Safety of Inulin and Sinistrin: Combining Several Sources for Pharmacovigilance Purposes.

Introduction: Inulin and its analog sinistrin are fructose polymers used in the food and pharmaceutical industries. In 2018, The French National Agency for the Safety of Medicines and Health Products (ANSM) decided to withdraw products containing sinistrin and inulin due to several reports of serious hypersensitivity reactions, including a fatal outcome. Objective: To assess the safety of inulin and sinistrin use in France. Methods: We searched multiple sources to identify adverse reactions (ARs) to inulin or sinistrin: first, classical pharmacovigilance databases including the French Pharmacovigilance (FPVD) and the WHO Database (VigiBase); second, data from a clinical trial, MultiGFR; third, data regarding current use in an hospital. All potential ARs to inulin or sinistrin were analyzed with a focus on hypersensitivity reactions and relationships to batches of sinistrin. Results: From 1991 to 2018, 134 ARs to inulin or sinistrin were registered in the FPVD or VigiBase. Sixty-three cases (47%) were classified as serious, and 129 cases (96%) were hypersensitivity reactions. We found an association between a batch of sinistrin and the occurrence of hypersensitivity reactions. During the MultiGFR clinical trial, 7 patients (7/163 participants) had an Adverse reaction; of these, 4 were hypersensitivity reactions including one case of grade 4 anaphylactic shock. In the hospital, no ARs were observed. In the literature, ARs to inulin and sinistrin are very rarely reported and mostly benign. Conclusion: Most ARs to inulin and sinistrin are hypersensitivity reactions that appear to be associated with sinistrin batches.

The Role of Sulfur Dioxide in Stratospheric Aerosol Formation Evaluated Using In-Situ Measurements in the Tropical Lower Stratosphere.

Stratospheric aerosols (SAs) are a variable component of the Earth's albedo that may be intentionally enhanced in the future to offset greenhouse gases (geoengineering). The role of tropospheric-sourced sulfur dioxide (SO2) in maintaining background SAs has been debated for decades without in-situ measurements of SO2 at the tropical tropopause to inform this issue. Here we clarify the role of SO2 in maintaining SAs by using new in-situ SO2 measurements to evaluate climate models and satellite retrievals. We then use the observed tropical tropopause SO2 mixing ratios to estimate the global flux of SO2 across the tropical tropopause. These analyses show that the tropopause background SO2 is about 5 times smaller than reported by the average satellite observations that have been used recently to test atmospheric models. This shifts the view of SO2 as a dominant source of SAs to a near-negligible one, possibly revealing a significant gap in the SA budget.

Decrease in the incidence of culture-positive meningitis and cerebral tuberculomas in France from 1990 to 2007.

We evaluated the incidence rate of culture-positive central nervous system tuberculosis (CNS TB) in France in 2007 and its time trend between 1990 and 2007. We used a capture-recapture analysis by using data recorded in 2007 by the mandatory notification system and the national network of the National Reference Centre (NRC). The 2007 sensitivity of the NRC was 79·4%. The previous sensitivity for 2000 (75·6%) and that for 2007 yielded a pooled estimate of 77·4% (95% confidence interval 64·8-88·0), which was used to extrapolate the number of culture-positive CNS TB cases from those reported in four surveys (1990, 1995, 2000, 2007). The extrapolated number of culture-positive CNS TB cases fell from 90 to 35 between 1990 and 2007, and the extrapolated incidence rates fell from 1·6 to 0·55 cases/million (P < 0·001). This favourable trend should be closely monitored following the change of the BCG vaccination policy in 2007.

Imatinib resistance associated with BCR-ABL upregulation is dependent on HIF-1alpha-induced metabolic reprograming.

As chronic myeloid leukemia (CML) progresses from the chronic phase to blast crisis, the levels of BCR-ABL increase. In addition, blast-transformed leukemic cells display enhanced resistance to imatinib in the absence of BCR-ABL-resistance mutations. In this study, we show that when BCR-ABL-transformed cell lines were selected for imatinib resistance in vitro, the cells that grew out displayed a higher BCR-ABL expression comparable to the increase seen in accelerated forms of the disease. This enhanced expression of BCR-ABL was associated with an increased rate of glycolysis but with a decreased rate of proliferation. The higher level of BCR-ABL expression in the selected cells correlated with a nonhypoxic induction of hypoxia-inducible factor-1alpha (HIF-1alpha) that was required for cells to tolerate enhanced BCR-ABL signaling. HIF-1alpha induction resulted in an enhanced rate of glycolysis but with reduced glucose flux through both the tricarboxylic acid cycle and the oxidative arm of the pentose phosphate pathway (PPP). The reduction in oxidative PPP-mediated ribose synthesis was compensated by the HIF-1alpha-dependent activation of the nonoxidative PPP enzyme, transketolase, in imatinib-resistant CML cells. In both primary cultures of cells from patients exhibiting blast transformation and in vivo xenograft tumors, use of oxythiamine, which can inhibit both the pyruvate dehydrogenase complex and transketolase, resulted in enhanced imatinib sensitivity of tumor cells. Together, these results suggest that oxythiamine can enhance imatinib efficacy in patients who present an accelerated form of the disease.

Comparison of the morphological and electrotonic properties of Renshaw cells, Ia inhibitory interneurons, and motoneurons in the cat.

The morphological and electrotonic properties of 4 motoneurons, 8 Ia inhibitory interneurons, and 4 Renshaw cells were compared. The morphological analysis, based on 3-D reconstructions of the cells, revealed that dendrites of motoneurons are longer and more extensively branched. Renshaw cells have dendrites that are shorter and simpler in structure. Dendrites of Ia inhibitory interneurons could be as long as those of motoneurons but the branching structure resembled that of Renshaw cells. Compartmental models were used to determine the electrotonic properties of the paths from each dendritic terminal to the soma. The attenuations of steady-state voltage changes in motoneurons were 3 and 7 times larger than in Ia inhibitory interneurons and Renshaw cells, respectively. The same relative order was observed for current attenuation and electrotonic length. The dendritic input resistances in Renshaw cells were 2 and 4 times larger than in Ia inhibitory interneurons and motoneurons, respectively. The difference in these electrotonic properties increased during higher synaptic activity as modeled by a decrease of Rm. The peak amplitudes of voltage transients at sites of brief, synaptic-like changes in conductance were highly dependent on cell class and were largest in Renshaw cells and smallest in motoneurons. In combination with class-specific differences in the attenuation of transient voltage signals, this led to large differences in the peak amplitudes of somatic voltage transients. Differences in the rise times and half-widths of the voltage transients were observed as well. Thus, based on passive properties, each cell class has a unique set of input/output properties.

Effects of premilking stimulation on complete lactation milk yield and milking performance.

Effects of premilking preparation on complete lactation performance were measured with two groups of multiparous Holstein cows; 1) 17 cows received full stimulation, a 60-s routine, and 2) 16 cows received minimum stimulation, a 15-s routine, before machine attachment. Actual unadjusted average lactation milk yield for cows receiving full stimulation was 5.4% less than that for cows receiving minimum stimulation. When postpeak persistencies were compared by linear regression of either 1) daily milk weights or 2) 3.5% FCM from DHI records of milk yield and milk fat percent and fitted to lactation curves using an incomplete gamma function, cows receiving full stimulation produced 1) 2.8 or 2) 2.5% more milk per lactation than did cows receiving minimal stimulation. However, none of the treatment differences in mean milk yield was significant statistically. Milk flow rates, strip yields, and machine on-times were measured at 8-wk intervals throughout lactation. Cows receiving full stimulation had significantly higher average milk flow rates and shorter machine on-times starting at wk 32. There were no significant differences in strip yields or percent residual milk between cows receiving full and minimum stimulation.