Unpredicted adverse reaction to omalizumab

Despite promising reports of the use of omalizumab as add-on therapy in patients with systemic mastocytosis and recurrent anaphylaxis during specific venom immunotherapy (VIT), unpredicted adverse effects may lead to therapy failure. We present the case of a patient with systemic mastocytosis and Hymenoptera venom allergy who was administered omalizumab as add-on therapy to improve VIT tolerability after repeated severe adverse reactions despite H1/H2-antihistamine prophylaxis. We describe an unexpected discontinuation of omalizumab following successful initiation of VIT in a patient with systemic mastocytosis, with subsequent lack of tolerability of VIT. An interesting aspect of this case is the correlation of basophil activation test results with both clinical tolerability and VIT intolerance.

No adverse effect of genetically modified antifungal wheat on decomposition dynamics and the soil fauna community - a field study

The cultivation of genetically modified (GM) plants has raised several environmental concerns. One of these concerns regards non-target soil fauna organisms, which play an important role in the decomposition of organic matter and hence are largely exposed to GM plant residues. Soil fauna may be directly affected by transgene products or indirectly by pleiotropic effects such as a modified plant metabolism. Thus, ecosystem services and functioning might be affected negatively. In a litterbag experiment in the field we analysed the decomposition process and the soil fauna community involved. Therefore, we used four experimental GM wheat varieties, two with a race-specific antifungal resistance against powdery mildew (Pm3b) and two with an unspecific antifungal resistance based on the expression of chitinase and glucanase. We compared them with two non-GM isolines and six conventional cereal varieties. To elucidate the mechanisms that cause differences in plant decomposition, structural plant components (i.e. C:N ratio, lignin, cellulose, hemicellulose) were examined and soil properties, temperature and precipitation were monitored. The most frequent taxa extracted from decaying plant material were mites (Cryptostigmata, Gamasina and Uropodina), springtails (Isotomidae), annelids (Enchytraeidae) and Diptera (Cecidomyiidae larvae). Despite a single significant transgenic/month interaction for Cecidomyiidae larvae, which is probably random, we detected no impact of the GM wheat on the soil fauna community. However, soil fauna differences among conventional cereal varieties were more pronounced than between GM and non-GM wheat. While leaf residue decomposition in GM and non-GM wheat was similar, differences among conventional cereals were evident. Furthermore, sampling date and location were found to greatly influence soil fauna community and decomposition processes. The results give no indication of ecologically relevant adverse effects of antifungal GM wheat on the composition and the activity of the soil fauna community.

Effects of epinephrine, norepinephrine, and phenylephrine on microcirculatory blood flow in the gastrointestinal tract in sepsis

OBJECTIVE: The use of vasopressors for treatment of hypotension in sepsis may have adverse effects on microcirculatory blood flow in the gastrointestinal tract. The aim of this study was to measure the effects of three vasopressors, commonly used in clinical practice, on microcirculatory blood flow in multiple abdominal organs in sepsis. DESIGN: Random order, cross-over design. SETTING: University laboratory. SUBJECTS: Eight sedated and mechanically ventilated pigs. INTERVENTIONS: Pigs were exposed to fecal peritonitis-induced septic shock. Mesenteric artery flow was measured using ultrasound transit time flowmetry. Microcirculatory flow was measured in gastric, jejunal, and colon mucosa; jejunal muscularis; and pancreas, liver, and kidney using multiple-channel laser Doppler flowmetry. Each animal received a continuous intravenous infusion of epinephrine, norepinephrine, and phenylephrine in a dose increasing mean arterial pressure by 20%. The animals were allowed to recover for 60 mins after each drug before the next was started. MEASUREMENTS AND MAIN RESULTS: During infusion of epinephrine (0.8 +/- 0.2 mug/kg/hr), mean arterial pressure increased from 66 +/- 5 to 83 +/- 5 mm Hg and cardiac index increased by 43 +/- 9%. Norepinephrine (0.7 +/- 0.3 mug/kg/hr) increased mean arterial pressure from 70 +/- 4 to 87 +/- 5 mm Hg and cardiac index by 41 +/- 8%. Both agents caused a significant reduction in superior mesenteric artery flow (11 +/- 4%, p < .05, and 26 +/- 6%, p < .01, respectively) and in microcirculatory blood flow in the jejunal mucosa (21 +/- 5%, p < .01, and 23 +/- 3%, p < .01, respectively) and in the pancreas (16 +/- 3%, p < .05, and 8 +/- 3%, not significant, respectively). Infusion of phenylephrine (3.1 +/- 1.0 mug/kg/min) increased mean arterial pressure from 69 +/- 5 to 85 +/- 6 mm Hg but had no effects on systemic, regional, or microcirculatory flow except for a 30% increase in jejunal muscularis flow (p < .01). CONCLUSIONS: Administration of the vasopressors phenylephrine, epinephrine, and norepinephrine failed to increase microcirculatory blood flow in most abdominal organs despite increased perfusion pressure and-in the case of epinephrine and norepinephrine-increased systemic blood flow. In fact, norepinephrine and epinephrine appeared to divert blood flow away from the mesenteric circulation and decrease microcirculatory blood flow in the jejunal mucosa and pancreas. Phenylephrine, on the other hand, appeared to increase blood pressure without affecting quantitative blood flow or distribution of blood flow.

Toxic effects of lipid-mediated gene transfer in ventral mesencephalic explant cultures

Adverse effects of cDNA and oligonucleotide delivery methods have not yet been systematically analyzed. We introduce a protocol to monitor toxic effects of two non-viral lipid-based gene delivery protocols using CNS primary tissue. Cell membrane damage was monitored by quantifying cellular uptake of propidium iodide and release of cytosolic lactate dehydrogenase to the culture medium. Using a liposomal transfection reagent, cell membrane damage was already seen 24 hr after transfection. Nestin-positive target cells, which were used as morphological correlate, were severely diminished in some areas of the cultures after liposomal transfection. In contrast, the non-liposomal transfection reagent revealed no signs of toxicity. This approach provides easily accessible information of transfection-associated toxicity and appears suitable for prescreening of transfection reagents.

The consequences of growth hormone deficiency in adulthood, and the effects of growth hormone replacement

The availability of recombinant human growth hormone (GH) has resulted in investigation of the role of GH in adulthood and the effects of GH replacement in the GH-deficient adult. These studies have led to the recognition of a specific syndrome of GH-deficiency, characterized by symptoms, signs and investigative findings. Adults with long-standing growth hormone deficiency are often overweight, have altered body composition, with reduced lean body mass (LBM), increased fat mass (FM), reduced total body water and reduced bone mass. In addition, there is reduced physical and cardiac performance, altered substrate metabolism and an abnormal lipid profile predisposing to the development of cardiovascular disease. Adults with GH deficiency report reduced psychological well-being and quality of life. These changes may contribute to the morbidity and premature mortality observed in hypopituitary adults on conventional replacement therapy. GH treatment restores LBM, reduces FM, increases total body water and increases bone mass. Following GH therapy, increases are recorded in exercise capacity and protein synthesis, and "favourable" alterations occur in plasma lipids. In addition, psychological well-being and quality of life improve with replacement therapy. GH is well tolerated; adverse effects are largely related to fluid retention and respond to dose adjustment. It is likely that GH replacement will become standard therapy for the hypopituitary adult in the near future. The benefits of GH replacement in the GH-deficient adult have been unequivocally demonstrated in studies lasting up to 3 years. The results of longer term studies are awaited to determine whether these benefits are sustained over a lifetime.

Immunotoxic effects of environmental toxicants in fish - how to assess them?

Numerous environmental chemicals, both long-known toxicants such as persistent organic pollutants as well as emerging contaminants such as pharmaceuticals, are known to modulate immune parameters of wildlife species, what can have adverse consequences for the fitness of individuals including their capability to resist pathogen infections. Despite frequent field observations of impaired immunocompetence and increased disease incidence in contaminant-exposed wildlife populations, the potential relevance of immunotoxic effects for the ecological impact of chemicals is rarely considered in ecotoxicological risk assessment. A limiting factor in the assessment of immunotoxic effects might be the complexity of the immune system what makes it difficult (1) to select appropriate exposure and effect parameters out of the many immune parameters which could be measured, and (2) to evaluate the significance of the selected parameters for the overall fitness and immunocompetence of the organism. Here, we present - on the example of teleost fishes - a brief discussion of how to assess chemical impact on the immune system using parameters at different levels of complexity and integration: immune mediators, humoral immune effectors, cellular immune defenses, macroscopical and microscopical responses of lymphoid tissues and organs, and host resistance to pathogens. Importantly, adverse effects of chemicals on immunocompetence may be detectable only after immune system activation, e.g., after pathogen challenge, but not in the resting immune system of non-infected fish. Current limitations to further development and implementation of immunotoxicity assays and parameters in ecotoxicological risk assessment are not primarily due to technological constraints, but are related from insufficient knowledge of (1) possible modes of action in the immune system, (2) the importance of intra- and inter-species immune system variability for the response against chemical stressors, and (3) deficits in conceptual and mechanistic assessment of combination effects of chemicals and pathogens.

Being optimally aroused matters: Effects of a weak stress manipulation on children’s executive functions are moderated by temperament and age

We tested a core assumption of the bidirectional model of executive function (EF) (Blair & Ursache, 2011) indicating that EF is dependent on arousal. From a bottom-up perspective the performance on EF tasks is assumed to be curvilinearly related to arousal, with very high or low levels of arousal impairing EF. N = 107 4-and 6-year-olds’ performance on EF tasks was explored as a function of a weak stress manipulation aiming to raise children’s emotional arousal. EF (Stroop, Flanker, Go/no-go, and Backwards Color Recall) was assessed and stress was induced in half of the children by imposing a mild social evaluative threat. Furthermore, children’s temperament was assessed as a potential moderator. We found that stress effects on children’s EF performance were moderated by age and temperament: 4-year-olds with high Inhibitory Control and high Attentional Focusing were negatively affected by the stressor. However, it is unclear whether these effects were mediated by self-reported arousal. Our findings disconfirmed the hypotheses that adverse effects of the stressor are particularly high in children high on emotional reactivity aspects of temperament and low on self-regulatory aspects of temperament. Further, 6-year-olds did not show any stress effects. Results will be discussed within the framework of the Yerkes-Dodson law and with regard to stress manipulations in children.