Publications by authors named "Nieminen T"

323 Publications

A Truncating Germline Mutation of in Individuals with Thyroid Cancer or Melanoma Results in Longer Telomeres.

Thyroid 2020 02;30(2):204-213

Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Our genome sequencing analysis revealed a frameshift mutation in the shelterin gene in a large family with individuals affected with papillary thyroid carcinoma (PTC) and melanoma. Here, we further characterized the mutation and screened for coding variants in the 6 shelterin genes in 24 families. Sanger sequencing was performed to screen for the mutation in the key family. Quantitative reverse transcription-polymerase chain reaction (PCR) was used for gene expression analysis. Exogenous expression and co-immunoprecipitation techniques were used for assessing TINF2 binding to TERF1. Relative telomere length (RTL) was quantified in DNAs from lymphocytes by using quantitative real-time PCR. Whole exome sequencing (WES) was performed in seven families with individuals affected with PTC and other cancer types. Screening for DNA variants in shelterin genes was performed by using whole genome sequencing data from 17 families and WES data from 7 further families. The mutation (TINF2 p.Trp198fs) showed complete co-segregation with PTC and melanoma in the key family. The mutation is not reported in databases and not identified in 23 other families we screened. The expression of was borderline reduced in individuals with the mutation. The truncated TINF2 protein showed abolished binding to TERF1. The RTL in the individuals with the mutation was significantly longer when compared with those without the mutation from the same family as well as compared with 62 healthy controls. Among the 24 families, we identified 3 missense and 1 synonymous variant(s) in 2 shelterin genes ( and ). The rare frameshift mutation in the gene and the associated longer telomere length suggest that dysregulated telomeres could be a mechanism predisposing to PTC and melanoma. DNA coding variants in shelterin genes are rare. Further studies are required to evaluate the roles of variants in shelterin genes in thyroid cancer and melanoma.
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http://dx.doi.org/10.1089/thy.2019.0156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047085PMC
February 2020

Long-term prognostic significance of the ST level and ST slope in the 12‑lead ECG in the general population.

J Electrocardiol 2020 Jan - Feb;58:176-183. Epub 2019 Dec 16.

Faculty of Medicine and Health Technology, Tampere University, and Finnish Cardiovascular Research Center, Tampere, Finland; Heart Center, Department of Cardiology, Tampere University Hospital, Tampere, Finland.

Background: Even minor ST depression in the electrocardiogram (ECG) is associated with cardiovascular disease and increased mortality. There is limited data on the prognostic significance of ST-level changes in the general population.

Subjects And Methods: A random sample of Finnish subjects (n = 6354) aged over 30 years (56.1% women) underwent a health examination including a 12‑lead ECG in the Health 2000 survey. The effects of relative ST level as a continuous variable and ST slope (upsloping, horizontal, downsloping) in three different lead groups were analyzed using a multi-adjusted Cox proportional hazard model separately for men and women with total mortality as endpoint.

Results: The follow-up lasted for 13.7 (SD 3.3) years for men and 13.9 (SD 3.1) years for women. Lower lateral ST levels were associated with all-cause mortality in multi-adjusted models in both genders (at J + 80 ms hazard ratio [HR] 0.64 for a change of 1.0 mm [95% confidence interval 0.49-0.84, p = 0.002] for men and HR 0.61 [0.48-0.78, p < 0.001] for women). Associated coronary heart disease had no major influence on the results. Exclusion of subjects with ECG signs of left ventricular hypertrophy from the analyses increased the mortality risk of lower lateral ST levels in men but decreased it in women. For the anterior and inferior lead groups, no statistically significant difference was seen after multivariate adjustment. ST slope was not an independent predictor of mortality after multivariate adjustment.

Conclusion: Lower ST level in the lateral ECG leads is an independent prognostic factor to predict all-cause mortality in the general population.
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http://dx.doi.org/10.1016/j.jelectrocard.2019.12.010DOI Listing
June 2021

Future Perspectives on the Role of Frailty in Cardiovascular Diseases.

Adv Exp Med Biol 2020 ;1216:149-152

Department of Internal Medicine of University of Helsinki, Helsinki University Hospital and Päijät Häme Central Hospital, Helsinki, Lahti, Finland.

Frailty is a clinical concept which is gaining increased momentum not only in geriatrics, but in all specialties treating adult patients. In these Future Perspectives, the following roles of frailty in the field of cardiovascular diseases (CVD) will be discussed as a narrative review: (1) Frailty as an adjunct to assess CVD patients in addition to traditional risk scores; (2) bidirectional relationship between frailty and CVD; (3) widening the scope of endpoints in CVD trials-inclusion of frailty; (4) finally, the relationship between geriatrics and cardiology will be shortly discussed.
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http://dx.doi.org/10.1007/978-3-030-33330-0_14DOI Listing
February 2020

Optical-trapping of particles in air using parabolic reflectors and a hollow laser beam.

Opt Express 2019 Nov;27(23):33061-33069

We present an advanced optical-trapping method that is capable of trapping arbitrary shapes of transparent and absorbing particles in air. Two parabolic reflectors were used to reflect the inner and outer parts of a single hollow laser beam, respectively, to form two counter-propagating conical beams and bring them into a focal point for trapping. This novel design demonstrated high trapping efficiency and strong trapping robustness with a simple optical configuration. Instead of using expensive microscope objectives, the parabolic reflectors can not only achieved large numerical aperture (N.A.) focusing, but were also able to focus the beam far away from optical surfaces to minimize optics contamination. This design also offered a large free space for flexible integration with other measuring techniques, such as optical-trapping Raman spectroscopy, for on-line single particle characterization.
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http://dx.doi.org/10.1364/OE.27.033061DOI Listing
November 2019

Childhood nontuberculous mycobacterial lymphadenitis-observation alone is a good alternative to surgery.

Int J Pediatr Otorhinolaryngol 2020 Feb 12;129:109778. Epub 2019 Nov 12.

Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. Electronic address:

Objective: Cervicofacial lymphadenitis caused by nontuberculous mycobacteria (NTM) is commonly treated with surgery or antimicrobial therapy. The aim of this study was to analyze the utility of our new blood-based diagnostic method and the treatment protocol, surgery or observation alone, in NTM lymphadenitis in children.

Methods: All patients under 16 years of age with cervicofacial NTM lymphadenitis diagnosed and treated at Children's Hospital or at the Department of Otorhinolaryngology, Helsinki University Hospital (Helsinki, Finland) in 2007-2017 were retrospectively reviewed.

Results: Fifty-two patients, 33 (63%) of whom were girls, were included in the study. The median age at initial presentation of the NTM lymphadenitis was 2.9 years. The novel blood-test had been performed on 49 (94%) of the patients and in all of them it was indicative of NTM infection. A sample for mycobacterial culture was available from 34 patients, and Mycobacterium avium was the most common species detected. Most patients (n = 33, 63%) were treated conservatively with observation alone. Of these, nine patients (27%) did not develop a skin fistula, and the lymphadenitis resolved without drainage.

Conclusions: The novel blood test is clinically feasible method for diagnosing childhood cervicofacial NTM lymphadenitis noninvasively. Observation alone is a good alternative to surgery, without the risk of complications.
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http://dx.doi.org/10.1016/j.ijporl.2019.109778DOI Listing
February 2020

Global Burden of Small Vessel Disease-Related Brain Changes on MRI Predicts Cognitive and Functional Decline.

Stroke 2020 01 8;51(1):170-178. Epub 2019 Nov 8.

From the Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital (H.J., H.M.L., S. Melkas, T.E.), Finland.

Background and Purpose- Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease-related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods- Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results- The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (<0.001 for global cognitive function, processing speed, executive functions, and memory and <0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on scores strongly predicted cognitive and functional outcomes (<0.001) even above the contribution of the individual brain changes. Conclusions- Global burden of small vessel disease-related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.
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http://dx.doi.org/10.1161/STROKEAHA.119.026170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924941PMC
January 2020

Combination of low blood pressure response, low exercise capacity and slow heart rate recovery during an exercise test significantly increases mortality risk.

Ann Med 2019 Nov - Dec;51(7-8):390-396. Epub 2019 Nov 7.

Department of Clinical Physiology and Nuclear Medicine, Tampere University Hospital, Tampere, Finland.

We investigated the combination of low systolic blood pressure (SBP) response, low exercise capacity (EC) and slow heart rate recovery (HRR) during an exercise test in mortality prediction. Our population consisted of 3456 patients from the Finnish Cardiovascular Study. A failure of SBP to increase >42 mmHg was defined as a low response. Low EC was defined as  < 8 metabolic equivalents. 1-minute HRR ≤18 bpm from maximum was defined as slow HRR. During a median follow up of 10.0 years, 537 participants died. Reduced SBP response, low EC and slow HRR were independent predictors of all-cause and CV mortality ( < .001 for all). Patients with reduced SBP response, low EC and slow HRR had a very high mortality rate of 42.1% during follow up compared to only 4.5% of the patients without any of these risk factors. The hazard ratios for all-cause mortality in patients with one, two or three of the studied risk factors were 3.2, 6.0, and 10.6, respectively ( < .001 for all). The combination of reduced SBP response, low exercise capacity, and reduced HRR in an exercise test is associated with very high mortality and can be used in risk stratification.Key messagesThe combination of low blood pressure response, low exercise capacity and slow heart rate recovery in an exercise test is able to identify a group of patients in a very high mortality risk.These parameters are easily derived from an exercise test.All parameters are commonly available in clinical practice.
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http://dx.doi.org/10.1080/07853890.2019.1684550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877875PMC
July 2020

Cardiorespiratory fitness and heart rate recovery predict sudden cardiac death independent of ejection fraction.

Heart 2020 03 17;106(6):434-440. Epub 2019 Aug 17.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Objective: To evaluate whether cardiorespiratory fitness (CRF) and heart rate recovery (HRR) associate with the risk of sudden cardiac death (SCD) independently of left ventricular ejection fraction (LVEF).

Methods: The Finnish Cardiovascular Study is a prospective clinical study of patients referred to clinical exercise testing in 2001-2008 and follow-up until December 2013. Patients without pacemakers undergoing first maximal or submaximal exercise testing with cycle ergometer were included (n=3776). CRF in metabolic equivalents (METs) was estimated by achieving maximal work level. HRR was defined as the reduction in heart rate 1 min after maximal exertion. Adjudication of SCD was based on death certificates. LVEF was measured for clinical indications in 71.4% of the patients (n=2697).

Results: Population mean age was 55.7 years (SD 13.1; 61% men). 98 SCDs were recorded during a median follow-up of 9.1 years (6.9-10.7). Mean CRF and HRR were 7.7 (SD 2.9) METs and 25 (SD 12) beats/min/min. Both CRF and HRR were associated with the risk of SCD in the entire study population (HR0.47 (0.37-0.59), p<0.001 and HR0.57 (0.48-0.67), p<0.001 with HR estimates corresponding to one SD increase in the exposure variables) and with CRF, HRR and LVEF in the same model (HR0.60 (0.45-0.79), p<0.001, HR0.65 (0.51-0.82), p<0.001) or adjusting additionally for all significant risk factors for SCD (LVEF, sex, creatinine level, history of myocardial infarction and atrial fibrillation, corrected QT interval) (HR0.69 (0.52-0.93), p<0.01, HR0.74 (0.58-0.95) p=0.02).

Conclusions: CRF and HRR are significantly associated with the risk of SCD regardless of LVEF.
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http://dx.doi.org/10.1136/heartjnl-2019-315198DOI Listing
March 2020

Mycoplasma pneumoniae outbreak, Southeastern Finland, 2017-2018: molecular epidemiology and laboratory diagnostic lessons.

Eur J Clin Microbiol Infect Dis 2019 Oct 1;38(10):1867-1871. Epub 2019 Jul 1.

Kymenlaakso Central Hospital, Kotka, Finland.

This study characterizes a large Mycoplasma pneumoniae outbreak observed in Kymenlaakso in Southeastern Finland during August 2017-January 2018. The first part of the investigation included 327 patients, who sought healthcare consultation at local GPs or hospitals due to clinical symptoms, and were tested for M. pneumoniae antibodies (Patient cohort). The second part of the investigation, conducted approximately 4 weeks after the peak of the outbreak, consisted of school screening of pupils (N = 239) in three different school buildings by PCR on respiratory specimens and questionnaires (Screening cohort). PCR positive respiratory specimens were subsequently utilized for molecular typing. The outbreak peaked in late October 2017. Of the Patient cohort, 9/106 (8.5%) respiratory specimens were PCR positive. In contrast, 3/182 (1.6%) of the Screening cohort were PCR positive. Asymptomatic carriage was observed. Multiple-locus variable-number tandem-repeat analysis (MLVA) identified two distinct MLVA types. All typed M. pneumoniae strains belonged to P1 type 1. No mutations leading to macrolide resistance were observed. In total, 61/327 (19%) of the Patient cohort had a serological indication of recent infection. The IgM test reactivity at the time of a negative PCR test result varied from a completely non-reactive value up to very strong reactivity, highlighting the difficulty in a single specimen serodiagnosis.
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http://dx.doi.org/10.1007/s10096-019-03619-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778538PMC
October 2019

Detected during a Pneumonia Outbreak in Southeastern Finland, in 2017⁻2018.

Microorganisms 2019 May 17;7(5). Epub 2019 May 17.

Department of Virology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland.

Community-acquired pneumonia (CAP) is a common disease responsible for significant morbidity and mortality. However, the definite etiology of CAP often remains unresolved, suggesting that unknown agents of pneumonia remain to be identified. The recently discovered members of the order Chlamydiales, Chlamydia-related bacteria (CRB), are considered as possible emerging agents of CAP. is the most studied candidate. It survives and replicates inside free-living amoeba, which it might potentially use as a vehicle to infect animals and humans. A outbreak was observed in Kymenlaakso region in Southeastern Finland during August 2017-January 2018. We determined the occurrence of Chlamydiales bacteria and their natural host, free-living amoeba in respiratory specimens collected during this outbreak with molecular methods. Altogether, 22/278 (7.9%) of the samples contained Chlamydiales DNA. By sequence analysis, majority of the CRBs detected were members of the Parachlamydiaceae family. Amoebal DNA was not detected within the sample material. Our study further proposes that Parachlamydiaceae could be a potential agent causing atypical CAP in children and adolescents.
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http://dx.doi.org/10.3390/microorganisms7050141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560421PMC
May 2019

Machine learning wall effects of eccentric spheres for convenient computation.

Phys Rev E 2019 Apr;99(4-1):043304

The University of Queensland, School of Mathematics and Physics, Brisbane QLD 4072, Australia.

In confined systems, such as the inside of a biological cell, the outer boundary or wall can affect the dynamics of internal particles. In many cases of interest both the internal particle and outer wall are approximately spherical. Therefore, quantifying the wall effects from an outer spherical boundary on the motion of an internal eccentric sphere is very useful. However, when the two spheres are not concentric, the problem becomes nontrivial. In this paper we improve existing analytical methods to evaluate these wall effects and then train a feed-forward artificial neural network within a broader model. The final model generally performed with ∼0.001% error within the training domain and ∼0.05% when the outer spherical wall was extrapolated to an infinite plane. Through this model, the wall effects of an outer spherical boundary on the arbitrary motion of an internal sphere for all experimentally achievable configurations can now be conveniently and efficiently determined.
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http://dx.doi.org/10.1103/PhysRevE.99.043304DOI Listing
April 2019

Continuous 4-week ECG monitoring with adhesive electrodes reveals AF in patients with recent embolic stroke of undetermined source.

Ann Noninvasive Electrocardiol 2019 09 2;24(5):e12649. Epub 2019 May 2.

Department of Internal medicine, Päijät-Häme Central Hospital, Lahti, Finland.

Background: Atrial fibrillation (AF) frequently escapes routine stroke workup due to its unpredictable and often asymptomatic nature, leaving a significant portion of patients at high risk of recurrent stroke. Recent trials emphasized continuous electrocardiogram (ECG) monitoring in the detection of occult AF. We screened AF in patients meeting the embolic stroke of unknown source (ESUS) criteria using an external miniaturized recorder with an adhesive electrode.

Methods: Patients aged ≥50 with recent ESUS were prospectively screened and assigned to wear a 1-lead ECG device capable to record continuous ECG for up to 4 weeks. Electrodes were replaced every 3-4 days. Primary outcome was proportion of patients completing at least 80% of monitoring. Secondary outcome measures included incidence of AF and initiation of oral anticoagulation therapy after AF detection.

Results: Fifty-seven patients were monitored (mean age 64.5 ± 8.2 years, median delay from stroke to the start of monitoring 8 days, IQR 4-44). Of these, 51 patients (89.5%) completed at least 80% of the desired monitoring period. We detected AF ≥30 s in seven patients (12.3%), all of whom initiated anticoagulation therapy. Atrial fibrillation was revealed in six patients (85.7%) within the first week of monitoring. Compared to patients without AF, patients with AF were older (70.6 ± 5.1 vs. 63.6 ± 8.3 years, p < 0.011) and more obese (body mass index 30.0 ± 3.4 vs. 26.6 ± 4.6, p < 0.039).

Conclusions: Prolonged ECG monitoring with an external device using adhesive electrodes is feasible in ESUS patients, since nine out of ten patients used the device appropriately and AF was detected in one out of eight patients.
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http://dx.doi.org/10.1111/anec.12649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850068PMC
September 2019

High-speed transverse and axial optical force measurements using amplitude filter masks.

Opt Express 2019 Apr;27(7):10034-10049

Direct optical force measurement is a versatile method used in optical tweezers experiments, providing accurate measurements of forces for a wide range of particles and trapping beams. It is based on the detection of the change of the momentum of light scattered by a trapped object. A digital micromirror device can be used to selectively reflect light in different directions using an appropriately defined mask. We have developed position-sensitive masked detection (PSMD) for measuring transverse (radial) and axial forces. The method is comparable in performance to the fastest split detectors, while maintaining the linearity and customizability similar to duo-lateral position-sensitive detectors (PSD) and cameras. We show an order of magnitude increase in the bandwidth compared to a conventional PSD for radial forces. We measure axial force and verify the measurement using the Stokes drag for the particle. Combining both detectors (PSMD and PSD), we can perform full 3-D optical force measurements in real time.
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http://dx.doi.org/10.1364/OE.27.010034DOI Listing
April 2019

Response to Yang et al.

Genet Med 2019 11 2;21(11):2652-2653. Epub 2019 May 2.

Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

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http://dx.doi.org/10.1038/s41436-019-0530-1DOI Listing
November 2019

Identification of Rare Variants Predisposing to Thyroid Cancer.

Thyroid 2019 07 13;29(7):946-955. Epub 2019 May 13.

1Human Cancer Genetics Program and Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Familial non-medullary thyroid cancer (NMTC) accounts for a relatively small proportion of thyroid cancer cases, but it displays strong genetic predisposition. So far, only a few NMTC susceptible genes and low-penetrance variants contributing to NMTC have been described. This study aimed to identify rare germline variants that may predispose individuals to NMTC by sequencing a cohort of 17 NMTC families. Whole-genome sequencing and genome-wide linkage analysis were performed in 17 NMTC families. MendelScan and BasePlayer were applied to screen germline variants followed by customized filtering. The remaining candidate variants were subsequently validated by Sanger sequencing. A panel of 277 known cancer predisposition genes was also screened in these families. A total of 41 rare coding candidate variants in 40 genes identified by whole-genome sequencing are reported, including 24 missense, five frameshift, five splice change, and seven nonsense variants. Sanger sequencing confirmed all 41 rare variants and proved their co-segregation with NMTC in the extended pedigrees. functional analysis of the candidate genes using Ingenuity Pathway Analysis showed that cancer was the top category of "Diseases and Disorders." Additionally, a targeted search displayed six variants in known cancer predisposition genes, including one frameshift variant and five missense variants. The data identify rare germline variants that may play important roles in NMTC predisposition. It is proposed that in future research including functional characterization, these variants and genes be considered primary candidates for thyroid cancer predisposition.
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http://dx.doi.org/10.1089/thy.2018.0736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648188PMC
July 2019

Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes.

Annu Rev Biophys 2019 05;48:421-439

Computational Physics Laboratory, Tampere University, FI-33014 Tampere, Finland.

Cell signaling controls essentially all cellular processes. While it is often assumed that proteins are the key architects coordinating cell signaling, recent studies have shown more and more clearly that lipids are also involved in signaling processes in a number of ways. Lipids do, for instance, act as messengers, modulate membrane receptor conformation and dynamics, and control membrane receptor partitioning. Further, through structural modifications such as oxidation, the functions of lipids as part of signaling processes can be modified. In this context, in this article we discuss the understanding recently revealed by atomistic and coarse-grained computer simulations of nanoscale processes and underlying physicochemical principles related to lipids' functions in cellular signaling.
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http://dx.doi.org/10.1146/annurev-biophys-052118-115553DOI Listing
May 2019

Axon Guidance-Related Factor FLRT3 Regulates VEGF-Signaling and Endothelial Cell Function.

Front Physiol 2019 12;10:224. Epub 2019 Mar 12.

A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.

Vascular endothelial growth factors (VEGFs) are key mediators of endothelial cell (EC) function in angiogenesis. Emerging knowledge also supports the involvement of axon guidance-related factors in the regulation of angiogenesis and vascular patterning. In the current study, we demonstrate that fibronectin and leucine-rich transmembrane protein-3 (FLRT3), an axon guidance-related factor connected to the regulation of neuronal cell outgrowth and morphogenesis but not to VEGF-signaling, was upregulated in ECs after VEGF binding to VEGFR2. We found that FLRT3 exhibited a transcriptionally paused phenotype in non-stimulated human umbilical vein ECs. After VEGF-stimulation its nascent RNA and mRNA-levels were rapidly upregulated suggesting that the regulation of FLRT3 expression is mainly occurring at the level of transcriptional elongation. Blockage of FLRT3 by siRNA decreased survival of ECs and their arrangement into capillary-like structures but enhanced cell migration and wound closure in wound healing assay. Bifunctional role of FLRT3 in repulsive vs. adhesive cell signaling has been already detected during embryogenesis and neuronal growth, and depends on its interactions either with UNC5B or another FLRT3 expressed by adjacent cells. In conclusion, our findings demonstrate that besides regulating neuronal cell outgrowth and morphogenesis, FLRT3 has a novel role in ECs via regulating VEGF-stimulated EC-survival, migration, and tube formation. Thus, FLRT3 becomes a new member of the axon guidance-related factors which participate in the VEGF-signaling and regulation of the EC functions.
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http://dx.doi.org/10.3389/fphys.2019.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423482PMC
March 2019

Chronic kidney disease and acute kidney injury in arthroplasty patients over 65 years of age.

Acta Anaesthesiol Scand 2019 08 19;63(7):859-870. Epub 2019 Mar 19.

Department of Anaesthesiology, Medical Research Center Oulu, University of Oulu, Oulu University Hospital, Oulu, Finland.

Background: The purpose of this study was to evaluate the prevalence of chronic kidney disease (CKD) and the incidence of perioperative acute kidney injury (AKI) in primary arthroplasty patients over 65 years of age. Risk factors, perioperative events and the outcome of surgery were evaluated.

Methods: This retrospective, hospital register-based study consists of patients operated in 2014 in the area of Oulu, Finland. The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula. The incidence of AKI was evaluated based on the serum creatinine criteria of the KDIGO (Kidney Disease, Improving Global Outcomes) classification.

Results: Of the 807 patients, 60.8% had mildly decreased (60-89 ml/min/1.73 m ) and 13.5% moderately to severely decreased eGFR (<60 ml/min/1.73 m ) preoperatively. Only 33.9% of patients with an eGFR < 60 ml/min/1.73 m had a diagnosis of a kidney disease. In emergencies, 46.9% of patients with an eGFR < 60 ml/min/1.73 m were deceased at the 12-month follow-up point. The measurement of postoperative sCr was not complete (477/807) and was allocated to emergencies and older patient with more comorbidities. Of those whose postoperative sCr was available, 14 (2.9%) fulfilled AKI criteria. Most of the AKI cases had a decrease in eGFR preoperatively, a diagnosed kidney disease or diabetes mellitus.

Conclusions: Impairment of kidney function was common and was related to mortality in emergency arthroplasties. Measurements of postoperative sCr were allocated to high risk patients. Preoperative kidney function, kidney disease and diabetes mellitus were important determinants for perioperative AKI.
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http://dx.doi.org/10.1111/aas.13352DOI Listing
August 2019

Measuring local properties inside a cell-mimicking structure using rotating optical tweezers.

J Biophotonics 2019 07 20;12(7):e201900022. Epub 2019 Mar 20.

Department of Physics, School of Mathematics and Physics, The University of Queensland, Brisbane, Queensland, Australia.

Exploring the rheological properties of intracellular materials is essential for understanding cellular and subcellular processes. Optical traps have been widely used for physical manipulation of micro and nano objects within fluids enabling studies of biological systems. However, experiments remain challenging as it is unclear how the probe particle's mobility is influenced by the nearby membranes and organelles. We use liposomes (unilamellar lipid vesicles) as a simple biomimetic model of living cells, together with a trapped particle rotated by optical tweezers to study mechanical and rheological properties inside a liposome both theoretically and experimentally. Here, we demonstrate that this system has the capacity to predict the hydrodynamic interaction between three-dimensional spatial membranes and internal probe particles within submicron distances, and it has the potential to aid in the design of high resolution optical micro/nanorheology techniques to be used inside living cells.
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http://dx.doi.org/10.1002/jbio.201900022DOI Listing
July 2019

Long-term prognostic impact of hyperuricemia in community.

Scand J Clin Lab Invest 2019 May 19;79(3):148-153. Epub 2019 Feb 19.

a Department of Internal Medicine , Päijät-Häme Central Hospital , Lahti , Finland.

The debate whether an elevated level of serum uric acid (SUA) is an independent marker of cardiovascular risk is still going on. We examined morbidity and mortality related to SUA and hyperuricemia in a well-characterized population with very long follow-up. Study included 4696 participants (aged 30-59 years at baseline) of the coronary heart disease (CHD) Study of the Finnish Mobile Clinic Health Examination Survey. Adjusted hazard ratios (HRs) of hyperuricemia (defined as ≥360 µmol/l and ≥420 µmol/l) and SUA quintiles for mortality and adverse cardiovascular outcomes are reported. During the mean follow up of 30.6 years there were 2723 deaths, 887 deaths for CHD of which 340 were classified as sudden cardiac deaths, 1642 hospitalizations due to CHD and 798 hospitalizations due to congestive heart failure. After adjusting to baseline risk factors and presence of cardiovascular diseases as well as the use of diuretics there were no significant differences in the risk of any of the outcomes when analyzed either according to quintiles of SUA or using a cut-off point SUA ≥360 µmol/l for hyperuricemia. Only a rare finding of hyperuricemia SUA ≥420 µmol/l among women (n = 17, 0.9%) was independently associated with significantly higher risk of mortality (adjusted HR: 2.59, 95% CI: 1.54-4.34) and a combination end-point of major adverse cardiac events (MACEs) (HR: 2.69; 95% CI: 1.56-4.66). SUA was not an independent indicator of morbidity and mortality, with the exception of particularly high levels of SUA among women.
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http://dx.doi.org/10.1080/00365513.2019.1576098DOI Listing
May 2019

Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.

Genet Med 2019 08 21;21(8):1868-1873. Epub 2018 Dec 21.

Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland.

Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes.

Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility.

Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability.

Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
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http://dx.doi.org/10.1038/s41436-018-0405-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752675PMC
August 2019

Stroke Risk Period After Acute Myocardial Infarction Revised.

J Am Heart Assoc 2018 11;7(22):e011200

3 Internal Medicine University of Helsinki and Helsinki University Hospital and South Karelia Central Hospital Lappeenranta Finland.

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http://dx.doi.org/10.1161/JAHA.118.011200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404430PMC
November 2018

Population Genetics and Characterization of Campylobacter jejuni Isolates from Western Jackdaws and Game Birds in Finland.

Appl Environ Microbiol 2019 02 6;85(4). Epub 2019 Feb 6.

Department of Food Hygiene and Environmental Health, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland

Poultry are considered a major reservoir and source of human campylobacteriosis, but the roles of environmental reservoirs, including wild birds, have not been assessed in depth. In this study, we isolated and characterized from western jackdaws ( = 91, 43%), mallard ducks ( = 82, 76%), and pheasants ( = 9, 9%). Most of the western jackdaw and mallard duck isolates represented multilocus sequence typing (MLST) sequence types (STs) that diverged from those previously isolated from human patients and various animal species, whereas all pheasant isolates represented ST-19, a common ST among human patients and other hosts worldwide. Whole-genome MLST revealed that mallard duck ST-2314 and pheasant ST-19 isolates represented bacterial clones that were genetically highly similar to human isolates detected previously. Further analyses revealed that in addition to a divergent ClonalFrame genealogy, certain genomic characteristics of the western jackdaw isolates, e.g., a novel gene cluster and the type VI secretion system (T6SS), may affect their host specificity and virulence. Game birds may thus pose a risk for acquiring campylobacteriosis; therefore, hygienic measures during slaughter and meat handling warrant special attention. The roles of environmental reservoirs, including wild birds, in the molecular epidemiology of have not been assessed in depth. Our results showed that game birds may pose a risk for acquiring campylobacteriosis, because they had genomotypes highly similar to human isolates detected previously. Therefore, hygienic measures during slaughter and meat handling warrant special attention. On the contrary, a unique phylogeny was revealed for the western jackdaw isolates, and certain genomic characteristics identified among these isolates are hypothesized to affect their host specificity and virulence. Comparative genomics within sequence types (STs), using whole-genome multilocus sequence typing (wgMLST), and phylogenomics are efficient methods to analyze the genomic relationships of isolates.
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http://dx.doi.org/10.1128/AEM.02365-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365822PMC
February 2019

Multicomponent new particle formation from sulfuric acid, ammonia, and biogenic vapors.

Sci Adv 2018 Dec 12;4(12):eaau5363. Epub 2018 Dec 12.

Institute for Atmospheric and Earth System Research/Physics, Faculty of Science, University of Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland.

A major fraction of atmospheric aerosol particles, which affect both air quality and climate, form from gaseous precursors in the atmosphere. Highly oxygenated organic molecules (HOMs), formed by oxidation of biogenic volatile organic compounds, are known to participate in particle formation and growth. However, it is not well understood how they interact with atmospheric pollutants, such as nitrogen oxides (NO ) and sulfur oxides (SO ) from fossil fuel combustion, as well as ammonia (NH) from livestock and fertilizers. Here, we show how NO suppresses particle formation, while HOMs, sulfuric acid, and NH have a synergistic enhancing effect on particle formation. We postulate a novel mechanism, involving HOMs, sulfuric acid, and ammonia, which is able to closely reproduce observations of particle formation and growth in daytime boreal forest and similar environments. The findings elucidate the complex interactions between biogenic and anthropogenic vapors in the atmospheric aerosol system.
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http://dx.doi.org/10.1126/sciadv.aau5363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291317PMC
December 2018

Long Non-Coding RNA Modulation of VEGF-A during Hypoxia.

Noncoding RNA 2018 Nov 20;4(4). Epub 2018 Nov 20.

The Center for Gene Therapy, Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.

The role and function of long non-coding RNAs (lncRNAs) in modulating gene expression is becoming apparent. Vascular endothelial growth factor A (VEGF-A) is a key regulator of blood vessel formation and maintenance making it a promising therapeutic target for activation in ischemic diseases. In this study, we uncover a functional role for two antisense VEGF-A lncRNAs, and , in transcriptional regulation of during hypoxia. We find here that both lncRNAs are polyadenylated, concordantly upregulated with , localize to the promoter and upstream elements in a hypoxia dependent manner either as a single-stranded RNA or DNA bound RNA, and are associated with enhancer marks H3K27ac and H3K9ac. Collectively, these data suggest that VEGF-A antisense lncRNAs, and , function as promoter enhancer-like elements, possibly by acting as a local scaffolding for proteins and also small RNAs to tether.
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http://dx.doi.org/10.3390/ncrna4040034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315885PMC
November 2018

The Duke treadmill score with bicycle ergometer: Exercise capacity is the most important predictor of cardiovascular mortality.

Eur J Prev Cardiol 2019 01 24;26(2):199-207. Epub 2018 Oct 24.

13 Department of Internal Medicine, University of Helsinki, Finland.

Background: The Duke treadmill score, a widely used treadmill testing tool, is a weighted index combining exercise time or capacity, maximum ST-segment deviation and exercise-induced angina. No previous studies have investigated whether the Duke treadmill score and its individual components based on bicycle exercise testing predict cardiovascular death.

Design: Two populations with a standard bicycle testing were used: 3936 patients referred for exercise testing (2371 men, age 56 ± 13 years) from the Finnish Cardiovascular Study (FINCAVAS) and a population-based sample of 2683 men (age 53 ± 5.1 years) from the Kuopio Ischaemic Heart Disease study (KIHD).

Methods: Cox regression was applied for risk prediction with cardiovascular mortality as the primary endpoint.

Results: In FINCAVAS, during a median 6.3-year (interquartile range (IQR) 4.5-8.2) follow-up period, 180 patients (4.6%) experienced cardiovascular mortality. In KIHD, 562 patients (21.0%) died from cardiovascular causes during the median follow-up of 24.1 (IQR 18.0-26.2) years. The Duke treadmill score was associated with cardiovascular mortality in both populations (FINCAVAS, adjusted hazard ratio (HR) 3.15 for highest vs. lowest Duke treadmill score tertile, 95% confidence interval (CI) 1.83-5.42, P < 0.001; KIHD, adjusted HR 1.71, 95% CI 1.34-2.18, P < 0.001). However, after progressive adjustment for the Duke treadmill score components, the score was not associated with cardiovascular mortality in either study population, as exercise capacity in metabolic equivalents of task was the dominant harbinger of poor prognosis.

Conclusions: The Duke treadmill score is associated with cardiovascular mortality among patients who have undergone bicycle exercise testing, but metabolic equivalents of task, a component of the Duke treadmill score, proved to be a superior predictor.
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http://dx.doi.org/10.1177/2047487318804618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330693PMC
January 2019

Performance of CHADS-VASc score for stroke prediction after surgical aortic valve replacement.

J Thorac Cardiovasc Surg 2019 Mar 29;157(3):896-904. Epub 2018 Jul 29.

Heart Center, Turku University Hospital and University of Turku, Turku, Finland; Department of Surgery, Oulu University Hospital, Oulu, Finland.

Objective: Stroke is a frequent complication occurring early and late after surgical aortic valve replacement. There is an unmet clinical need for simple tools to assess postoperative stroke risk. We sought to assess the predictive performance of Congestive heart failure; Hypertension; Age ≥75 (doubled); Diabetes mellitus; prior Stroke, transient ischemic attack or thromboembolism (doubled); Vascular disease; Age 65 to 74; Sex category (female) (CHADS-VASc) score in patients undergoing surgical aortic valve replacement with a bioprosthesis.

Methods: Seven hundred fourteen patients undergoing isolated surgical aortic valve replacement with a bioprosthesis at 4 university hospitals were included. Data were collected retrospectively from patient records and monitored by an independent party.

Results: Median follow-up time was 4.8 years. Mean CHADS-VASc score was 4.1 ± 1.6. Low (scores, 0-1), high (scores, 2-4), and very high (scores, 5-9) CHADS-VASc scores were observed in 39 (5.5%), 400 (56.0%), and 262 (38.5%) patients, respectively. Incidences of stroke or transient ischemic attack at 1 year were 2.6%, 4.8%, and 10.7%; at 5 years incidences were 5.2%, 14.0%, and 21.9%; and at 10 years incidence were 5.2%, 20.7%, and 37.9% for patients in low, high, and very high scores, respectively. Incidences of major bleeds at 1 year were 0%, 1.8%, and 2.7%; at 5 years incidences were 0%, 5.4%, and 8.7%; and at 10 years incidences were 0%, 9.0%, and 27.1%, respectively. Competing risk analysis showed that patients with CHADS-VASc score of 5 through 9 had a significantly increased risk of stroke or transient ischemic attack (hazard ratio, 4.75; 95% confidence interval, 1.09-20.6; P = .037) irrespective of preoperative or new-onset in-hospital atrial fibrillation compared with low-risk patients.

Conclusions: CHADS-VASc is a valuable tool to identify patients with increased risk of stroke and major bleeding, and for whom alternative strategies for prevention of late neurologic complications should be adopted.
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http://dx.doi.org/10.1016/j.jtcvs.2018.06.096DOI Listing
March 2019

Rapid growth of organic aerosol nanoparticles over a wide tropospheric temperature range.

Proc Natl Acad Sci U S A 2018 09 28;115(37):9122-9127. Epub 2018 Aug 28.

Institute for Atmospheric and Environmental Sciences, Goethe University Frankfurt, 60438 Frankfurt am Main, Germany.

Nucleation and growth of aerosol particles from atmospheric vapors constitutes a major source of global cloud condensation nuclei (CCN). The fraction of newly formed particles that reaches CCN sizes is highly sensitive to particle growth rates, especially for particle sizes <10 nm, where coagulation losses to larger aerosol particles are greatest. Recent results show that some oxidation products from biogenic volatile organic compounds are major contributors to particle formation and initial growth. However, whether oxidized organics contribute to particle growth over the broad span of tropospheric temperatures remains an open question, and quantitative mass balance for organic growth has yet to be demonstrated at any temperature. Here, in experiments performed under atmospheric conditions in the Cosmics Leaving Outdoor Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN), we show that rapid growth of organic particles occurs over the range from [Formula: see text]C to [Formula: see text]C. The lower extent of autoxidation at reduced temperatures is compensated by the decreased volatility of all oxidized molecules. This is confirmed by particle-phase composition measurements, showing enhanced uptake of relatively less oxygenated products at cold temperatures. We can reproduce the measured growth rates using an aerosol growth model based entirely on the experimentally measured gas-phase spectra of oxidized organic molecules obtained from two complementary mass spectrometers. We show that the growth rates are sensitive to particle curvature, explaining widespread atmospheric observations that particle growth rates increase in the single-digit-nanometer size range. Our results demonstrate that organic vapors can contribute to particle growth over a wide range of tropospheric temperatures from molecular cluster sizes onward.
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http://dx.doi.org/10.1073/pnas.1807604115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140529PMC
September 2018

Calibration of force detection for arbitrarily shaped particles in optical tweezers.

Sci Rep 2018 07 17;8(1):10798. Epub 2018 Jul 17.

School of Mathematics and Physics, The University of Queensland, St. Lucia, QLD, 4072, Australia.

Force measurement with an optical trap requires calibration of it. With a suitable detector, such as a position-sensitive detector (PSD), it is possible to calibrate the detector so that the force can be measured for arbitrary particles and arbitrary beams without further calibration; such a calibration can be called an "absolute calibration". Here, we present a simple method for the absolute calibration of a PSD. Very often, paired position and force measurements are required, and even if synchronous measurements are possible with the position and force detectors used, knowledge of the force-position curve for the particle in the trap can be highly beneficial. Therefore, we experimentally demonstrate methods for determining the force-position curve with and without synchronous force and position measurements, beyond the Hookean (linear) region of the trap. Unlike the absolute calibration of the force and position detectors, the force-position curve depends on the particle and the trapping beam, and needs to be determined in each individual case. We demonstrate the robustness of our absolute calibration by measuring optical forces on microspheres as commonly trapped in optical tweezers, and other particles such a birefringent vaterite microspheres, red blood cells, and a deformable "blob".
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http://dx.doi.org/10.1038/s41598-018-28876-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050307PMC
July 2018

Structure and dynamics of a human myelin protein P2 portal region mutant indicate opening of the β barrel in fatty acid binding proteins.

BMC Struct Biol 2018 06 25;18(1). Epub 2018 Jun 25.

Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland.

Background: Myelin is a multilayered proteolipid sheath wrapped around selected axons in the nervous system. Its constituent proteins play major roles in forming of the highly regular membrane structure. P2 is a myelin-specific protein of the fatty acid binding protein (FABP) superfamily, which is able to stack lipid bilayers together, and it is a target for mutations in the human inherited neuropathy Charcot-Marie-Tooth disease. A conserved residue that has been proposed to participate in membrane and fatty acid binding and conformational changes in FABPs is Phe57. This residue is thought to be a gatekeeper for the opening of the portal region upon ligand entry and egress.

Results: We performed a structural characterization of the F57A mutant of human P2. The mutant protein was crystallized in three crystal forms, all of which showed changes in the portal region and helix α2. In addition, the behaviour of the mutant protein upon lipid bilayer binding suggested more unfolding than previously observed for wild-type P2. On the other hand, membrane binding rendered F57A heat-stable, similarly to wild-type P2. Atomistic molecular dynamics simulations showed opening of the side of the discontinuous β barrel, giving important indications on the mechanism of portal region opening and ligand entry into FABPs. The results suggest a central role for Phe57 in regulating the opening of the portal region in human P2 and other FABPs, and the F57A mutation disturbs dynamic cross-correlation networks in the portal region of P2.

Conclusions: Overall, the F57A variant presents similar properties to the P2 patient mutations recently linked to Charcot-Marie-Tooth disease. Our results identify Phe57 as a residue regulating conformational changes that may accompany membrane surface binding and ligand exchange in P2 and other FABPs.
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http://dx.doi.org/10.1186/s12900-018-0087-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020228PMC
June 2018
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