Immunomonitoring of MSC-Treated GvHD Patients Reveals Only Moderate Potential for Response Prediction but Indicates Treatment Safety

Mesenchymal stromal cells (MSCs) are used as salvage therapy to treat steroid-refractory acute graft-versus-host disease (aGvHD). We studied the immunological response to MSC treatment in 16 aGvHD patients by assessing lymphocyte profiles and three proposed aGvHD serum markers during the MSC treatment. Surprisingly, there were no obvious differences in the lymphocyte profiles between the responders and non-responders. The numbers of T, B, and NK cells were below the normal reference interval in all patients. CD4+ T helper (Th) cell levels remained particularly low throughout the follow-up period. The relative proportion of Th1 cells decreased, while regulatory T cells remained unaltered, and only very few Th2 and Th17 cells could be detected. Serum concentrations of regenerating islet-derived protein 3-alpha, cytokeratin-18 fragments (CK18F), and elafin were significantly elevated in patient samples compared with healthy controls, but only CK18F showed any potential in the prediction of patients’ response to MSCs. No obvious markers for MSC therapy response were revealed in this study, but the results suggest that allogeneic MSCs do not provoke overt T cell-mediated immune responses at least in immunosuppressed aGvHD patients. The results advocate for the safety of MSC therapy and bring new insights in MSC immunomodulation mechanisms.</p

Selvitys eräiden jätteiden ja rejektien käsittelykapasiteetin sekä muutaman jäteperäisen materiaalin markkinan tilanteesta Suomessa

Tässä työssä selvitettiin ympäristöministeriön toimeksiannosta eräiden keskeiseksi arvioitujen orgaanispitoisten jätteiden ja rejektien käsittelykapasiteetin sekä muutaman jäteperäisen kierrätysmateriaalin markkinan tilannetta Suomessa. Tarkastelu kohdistui tässä lähinnä jätteiden ja materiaalien ominaisuuksiin sekä yleisellä tasolla käsittelytavan teknistaloudellisiin reunaehtoihin sekä niiden vaikutuksiin käsittelymahdollisuuksien kannalta. Selvityksen perusteella runsaasti orgaanista ainesta sisältävien, erityisesti energia-hyödyntämiseen tai kemialliseen kierrätykseen soveltuvien teollisuuden ja kaupan jätteiden käsittelykapasiteettiin liittyy tällä hetkellä Suomessa merkittäviä haasteita. Näiden jätteiden kotimainen vastaanotto- ja varastointikapasiteetti on maksimissaan, mikä edellyttää lyhyellä tähtäimellä viennin lisäämistä ja energiahyödyntämiskapasiteetin kasvattamista. Myös uusia kierrätyssovelluksia tulisi alkaa aktiivisemmin kehittää ja ottaa käyttöön. Nykyisin kierrätysmarkkinoilla olevien jäteperäisten kierrätysmateriaalien kysyntä on sekä energiantuotannossa että kierrätysraaka-ainemarkkinoilla erittäin heikkoa. Vuoden vaihteessa 2018 Kiina lisäksi kielsi jätemuovin tuonnin ulkomailta. Osa Suomenkin kaupan ja teollisuuden muovipakkausjätteitä on aiemmin kuljetettu Kiinaan kierrätettäväksi. Heikko teollisuuden ja kaupan jätteistä valmistettujen kierrätysmateriaalien kysyntätilanne heijastuu käsittelykeskuksissa varastointitarpeen kasvuna, mitä on edelleen lisännyt talouden elpymisestä sekä vilkkaasta rakentamisesta ja korjausrakentamisesta johtuva kasvava käsittelyyn tulevan jätteen määrä ja näin myös tuotetun kierrätysmateriaalien määrää

Increased ventilatory response to exercise in symptomatic and asymptomatic LMNA mutation carriers : a follow-up study

BackgroundLMNA mutations are an important cause of cardiomyopathy often leading to cardiac arrhythmias, heart failure and even heart transplantation. An increasing number of asymptomatic mutation carriers are identified, as family members of the index patients are screened. Our aim was to study the disease progression in asymptomatic LMNA mutation carriers and in patients with symptomatic cardiolaminopathy by repeated spiroergometric testing in a prospective clinical follow-up study. Methods and ResultsWe studied 26 LMNA mutation carriers once a year during 5years up to 6 times by spiroergometry, clinical assessment, laboratory tests and echocardiography. The 23 control subjects underwent clinical assessment and spiroergometry once. Twelve of the mutation carriers were asymptomatic, and 14 had some clinical manifestations of the mutation ranging from clinically relevant rhythm disturbances to DCM and heart failure. Compared to controls, the symptomatic carriers showed a higher slope of the ventilatory equivalent for CO2 (VE/VCO2 slope) and a lower fraction of end-tidal CO2 (FetCO(2)). The asymptomatic mutation carriers also showed an increased ventilatory response to exercise during the follow-up as indicated by increased VE/VCO2 slope and decreased FetCO(2). ConclusionsThe study suggests that an increased ventilatory response during exercise might reveal a preclinical manifestation of DCM in LMNA mutation carriers.Peer reviewe

Late gadolinium enhanced cardiovascular magnetic resonance of lamin A/C gene mutation related dilated cardiomyopathy

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Phase 1 Lymfactin® Study: 24-month Efficacy and Safety Results of Combined Adenoviral VEGF-C and Lymph Node Transfer Treatment for Upper Extremity Lymphedema

BACKGROUNDLymphedema is a common problem after breast cancer treatment. Lymfactin® is a prolymphangiogenic growth factor vector inducing the expression of human vascular endothelial growth factor C (VEGF-C). It promotes growth and repair of lymphatic vessels.METHODSLymfactin® was combined with microvascular lymph node transfer surgery (VLNT) to study the safety and efficacy of the treatment in breast cancer-related upper limb lymphedema (BCRL) patients. This is a continuation study with a 3 year efficacy and 5 year safety follow-up.RESULTSFifteen patients were recruited in the study between June 2016 and February 2018. Three patients received a lower dose (1 × 1010 viral particles (vp)), and 12 patients received a higher dose (1 × 1011 vp) of Lymfactin®, respectively. In the higher dose group, the reduction of excess arm volume was on average 46% after the 12 month follow-up, and the transport index was improved in 7/12 patients. At baseline, removal of the compression garment for 7 days resulted in significant arm swelling (105.7±161.0 ml, p=0.0253). However, at 12 months, there was less and not significant swelling after removal of the garment (84.4±143.0 ml, p=0.0682). Lymphedema Quality of Life Inventory (LQOLI or LyQLI) questionnaire showed significant and sustained improvement of quality of life.CONCLUSIONSDuring 24 months' of follow-up, the results indicate that Lymfactin® is well tolerated. The most promising findings were a 46% reduction in excess arm volume and a nonsignificant volume increase after garment removal at 12 months, suggesting that there is potential for the reduction of lymphedema.</p

Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy

Aims Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published. Methods and results We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 +/- 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P <0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P <0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P <0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden. Conclusions We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually.Peer reviewe

Serum Lipidomics Meets Cardiac Magnetic Resonance Imaging: Profiling of Subjects at Risk of Dilated Cardiomyopathy

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A High-Protein, Low Glycemic Index Diet Suppresses Hunger but Not Weight Regain After Weight Loss : Results From a Large, 3-Years Randomized Trial (PREVIEW)

Correction Volume 8 Article Number 736531 DOI 10.3389/fnut.2021.736531 Published JUL 23 2021Background: Previous studies have shown an increase in hunger during weight-loss maintenance (WLM) after diet-induced weight loss. Whether a combination of a higher protein, lower glycemic index (GI) diet and physical activity (PA) can counteract this change remains unclear. Aim: To compare the long-term effects of two diets [high protein (HP)-low GI vs. moderate protein (MP)-moderate GI] and two PA programs [high intensity (HI) vs. moderate intensity (MI)] on subjective appetite sensations during WLM after >= 8% weight loss (WL). Methods: Data derived from the 3-years PREVIEW randomized intervention study. An 8-weeks WL phase using a low-energy diet was followed by a 148-weeks randomized WLM phase. For the WLM phase, participants were assigned to one of the four groups: HP-MI, HP-HI, MP-MI, and MP-HI. Available data from 2,223 participants with overweight or obesity (68% women; BMI >= 25 kg/m(2)). Appetite sensations including satiety, hunger, desire to eat, and desire to eat something sweet during the two phases (at 0, 8 weeks and 26, 52, 104, and 156 weeks) were assessed based on the recall of feelings during the previous week using visual analogue scales. Differences in changes in appetite sensations from baseline between the groups were determined using linear mixed models with repeated measures. Results: There was no significant diet x PA interaction. From 52 weeks onwards, decreases in hunger were significantly greater in HP-low GI than MP-moderate GI (P-time x diet = 0.018, P-dietgroup = 0.021). Although there was no difference in weight regain between the diet groups (P-time x diet = 0.630), hunger and satiety ratings correlated with changes in body weight at most timepoints. There were no significant differences in appetite sensations between the two PA groups. Decreases in hunger ratings were greater at 52 and 104 weeks in HP-HI vs. MP-HI, and greater at 104 and 156 weeks in HP-HI vs. MP-MI. Conclusions: This is the first long-term, large-scale randomized intervention to report that a HP-low GI diet was superior in preventing an increase in hunger, but not weight regain, during 3-years WLM compared with a MP-moderate GI diet. Similarly, HP-HI outperformed MP-HI in suppressing hunger. The role of exercise intensity requires further investigation.Peer reviewe

Lamin A/C mutation affecting primarily the right side of the heart

LMNA mutations are amongst the most important causes of familial dilated cardiomyopathy. The most important cause of arrhythmogenic right ventricular cardiomyopathy (ARVC) is desmosomal pathology. The aim of the study was to elucidate the role of LMNA mutations among Finnish cardiomyopathy patients. We screened 135 unrelated cardiomyopathy patients for LMNA mutations. Because of unusual phenotype, two patients were screened for the known Finnish ARVC-related mutations of desmosomal genes, and their Plakophilin-2b gene was sequenced. Myocardial samples from two patients were examined by immunohistochemical plakoglobin staining and in one case by electron microscopy. We found a new LMNA mutation Phe237Ser in a family of five affected members with a cardiomyopathy affecting primarily the right side of the heart. The phenotype resembles ARVC but does not fulfill the Task Force Criteria. The main clinical manifestations of the mutation were severe tricuspid insufficiency, right ventricular enlargement and failure. Three of the affected patients died of the heart disease, and the two living patients received heart transplants at ages 44 and 47. Electron microscopy showed nuclear blebbing compatible with laminopathy. Immunohisto - chemical analysis did not suggest desmosomal pathology. No desmosomal mutations were found. The Phe237Ser LMNA mutation causes a phenotype different from traditional cardiolaminopathy. Our findings suggest that cardiomyopathy affecting primarily the right side of the heart is not always caused by desmosomal pathology. Our observations highlight the challenges in classifying cardiomyopathies, as there often is significant overlap between the traditional categories.Peer reviewe