Case Report: Imaging immune checkpoint inhibitor-induced yin-yang effects in the brain.

Background: Treatment with immune checkpoint inhibitors (ICI) can induce durable responses in cancer patients, but it is commonly associated with serious immune-related side effects. Both effects are suggested to be mediated by CD8+ T-cell infiltration. Whole body CD8+ T-cell distribution can be visualized by PET imaging of a 89Zr-labeled anti-humanCD8a minibody, currently investigated in a phase 2b trial. Main body: An adult patient diagnosed with metastatic melanoma developed ICI-related hypophysitis after two courses of combined immunotherapy (ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) at 3 weeks interval). On a [89Zr]Zr-crefmirlimab berdoxam PET/CT scan, made 8 days before clinical symptoms occurred, increased CD8+ T-cell infiltration in the pituitary gland was detected. Simultaneously, tracer uptake in a cerebral metastasis was increased, indicating ICI-induced tumor infiltration by CD8+ T-cells. Conclusions: The observations in this case report underscore the role of CD8+ T-cell in non-tumor tissues in ICI-related toxicity. In addition, it illustrates a potential role for molecular imaging by PET/CT for investigation and monitoring of ICI-induced effects.

Influence of extended dwell time during pre- and main compression on the properties of ibuprofen tablets.

The low melting point, poor flow, physico-mechanical properties (particle size distribution, shape, particle surface roughness) and deformation mechanism of ibuprofen in combination with its high dose in tablets all contribute to the problems observed during the compaction of ibuprofen-based formulations. Since ibuprofen is plastically and elastically deforming, the rate of compaction plays an important role in both the final tablet properties and the risk of capping, laminating and sticking to the punches. While the compaction rate in most tableting machines is only determined by the tableting speed, the high speed rotary tableting machine used in this research project (MODUL™ P, GEA Process Engineering, Halle, Belgium) can adjust and control the dwell time independently from the tableting speed, using an air compensator which allows displacement of the upper (pre-) compression roller. The effect of this machine design on process parameters and tablet properties was investigated. Granules containing 80% ibuprofen were compressed into tablets at 250, 500 and 1000 tablets per minute via double compression (pre- and main compression) with or without extended dwell time. Prior to tableting, granule properties were determined. Process parameters and tablet properties were analyzed using Multivariate Data Analysis. Principal Component Analysis provided an overview of the main phenomena determining the tableting process and Partial Least Squares Analysis unveiled the main variables contributing to the observed differences in the tablet properties.

Comparison of solid-phase cytometry and the plate count method for the evaluation of the survival of bacteria in pharmaceutical oils.

AIM: To compare the survival of four bacterial strains (Escherichia coli, Proteus mirabilis, Staphylococcus aureus, Pseudomonas aeruginosa) in pharmaceutical oils, including jojoba oil/tea tree oil, carbol oil, jojoba oil and sesame oil. METHODS AND RESULTS: Oils were spiked with the test bacteria in a concentration of 10(4) CFU ml(-1). Bacteria were extracted from oils with phosphate-buffered saline containing 0.5% Tween 20. Aliquots of the pooled water layers were analysed by solid-phase cytometry and plate counting. Plate counts dropped to zero for all test strains exposed for 24 h to three of the four oils. In contrast, significant numbers of viable cells were still detected by SPC, except in the jojoba oil/tea tree oil mixture and partly in sesame oil. CONCLUSIONS: Exposure of bacteria for 24 h to the two oils containing an antimicrobial led to a loss of their culturability but not necessarily of their viability. The antibacterial activity of the jojoba oil/tea tree oil mixture supersedes that of carbol oil. SIGNIFICANCE AND IMPACT OF THE STUDY: These in vitro data suggest that the jojoba oil/tea tree oil mixture more than carbol oil inhibits bacterial proliferation when used for intermittent self-catherization.

Influence of supplemental magnesium, tryptophan, vitamin C, vitamin E, and herbs on stress responses and pork quality.

This study investigated the effects of supplemental Mg, Trp, vitamin C, vitamin E, and herbs on stress responses, skin lesions, and meat quality of slaughter pigs (106.0 +/- 8.6 kg of BW). These 5 supplements were tested in 4 similar experiments. In Exp. 1, 2 treatments were tested: 1) control treatment without supplementation, and 2) supplementation of an herbal product (2.5 g/L of drinking water for 2 d). Eighty-eight pigs per treatment were involved, of which 40 were selected for meat quality measurements (over 4 replicates). The experimental design of Exp. 2 and 3 was the same as Exp. 1, except that in Exp. 2 Mg (3 g/L of drinking water for 2 d) was supplemented and in Exp. 3 Trp (6 g/kg of feed, as-fed basis) was supplemented. In Exp. 4, 3 treatments were tested: 1) control treatment without supplementation, 2) supplementation of vitamin C (300 mg/kg of feed for 21 d, as-fed basis), and 3) supplementation of vitamin E (150 mg/kg of feed for 21 d, as-fed basis). In Exp. 4, 66 pigs per treatment were used, of which 42 were evaluated for meat quality (over 6 replicates). Pigs supplemented with vitamin E ate less than control (P = 0.03) or vitamin C-supplemented pigs (P = 0.03). Pigs were transported to a commercial slaughterhouse and were slaughtered after a lairage period. Blood sampling at slaughter revealed no differences between the control and supplemented pigs in plasma cortisol, glucose, lactate, or creatine kinase concentrations. Pigs provided with Mg (P = 0.002) or Trp (P = 0.04) had lower plasma NEFA concentrations than control pigs, and pigs supplemented with vitamin C had greater concentrations than the control (P = 0.03) or vitamin E-supplemented pigs (P = 0.01). Supplementation of the herbal product increased the frequency of pigs with shoulder (P = 0.05) and loin lesions (P = 0.03), whereas Mg lowered the incidence of loin lesions (P = 0.01). Measurements of pH and temperature in the LM and biceps femoris 45 min postmortem revealed no differences among treatments, and no influence of treatments on LM pH, electrical conductivity, and water holding capacity was observed 48 h postmortem. Compared with the control loins, loins of pigs supplemented with vitamin C (Japanese color scale, L*, and a* value; P < 0.05) or vitamin E (Japanese color scale and a* value; P < 0.03) were redder and less pale, and the loin of vitamin E-supplemented pigs was more yellow (b* value; P = 0.04). Generally, Mg could lower loin damage, whereas vitamin C and vitamin E supplementation resulted in a color improvement of the loin.

Influence of supplemental magnesium, tryptophan, vitamin C, and vitamin E on stress responses of pigs to vibration.

Our objectives were to investigate and compare the effects of supplemental Mg, Trp, vitamin E (vit E), and vitamin C (vit C) on stress responses of pigs undergoing transport simulation. In this study, 126 pigs (25.1 +/- 4.4 kg BW) were allocated to one of the six following treatments: 1) negative control (no supplementation); 2) positive control (i.m. injection with 0.5 mg of carazolol/20 kg BW 12 h before vibration, beta-blocker); 3) Trp (additional amount of 6 g/kg of feed for 5 d, as-fed basis); 4) Mg (3 g/L drinking water for 2 d); 5) vit E (additional amount of 150 mg/kg of feed for 21 d, as-fed basis); 6) or vit C (additional amount of 300 mg/kg of feed for 21 d, as-fed basis). Pigs were treated in groups of three, and each treatment was replicated seven times. Feed and water intake were not different among treatments. Heart rate variables (mean, peak, and minimum heart rate, ventricular ectopic beats, and ST elevation of Channels A and B) and heart rate variability were registered from the night before vibration. Pigs were subjected to vibration in a transport simulator (8 Hz, 3 m/s) for 2 h and allowed to recover for 2 h. Generally, the positive control pigs had the lowest heart rate values (mean, peak, minimum heart rate, ST elevation of Channel A; P < 0.05), whereas Mg and Trp decreased ventricular ectopic beats and ST elevation of Channel B, respectively. The effect of vit C and E as vagal stimulators was clearly visible, whereas carazolol and Mg clearly blocked the sympathetic pathways of the autonomic nervous system. During vibration, the negative control pigs lay the least, and Mg pigs the most (P < 0.05). Salivary cortisol concentrations (taken before and after vibration and after recovery) showed that vit E pigs produced the least cortisol during stress periods. Intermediary metabolites (glucose, lactate, creatine kinase, and NEFA) were analyzed in plasma from blood taken before and after vibration. At the two sampling points, the vit E and Mg pigs had the lowest NEFA concentrations (P < 0.05), and the vit E pigs also had the lowest lactate concentrations before vibration. Urine samples were collected before and after vibration to determine catecholamine concentrations; only negative control pigs had an increase (P = 0.04) in epinephrine concentration, despite large individual variation. In general, these results indicate that the supplementation of Trp, Mg, vit E, or vit C improved coping ability of pigs during vibration comparison with the negative control treatment. A muscular injection of carazolol influenced only the heart rate variables.

Effect of supplemental tryptophan, vitamin E, and a herbal product on responses by pigs to vibration.

Economic losses related to increased stress during the transport of pigs are well documented. The effects of supplementing of tryptophan (Trp), vitamin E, or a herbal product via feed or drinking water were investigated in terms of effects on stress response in pigs during transport simulation. The study consisted of three analogous experiments. For the testing in each experiment, the pigs (23.5+/-3.2 kg) were allocated to one of two treatments, with and without supplementation of a product. The applied doses were Trp (5 g/L drinking water for 3 d), vitamin E (additional amount of 300 mg/kg feed for 21 d, as-fed basis), and Sedafit (2.5 g/L drinking water for 2 d). Sedafit is a commercial herbal product containing Valeriana officinalis L. and Passiflora incarnata L. as active components. In each experiment of the study, at least 47 pigs were involved, which were treated in groups of 3. The day before transport simulation, a Holter device was attached to the pigs to produce an electrocardiogram during the night (rest values), as well as during vibration in the transport simulator (1.2 Hz, 1 m/s2), where the behavior of the pigs (standing-sitting-lying) was also observed. Samples of saliva (taken before, during, and after [3x] vibration) and blood (taken before and after vibration) were analyzed for cortisol and intermediate metabolites (glucose, lactate, creatine kinase, and nonesterified fatty acids), respectively. Pigs supplemented with Trp tended to spend more time lying down during the second hour of vibration (P < 0.05). Vitamin E decreased the peak heart rate (P < 0.05), ventricular ectopic beats (P < 0.01), and ST elevation (P < 0.10). The supplementation of Sedafit resulted in smaller increases of the investigated heart variables (minimum heart rate, P < 0.05; ventricular ectopic beats, P < 0.05; ST elevation, P < 0.01) during and after stress evocation compared with the control group. None of the tested products influenced the intermediate metabolites; one possible explanation for this finding may be that peak values were reached before the time of bleeding. In conclusion, Trp had a positive behavioral effect in this experiment, and vitamin E and Sedafit mediated an increase in some heart variables, suggesting sedative and antianxiety effects.

[The teenager who finds it difficult to wake up in the morning: aberrant behavior, misperception or an underlying sleep disorder?]. / 's Morgens moeilijk wakker worden bij tieners: gedragsprobleem, misperceptie of slaapstoornis?

Three teenagers, two girls aged 14 years and one boy aged 10 years, had had difficulty with getting to sleep in the evening and waking up in the morning from a very early age. These difficulties led to underperformance at school and/or tension in the household. The anamneses and a sleep study led to the following conclusions: 'delayed sleep phase syndrome', 'sleep state misperception' and 'aberrant interaction between the child and its parents'. Treatment with phototherapy and regulation of the bedtimes, information and regulation of the bedtimes, and pedagogic advice, respectively, was successful within a few months. Teenagers often complain about problems with sleeping, in particular about late onset of sleep and difficulties with awakening. These problems are self-limiting in most cases, but can have a disastrous influence on social life and education.

Evaluation of bioassays versus contaminant concentrations in explaining the macroinvertebrate community structure in the Rhine-Meuse delta, The Netherlands.

It is often assumed that bioassays are better descriptors of sediment toxicity than toxicant concentrations and that ecological factors are more important than toxicants in structuring macroinvertebrate communities. In the period 1992 to 1995, data were collected in the enclosed Rhine-Meuse delta, The Netherlands, on macroinvertebrates, sediment toxicity, sediment contaminant concentrations, and ecological factors. The effect of various groups of pollutants (polycyclic aromatic hydrocarbons, trace metals, oil, polychlorinated biphenyls) and of ecological variables on the structure of the macroinvertebrate community were quantified. Ecological factors explained 17.3% of the macroinvertebrate variation, while contaminants explained 13.8%. Another 14.7% was explained by the covariation between ecological variables and contaminants. Polycyclic aromatic hydrocarbons explained a larger part of the variation than trace metals. The contributions of oil and polychlorinated biphenyls were small but significant. Elevated contaminant concentrations were significantly associated with differences in the macroinvertebrate food web structure. The response in bioassays (Vibrio fischeri, Daphnia magna, Chironomus riparius) was susceptible to certain contaminants but also to certain ecological factors. There was a weak correlation between in situ species composition and bioassays; 1.9% of in situ macroinvertebrate variation was explained by the bioassay responses. This seems to contradict the validity of using bioassays for a system-oriented risk assessment. Possible reasons for this discrepancy might be the manipulations of the sediment before the test and a higher pollutant tolerance of the in situ macroinvertebrates. Thus, macroinvertebrate field surveys and laboratory bioassays yield different types of information on ecotoxicological effects, and both are recommended in sediment risk assessment procedures.

The possible influence of the components of the soil and the lithosphere on the development and growth of neoplasms.

The author reviews the background of the soil-cancer relationship. The study then goes into geocarcinogenic diseases in relation to soil composition, looking first at general factors: soil concentrations of selenium, caesium-rubidium-potassium, trace elements; natural radioactivity risks; cancer risks in connection with recycled waste water. In its final part, the study examines geocarcinogenic diseases linked with soil composition covering gastric cancer, cancer of the esophagus, urinary, breast, and bronchial cancer, pleural mesotheliomae and bone cancer.