Evidence for inflammasome activation in the brain of mucopolysaccharidosis type II mice.

Hunter syndrome or mucopolysaccharidosis type II (MPS II) is an X-linked recessive disease caused by the deficiency of iduronate 2-sulfatase (IDS), leading to storage of undegraded heparan and dermatan sulfate. Patients with the severe form present neurological abnormalities, but the mechanisms of such alterations are unknown. Here, we hypothesized that the undegraded substances found in this disease could be recognized as damage-associated molecular patterns (DAMPS), leading to activation of the inflammasome. Brains from 2 and 5 months normal and MPS II mice were studied. We observed an increase in cathepsin B activity in the brain tissue and leakage of this enzyme from the lysosome to the cytoplasm in a MPS II neuronal cell line, which is a known activator of the inflammasome. Furthermore, Caspase-1 activity and IL-1-beta levels were elevated at 5 months, confirming that this pathway is indeed altered. Our results suggest that undegraded GAG activate the inflammasome pathway in MPS II and future studies could focus on blocking such pathway to better understand the role of this process to the pathogenesis of MPS II.

Worldwide distribution of common IDUA pathogenic variants.

Mucopolysaccharidosis type I (MPS I) is a rare disorder caused by deleterious sequence variants in the α-L-iduronidase (IDUA) gene. More than 200 pathogenic variants have been described so far, but their frequencies have not yet been analyzed on a worldwide scale. To address this, we analyzed the genotypes of MPS I patients from 35 published studies papers. The most common pathogenic variant observed was p.Trp402Ter. With frequencies of up to 63%, it was the major allele in most European countries, America and Australia. The variant p.Gln70Ter was also frequent; it was found mainly in Northern and Eastern Europe. The most frequent variant in North African countries was p.Pro533Arg; in Morocco, it represented more than 90% of mutant alleles. Variants observed in East Asians were not found in Western populations, including c.1190-1G>A, p.Ala79Val, p.Leu346Arg and c.613_617dupTGCTC. Conversely, p.Trp402Ter and p.Pro533Arg were not found in patients from East Asia. In conclusion, the most common pathogenic IDUA variant in MPS I patients are p.Trp402Ter, p.Gln70Ter and p.Pro533Arg. Knowledge about the genetic background of MPS I for each population is essential when developing new genotype-targeted therapies, as well as to enable faster genetic analysis and improve patient management.

Risk factors and survival outcomes in patients with brain metastases from breast cancer.

Development of central nervous system (CNS) metastases in breast cancer (BC) is associated with poor prognosis. The incidence of CNS metastases in metastatic BC is reported to be about 10-16 %, but different subtypes of BC are associated with different risk of developing CNS metastases. We retrospectively analysed the risk of CNS metastases and the outcome in a cohort of 473 patients with metastatic BC. CNS metastases were diagnosed in 15.6 % of patients and median survival from diagnosis of CNS metastases was 7.53 (25th-75th 2.8-18.9) months. The risk of developing CNS metastases was higher in patients with grade 3, hormone receptor negative, HER2-positive, high Ki-67 BC. When compared to luminal A subtype, only HER2-positive BC was associated with increased risk of CNS metastases. Survival from diagnosis of CNS metastases was longer in patients with HER2-positive BC, while it was shorter in patients that did not receive any locoregional treatment, or with extra-CNS disease, or with more than 3 CNS lesions.

Hemangiopericytoma of the skull base and Collet-Sicard syndrome: a case report.

Hemangiopericytoma (HP) is a mesenchymal tumor that originates from the pericytes of the capillary walls. This is a rare neoplasm, particularly in the head and neck; the skull base is involved exceptionally. We report a case of a large HP located in the jugular foramen. The last four cranial nerves were involved, causing a Collet-Sicard syndrome associated with facial palsy. Only one case of HP and Collet-Sicard syndrome is reported in the literature. The clinical course of the disease is described, emphasizing the long period of elapsed time between onset of the complaints and the final diagnosis. Diagnostic procedures and immunohistochemical evaluation are analyzed, along with the possible differential diagnosis with other pathological processes that more frequently involve the jugular foramen.

[Idiopathic cupulolithiasis: vasomotor reactivity evaluation of the vertebro-basilar artery by transcranial doppler ultrasonography and acetazolamide test]. / La cupulolitiasi idiopatica: studio della reattività vasomotoria del circolo vertebro-basilare con sonografia Doppler transcranica e test all'acetazolamide.

Benign paroxysmal positional vertigo (BPPV) or cupulolithiasis is one of the more common peripheral vestibular disorders. Diagnosis is made on the observation of typical positioning nystagmus brought about by the Hallpike manoeuver. In most cases of BPPV, etiology is unknown. Microcirculatory disorders have often been considered responsible for idiopathic BPPV. Few reports have been published on this specific aspect of the problem. In our study we evaluated vertebro-basilar haemodynamics and vasomotory reactivity after Acetazolamide administration in 12 patients with idiopathic BPPV. The results obtained reveal the absence of macrocirculatory impairment in the vertebro-basilar district in basal conditions, but significative vasoreactivity variation after acetazolamide, both in vertebral and basilar arteries. Poor vasomotor reactivity in one vertebral artery was observed in 5 patients and, in two cases, in the basilar artery. Altered vasoreactivity in the middle cerebral arteries was not observed in any case. In the light of these findings, we suggest that a possible inadequate response if microcirculation in the labyrinth, in some particular haemodynamic situations, might cause otolithic damage.

Menière's disease in congenital nephrogenic diabetes insipidus: report of two twins.

Two cases, twins, affected by congenital nephrogenic diabetes insipidus (CNDI) with a high daily volume of dilute urine excretion and periods of compensatory high levels of antidiuretic hormone (ADH) simultaneously developed a fluctuating Menière-type hearing loss. It is well known that the kidney and the cochlea are linked by structural and anatomic characteristics, as well as by the physiologic mechanism of electrolytes and fluid regulation. The patients herein described seem to be paradoxical, because they suffered from hydropic hearing loss despite the pathophysiologic mechanism of CNDI and the possible role played by ADH in water regulation in the inner ear. The consequences on Menière's disease of the different therapeutic regimens followed by the two CNDI patients are discussed. To our knowledge these are the first cases of CNDI with Menière's disease described in the literature.