Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.

BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ±â€Š1.68 mg/L (mean ±â€ŠSD) and 106 ±â€Š32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ±â€Š0.03, 0.94 ±â€Š0.46 and 27.1 ±â€Š17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ±â€Š32.1, 1.68 ±â€Š0.72, 22.6 ±â€Š11.0 and 650 ±â€Š426 mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.

First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues.

PURPOSE: Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer's and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues. METHODS: Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h- 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology. RESULTS: Mean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h- 1 (- 4 ± 24%), cerebellum: 0.033 ± 0.009 h- 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h- 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h- 1 (30 ± 38%), lungs: 0.875 ± 0.095 h- 1 (- 3 ± 11%), myocardium: 0.641 ± 0.105 h- 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h- 1 (14 ± 16%), and liver: 0.685 ± 0.072 h- 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women. CONCLUSION: LAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans. TRIAL REGISTRATION: EudraCT 2021-006348-29. Registered 15 December 2021.

Seasonal Effects on the Performance of Finishing Pigs' Carcass and Meat Quality in Indoor Environments.

Most retailers in EU countries pay pig breeders for their animals' lean meat percentage, which does not align fully with measures of pork quality (such as colour). In this study, we investigated the effects of season (summer vs. autumn) on finishing pigs' performance, carcass characteristics, and meat quality parameters in 24 slaughter pigs. Growing performance traits (live weights, average daily weight gain), slaughter values (warm and cold carcass weights, trunk length, fat thickness) and meat quality parameters (pH at 45 min and 24 h postmortem, colour, drip loss, thawing loss, cooking loss, shear force, and meat composition) were recorded. Seasonal differences were more pronounced for the initial age, the number of days in the growing-finishing phase, and the average daily gain. There was also a significant difference in the trunk length between groups, the fat thickness on withers and loin, and also in mean fat thickness. A significant difference was found in the case of pH, total drip loss, and meat colour (L*). The intramuscular fat and collagen content of meat was significantly higher in summer; in contrast, the protein content of meat samples was considerably lower in summer. In conclusion, seasonal effects on finishers' performance, lean meat values, and several meat quality parameters highlight the importance of more profound seasonal settings of climate control to fulfil the progressively changing quantitative and qualitative requests of pork sector participants from farm to fork.

St. John's wort extract with a high hyperforin content does not induce P-glycoprotein activity at the human blood-brain barrier.

St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P-gp activity at the human blood-brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)-targeted P-gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P-gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3-6%) for 12-19 days (1800 mg/day), the activity of P-gp at the BBB was assessed by means of PET imaging with the P-gp substrate [11C]metoclopramide and the activity of peripheral P-gp and CYPs was assessed by administering a low-dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P-gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P-gp-mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P-gp induction at the human BBB despite its ability to induce peripheral P-gp and CYPs. Simultaneous intake of SJW with CNS-targeted P-gp substrate drugs is not expected to lead to P-gp-mediated drug interactions at the BBB.

Reproducibility of LPS-Induced ex vivo Cytokine Response of Healthy Volunteers Using a Whole Blood Assay.

Introduction: Lipopolysaccharide (LPS) stimulation of human whole blood ex vivo has been widely used to investigate human innate immune responses. However, there are uncertainties regarding the reproducibility and reliability of this assay. Methods: In this prospective, single-center study, cytokine responses (interleukin 8, interferon-α, interferon-γ, interleukin 10, interleukin 1-ß, interleukin 6, and tumor necrosis factor-α) to ex vivo whole blood LPS stimulation were assessed in 12 healthy volunteers. Cytokine levels were measured at 0, 2, and 4 h using a multiplex immunoassay (Luminex ®). Stimulation was repeated after six weeks. We examined reproducibility across technical and biological replicates at baseline and between repeated experiments after 6 weeks based on the area under the curve (AUC) of the individual cytokines using Pearson's correlation coefficient and the mean coefficient of variation. Results: The lowest mean coefficients of variation were observed for the technical replicates (5.4 to 9.2%), followed by the biological replicates (8.1 to 24.8%), and the repeated experiments after 6 weeks (17 to 31.2%). Between the baseline and 6-week AUCs, the following Pearson correlation coefficients R were observed: interleukin 10, 0.97; interferon-α, 0.84; interleukin 1-ß, 0.83; interleukin 8, 0.79; interleukin 6, 0.73; interferon-γ, 0.73; and tumor necrosis factor-α, 0.63. Discussion: The level of agreement between the baseline and week-6 cytokine response to ex vivo LPS stimulation was high across the seven cytokines analyzed. While interleukin 10 exhibited the lowest level of variability over time, tumor necrosis factor-α showed the highest variability in repeated experiments, which should be considered in the design and interpretation of future studies.

Effect of Lighting Methods on the Production, Behavior and Meat Quality Parameters of Broiler Chickens.

Many farms have been replacing traditional lighting sources with light-emitting diode (LED) bulbs because of technological modernization. We aimed to investigate the effects of incandescent lighting (IL) and LED lighting on Cobb 500 broiler chickens for six weeks. Production parameters (body weight, feed consumption, feed conversion ratio), calculated slaughter values (yield%, relative breast%, thigh%) and breast meat quality parameters (pH at 45 min and 24 h postmortem, color, drip loss, kitchen equipment losses, shear force, meat composition) were recorded. Non-stop recordings were used to analyze the behavior of the birds during several periods of rearing. The LED group was significantly better in the body weight parameter between week 1 and 5 and the feed conversion ratio between week 2 and 3. The most significant difference in behavior was observed in the middle of the rearing period. The chickens in the LED group spent more time eating, drinking and interacting, and rested less. There was no difference in the meat quality parameters; only shear force was significantly lower in the LED group (1781.9 g/s vs. 2098.8 g/s). According to our results, LED lighting can bring about positive changes in animal production efficiency, behavior and other important characteristics for meat consumers.

Factors Affecting Poultry Producers' Attitudes towards Biosecurity.

Poultry producers' attitudes towards biosecurity practices were assessed by using the ADKAR® (Awareness, Desire, Knowledge, Ability, and Reinforcement) behavioral change model. Conventional poultry producers (n = 155) from different production types including broilers (n = 35), layers (n = 22), breeders (n = 24), turkeys (n = 19), ducks (n = 23), free-range broilers (n = 11), free-range layers (n = 11), and hatcheries (n = 10) from seven European countries were scored for each ADKAR element (1 = total absence to 5 = perfect fulfilment). Each country performed selected interventions (e.g., coaching, participatory meetings, etc.) to improve biosecurity compliance. After the interventions, significant change was observed in three of the four attitude elements. The overall mean scores (x¯ ± SD) obtained during the initial assessment (n = 130) were 4.2 ± 0.6 for Awareness, 4.1 ± 0.7 for Desire, 3.8 ± 0.8 for Knowledge, and 4.0 ± 0.7 for Ability, whereas after intervention, the scores were A = 4.3 ± 0.6, D = 4.2 ± 0.7, K = 4.1 ± 0.7, and Ab = 4.1 ± 0.7. The Reinforcement component was only evaluated after the change and obtained a score of 3.7 ± 0.7 on average. Identifying the elements influencing poultry producers and their behavior related to farm management decisions was useful in guiding our educational interventions to effectively change their behavior.

Doença Cria Giz Ascosphaera apis (Maassen ex Claussen) Olive & Spiltoir em abelhas Apis mellifera L. na Depressão Central do Rio Grande do Sul / Chalk brood disease Ascosphaera apis (Maassen ex Claussen) Olive & Spiltoir in the honey bee Apis mellifera L. in Central Depression of Rio Grande do Sul

A ocorrência da doença apícola "cria giz", em colônias de abelhas Apis mellifera no apiário do Departamento de Zootecnia da Universidade Federal de Santa Maria (UFSM), RS, Brasil, foi constatada em 2004. Foram coletadas amostras de crias de abelhas duras e mumificadas em favos falhados nas colônias com pequena população. Essas amostras foram analisadas no Laboratório de Fitopatologia do Departamento de Defesa Fitossanitária da UFSM, onde se observou a presença de estruturas fúngicas com formação típica do fungo Ascosphaera apis, conhecido como causador da doença "cria giz". Até então não existiam notificações da presença dessa doença na região central do Estado do Rio Grande do Sul, o que pode caracterizar um avanço dessa enfermidade para o interior, a partir de regiões próximas à fronteira com o Uruguai e a Argentina.

The occurrence of chalk brood disease in colonies of the honey bee Apis mellifera located at the apiary of the Department of Zootecnia of the Federal University of Santa Maria (UFSM), Brazil, was evidenced in 2004. Hard and mummified honey bee larvae were collected from failed combs found in poorly populated colonies. These samples were analyzed in the Laboratory of Phytopathology, at the Plant Protection Department (UFSM), where the presence of fungal structures typical of Ascosphaera apis were observed. This fungus is known to cause chalk-brood disease. This is the first record of the presence of this disease in the central region of the State of Rio Grande do Sul, Brazil, characterizing the dissemination of the disease coming from the border with Uruguay and Argentina.

Identificação de locais com potencial de transmissão de dengue em Porto Alegre através de técnicas de geoprocessamento / Identification of places with potential transmission of dengue fever in Porto Alegre using Geographical Information Systems

Ainda pouco se conhece sobre as condições socioambientais que favorecem a permanência do Aedes aegypti em áreas urbanas e sua capacidade de transmissão de dengue. A proposta desse trabalho é localizar os casos da doença e a presença do vetor, e identificar fatores sócio-ambientais que caracterizam esses locais, através de técnicas de geoprocessamento, procurando desenvolver um modelo de prevenção de dengue. O vetor foi encontrado principalmente nas zonas sul e leste da cidade, apresentando uma grande dispersão no município, enquanto a maior parte dos casos está localizada na parte central da cidade. Os setores que apresentaram casos possuem características de alta renda. Por outro lado, nos setores com a presença de vetor são verificadas a predominância de casas e boa infraestrutura de saneamento. A diferença dos padrões de distribuição de casos e vetor assegurou para o ano de 2002 a ausência detransmissão do vírus no município.

Espécies e prevalência das infestações por carrapatos em cães de rua da cidade de Porto Alegre, RS, Brasil / Species and prevalence of ticks infestations on stray dogs in Porto Alegre city, RS, Brazil

O objetivo deste trabalho foi identificar as espécies de carrapatos que parasitam os cães da área urbana de Porto Alegre e conhecer suas prevalências nesta população. Para isso, foram examinados 450 cães de rua de Porto Alegre, colhidos os carrapatos nos animais infestados e estes identificados ao estereomicroscópio por espécie e por estágio. Dentre os animais examinados, 52,44 por cento albergavam carrapatos e destes, 93,22 por cento estavam parasitados por Rhipicephalus sanguineus, 2,97 por cento por Amblyomma aureolatum e 3,81 por cento pelas duas espécies simultaneamente. Do total de carrapatos colhidos, a espécie mais abundante nos animais foi R. sanguineus representando 99,43 por cento desse total; foram encontrados ínstares de todos os estágios parasitários de R. sanguineus e só do estágio adulto de A.aureolatum.

The purpose of this study was to identify and to know the prevalence of ticks recovered from dogs of urban area of Porto Alegre, RS. Four hundred and fifty stray dogs were examined and the ticks found were identified according to the species and parasitic stage. A percentage of 52.44 percent of those dogs were infested with ticks, among these, 93.22 percent were parasitized by Rhipicephalus sanguineus, 2.97 percent by Amblyomma aureolatum and 3.81 percent by both species. R. sanguineus was the more prevalent species among infested animals representing 99.43 percent of the total number of ticks sampled. All parasitic stages of R. sanguineus were present on the stray dogs but only the adult stage of A. aureolatum was found.

Avaliaçäo da imunidade periférica, pela técnica do linfonodo poplieteal após a injeçäo intratímica de antígenos do doador / Evaluation of peripherical immunity trough popliteal linfonode technic after intrathymic injection of donor antigens

A injeçäo intratímica (IT) é uma técnica eficiente nainduçäo de tolerância imunológica em modelos experimentais, nos quais se pode alcançar uma imunossupressäoespecífica sem comprometer o restante do sistema imune. Utilizou-se o modelo da técnica do linfonodo popliteal (TLP) para avaliar a resposta imune periférica aos aloantígenos previamente apresentados ao receptor pela IT. Camundongos entre 6 e 8 semanas, BALB/c (H2)foram usados como recptores. Esplenócitos foram isolados de camundongos DBA/2(H2), C57BL/6(H2) e C3H/He(H2), todos com a mesma faixa etária. A IT foi realizada7 dias do estímulo na pata (10 células). Os linfonodos foram retirados e pesados 7 dias após a TLP. Estímulo com células alogênicas aumentaram 3 vezes o peso do linfonodo quando comparado a células isogênicas (5,7+- 1,5 vs 2,6+-0,8p<0,001). IT com C57BL/6 reduziu as células C3H/He näo reduziram o peso do linfonodo subseqüente ao estímulo com C57BL/6 (8,9 +-3,4vc 5,7 +-1,7, p0,01. especificamente as células C3H/He näo reduziram o peso do linfonodo subseqüente ao estímulo com C57BL/6 (8,9 +-3,4 vs 5,7 +-1,5, p=0,08). A IT capaz de reduzir especificamente a resposta imune periférica aos aloantígenos verificada pela TLP