Evaluation of miglustat as maintenance therapy after enzyme therapy in adults with stable type 1 Gaucher disease: a prospective,open-label non-inferiority study

Background

Previous studies have provided equivocal data on the use of miglustat as maintenance therapy in Gaucher disease type 1. We report findings from a clinical trial evaluating the effects of miglustat treatment in patients with stable type 1 Gaucher disease after enzyme therapy.

Methods

Adult type 1 Gaucher disease patients stabilized during at least 3 years of previous enzyme therapy were included in this 2-year, prospective, open-label non-inferiority study. The primary endpoint was percent change from baseline in liver volume. Secondary endpoints included changes in spleen volume, hemoglobin concentration and platelet count.

Results

Forty-two patients were enrolled (mean±SD age, 45.1±12.7 years; previous enzyme therapy duration 9.5±4.0 years). Median (range) exposure to miglustat 100 mg t.i.d. was 658 (3–765) days. Twenty-one patients discontinued treatment prematurely; 13 due to adverse events, principally gastrointestinal. The upper 95% confidence limit of mean percent change in liver volume from baseline to end of treatment was below the non-inferiority margin of 10% (–1.1%; 95%CI ?6.0, 3.9%). Mean (95%CI) changes in spleen volume, hemoglobin concentration and platelet count were 102 (24,180) mL, –0.95 (?1.38, –0.53) g/dL and ?44.1 (–57.6, –30.7) ×10⁹/L, respectively.

Conclusions

The primary efficacy endpoint was met; overall there was no change in liver volume during 24 months of miglustat therapy. Several patients showed a gradual deterioration in some disease manifestations, suggesting that miglustat could maintain clinical stability, but not in all patients. Miglustat demonstrated a predictable profile of safety and tolerability that was consistent with that reported in previous clinical trials and experience in clinical practice.

Trial registration

Clinicaltrials.gov identifier NCT00319046

     

Ciliary neurotrophic factor,unlike nerve growth factor,supports neurite outgrowth but not synapse formation by adult Lymnaea neurons

The nerve growth factor (NGF) family and ciliary neurotrophic factor (CNTF) support survival and/or neurite outgrowth of many cell types. However, it is not known whether the neurite outgrowth induced by neurotrophic factors results in the formation of synapses. We tested NGF and CNTF for their ability to induce neurite outgrowth and synapse formation in vitro by interneurons from the mollusc Lymnaea. Dopaminergic and peptidergic interneurons survived in the absence of neurotrophic factors but exhibited robust outgrowth in response to both NGF and CNTF. Chemical synapses formed between these interneurons and their target neurons cultured in NGF, but synapses were absent in CNTF. Survival, neurite outgrowth, and synaptogenesis are therefore differentially regulated in these neurons. © 1996 John Wiley & Sons, Inc.     

EFFECTS OF MORINGA OLEIFERA SEED EXTRACT ON RUMEN FERMENTATION IN VITRO

Moringa oleifera is a pantropical tree of the family Moringaceae. A previously undescribed property of an aqueous extract from the seeds of this plant is the modulation of ruminal fermentation patterns, especially protein degradation, as demonstrated in a short-term batch incubation system. Gas, short chain fatty acids (SCFA) and cellulolytic enzyme activities were determined as general fermentation parameters. A dot blot assay able to directly detect true protein in rumen fluid samples was used to quantify protein degradation. For complex substrates the interpretation of protein degradation profiles was amended by polyacrylamide gel electrophoresis (PAGE) of the samples. When incubated with pure carbohydrates at a concentration of 1 mg ml^–1, the extract reduced microbial degradation of the model protein, bovine serum albumin (BSA), such that its concentration was at least 40% above the control after 12 h of incubation. Total protein degradation was thus delayed by approximately 9 h. When fermented along with wheat straw, leaf protein (Rubisco) was almost entirely protected during 12 h of fermentation. The degradation of soy proteins was retarded by at least 4- 6 h, depending on the protein band. There were strong side effects on the fermentation of pure cellulose (SCFA yield -60% after 12 h), whereas cellobiose and starch fermentation were less affected (-18 and -8%, respectively). When the complex substrates were fermented, SCFA yield was reduced by approximately 30% after 12 h. In our work we clearly demonstrate the efficacy of the new substance, which is neither a tannin nor a saponin, in an in vitro system, using pure as well as complex substrates. The properties shown in vitro for the crude extract suggest that it could have a positive effect on the protein metabolism of ruminants under intensive management and that negative side effects can be overcome by an optimized dosage. If the chemical nature of the active substance and its mechanism of action can be clarified, it may provide an alternative to replace critical synthetic feed additives (such as antibiotics) for high yielding dairy cows.     

Microbial Transport, Survival, and Succession in a Sequence of Buried Sediments

Abstract Two chronosequences of unsaturated, buried loess sediments, ranging in age from <10,000 years to >1 million years, were investigated to reconstruct patterns of microbial ecological succession that have occurred since sediment burial. The relative importance of microbial transport and survival to succession was inferred from sediment ages, porewater ages, patterns of abundance (measured by direct counts, counts of culturable cells, and total phospholipid fatty acids), activities (measured by radiotracer and enzyme assays), and community composition (measured by phospholipid fatty acid patterns and Biolog substrate usage). Core samples were collected at two sites 40 km apart in the Palouse region of eastern Washington State, near the towns of Washtucna and Winona. The Washtucna site was flooded multiple times during the Pleistocene by glacial outburst floods; the Winona site elevation is above flood stage. Sediments at the Washtucna site were collected from near surface to 14.9 m depth, where the sediment age was approximately 250 ka and the porewater age was 3700 years; sample intervals at the Winona site ranged from near surface to 38 m (sediment age: approximately 1 Ma; porewater age: 1200 years). Microbial abundance and activities declined with depth at both sites; however, even the deepest, oldest sediments showed evidence of viable microorganisms. Same-age sediments had equal quantities of microorganisms, but different community types. Differences in community makeup between the two sites can be attributed to differences in groundwater recharge and paleoflooding. Estimates of the microbial community age can be constrained by porewater and sediment ages. In the shallower sediments (<9 m at Washtucna, <12 m at Winona), the microbial communities are likely similar in age to the groundwater; thus, microbial succession has been influenced by recent transport of microorganisms from the surface. In the deeper sediments, the populations may be considerably older than the porewater ages, since microbial transport is severely restricted in unsaturated sediments. This is particularly true at the Winona site, which was never flooded.     

Transplantation and functional integration of an identified respiratory interneuron in Lymnaea stagnalis.

The possibility that damaged neural circuitries can be repaired through grafting has raised questions regarding the cellular mechanisms required for functional integration of transplanted neurons. Invertebrate models offer the potential to examine such mechanisms at the resolution of single identified neurons within well-characterized neural networks. Here it is reported that a specific deficit in the respiratory behavior of a pulmonate mollusc, caused by the ablation of a solitary interneuron, can be restored by grafting an identical donor interneuron. The transplanted interneuron not only survives and extends neurites within the host nervous system, but under specific conditions forms synapses with appropriate target neurons and is physiologically integrated into the host's circuitry, thereby restoring normal behavior.     

Connectivity changes in an isolated molluscan ganglion during in vivo culture

The stability of neuronal connections in the isolated buccal ganglia of Helisoma trivolvis was examined during in vivo culture for periods up to one month. After 4--8 days the characteristic IPSP input to protractor motoneurons (PMNs) was either abolished or reduced in efficacy. This is apparently due to reduced efficacy of chemical synapses, since the input resistance and resting potential of the motoneurons is unchanged and a fraction of spike-evoked IPSPs from premotor neurons (cyberchrons) onto PMNs was absent. PMNs lacking IPSP input nevertheless exhibit vigorous cyclical bursts of action potentials driven by electrical EPSPs. The IPSP of PMNs showed partial or full restoration after 14--32 days of culture despite the lack of reinnervation of normal targets. Existing electrical synapses were apparently more stable during culture, but electrical connections between cyberchrons and PMNs were strengthened. Probably because of the reinforcement of these electrical synapses, regenerative cycles of activity in both cyberchrons and PMNs may often be initiated by brief stimulating of a single PMN in cultured ganglia. This is in marked contrast to normal ganglia in which PMNs possess a limited ability to generate such activity. It is concluded that isolation of the buccal ganglia results in a predictable, functional alteration of its neuronal circuitry. Such a perturbation of connectivity indicates that a significant degree of plasticity can be exhibited by adult molluscan neurons.