Komplizierte Malaria

Notfall + Rettungsmedizin -     

Inhalation delivery dramatically improves the efficacy of topotecan for the treatment of local and distant lung cancer

Topotecan is potent anti-cancer drug approved for various malignancies but hematopoietic toxicities undermine its wider application and use of its most effective dose. This study aims to improve these limitations through inhalation-delivery. The pharmacokinetics, efficacy, and toxicity of 2–5 times lower inhalation doses of topotecan dry-powder were compared with the standard intravenous (IV) delivery once/twice-a-week. Human-derived EGFR-mutant (H1975), KRAS-mutant (A549), and EGFR/KRAS wild-type (H358) orthotopic and distant lung tumors were evaluated in murine models. Inhalation of 1 mg/kg topotecan significantly improved the half-life and drug exposure (area under the curve, AUC) compared to 5 mg/kg via IV-delivery. AUCs (h*ng/mL) for inhaled/IV topotecan in plasma, lung, liver, and brain were, 831/888, 60,000/1080, 8380/4000, and 297/15, respectively; while the half-life was also greatly increased in these tissues. The average lung tumor burden of H358-derived tumors was reduced from 15.0 g to 8.4 g (44%) in rats treated once-a-week with 2 mg/kg IV and 1.8 g (88%) with 1 mg/kg inhaled topotecan, corroborating previous findings using A549- and H1975-derived orthotopic lung tumors. Importantly, inhaled topotecan showed superior efficacy in suppressing lung tumors at distant sites. The growth of H1975- and H358-derived subcutaneous xenografts were completely arrested and A549-derived tumors were significantly reduced in mice treated twice-a-week with 1 mg/kg inhaled topotecan compared to a minor (H1975 and H358) or no reduction (A549) with twice-a-week 5 mg/kg IV topotecan.     

Ethnic Differences in Gestational Weight Gain: A Population-Based Cohort Study in Norway

Objectives To explore ethnic differences in gestational weight gain (GWG). Methods This was a population-based cohort study conducted in primary care child health clinics in Groruddalen, Oslo, Norway. Participants were healthy pregnant women (n = 632) categorised to six ethnic groups (43 % were Western European women, the reference group). Body weight was measured at 15 and 28 weeks’ gestation on average. Data on pre-pregnancy weight and total GWG until delivery were self-reported. The main method of analysis was linear regression adjusting for age, weeks’ gestation, pre-pregnancy body mass index, education and severe nausea. Results No ethnic differences were observed in GWG by 15 weeks’ gestation. By 28 weeks’ gestation, Eastern European women had gained 2.71 kg (95 % confidence interval, CI 1.10–4.33) and Middle Eastern women 1.32 kg (95 % CI 0.14–2.50) more weight on average than the Western European women in the fully adjusted model. Among Eastern European women, the total adjusted GWG was 3.47 kg (95 % CI 1.33–5.61) above the reference group. Other ethnic groups (South Asian, East Asian and African) did not differ from the reference group. When including non-smokers (n = 522) only, observed between-group differences increased and Middle Eastern women gained more weight than the reference group by all time points. Conclusions Eastern European and Middle Eastern women had higher GWG on average than Western European women, especially among the non-smokers. Although prevention of excessive GWG is important for all pregnant women, these ethnic groups might need special attention during pregnancy.     

Molecular Motion in Viscous DGEBA with Nanoparticles as Seen by Quasi‐Elastic Neutron Scattering

Pure and filled epoxies are widely used in industry. Nanocomposites especially are affected by interphase regions where properties deviate from bulk. The study of molecular mobility in epoxy monomers is a first step to understanding the molecular dynamics in nanocomposites and their effect on crosslinking in epoxy networks. Here, quasi‐elastic neutron scattering is used to disentangle the molecular motions of monomeric diglycidylether of Bisphenol A (DGEBA) and a suspension of zeolite nanoparticles in DGEBA on a timescale from 2 ps to 5.5 ns. Regarding molecular transport of DGEBA inside the suspension, the particles have no impact on the faster rotational motions. A combination of neutron time‐of‐flight and backscattering spectroscopy reveals a pronounced hindrance of DGEBA molecular dynamics on/in the zeolite particles along with a new type of molecular motion occurring on intermediate timescales. That localized motion is attributed to jump diffusion motions, emanating from interphase effects at the zeolite particles.     

Anti-TNF antibody in Crohn's disease--status of information, comments and recommendations of an international working group.

The chimeric anti-TNF antibody Remicade (Infliximab) has recently been approved for human use by the FDA and is now available on the market. Since there is considerable interest in this kind of treatment among patients with Crohn's disease, an international working group has summarized the presently available information about efficacy, side effects and possible problems of this treatment. Studies show that Remicade is effective in the treatment of active Crohn's disease, maintaining remission and fistulae. The working group does not see Infliximab as a first-line treatment for Crohn's disease. It may be used in active phase recurrent disease, chronic active disease and fistulae if standard treatment was not successful. For the surveillance special attention has to be given to the unknown malignancy rate of Infliximab. Infusion should be performed in an institution, routinely performing intravenous infusions and a two-hour surveillance of the patients should be guaranteed to recognize anaphylactic reactions or acute side effects. There is presently no information indication that the combination with immunosuppressants might increase risks or side effects of this treatment. Due to the limited information available the working group would prefer to use Remicade in studies only and recommends central collection and documentation of all data on efficacy and side effects for the next year.     

The effects of living in an outdoor enclosure on hippocampal plasticity and anxiety‐like behavior in response to nematode infection

The hippocampus of rodents undergoes structural remodeling throughout adulthood, including the addition of new neurons. Adult neurogenesis is sensitive to environmental enrichment and stress. Microglia, the brain's resident immune cells, are involved in adult neurogenesis by engulfing dying new neurons. While previous studies using laboratory environmental enrichment have investigated alterations in brain structure and function, they do not provide an adequate reflection of living in the wild, in which stress and environmental instability are common. Here, we compared mice living in standard laboratory settings to mice living in outdoor enclosures to assess the complex interactions among environment, gut infection, and hippocampal plasticity. We infected mice with parasitic worms and studied their effects on adult neurogenesis, microglia, and functions associated with the hippocampus, including cognition and anxiety regulation. We found an increase in immature neuron numbers of mice living in outdoor enclosures regardless of infection. While outdoor living prevented increases in microglial reactivity induced by infection in both the dorsal and ventral hippocampus, outdoor mice with infection had fewer microglia and microglial processes in the ventral hippocampus. We observed no differences in cognitive performance on the hippocampus‐dependent object location task between infected and uninfected mice living in either setting. However, we found that infection caused an increase in anxiety‐like behavior in the open field test but only in outdoor mice. These findings suggest that living conditions, as well as gut infection, interact to produce complex effects on brain structure and function.