The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of ...circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
To determine whether enzyme therapy with imiglucerase/alglucerase demonstrates dose-response relationships with doses and disease parameters used in routine clinical practice for Gaucher disease type ...1 patients.
Analyses included all patients with Gaucher disease type 1 on enzyme therapy and with intact spleens in the large observational database of the International Collaborative Gaucher Group Gaucher Registry. Propensity scoring was used to match patients between enzyme therapy dose groups categorized as Group A (5 U to <29 U/kg/2 weeks), Group B (29 U to <48 U/kg/2 weeks), Group C (48 U to <75 U/kg/2 weeks). Hemoglobin concentration, platelet count, and hepatic and splenic volumes were assessed after initiation of enzyme therapy using nonlinear mixed effects models. The maximal effect (Emax) and half-time to Emax (T50) of enzyme therapy for each parameter were compared across dosing groups.
Propensity score matching resulted in three comparable groups of 122 patients each (enzyme therapy in Groups A, B, and C). Dose-response relationships were found with regard to Emax and T50 over 96 months for each disease parameter.
Enzyme therapy with imiglucerase/alglucerase displays a dose-dependent improvement in hematological and visceral parameters in Gaucher disease type 1 patients. Group C displayed greater treatment effects than Groups A or B. Propensity score matching and nonlinear mixed effects model analyses provide a prototype for assessment of treatment outcomes based on observational data from international rare disease registries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with Gaucher disease (GD) are alleged to be at an increased risk of malignant disorders, possibly due to potential chronic stimulation of the immune system and lymphoproliferation associated ...with storage of glucocerebroside in tissue macrophages. Because previous reports of increased risk of malignancy in GD may have been affected by small patient numbers and ascertainment bias, 2742 patients with GD from the International Gaucher Registry were studied. The number of cancers identified among patients in the registry was compared with that expected in the US population of similar attained age and sex. The majority of patients were young or middle-aged adults at the time of last follow-up, with only 14% older than age 60. There were 10 patients with multiple myeloma, yielding an estimated relative risk of 5.9 (95% confidence interval 95% CI: 2.8, 10.8). The relative risk of cancer overall was 0.79 (95% CI: 0.67, 0.94), and the subgroups for cancers of the breast, prostate, colon and rectum, lung, and hematologic malignancies other than myeloma did not yield statistically significant higher risks. This study suggests that, in general, patients with Gaucher disease are not at highly increased risk of cancer, at least during early and middle age. However, there appears to be a significantly higher risk of multiple myeloma of which physicians should be aware when caring for these patients. (Blood. 2005;105:4569-4572)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
Background and Objective
Porcine translational models have become the gold-standard translational tool to study the effects of major injury and hemorrhagic shock because of their similarity ...to the human immunologic response to trauma. Segmental bone defects (SBDs) typically occur in warfighters with associated severe limb trauma. The purpose of this study was to develop a translational porcine diaphyseal SBD model in Yucatan minipigs (YMPs), which could be used in bone healing investigations that simulate injury-relevant conditions. We were specifically working toward developing a critical sized defect (CSD).
Methods
We used an adaptive experimental design in which both 25.0 mm and 40.0 mm SBDs were created in the tibial mid-diaphysis in skeletally mature YMPs. Initially, eight YMPs were subjected to a 25.0 mm SBD and treated with intramedullary nailing (intramedullary nail IMN 25mm). Due to unanticipated wound problems, we subsequently treated four specimens with identical 25.0 mm defect with dual plating (open reduction with internal fixation ORIF 25mm). Finally, a third group of four YMPs with 40.0 mm defects were treated with dual plating (ORIF 40mm). Monthly radiographs were made until sacrifice. Modified Radiographic Union Score for Tibia fractures (mRUST) measurements were made by three trauma-trained orthopedic surgeons. CT scans of the tibias were used to verify the union results.
Results
At 4 months post-surgery, mean mRUST scores were 11.7 (SD ± 1.8) in the ORIF 25mm YMPs vs. 8.5 (SD ± 1.4) in the IMN 25mm YMPs (P < .0001). All four ORIF 25mm YMPs were clinically healed. In contrast, none of the IMN 25mm YMPs were clinically healed and seven of eight IMN 25mm YMPs developed delayed wound breakdown. All four of the ORIF 40mm YMPs had flail nonunions with complete hardware failure by 3 months after surgery and were sacrificed early. CT scanning confirmed that none of the IMN 25mm YMPs, none of the ORIF 40mm YMPs, and two of four ORIF 25mm YMPs were healed. A third ORIF 25mm specimen was nearly healed on CT scanning. Inter-rater and intra-rater reliability interclass coefficients using the mRUST scale were 0.81 and 0.80, respectively.
Conclusions
YMPs that had a 40 mm segment of bone removed from their tibia and were treated with dual plating did not heal and could be used to investigate interventions that accelerate bone healing. In contrast, a 25 mm SBD treated with dual plating demonstrated delayed but successful healing, indicating it can potentially be used to investigate bone healing adjuncts or conversely how concomitant injuries may impair bone healing. Pigs treated with IMN failed to heal and developed consistent delayed wound breakdown presumably secondary to chronic limb instability. The porcine YMP SBD model has the potential to be an effective translational tool to investigate bone healing under physiologically relevant injury conditions.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The effect of ERT with imiglucerase on BMD in type 1 GD was studied using BMD data from the International Collaborative Gaucher Group Gaucher Registry. Data were analyzed for 160 untreated patients ...and 342 ERT‐treated patients. Imiglucerase significantly improves BMD in patients with GD, with 8 years of ERT leading to normal BMD.
Introduction: The objective was to determine the effect of enzyme replacement therapy (ERT; Cerezyme, imiglucerase) on BMD in type 1 Gaucher disease (GD).
Materials and Methods: The study population included all adults (men, 18–70 years; women, 18–50 years) enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry for whom lumbar spine BMD measurements were available. BMD data with up to 8 years of follow‐up were analyzed for 160 patients who received no ERT and 342 patients treated with ERT alone. BMD was assessed by DXA of the lumbar spine. Z scores for patients with GD were compared with a reference population. From the model's estimate, percent of patients by age and sex with osteoporosis (T score ⩽ −2.5) were calculated.
Results: DXA Z scores for patients with GD in the no ERT (untreated) group were significantly below normal (y intercept = −0.80 Z score units, p < 0.001) and remained ˜1 SD below the reference population over time (slope = −0.010 Z score units per year, p = 0.68). The DXA Z scores for patients with GD who received ERT at a dose of 60 U/kg/2 weeks were significantly lower than the reference population at baseline (y‐intercept = −1.17 Z score units, p < 0.001), but improved significantly over time (slope = +0.132 Z score units per year, p < 0.001). A significant dose–response relationship was noted for the ERT group, with the slopes for the three main dosing groups of 15, 30, and 60 U/kg/2 weeks of +0.064, +0.086, and +0.132 Z score units per year, respectively. The BMD of patients with GD treated with ERT increased to −0.12 (60 U/kg/2 weeks), −0.48 (30 U/kg/2 weeks), and −0.66 (15 U/kg/2 weeks) SD of the mean of the reference population after 8 years of ERT, approaching the reference population. Estimated risk of osteoporosis of this GD population, if left untreated, ranged from ˜10 to 30% in women and 10% to 25% in men.
Conclusions: ERT with imiglucerase (Cerezyme) may increase BMD in patients with GD. Response to treatment with imiglucerase is slower for BMD than for hematologic and visceral aspects of GD. A normal (age‐ and sex‐adjusted) BMD should be a therapeutic goal for patients with type 1 GD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The epidemiology of tuberculosis remains poorly understood. We investigated the relative importance of within-household and community transmission of infection among children aged 6 months to 14 ...years living in a Peruvian shanty-town. The prevalence of Mycobacterium tuberculosis exposure among 175 contact children (sharing a household with a person who had confirmed pulmonary tuberculosis) and 382 control children (living in nearby households free of active tuberculosis) was defined as the proportion of children with a positive purified protein derivative (PPD) skin-test. 97 (55%) contact children and 129 (34%) controls were PPD positive. Living in a contact household (odds ratio 1·74, 95% Cl 1·11-2·73) and age (1·11, 1·06-1·18) were significant risk factors for PPD positivity. We calculated the community infection ratio (CIR) as the odds ratio of PPD-positive controls to PPD-positive contacts: CIR=Prevalence in controls/(1-prevalence in controls) Prevalence in contacts/(1-prevalence in contacts) A low CIR therefore suggests mainly household spread of infection, whereas a high value suggests frequent transmission outside the household. The adjusted odds ratio (for age, sex, within-household correlation, and household size) was 0·40 (95% Cl 0·26-0·64), compared with values of 0·18-0·37 in studies elsewhere. Currently recommended tuberculosis control strategies are suitable for areas with low CIRs. Different strategies may be needed for areas, such as that we studied, with high values.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SIK, UILJ, UKNU, UL, UM, UPCLJ, UPUK, VSZLJ
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