Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues

: Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases

The glucose transporter 2 regulates CD8⁺ T cell function via environment sensing

T cell activation is associated with a profound and rapid metabolic response to meet increased energy demands for cell division, differentiation and development of effector function. Glucose uptake and engagement of the glycolytic pathway are major checkpoints for this event. Here we show that the low-affinity, concentration-dependent glucose transporter 2 (Glut2) regulates the development of CD8+ T cell effector responses in mice by promoting glucose uptake, glycolysis and glucose storage. Expression of Glut2 is modulated by environmental factors including glucose and oxygen availability and extracellular acidification. Glut2 is highly expressed by circulating, recently primed T cells, allowing efficient glucose uptake and storage. In glucose-deprived inflammatory environments, Glut2 becomes downregulated, thus preventing passive loss of intracellular glucose. Mechanistically, Glut2 expression is regulated by a combination of molecular interactions involving hypoxia-inducible factor-1 alpha, galectin-9 and stomatin. Finally, we show that human T cells also rely on this glucose transporter, thus providing a potential target for therapeutic immunomodulation

The isolated carboxy-terminal domain of human mitochondrial leucyl-tRNA synthetase rescues the pathological phenotype of mitochondrial tRNA mutations in human cells.

Mitochondrial (mt) diseases are multisystem disorders due to mutations in nuclear or mtDNA genes. Among the latter, more than 50% are located in transfer RNA (tRNA) genes and are responsible for a wide range of syndromes, for which no effective treatment is available at present. We show that three human mt aminoacyl-tRNA syntethases, namely leucyl-, valyl-, and isoleucyl-tRNA synthetase are able to improve both viability and bioenergetic proficiency of human transmitochondrial cybrid cells carrying pathogenic mutations in the mt-tRNA(Ile) gene. Importantly, we further demonstrate that the carboxy-terminal domain of human mt leucyl-tRNA synthetase is both necessary and sufficient to improve the pathologic phenotype associated either with these "mild" mutations or with the "severe" m.3243A>G mutation in the mt-tRNA(L)(eu(UUR)) gene. Furthermore, we provide evidence that this small, non-catalytic domain is able to directly and specifically interact in vitro with human mt-tRNA(Leu(UUR)) with high affinity and stability and, with lower affinity, with mt-tRNA(Ile). Taken together, our results sustain the hypothesis that the carboxy-terminal domain of human mt leucyl-tRNA synthetase can be used to correct mt dysfunctions caused by mt-tRNA mutations

GIOVANNI CARANO DONVITO. Scritti scelti di scienza delle finanze e di diritto finanziario.

Sommario: Parte Prima. I teoremi fondamentali della statica e dinamica finanziaria. Parte Seconda. Scritti giuridici finanziari. appunti sulla codificazione del diritto tributario. Questione meridionale e sistema tributario. principi di diritto penale finanziario. Dazi e istituzioni doganali. Appunti per una finanza e diritto finanziario internazionale

ISTITUZIONI DI DIRITTO TRIBUTARIO

Il manuale affronta gli istituti di diritto tributario e le recenti riform

LA SIMMETRIA IMPERFETTA

Sommario: Le opere finanziarie di Maffeo Pantaleoni. Concetto della traslazione e valore pratico di essa. Ricordo di Francesco Antonio R�paci. Teoria dell'imposta economica. Ricordo di Giovanni Corano Donvito. Idee fondamentali sul diritto penale finanziario. Attilio Da Empoli: breve ricordo.Effetti del prelievo delle imposte ed effetti del prelievo della spesa. Ricordo di Giorgio Tesoro. Sull'autonomia del diritto finanziario. Mio caro Giannini, vecchio amico di quarant'anni....La personalit� e l'opera di A.d. Giannini. Ricordo di A.D. Giannini in occasione dell'attivazione dell'Universit� di Foggia. Intorno alla c.d. autonomia del diritto tributario. In memoria di Gian Antoio Micheli. Profili critici in tema di potest� di imposizione. Ricordando Sica. Osservazioni sulla "Legge di bilancio" (art. 81 della Costituzione). Ricordo di Filippo Stella Maranca. Aerarium. Ricordo di Giuseppe Abbamonte. I limiti della legge finanziaria. Ricordo di Corrado Vocino. "Iudicium Vectigale". Il contributo di Filippo Serafini alla teoria dei riflessi metafisici delle leggi tributarie. Il nostro sistema tributario dopo la riforma

Neuromuscular relaxants in non-cardiac surgery after cardiomyoplasty

Purpose: Dynamic cardiomyoplasty is a therapeutic alternative to heart transplantation in irreversible cardiac insufficiency. Little information exists about the use of muscle relaxants in patients with cardiomyoplasty, in particular, it is not clear if the muscle flap is responsive to neuromuscular blockers, The purpose of this report is to describe the safe use of vecuronium in a patient with cardiomyoplasty. Clinical features: A 59-yr-old man, after cardiomyoplasty for dilated cardiomyopathy two years earlier, underwent general anaesthesia with fentanyl, propofol and vecuronium during surgery for intestinal ischaemia, Intraoperative transthoracic echocardiography showed that vecuronium did not affect muscle flap motion, Two days after surgery he died in septic shock. Post-mortem histological and immunohistochemical examination showed nervous degeneration of the flap probably as a result of the chronic low frequency pacing. There was also an increase in extrajunctional receptors and an alteration in junctional receptors, as demonstrated by the negative reaction to anti-synaptophysin antibodies, used to identify the neuromuscular plate. Conclusion: In patients undergoing non-cardiac surgery after previous cardiomyoplasty, muscle relaxants, such as vecuronium, may be used safely. Depolarising agents, such as succinylcholine, should probably be avoided because of the possible exaggerated actions on extrajunctional receptors

HISTOMORPHOMETRIC FEATURES PREDICT 1-YEAR OUTCOME OF PATIENTS WITH IDIOPATHIC DILATED CARDIOMYOPATHY CONSIDERED TO BE AT LOW PRIORITY FOR CARDIAC TRANSPLANTATION

Cardiac transplantation for patients with idiopathic dilated cardiomyopathy (IDC) and poor left ventricular function usually is postponed until symptoms have become intolerable. However, the short-term prognosis of this subset of patients has been defined poorly. Accordingly, the 1-year outcome was investigated in 30 patients with IDC with an ejection fraction less than or equal to 25% who showed a stabilized clinical condition at assessment for transplantation and were therefore considered at low priority for surgery. During follow-up, 10 patients (group A) showed a poor outcome: 2 died suddenly, and 8 had hemodynamic failure (4 of whom underwent transplantation and 4 of whom died from heart failure while on the waiting list). The remaining 20 patients (group B) had a benign outcome. At assessment for cardiac transplantation, clinical and electrocardiographic features, left ventricular dimension, and ejection fraction were similar between the two groups. However, group A patients had higher left ventricular end-diastolic pressure (p 50 mu m(2) was found in all group A patients (sensitivity 100%) but in only 2 group B patients (specificity 90%). It is concluded that in patients with IDC considered at low priority for cardiac transplantation: (1) the 1-year freedom from a cardiac event is lower than that currently expected with surgery; (2) histomorphometric features, that is, the concurrency of low myofibril volume fraction and increased nuclear area, predict short-term outcome; and (3) endomyocardial biopsy at assessment for cardiac transplantation might improve the rationalization of the timing of the procedure

Differential P-Glycoprotein/CD31 Expression as Markers of Vascular Co-Option in Primary Central Nervous System Tumors

Background: Vascular co-option is one of the main features of brain tumor progression. It is identified using histopathological analysis, but no antibody-specific markers were found, and no universally accepted histological features were defined. Methods: We employed double immunohistochemical stainings for CD31, P-gp, S100A10, and mitochondria on formalin-fixed, paraffin-embedded human samples of IDH-WT glioblastoma, IDH-mutant astrocytoma, and meningioma to study vascular co-option across different brain tumors and across normal, peritumoral, and intratumoral areas using the Aperio colocalization algorithm, which is a valid and robust method to handle and investigate large data sets. Results: The results have shown that (i) co-opted vessels could be recognized by the presence of metabolically overactive (evaluated as mitochondria expression) and P-gp(+) or S100A10(+) tumor cells surrounding CD31(+) endothelial cells; (ii) vascular co-option occurs in the intratumoral area of meningioma and astrocytoma; and (iii) vascular co-option is prevalent in peritumoral glioblastoma area. Conclusions: The described approach identifies new markers for cellular components of the vessel wall and techniques that uncover the order and localization of vascularization mechanisms, which may contribute to developing new and possibly more effective therapeutic strategies

Reproductive and Oncologic Outcomes in Young Women with Stage IA and Grade 2 Endometrial Carcinoma Undergoing Fertility-Sparing Treatment: A Systematic Review

Background: Endometrial cancer (EC) is the most common gynecological malignancy in both Europe and the USA. Approximately 3-5% of cases occur in women of reproductive age. Fertility-sparing treatment (FST) options are available, but very limited evidence regarding grade 2 (G2) ECs exists in the current literature. This systematic review aimed to comprehensively evaluate reproductive and oncologic outcomes among young women diagnosed with stage IA or G2EC disease who underwent FST. Methods: A comprehensive search of the literature was carried out on the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), the Health Technology Assessment Database, and Web of Science. Only original studies that reported the oncologic and reproductive outcomes of patients with stage IA and G2EC tumors who underwent FST were considered eligible for inclusion in this systematic review (CRD42023484892). Studies describing only the FST for endometrial hyperplasia or G1 EC were excluded. Results: Twenty-two papers that met the abovementioned inclusion criteria were included in the present systematic review. Preliminary analysis suggested encouraging oncologic and reproductive outcomes after FST. Conclusions: The FST approach may represent a feasible and safe option for women of childbearing age diagnosed with G2EC. Despite these promising findings, cautious interpretation is warranted due to inherent limitations, including heterogeneity in study designs and potential biases. Further research with standardized methodologies and larger sample sizes is imperative for obtaining more robust conclusions