Antibiotic residues and antibiotic-resistant bacteria in pig slurry used to fertilize agricultural fields

Pig manure may contain antibiotic residues, antibiotic-resistant bacteria or pathogens, which may reach the environment upon fertilization. During this study, 69 antibiotic residues belonging to 12 classes were quantified in 89 pig slurry samples. These samples were also studied for the presence of Salmonella and for E. coli resistant to meropenem, colistin, ciprofloxacin, or cefotaxim. The obtained isolates were further tested for antibacterial susceptibility. No antibiotic residues were detected in four samples, whereas in the other samples, up to 12 antibiotics were found. The most frequently detected antibiotic residues were doxycycline, sulfadiazine, and lincomycin. Doxycycline was found in the highest concentration with a mean of 1476 mu g/kg manure (range: 18-13632 mu g/kg). Tylosin and oxytetracycline were found with mean concentrations of 784 mu g/kg (range: 17-5599 mu g/kg) and 482 mu g/kg (range: 11-3865 mu g/kg), respectively. Lincomycin, had a mean concentration of 177 mu g/kg manure (range: 9-3154 mu g/kg). All other 18 antibiotic residues were found with mean concentrations of less than 100 mu g/kg manure. Fifty-one slurry samples harbored Salmonella; 35% of the Salmonella isolates were sensitive to a panel of 14 antibiotics, whereas the other 65% were resistant up to five antibiotics. For E. coli, 52 manure samples contained E. coli isolates which were resistant to ciprofloxacin and 22 resistant to cefotaxime. All ciprofloxacin and cefotaxime-resistant isolates were multi-resistant, with resistance up to nine and eight antibiotics, respectively. This research indicates that pig slurry used for fertilization often contains antibiotic residues and antibiotic-resistant bacteria, including pathogens

Low Caspofungin Exposure in Patients in Intensive Care Units

In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in Intensive Care Unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands, from November 2013 to October 2015. Patients received standard caspofungin treatment and the exposure was determined on day 3 of treatment. An area under the concentration-time curve over 24 hours (AUC0-24h) of 98 mg*h/L was considered adequate exposure. In case of low exposure (i.e. <79 mg*h/L; ≥20% lower AUC0-24h), the caspofungin dose was increased and the exposure re-evaluated. Twenty patients were included in the study, of which 5 had a positive blood culture. The median caspofungin AUC0-24h at day 3 was 78 mg*h/L (interquartile range (IQR), 69 - 97 mg*h/L). A low AUC0-24h (<79 mg*h/L) was seen in 10 patients. The AUC0-24h was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC0-24h with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg*h/L (IQR, 103.2 - 143.5 mg*h/L). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with healthy volunteers and other (non-)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution

The expression of the sodium/iodide symporter is up-regulated in the thyroid of fetuses of iodine-deficient rats

6 pages, 6 figures.-- Part of the study was presented, in preliminary form, at the 25th Annual Meeting of the European Thyroid Association, Athens, Greece, May 31–June 3, 1998, and the American Thyroid Association, Colorado Springs, Colorado, September 16–19, 1998.-- et al.Is the fetal thyroid already capable to increase its iodide uptake in response to iodine deficiency? To answer this question, we analyzed the expression of the Na(+)/I(-) symporter and several other genes in the thyroid of rat fetuses at 21 d of gestation from control mothers presenting a mild or more severe iodine deficiency. Female rats were placed on a low iodine diet, not supplemented, or supplemented with iodide or perchlorate for 3 months. The maternal and fetal thyroidal iodide uptake was measured 24 h after injection of 10 microCi Na (125)I into the dams. The absolute iodide uptake of the maternal thyroid was unchanged in a low iodine diet, not supplemented, compared with one supplemented with iodide. In contrast, the fetal thyroid absolute iodide uptake of a low iodine diet, not supplemented, and one supplemented with perchlorate was decreased by 70% and 95% compared with that supplemented with iodide. Na(+)/I(-) symporter mRNA was detected in the fetal thyroid of supplemented with iodide and increased about 2- and 4- fold in the thyroid of fetuses from a low iodine diet, not supplemented, and one supplemented with perchlorate, respectively. Na(+)/I(-) symporter expression was induced in the fetal side of the placenta in both a low iodine diet, not supplemented, and one supplemented with perchlorate; in contrast, Na(+)/I(-) symporter mRNA was never detected in the maternal side of the placenta. Fetal thyroid thyroglobulin and type I deiodinase mRNA contents were only significantly increased with a diet supplemented with perchlorate. Glucose transporter 4 mRNA was decreased in the fetal thyroid of both a low iodine diet, not supplemented, and one supplemented with perchlorate compared with one supplemented with iodide. In conclusion, although the up-regulation of Na(+)/I(-) symporter expression in fetal thyroid and placenta in the low iodine diet, not supplemented group did not lead to restoration of a normal absolute iodide uptake, our data show that all adaptive and/or defending mechanisms against iodine deficiency are already present in the fetus.J.P.S. is the recipient of Training and Mobility of Researchers Grant (Marie Curie) ERBFMBICT 960663.Peer reviewe

Synthetic flavonoids cross the placenta in the rat and are found in fetal brain

5 pages, 1 figure, 1 table.-- Part of this work was presented at the XIth meeting of the International Thyroid Congress, Toronto, Canada, September 10–15, 1995.-- et al.The synthetic flavonoid EMD-49209 is a potent inhibitor of the in vivo and in vitro binding of thyroxine (T4) to transthyretin (TTR). We studied the distribution of 125I-labeled EMD-49209 in maternal tissues, intestinal contents, and fetal tissues in rats that were 20 days pregnant (from 1 to 24 h after intravenous injection). The percent dose of EMD decreased quickly with time. In maternal brain no radioactive flavonoid could be detected. EMD was excreted very rapidly from the intestines. In the fetal compartment the percent dose of EMD increased with time; after 24 h it contained 17% of the EMD. The flavonoid was found in all fetal tissues investigated and also in the fetal brain. Because TTR concentrations are high in the fetal rat, especially in the brain, the transfer of flavonoid to the fetal brain might be linked to TTR expression. The presence of flavonoid in the fetal brain raises the possibility of an essential interference of flavonoids with the availability of T4 in the fetal compartment.This work was supported by a grant from the European Community Science Program (ERB SCI*CT-92–0831).Peer reviewe

Different tissue distribution, elimination, and kinetics of thyroxine and its conformational analog, the synthetic flavonoid EMD 49209 in the rat

6 pages, 2 figures, 3 tables.-- et al.The synthetic flavonoids EMD 23188 and EMD 49209, developed as T4 analogs, displace T4 from transthyretin, and in vitro they inhibit 5'-deiodinase activity. In vivo EMD 21388 causes tissue-specific changes in thyroid hormone metabolism. In tissues that are dependent on T3 locally produced from T4, total T3 was diminished. It was not known whether it was the presence of EMD interfering with 5'-deiodinase type II in tissues or the decreased T4 (substrate) availability that caused the lowered T3. To study whether the flavonoids enter tissues and, if this were the case, whether they enter tissues similarly, [125I]EMD 49209 together with [131I]T4 were injected into female rats and rats pretreated with EMD 21388. Tissues were extracted and submitted to HPLC. [125I]EMD 49209 disappeared quickly from plasma and enters peripheral tissues; peak values were reached after 0.25-0.5 h. Then [125I]EMD 49209 appeared in the intestines (after 6 h 40% of the dose). Tissue uptake of [131I]T4 was very rapid. EMD 21388 pretreatment caused an increase in the excretion of [125I]EMD 49209 into the intestines (40% after 0.25 h). The uptake of [131I]T4 increased, but not high enough to ensure normal tissue T4 concentrations. In the 5'-deiodinase type II-expressing tissues, no [125I]EMD 49209 could be detected. We conclude that the decrease in T3 locally produced from T4 is caused by the shortage of T4 as substrate and not to a direct effect of EMD on the activity of 5'-deiodinases I and II.This work was supported by a grant from the European Community Science Program (ERB SCI*CT-92-0831).Peer reviewe

Production of toxic pavettamine and pavettamine conjugates in the gousiekte-causing **Fadogia homblei** plant and its relation to the bacterial endosymbiont

Plant poisoning of livestock is responsible for considerable economic losses in southern Africa. Six plant species of the Rubiaceae family are known to cause gousiekte, a cardiac syndrome of ruminants induced by ingestion of the toxic compound pavettamine. Progress in understanding the aetiology of this disease is largely hampered by the variable toxicity of the plants and the absence of a quantification method for pavettamine. The pavettamine concentration in leaf samples of Fadogia homblei, a known gousiekte causing plant, was analyzed by massspectrometry. In the most apical leaf pair, the highest concentration of pavettamine was detected. Distal leaves contained progressively less pavettamine. Besides a significant amount of free pavettamine, most pavettamine was found to occur in a conjugated form. To which molecules the pavettamine is conjugated remains unknown as is the function of conjugated pavettamine in the development of gousiekte. All know gousiekte-causing plants contain symbiotic bacteria in their leaves; it was hypothesized that these bacteria might be involved in the production of pavettamine. However, analysis of in vitro cultures of the Fadogia homblei endosymbiont revealed no production of pavettamine. Pavettamine is therefore not produced by the bacteria alone. It is either the product of the interaction with the plant or solely produced by the host.This research was supported financially by the Fund for Scientific Research, Flanders (F.W.O., G.0343.09N). D.V.E. holds a Ph.D. research grant from the Fund for Scientific Research, Flanders (F.W.O., no. 1.1.722.10.N.00).http://www.journals.elsevier.com/phytochemistry/hb201

Iodothyronine deiodinase activities in fetal rat tissues at several levels of iodine deficiency: a role for the skin in 3,5,3'-triiodothyronine economy?

6 pages, 8 figures, 1 table.-- Part of the study was presented, in preliminary form, at the 24th Annual Meeting of The European Thyroid Association, Munich, August 31-September 3, 1997.Iodothyronine deiodinases, types I, II, and III (D1, D2, and D3) activities were measured in tissues of fetal rats, at 18 and 21 days of gestation, at several levels of iodine deficiency (ID): mild ID diet (MID) and moderately severe ID, MID + 0.005% perchlorate (MID+P). D2 was present in fetal skin, increased between days 18 and 21, and also in MID and MID+P. In skin, D3 increased during ID at day 18, whereas there was a decrease at day 21. Skin T4 decreased in MID and MID+P, showing an inverse relationship with D2. Skin T3 decreased at day 18 in MID and MID+P but increased at day 21, probably because of the increased D2 and decreased D3, maintaining T3 concentrations. No effect of ID was observed on hepatic D1. D2 increased in brain and brown adipose tissue at day 21 in MID+P. No changes were found in maternal placental D2 and D3, but D2 and D3 increased in the fetal placenta at day 18 in MID+P. A higher level of D2 is present in fetal skin than in the brain. As the activity is increased, in even mild ID (and already at 18 days) it can be concluded that skin D2 is likely to be of considerable physiological importance, at least for fetal thyroid hormone economy, by contributing to the intracellular T3 content of the skin and, possibly, to the plasma T3.This work was supported by Training and Mobility of Researchers Grant ERBFMBICT 960663 and Research Grant PB 95–0097 from Promoción General del Conocimiento.Peer reviewe

Distribution of the cardiotoxin pavettamine in the coffee family (Rubiaceae) and its significance for gousiekte, a fatal poisoning of ruminants

Gousiekte, a cardiac syndrome of ruminants in southern Africa, is caused by the ingestion of plants containing the polyamine pavettamine. All the six known gousiekte-causing plants are members of the Rubiaceae or coffee family and house endosymbiotic Burkholderia bacteria in their leaves. It was therefore hypothesized that these bacteria could be involved in the production of the toxin. The pavettamine level in the leaves of 82 taxa from 14 genera was determined. Included in the analyses were various nodulated and non-nodulated members of the Rubiaceae. This led to the discovery of other pavettamine producing Rubiaceae, namely Psychotria kirkii and Psychotria viridiflora. Our analysis showed that many plant species containing bacterial nodules in their leaves do not produce pavettamine. It is consequently unlikely that the endosymbiont alone can be accredited for the synthesis of the toxin. Until now the inconsistent toxicity of the gousiekte-causing plants have hindered studies that aimed at a better understanding of the disease. In vitro dedifferentiated plant cell cultures are a useful tool for the study of molecular processes. Plant callus cultures were obtained from pavettamine-positive species. Mass spectrometric analysis shows that these calli do not produce pavettamine but can produce common plant polyamines.This research was supported financially by the Fund for Scientific Research, Flanders (FWO, G.0343.09N). D.V.E. holds a PhD research grant from the Fund for Scientific Research, Flanders (FWO, no. 1.1.722.10.N.00). B.V. holds a PhD research grant from the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT, no. 91158).http://www.elsevier.com/locate/plaphyhb201