The long-term international safety experience of imiglucerase therapy for Gaucher disease

BackgroundGaucher disease is a lysosomal storage disorder resulting from a deficiency of the lysosomal enzyme glucocerebrosidase. Since approval by the FDA in 1994 and EMEA in 1997, enzyme replacement therapy with Cerezyme^® (imiglucerase for injection) has been the standard of care for the treatment of Gaucher disease.ObjectiveTo review the long-term international safety experience of imiglucerase from 1994 through 2004.Materials and methodsAll spontaneous adverse event reports captured in the pharmacovigilance database for imiglucerase from 1994 through 2004 were analyzed. All adverse events were classified using the current version of the Medical Dictionary for Regulatory Activities (MedDRA). Patients without prior exposure to imiglucerase from 1994 through 2005 were assessed for the development of antibodies to imiglucerase as detected by enzyme-linked immunosorbant and radioimmunoprecipitation assays.ResultsAnalysis of the long-term safety experience with imiglucerase therapy demonstrates a stable and low rate of adverse events and seroconversion from 1994 through 2005. The majority of frequently reported adverse events related to imiglucerase were infusion-associated reactions which were predominantly self-limiting in nature and did not require discontinuation of treatment. Between 1994 and 2005, IgG antibodies to imiglucerase were detected in approximately 15% of treatment-naïve patients.ConclusionsThe long-term stability of reported events and seroconversion is a reflection of a well-characterized cell expression system and a mature quality-controlled manufacturing process. Imiglucerase is a safe therapy for the treatment of Gaucher disease with a stable and low rate of reported adverse events and seroconversion.     

Disparity between skin perfusion and sublingual microcirculatory alterations in severe sepsis and septic shock: a prospective observational study

OBJECTIVE: Measurement of central-to-toe temperature difference has been advocated as an index of severity of shock and as a guide for circulatory therapy in critically ill patients. However, septic shock, in contrast to other forms of shock, is associated with a distributive malfunction resulting in a disparity between vascular compartments. Although this disparity has been established between systemic and microcirculatory parameters, it is unclear whether such disparity exists between skin perfusion and microcirculation. To test this hypothesis of disparity, we simultaneously measured parameters of the two vascular compartments, in the early phase of sepsis. DESIGN: Prospective observational study in patients with severe sepsis/septic shock in the first 6 h of ICU admission. Simultaneous measurements of central-to-toe temperature difference and sublingual microcirculatory orthogonal polarization spectral imaging, together with parameters of systemic hemodynamics. SETTING: 22 bed mixed-ICU in a tertiary teaching hospital. PATIENTS: 35 consecutive patients in a 12-month period. MEASUREMENTS AND RESULTS: In 35 septic patients and a median APACHE II score of 20, no correlation between central-to-toe temperature gradient and microvascular flow index was observed (r (s) = -0.08, p =0.65). Also no significant correlation between temperature gradient/microvascular flow index and systemic hemodynamic parameters could be demonstrated. CONCLUSIONS: During the early phase of resuscitated severe sepsis and septic shock there appears to be no correlation between sublingual microcirculatory alterations and the central-to-toe temperature difference. This finding adds to the concept of a dispersive nature of blood flow under conditions of sepsis between microcirculatory and systemic hemodynamics.     

Nurturing gerontology students’ intrinsic motivation to cocreate: The design of a powerful learning environment

Professionals such as gerontologists play an important role in the design, development and implementation of age-friendly services. and products, by using working methods and principles of co-creation. A Dutch undergraduate applied gerontology programme aims to train students in the why, how and what of co-creation. The degree to which students are intrinsically motivated to develop competencies depends on how their psychological needs are met. These needs are autonomy, an awareness of competence and a sense of relatedness, as described in the self-determination theory. To nurture the intrinsic motivation of the applied gerontology students, a realistic, powerful learning environment called the Living Lab Applied Gerontology was designed and implemented. The aim of this paper is to present the design of this powerful learning environment and to discuss its value for nurturing the students’ intrinsic motivation for co-creation. Based on a focus group with eight students, we identify directions for further research and development of living labs.     

Increased systolic blood pressure after mild cold and rewarming: relation to cold-induced thermogenesis and age

Aim: Higher winter mortality in elderly has been associated with augmented systolic blood pressure (SBP) response and with impaired defense of core temperature. Here we investigated whether the augmented SBP upon mild cold exposure remains after a rewarming period, and whether SBP changes are linked to thermoregulation. Therefore, we tested the following hypotheses: cold‐induced increase in SBP (1) remains augmented after rewarming in elderly compared to young adults (2) is related to non‐shivering thermogenesis (NST) upon mild cold (3) is related to vasoconstriction upon mild cold. Methods: Blood pressure, energy expenditure (EE), skin and core temperature, skin perfusion (abdomen, forearm, both sides of hand) and % body fat were measured in 12 young adults (Y) and 12 elderly (E). Supine subjects were exposed to a thermoneutral baseline 0.5 h (T_air = 30.1 °C), 1 h mild cold (T_air = 20.7 °C), 1 h rewarming (T_air = 34.8 °C) and 1 h baseline (T_air = 30.5 °C). Results: Upon mild cold only the young adults showed significant NST (Y: +2.5 ± 0.6 W m^?2, P < 0.05). No significant age effects in vasoconstriction were observed. After rewarming per cent change in SBP (%ΔSBP) remained significantly increased in both age groups and was augmented in elderly (Y: +5.0% ± 1.2% vs. E: +14.7% ± 3.1%, P < 0.05). Regression analysis revealed that %ΔSBP significantly related to ΔEE upon mild cold (P < 0.01, r² = 0.35) and in elderly also to %body fat (P < 0.02, r² = 0.57). Conclusion: Individual changes in SBP after rewarming correlate negatively to NST. Elderly did not show NST, which explains the greater SBP increase in this group. In elderly a relatively large %body fat protected against the adverse effects of mild cold.     

Pulmonary maturational arrest and death in a patient with pulmonary interstitial glycogenosis

We present the clinical presentation and pathological findings from a term infant with atypical neonatal lung disease. A full term Caucasian male presented at birth with signs of respiratory distress. The respiratory condition continued to deteriorate despite maximum intervention and the patient was placed on ECMO for further cardiorespiratory assistance. An open lung biopsy demonstrated findings consistent with severe lung growth abnormality with non-uniform pulmonary interstitial glycogenosis. The patient consequently developed a pulmonary hemorrhage that required discontinuation of ECMO. The patient died shortly after decannulation. Most literature suggests that PIG is one of the few pediatric interstitial lung diseases that has a favorable prognosis with rare mortality in the absence of co-morbidities. However, the current case suggests prognosis may depend more on the underlying diagnosis than on the histological finding of PIG. In addition, this case may provide insight into the pathogenesis and potential modifiers of this idiopathic disorder.