Particle number and mass exposure concentrations by commuter transport modes in Milan, Italy

There is increasing awareness amongst the general public about exposure to atmospheric pollution while travelling in urban areas especially when taking active travelling modes such as walking and cycling. This study presents a comparative investigation of ultrafine particles (UFP), PM10, PM2.5, PM1 exposure levels associated with four transport modes (i.e., walking, cycling, car, and subway) in the city of Milan measured by means of portable instruments. Significant differences in particle exposure between transport modes were found. The subway mode was characterized by the highest PM mass concentrations: PM10, PM2.5, PM1 subway levels were respectively about 2-4-3 times higher than those of the car and open air active modes (i.e. cycling and walking). Conversely, these latter modes displayed the highest UFP levels about 2 to 3 times higher than the subway and car modes, highlighting the influence of direct traffic emissions. The car mode (closed windows, air conditioning and air recirculation on) reported the lowest PM and UFP concentration levels. In particular, the open-air/car average concentration ratio varied from about 2 for UFP up to 4 for PM1 and 6 for PM10 and PM2.5, showing differences that increase with increasing particle size. This work points out that active mode travelling in Milan city centre in summertime results in higher exposure levels than the car mode. Walkers’ and cyclists’ exposure levels is expected to be even higher during wintertime, due to the higher ambient PM and UFP concentration. Interventions intended to re-design the urban mobility should therefore include dedicated routes in order to limit their exposure to PM and UFP by increasing their distance from road traffic

Visual electrophysiological responses in subjects with cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Objectives: To evaluate visual electrophysiological responses in subjects with cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Methods: Three subjects tone male and two females, mean age 55.3 +/- 2.9 years) belonging to an Italian family already diagnosed with CADASIL through clinicopathological and genetic studies and 14 control subjects (6 males and 8 females, mean age 52.7 +/- 3.6 years) were enrolled in the study. Flash electroretinogram (ERG), oscillatory potentials (OPs) and simultaneous recordings of pattern electroretinogram (PERG) and visual evoked potentials (VEPs) were assessed in all 3 subjects with CADASIL and age-matched controls. Results: Subjects with CADASIL showed: reduced ERG, OP and PERG (N35-P50, P50-N95) amplitudes with respect to our normal limits; delayed PERG (N35, P50) and VEP (P100) implicit times when compared with our normal limits; and VEP (N75-P100) amplitudes and retinocortical times within our normal limits. Conclusions: Subjects with CADASIL present a dysfunction in the outer, middle and innermost retinal layers when the index of neural conduction in the postretinal visual pathways is normal. The delay in visual cortical responses observed in subjects with CADASIL may be ascribable to retinal impairment with a possible functional sparing of the postretinal visual structures. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved

Esiti di salute e performance del Servizio Sanitario Nazionale

Capitolo del Rapporto OASI incentrato sugli esiti di salute e performance del Servizio Sanitario Nazionale

Next-generation sequencing approach to hyperCKemia: A 2-year cohort study

Next-generation sequencing (NGS) was applied in molecularly undiagnosed asymptomatic or paucisymptomatic hyperCKemia to investigate whether this technique might allow detection of the genetic basis of the condition

Neuromyopathy with congenital cataracts and glaucoma: A distinct syndrome caused by POLG variants

We identified three non-related patients manifesting a childhood-onset progressive neuromyopathy with congenital cataracts, delayed walking, distal weakness and wasting, glaucoma and swallowing difficulties. Electrophysiology and nerve biopsies showed a mixed axonal and demyelinating neuropathy, while muscle biopsy disclosed both neurogenic and myopathic changes with ragged red fibers, and muscle MRI showed consistent features across patients, with a peculiar concentric disto-proximal gradient of fatty replacement. We used targeted next generation sequencing and candidate gene approach to study these families. Compound biallelic heterozygous variants, p.[(Pro648Arg)]; [(His932Tyr)] and p.[(Thr251Ile),(Pro587Leu)]; [(Arg943Cys)], were found in the three patients causing this homogeneous phenotype. Our report on a subset of unrelated patients, that showed a distinct autosomal recessive childhood-onset neuromyopathy with congenital cataracts and glaucoma, expands the clinical spectrum of POLG-related disorders. It also confirms the association between cataracts and neuropathy with variants in POLG. Early onset cataract is otherwise rare in POLG-related disorders and so far reported only in a few patients with the clinical pattern of distal myopathy or neuromyopathy

Congenital myopathies: Clinical phenotypes and new diagnostic tools

Congenital myopathies are a group of genetic muscle disorders characterized clinically by hypotonia and weakness, usually from birth, and a static or slowly progressive clinical course. Historically, congenital myopathies have been classified on the basis of major morphological features seen on muscle biopsy. However, different genes have now been identified as associated with the various phenotypic and histological expressions of these disorders, and in recent years, because of their unexpectedly wide genetic and clinical heterogeneity, next-generation sequencing has increasingly been used for their diagnosis. We reviewed clinical and genetic forms of congenital myopathy and defined possible strategies to improve cost-effectiveness in histological and imaging diagnosis

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common and best known monogenic small vessel disease. Here, we review the clinical, neuroimaging, neuropathological, genetic, and therapeutic aspects based on the most relevant articles published between 1994 and 2016 and on the personal experience of the authors, all directly involved in CADASIL research and care. We conclude with some suggestions that may help in the clinical practice and management of these patients

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263

Next Generation Molecular Diagnosis of Hereditary Spastic Paraplegias: An Italian Cross-Sectional Study

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity-there are over 80 potential disease-associated genes-and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy