Enzyme replacement therapy for Mucopolysaccharidosis Type I among patients followed within the MPS Brazil Network

Mucopolysaccharidosis type I (MPS I) is a rare lysosomal disorder caused by deficiency of alpha-L-iduronidase. Few clinical trials have assessed the effect of enzyme replacement therapy (ERT) for this condition. We conducted an exploratory, open-label, non-randomized, multicenter cohort study of patients with MPS I. Data were collected from questionnaires completed by attending physicians at the time of diagnosis (T1; n = 34) and at a median time of 2.5 years later (T2; n = 24/34). The 24 patients for whom data were available at T2 were allocated into groups: A, no ERT (9 patients; median age at T1 = 36 months; 6 with severe phenotype); B, on ERT (15 patients; median age at T1 = 33 months; 4 with severe phenotype). For all variables in which there was no between-group difference at baseline, a delta of ≥ ± 20% was considered clinically relevant. The following clinically relevant differences were identified in group B in T2: lower rates of mortality and reported hospitalization for respiratory infection; lower frequency of hepatosplenomegaly; increased reported rates of obstructive sleep apnea syndrome and hearing loss; and stabilization of gibbus deformity. These changes could be due to the effect of ERT or of other therapies which have also been found more frequently in group B. Our findings suggest MPS I patients on ERT also receive a better overall care. ERT may have a positive effect on respiratory morbidity and overall mortality in patients with MPS I. Additional studies focusing on these outcomes and on other therapies should be performed.

Mucopolysaccharidoses in northern Brazil: targeted mutation screening and urinary glycosaminoglycan excretion in patients undergoing enzyme replacement therapy

Mucopolysaccharidoses (MPS) are rare lysosomal disorders caused by the deficiency of specific lysosomal enzymes responsible for glycosaminoglycan (GAG) degradation. Enzyme Replacement Therapy (ERT) has been shown to reduce accumulation and urinary excretion of GAG, and to improve some of the patients' clinical signs. We studied biochemical and molecular characteristics of nine MPS patients (two MPS I, four MPS II and three MPS VI) undergoing ERT in northern Brazil. The responsiveness of ERT was evaluated through urinary GAG excretion measurements. Patients were screened for eight common MPS mutations, using PCR, restriction enzyme tests and direct sequencing. Two MPS I patients had the previously reported mutation p.P533R. In the MPS II patients, mutation analysis identified the mutation p.R468W, and in the MPS VI patients, polymorphisms p.V358M and p.V376M were also found. After 48 weeks of ERT, biochemical analysis showed a significantly decreased total urinary GAG excretion in patients with MPS I (p < 0.01) and MPS VI (p < 0.01). Our findings demonstrate the effect of ERT on urinary GAG excretion and suggest the adoption of a screening strategy for genotyping MPS patients living far from the main reference centers.

Electromyographic reaction time in older female fallers and non-fallers after postural perturbation

O tempo de reação eletromiográfica (TRE) reflete a magnitude e a velocidade com que os músculos são ativados para realizar movimentos, evitar lesões ou posicionar uma articulação e pode ser avaliado após uma perturbação externa para análise do desempenho do controle postural e relacioná-lo com a possibilidade de quedas em idosos. O objetivo do estudo foi verificar o TRE dos músculos oblíquo interno (OI), reto femoral (RF), vasto lateral (VL), tibial anterior (TA), multífido (MU), glúteo máximo (GM), bíceps femoral (BF) e gastrocnêmio lateral (GL) em situações de perturbação do equilíbrio em idosos com e sem histórico de quedas. Para isso, foram avaliadas vinte e nove mulheres com 60 anos ou mais, fisicamente ativas e não-institucionalizadas e separadas em dois grupos de acordo com o relato de quedas nos 12 meses pregressos ao estudo: Grupo de Idosas Caidoras (GIC) (n=13; 72,4 ± 8,0 anos) e Grupo de Idosas Não-Caidoras (GINC) (n=16; 67,8 ± 6,8 anos). O TRE dos músculos avaliados durante o teste de desequilíbrio postural anterior e posterior não foram significativamente diferentes entre os grupos. Os resultados sugerem que a ativação muscular dos músculos avaliados, tanto durante o desequilíbrio anterior quanto no desequilíbrio posterior, não podem ser considerados um fator determinante para quedas.

Reação postural de pacientes com doença de Parkinson e idosos sadios no teste de retropulsão instrumentado

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

The use of Ground Penetrating Radar and alternative geophysical techniques for assessing embankments and dykes safety

The research is part of a survey for the detection of the hydraulic and geotechnical conditions of river embankments funded by the Reno River Basin Regional Technical Service of the Region Emilia-Romagna. The hydraulic safety of the Reno River, one of the main rivers in North-Eastern Italy, is indeed of primary importance to the Emilia-Romagna regional administration. The large longitudinal extent of the banks (several hundreds of kilometres) has placed great interest in non-destructive geophysical methods, which, compared to other methods such as drilling, allow for the faster and often less expensive acquisition of high-resolution data. The present work aims to experience the Ground Penetrating Radar (GPR) for the detection of local non-homogeneities (mainly stratigraphic contacts, cavities and conduits) inside the Reno River and its tributaries embankments, taking into account supplementary data collected with traditional destructive tests (boreholes, cone penetration tests etc.). A comparison with non-destructive methodologies likewise electric resistivity tomography (ERT), Multi-channels Analysis of Surface Waves (MASW), FDEM induction, was also carried out in order to verify the usability of GPR and to provide integration of various geophysical methods in the process of regular maintenance and check of the embankments condition. The first part of this thesis is dedicated to the explanation of the state of art concerning the geographic, geomorphologic and geotechnical characteristics of Reno River and its tributaries embankments, as well as the description of some geophysical applications provided on embankments belonging to European and North-American Rivers, which were used as bibliographic basis for this thesis realisation. The second part is an overview of the geophysical methods that were employed for this research, (with a particular attention to the GPR), reporting also their theoretical basis and a deepening of some techniques of the geophysical data analysis and representation, when applied to river embankments. The successive chapters, following the main scope of this research that is to highlight advantages and drawbacks in the use of Ground Penetrating Radar applied to Reno River and its tributaries embankments, show the results obtained analyzing different cases that could yield the formation of weakness zones, which successively lead to the embankment failure. As advantages, a considerable velocity of acquisition and a spatial resolution of the obtained data, incomparable with respect to other methodologies, were recorded. With regard to the drawbacks, some factors, related to the attenuation losses of wave propagation, due to different content in clay, silt, and sand, as well as surface effects have significantly limited the correlation between GPR profiles and geotechnical information and therefore compromised the embankment safety assessment. Recapitulating, the Ground Penetrating Radar could represent a suitable tool for checking up river dike conditions, but its use has significantly limited by geometric and geotechnical characteristics of the Reno River and its tributaries levees. As a matter of facts, only the shallower part of the embankment was investigate, achieving also information just related to changes in electrical properties, without any numerical measurement. Furthermore, GPR application is ineffective for a preliminary assessment of embankment safety conditions, while for detailed campaigns at shallow depth, which aims to achieve immediate results with optimal precision, its usage is totally recommended. The cases where multidisciplinary approach was tested, reveal an optimal interconnection of the various geophysical methodologies employed, producing qualitative results concerning the preliminary phase (FDEM), assuring quantitative and high confidential description of the subsoil (ERT) and finally, providing fast and highly detailed analysis (GPR). Trying to furnish some recommendations for future researches, the simultaneous exploitation of many geophysical devices to assess safety conditions of river embankments is absolutely suggested, especially to face reliable flood event, when the entire extension of the embankments themselves must be investigated.

Morbus Hunter : Neutralisationskapazität von Antikörpern unter Enzymersatztherapie und deren klinischen Auswirkungen

Morbus Hunter, eine lysosomale Speicherkrankheit, ist eine seltene, progrediente, x-chromosomal vererbte Stoffwechselkrankheit, die durch ein Defizit an Iduronat-2-sulfatase (IDS) hervorgerufen wird. Als Folge daraus erfolgt kein Abbau von Heparan- und Dermatansulfat und die Glykosaminoglykane reichern sich in de Lysosomen der Zelle an. M. Hunter ist eine Multisystemerkrankung und weist ein breites klinisches Spektrum mit interindividuell unterschiedlichem Krankheitsbeginn, Ausprägungen und Progression der Symptome auf. Seit 2007 besteht die Therapieoption einer Enzymersatztherapie (ERT) mit Elaprase®. Einige Patienten entwickeln Antikörper gegen das substituierte Enzym, welche partiell neutralisierende Eigenschaften besitzen. Ziel dieser Untersuchung war es zu klären, ob die Neutralisationskapazität der gebildeten Antikörper mittels einer Bestimmung im Mischserum festgestellt werden kann und ob persistierende Antikörper mit Neutralisationskapazität zu einer Einschränkung der Wirksamkeit der Enzymersatztherapie führen. Es sollte weiterhin untersucht werden, ob sich mittels Messung der neuronenspezifischen Enolase (NSE) und S-100 Rückschlüsse auf eine neuropathische Beteiligung ziehen lassen, da bis jetzt noch keine klinische oder biochemische Messmethode existiert, die für M. Hunter-Patienten eine verlässliche Vorhersage für eine neuropathische Beteiligung bietet. 30 Patienten wurden in die retrospektive/prospektive Kohortenstudie eingeschlossen. Bei der Bestimmung der IDS-Aktivität im Mischserum mit einem gesunden Menschen zeigten fünf der Patienten (17%) in zwölf Mischseren eine um ≥ 40% reduzierte Aktivität. Zwei (7%) der 30 untersuchten Patienten wurden mit dieser Methode als positiv für persistierende neutralisierende Antikörper identifiziert. Zum gleichen Ergebnis bezüglich der persistierenden neutralisierenden Antikörper führten die Anti-Elaprase®-Immunglobulin-Bestimmungen unter Berücksichtigung des Bestimmungszeitpunkts, die bei Shire Pharmaceuticals durchgeführt wurden. Die Untersuchungsergebnisse lassen den Schluss zu, dass die gebildeten Antikörper auch intraindividuell unterschiedlich sind. Zudem interagieren sie mit den verschiedensten Epitopen des Enzyms der ERT und besitzen nicht alle neutralisierende Eigenschaften. Aufgrund der heterogenen Zusammensetzung folgt die Hemmung der Enzymaktivität vermutlich keiner eindeutigen Kinetik. Anti-Elaprase®-Immunglobulin G spielt für die Neutralisationskapazität jedoch eine wichtige Rolle. Die Auswertung und Beurteilung der Einschränkung der Wirksamkeit der Therapie hervorgerufen durch die Antikörper mit Neutralisationskapazität gestaltete sich kompliziert. Im Ergebnis zeigte sich, dass sich die beiden Patienten mit persistierenden neutralisierenden Antikörpern in der Entwicklung der klinischen Parameter interindividuell stark unterschieden. Um einen Zusammenhang zwischen klinischem Verlauf und Antikörperbildung gegen die ERT zu finden, müssen in einem größeren Patientenkollektiv mehr Patienten mit persistierenden neutralisierenden Antikörpern identifiziert werden und der Einfluss der Antikörper untersucht werden. Die Untersuchung der NSE und S-100 ergab, dass weder die Konzentration der NSE noch der S-100 Rückschlüsse auf die neuropathische Beteiligung des Patienten zulässt.

Indagini di tomografia geoelettrica sulle dune costiere della Provincia di Ravenna

Questa tesi Magistrale è frutto di un'attività di ricerca, che consiste nella realizzazione di un'indagine geofisica di tipo geoelettrico (ERT Electrical Resistivity Tomography). Lo scopo è quello di caratterizzare l'idrogeologia di una porzione limitata dell'acquifero freatico costiero ravennate, situato nella Pineta Ramazzotti di Lido di Dante, cercando di apportare nuove conoscenze sulle dinamiche che favoriscono l'ingressione marina (problema di forte attualità)che potrebbero contribuire a migliorare la gestione e la tutela delle risorse idriche. In questo contesto la tesi si pone come obiettivo quello di valutare l'applicabilità del metodo geoelettrico verificando se questo è in grado d'individuare efficacemente l'interfaccia acqua dolce-salata e le strutture presenti nel sottosuolo, in due tipologie di ambiente, con e senza un sistema di dune. I risultati dimostrano che dal punto di vista scientifico, il metodo geoelettrico ha verificato il principio di Ghyben-Herzberg, il quale suppone che vi sia una relazione inversa tra quota topografica e limite superiore della zona satura con acqua salata, inoltre si è riscontrata una certa stagionalità tra i profili acquisiti in momenti diversi (influenzati dalla piovosità). Mentre dal punto di vista tecnologico, il metodo, è di difficile utilizzo negli ambienti di transizione tanto ché chi si occupa professionalmente di questi rilievi preferisce non eseguirli. Questo è dovuto alla mancanza di un protocollo per le operazioni di acquisizione e a causa dell'elevato rumore di fondo che si riscontra nelle misurazioni. Con questo studio è stato possibile calibrare e sviluppare un protocollo, utilizzabile con diverse spaziature tra gli elettrodi, che è valido per l'area di studio indagata. Si è riscontrato anche che l'utilizzo congiunto delle informazioni delle prospezioni e quelle dei rilievi classici (monitoraggio della superficie freatica, parametri chimico-fisici delle acque sotterranee, rilievo topografico e sondaggi geognostici), generino un prodotto finale di semplice interpretazione e di facile comprensione per le dinamiche in atto.

Metodi di valutazione diretta ed indiretta della conducibilità idraulica verticale dei terreni sciolti Esempi applicativi nella Alta e Bassa Pianura Friulana

Nel corso del tempo, nell’ambito dell’idrogeologia sono state sviluppate diverse tecniche per la determinazione conducibilità idraulica (K). Negli ultimi decenni sempre maggiori sforzi sono stati compiuti per integrare le tecniche geofisiche a questo specifico settore di ricerca; in particolare le metodologie geoelettriche sono state fonte di molteplici studi per la determinazione indiretta di K. Su questa idea è stato impostato il lavoro presentato in questo elaborato di tesi. Ciò che questo propone è infatti l’esecuzione di test in campo che prevedono il monitoraggio time lapse con tecnologia ERT (Electrical Resistivity Tomography) di un tracciante salino iniettato nel terreno. Il fine ultimo è quello di poter sviluppare una tecnica indiretta per la stima della conducibilità idraulica verticale dei terreni sciolti. Le immagini tomografiche, realizzate in sequenza nel tempo, premettono la visualizzazione l’avanzamento del plume basso resistivo in movimento nel terreno (causato dalla salamoia iniettata). Un successivo confronto grafico fra queste permette di quantificare lo spostamento nel tempo, in modo da calcolare in seguito la velocità di infiltrazione del tracciante, e in ultimo stimare la K del terreno in analisi. I risultati ottenuti con tale metodologia sperimentale, opportunamente elaborati tramite specifici software, sono stati confrontati, dove possibile, con i valori forniti dall’impiego di altre tecniche più tradizionali, in modo da poter valutare la bontà del dato ottenuto. Le aree studio individuate per condurre tali sperimentazioni ricadono all’interno del territorio regionale del Friuli Venezia Giulia, in particolare nell’area di Alta e Bassa pianura friulana. La strumentazione (resistivimetro multicanale VHR X612-EM della MAE-Molisana Apparecchiature Elettroniche) e il software (Res2dinv) per la raccolta e l’elaborazione delle immagini tomografiche sono stati gentilmente messi a disposizione dalla società Geomok s.r.l. del Dott. Geol. Mocchiutti (Udine) con la cui collaborazione è stato realizzato questo elaborato di tesi.

Challenges of the Cooperative Movement In Addressing Issues of Human Security In the Context of a Neoliberal World: the Case of Argentina

The response of some Argentine workers to the 2001 crisis of neoliberalism gave rise to a movement of worker-recovered enterprises (empresas recuperadas por sus trabajadores or ERTs). The ERTs have emerged as former employees took over the control of generally fraudulently bankrupt factories and enterprises. The analysis of the ERT movement within the neoliberal global capitalist order will draw from William Robinson’s (2004) neo-Gramscian concept of hegemony. The theoretical framework of neo-Gramscian hegemony will be used in exposing the contradictions of capitalism on the global, national, organizational and individual scales and the effects they have on the ERT movement. The ERT movement has demonstrated strong level of resilience, despite the numerous economic, social, political and cultural challenges and limitations it faces as a consequence of the implementation of neoliberalism globally. ERTs have shown that through non-violent protests, democratic principles of management and social inclusion, it is possible to start constructing an alternative social order that is based on the cooperative principles of “honesty, openness, social responsibility and caring for others” (ICA 2007) as opposed to secrecy, exclusiveness, individualism and self-interestedness. In order to meet this “utopian” vision, it is essential to push the limits of the possible within the current social order and broaden the alliance to include the organized members of the working class, such as the members of trade unions, and the unorganized, such as the unemployed and underemployed. Though marginal in number and size, the members of ERTs have given rise to a model that is worth exploring in other countries and regions burdened by the contradictory workings of capitalism. Today, ERTs serve as living proofs that workers too are capable of successfully running businesses, not capitalists alone.

Antibiotic susceptibility and molecular diversity of Bacillus anthracis strains in Chad: detection of a new phylogenetic subgroup

We genotyped 15 Bacillus anthracis isolates from Chad, Africa, using multiple-locus variable-number tandem repeat analysis and three additional direct-repeat markers. We identified two unique genotypes that represent a novel genetic lineage in the A cluster. Chadian isolates were susceptible to 11 antibiotics and free of 94 antibiotic resistance genes.

Parkinsonism in Gaucher's disease type 1: ten new cases and a review of the literature

Parkinsonism has been described in patients with Gaucher's disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting.

The effect of idursulfase on growth in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS)

Hunter syndrome (mucopolysaccharidosis type II) is a rare and life-limiting multisystemic disorder with an X-linked recessive pattern of inheritance. Short stature is a prominent feature of this condition. This analysis aimed to investigate the effects of enzyme replacement therapy with idursulfase on growth in patients enrolled in HOS - the Hunter Outcome Survey which is a multinational observational database. As of Jan 2012, height data before treatment were available for 567 of 740 males followed prospectively after HOS entry. Cross-sectional analysis showed that short stature became apparent after approximately 8 years of age; before this, height remained within the normal range. Age-corrected standardized height scores (z-scores) before and after treatment were assessed using piecewise regression model analysis in 133 patients (8-15 years of age at treatment start; data available on ≥ 1 occasion within +/-24 months of treatment start; growth hormone-treated patients excluded). Results showed that the slope after treatment (slope=-0.005) was significantly improved compared with before treatment (slope=-0.043) (difference=0.038, p=0.004). Analysis of covariates (age at treatment start, cognitive involvement, presence of puberty at the start of ERT, mutation type, functional classification), showed a significant influence on growth of mutation type (height deficit in terms of z-scores most pronounced in patients with deletions/large rearrangements/nonsense mutations, p<0.0001) and age (most pronounced in the 12-15-year group, p<0.0001). Cognitive involvement, pubertal status at the start of ERT and functional classification were not related to the growth deficit or response to treatment. In conclusion, the data showed an improvement in growth rate in patients with Hunter syndrome following idursulfase treatment.

Swiss national guideline for reimbursement of enzyme replacement therapy in late-onset Pompe disease.

Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late-onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored.

Cessation and resuming of alglucosidase alfa in Pompe disease: a retrospective analysis.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

Bacillus anthracis Diversity and Geographic Potential across Nigeria, Cameroon and Chad: Further Support of a Novel West African Lineage.

Zoonoses, diseases affecting both humans and animals, can exert tremendous pressures on human and veterinary health systems, particularly in resource limited countries. Anthrax is one such zoonosis of concern and is a disease requiring greater public health attention in Nigeria. Here we describe the genetic diversity of Bacillus anthracis in Nigeria and compare it to Chad, Cameroon and a broader global dataset based on the multiple locus variable number tandem repeat (MLVA-25) genetic typing system. Nigerian B. anthracis isolates had identical MLVA genotypes and could only be resolved by measuring highly mutable single nucleotide repeats (SNRs). The Nigerian MLVA genotype was identical or highly genetically similar to those in the neighboring countries, confirming the strains belong to this unique West African lineage. Interestingly, sequence data from a Nigerian isolate shares the anthrose deficient genotypes previously described for strains in this region, which may be associated with vaccine evasion. Strains in this study were isolated over six decades, indicating a high level of temporal strain stability regionally. Ecological niche models were used to predict the geographic distribution of the pathogen for all three countries. We describe a west-east habitat corridor through northern Nigeria extending into Chad and Cameroon. Ecological niche models and genetic results show B. anthracis to be ecologically established in Nigeria. These findings expand our understanding of the global B. anthracis population structure and can guide regional anthrax surveillance and control planning.