Idiopathic noncirrhotic portal hypertension: current perspectives

The term idiopathic noncirrhotic portal hypertension (INCPH) has been recently proposed to replace terms, such as hepatoportal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia, used to describe patients with a hepatic presinusoidal cause of portal hypertension of unknown etiology, characterized by features of portal hypertension (esophageal varices, nonmalignant ascites, porto-venous collaterals), splenomegaly, patent portal, and hepatic veins and no clinical and histological signs of cirrhosis. Physicians should learn to look for this condition in a number of clinical settings, including cryptogenic cirrhosis, a disease known to be associated with INCPH, drug administration, and even chronic alterations in liver function tests. Once INCPH is clinically suspected, liver histology becomes mandatory for the correct diagnosis. However, pathologists should be familiar with the histological features of INCPH, especially in cases in which histology is not only requested to exclude liver cirrhosis

Defective Mitochondrial Pyruvate Flux Affects Cell Bioenergetics in Alzheimer's Disease-Related Models

Summary: Mitochondria are key organelles for brain health. Mitochondrial alterations have been reported in several neurodegenerative disorders, including Alzheimer's disease (AD), and the comprehension of the underlying mechanisms appears crucial to understand their relationship with the pathology. Using multiple genetic, pharmacological, imaging, and biochemical approaches, we demonstrate that, in different familial AD cell models, mitochondrial ATP synthesis is affected. The defect depends on reduced mitochondrial pyruvate oxidation, due to both lower Ca2+-mediated stimulation of the Krebs cycle and dampened mitochondrial pyruvate uptake. Importantly, this latter event is linked to glycogen-synthase-kinase-3β (GSK-3β) hyper-activation, leading, in turn, to impaired recruitment of hexokinase 1 (HK1) to mitochondria, destabilization of mitochondrial-pyruvate-carrier (MPC) complexes, and decreased MPC2 protein levels. Remarkably, pharmacological GSK-3β inhibition in AD cells rescues MPC2 expression and improves mitochondrial ATP synthesis and respiration. The defective mitochondrial bioenergetics influences glutamate-induced neuronal excitotoxicity, thus representing a possible target for future therapeutic interventions. : Mitochondria are key organelles for brain health. Rossi et al. show that, in different Alzheimer's disease cell models, lower mitochondrial Ca2+ signal and pyruvate uptake reduce ATP synthesis. GSK-3β hyper-activation contributes to the defect by impairing HK1-mitochondria association, decreasing MPC2 levels and destabilizing MPC complexes. Defective bioenergetics affects neuronal functionality. Keywords: Alzheimer's disease, presenilin, mitochondrial metabolism, bioenergetics, calcium homeostasis, pyruvate, mitochondrial pyruvate carrier, hexokinase 1, GSK-3

Application of Small Epigenetic Modulators in Pediatric Medulloblastoma

Medulloblastoma is one of the most frequent among pediatric brain tumors, and it has been classified in various subgroups. Some of them already benefit from quite good therapeutic options, whereas others urgently need novel therapeutic approaches. Epigenetic modulators have long been studied in various types of cancer. Within this review, we summarize the main preclinical studies regarding epigenetic targets (such as HDAC, SIRT, BET, EZH2, G9a, LSD1, and DNMT) inhibitors in medulloblastoma. Furthermore, we shed light on the increasing number of applications of drug combinations as well as hybrid compounds involving epigenetic mechanisms. Nevertheless, in the studies published so far, mainly un-specific or old modulators have been used, and the PKs (brain permeability) have not been well-evaluated. Thus, these findings should be considered as a starting point for further improvement and not as a final result

Primary neuroendocrine carcinoma of the breast: A case report of liver and lymph node metastases after eight years from diagnosis.

Primary neuroendocrine carcinoma of the breast (NECB) is one of the rarest subtypes of breast tumor, and for this reason, there are no data from prospective clinical trials on its optimal management. Its incidence is <0.1% of all breast cancers and <1% of all neuroendocrine tumors. The diagnosis of NECB requires the expression of neuroendocrine markers (chromogranin, synaptophysin, NSE) and the lack of simultaneous neuroendocrine carcinoma in extramammary sites. We present a case of a poorly differentiated neuroendocrine carcinoma (PD-NEC) metastasized in liver and lymph node after eight years. Mammography, ultrasound imaging, CT, and pathology findings are described

O trabalho doméstico no Brasil: uma análise interseccional e materialista a partir das perspectivas de raça, gênero e classe

O presente trabalho busca analisar de forma crítica e sob o viés sociológico materialista, as questões interseccionais atreladas ao trabalho doméstico, assim como um detalhamento do conceito de interseccionalidade, com foco principal no que tange a raça, gênero e classe, além disso, a forma de reconhecimento da mão de obra feminina e negra. A partir disso se pretende discorrer sobre a interseccionalidade e seus desdobramentos, bem como a evolução do trabalho doméstico no Brasil, traçando uma rota histórica desde a escravidão, o período pósabolição, até criação da Lei Complementar n.150/2015, a qual atualmente regula o trabalho doméstico. Ainda, este trabalho busca mostrar como tem funcionado a organização sindical e o exercício de direitos para as empregadas domésticas na atual conjuntura, mostrando a recente criação do aplicativo Laudelina. Faz-se necessária a análise de tal forma de trabalho, pois com a evolução histórica e social do trabalho, têm-se observado o crescimento do empoderamento feminino e negro no âmbito laboral

Temi ricorrenti in racconti relativi all’esperienza di malattia oncologica: analisi del testo letterario

L’incontro fra medicina e letteratura contribuisce a ricondurre la pratica della cura alla sua finalità originaria: essere una medicina per l’uomo. Il mondo narrato da pazienti e operatori della salute è molto variegato rispetto a quanto la letteratura scientifica descrive. Nel percorso di malattia non emerge solo la sofferenza, ma anche il tema della speranza.

Effect of the Italian Smoking Ban on Population Rates of Acute Coronary Events

Background— Several countries in the world have not yet prohibited smoking in public places. Few studies have been conducted on the effects of smoking bans on cardiac health. We evaluated changes in the frequency of acute coronary events in Rome, Italy, after the introduction of legislation that banned smoking in all indoor public places in January 2005. Methods and Results— We analyzed acute coronary events (out-of-hospital deaths and hospital admissions) between 2000 and 2005 in city residents 35 to 84 years of age. We computed annual standardized rates and estimated rate ratios by comparing the data from prelegislation (2000–2004) and postlegislation (2005) periods. We took into account several time-related potential confounders, including particulate matter (PM 10 ) air pollution, temperature, influenza epidemics, time trends, and total hospitalization rates. The reduction in acute coronary events was statistically significant in 35- to 64-year-olds (11.2%, 95% CI 6.9% to 15.3%) and in 65- to 74-year-olds (7.9%, 95% CI 3.4% to 12.2%) after the smoking ban. No evidence was found of an effect among the very elderly. The reduction tended to be greater in men and among lower socioeconomic groups. Conclusions— We found a statistically significant reduction in acute coronary events in the adult population after the smoking ban. The size of the effect was consistent with the pollution reduction observed in indoor public places and with the known health effects of passive smoking. The results affirm that public interventions that prohibit smoking can have enormous public health implications

Response to Letter Regarding Article, "Effect of the Italian Smoking Ban on Population Rates of Acute Coronary Events"

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Altered modulation of lamin A/C-HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson-Gilford progeria, a severe LMNA-linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C-HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C-HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms

X-Linked Parkinsonism: phenotypic and genetic heterogeneity

X-linked parkinsonism encompasses rare heterogeneous disorders mainly inherited as a recessive trait, therefore being more prevalent in males. Recent developments have revealed a complex underlying panorama, including a spectrum of disorders in which parkinsonism is variably associated with additional neurological and non-neurological signs. In particular, a childhood-onset encephalopathy with epilepsy and/or cognitive disability is the most common feature. Their genetic basis is also heterogeneous, with many causative genes and different mutation types ranging from "classical" coding variants to intronic repeat expansions. In this review, we provide an updated overview of the phenotypic and genetic spectrum of the most relevant X-linked parkinsonian syndromes, namely X-linked dystonia-parkinsonism (XDP, Lubag disease), fragile X-associated tremor/ataxia syndrome (FXTAS), beta-propeller protein-associated neurodegeneration (BPAN, NBIA/PARK-WDR45), Fabry disease, Waisman syndrome, methyl CpG-binding protein 2 (MeCP2) spectrum disorder, phosphoglycerate kinase-1 deficiency syndrome (PGK1) and X-linked parkinsonism and spasticity (XPDS). All clinical and radiological features reported in the literature have been reviewed. Epilepsy occasionally represents the symptom of onset, predating parkinsonism even by a few years; action tremor is another common feature along with akinetic-rigid parkinsonism. A focus on the genetic background and its pathophysiological implications is provided. The pathogenesis of these disorders ranges from well-defined metabolic alterations (PGK1) to non-specific lysosomal dysfunctions (XPDS) and vesicular trafficking alterations (Waisman syndrome). However, in other cases it still remains poorly defined. Recognition of the phenotypic and genetic heterogeneity of X-linked parkinsonism has important implications for diagnosis, management, and genetic counseling. \ua9 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society