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Summary: Organic and inorganic antigens were studied simultaneously in the same cohort of sarcoidosis patients to investigate whether correlations between clinical characteristics and immunological sensitization could reveal new phenotypes. Sensitization to antigens of mycobacteria, Propionibacterium acnes catalase and vimentin was investigated in 201 sarcoidosis and 51 obstructive sleep apnoea patients, serving as control group. Sensitization to aluminium, beryllium, silica and zirconium was also studied in 105 of the sarcoidosis patients and in 24 of the controls. A significantly higher percentage of sarcoidosis patients (27·6%) than controls (4·2%) had an immunological response to metals or silica (P = 0·014). A higher percentage of these sarcoidosis patients showed fibrosis on chest X‐ray 5 years after the diagnosis (69·2 versus 30·3%, P = 0·016). No significant differences in mycobacterial or vimentin enzyme‐linked immunospot (ELISPOT) assay results were observed between sarcoidosis and control patients. A significantly lower percentage of sarcoidosis patients (3·5%) than control patients (15·7%) had a positive ELISPOT for P. acnes catalase (P = 0·003). However, sarcoidosis patients sensitized to P. acnes catalase were more likely to have skin involvement, while sarcoidosis patients sensitized to mycobacterial antigens were more likely to have cardiac involvement. Our study suggests a more prominent role for inorganic triggers in sarcoidosis pathogenesis than previously thought. Immunological sensitization to inorganic antigens was associated with development of fibrotic sarcoidosis. No association was found between sensitization to bacterial antigens or vimentin and sarcoidosis in Dutch patients. However, our data suggest that trigger‐related phenotypes can exist in the heterogeneous population of sarcoidosis patients. [ABSTRACT FROM AUTHOR]

The dog is the main reservoir of Leishmania infantum, the causative agent of visceral leishmaniasis (VL) in humans in Southern Europe. In order to identify the risk of dogs from a Leishmania non-endemic area traveling to a Leishmania-endemic area becoming infected and the risk of transmitting infection to humans in non-endemic areas an investigation was performed, in which the results of a questionnaire were combined with the results of a serologic survey. The questionnaire was sent to 1478 at random chosen families in the Netherlands. Of the 59.0% responders 28.0% had one or more dogs and 4.8% of these dogs had visited Southern Europe during the summer period of that year. On a total population of 1,200,000 dogs in the Netherlands, this means that each year some 58,000 dogs are at risk of being exposed to a Leishmania infection in Southern Europe. During the period 1990-1992 blood was collected for serology in 1911 dogs presented to the Utrecht University Clinic because of clinical problems not related to leishmaniasis, of which 434 had been in Southern Europe in the foregoing years. None was serologically positive. From these data it can be deduced that the highest chance to obtain leishmaniasis during a vacation in Southern Europe is mathematically less than 1/434 or less than 0.23%. Serology was also performed during the period 1989-1993 in 597 dogs that had been in Southern Europe and were suspected of leishmaniasis. Titers were positive in 145 of these samples. Sixty-four of these dogs were born in the Mediterranean and had been imported into the Netherlands. Excluding these imported dogs, it was calculated that at least 0.027% of the 58,000 dogs yearly taken to Southern Europe during holidays become infected with Leishmania. In order to establish the risk of disease transmission for people in close contact with an infected dog, serum samples of owners and house mates of 37 dogs with leishmaniasis were tested. All 112 sera tested negative. It was concluded that the risk to get leishmaniasis was between 0.027% and 0.23% for the dog when taken to Southern Europe during vacation, and that the risk for owners in non-endemic areas to get leishmaniasis from an infected dog is minimal. [ABSTRACT FROM AUTHOR]

The dog is the main reservoir of Leishmania infantum, the causative agent of visceral leishmaniasis (VL) in humans in Southern Europe. In order to identify the risk of dogs from a Leishmania non-endemic area traveling to a Leishmania-endemic area becoming infected and the risk of transmitting infection to humans in non-endemic areas an investigation was performed, in which the results of a questionnaire were combined with the results of a serologic survey. The questionnaire was sent to 1478 at random chosen families in the Netherlands. Of the 59.0% responders 28.0% had one or more dogs and 4.8% of these dogs had visited Southern Europe during the summer period of that year. On a total population of 1,200,000 dogs in the Netherlands, this means that each year some 58,000 dogs are at risk of being exposed to a Leishmania infection in Southern Europe. During the period 1990–1992 blood was collected for serology in 1911 dogs presented to the Utrecht University Clinic because of clinical problems not related to leishmaniasis, of which 434 had been in Southern Europe in the foregoing years. None was serologically positive. From these data it can be deduced that the highest chance to obtain leishmaniasis during a vacation in Southern Europe is mathematically less than 1/434 or less than 0.23%. Serology was also performed during the period 1989–1993 in 597 dogs that had been in Southern Europe and were suspected of leishmaniasis. Titers were positive in 145 of these samples. Sixty-four of these dogs were born in the Mediterranean and had been imported into the Netherlands. Excluding these imported dogs, it was calculated that at least 0.027% of the 58,000 dogs yearly taken to Southern Europe during holidays become infected with Leishmania. In order to establish the risk of disease transmission for people in close contact with an infected dog, serum samples of owners and house mates of 37 dogs with leishmaniasis were tested. All 112 sera tested negative. It was concluded that the risk to get leishmaniasis was between 0.027% and 0.23% for the dog when taken to Southern Europe during vacation, and that the risk for owners in non-endemic areas to get leishmaniasis from an infected dog is minimal.

Background: The endothelial angiopoietin/Tie2 system is an important regulator of endothelial permeability and targeting Tie2 reduces hemorrhagic shock-induced organ edema in males. However, sexual dimorphism of the endothelium has not been taken into account. This study investigated whether there are sex-related differences in the endothelial angiopoietin/Tie2 system and edema formation., Methods: Adult male and female heterozygous Tie2 knockout mice (Tie2+/-) and wild-type controls (Tie2+/+) were included (n = 9 per group). Renal and pulmonary injury were determined by wet/dry weight ratio and H&E staining of tissue sections. Protein levels were studied in plasma by ELISA and pulmonary and renal mRNA expression levels by RT-qPCR., Results: In Tie2+/+ mice, females had higher circulating angiopoietin-2 (138%, p<0.05) compared to males. Gene expression of angiopoietin-1 (204%, p<0.01), angiopoietin-2 (542%, p<0.001) were higher in females compared to males in kidneys, but not in lungs. Gene expression of Tie2, Tie1 and VE-PTP were similar between males and females in both organs. Renal and pulmonary wet/dry weight ratio did not differ between Tie2+/+ females and males. Tie2+/+ females had lower circulating NGAL (41%, p<0.01) compared to males, whereas renal NGAL and KIM1 gene expression was unaffected. Interestingly, male Tie2+/- mice had 28% higher renal wet/dry weight ratio (p<0.05) compared to Tie2+/+ males, which was not observed in females nor in lungs. Partial deletion of Tie2 did not affect circulating angiopoietin-1 or angiopoietin-2, but soluble Tie2 was 44% and 53% lower in males and females, respectively, compared to Tie2+/+ mice of the same sex. Renal and pulmonary gene expression of angiopoietin-1, angiopoietin-2, estrogen receptors and other endothelial barrier regulators was comparable between Tie2+/- and Tie2+/+ mice in both sexes., Conclusion: Female sex seems to protect against renal, but not pulmonary edema in heterozygous Tie2 knock-out mice. This could not be explained by sex dimorphism in the endothelial angiopoietin/Tie2 system., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 van Leeuwen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The objective of this study was to determine whether there is an association between sex and outcome in trauma patients presented with severe traumatic brain injury (TBI). A retrospective multicenter study was performed in trauma patients aged ≥ 16 years who presented with severe TBI (Head Abbreviated Injury Scale (AIS) ≥ 4) over a 4-year-period. Subgroup analyses were performed for ages 16-44 and ≥45 years. Also, patients with isolated severe TBI (other AIS ≤ 2) were assessed, likewise, with subgroup analysis for age. Sex differences in mortality, Glasgow Outcome Score (GOS), ICU admission/length of stay (LOS), hospital LOS, and mechanical ventilation (MV) were examined. A total of 1566 severe TBI patients were included (831 patients with isolated TBI). Crude analysis shows an association between female sex and lower ICU admission rates, shorter ICU/hospital LOS, and less frequent and shorter MV in severe TBI patients ≥ 45 years. After adjusting, female sex appears to be associated with shorter ICU/hospital LOS. Sex differences in mortality and GOS were not found. In conclusion, this study found sex differences in patient outcomes following severe TBI, potentially favoring (older) females, which appear to indicate shorter ICU/hospital LOS (adjusted analysis). Large prospective studies are warranted to help unravel sex differences in outcomes after severe TBI.

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases ( p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.

Presence of C. acnes in granulomas is not unique to sarcoidosis but can also be found in patients with HP or EGPA. C. acnes may be involved in the pathogenesis of those granulomatous diseases in a mitogenic way. https://bit.ly/3pU0PeC., Competing Interests: Conflicts of interest: E. Beijer has nothing to disclose. Conflicts of interest: K. Seldenrijk has nothing to disclose. Conflicts of interest: B. Meek has nothing to disclose. Conflicts of interest: J. Damen has nothing to disclose. Conflicts of interest: M.J.R. Quanjel has nothing to disclose. Conflicts of interest: J.C. Grutters has nothing to disclose. Conflicts of interest: M. Veltkamp has nothing to disclose., (Copyright ©The authors 2021.)

Background: The nutrition of calves from birth until weaning is predominantly from liquid (milk or milk-based) feeds. Liquid feed allowances are often restricted during artificial rearing to accelerate the development of the rumen by promoting solid feed intake. Liquid feeds bypass the rumen and are digested in the lower digestive tract, however, the influence of different types of milk feeds, and their allowances, on the calf hindgut microbiota is not well understood. In this study, faecal samples from 199 calves raised on three different allowances of milk replacer: 10% of initial bodyweight (LA), 20% of initial bodyweight (HA), and ad libitum (ADLIB), were collected just prior to weaning. Bacterial community structures and fermentation products were analysed, and their relationships with calf growth and health parameters were examined to identify potential interactions between diet, gut microbiota and calf performance., Results: Differences in the total concentrations of short-chain fatty acids were not observed, but higher milk replacer allowances increased the concentrations of branched short-chain fatty acids and decreased acetate to propionate ratios. The bacterial communities were dominated by Ruminococcaceae, Lachnospiraceae and Bacteroides, and the bacterial diversity of the ADLIB diet group was greater than that of the other diet groups. Faecalibacterium was over three times more abundant in the ADLIB compared to the LA group, and its abundance correlated strongly with girth and body weight gains. Milk replacer intake correlated strongly with Peptococcus and Blautia, which also correlated with body weight gain. Bifidobacterium averaged less than 1% abundance, however its levels, and those of Clostridium sensu stricto 1, correlated strongly with initial serum protein levels, which are an indicator of colostrum intake and passive transfer of immunoglobulins in early life., Conclusions: Higher milk replacer intakes in calves increased hindgut bacterial diversity and resulted in bacterial communities and short chain fatty acid profiles associated with greater protein fermentation. Increased abundances of beneficial bacteria such as Faecalibacterium, were also observed, which may contribute to development and growth. Moreover, correlations between microbial taxa and initial serum protein levels suggest that colostrum intake in the first days of life may influence microbiota composition at pre-weaning.

Several studies demonstrated that Propionibacterium acnes may be involved in sarcoidosis pathogenesis. Presence of P. acnes was found in granulomas of the majority of Japanese sarcoidosis patients. However, presence of P. acnes in tissue has never been related to sarcoidosis phenotypes and clinical outcome. Therefore, the aims of our study were to demonstrate whether P. acnes can be detected in granulomas of Dutch sarcoidosis patients and to investigate whether its presence is related to a clinical phenotype and/or course of disease. Sections of formalin-fixed paraffin-embedded tissue blocks of 76 sarcoidosis patients were examined by immunostaining with a P. acnes- specific monoclonal antibody (PAB antibody) using a Ventana BenchMark ULTRA. Clinical outcome status (COS) was determined and classified into two phenotype groups: A: resolved, minimal or persistent disease without treatment (COS 1-6) and B: persistent disease with need for treatment (COS 7-9). P. acnes was detected in samples of 31 patients (41%) and located within granulomas in samples of 13 patients (17%). The frequency of P. acnes detected in granulomas at diagnosis was significantly higher in patients with phenotype B compared to patients with phenotype A (29% versus 0%, p=0.021). Presence of P. acnes in granulomas can be confirmed in Dutch sarcoidosis patients. It is intriguing that presence of P. acnes in granulomas is more frequently found in patients with chronic disease requiring treatment. This adds to the rationale that a subgroup of sarcoidosis patients might benefit from antibiotic therapy., Competing Interests: Conflict of interest: E. Beijer has nothing to disclose. Conflict of interest: K. Seldenrijk has nothing to disclose. Conflict of interest: Y. Eishi has nothing to disclose. Conflict of interest: K. Uchida has nothing to disclose. Conflict of interest: J. Damen has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: M. Veltkamp has nothing to disclose., (Copyright ©ERS 2021.)

Elevated Serum Amyloid A (SAA) levels have been found in several inflammatory diseases, including sarcoidosis. SAA is suggested to be involved in sarcoidosis pathogenesis by involvement in granuloma formation and maintenance. We hypothesized that SAA serum levels would be higher in sarcoidosis compared to other non-infectious granulomatous and non-granulomatous diseases. SAA levels were measured in serum from sarcoidosis, Hypersensitivity pneumonitis (HP), and (eosinophilic) granulomatosis with polyangiitis ((E)GPA) patients. Idiopathic pulmonary fibrosis (IPF) patients were included as non-granulomatous disease group. SAA levels of patients with sarcoidosis (31.0 µg/mL), HP (23.4 µg/mL), (E)GPA (36.9 µg/mL), and IPF (22.1 µg/mL) were all higher than SAA levels of healthy controls (10.1 µg/mL). SAA levels did not differ between the diagnostic groups. When SAA serum levels were analyzed in sarcoidosis subgroups, fibrotic sarcoidosis patients showed higher SAA levels than sarcoidosis patients without fibrosis (47.8 µg/mL vs. 29.4 µg/mL, p = 0.005). To conclude, the observation that fibrotic sarcoidosis patients have higher SAA levels, together with our finding that SAA levels were also increased in IPF patients, suggests that SAA may next to granulomatous processes also reflect the process of fibrogenesis. Further studies should clarify the exact role of SAA in fibrosis and the underlying mechanisms involved.

Background: Sarcoidosis is a systemic disease characterized by formation of non-caseating granulomas. About 5% of patients have symptoms of cardiac sarcoidosis. Identification of cardiac involvement is important since it is a major cause of death. Mycobacterial antigens have been linked to sarcoidosis pathogenesis. Previous findings suggest that a latent tuberculosis infection (LTBI) might associate with development of cardiac involvement in patients with sarcoidosis. The aim of the present study was to further evaluate these findings in another cohort of cardiac sarcoidosis patients., Methods: Interferon release assays (IGRAs) or tuberculin skin tests (TST) were analysed in a cohort of cardiac sarcoidosis patients (n=103) and compared to non-cardiac sarcoidosis patients (n=153)., Results: In the cohort of patients with cardiac sarcoidosis, 7 could be diagnosed with a LTBI (6.8%) compared to only one of the non-cardiac patients (0.7%), p = 0.008., Conclusions: To conclude, we were able to show an association between a LTBI and cardiac involvement in patients with sarcoidosis. Future research is however required to unravel the mechanism involved in this association. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (3): e2020005) ., (Copyright: © 2020 SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES.)

Until a few years ago, adult humans were not thought to have brown adipose tissue (BAT). Now, this is a rapidly evolving field of research with perspectives in metabolic syndromes such as obesity and new therapies targeting its bio-energetic pathways. White, brown and so-called brite adipose fat seem to be able to trans-differentiate into each other, emphasizing the dynamic nature of fat tissue for metabolism. Human and animal data in cancer cachexia to date provide some evidence for BAT activation, but its quantitative impact on energy expenditure and weight loss is controversial. Prospective clinical studies can address the potential role of BAT in cancer cachexia using (18)F-fluoro- deoxyglucose positron emission tomography-computed tomography scanning, with careful consideration of co-factors such as diet, exposure to the cold, physical activity and body mass index, that all seem to act on BAT recruitment and activity.