Networks, districts, cities, regions: Evidence from the Third Italy.

For over three hundred years, including its most recent, "Fordist" phase, industrial capitalism has been shaping the organisation of territory, fostering urbanisation and the emergence of the great cities and industrial regions. Recently, many observers have suggested that Fordism is in crisis and a period of transition is underway to a "post-Fordist" economy, the characteristics of which are antithetical to those of Fordism. Though territorial aspects are in many ways at the core of the post-Fordist school, particularly the so-called "rise" of the industrial district, regional and especially urban factors are not systematically dealt with in the literature. There is scant empirical evidence of the territorial organisation of the post- Fordist productive systems, nor a clear delineation of the logic behind this particular structure of territorial organisation. Drawing on evidence of three case studies of industrial districts in the Third Italy, the central thesis put forward is that the pattern of cities and regions that has been evolving relatively smoothly since the beginning of the industrial era is currently undergoing a dramatic reorganisation, as a result of a new logic of post-Fordist capital accumulation. New patterns of uneven development are being forged, that are in many ways a reversal of previous and long-standing urban and regional evolutionary trends. The role of spatial and territorial factors in the evolution of certain forms of post-Fordist organisation of production are also explored. In basic outline, the thesis: o argues that we are entering a post-Fordist era and industrial districts can be marshalled as evidence of this; o offers explanations as to why these particular territorial systems of production emerged in the Third Italy, and how they relate to the logic of post-Fordist accumulation; and o concludes that post-Fordism is associated with a reorganisation of urban and regional territory at all geographical scales: regions, urban systems and the urban hierarchy, intra-urban and intra-district space

Lentivirus-mediated gene therapy for Fabry disease

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy

Neonatal Urine Screening Program in the Province of Quebec: Technological Upgrade from Thin Layer Chromatography to Tandem Mass Spectrometry

The Quebec Neonatal Urine Screening Program was initiated in 1971 with overall screening inception of newborns in 1973. Forty-seven years later, over 3.5 million babies have been screened for up to 25 inborn errors of metabolism divided into two groups: (1) urea cycle disorders and organic acidurias; and (2) disorders of amino acid metabolism and transport. The main goal of this preventive genetic medicine program is the detection of treatable diseases before the onset of clinical symptoms. Urine specimens from 21-day-old babies are collected and dried on filter paper by parents at home. The participation is voluntary with a high compliance rate over the years (~90%). Specimens are analyzed by thin layer chromatography (TLC). The main objective of this evaluative research project was to assess the feasibility of a technological upgrade towards mass spectrometry. A 2.85-min flow injection method was devised, normal values established, and abnormal profiles confirmed using second-tier tests. The validated assays are sensitive, specific, and suitable for populational screening, as well as for high-risk screening laboratories. Triple H syndrome, which would not be detected in newborns by blood screening at two days of age was found to be positive in the urine of an affected patient

Multiplex Analysis of Novel Urinary Lyso-Gb₃‑Related Biomarkers for Fabry Disease by Tandem Mass Spectrometry

Fabry disease is a lysosomal storage disorder caused by the absence or reduction of α-galactosidase A enzyme activity. The enzymatic deficiency results in the impaired catabolism of neutral sphingolipids with terminal α-galactosyl residues and subsequent accumulation in several tissues. Biomarkers reflecting disease severity and progression, the response to therapeutic intervention, and details of molecular pathogenesis are needed. Until now, two sphingolipids were targeted as biomarkers in urine and plasma of Fabry patients: globotriaosylceramide (Gb₃) and globotriaosylsphingosine (lyso-Gb₃). Using metabolomic approaches, our group recently discovered seven novel urinary lyso-Gb₃-related Fabry disease biomarkers with mass-to-charge ratios (<i>m</i>/<i>z</i>) of 758, 774, 784, 800, 802, 820, and 836. All these biomarkers exhibited modifications of the lyso-Gb₃ sphingosine moiety. The aims of the present study were to devise and validate a specific tandem mass spectrometry multiplex methodology for the relative quantification of these seven analogues and to evaluate their urinary excretion levels in samples from 164 Fabry patients and 94 healthy controls. We found no detectable analogues in healthy controls, except for trace amounts of the analogue with <i>m</i>/<i>z</i> 836. Significant correlations were established between lyso-Gb₃ analogue levels in urine and gender (<i>p</i> < 0.001). Fabry males had higher excretion levels compared to females with the disease. Lyso-Gb₃ analogue levels correlated well with enzyme replacement therapy (ERT) status in males (<i>p</i> < 0.05). The urinary analogue distributions varied among Fabry patients. However, the analogues with <i>m</i>/<i>z</i> 802, 820, and 836 were generally more abundant in the majority of patients. Lyso-Gb₃ analogues are promising urinary biomarkers for Fabry disease

Mass Spectrometry Analysis of Globotriaosylsphingosine and Its Analogues in Dried Blood Spots

Fabry disease (FD) is an X-linked lysosomal storage disorder where impaired α-galactosidase A enzyme activity leads to the intracellular accumulation of undegraded glycosphingolipids, including globotriaosylsphingosine (lyso-Gb3) and related analogues. Lyso-Gb3 and related analogues are useful biomarkers for screening and should be routinely monitored for longitudinal patient evaluation. In recent years, a growing interest has emerged in the analysis of FD biomarkers in dried blood spots (DBSs), considering the several advantages compared to venipuncture as a technique for collecting whole-blood specimens. The focus of this study was to devise and validate a UHPLC-MS/MS method for the analysis of lyso-Gb3 and related analogues in DBSs to facilitate sample collection and shipment to reference laboratories. The assay was devised in conventional DBS collection cards and in Capitainer®B blood collection devices using both capillary and venous blood specimens from 12 healthy controls and 20 patients affected with FD. The measured biomarker concentrations were similar in capillary and venous blood specimens. The hematocrit (Hct) did not affect the correlation between plasma and DBS measurements in our cohort (Hct range: 34.3–52.2%). This UHPLC-MS/MS method using DBS would facilitate high-risk screening and the follow-up and monitoring of patients affected with FD

Mass Spectrometry Analysis of Globotriaosylsphingosine and Its Analogues in Dried Blood Spots

Fabry disease (FD) is an X-linked lysosomal storage disorder where impaired &alpha;-galactosidase A enzyme activity leads to the intracellular accumulation of undegraded glycosphingolipids, including globotriaosylsphingosine (lyso-Gb3) and related analogues. Lyso-Gb3 and related analogues are useful biomarkers for screening and should be routinely monitored for longitudinal patient evaluation. In recent years, a growing interest has emerged in the analysis of FD biomarkers in dried blood spots (DBSs), considering the several advantages compared to venipuncture as a technique for collecting whole-blood specimens. The focus of this study was to devise and validate a UHPLC-MS/MS method for the analysis of lyso-Gb3 and related analogues in DBSs to facilitate sample collection and shipment to reference laboratories. The assay was devised in conventional DBS collection cards and in Capitainer&reg;B blood collection devices using both capillary and venous blood specimens from 12 healthy controls and 20 patients affected with FD. The measured biomarker concentrations were similar in capillary and venous blood specimens. The hematocrit (Hct) did not affect the correlation between plasma and DBS measurements in our cohort (Hct range: 34.3&ndash;52.2%). This UHPLC-MS/MS method using DBS would facilitate high-risk screening and the follow-up and monitoring of patients affected with FD