Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Embrião não Mamífero , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Humanos , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Melanoma/genética , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Metástase Neoplásica , Piridinas/farmacologia , Piridinas/uso terapêutico , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-ZebraRESUMO
Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a subset of melanomas, the collagen prolyl 4-hydroxylase family members P4HA1, P4HA2, and P4HA3 are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation, and particularly invasiveness, of melanoma cells. Pharmacological inhibition with multiple selective collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells.
Assuntos
Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Prolil Hidroxilases/genética , Neoplasias Cutâneas/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Colágeno/metabolismo , Metilação de DNA/genética , Humanos , Melanoma/patologia , Processamento de Proteína Pós-Traducional/genética , Valores de Referência , Neoplasias Cutâneas/patologiaRESUMO
The neural correlates of human personality have been of longstanding interest; however, most studies in the field have relied on modest sample sizes and few replicable results have been reported to date. We investigated relationships between personality and brain gray matter in a sample of generally healthy, older (mean age 73 years) adults from Scotland drawn from the Lothian Birth Cohort 1936. Participants (Nâ¯=â¯578) completed a brain MRI scan and self-reported Big Five personality trait measures. Conscientiousness trait scores were positively related to brain cortical thickness in a range of regions, including bilateral parahippocampal gyrus, bilateral fusiform gyrus, left cingulate gyrus, right medial orbitofrontal cortex, and left dorsomedial prefrontal cortex. These associations - most notably in frontal regions - were modestly-to-moderately attenuated by the inclusion of biomarker variables assessing allostatic load and smoking status. None of the other personality traits showed robust associations with brain cortical thickness, nor did we observe any personality trait associations with cortical surface area and gray matter volume. These findings indicate that brain cortical thickness is associated with conscientiousness, perhaps partly accounted for by allostatic load and smoking status.
Assuntos
Córtex Cerebral/anatomia & histologia , Substância Cinzenta/anatomia & histologia , Personalidade/fisiologia , Idoso , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/anatomia & histologia , Inventário de PersonalidadeRESUMO
The incidence of cutaneous squamous cell carcinoma (cSCC) is rising. Whilst the majority are cured surgically, aggressive metastatic cSCC carry a poor prognosis. Inactivating mutations in transforming growth factor beta (TGF-ß) receptors have been identified amongst genetic drivers of sporadic tumours and murine models of cSCC, suggesting a tumour suppressor function for TGF-ß in normal skin. However, paradoxically, TGF-ß acts as a tumour promoter in some murine model systems. Few studies have analysed the role of TGF-ß/activin signalling in human normal skin, hyper-proliferative skin disorders and cSCC. Antibodies recognising phospho-SMAD proteins which are activated during canonical TGF-ß/activin signalling were validated for use in immunohistochemistry. A tissue microarray comprising FFPE lesional and perilesional tissue from human primary invasive cSCC (n=238), cSCC in-situ (n=2) and keratocanthoma (n=9) were analysed in comparison with tissues from normal human scalp (n=10). Phosphorylated SMAD2 and SMAD3 were detected in normal interfollicular epidermal keratinocytes and were also highly localised to inner root sheath, matrix cells and Keratin 15 positive cells. Lesional cSCC tissue had significantly reduced activated SMAD2/3 compared to perilesional tissue, consistent with a tumour suppressor role for SMAD2/3 activators in cSCC. Increased cSCC tumour thickness inversely correlated with the presence of phospho-SMADs in tumour tissue suggesting that a reduction in canonical TGF-ß/activin signalling may be associated with disease progression.
RESUMO
Cutaneous squamous cell carcinomas (cSCC) are among the most common and highly mutated human malignancies. Solar UV radiation is the major factor in the etiology of cSCC. Whole-exome sequencing of 18 microdissected tumor samples (cases) derived from SKH-1 hairless mice that had been chronically exposed to solar-simulated UV (SSUV) radiation showed a median point mutation (SNP) rate of 155 per Mb. The majority (78.6%) of the SNPs are C.G>T.A transitions, a characteristic UVR-induced mutational signature. Direct comparison with human cSCC cases showed high overlap in terms of both frequency and type of SNP mutations. Mutations in Trp53 were detected in 15 of 18 (83%) cases, with 20 of 21 SNP mutations located in the protein DNA-binding domain. Strikingly, multiple nonsynonymous SNP mutations in genes encoding Notch family members (Notch1-4) were present in 10 of 18 (55%) cases. The histopathologic spectrum of the mouse cSCC that develops in this model resembles very closely the spectrum of human cSCC. We conclude that the mouse SSUV cSCCs accurately represent the histopathologic and mutational spectra of the most prevalent tumor suppressors of human cSCC, validating the use of this preclinical model for the prevention and treatment of human cSCC. Cancer Prev Res; 10(1); 67-75. ©2016 AACR.
Assuntos
Carcinoma de Células Escamosas/terapia , Receptores Notch/genética , Neoplasias Cutâneas/terapia , Proteína Supressora de Tumor p53/genética , Animais , Carcinogênese/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Análise Mutacional de DNA/métodos , Exoma , Feminino , Humanos , Camundongos , Camundongos Pelados , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapia , Mutação Puntual , Polimorfismo de Nucleotídeo Único , Domínios Proteicos/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND AND PURPOSE: We assessed cross-sectional and longitudinal relationships between whole brain white matter hyperintensity (WMH) volume and regional cortical thickness. METHODS: We measured WMH volume and regional cortical thickness on magnetic resonance imaging at ≈73 and ≈76 years in 351 community-dwelling subjects from the Lothian Birth Cohort 1936. We used multiple linear regression to calculate cross-sectional and longitudinal associations between regional cortical thickness and WMH volume controlling for age, sex, Mini Mental State Examination, education, intelligence quotient at age 11, and vascular risk factors. RESULTS: We found cross-sectional associations between WMH volume and cortical thickness within and surrounding the Sylvian fissure at 73 and 76 years (rho=-0.276, Q=0.004). However, we found no significant longitudinal associations between (1) baseline WMH volume and change in cortical thickness; (2) baseline cortical thickness and change in WMH volume; or (3) change in WMH volume and change in cortical thickness. CONCLUSIONS: Our results show that WMH volume and cortical thinning both worsen with age and are associated cross-sectionally within and surrounding the Sylvian fissure. However, changes in WMH volume and cortical thinning from 73 to 76 years are not associated longitudinally in these relatively healthy older subjects. The underlying cause(s) of WMH growth and cortical thinning have yet to be fully determined.
Assuntos
Córtex Cerebral/patologia , Transtornos Cognitivos/patologia , Vida Independente , Leucoencefalopatias/patologia , Substância Branca/patologia , Idoso , Doenças Cardiovasculares/epidemiologia , Transtornos Cognitivos/epidemiologia , Estudos Transversais , Diabetes Mellitus/epidemiologia , Progressão da Doença , Feminino , Humanos , Hipercolesterolemia/epidemiologia , Hipertensão/epidemiologia , Leucoencefalopatias/epidemiologia , Modelos Lineares , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Fatores de Risco , Escócia/epidemiologia , Fumar/epidemiologiaRESUMO
The aim of this study was to investigate the brain iron accumulation in subcortical ischemic vascular dementia (SIVD) and its correlation with the severity of cognitive impairment. Thirty five patients with SIVD and 35 healthy controls underwent high-resolution susceptibility-weighted imaging. The phase shift value of the bilateral hippocampus (HP), caudate nucleus (CN), globus pallidus (GP), putamen (PU), thalamus (TH), red nucleus (RN), substantia nigra (SN), anterior cingulate cortex (ACC), posterior cingulate (PCC), parietal cortex (PC) and frontal white matter (FWM) were examined and correlated with neuropsychological scores for SIVD patients. They exhibited significant increased phase shift values in the bilateral HP, CN, PU, right GP and left SN (P<0.05). Close correlations were found between the phase shift value of the left HP, right CN and neuropsychological scores. Our results suggest that brain iron deposition may be a biomarker of SIVD and play an important role in the pathophysiological mechanism.
Assuntos
Encéfalo/metabolismo , Demência Vascular/metabolismo , Ferro/metabolismo , Idoso , Biomarcadores/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/psicologia , Transtornos Cognitivos/metabolismo , Demência Vascular/psicologia , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Testes NeuropsicológicosRESUMO
The relationship between anxious/depressed traits and neuromaturation remains largely unstudied. Characterizing this relationship during healthy neurodevelopment is critical to understanding processes associated with the emergence of child/adolescent onset mood/anxiety disorders. In this study, mixed-effects models were used to determine longitudinal cortical thickness correlates of Child Behavior Checklist (CBCL) and Young Adult Self Report Anxious/Depressed scores in healthy children. Analyses included 341 subjects from 4.9 to 22.3 year-old with repeated MRI at up to 3 time points, at 2-year intervals (586 MRI scans). There was a significant "CBCL Anxious/Depressed by Age" interaction on cortical thickness in the right ventromedial prefrontal cortex (vmPFC), including the medial orbito-frontal, gyrus rectus, and subgenual anterior cingulate areas. Anxious/Depressed scores were negatively associated with thickness at younger ages (<9 years), but positively associated with thickness at older ages (15-22 years), with the shift in polarity occurring around age 12. This was secondary to a slower rate of vmPFC cortical thinning in subjects with higher scores. In young adults (18-22 years), Anxious/Depressed scores were also positively associated with precuneus/posterior cingulate cortical thickness. Potential neurobiological mechanisms underlying this maturation pattern are proposed. These results demonstrate the dynamic impact of age on relations between vmPFC and negative affect in the developing brain.
Assuntos
Ansiedade/patologia , Depressão/patologia , Lateralidade Funcional/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/patologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Autorrelato , Estatística como Assunto , Adulto JovemRESUMO
An accurate and complete pathology report is critical for the optimal management of cutaneous melanoma patients. Protocols for the pathologic reporting of melanoma have been independently developed by the Royal College of Pathologists of Australasia (RCPA), Royal College of Pathologists (United Kingdom) (RCPath), and College of American Pathologists (CAP). In this study, data sets, checklists, and structured reporting protocols for pathologic examination and reporting of cutaneous melanoma were analyzed by an international panel of melanoma pathologists and clinicians with the aim of developing a common, internationally agreed upon, evidence-based data set. The International Collaboration on Cancer Reporting cutaneous melanoma expert review panel analyzed the existing RCPA, RCPath, and CAP data sets to develop a protocol containing "required" (mandatory/core) and "recommended" (nonmandatory/noncore) elements. Required elements were defined as those that had agreed evidentiary support at National Health and Medical Research Council level III-2 level of evidence or above and that were unanimously agreed upon by the review panel to be essential for the clinical management, staging, or assessment of the prognosis of melanoma or fundamental for pathologic diagnosis. Recommended elements were those considered to be clinically important and recommended for good practice but with lesser degrees of supportive evidence. Sixteen core/required data elements for cutaneous melanoma pathology reports were defined (with an additional 4 core/required elements for specimens received with lymph nodes). Eighteen additional data elements with a lesser level of evidentiary support were included in the recommended data set. Consensus response values (permitted responses) were formulated for each data item. Development and agreement of this evidence-based protocol at an international level was accomplished in a timely and efficient manner, and the processes described herein may facilitate the development of protocols for other tumor types. Widespread utilization of an internationally agreed upon, structured pathology data set for melanoma will lead not only to improved patient management but is a prerequisite for research and for international benchmarking in health care.
Assuntos
Melanoma/patologia , Patologia Clínica/normas , Projetos de Pesquisa/normas , Neoplasias Cutâneas/patologia , HumanosRESUMO
Transcriptional silencing of tissue factor pathway inhibitor 2 (TFPI2) occurs in several human tumors including melanoma. We investigated methylated TFPI2 as a biomarker of metastatic melanoma using qRT-PCR to assess TFPI2 expression and pyrosequencing to analyze CpG island methylation in malignant melanoma cell lines, in benign nevi, in 112 primary and metastatic melanomas, and in serum from 6 healthy individuals and 35 patients: 20 patients with primary and 15 patients with metastatic melanoma. The TFPI2 CpG island is unmethylated in nevi but methylation is associated with metastatic melanoma. Circulating methylated TFPI2 DNA is undetectable in sera from healthy individuals and detectable in sera from patients with primary and metastatic melanomas, but the presence of methylated TFPI2 DNA in serum is strongly associated with metastatic disease (P<0.01). Detection of TFPI2-methylated DNA in the serum of patients with resected melanoma is a sensitive and specific biomarker of metastatic melanoma. Confirmation of our results in independent patient cohorts would encourage prospective evaluation as a biomarker of disease state.
Assuntos
Biomarcadores Tumorais/sangue , DNA de Neoplasias/sangue , Glicoproteínas/genética , Melanoma/diagnóstico , Metástase Neoplásica/diagnóstico , Neoplasias Cutâneas/diagnóstico , Estudos de Casos e Controles , Linhagem Celular Tumoral , Ilhas de CpG/genética , Metilação de DNA , Humanos , Melanoma/sangue , Melanoma/secundário , Nevo/sangue , Nevo/diagnóstico , Sensibilidade e Especificidade , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/secundárioRESUMO
Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on the palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK, we report heterozygous loss-of-function mutations in AAGAB, encoding α- and γ-adaptin-binding protein p34, located at a previously linked locus at 15q22. α- and γ-adaptin-binding protein p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicating a role in membrane trafficking. Ultrastructurally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of AAGAB in keratinocytes led to increased cell division, which was linked to greatly elevated epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and cellular proliferation.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular , Proteínas de Transporte/genética , Haploinsuficiência , Poroceratose/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Mapeamento Cromossômico , Citosol/ultraestrutura , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Células HeLa , Humanos , Queratinócitos/metabolismo , Queratinócitos/patologia , Linhagem , Poroceratose/metabolismo , Ligação Proteica , Proteínas/genética , Proteínas/metabolismoRESUMO
AIM: The aim of this study was to compare total and regional cerebral volumes in children with isolated cerebellar malformations (CBMs) with those in typically developing children, and to examine the extent to which cerebellar volumetric reductions are associated with total and regional cerebral volumes. METHOD: This is a case-control study of children diagnosed with isolated CBMs. Each child was matched on age and sex to two typically developing children. Using advanced three-dimensional volumetric magnetic resonance imaging, the cerebrum was segmented into tissue classes and partitioned into eight regions. Analysis of variance was used to compare cerebral volumes between children with CBMs and control children, and linear regressions to examine the impact of cerebellar volume reduction on cerebral volumes. RESULTS: Magnetic resonance imaging was performed at a mean age of 27 months in 20 children (10 males, 10 females) with CBMs and 40 typically developing children. Children with CBMs showed significantly smaller deep grey matter nuclei (p < 0.001), subgenual white matter (p = 0.03), midtemporal white matter (p = 0.02), and inferior occipital grey matter (p = 0.03) volumes than typically developing children. Greater cerebellar volumetric reduction in children with CBMs was associated with decreased total cerebral volume and deep grey matter nuclei (p = 0.02), subgenual white/grey matter (p = 0.001), midtemporal white (p = 0.02) and grey matter (p = 0.01), and parieto-occipital grey matter (p = 0.004). INTERPRETATION: CBMs are associated with impaired regional cerebral growth, suggesting deactivation of principal cerebello-cerebral pathways.