Associated features in females with an FMR1 premutation

Abstract Changes in the fragile X mental retardation 1 gene (FMR1) have been associated with specific phenotypes, most specifically those of fragile X syndrome (FXS), fragile X tremor/ataxia syndrome (FXTAS), and fragile X primary ovarian insufficiency (FXPOI). Evidence of increased risk for additional medical, psychiatric, and cognitive features and conditions is now known to exist for individuals with a premutation, although some features have been more thoroughly studied than others. This review highlights the literature on medical, reproductive, cognitive, and psychiatric features, primarily in females, that have been suggested to be associated with changes in the FMR1 gene. Based on this review, each feature is evaluated with regard to the strength of evidence of association with the premutation. Areas of need for additional focused research and possible intervention strategies are suggested

On the effect of building direction on the microstructure and grain morphology of a selective laser melted maraging stainless steel

In this study, cylindrical rods of a low carbon Fe–Cr–Ni–Al maraging stainless steel (CX) were fabricated through selective laser melting (SLM) technique for both horizontal direction and cube samples with the dimensions of 15 × 15 × 15 mm. The microstructure and grain morphology of the as-built sample were studied using scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), and transmission electron microscopy (TEM). It was observed that in both cases the microstructure of the as-built sample consists of columnar dendrites aligned in the building direction because of the fast-directional cooling presents in the SLM process. However, the microstructural studies revealed that by changing the building method from cube to horizontal, both dendritic and grain structures have a tendency to change. Furthermore, the TEM results showed that different volume fractions of austenite and martensite phases were detected in both directions resulting from complex heat history and wide temperature range during the SLM process

Shear-induced variability in the United States pharmacopeia apparatus 2: Modifications to the existing system

The hydrodynamics within the United States Pharmacopeia Apparatus 2 have been shown to be highly non-uniform with a potential to yield substantial variability in dissolution rate measurements. Through the use of readily available engineering tools, several geometric modifications to the device were evaluated in this study. Specifically, we examined the influence of impeller clearance, agitator type (radial and axial), and vessel geometry (PEAK vessel) on the fluid flow properties and their relation to measured dissolution rates. Increasing the impeller clearance was observed to exacerbate the heterogeneity in shear and would likely result in greater variability in dissolution measurements. Altering the impeller type was shown to yield changes in the hydrodynamic behavior; however, the overall properties and problems with the test remain the same. Use of the PEAK vessel was observed to reduce shear heterogeneity in the regions where tablets are most likely to visit during testing; however, higher shear rates may result in the inability to discriminate between true differences in dissolution rates

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, II: investigations of mechanism

<p>Abstract</p> <p>Background</p> <p>Olanzapine long-acting injection (LAI) is a salt-based depot antipsychotic combining olanzapine and pamoic acid. The slow intramuscular dissolution of this practically insoluble salt produces an extended release of olanzapine lasting up to 4 weeks. However, in a small number of injections (< 0.1%), patients experienced symptoms suggestive of olanzapine overdose, a phenomenon that has been termed "post-injection delirium/sedation syndrome" (PDSS). The authors conducted a series of parallel investigations into the possible reasons PDSS events occur.</p> <p>Methods</p> <p>Healthcare providers involved in the PDSS cases were queried for clinical information around the events. Plasma samples from patients experiencing PDSS were collected when possible (12/30 cases) and olanzapine concentrations compared with the known pharmacokinetic profile for olanzapine LAI. Product batches and used vials from the PDSS cases were evaluated for compliance with established manufacturing standards and/or possible user error. Because this depot formulation depends upon slow dissolution at the intramuscular injection site, in-vitro experiments were conducted to assess solubility of olanzapine pamoate in various media.</p> <p>Results</p> <p>Injection administrators reported no unusual occurrences during the injection. No anomalies were found with the product batches or the remaining suspension in the used vials. Olanzapine concentrations during PDSS events were higher than the expected 5-73 ng/mL range, with concentrations exceeding 100 ng/mL and in some cases reaching >600 ng/mL during the first hours after injection but then returning to the expected therapeutic range within 24 to 72 hours. Solubility and dissolution rate of olanzapine pamoate were also found to be substantially greater in plasma than in other media such as those approximating the environment in muscle tissue.</p> <p>Conclusions</p> <p>Manufacturing irregularities, improper drug reconstitution, and inappropriate dosing were ruled out as possible causes of PDSS. In-vitro solubility and in-vivo pharmacokinetic investigations suggest that PDSS is related to exposure of the injected product to a substantial volume of blood. This exposure is most likely the result of unintended partial intravascular injection or blood vessel injury during the injection (occurring even with proper injection technique) with subsequent seepage of the medication into the vasculature, which would produce higher than intended olanzapine concentrations and symptoms consistent with PDSS.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID; URL: <url>http://http//www.clinicaltrials.gov/</url>: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489</p