Browsing by Subject "Human "

Sort by: Order: Results:

Now showing items 1-19 of 19
  • Lund, Carina; Yellapragada, Venkatram; Vuoristo, Sanna; Balboa, Diego; Trova, Sara; Allet, Cecile; Eskici, Nazli; Pulli, Kristiina; Giacobini, Paolo; Tuuri, Timo; Raivio, Taneli (2020)
    Gonadotropin-releasing hormone (GnRH) neurons provide a fundamental signal for the onset of puberty and subsequent reproductive functions by secretion of gonadotropin-releasing hormone. Their disrupted development or function leads to congenital hypogonadotropic hypogonadism (CHH). To model the development of human GnRH neurons, we generated a stable GNRH1-TdTomato reporter cell line in human pluripotent stem cells (hPSCs) using CRISPR-Cas9 genome editing. RNA-sequencing of the reporter clone, differentiated into GnRH neurons by dual SMAD inhibition and FGF8 treatment, revealed 6461 differentially expressed genes between progenitors and GnRH neurons. Expression of the transcription factor ISL1, one of the top 50 most upregulated genes in the TdTomato-expressing GnRH neurons, was confirmed in 10.5 gestational week-old human fetal GnRH neurons. Among the differentially expressed genes, we detected 15 genes that are implicated in CHH and several genes that are implicated in human puberty timing. Finally, FGF8 treatment in the neuronal progenitor pool led to upregulation of 37 genes expressed both in progenitors and in TdTomato-expressing GnRH neurons, which suggests upstream regulation of these genes by FGF8 signaling during GnRH neuron differentiation. These results illustrate how hPSC-derived human GnRH neuron transcriptomic analysis can be utilized to dissect signaling pathways and gene regulatory networks involved in human GnRH neuron development.This article has an associated First Person interview with the first author of the paper.
  • Ekman, Ilse; Ihantola, Emmi-Leena; Viisanen, Tyyne; Rao, Deepak A.; Näntö-Salonen, Kirsti; Knip, Mikael; Veijola, Riitta; Toppari, Jorma; Ilonen, Jorma; Kinnunen, Tuure (2019)
    Aims/hypothesis Type 1 diabetes is preceded by a period of asymptomatic autoimmunity characterised by positivity for islet autoantibodies. Therefore, T helper cell responses that induce B cell activation are likely to play a critical role in the disease process. Here, we aimed to evaluate the role of a recently described subset, C-X-C motif chemokine receptor type 5-negative, programmed cell death protein 1-positive (CXCR5(-)PD-1(hi)) peripheral T helper (Tph) cells, in human type 1 diabetes. Methods The phenotype of blood CXCR5(-)PD-1(hi) CD4(+) T cells was analysed by multicolour flow cytometry. The frequencies of circulating CXCR5(-)PD-1(hi) T cells were analysed in a cohort of 44 children with newly diagnosed type 1 diabetes, 40 autoantibody-positive (AAb(+)) at-risk children and 84 autoantibody-negative healthy control children, and the findings were replicated in a separate cohort of 15 children with newly diagnosed type 1 diabetes and 15 healthy control children. Results Circulating CXCR5(-)PD-1(hi) Tph cells share several features associated with B cell helper function with circulating CXCR5(+)PD-1(hi) follicular T helper (Tfh) cells. Moreover, the frequency of circulating Tph cells was increased in children with newly diagnosed type 1 diabetes, especially in those who are positive for multiple autoantibodies. Importantly, circulating Tph cells were also increased in autoantibody-positive at-risk children who later progressed to type 1 diabetes. Conclusions/interpretation Our results demonstrate that circulating CXCR5(-)PD-1(hi) Tph cells are associated with progression to clinical type 1 diabetes. Consequently, Tph cells could have potential both as a biomarker of disease progression and as a target for immunotherapy in type 1 diabetes.
  • Tharmalingam, Melissa D.; Matilionyte, Gabriele; Wallace, William H. B.; Stukenborg, Jan-Bernd; Jahnukainen, Kirsi; Oliver, Elizabeth; Goriely, Anne; Lane, Sheila; Guo, Jingtao; Cairns, Bradley; Jorgensen, Anne; Allen, Caroline M.; Lopes, Federica; Anderson, Richard A.; Spears, Norah; Mitchell, Rod T. (2020)
    Background Clinical studies indicate chemotherapy agents used in childhood cancer treatment regimens may impact future fertility. However, effects of individual agents on prepubertal human testis, necessary to identify later risk, have not been determined. The study aimed to investigate the impact of cisplatin, commonly used in childhood cancer, on immature (foetal and prepubertal) human testicular tissues. Comparison was made with carboplatin, which is used as an alternative to cisplatin in order to reduce toxicity in healthy tissues. Methods We developed an organotypic culture system combined with xenografting to determine the effect of clinically-relevant exposure to platinum-based chemotherapeutics on human testis. Human foetal and prepubertal testicular tissues were cultured and exposed to cisplatin, carboplatin or vehicle for 24 h, followed by 24-240 h in culture or long-term xenografting. Survival, proliferation and apoptosis of prepubertal germ stem cell populations (gonocytes and spermatogonia), critical for sperm production in adulthood, were quantified. Results Cisplatin exposure resulted in a significant reduction in the total number of germ cells (- 44%, p <0.0001) in human foetal testis, which involved an initial loss of gonocytes followed by a significant reduction in spermatogonia. This coincided with a reduction (- 70%, p <0.05) in germ cell proliferation. Cisplatin exposure resulted in similar effects on total germ cell number (including spermatogonial stem cells) in prepubertal human testicular tissues, demonstrating direct relevance to childhood cancer patients. Xenografting of cisplatin-exposed human foetal testicular tissue demonstrated that germ cell loss (- 42%, p <0.01) persisted at 12 weeks. Comparison between exposures to human-relevant concentrations of cisplatin and carboplatin revealed a very similar degree of germ cell loss at 240 h post-exposure. Conclusions This is the first demonstration of direct effects of chemotherapy exposure on germ cell populations in human foetal and prepubertal testis, demonstrating platinum-induced loss of all germ cell populations, and similar effects of cisplatin or carboplatin. Furthermore, these experimental approaches can be used to determine the effects of established and novel cancer therapies on the developing testis that will inform fertility counselling and development of strategies to preserve fertility in children with cancer.
  • Hajkarim, Morteza Chalabi; Karjalainen, Ella; Osipovitch, Mikhail; Dimopoulos, Konstantinos; Gordon, Sandra L.; Ambri, Francesca; Rasmussen, Kasper Dindler; Gronbaek, Kirsten; Helin, Kristian; Wennerberg, Krister; Won, Kyoung-Jae (2022)
    Large-scale multiparameter screening has become increasingly feasible and straightforward to perform thanks to developments in technologies such as high-content microscopy and high-throughput flow cytometry. The automated toolkits for analyzing similarities and differences between large numbers of tested conditions have not kept pace with these technological developments. Thus, effective analysis of multiparameter screening datasets becomes a bottleneck and a limiting factor in unbiased interpretation of results. Here we introduce compaRe, a toolkit for large-scale multiparameter data analysis, which integrates quality control, data bias correction, and data visualization methods with a mass-aware gridding algorithm-based similarity analysis providing a much faster and more robust analyses than existing methods. Using mass and flow cytometry data from acute myeloid leukemia and myelodysplastic syndrome patients, we show that compaRe can reveal interpatient heterogeneity and recognizable phenotypic profiles. By applying compaRe to high-throughput flow cytometry drug response data in AML models, we robustly identified multiple types of both deep and subtle phenotypic response patterns, highlighting how this analysis could be used for therapeutic discoveries. In conclusion, compaRe is a toolkit that uniquely allows for automated, rapid, and precise comparisons of large-scale multiparameter datasets, including high-throughput screens.
  • Smeds, Eero; Vanhatalo, Sampsa; Piitulainen, Harri; Bourguignon, Mathieu; Jousmaki, Veikko; Hari, Riitta (2017)
    Objective: Somatosensory evoked potentials have high prognostic value in neonatal intensive care, but their recording from infants is challenging. Here, we studied the possibility to elicit cortical responses in newborns by simple passive hand movements. Methods: We examined 13 newborns (postnatal age 1-46 days) during clinically indicated 19-channel electroencephalography (EEG) recordings in the neonatal intensive care unit; EEG indications included birth asphyxia and suspected epileptic seizures. The experimenter moved the infant's wrist or fingers at 1 or 2 Hz for 5-10 min, separately on both sides. We measured movement kinematics with an accelerometer attached to the infant's hand and computed coherence between the EEG and acceleration signals (corticokinematic coherence, CKC). Results: Statistically significant CKC (amplitude 0.020-0.511) with characteristic scalp topography was observed in all infants at twice the movement frequency. CKC was contralaterally dominant on the central scalp (median laterality index 0.48 for right-hand and -0.63 for left-hand movements). Conclusions: Passive movements elicit cortical responses that can be readily observed in clinical EEG recordings from newborns in the intensive-care environment. (C) 2017 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd.
  • Lietzen, Niina; An, Le T. T.; Jaakkola, Maria K.; Kallionpää, Henna; Oikarinen, Sami; Mykkänen, Juha; Knip, Mikael; Veijola, Riitta; Ilonen, Jorma; Toppari, Jorma; Hyoty, Heikki; Lahesmaa, Riitta; Elo, Laura L. (2018)
    Aims/hypothesis Enterovirus infections have been associated with the development of type 1 diabetes in multiple studies, but little is known about enterovirus-induced responses in children at risk for developing type 1 diabetes. Our aim was to use genome-wide transcriptomics data to characterise enterovirus-associated changes in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Methods Longitudinal whole-blood samples (356 samples in total) collected from 28 pairs of children at increased risk for developing type 1 diabetes were screened for the presence of enterovirus RNA. Seven of these samples were detected as enterovirus-positive, each of them collected from a different child, and transcriptomics data from these children were analysed to understand the individual-level responses associated with enterovirus infections. Transcript clusters with peaking or dropping expression at the time of enterovirus positivity were selected as the enterovirus-associated signals. Results Strong signs of activation of an interferon response were detected in four children at enterovirus positivity, while transcriptomic changes in the other three children indicated activation of adaptive immune responses. Additionally, a large proportion of the enterovirus-associated changes were specific to individuals. An enterovirus-induced signature was built using 339 genes peaking at enterovirus positivity in four of the children, and 77 of these genes were also upregulated in human peripheral blood mononuclear cells infected in vitro with different enteroviruses. These genes separated the four enterovirus-positive samples clearly from the remaining 352 blood samples analysed. Conclusions/interpretation We have, for the first time, identified enterovirus-associated transcriptomic profiles in whole-blood samples from children with genetic susceptibility to type 1 diabetes. Our results provide a starting point for understanding the individual responses to enterovirus infections in blood and their potential connection to the development of type 1 diabetes.
  • Hodel, F.; Chong, A. Y.; Scepanovic, P.; Xu, Z. M.; Naret, O.; Thorball, C. W.; Rüeger, S.; Marques-Vidal, P.; Vollenweider, P.; Begemann, M.; Ehrenreich, H.; Brenner, N.; Bender, N.; Waterboer, T.; Mentzer, A. J.; Hill, A. V.S.; Hammer, C.; Fellay, J. (2021)
    Human polyomaviruses are widespread in humans and can cause severe disease in immunocompromised individuals. To identify human genetic determinants of the humoral immune response against polyomaviruses, we performed genome-wide association studies and meta-analyses of qualitative and quantitative immunoglobulin G responses against BK polyomavirus (BKPyV), JC polyomavirus (JCPyV), Merkel cellpolyomavirus (MCPyV), WU polyomavirus (WUPyV), and human polyomavirus 6 (HPyV6) in 15,660 individuals of European ancestry from three independent studies. We observed significant associations for all tested viruses: JCPyV, HPyV6, and MCPyV associated with human leukocyte antigen class II variation, BKPyV and JCPyV with variants in FUT2, responsible for secretor status, MCPyV with variants in STING1, involved in interferon induction, and WUPyV with a functional variant in MUC1, previously associated with risk for gastric cancer. These results provide insights into the genetic control of a family of very prevalent human viruses, highlighting genes and pathways that play a modulating role in human humoral immunity.
  • Faridnia, Roghiyeh; Soosaraei, Masoud; Kalani, Hamed; Fakhar, Mandi; Jokelainen, Pikka; Emameh, Reza Zolfaghari; Banimostafavi, Elham Sadat; Hezarjaribi, Hajar Ziaei (2019)
    The public health importance of myiasis [infestation with dipterous (fly) larvae] remains unknown. This disease is spread worldwide in animals and humans, but baseline data on its prevalence are limited. In particular, knowledge on human urogenital myiasis (UGM) is scattered. As such, a systematic search was undertaken of five English and five Persian databases for publications describing UGM cases in English or Persian published between 1975 and 2017. In total, 45 papers reporting 59 UGM cases from various regions of the world are included in this review. All included papers were from the English databases. The age of patients ranged from 5 to 89 years, and the mean age was 40.6 years. Thirty-six of the patients were female and 19 were male. The highest number of cases (n = 12) was reported from Brazil. The most common genera causing UGM were Psychoda spp. (23.7%) and Cochliomyia spp. (11.8%). The vagina was the most commonly reported anatomical location of UGM for women, and the urogenital tract was the most commonly reported location for men. Thirteen cases were reported from rural areas and eight cases from urban areas; the location of other cases was not specified. The incidence of UGM is likely to be substantially underestimated when evaluated based on published case reports. Epidemiological studies, such as questionnaires to medical doctors, could help to gather the necessary baseline data on the occurrence of UGM. (C) 2019 Elsevier B.V. All rights reserved.
  • Turunen, Soile; Puurunen, Jenni; Auriola, Seppo; Kullaa, Arja M.; Kärkkäinen, Olli; Lohi, Hannes; Hanhineva, Kati (2020)
    Introduction Saliva metabolites are suggested to reflect the health status of an individual in humans. The same could be true with the dog (Canis lupus familiaris), an important animal model of human disease, but its saliva metabolome is unknown. As a non-invasive sample, canine saliva could offer a new alternative material for research to reveal molecular mechanisms of different (patho)physiological stages, and for veterinary medicine to monitor dogs' health trajectories. Objectives To investigate and characterize the metabolite composition of dog and human saliva in a non-targeted manner. Methods Stimulated saliva was collected from 13 privately-owned dogs and from 14 human individuals. We used a non-targeted ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-qTOF-MS) method to measure metabolite profiles from saliva samples. Results We identified and classified a total of 211 endogenous and exogenous salivary metabolites. The compounds included amino acids, amino acid derivatives, biogenic amines, nucleic acid subunits, lipids, organic acids, small peptides as well as other metabolites, like metabolic waste molecules and other chemicals. Our results reveal a distinct metabolite profile of dog and human saliva as 25 lipid compounds were identified only in canine saliva and eight dipeptides only in human saliva. In addition, we observed large variation in ion abundance within and between the identified saliva metabolites in dog and human. Conclusion The results suggest that non-targeted metabolomics approach utilizing UHPLC-qTOF-MS can detect a wide range of small compounds in dog and human saliva with partially overlapping metabolite composition. The identified metabolites indicate that canine saliva is potentially a versatile material for the discovery of biomarkers for dog welfare. However, this profile is not complete, and dog saliva needs to be investigated in the future with other analytical platforms to characterize the whole canine saliva metabolome. Furthermore, the detailed comparison of human and dog saliva composition needs to be conducted with harmonized study design.
  • Gazali, Ahmad M.; Schroderus, Anna-Mari; Näntö-Salonen, Kirsti; Rintamäki, Reeta; Pihlajamäki, Jussi; Knip, Mikael; Veijola, Riitta; Toppari, Jorma; Ilonen, Jorma; Kinnunen, Tuure (2020)
    Aims/hypothesis Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognise derivatives of bacterial riboflavin metabolites presented by MHC-Ib-related protein 1 (MR1) molecules and are important effector cells for mucosal immunity. Their development can be influenced by the intestinal microbiome. Since the development of type 1 diabetes has been associated with changes in the gut microbiome, this can be hypothesised to lead to alterations in circulating MAIT cells. Accordingly, peripheral blood MAIT cell alterations have been reported previously in patients with type 1 diabetes. However, a comprehensive analysis of the frequency and phenotype of circulating MAIT cells at different stages of type 1 diabetes progression is currently lacking. Methods We analysed the frequency, phenotype and functionality of peripheral blood MAIT cells, as well as gamma delta T cells, invariant natural killer T (iNKT) cells and natural killer (NK) cells with flow cytometry in a cross-sectional paediatric cohort (aged 2-15) consisting of 51 children with newly diagnosed type 1 diabetes, 27 autoantibody-positive (AAb(+)) at-risk children, and 113 healthy control children of similar age and HLA class II background. The frequency of MAIT cells was also assessed in a separate cross-sectional adult cohort (aged 19-39) of 33 adults with established type 1 diabetes and 37 healthy individuals of similar age. Results Children with newly diagnosed type 1 diabetes displayed a proportional increase of CD8(-)CD27(-)MAIT cells compared with healthy control children (median 4.6% vs 3.1% of MAIT cells, respectively, p = 0.004), which was associated with reduced expression of C-C chemokine receptor (CCR)5 (median 90.0% vs 94.3% of MAIT cells, p = 0.02) and beta 7 integrin (median 73.5% vs 81.7% of MAIT cells, p = 0.004), as well as decreased production of IFN-gamma (median 57.1% vs 69.3% of MAIT cells, p = 0.04) by the MAIT cells. The frequency of MAIT cells was also decreased in AAb(+)children who later progressed to type 1 diabetes compared with healthy control children (median 0.44% vs 0.96% of CD3(+)T cells, p = 0.04), as well as in adult patients with a short duration of type 1 diabetes (less than 6 years after diagnosis) compared with control individuals (median 0.87% vs 2.19% of CD3(+)T cells, p = 0.007). No alterations in gamma delta T cell, iNKT cell or NK cell frequencies were observed in children with type 1 diabetes or in AAb(+) children, with the exception of an increased frequency of IL-17A(+)gamma delta T cells in children with newly diagnosed diabetes compared with healthy control children (median 1.58% vs 1.09% of gamma delta T cells, p = 0.002). Conclusions/interpretation Changes in the frequency and phenotype of circulating MAIT cells were detectable before, at the onset and after diagnosis of type 1 diabetes in cross-sectional cohorts. Our results suggest a possible temporal association between peripheral blood MAIT cell alterations and the clinical onset of type 1 diabetes.
  • Lou, Yan-Ru; Leung, Alan W. (2018)
    Organoids are in vitro cultures of miniature fetal or adult organ-like structures. Their potentials for use in tissue and organ replacement, disease modeling, toxicology studies, and drug discovery are tremendous. Currently, major challenges facing human organoid technology include (i) improving the range of cellular heterogeneity for a particular organoid system, (ii) mimicking the native micro- and matrix-environment encountered by cells within organoids, and (iii) developing robust protocols for the in vitro maturation of organoids that remain mostly fetal-like in cultures. To tackle these challenges, we advocate the principle of reverse engineering that replicates the inner workings of in vivo systems with the goal of achieving functionality and maturation of the resulting organoid structures with the input of minimal intrinsic (cellular) and environmental (matrix and niche) constituents. Here, we present an overview of organoid technology development in several systems that employ cell materials derived from fetal and adult tissues and pluripotent stem cell cultures. We focus on key studies that exploit the self-organizing property of embryonic progenitors and the role of designer matrices and cell-free scaffolds in assisting organoid formation. We further explore the relationship between adult stem cells, niche factors, and other current developments that aim to enhance robust organoid maturation. From these works, we propose a standardized pipeline for the development of future protocols that would help generate more physiologically relevant human organoids for various biomedical applications.
  • Knaapila, Antti; Laaksonen, Oskar; Virtanen, Markus; Yang, Baoru; Lagstrom, Hanna; Sandell, Mari (2017)
    The primary dimension of odor is pleasantness, which is associated with a multitude of factors. We investigated how the pleasantness, familiarity, and identification of spice odors were associated with each other and with the use of the respective spice, overall use of herbs, and level of food neophobia. A total of 126 adults (93 women, 33 men; age 25-61 years, mean 39 years) rated the odors from 12 spices (oregano, anise, rosemary, mint, caraway, sage, thyme, cinnamon, fennel, marjoram, garlic, and clove) for pleasantness and familiarity, and completed a multiple-choice odor identification. Data on the use of specific spices, overall use of herbs, and Food Neophobia Scale score were collected using an online questionnaire. Familiar odors were mostly rated as pleasant (except garlic), whereas unfamiliar odors were rated as neutral (r = 0.63). We observed consistent and often significant trends that suggested the odor pleasantness and familiarity were positively associated with the correct odor identification, consumption of the respective spice, overall use of herbs, and food neophilia. Our results suggest that knowledge acquisition through repetitive exposure to spice odor with active attention may gradually increase the odor pleasantness within the framework set by the chemical characteristics of the aroma compound. (C) 2016 Elsevier Ltd. All rights reserved.
  • Knip, Mikael; Selvenius, Jenni; Siljander, Heli; Veijola, Riitta (2017)
    Type 1 diabetes is an immune-mediated disease leading to almost total beta cell destruction and permanent exogenous insulin dependency. The appearance of clinical symptoms is preceded by an asymptomatic preclinical period, the duration of which is highly individual. The emergence of diabetes-associated autoantibodies into the peripheral circulation is the first detectable sign of beta cell autoimmunity. If type 1 diabetes is diagnosed in childhood the preclinical period lasts for an average of 2.5-3 years, but clinical symptoms may in some cases appear within a few months or be delayed for more than 20 years. In this issue of Diabetologia, Bonifacio and colleagues (doi:) suggest that asymptomatic beta cell autoimmunity should be considered as a pathological and diagnostic entity. Although such a strategy may have some positive consequences, it might also have serious drawbacks. To label an asymptomatic child that may have 10-20 years of a healthy life ahead of him/her as a patient will most likely affect both the life of the family and the child. Therefore, we think that one should not adapt the new diagnosis before the psychological consequences of such a strategy have been assessed. Instead, since metabolic abnormalities precede the appearance of clinical symptoms of type 1 diabetes, analysis of a combination of immunological and metabolic markers will provide better insight into the likelihood of progression to clinical disease, with a shorter 'sickness' period.
  • Zheng, Xiaowei; Narayanan, Sampath; Xu, Cheng; Eliasson Angelstig, Sofie; Grunler, Jacob; Zhao, Allan; Di Toro, Alessandro; Bernardi, Luciano; Mazzone, Massimiliano; Carmeliet, Peter; Del Sole, Marianna; Solaini, Giancarlo; Forsberg, Elisabete A.; Zhang, Ao; Brismar, Kerstin; Schiffer, Tomas A.; Rajamand Ekberg, Neda; Botusan, Ileana Ruxandra; Palm, Fredrik; Catrina, Sergiu-Bogdan (2022)
    Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.
  • Kolmeder, Carolin A.; de Vos, Willem M. (2021)
    It is known for more than 100 years that the intestinal microbes are important for the host's health and the last decade this is being intensely studied with a focus on the mechanistic aspects. Among the fundamental functions of the intestinal microbiome are the priming of the immune system, the production of essential vitamins and the energy harvest from foods. By now, several dozens of diseases, both intestinal and non-intestinal related, have been associated with the intestinal microbiome. Initially, this was based on the description of the composition between groups of different health status or treatment arms based on phylogenetic approaches based on the 16S rRNA gene sequences. This way of analysis has mostly moved to the analysis of all the genes or transcripts of the microbiome i.e. metagenomics and meta-transcriptomics. Differences are regularly found but these have to be taken with caution as we still do not know what the majority of genes of the intestinal microbiome are capable of doing. To circumvent this caveat researchers are studying the proteins and the metabolites of the microbiome and the host via metaproteomics and metabolomics approaches. However, also here the complexity is high and only a fraction of signals obtained with high throughput instruments can be identified and assigned to a known protein or molecule. Therefore, modern microbiome research needs advancement of existing and development of new analytical techniques. The usage of model systems like intestinal organoids where samples can be taken and processed rapidly as well as microfluidics systems may help. This review aims to elucidate what we know about the functionality of the human intestinal microbiome, what technologies are advancing this knowledge, and what innovations are still required to further evolve this actively developing field. (C) 2020 The Authors. Published by Elsevier B.V.
  • Kinnunen, Susanna; Karhapää, Pauli; Juutilainen, Auni; Finne, Patrik; Helanterä, Ilkka (2018)
    Background and objectives Infections are the most common noncardiovascular causes of death after kidney transplantation. We analyzed the current infection-related mortality among kidney transplant recipients in a nationwide cohort in Finland. Design, setting, participants, & measurements Altogether, 3249 adult recipients of a first kidney transplant from 1990 to 2012 were included. Infectious causes of death were analyzed, and the mortality rates for infections were compared between two eras (1990-1999 and 2000-2012). Risk factors for infectious deaths were analyzed with Cox regression and competing risk analyses. Results Altogether, 953 patients (29%) died during the follow-up, with 204 infection-related deaths. Mortality rate (per 1000 patient-years) due to infections was lower in the more recent cohort (4.6; 95% confidence interval, 3.5 to 6.1) compared with the older cohort (9.1; 95% confidence interval, 7.6 to 10.7); the incidence rate ratio of infectious mortality was 0.51 (95% confidence interval, 0.30 to 0.68). The main causes of infectious deaths were common bacterial infections: septicemia in 38% and pulmonary infections in 45%. Viral and fungal infections caused only 2% and 3% of infectious deaths, respectively (such as individual patients with Cytomegalovirus pneumonia, Herpes simplex virus meningoencephalitis, Varicella zoster virus encephalitis, and Pneumocystis jirovecii infection). Similarly, opportunistic bacterial infections rarely caused death; only one deathwas caused by Listeria monocytogenes, and two were caused by Mycobacterium tuberculosis. Only 23 (11%) of infection-related deaths occurred during the first post-transplant year. Older recipient age, higher plasma creatinine concentration at the end of the first post-transplant year, diabetes as a cause of ESKD, longer pretransplant dialysis duration, acute rejection, low albumin level, and earlier era of transplantation were associated with increased risk of infectious death in multivariable analysis. Conclusions The risk of death due to infectious causes after kidney transplantation in Finland dropped by one half since the 1990s. Common bacterial infections remained the most frequent cause of infection-related mortality, whereas opportunistic viral, fungal, or unconventional bacterial infections rarely caused deaths after kidney transplantation.
  • Schütt, Marcel; The Duy Nguyen; Kalff-Suske, Martha; Wagner, Uwe; Macharey, Georg; Ziller, Volker (2021)
    Objective: Progesterone application for luteal phase support is a well-established concept in in vitro fertilization (IVF) treatment. Water-soluble subcutaneous progesterone injections have shown pregnancy rates equivalent to those observed in patients receiving vaginal administration in randomized controlled trials. Our study aimed to investigate whether the results from those pivotal trials could be reproduced in daily clinical practice in an unselected patient population. Methods: In this retrospective cohort study in non-standardized daily clinical practice, we compared 273 IVF cycles from 195 women undergoing IVF at our center for luteal phase support with vaginal administration of 200 mg of micronized progesterone three times daily or subcutaneous injection of 25 mg of progesterone per day. Results: Various patient characteristics including age, weight, height, number of oocytes, and body mass index were similar between both groups. We observed no significant differences in the clinical pregnancy rate (CPR) per treatment cycle between the subcutaneous (39.9%) and vaginal group (36.5%) (p=0.630). Covariate analysis showed significant correlations of the number of transferred embryos and the total dosage of stimulation medication with the CPR. However, after adjustment of the CPR for these covariates using a regression model, no significant difference was observed between the two groups (odds ratio, 0.956; 95% confidence interval, 0.512-1.786; p=0.888). Conclusion: In agreement with randomized controlled trials in study populations with strict selection criteria, our study determined that subcutaneous progesterone was equally effective as vaginally applied progesterone in daily clinical practice in an unselected patient population.
  • Manninen, Suvi; Lankinen, Maria; Erkkilä, Arja; Nguyen, Su Duy; Ruuth, Maija; de Mello, Vanessa; Öörni, Katariina; Schwab, Ursula (2019)
    Background and aims: Omega-3 fatty acids are known to have several cardioprotective effects. Our aim was to investigate the effects of intakes of fish and Camelina sativa oil (CSO), rich in alpha-linolenic acid, on the atherogenic and anti-atherogenic functions of LDL and HDL particles. Methods: Altogether, 88 volunteers with impaired glucose metabolism were randomly assigned to CSO (10 g of alpha-linolenic acid/day), fatty fish (4 fish meals/week), lean fish (4 fish meals/week) or control group for 12 weeks. 79 subjects completed the study. The binding of lipoproteins to aortic proteoglycans, LDL aggregation and activation of endothelial cells by LDL and cholesterol efflux capacity of HDL were determined in vitro. Results: Intake of CSO decreased the binding of lipoproteins to aortic proteoglycans in a non-normalized model (p = 0.006). After normalizing with serum concentrations of non-HDL cholesterol, apolipoprotein B (apoB) or LDL cholesterol, which decreased in the CSO group, the change was no longer statistically significant. In the fish groups, there were no changes in the binding of lipoproteins to proteoglycans. Regarding other lipoprotein functions, there were no changes in any of the groups. Conclusions: Intake of CSO decreases the binding of lipoproteins to aortic proteoglycans by decreasing serum LDL cholesterol concentration, which suggests that the level of apoB-containing lipoproteins in the circulation is the main driver of lipoprotein retention within the arterial wall. Intake of fish or CSO has no effects on other lipoprotein functions.
  • Lintula, Susanna; Mirtti, Tuomas; Rannikko, Antti; Bützow, Anna; Lempiäinen, Anna; Stenman, Jakob; Stenman, Ulf-Hakan; Hotakainen, Kristina (2019)
    The beta subunit of human chorionic gonadotropin (hCG beta) is encoded by six genes (CGB) classified as type I and type II. CGB mRNA is produced in large amounts by trophoblastic tissues and in small amounts by several cancerous tissues including prostate cancer and by a few benign tissues, including the prostate. Quantitative reverse-transcription polymerase chain reaction (RT-qPCR) was used to study the expression levels of all CGB mRNAs together (total CGB mRNA) and the two types of CGB mRNA separately in non-cancerous (n = 74) and cancerous prostatic tissue obtained by radical prostatectomy (n = 193). RNA was isolated from formalin-fixed paraffin-embedded (FFPE) samples and mRNA levels of CGB were correlated with disease-specific survival. Total CGB mRNA concentrations were significantly lower (p <.0001) in cancerous than non-cancerous prostatic tissue. Separate analysis of type I CGB and type II CGB mRNA showed that both type I CGB (p <.0001) and type II CGB mRNA (p = .007) are lower in cancerous tissue than in non-cancerous tissue. Low type II CGB mRNA level in cancerous tissue was associated with shorter cancer-specific survival (p = .001) of prostate cancer patients treated by radical prostatectomy.