The effect of diphenylethane side-chain substituents on dibenzocyclohexadiene formation and their inhibition of α-synuclein aggregation in vitro.

The naturally-occurring di-catechol lignan nordihydroguaiaretic acid (NDGA) and an analog without methyl groups on the butyl linker both undergo intramolecular cyclization at pH 7.4 to form dibenzocyclooctadienes. Both NDGA and these dibenzocyclooctadienes have been shown to prevent in vitro aggregation of α-synuclein, an intrinsically disordered protein associated with Parkinson's disease. NDGA possesses two vicinal methyl groups on the butyl linker and the presence of these methyl groups attenuates the rate of intramolecular cyclization versus the unsubstituted analog, in opposition to the anticipated Thorpe-Ingold effect, likely due to steric repulsions during cyclization. Numerous 1,2-bis-ethane di-catechols are known to inhibit α-synuclein aggregation in vitro and we hypothesize that these compounds undergo a similar intramolecular cyclization and the cyclized products may be responsible for the activity. To test this hypothesis we prepared a series of 1,2-bis-ethane di-catechols with 0, 2 and 4 methyl substituents on the linker. We have confirmed that these compounds undergo intramolecular cyclization to form dibenzocyclohexadienes and that steric interactions between the methyl substituents leads to an increase in the rate of intramolecular cyclization, which is in contrast to what was observed for lignan di-catechols. The rate of cyclization to form six-membered rings is 10-30 times more rapid than formation of eight membered rings and the dibenzocyclohexadienes also prevent in vitro aggregation of α-synuclein.

In vitro hepatic metabolism of the natural product quebecol.

Quebecol (2,3,3-tri-(3-methoxy-4-hydroxyphenyl)-1-propanol) is a polyphenolic compound, which is formed during maple syrup production from Acer spp. Quebecol bears structural similarities to the chemotherapy drug tamoxifen, which has led to synthesis of structural analogues and investigations into their pharmacological properties, however there are no reports on the hepatic metabolism of quebecol.This interest in therapeutic properties spurred us to investigate the in vitro microsomal Phase I and II metabolism of quebecol. We were unable to detect any P450 metabolites for quebecol in either human liver microsomes (HLM) or rat liver microsomes (RLM). In contrast we observed marked formation of three glucuronide metabolites in both RLM and HLM, suggesting that clearance via Phase II pathways is likely to predominate.To further understand the hepatic contribution to first-pass glucuronidation we have validated an HPLC method following FDA and EMA guidelines (selectivity, linearity, accuracy, and precision) to quantify quebecol in microsomes. In vitro enzyme kinetics were performed for quebecol glucuronidation by HLM including 8 concentrations from 5-30 µM. We determined a Michaelis-Menten constant (KM) of 5.1 µM, intrinsic clearance (Clint,u) of 0.038 ± 0.001 mL/min/mg, and maximum velocity (Vmax) of 0.22 ± 0.01 µmol/min/mg.

Cerebral effects of glucagon-like peptide-1 receptor blockade before and after Roux-en-Y gastric bypass surgery in obese women: A proof-of-concept resting-state functional MRI study.

AIM: To assess the effects of Roux-en-Y gastric bypass surgery (RYGB)-related changes in glucagon-like peptide-1 (GLP-1) on cerebral resting-state functioning in obese women. MATERIALS AND METHODS: In nine obese females aged 40-54 years in the fasted state, we studied the effects of RYGB and GLP-1 on five a priori selected networks implicated in food- and reward-related processes as well as environment monitoring (default mode, right frontoparietal, basal ganglia, insula/anterior cingulate and anterior cingulate/orbitofrontal networks). RESULTS: Before surgery, GLP-1 receptor blockade (using exendin9-39) was associated with increased right caudate nucleus (basal ganglia network) and decreased right middle frontal (right frontoparietal network) connectivity compared with placebo. RYGB resulted in decreased right orbitofrontal (insula/anterior cingulate network) connectivity. In the default mode network, after surgery, GLP-1 receptor blockade had a larger effect on connectivity in this region than GLP-1 receptor blockade before RYGB (all PFWE < .05). Results remained similar after correction for changes in body weight. Default mode and right frontoparietal network connectivity changes were related to changes in body mass index and food scores after RYGB. CONCLUSIONS: These findings suggest GLP-1 involvement in resting-state networks related to food and reward processes and monitoring of the internal and external environment, pointing to a potential role for GLP-1-induced changes in resting-state connectivity in RYGB-mediated weight loss and appetite control.

Anosognosia for memory in dementia with Lewy bodies compared with Alzheimer's disease.

OBJECTIVES: Anosognosia is the inability to recognize one's own symptoms. Although dementia with Lewy bodies (DLB) is the second most common degenerative dementia, there is little evidence of memory deficit awareness in this condition. The objectives of this research were to compare anosognosia between individuals with DLB and dementia due to Alzheimer's disease (AD) and to evaluate whether medial temporal atrophy, a marker of AD pathology, could help to explain different rates of anosognosia in DLB and dementia due to AD. METHODS/DESIGN: This is a cross-sectional study that took place at the Memory Clinic of D'Or Institute for Research and Education (IDOR). Twenty individuals with DLB and 20 with dementia due to AD were included in this study. We assessed anosognosia for memory using an index derived from subjective memory complaints (using the Memory Complaint Questionnaire) and from the performance in memory neuropsychological testing (Rey Auditory Verbal Learning Test). Thirty-one participants also underwent brain Magnetic Resonance Imaging to evaluate hippocampal atrophy with a visual scale (MTA-score [medial temporal atrophy score]). RESULTS: There was no significant difference between groups regarding age, years of education, sex or time of disease. Individuals with DLB had a higher index of anosognosia than dementia due to AD (2.92 and 1.87; p = 0.024), meaning worse awareness of memory deficits. MTA-score was slightly higher in dementia due to AD than in DLB, albeit without statistical significance. CONCLUSION: Our study was the first to demonstrate that anosognosia for memory is worse in DLB than in dementia due to AD. This finding supports the hypothesis that anosognosia in DLB is a heterogeneous phenomenon.

Cortical and subcortical gray matter structural alterations in normoglycemic obese and type 2 diabetes patients: relationship with adiposity, glucose, and insulin.

Type 2 diabetes (T2DM) is associated with structural cortical and subcortical alterations, although it is insufficiently clear if these alterations are driven by obesity or by diabetes and its associated complications. We used FreeSurfer5.3 and FSL-FIRST to determine cortical thickness, volume and surface area, and subcortical gray matter volume in a group of 16 normoglycemic obese subjects and 28 obese T2DM patients without clinically manifest micro- and marcoangiopathy, and compared them to 31 lean normoglycemic controls. Forward regression analysis was used to determine demographic and clinical correlates of altered (sub)cortical structure. Exploratively, vertex-wise correlations between cortical structure and fasting glucose and insulin were calculated. Compared with controls, obese T2DM patients showed lower right insula thickness and lower left lateral occipital surface area (PFWE < 0.05). Normoglycemic obese versus controls had lower thickness (PFWE < 0.05) in the right insula and inferior frontal gyrus, and higher amygdala and thalamus volume. Thalamus volume and left paracentral surface area were also higher in this group compared with obese T2DM patients. Age, sex, BMI, fasting glucose, and cholesterol were related to these (sub)cortical alterations in the whole group (all P < 0.05). Insulin were related to temporal and frontal structural deficits (all PFWE < 0.05). Parietal/occipital structural deficits may constitute early T2DM-related cerebral alterations, whereas in normoglycemic obese subjects, regions involved in emotion, appetite, satiety regulation, and inhibition were affected. Central adiposity and elevated fasting glucose may constitute risk factors.

Association of Androgenic Regulation and MicroRNAs in Acinar Adenocarcinoma of Prostate.

BACKGROUND: Prostate cancer represents 3.8% of cancer deaths worldwide. For most prostate cancer cells to grow, androgens need to bind to a cellular protein called the androgen receptor (AR). This study aims to demonstrate the expression of five microRNAs (miRs) and its influence on the AR formation in patients from the northern region of Brazil. MATERIAL AND METHODS: Eighty-four tissue samples were investigated, including nodular prostatic hyperplasia (NPH) and acinar prostatic adenocarcinoma (CaP). Five miRs (27a-3p, 124, 130a, 488-3p, and 506) were quantified using the TaqMan® Real Time PCR method and AR was measured using Western blotting. RESULTS: Levels of miRs 124, 130a, 488-3p, and 506 were higher in NPH samples. Conversely, in the CaP cases, higher levels of miR 27a-3p and AR were observed. CONCLUSION: In the future, these microRNAs may be tested as markers of CaP at the serum level. The relative expression of AR was 20% higher in patients with prostate cancer, which suggests its potential as a biomarker for prostate malignancy.

Structural Gray and White Matter Correlates of Awareness in Alzheimer's Disease.

BACKGROUND: Unawareness of disease is a common feature of Alzheimer's disease (AD), but few studies explored its neural correlates. Additionally, neural correlates according to the object of awareness are unexplored. OBJECTIVE: To investigate structural brain correlates in relation to different objects of awareness. METHODS: 27 people with AD underwent MRI scanning on a 3T Siemens Prisma. T1-MPRAGE was used to investigate cortical thickness and white matter microstructure was defined by DTI as fractional anisotropy, mean, axial, and radial diffusivity. Preprocessing used FreeSurfer6.0, ExploreDTI, and FSL-TBSS. Awareness of disease, cognitive deficits, emotional state, relationships, and functional capacity were assessed with the short version of the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia. Voxel-wise correlations between brain structure and awareness were determined by FSL-PALM. Analyses were corrected for multiple comparisons using Threshold Free Cluster Enhancement and FWE. RESULTS: Lower left hemisphere cortical thickness was related to poorer disease awareness uncorrected and corrected for age, sex, and MMSE. In the uncorrected model, mainly right-sided, but also left temporal lower cortical thickness was related to decreased awareness of cognitive deficits. Correcting for age, sex, and MMSE eliminated correlations for the right hemisphere, but extensive correlations in the left hemisphere remained. For white matter integrity, higher right hemisphere MD was related to lower cognitive awareness deficits, and lower FA was related to lower functional capacity awareness. CONCLUSION: Findings suggest that extensive regions of the brain are linked to self-awareness, with particular frontal and temporal alterations leading to unawareness, in agreement with theoretical models indicating executive and mnemonic forms of anosognosia in AD.

Network analysis of narrative discourse and attention-deficit hyperactivity symptoms in adults.

Previous research investigating language in attention-deficit hyperactivity disorder (ADHD) has demonstrated several deficits in many aspects. However, no previous study employed quantitative methodology providing objective measures that could be compared among different studies with diverse samples. To fill this gap, we used network analysis to investigate how ADHD symptomatology impacts narrative discourse, a complex linguistic task considered to be an ecological measure of language. Fifty-eight adults (34 females and 24 males) with a mean age of 26 years old and a mean of 17 years of educational level were administered the Adult Self-Rating Scale for ADHD symptomatology. They also completed the State-Trait Anxiety Inventory, the Beck Depression Inventory and the Urgency, Premeditation, Perseverance, Sensation Seeking Behavior Scale. Intelligence quotient was calculated. Individuals were asked to tell a story based on a wordless picture book. Speech was recorded and transcribed as an input to SpeechGraphs software. Parameters were total number of words (TNW), number of loops of one node (L1), repeated edges (RE), largest strongly connected component (LSC) and average shortest path (ASP). Verbosity was controlled. Statistical analysis was corrected for multiples comparisons and partial correlations were performed for confounding variables. After controlling for anxiety, depression, IQ, and impulsiveness ADHD symptomatology was positively correlated with L1 and negatively correlated with LSC. TNW was positively correlated with ADHD symptoms. In a subdomain analysis, both inattention and hyperactivity-impulsivity were negatively correlated with LSC. Only hyperactivity-impulsivity positively correlated with TNW and L1. Results indicated a correlation between ADHD symptoms and lower connectedness in narrative discourse (as indicated by higher L1 and lower LSC), as well as higher total number of words (TNW). Our results suggest that the higher the number of ADHD symptoms, the less connectivity among words, and a higher number of words in narrative discourse.

Mild Cognitive Impairment or Attention-Deficit/Hyperactivity Disorder in Older Adults? A Cross Sectional Study.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly prevalent neurodevelopmental condition, which may be associated with life-enduring cognitive dysfunction. It has been hypothesized that age-related cognitive decline may overlap with preexisting deficits in older ADHD patients, leading to increased problems to manage everyday-life activities. This phenomenon may mimic neurodegenerative disorders, in particular Mild Cognitive Impairment (MCI). This cross-sectional study aims to assess cognitive and behavioral differences between older subjects with ADHD and MCI. Methods: A total of 107 older participants (41 controls; 40 MCI and 26 ADHD; mean age = 67.60 ± 7.50 years; mean schooling = 15.14 ± 2.77 years; 65.4% females) underwent clinical, cognitive, and behavioral assessments by a multidisciplinary team at the Memory Clinic, D'Or Institute for Research and Education, Rio de Janeiro, Brazil. Mean scores in neuropsychological tasks and behavioral scales were compared across groups. Results: Participants with ADHD showed poorer performances than controls in episodic memory and executive function with large effect-sizes. Performances were comparable between MCI and ADHD for all domains. Discussion: MCI and ADHD in older individuals are dissociated clinical entities with overlapping cognitive profiles. Clinicians ought to be aware of these converging phenotypes to avoid misdiagnosis.

Os enfermeiros e a síndrome de burnout no contexto da pandemia da COVID-19 / Nurses and burnout syndrome in the context of the COVID-19 pandemic

Introdução: A pandemia da COVID-19 tem impactado signicativamente a saúde mental dos profissionais de saúde, especialmente dos enfermeiros que estão na linha de frente do combate à doença. Nesse contexto, a síndrome de Burnout é um fenômeno que tem recebido destaque, pois pode levar ao esgotamento físico e emocional desses profissionais. Objetivo: Este artigo tem como objetivo analisar a relação entre enfermeiros e a síndrome de Burnout diante da pandemia da COVID-19. Método: Trata-se de revisão de literatura cientíca que abordam a temática em questão. Resultados: Os resultados apontam que a pandemia da COVID-19 aumentou a sobrecarga de trabalho dos enfermeiros, que têm enfrentado condições adversas de trabalho, como falta de equipamentos de proteção individual e o medo de contaminação. Essas condições têm levado a um aumento dos níveis de estresse e ansiedade entre os enfermeiros, o que pode contribuir para o desenvolvimento da síndrome de Burnout. Portanto, é necessário que sejam implementadas medidas de proteção aos profissionais de saúde, como a oferta de suporte emocional e psicológico, além de uma carga de trabalho adequada. Conclusão: A pandemia da COVID-19 teve um impacto signicativo na saúde mental dos profissionais da equipe de enfermagem, com aumento da prevalência de sintomas de depressão, ansiedade e estresse. É essencial fornecer suporte psicológico e emocional, melhorar as condições de trabalho e garantir o acesso a equipamentos de proteção adequados. Investir na saúde mental desses profissionais é fundamental para o bem-estar individual e a qualidade do cuidado aos pacientes. Instituições de saúde, gestores e profissionais devem reconhecer essa importância e trabalhar juntos para fornecer o suporte necessário durante e após a pandemia.(AU)

ntroduction: The COVID-19 pandemic has signicantly impacted the mental health of health professionals, especially nurses who are on the front lines of ghting the disease. In this context, the Burnout syndrome is a phenomenon that has been highlighted, as it can lead to physical and emotional exhaustion of these professionals. Objective: This article aims to analyze the relationship between nurses and the Burnout syndrome in the face of the COVID-19 pandemic. Method: For this purpose, books and scientic articles that address the subject in question were consulted. Results: The results show that the COVID-19 pandemic has increased the workload of nurses, who have been facing adverse working conditions, such as lack of personal protective equipment and fear o f contamination. These conditions have led to increased levels of stress and anxiety among nurses, which may contribute to the development of the Burnout syndrome. Therefore, it is necessary to implement protective measures for health professionals, such as offering emotional and psychological support, in addition to an adequate workload. Conclusion: The COVID-19 pandemic had a signicant impact on the mental health of nursing staff, with an increased prevalence of symptoms of depression, anxiety and stress. It is essential to provide psychological and emotional support, improve working conditions and ensure access to adequate protective equipment. Investing in the mental health of these professionals is essential for individual well-being and the quality of patient care. Health institutions, managers and professionals must recognize this importance and work together to provide the necessary support during and after the pandemic.(AU)

Introducción: La pandemia de COVID-19 ha impactado signi cativamente la salud mental de los profesionales de la salud, especialmente las enfermeras que están en primera línea luchando contra la enfermedad. En este contexto, el síndrome de Burnout es un fenómeno que ha recibido atención, ya que puede provocar agotamiento físico y emocional de estos profesionales. Objetivo: Este artículo tiene como objetivo analizar la relación entre enfermeras y síndrome de Burnout ante la pandemia de COVID-19. Método: Se trata de una revisión de la literatura cientí ca que aborda el tema en cuestión. Resultados: Los resultados indican que la pandemia de COVID-19 ha aumentado la carga de trabajo de las enfermeras, quienes han enfrentado condiciones laborales adversas, como falta de equipos de protección personal y miedo a la contaminación. Estas condiciones han provocado mayores niveles de estrés y ansiedad entre las enfermeras, lo que puede contribuir al desarrollo del síndrome de Burnout. Por ello, es necesario implementar medidas de protección para los profesionales sanitarios, como ofrecer apoyo emocional y psicológico, además de una carga de trabajo adecuada. Conclusión: La pandemia de COVID-19 tuvo un impacto signi cativo en la salud mental de los profesionales del equipo de enfermería, con aumento en la prevalencia de síntomas de depresión, ansiedad y estrés. Es fundamental brindar apoyo psicológico y emocional, mejorar las condiciones laborales y garantizar el acceso a equipos de protección adecuados. Invertir en la salud mental de estos profesionales es fundamental para el bienestar individual y la calidad de la atención al paciente. Las instituciones, gestores y profesionales de la salud deben reconocer esta importancia y trabajar juntos para brindar el apoyo necesario durante y después de la pandemia. (AU)

Inter-method and anatomical correlates of episodic memory tests in the Alzheimer's Disease spectrum.

BACKGROUND: Episodic memory impairments have been described as initial clinical findings in the Alzheimer's Disease (AD) spectrum, which could be associated with the presence of early hippocampal dysfunction. However, correlates between performances in neuropsychological tests and hippocampal volumes in AD were inconclusive in the literature. Divergent methods to assess episodic memory have been depicted as a major source of heterogeneity across studies. METHODS: We examined correlates among performances in three different delayed-recall tasks (Rey-Auditory Verbal-Learning Test-RAVLT, Logical Memory and Visual Reproduction subtests from the Wechsler Memory Scale) and fully-automated volumetric measurements of the hippocampus (estimated using Neuroquant®) of 83 older subjects (47 controls, 27 Mild Cognitive Impairment individuals and 9 participants with Dementia due to AD). RESULTS: Inter-method correlations of episodic memory performances were at most moderate. Scores in the RAVLT predicted up to 48% of variance in HOC (Hippocampal Occupancy Score) among subjects in the AD spectrum. DISCUSSION: Tests using different stimuli (verbal or visual) and presenting distinct designs (word list, story or figure learning) may assess divergent aspects in episodic memory, with heterogeneous anatomical correlates. CONCLUSIONS: Different episodic memory tests might not assess the same construct and should not be used interchangeably. Scores in RAVLT may correlate with the presence of neurodegeneration in AD.