Long-term follow-up of renal function in patients treated with migalastat for Fabry disease

The effect of migalastat on long-term renal outcomes in enzyme replacement therapy (ERT)–naive and ERT-experienced patients with Fabry disease is not well defined. An integrated posthoc analysis of the phase 3 clinical trials and open-label extension studies was conducted to evaluate long-term changes in renal function in patients with Fabry disease and amenable GLA variants who were treated with migalastat for ≥2 years during these studies. The analysis included ERT-naive (n = 36 [23 females]; mean age 45 years; mean baseline estimated glomerular filtration rate (eGFR), 91.4 mL/min/mL/1.73 m2) and ERT-experienced (n = 42 [24 females]; mean age, 50 years; mean baseline eGFR, 89.2 mL/min/1.73m2) patients with amenable variants who received migalastat 123 mg every other day for ≥2 years. The annualized rate of change from baseline to last observation in estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) was calculated by both simple linear regression and a random coefficient model. In ERT-naive patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 1.8 mL/min/1.73 m2 and − 1.4 mL/min/1.73 m2 in male and female patients, respectively, as estimated by simple linear regression. In ERT-experienced patients, mean annualized rates of change from baseline in eGFRCKD-EPI were − 1.6 mL/min/1.73 m2 overall and − 2.6 mL/min/1.73 m2 and − 0.8 mL/min/1.73 m2 in male and female patients, respectively. Mean annualized rate of change in eGFRCKD-EPI in ERT-naive patients with the classic phenotype (defined by white blood cell alpha galactosidase A [α-Gal A] activity of <3% of normal and multiorgan system involvement) was −1.7 mL/min/1.73 m2. When calculated using the random coefficient model, which adjusted for sex, age, and baseline renal function, the annualized eGFRCKD-EPI change was minimal (mean: −0.1 and 0.1 mL/min/1.73 m2 in ERT-naive and ERT-experienced patients, respectively). In conclusion, patients with Fabry disease and amenable GLA variants receiving long-term migalastat treatment (≤8.6 years) maintained renal function irrespective of treatment status, sex, or phenotype

Assessment of plasma lyso-Gb(3)for clinical monitoring of treatment response in migalastat-treated patients with Fabry disease

Purpose To assess the utility of globotriaosylsphingosine (lyso-Gb(3)) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenableGLAvariants from FACETS (NCT00925301) and ATTRACT (NCT01218659) and subsequent open-label extension studies. The relationship between plasma lyso-Gb(3)and measures of Fabry disease progression (left ventricular mass index [LVMi], estimated glomerular filtration rate [eGFR], and pain) and the relationship between lyso-Gb(3)and incidence of Fabry-associated clinical events (FACEs) were assessed in both groups. The relationship between changes in lyso-Gb(3)and kidney interstitial capillary (KIC) globotriaosylceramide (Gb(3)) inclusions was assessed in treatment-naive patients. Results No significant correlations were identified between changes in lyso-Gb(3)and changes in LVMi, eGFR, or pain. Neither baseline lyso-Gb(3)levels nor the rate of change in lyso-Gb(3)levels during treatment predicted FACE occurrences in all patients or those receiving migalastat for >= 24 months. Changes in lyso-Gb(3)correlated with changes in KIC Gb(3)inclusions in treatment-naive patients. Conclusions Although used as a pharmacodynamic biomarker in research and clinical studies, plasma lyso-Gb(3)may not be a suitable biomarker for monitoring treatment response in migalastat-treated patients.Medical Biochemistr

Long-term efficacy and safety of migalastat treatment in Fabry disease: 30-month results from the open-label extension of the randomized, phase 3 ATTRACT study

Results from the 18-month randomized treatment period of the phase 3 ATTRACT study demonstrated the efficacy and safety of oral migalastat compared with enzyme replacement therapy (ERT) in patients with Fabry disease who previously received ERT. Here, we report data from the subsequent 12-month, migalastat-only, open-label extension (OLE) period. ATTRACT (Study AT1001–012; NCT01218659) was a randomized, open-label, active-controlled study in patients aged 16–74 years with Fabry disease, an amenable GLA variant, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. During the OLE, patients who received migalastat 150 mg every other day (QOD) during the randomized period continued receiving migalastat (Group 1 [MM]); patients who received ERT every other week discontinued ERT and started migalastat treatment (Group 2 [EM]). Outcome measures included eGFR, left ventricular mass index (LVMi), composite clinical outcome (renal, cardiac or cerebrovascular events), and safety. Forty-six patients who completed the randomized treatment period continued into the OLE (Group 1 [MM], n = 31; Group 2 [EM], n = 15). eGFR remained stable in both treatment groups. LVMi decreased from baseline at month 30 in Group 1 (MM) in patients with left ventricular hypertrophy at baseline. Only 10% of patients experienced a new composite clinical event with migalastat treatment during the OLE. No new safety concerns were reported. In conclusion, in patients with Fabry disease and amenable GLA variants, migalastat 150 mg QOD was well tolerated and demonstrated durable, long-term stability of renal function and reduction in LVMi

Phenology of brown bear breeding season and related geographical cues

© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited[EN] Knowledge about breeding biology is often incomplete in species with complex reproductive strategies. The brown bear Ursus arctos is a polygamous seasonal breeder inhabiting a wide variety of habitats and environmental conditions. We compiled information about brown bear breeding season dates from 36 study areas across their distribution range in the Palearctic and Nearctic regions and investigated how their breeding phenology relates to geographical factors (latitude, photoperiod, altitude and region). Brown bear matings were observed for 8 months, from April to November, with a peak in May–July. We found a 59-day difference in the onset of bear breeding season among study areas, with an average 2.3 days delay for each degree of latitude northwards. The onset of the breeding season showed a strong relationship with photoperiod and latitude, but not with region (i.e. Palearctic vs Nearctic) and altitude. First observations of bear mating occurred earlier in areas at lower latitudes. Photoperiod ranged between 14 and 18 hours at the beginning of the season for most of the study areas. The duration of the breeding season ranged from 25 to 138 days among study areas. None of the investigated factors was related to the length of the breeding season. Our results support the relevance of photoperiod to the onset of breeding, as found in other ursids, but not a shorter breeding season at higher latitudes, a pattern reported in other mammals. Our findings suggest a marked seasonality of bear reproductive behaviour, but also certain level of plasticity. Systematic field observations of breeding behaviour are needed to increase our knowledge on the factors determining mating behaviour in species with complex systems and how these species may adapt to climate change.SIWe thank Marjan Artnak, Peter Bajc, Matic Brenk, Tomáš Flajs, Uroš Grželj, Robert Hlavica, Aleš Jagodnik, Peter Klančar, Anton Marinčič, Mariusz Nędzyński, Borut Semenič and Vladimir Vician for providing information about their observations of bear mating. Robert Gatzka assisted with data collection in the Biezszcady Mountains. We thank Jon Swenson and Jumpei Tomiyasu for their help in the literature search. AGR and NS were supported by the BearConnect project funded by the National Science Centre in Poland (2016/22/Z/NZ8/00121) through the 2015-2016 BiodivERsA COFUND call for research proposals, with the national funders ANR/DLR-PT/UEFISCDI/NCN/RCN. Additional funding from the Polish Ministry of Science and Higher Education (project NN304- 294037, NS, IEC, KB), the National Science Centre in Poland (project DEC-2013/08/M/NZ9/ 00469, NS), the National Centre for Research and Development (GLOBE, POL-NOR/198352/85/ 2013, NS, TZK, FZ) and Slovenian Research Agency (P4-0059, MK) is acknowledged. AGR and NS conceived the study and wrote a first draft of the paper; AGR and NS compiled the data, AGR analyzed the data; all authors provided data and comments that improved the manuscript. We thank two anonymous reviewers for useful comments on the previous versions of the manuscript

Historical Everyday Geopolitics on the Chile-Peru Border

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Geopolitics is increasingly seen by scholars as occurring in everyday spaces and performed by ordinary people. This paper extends this idea to historical work to examine how citizens themselves (re)produce geopolitics at the time of historical events. It does so through a case study of geopolitical tension on the Chile‐Peru border in the 1970s. Through oral histories and newspaper analysis, a historical everyday geopolitics approach reveals how those living in the Chilean border city of Arica played a part in promoting national and border security. This centres the embodied and emotional experiences of those affected by violence and conflict

Lyso-Gb3 is not a predictive biomarker of treatment response in migalastat-treated patients with migalastat-amenable variants

Medical Biochemistr

Uridine activates fast transmembrane Ca2+ ion fluxes in rat brain homogenates

Excitatory receptors responsive to extracellular pyrimidine nucleotides have been identi®ed [1±6]. Although there is evidence for uridine acting as a CNS depressant [7,8], suggestions for an excitatory role in the CNS have so far not been supported by any direct evidence at the molecular level [9]. Hepatic uridine [10] enters the extracellular space of the brain, and subsequently brain cells, from the blood, where it can be phosphorylated and incorporated into RNA or be catabolized to uracil [11,12]. Since the extracellular concentration of uridine has been found to be increased by high K+ in the rat thalamus [13], it was of interest to study uridineresponsive cation ¯uxes through brain membranes. Here we describe a ¯uorescent tracer method to study uridine-activated Ca2+ and K+ ion translocation in suspensions of resealed plasmalemma fragments and nerve endings on the time scale achievable by stopped-¯ow spectroscopy. Uptake, release and binding of radiolabeled uridine in suspensions of synaptosomes and synaptosomal membranes, respectively, were also measured. Cerebral ±cortical suspensions were controlled by HPLC analyses of endogenous purines and pyrimidines