Evaluation of Glass Delamination Risk in Pharmaceutical 10 mL/10R Vials

Glass delamination is characterized by the dissociation of glass flakes from the glass surface. Since glass delamination is time dependent, 5 vial types were investigated to assess delamination under accelerated stress conditions published as quick tests in literature and compared to stress testing recommended per United States Pharmacopoeia <1660>. A broad panel of analytical techniques was employed to test the solution for visible/subvisible particles and leachables and characterize topography and composition of the surface. The vial types showed significant differences in surface durability when applying the same stress conditions. An increase in glass leachables and change in topography were shown for uncoated vials. An indication for an elevated delamination risk was confirmed for Expansion 33 vials only by the compiled analytical data set including particle assessment and change in elemental composition of the near glass surface investigated by dynamic secondary ion mass spectrometry. The delamination test protocols differ in test solution, handling, and time. Before choosing the most appropriate protocol to predict delamination propensity and mimic real-time conditions, long-term storage data are needed. A combination of analytical techniques to study the risk for long-term corrosion of glass is highly recommended covering the 3 aspects: visible/subvisible particle assessment, solution analysis, and surface characterization.     

Maternal Multivitamin Intake,Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring

Background

To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B₁₂ levels at birth and child's Autism Spectrum Disorder (ASD) risk.

Methods

This report included 1257 mother–child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B₁₂ were measured from samples taken 2–3 days after birth.

Results

Moderate (3–5 times/week) self‐reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B₁₂ (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5).

Conclusion

There was a ‘U shaped’ relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B₁₂ levels at birth were associated with ASD risk. This hypothesis‐generating study does not question the importance of consuming adequate folic acid and vitamin B₁₂ during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B₁₂ exposure in‐utero on early brain development.     

Motion-form interaction: Motion and form aftereffects induced by distorted static natural scenes

Spatially varying distortions (SVDs) are common artifacts of spectacles like progressive additional lenses (PALs). To habituate to distortions of PALs, the visual system has to adapt to distortion-induced image alterations, termed skew adaptation. But how this visual adjustment is achieved is largely unknown. This study examines the properties of visual adaptation to distortions of PALs in natural scenes. The visual adaptation in response to altered form and motion features of the natural stimuli were probed in two different psychophysical experiments. Observers were exposed to distortions in natural images, and form and motion aftereffects were tested subsequently in a constant stimuli procedure where subjects were asked to judge the skew, or the motion direction of an according test stimulus.Exposure to skewed natural stimuli induced a shift in perceived undistorted form as well as motion direction, when viewing distorted dynamic natural scenes, and also after exposure to static distorted natural images. Therefore, skew adaptation occurred in form and motion for dynamic visual scenes as well as static images. Thus, specifically in the condition of static skewed images and the test feature of motion direction, cortical interactions between motion-form processing presumably contributed to the adaptation process.In a nutshell, interfeature cortical interactions constituted the adaptation process to distortion of PALs. Thus, comprehensive investigation of adaptation to distortions of PALs would benefit from taking into account content richness of the stimuli to be used, like natural images.     

Primary motor cortex long‐term plasticity in multiple system atrophy

In humans, intermittent and continuous theta‐burst stimulation (iTBS and cTBS) elicit long‐term changes in motor‐evoked potentials (MEPs) reflecting long‐term potentiation (LTP)‐ and depression (LTD)‐like plasticity in the primary motor cortex (M1). In this study, we used TBS to investigate M1 plasticity in patients with MSA. We also assessed whether responses to TBS reflect M1 excitability as tested by short‐interval intracortical inhibition (SICI), intracortical facilitation (ICF), short‐interval intracortical facilitation (SICF), and the input/output curves. We studied 20 patients with MSA and 20 healthy subjects (HS). Patients were clinically evaluated with the Unified Multiple System Atrophy Rating Scale. The left M1 was conditioned with TBS. Twenty MEPs were recorded from the right first dorsal interosseous muscle before TBS and 5, 15, and 30 minutes thereafter. In a subgroup of 10 patients, we also tested MEPs elicited by SICI, ICF, SICF, and input/output curves, before TBS. Between‐group analysis of variance showed that at all time points after iTBS MEPs increased, whereas after cTBS they decreased only in HS. In both subgroups tested, patients with predominant parkinsonian and cerebellar features, iTBS and cTBS left MEPs unchanged. MSA patients had reduced SICI, but normal ICF, SICF, and input/output curves. No correlation was found between patients' clinical features and responses to TBS and M1 excitability variables. These findings suggest impaired M1 plasticity in MSA. © 2013 International Parkinson and Movement Disorder Society     

Prophylactic antithrombotic therapy for patients with systemic lupus erythematosus with or without antiphospholipid antibodies: do the benefits outweigh the risks? A decision analysis

BACKGROUND: A high incidence of both arterial and venous thromboembolic events has been reported in patients with systemic lupus erythematosus (SLE), but the risks and benefits of primary prophylactic antithrombotic therapy have not been assessed. We measured the clinical benefit of 3 antithrombotic regimens in patients with SLE without antiphospholipid antibodies, with anticardiolipin antibodies, or with lupus anticoagulant. METHODS: A Markov decision analysis was used to evaluate prophylactic aspirin therapy, prophylactic oral anticoagulant therapy, and observation. Input data were obtained by literature review. Clinical practice was simulated in a hypothetical cohort of patients with SLE who had not experienced any previous episode of arterial or venous thromboembolic events. For each strategy, we measured numbers of thromboembolic events prevented and major bleeding episodes induced, and quality-adjusted survival years. RESULTS: Prophylactic aspirin therapy was the preferred strategy in all settings, the number of prevented thrombotic events exceeding that of induced bleeding episodes. In the baseline analysis (40-year-old patients with SLE), the gain in quality-adjusted survival years achieved by prophylactic aspirin compared with observation ranged from 3 months in patients without antiphospholipid antibodies to 11 months in patients with anticardiolipin antibodies or lupus anticoagulant. Prophylactic oral anticoagulant therapy provided better results than prophylactic aspirin only in patients with lupus anticoagulant and an estimated bleeding risk of 1% per year or less. CONCLUSIONS: Prophylactic aspirin should be given to all patients with SLE to prevent both arterial and venous thrombotic manifestations, especially in patients with antiphospholipid antibodies. In selected patients with lupus anticoagulant and a low bleeding risk, prophylactic oral anticoagulant therapy may provide a higher utility.     

Safety and feasibility of high-dose dobutamine-atropine stress cardiovascular magnetic resonance for diagnosis of myocardial ischaemia: experience in 1000 consecutive cases.

AIMS: To determine the safety of high-dose dobutamine-atropine stress cardiovascular magnetic resonance (stress-CMR), which recently emerged as a highly accurate modality for diagnosis of inducible myocardial ischaemia. METHOD AND RESULTS: From 1997 to 2002, 1000 consecutive stress-CMR examinations were performed. Images were acquired at rest and during a high-dose dobutamine-atropine protocol in 3 short-axis, a 4- and a 2-chamber view. Stress testing was discontinued when > or =85% of age-predicted heart rate was reached, on patient request, maximum pharmacologic infusion, or when new or worsening wall motion abnormalities, severe angina, dyspnoea, increase or decrease in blood pressure, or severe arrhythmias occurred. Stress-CMR was successfully performed in all but four patients (0.4%; insufficient ECG-triggering). Target heart rate was not reached in 95 cases (9.5%), due to maximum pharmacologic infusion in submaximal negative examinations in 21 cases (2.1%), and limiting side effects in 74 (7.4%). Side effects included one case (0.1%) of sustained and four cases (0.4%) of non-sustained ventricular tachycardia, 16 cases (1.6%) of atrial fibrillation, and two cases (0.2%) of transient second degree AV block. CONCLUSION: The safety profile of stress-CMR is similar to other methodologies using dobutamine infusions. Patients must be closely monitored, and resuscitation equipment and trained personnel must be available.     

Monovalent binding of autoantibodies to beta2-glycoprotein I, detected using surface plasmon resonance at low antigen density

The precise mechanism of interaction between autoantibodies and beta2-glycoprotein I (beta2GPI) and the experimental conditions to be used for their detection are still under debate. Until now, these interactions have been studied under static conditions. We have investigated the interactions of purified IgG from 25 lupus anticoagulant-positive patients with immobilized beta2GPI under flow conditions by real-time analysis based on surface plasmon resonance technology. Sensor chips were coated with purified human beta2GPI coupled to dextran via amino groups at low densities (1.4, 1.8 or 2. 4 ng beta2GPI/mm2). Four patients' IgG displayed efficient binding and had the highest so-called antiphospholipid IgG levels by enzyme-linked immunosorbent assay (ELISA) and the highest absorbance values in an anti- beta2GPI ELISA at a beta2GPI density reported to be around 12 ng/mm2. Binding of antibodies to the beta2GPI sensor chips proved to be dependent upon the IgG concentration and beta2GPI density and was inhibited by a rabbit antibody against beta2GPI. Similar association and dissociation profiles were observed for the four efficient binders. The fast rate of dissociation limited the binding of autoantibodies to beta2GPI and was highly suggestive of a monovalent association, confirmed by binding of Fab fragments under similar experimental conditions. In conclusion, monovalent binding of low-affinity antibodies to beta2GPI immobilized at a density as low as 1.8 ng/mm2 could be detected using surface plasmon resonance.     

Amplified human MYC oncogenes localized to replicating submicroscopic circular DNA molecules.

Amplification of genes can sometimes be detected by molecular hybridization but not by cytogenetic methods, suggesting that in some cases the units of amplification may be too small to be detected by light microscopy. The experiments reported here investigate whether submicroscopic amplification units are present in early passages of the human tumor cell lines HL-60 and COLO 320. The results show that such cells do contain submicroscopic, extrachromosomal, supercoiled circular molecules harboring MYC genes. The molecules in HL-60 are approximately 250 kilobase pairs (kbp), while those in COLO 320 are 120-160 kbp. The extrachromosomal molecules in HL-60 are shown to replicate semiconservatively and approximately once in one cell cycle. We propose that these submicroscopic elements are precursors of double-minute chromosomes, the usual extrachromosomal manifestation of gene amplification, since both are structurally similar and replicate autonomously.