Browsing by Subject "DOUBLE-BLIND"

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  • Sartelli, Massimo; Guirao, Xavier; Hardcastle, Timothy C.; Kluger, Yoram; Boermeester, Marja. A.; Rasa, Kemal; Ansaloni, Luca; Coccolini, Federico; Montravers, Philippe; Abu-Zidan, Fikri M.; Bartoletti, Michele; Bassetti, Matteo; Ben-Ishay, Offir; Biffl, Walter L.; Chiara, Osvaldo; Chiarugi, Massimo; Coimbra, Raul; De Rosa, Francesco Giuseppe; De Simone, Belinda; Di Saverio, Salomone; Giannella, Maddalena; Gkiokas, George; Khokha, Vladimir; Labricciosa, Francesco M.; Leppäniemi, Ari; Litvin, Andrey; Moore, Ernest E.; Negoi, Ionut; Pagani, Leonardo; Peghin, Maddalena; Picetti, Edoardo; Pintar, Tadeja; Pupelis, Guntars; Rubio-Perez, Ines; Sakakushev, Boris; Segovia-Lohse, Helmut; Sganga, Gabriele; Shelat, Vishal; Sugrue, Michael; Tarasconi, Antonio; Trana, Cristian; Ulrych, Jan; Viale, Pierluigi; Catena, Fausto (2018)
    Skin and soft-tissue infections (SSTIs) encompass a variety of pathological conditions that involve the skin and underlying subcutaneous tissue, fascia, or muscle, ranging from simple superficial infections to severe necrotizing infections. SSTIs are a frequent clinical problem in surgical departments. In order to clarify key issues in the management of SSTIs, a task force of experts met in Bertinoro, Italy, on June 28, 2018, for a specialist multidisciplinary consensus conference under the auspices of the World Society of Emergency Surgery (WSES) and the Surgical Infection Society Europe (SIS-E). The multifaceted nature of these infections has led to a collaboration among general and emergency surgeons, intensivists, and infectious disease specialists, who have shared these clinical practice recommendations.
  • ARIA Working Grp; Bousquet, J; Pfaar, O; Togias, A; Haahtela, T; Toppila-Salmi, S (2019)
    Allergen immunotherapy (AIT) is a proven therapeutic option for the treatment of allergic rhinitis and/or asthma. Many guidelines or national practice guidelines have been produced but the evidence-based method varies, many are complex and none propose care pathways. This paper reviews care pathways for AIT using strict criteria and provides simple recommendations that can be used by all stakeholders including healthcare professionals. The decision to prescribe AIT for the patient should be individualized and based on the relevance of the allergens, the persistence of symptoms despite appropriate medications according to guidelines as well as the availability of good-quality and efficacious extracts. Allergen extracts cannot be regarded as generics. Immunotherapy is selected by specialists for stratified patients. There are no currently available validated biomarkers that can predict AIT success. In adolescents and adults, AIT should be reserved for patients with moderate/severe rhinitis or for those with moderate asthma who, despite appropriate pharmacotherapy and adherence, continue to exhibit exacerbations that appear to be related to allergen exposure, except in some specific cases. Immunotherapy may be even more advantageous in patients with multimorbidity. In children, AIT may prevent asthma onset in patients with rhinitis. mHealth tools are promising for the stratification and follow-up of patients.
  • Hungarian Pancreatic Study Grp; Farkas, Nelli; Hanak, Lilla; Miko, Alexandra; Sallinen, Ville; Hegyi, Peter (2019)
    Background: C-reactive protein level (CRP) and white blood cell count (WBC) have been variably used in clinical trials on acute pancreatitis (AP). We assessed their potential role. Methods: First, we investigated studies which have used CRP or WBC, to describe their current role in trials on AP. Second, we extracted the data of 1435 episodes of AP from our registry. CRP and WBC on admission, within 24 h from the onset of pain and their highest values were analyzed. Descriptive statistical tools as Kruskal-Wallis, Mann-Whitney U, Levene's F tests, Receiver Operating Characteristic (ROC) curve analysis and AUC (Area Under the Curve) with 95% confidence interval (CI) were performed. Results: Our literature review showed extreme variability of CRP used as an inclusion criterion or as a primary outcome or both in past and current trials on AP. In our cohort, CRP levels on admission poorly predicted mortality and severe cases of AP; AUC: 0.669 (CI:0.569-0.770); AUC:0.681 (CI: 0.601-0.761), respectively. CRP levels measured within 24 h from the onset of pain failed to predict mortality or severity; AUC: 0.741 (CI:0.627-0.854); AUC:0.690 (CI:0.586-0.793), respectively. The highest CRP during hospitalization had equally poor predictive accuracy for mortality and severity AUC:0.656 (CI:0.544-0.768); AUC:0.705 (CI:0.640-0.769) respectively. CRP within 24 h from the onset of pain used as an inclusion criterion markedly increased the combined event rate of mortality and severe AP (13% for CRP > 25 mg/l and 28% for CRP > 200 mg/l). Conclusion: CRP within 24 h from the onset of pain as an inclusion criterion elevates event rates and reduces the number of patients required in trials on AP.
  • Matthews, David R.; Paldanius, Päivi M.; Stumvoll, Michael; Han, Jackie; Bader, Giovanni; Chiang, YannTong; Proot, Pieter; Del Prato, Stefano (2019)
    Aims To ensure the integrity of the planned analyses and maximize the clinical utility of the VERIFY study results by describing the detailed concepts behind its statistical analysis plan (SAP) before completion of data collection and study database lock. The SAP will be adhered to for the final primary data analysis of the VERIFY trial. Materials and Methods Vildagliptin efficacy in combination with metformin for early treatment of T2DM (VERIFY) is an ongoing, multicentre, randomized controlled trial aiming to demonstrate the clinical benefits of glycaemic durability and glucose control achieved with an early combination therapy in newly-diagnosed type 2 diabetes (T2DM) patients. Results The SAP was initially designed at the study protocol conception phase and later modified, as reported here, in collaboration between the steering committee members, statisticians, and the VERIFY study leadership team. All authors were blinded to treatment allocation. An independent statistician has additionally retrieved and presented unblinded data to the independent data safety monitoring committee. An overview of the trial design with a focus on describing the fine-tuning of the analysis plan for the primary efficacy endpoint, risk of initial treatment failure, and secondary, exploratory and pre-specified subgroup analyses is provided here. Conclusion According to optimal trial practice, the details of the statistical analysis and data-handling plan prior to locking the database are reported here. The SAP accords with high-quality standards of internal validity to minimize analysis bias and will enhance the utility of the reported results for improved outcomes in the management of T2DM.
  • Kekkonen, Riina A.; Holma, Reetta; Hatakka, Katja; Suomalainen, Tarja; Poussa, Tuija; Adlercreutz, Herman; Korpela, Riitta (2011)
  • Palosuo, Kati; Karisola, Piia; Savinko, Terhi; Fyhrquist, Nanna; Alenius, Harri; Mäkelä, Mika J. (2021)
    BACKGROUND: Egg allergy is the second most common food allergy in children. Persistent food allergy increases the risk of anaphylaxis and reduces the quality of life. OBJECTIVE: To determine the efficacy of oral immunotherapy (OIT) with raw egg white powder and study its effects on humoral responses in children with persistent egg allergy. METHODS: Fifty children aged 6 to 17 years with egg allergy, diagnosed by double-blind, placebo-controlled food challenge, were randomized 3:2 to 8 months of OIT with a maintenance dose of 1 g of egg white protein or 6 months of avoidance after which the avoidance group crossed over to OIT. We examined changes in IgE, IgG4, and IgA concentrations to Gal d 1-4 during OIT compared with avoidance and assessed clinical reactivity at 8 and 18 months. RESULTS: After 8 months, 22 of 50 children (44%) on OIT and 1 of 21 (4.8%) on egg avoidance were desensitized to the target dose, 23 of 50 (46%) were partially desensitized (dose
  • Elsilä, Lauri V.; Korhonen, Nuppu; Hyytiä, Petri; Korpi, Esa R. (2020)
    While interest in psychedelic drugs in the fields of psychiatry and neuroscience has re-emerged in recent last decades, the general understanding of the effects of these drugs remains deficient. In particular, there are gaps in knowledge on executive functions and goal-directed behaviors both in humans and in commonly used animal models. The effects of acute doses of psychedelic lysergic acid diethylamide (LSD) on reward-driven decision making were explored using the mouse version of the Iowa Gambling Task. A total of 15 mice were trained to perform in a touch-screen adaptation of the rodent version of the Iowa Gambling Task, after which single acute doses of LSD (0.025, 0.1, 0.2, 0.4 mg/kg), serotonin 2A receptor-selective agonist 25CN-NBOH (1.5 mg/kg), d-amphetamine (2.0 mg/kg), and saline were administered before the trial. 25CN-NBOH and the three lowest doses of LSD showed no statistically significant changes in option selection or in general functioning during the gambling task trials. The highest dose of LSD (0.4 mg/kg) significantly decreased premature responding and increased the omission rate, but had no effect on option selection in comparison with the saline control. Amphetamine significantly decreased the correct responses and premature responding while increasing the omission rate. In conclusion, mice can perform previously learned, reward-driven decision-making tasks while under the acute influence of LSD at a commonly used dose range.
  • Moyano-Galceran, Lidia; Pietila, Elina A.; Turunen, S. Pauliina; Corvigno, Sara; Hjerpe, Elisabet; Bulanova, Daria; Joneborg, Ulrika; Alkasalias, Twana; Miki, Yuichiro; Yashiro, Masakazu; Chernenko, Anastasiya; Jukonen, Joonas; Singh, Madhurendra; Dahlstrand, Hanna; Carlson, Joseph W.; Lehti, Kaisa (2020)
    Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2(high), GPRC5A(high) cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.
  • Terevnikov, Viacheslav; Stenberg, Jan-Henry; Tiihonen, Jari; Burkin, Mark; Joffe, Grigori (2017)
    Aim: Sexual dysfunction, common in schizophrenia, may be further exaggerated by antipsychotics, especially those of First Generation (FGAs), and antidepressants, such as Selective Serotonin Reuptake Inhibitors (SSRs). Mirtazapine, an antidepressant characterized by its different action mechanism compared with that of the majority of other antidepressants, may improve SSRI-induced sexual dysfunction in patients with depression. It is unknown, however, whether mirtazapine improves sexual functioning in schizophrenia.Methods: This study randomly assigned FGA-treated patients with schizophrenia to receive either an add-on mirtazapine (n=20) or a placebo (n=19) for 6 weeks. Sexual functioning was prospectively measured using five relevant items from the Udvalg for Kliniske Undersogelser side-effect rating scale (UKU-SERS).Results: Orgasmic function improved with statistical significance in the mirtazapine group (p=.03), with no changes in any other sexual functions in either group.Conclusion: Add-on mirtazapine appears to relieve orgasmic dysfunction in FGA-treated patients with schizophrenia.
  • Kössi, Jyrki; Julkunen, Kristiina; Setälä, Marjaleena; Luostarinen, Markku (2016)
    Icodextrin (AdeptA (R)) has been shown to prevent postoperative adhesions in experimental and laparoscopic adhesiolysis surgery. However, the role of icodextrin in the prevention of adhesions in extensive gynecological surgery is unclear. The present study evaluated the effect of icodextrin on adhesion-related readmissions after extensive gynecological surgery. The hospital readmissions of 140 endometriosis patients operated on at Paijat-Hame Central Hospital in 2004-2008 with the use of icodextrin were retrospectively reviewed. The evaluation of readmissions focused on adhesion-related disorders and reoperations. If an abdominal or pelvic reoperation was performed, the extent of the adhesions was classified. The mean follow-up time was 6.53 years (range 0.21-9.83). After initial surgery, one patient (0.7 %) had adhesive small bowel obstruction. Another directly adhesion-related readmission occurred in two patients (1.4 %). The number of readmissions possibly related to adhesions was 3 (2.1 %). Abdominal or pelvic reoperation was performed on 54 patients (38.6 %): 4 in the open surgery group and 50 in the laparoscopic surgery group. The extent of the adhesions among the 54 reoperated patients was as follows: not mentioned in 16 patients, no adhesions in 14, mild in 18, moderate in 5, and severe in 1. There were two (3.7 %) bowel injuries (one enterotomy and one serosal lesion) in reoperations. The incidence of adhesion-related readmissions after the use of icodextrin is relatively low. This favorable result may be partly related to the laparoscopic technique. Despite the use of an anti-adhesion agent, in some patients, the extent of postoperative adhesions is severe.
  • Goncalves, Bronner P.; Pett, Helmi; Tiono, Alfred B.; Murry, Daryl; Sirima, Sodiomon B.; Niemi, Mikko; Bousema, Teun; Drakeley, Chris; ter Heine, Rob (2017)
    Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine.
  • Aro, Karoliina; Nieminen, Pekka; Louvanto, Karolina; Jakobsson, Maija; Virtanen, Seppo; Lehtinen, Matti; Dillner, Joakim; Kalliala, Ilkka (2019)
    Background and aim. Age-specific type-distribution of high-risk human papillomavirus (hrHPV) in cervical precancerous lesions is subject to change in the HPV vaccination era. Knowing the pre-vaccination type distribution helps to anticipate changes induced by mass vaccination and optimize screening. Methods. We recruited 1279 women referred to colposcopy for abnormal cytology into a population-based study on HPV type distribution in diagnostic cervical samples (ISRCTN10933736). The HPV genotyping findings were grouped as: HPV16/18+, other hrHPV+ (HPV31/33/35/39/45/51/52/56/58/59/66/68), non-vaccine targeted hrHPV+ (HPV35/39/51/56/59/66/68), low-risk HPV, and HPV negative. We estimated the HPV group-specific prevalence rates according to diagnostic histopathological findings in the age groups of = 45 (n = 326). Results. Altogether 503 cases with high grade squamous intraepithelial lesion or worse (HSIL+) were diagnosed. More than half, 285 (56.7%) of HSIL+ cases were associated with HPV16/18: 64.3% (101/157) in women = 45 years of age (RR 0.55, 95% CI 039-0.75). Conversely, other hrHPV's were associated with 191 (38.0%) of HSIL+: 31.9% (50/157) in women = 45 (RR 1.71, 95% CI 126-2.33). The proportion of non-vaccine targeted hrHPV and HPV negative HSIL+ increased with advancing age. Conclusions. Pre-vaccination HPV type distribution in HSIL+ was distinctly polarised by age with HPV16/18 attributed disease being markedly more prevalent in women aged
  • Nurmatov, U.; Dhami, S.; Arasi, S.; Pajno, G. B.; Fernandez-Rivas, M.; Muraro, A.; Roberts, G.; Akdis, C.; Alvaro-Lozano, M.; Beyer, K.; Bindslev-Jensen, C.; Burks, W.; du Toit, G.; Ebisawa, M.; Eigenmann, P.; Knol, E.; Mäkelä, Mika; Nadeau, K. C.; O'Mahony, L.; Papadopoulos, N.; Poulsen, L. K.; Sackesen, C.; Sampson, H.; Santos, A. F.; van Ree, R.; Timmermans, F.; Sheikh, A. (2017)
    Background: The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE-mediated Food Allergy. To inform the development of clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost-effectiveness of AIT in the management of food allergy. Methods: We undertook a systematic review and meta-analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT-NRS tool for quasi-RCTs. Random-effects meta-analyses were undertaken, with planned subgroup and sensitivity analyses. Results: We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty-five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty-seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta-analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease-specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta-analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses. Conclusions: AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE-mediated food allergy whilst receiving (i.e. desensitization) and post-discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost-effectiveness of AIT.
  • Jarvinen, Anna; Laine, Merja K.; Tikkanen, Roope; Castren, Maija L. (2019)
    Individuals with autism spectrum disorder (ASD) frequently display intensely repetitive, restricted thoughts, and behaviors. These behaviors have similarities to compulsions and/ or obsessions in obsessive compulsive disorder (OCD) and are primarily treated with behaviourally-based interventions and serotonin uptake inhibitors (SSRIs). Due to the lack of treatment responses in many cases, however, new treatments are being sought. Here we report beneficial effects of treatment with liraglutide, a glucagon-like peptide-1 (GLP-1) analog, on severe obsessive food craving, binge eating, weight gain, and behavioral problems in an adolescent male with infantile autism and moderate intellectual impairment. Liraglutide treatment reduced weight and unwanted behavior seemingly by preventing food-related repetitive thoughts and compulsions. Our report provides clinical evidence that GLP-1 signaling pathway may represent a novel target for treating food-related behavioral problems and aggressive behavior in ASD.
  • Hox, Valerie; Lourijsen, Evelijn; Jordens, Arnout; Aasbjerg, Kristian; Agache, Ioana; Alobid, Isam; Bachert, Claus; Boussery, Koen; Campo, Paloma; Fokkens, Wytske; Hellings, Peter; Hopkins, Claire; Klimek, Ludger; Makelä, Mika; Moesges, Ralph; Mullol, Joaquim; Pujols, Laura; Rondon, Carmen; Rudenko, Michael; Toppila-Salmi, Sanna; Scadding, Glenis; Scheire, Sophie; Tomazic, Peter-Valentin; Van Zele, Thibaut; Wagemann, Martin; van Boven, Job F. M.; Gevaert, Philippe (2020)
    Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosinusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that-potentially severe-side-effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease.
  • EFSA Panel Dietetic Prod Nutr All (2018)
    Following an application from Unilever NV, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Ireland, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to black tea and improvement of attention. The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence. The food proposed by the applicant as the subject of the health claim is black tea. The Panel considers that black tea characterised by its content of tea solids, caffeine and L-theanine, which is the subject of the health claim, is sufficiently characterised in relation to the claimed effect. The claimed effect proposed by the applicant is 'improves attention'. The Panel considers that improvement of attention is a beneficial physiological effect. Three human intervention studies provided by the applicant show an effect of black tea on attention under the conditions of used proposed by the applicant. The applicant proposed that the claimed effect depends on the concerted action of two substances, caffeine and L-theanine, both of which are present in black tea. The Panel considers that the effect of black tea on attention observed in the three human intervention studies provided by the applicant can be explained by its caffeine content. The Panel concludes that a cause and effect relationship has been established between the consumption of black tea and improvement of attention. The Panel considers that the effect of black tea on attention can be explained by its caffeine content. The following wording reflects the scientific evidence: 'Owing to its caffeine content, black tea improves attention'. In order to obtain the claimed effect, 2-3 servings of black tea providing at least 75 mg of caffeine in total should be consumed within 90 min. (C) 2018 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.
  • Valkama, Anita J.; Meinila, Jelena M.; Koivusalo, Saila B.; Lindstrom, Jaana; Rono, Kristiina; Tiitinen, Aila E.; Stach-Lempinen, Beata; Kautiainen, Hannu J.; Viljakainen, Heli; Andersson, Sture; Eriksson, Johan G. (2018)
    Obesity increases the risk of low 25-hydroxyvitamin D (25(OH) D) concentrations and gestational diabetes (GDM). We explored whether the association between GDM and change in 25(OH) D concentrations measured in the first (7-18 wk) and second (20-27 wk) trimesters of pregnancy is dependent on maternal BMI. The study was a prospective study of 219 women with BMI of >= 30 kg/m2, a history of GDM, or both. The participants were stratified by first-trimester BMI: BMI of = 35 kg/m(2). In the BMI group >= 35 kg/m(2), those who did not develop GDM during the follow-up showed higher increase in serum 25(OH) D concentrations compared with women who developed GDM (43.2 vs. 11.5%; P <0.001). No associations between 25(OH) D concentrations and GDM were observed in other BMI groups. These findings give an important aspect of the role of maternal body size in the association between vitamin D and GDM in high-risk women.
  • Ahonen, Marko T.; Diaconu, Iulia; Pesonen, Sari; Kanerva, Anna; Baumann, Marc; Parviainen, Suvi T.; Spiller, Brad; Cerullo, Vincenzo; Hemminki, Akseli (2010)
  • Huttunen, Henri J.; Saarma, Mart (2019)
    Neurotrophic factors (NTF) are a subgroup of growth factors that promote survival and differentiation of neurons. Due to their neuroprotective and neurorestorative properties, their therapeutic potential has been tested in various neurodegenerative diseases. Bioavailability of NTFs in the target tissue remains a major challenge for NTF-based therapies. Various intracerebral delivery approaches, both protein and gene transfer-based, have been tested with varying outcomes. Three growth factors, glial cell-line derived neurotrophic factor (GDNF), neurturin (NRTN) and platelet-derived growth factor (PDGF-BB) have been tested in clinical trials in Parkinson?s Disease (PD) during the past 20 years. A new protein can now be added to this list, as cerebral dopamine neurotrophic factor (CDNF) has recently entered clinical trials. Despite their misleading names, CDNF, together with its closest relative mesencephalic astrocyte-derived neurotrophic factor (MANF), form a novel family of unconventional NTF that are both structurally and mechanistically distinct from other growth factors. CDNF and MANF are localized mainly to the lumen of endoplasmic reticulum (ER) and their primary function appears to be modulation of the unfolded protein response (UPR) pathway. Prolonged ER stress, via the UPR signaling pathways, contributes to the pathogenesis in a number of chronic degenerative diseases, and is an important target for therapeutic modulation. Intraputamenally administered recombinant human CDNF has shown robust neurorestorative effects in a number of small and large animal models of PD, and had a good safety profile in preclinical toxicology studies. Intermittent monthly bilateral intraputamenal infusions of CDNF are currently being tested in a randomized placebo-controlled phase I?II clinical study in moderately advanced PD patients. Here, we review the history of growth factor-based clinical trials in PD, and discuss how CDNF differs from the previously tested growth factors.
  • Rasinkangas, Pia; Tytgat, Hanne L. P.; Ritari, Jarmo; Reunanen, Justus; Salminen, Seppo; Palva, Airi; Douillard, Francois P.; de Vos, Willem M. (2020)
    Lacticaseibacillus rhamnosusGG is one of the best studied lactic acid bacteria in the context of probiotic effects.L. rhamnosusGG has been shown to prevent diarrhea in children and adults and has been implicated to have mitigating or preventive effects in several disorders connected to microbiota dysbiosis. The probiotic effects are largely attributed to its adhesive heterotrimeric sortase-dependent pili, encoded by thespaCBA-srtC1gene cluster. Indeed, the strain-specific SpaCBA pili have been shown to contribute to adherence, biofilm formation and host signaling. In this work we set out to generate non-GMO derivatives ofL. rhamnosusGG that adhere stronger to mucus compared to the wild-type strain using chemical mutagenesis. We selected 13 derivatives that showed an increased mucus-adherent phenotype. Deep shotgun resequencing of the strains enabled division of the strains into three classes, two of which revealed SNPs (single nucleotide polymorphisms) in thespaAandspaCgenes encoding the shaft and tip adhesive pilins, respectively. Strikingly, the other class derivatives demonstrated less clear genotype - phenotype relationships, illustrating that pili biogenesis and structure is also affected by other processes. Further characterization of the different classes of derivatives was performed by PacBio SMRT sequencing and RNAseq analysis, which resulted in the identification of molecular candidates driving pilin biosynthesis and functionality. In conclusion, we report on the generation and characterization of three classes of strongly adherentL. rhamnosusGG derivatives that show an increase in adhesion to mucus. These are of special interest as they provide a window on processes and genes driving piliation and its control inL. rhamnosusGG and offer a variety of non-GMO derivatives of this key probiotic strain that are applicable in food products.