Adipocyte Microenvironment in Ovarian Cancer: A Critical Contributor?

Ovarian cancer is one of the most common gynecological malignancies and has low survival rates. One of the main determinants of this unfavorable prognosis is the high rate of peritoneal metastasis at diagnosis, closely related to its morbidity and mortality. The mechanism underlying peritoneal carcinomatosis is not clearly defined, but a clear preference for omental spread has been described. Growing evidence suggests that adipose tissue plays a role in promoting cancer onset and progression. Moreover, obesity can lead to changes in the original functions of adipocytes, resulting in metabolic and inflammatory changes in the adipose tissue microenvironment, potentially increasing the risk of tumor growth. However, the specific roles of adipocytes in ovarian cancer have not yet been fully elucidated. Due to the undeniable link between obesity and cancer, the adipose tissue microenvironment could also present a promising therapeutic target that warrants further research. This review discusses the complex relationship between ovarian cancer and the adipose tissue microenvironment.

Whipple's Disease: A Case Report.

Whipple's disease (WD) is caused by Tropheryma whipplei, frequently found in lamina propria's macrophages in the small intestine. It is a rare and chronic systemic infection, and the principal clinical manifestations are diarrhea, weight loss, abdominal pain, and arthralgia. The diagnosis is difficult mainly because of its rarity and should be considered in patients with arthralgias, diarrhea, abdominal pain, and weight loss after more common conditions have been excluded. The laboratory diagnosis is established by a duodenal biopsy. The treatment involves 14 days of intravenous antibiotics with good penetration in the cerebrospinal fluid (i.e., ceftriaxone) and one-year treatment with oral co-trimoxazole. Early diagnosis and proper treatment are crucial because it improves the prognosis. We report the case of a 58-year-old female with skin hyperpigmentation, loss of appetite and weight (16% of body weight in three months), nausea, upper abdominal pain, and diarrhea. Esophagogastroduodenoscopy and colonoscopy were performed to obtain biopsy samples, which, together with laboratory tests and microbiological studies, led to a diagnosis of Whipple's disease.

Splenic Infarction: A Rare Complication of Infectious Mononucleosis.

Infectious mononucleosis (IM) is caused by Epstein-Barr virus (EBV), and the condition is characterized by sore throat, fever, lymphadenopathy, and atypical lymphocytosis. These infections are common in early childhood, with a second peak occurring in late adolescence. EBV is spread by contact with oral secretions. Most cases of IM are self-limited. However, there are associated complications, some of which can be serious and fatal. We report the case of a 20-year-old man with splenic infarction and exuberant peritonsillar abscess secondary to an EBV infection. This case highlights the importance of accurate diagnoses and frequent monitoring in IM patients, given the risk of airway obstruction.

Unraveling the Aquaporin-3 Inhibitory Effect of Rottlerin by Experimental and Computational Approaches.

The natural polyphenolic compound Rottlerin (RoT) showed anticancer properties in a variety of human cancers through the inhibition of several target molecules implicated in tumorigenesis, revealing its potential as an anticancer agent. Aquaporins (AQPs) are found overexpressed in different types of cancers and have recently emerged as promising pharmacological targets. Increasing evidence suggests that the water/glycerol channel aquaporin-3 (AQP3) plays a key role in cancer and metastasis. Here, we report the ability of RoT to inhibit human AQP3 activity with an IC50 in the micromolar range (22.8 ± 5.82 µM for water and 6.7 ± 2.97 µM for glycerol permeability inhibition). Moreover, we have used molecular docking and molecular dynamics simulations to understand the structural determinants of RoT that explain its ability to inhibit AQP3. Our results show that RoT blocks AQP3-glycerol permeation by establishing strong and stable interactions at the extracellular region of AQP3 pores interacting with residues essential for glycerol permeation. Altogether, our multidisciplinary approach unveiled RoT as an anticancer drug against tumors where AQP3 is highly expressed providing new information to aquaporin research that may boost future drug design.

Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction.

Cystic Fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Currently, more than 2100 variants have been identified in the gene, with a large number being very rare. The approval of modulators that act on mutant CFTR protein, correcting its molecular defect and thus alleviating the burden of the disease, revolutionized the field of CF. However, these drugs do not apply to all patients with CF, especially those with rare mutations-for which there is a lack of knowledge on the molecular mechanisms of the disease and the response to modulators. In this work, we evaluated the impact of several rare putative class II mutations on the expression, processing, and response of CFTR to modulators. Novel cell models consisting of bronchial epithelial cell lines expressing CFTR with 14 rare variants were created. The variants studied are localized at Transmembrane Domain 1 (TMD1) or very close to the signature motif of Nucleotide Binding Domain 1 (NBD1). Our data show that all mutations analyzed significantly decrease CFTR processing and while TMD1 mutations respond to modulators, those localized in NBD1 do not. Molecular modeling calculations confirm that the mutations in NBD1 induce greater destabilization of CFTR structure than those in TMD1. Furthermore, the structural proximity of TMD1 mutants to the reported binding site of CFTR modulators such as VX-809 and VX-661, make them more efficient in stabilizing the CFTR mutants analyzed. Overall, our data suggest a pattern for mutation location and impact in response to modulators that correlates with the global effect of the mutations on CFTR structure.

Effects of neuromodulation on executive functions and food desires in individuals with obesity: a systematic review / Efectos de la neuromodulación sobre las funciones ejecutivas y los deseos alimentarios en pacientes con obesidad: revisión sistemática

Objective: to describe the effects of neuromodulation on the performance of executive functions in overweight and/or individuals with obesity. Methods: articles published in PubMed, ScienceDirect, BIREME, and Web of Science databases were selected using the following combination of descriptors: (“problem solving” OR “executive function” OR memory) AND (tDCS OR TMS) AND obesity. After applying the selection criteria, 08 articles were included for analysis. Results: the articles included had an average of 30.1 participants per study, with a minimum of 12 and a maximum of 76. The overall nutritional status ranged from underweight to grade 3 obesity, and the general mean body mass index was 28,1 kg/m2. Regarding the instruments used to assess executive functions, the most frequent were: the flanker paradigm; binocular rivalry for Continuous Flash Suppression (bCFS/NoCFS); Stroop task; Go/No-Go task; and N-back task. The primary outcomes were dependent on the neuromodulation target site. Reduced food craving and improved performance in the active group were observed from decreased response time and increased precision in cognitive tasks. Conclusion: neuromodulation can generate changes in executive functions, reducing food cravings in overweight and individuals with obesity. (AU)

Objetivo: describir los efectos de la neuromodulación en el desempeño de funciones ejecutivas en pacientes con sobrepeso y/o obesidad. Métodos: se seleccionaron artículos publicados en las bases de datos PubMed, ScienceDirect, BIREME y Web of Science utilizando la siguiente combinación de descriptores: (“resolución de problemas” O “función ejecutiva” O memoria) Y (tDCS O TMS) Y obesidad. Después de aplicar los criterios de selección, 08 artículos fueron incluidos para el análisis. Resultados: los artículos incluidos tuvieron un promedio de 30,1 participantes por estudio, con un mínimo de 12 y un máximo de 76. El estado nutricional general osciló entre bajo peso y obesidad grado 3, y el índice de masa corporal promedio general fue de 28,1 kg/m2. En cuanto a los instrumentos utilizados para evaluar las funciones ejecutivas, los más frecuentes fueron: paradigma del flanqueador; rivalidad binocular para la supresión continua de flash (bCFS/NoCFS); tarea de Stroop; Tarea Go/No-Go; y tarea N-back. Los resultados primarios dependieron del sitio objetivo de la neuromodulación. Se observó una reducción del antojo de alimentos y un mejor rendimiento en el grupo activo debido a la disminución del tiempo de respuesta y al aumento de la precisión en las tareas cognitivas.Conclusión: la neuromodulación puede generar cambios en las funciones ejecutivas, reduciendo el antojo de alimentos en personas con sobrepeso y obesidad. (AU)

Trastuzumab deruxtecan in patients with central nervous system involvement from HER2-positive breast cancer: The DEBBRAH trial.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) has shown durable antitumor activity in pretreated patients with HER2-positive advanced breast cancer (ABC), but its efficacy has not yet been evaluated in patients with active brain metastases (BMs). DEBBRAH aims to assess T-DXd in patients with HER2-positive or HER2-low ABC and central nervous system involvement. METHODS: This ongoing, five-cohort, phase II study (NCT04420598) enrolled patients with pretreated HER2-positive or HER2-low ABC with stable, untreated, or progressing BMs, and/or leptomeningeal carcinomatosis. Here, we report findings from HER2-positive ABC patients with non-progressing BMs after local therapy (n = 8; cohort 1), asymptomatic untreated BMs (n = 4; cohort 2), or progressing BMs after local therapy (n = 9; cohort 3). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was 16-week progression-free survival (PFS) for cohort 1 and intracranial objective response rate (ORR-IC) for cohorts 2 and 3. RESULTS: As of October 20, 2021, 21 patients received T-DXd. In cohort 1, 16-week PFS rate was 87.5% (95%CI, 47.3-99.7; P < .001). ORR-IC was 50.0% (95%CI, 6.7-93.2) in cohort 2 and 44.4% (95%CI, 13.7-78.8; P < .001) in cohort 3. Overall, the ORR-IC in patients with active BMs was 46.2% (95%CI, 19.2-74.9). Among patients with measurable intracranial or extracranial lesions at baseline, the ORR was 66.7% (12 out of 18 patients; 95%CI, 41.0-86.7), 80.0% (95%CI, 28.4-99.5) in cohort 1, 50.0% (95%CI, 6.7-93.2) in cohort 2, and 66.7% (95%CI, 29.9-92.5) in cohort 3. All responders had partial responses. The most common adverse events included fatigue (52.4%; 4.8% grade ≥3), nausea (42.9%; 0% grade ≥3), neutropenia (28.6%; 19% grade ≥3), and constipation (28.6%; 0% grade ≥3). Two (9.5%) patients suffered grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd showed intracranial activity with manageable toxicity and maintained the quality of life in pretreated HER2-positive ABC patients with stable, untreated, or progressing BMs. Further studies are needed to validate these results in larger cohorts.

Effects of neuromodulation on executive functions and food desires in individuals with obesity: a systematic review.

Introduction: Objective: to describe the effects of neuromodulation on the performance of executive functions in overweight and/or individuals with obesity. Methods: articles published in PubMed, ScienceDirect, BIREME, and Web of Science databases were selected using the following combination of descriptors: ("problem solving" OR "executive function" OR memory) AND (tDCS OR TMS) AND obesity. After applying the selection criteria, 08 articles were included for analysis. Results: the articles included had an average of 30.1 participants per study, with a minimum of 12 and a maximum of 76. The overall nutritional status ranged from underweight to grade 3 obesity, and the general mean body mass index was 28,1 kg/m2. Regarding the instruments used to assess executive functions, the most frequent were: the flanker paradigm; binocular rivalry for Continuous Flash Suppression (bCFS/NoCFS); Stroop task; Go/No-Go task; and N-back task. The primary outcomes were dependent on the neuromodulation target site. Reduced food craving and improved performance in the active group were observed from decreased response time and increased precision in cognitive tasks. Conclusion: neuromodulation can generate changes in executive functions, reducing food cravings in overweight and individuals with obesity.

Introducción: Objetivo: describir los efectos de la neuromodulación en el desempeño de funciones ejecutivas en pacientes con sobrepeso y/o obesidad. Métodos: se seleccionaron artículos publicados en las bases de datos PubMed, ScienceDirect, BIREME y Web of Science utilizando la siguiente combinación de descriptores: ("resolución de problemas" O "función ejecutiva" O memoria) Y (tDCS O TMS) Y obesidad. Después de aplicar los criterios de selección, 08 artículos fueron incluidos para el análisis. Resultados: los artículos incluidos tuvieron un promedio de 30,1 participantes por estudio, con un mínimo de 12 y un máximo de 76. El estado nutricional general osciló entre bajo peso y obesidad grado 3, y el índice de masa corporal promedio general fue de 28,1 kg/m2. En cuanto a los instrumentos utilizados para evaluar las funciones ejecutivas, los más frecuentes fueron: paradigma del flanqueador; rivalidad binocular para la supresión continua de flash (bCFS/NoCFS); tarea de Stroop; Tarea Go/No-Go; y tarea N-back. Los resultados primarios dependieron del sitio objetivo de la neuromodulación. Se observó una reducción del antojo de alimentos y un mejor rendimiento en el grupo activo debido a la disminución del tiempo de respuesta y al aumento de la precisión en las tareas cognitivas. Conclusión: la neuromodulación puede generar cambios en las funciones ejecutivas, reduciendo el antojo de alimentos en personas con sobrepeso y obesidad.

Diagnostic Challenges of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a disease characterized by clinical heterogeneity with unpredictable course. Several disease endotypes have been identified, including SLE with antiphospholipid syndrome (APS). We report a case of a pregnant woman with hypertension and proteinuria, diagnosed with APS, Libman-Sacks endocarditis that led to moderate to severe mitral valve insufficiency, and SLE. We describe the diagnostic steps, evolution, and complications. This case highlights the asynchrony behavior of SLE, emphasizing the importance of a multidisciplinary approach to an early diagnosis.

Isolated Left Ventricular Noncompaction Presenting With Heart Failure With Reduced Ejection Fraction and Intrahospital Cardiac Arrest: A Case Report and Literature Review.

Left ventricular noncompaction (LVNC) is characterized by a bilayered appearance of the myocardium with excessive trabeculations and deep intertrabecular recesses. Manifestations of this condition are widely variable, ranging from incidental findings in asymptomatic individuals to symptomatic heart failure, conduction abnormalities, tachyarrhythmia, and sudden cardiac death. Heart failure, ventricular arrhythmias, and systemic embolisms are the most frequent cardiovascular complications. We describe a case of a 53-year-old woman who presented to the emergency department with acute presentation of previously unknown heart failure with reduced ejection fraction and was diagnosed with LVNC. During hospitalization, the patient presented a defibrillated cardiac arrest rhythm, which was resuscitated after six minutes, and then treated with the placement of an implantable cardioverter defibrillator. After two years of follow-up with optimized medical therapy, the patient currently is asymptomatic and with a preserved ejection fraction.

Impact of the COVID-19 Pandemic on Breast Cancer Management in Portugal: A Cross-Sectional Survey-Based Study of Medical Oncologists.

INTRODUCTION: Cancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer. METHODS: An anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents' regions, case volumes, and practice type were explored. RESULTS: Of 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents' region and case volume were noted. CONCLUSION: Medical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.

This study was an online survey of Portuguese medical oncologists to determine how they managed patients with breast cancer during the COVID-19 pandemic. Forty-two questions covered topics such as how COVID testing was done, the types of cancer treatments used, and how this compared to before the pandemic. It also examined whether the geographic region, the number of patients each doctor was responsible for (caseload), and the type of medical institution influenced how patients with breast cancer were managed. One hundred and twenty-nine oncologists completed the survey, of whom 108 worked in the public health system, making this survey representative of breast cancer management during the COVID-19 pandemic across Portugal. Most (71%) said there were fewer visits for new cases of breast cancer during lockdown. The use of telemedicine increased, as did the use of pre-surgery hormone therapy or chemotherapy when access to surgery was difficult, and the use of anticancer medications taken orally or metronomically (low doses given frequently over a long time period). Chemotherapy given very frequently (dose-dense) was used less often, and fewer patients participated in clinical trials. Treatment decisions for patients with aggressive breast cancer types (e.g., triple-negative breast cancer) were largely unchanged, except for greater use of cyclin-dependent kinase 4/6 inhibitors­drugs targeting the cell cycle and cell division control. Geographic region and caseload influenced treatment decisions. All of these changes in breast cancer treatment during the COVID-19 pandemic were logical and reasonable for the circumstances, but their long-term impact is not yet known.

Refining Therapy in Patients with HER2-Positive Breast Cancer with Central Nervous System Metastasis.

Background: Brain metastasis (BM) is a major clinical problem in metastatic breast cancer (MBC), occurring in 50% of patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Historically omitted from clinical trials, recent studies of novel HER2-targeted agents have focused on HER2+ BM patients, addressing stable but also progressing BM and leptomeningeal carcinomatosis (LMC). Summary: This review aimed to summarize the most relevant data on treating patients with HER2+ BM and LMC. Key Messages: The treatment paradigm for patients with HER2+ MBC has changed. Local therapies play an important role, but accumulating evidence on the intracranial activity and clinical benefit of anti-HER2 targeting therapies might lead to a shift in the paradigm on treating BM in the next few years towards more widespread use of systemic therapy.

Next-Generation Sequencing in Breast Cancer Management: A Case Report of Genomic Tumour Evolution over Time.

The clinicopathological breast cancer subtypes are used in clinical practice to better anticipate biological behaviour and guide systemic treatment strategy. In the adjuvant setting, genomic assay recurrence scores became widely available for luminal-like disease. Recently, next-generation sequencing (NGS) platforms have been used, essentially, in more advanced disease setting, in situations refractory to conventional treatment, or even in rare cancers for which there are no established treatment guidelines. Moreover, subpopulations of cancer cells with unique genomes within the same patient may exist across different regions of a tumour or evolve over time, which is called intratumoural heterogeneity. We herein report a case of a 38-year-old woman with breast cancer whose primary and metastatic disease exhibited discordant expression of hormone receptors, with the former being positive and the latter negative. Furthermore, the NGS analysis revealed slight and dynamic changes of mutational profiles between different metastatic lesions, potentially impacting breast cancer management and prognosis. These alterations may reflect tissular and temporal changes in tumour subclones and may also be due to the selective pressure caused by antineoplastic treatment. The use of genomic analyses in order to improve cancer treatment has been studied prospectively with encouraging results. The widespread use of NGS tests in clinical practice also creates new challenges. The most relevant may be to know which genomic alterations detected should be valued and how they should be targeted.

Multiple Primary Malignancies in Head and Neck Cancer: A University Hospital Experience Over a Five-Year Period.

Introduction With an estimated incidence of 2%-4% per year, the development of a second primary malignancy (SPM) in patients with head and neck tumors (HNTs) is not a rare event. The present study aimed to (i) assess the frequency of SPMs in patients with HNTs treated in a university hospital over a five-year period and (ii) provide a demographic characterization of these patients. Methods Retrospective single-centre study of patients with more than one primary tumor (including at least one HNT) diagnosed between January 1, 2015, and December 31, 2019. Data were retrieved from patients' clinical records and anonymized for analysis purposes. Results A total of 53 out of 824 (6.43%) patients with multiple primary malignancies were identified, 18 of which synchronous and 35 metachronous. The median follow-up was 25 months. Thirteen patients were diagnosed with more than one HNT. Forty patients were diagnosed with at least one HNT and one non-HNT. The most frequently diagnosed non-HNT SPMs were lung cancer (n=17) and esophageal cancer (n=8). The five-year survival rate was 53% for patients with multiple HNSCCs and 47% for patients with at least one non-HNT (log-rank p=0.729). The median overall survival was 14 months for synchronous and 58 months for metachronous SPMs (log-rank p=0.002). Conclusion Findings from this study highlight the importance of long-term follow-up of HNT patients for early detection of SPMs, increasing the chance of providing treatment with curative intent and improving patient outcomes and survival.

Human Microbiota and Breast Cancer-Is There Any Relevant Link?-A Literature Review and New Horizons Toward Personalised Medicine.

Breast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Recently, gut microbiota dysbiosis emerged as a key player that may directly and/or indirectly influence development, treatment, and prognosis of BC through diverse biological processes: host cell proliferation and death, immune system function, chronic inflammation, oncogenic signalling, hormonal and detoxification pathways. Gut colonisation occurs during the prenatal period and is later diversified over distinct phases throughout life. In newly diagnosed postmenopausal BC patients, an altered faecal microbiota composition has been observed compared with healthy controls. Particularly, ß-glucuronidase bacteria seem to modulate the enterohepatic circulation of oestrogens and their resorption, increasing the risk of hormone-dependent BC. Moreover, active phytoestrogens, short-chain fatty acids, lithocholic acid, and cadaverine have been identified as bacterial metabolites influencing the risk and prognosis of BC. As in gut, links are also being made with local microbiota of tumoural and healthy breast tissues. In breast microbiota, different microbial signatures have been reported, with distinct patterns per stage and biological subtype. Total bacterial DNA load was lower in tumour tissue and advanced-stage BC when compared with healthy tissue and early stage BC, respectively. Hypothetically, these findings reflect local dysbiosis, potentially creating an environment that favours breast tumour carcinogenesis (oncogenic trigger), or the natural selection of microorganisms adapted to a specific microenvironment. In this review, we discuss the origin, composition, and dynamic evolution of human microbiota, the links between gut/breast microbiota and BC, and explore the potential implications of metabolomics and pharmacomicrobiomics that might impact BC development and treatment choices toward a more personalised medicine. Finally, we put in perspective the potential limitations and biases regarding the current microbiota research and provide new horizons for stronger accurate translational and clinical studies that are needed to better elucidate the complex network of interactions between host, microorganisms, and drugs in the field of BC.

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.

A longitudinal multimodal in vivo molecular imaging study of the 3xTg-AD mouse model shows progressive early hippocampal and taurine loss.

The understanding of the natural history of Alzheimer's disease (AD) and temporal trajectories of in vivo molecular mechanisms requires longitudinal approaches. A behavioral and multimodal imaging study was performed at 4/8/12 and 16 months of age in a triple transgenic mouse model of AD (3xTg-AD). Behavioral assessment included the open field and novel object recognition tests. Molecular characterization evaluated hippocampal levels of amyloid ß (Aß) and hyperphosphorylated tau. Magnetic resonance imaging (MRI) included assessment of hippocampal structural integrity, blood-brain barrier (BBB) permeability and neurospectroscopy to determine levels of the endogenous neuroprotector taurine. Longitudinal brain amyloid accumulation was assessed using 11C Pittsburgh compound B positron emission tomography (PET), and neuroinflammation/microglia activation was investigated using 11C-PK1195. We found altered locomotor activity at months 4/8 and 16 months and recognition memory impairment at all time points. Substantial early reduction of hippocampal volume started at month 4 and progressed over 8/12 and 16 months. Hippocampal taurine levels were significantly decreased in the hippocampus at months 4/8 and 16. No differences were found for amyloid and neuroinflammation with PET, and BBB was disrupted only at month 16. In summary, 3xTg-AD mice showed exploratory and recognition memory impairments, early hippocampal structural loss, increased Aß and hyperphosphorylated tau and decreased levels of taurine. In sum, the 3xTg-AD animal model mimics pathological and neurobehavioral features of AD, with early-onset recognition memory loss and MRI-documented hippocampal damage. The early-onset profile suggests temporal windows and opportunities for therapeutic intervention, targeting endogenous neuroprotectors such as taurine.

Qualidade dos serviços na Estratégia Saúde da Família sob interferência do PMAQ – AB: análise reflexiva / Quality of services in the family health strategy under PMAQ - AB interference: reflective analysis

Objetivo: apresentar uma reflexão acerca do modo como o Programa Nacional de Melhoria do Acesso e daQualidade da Atenção Básica (PMAQ-AB) pode ajudar na melhoria da qualidade dos serviços prestados nasUnidades Básicas de Saúde (UBS). Método: estudo reflexivo realizado a partir de literatura na LILACS eSciELO, resoluções e normativas referentes à temática em questão. Resultados: infere-se que o PMAQ-AB temsido uma ferramenta importante na gestão dos recursos destinados à saúde, fortalecendo a avaliação dosserviços pelos gestores. Contribuiu com melhorias como a implantação da comissão de gerenciamento de riscoe o controle no setor de regulação; facilitou o encaminhamento para especialidades e reduziu o tempo deespera pela consulta, garantindo a gestão da qualidade e, consequentemente, melhorando o desempenho dosindicadores de saúde. Conclusão: a partir das avaliações constantes da qualidade do serviço e forte apoio aoscentros de saúde, é possível visualizar possibilidades de mudança e fazer com que as metas possam seratingidas.