Publications by authors named "Lenka Novakova"

29 Publications

  • Page 1 of 1

A multicentre validation study of the diagnostic value of plasma neurofilament light.

Nat Commun 2021 06 7;12(1):3400. Epub 2021 Jun 7.

Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Montreal, QC, Canada.

Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.
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http://dx.doi.org/10.1038/s41467-021-23620-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185001PMC
June 2021

eIF3a Destabilization and TDP-43 Alter Dynamics of Heat-Induced Stress Granules.

Int J Mol Sci 2021 May 13;22(10). Epub 2021 May 13.

Institute of Microbiology, Czech Academy of Sciences, Videnska 1083, 14220 Prague, Czech Republic.

Stress granules (SGs) are membrane-less assemblies arising upon various stresses in eukaryotic cells. They sequester mRNAs and proteins from stressful conditions and modulate gene expression to enable cells to resume translation and growth after stress relief. SGs containing the translation initiation factor eIF3a/Rpg1 arise in yeast cells upon robust heat shock (HS) at 46 °C only. We demonstrate that the destabilization of Rpg1 within the PCI domain in the Rpg1-3 variant leads to SGs assembly already at moderate HS at 42 °C. These are bona fide SGs arising upon translation arrest containing mRNAs, which are components of the translation machinery, and associating with P-bodies. HS SGs associate with endoplasmatic reticulum and mitochondria and their contact sites ERMES. Although Rpg1-3-labeled SGs arise at a lower temperature, their disassembly is delayed after HS at 46 °C. Remarkably, the delayed disassembly of HS SGs after the robust HS is reversed by TDP-43, which is a human protein connected with amyotrophic lateral sclerosis. TDP-43 colocalizes with HS SGs in yeast cells and facilitates cell regrowth after the stress relief. Based on our results, we propose yeast HS SGs labeled by Rpg1 and its variants as a novel model system to study functions of TDP-43 in stress granules disassembly.
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http://dx.doi.org/10.3390/ijms22105164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8153170PMC
May 2021

Persons with suspicious onset of multiple sclerosis but with undetermined diagnosis had persistent lower cognition and reduced quality of life.

Mult Scler Relat Disord 2021 Apr 24;52:102977. Epub 2021 Apr 24.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gotheburg, Sweden; Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Backgound: Differential diagnosis of multiple sclerosis (MS) includes a variety of disorders and misdiagnosis is common.

Objective: To follow-up persons with suspected onset of MS but in whom the diagnostic investigation was negative.

Methods: In a prospective study including 271 persons with clinical features of suspected MS onset, 136 persons were diagnosed with MS or clinically isolated syndrome (PwMS), 46 had other disorders, and 89 persons had a negative diagnostic work-up, i.e. persons with undetermined diagnosis (PwUD). They underwent diagnostic reassessment, and those who remained without a diagnosis were investigated for signs of pathology including cognitive tests and assessments of quality of life (QoL). Results were compared with those of PwMS and 24 age and sex matched healthy controls (HC).

Results: After reassement 55 (20%) persons still had undetermined diagnosis (PwUD). They had similar age and gender distribution as PwMS. In 76% of PwUD, the suspected clinical onset included sensory symptoms. PwUD and PwMS scored similarly in cognitive tests and QoL but significantly lower than HC. At 3 years follow-up, PwMS and PwUD improved in most test parameters, but PwUD scored lower than PwMS in cognition.

Conclusion: PwUD constituted the dominating differential diagnosis in persons with suspected clinical onset of MS. QoL and cognition were comparable with those of PwMS but significantly lower than in HC.
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http://dx.doi.org/10.1016/j.msard.2021.102977DOI Listing
April 2021

The levels of the serine protease HTRA1 in cerebrospinal fluid correlate with progression and disability in multiple sclerosis.

J Neurol 2021 Mar 4. Epub 2021 Mar 4.

Department of Molecular Medicine- Neurobiology Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000, Odense, Denmark.

Background: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease.

Objective: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue.

Methods: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map.

Results: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons.

Conclusion: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
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http://dx.doi.org/10.1007/s00415-021-10489-7DOI Listing
March 2021

Autologous haematopoietic stem cell transplantation compared with alemtuzumab for relapsing-remitting multiple sclerosis: an observational study.

J Neurol Neurosurg Psychiatry 2021 02 26;92(2):189-194. Epub 2020 Oct 26.

Department of Neuroscience, Uppsala University, Uppsala, Sweden

Objective: To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis.

Methods: Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly.

Results: The Kaplan-Meier estimates of the primary outcome measure 'no evidence of disease activity' was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005.

Conclusions: In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining 'no evidence of disease activity'. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ.
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http://dx.doi.org/10.1136/jnnp-2020-323992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841472PMC
February 2021

Inflammation-related plasma and CSF biomarkers for multiple sclerosis.

Proc Natl Acad Sci U S A 2020 06 26;117(23):12952-12960. Epub 2020 May 26.

Neuroimmunology Unit, Center of Molecular Medicine, Department of Clinical Neuroscience, Karolinska University Hospital, Karolinska Institutet, SE-171 77 Stockholm, Sweden;

Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking. We have investigated a broad set of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve [AUC] = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease ( < 4 × 10, < 4 × 10), and plasma CCL20 was associated with disease severity ( = 4 × 10), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.
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http://dx.doi.org/10.1073/pnas.1912839117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293699PMC
June 2020

Cerebrospinal fluid growth-associated protein 43 in multiple sclerosis.

Sci Rep 2019 11 21;9(1):17309. Epub 2019 Nov 21.

Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Neurodegeneration in multiple sclerosis (MS) correlates with disease progression and reparative processes may be triggered. Growth-associated protein 43 (GAP-43) exhibits induced expression during axonal growth and reduced expression during MS progression. We aimed to evaluate if GAP-43 can serve as a biomarker of regeneration in relapsing-remitting MS (RRMS) and whether disease-modifying therapies (DMTs) influence GAP-43 concentration in cerebrospinal fluid (CSF). GAP-43 was measured using an enzyme-linked immunosorbent assay in 105 MS patients (73 RRMS, 12 primary progressive MS, 20 secondary progressive MS) and 23 healthy controls (HCs). In 35 of the patients, lumbar puncture, clinical assessment, and magnetic resonance imaging was performed before initiation of therapeutic intervention, and at follow-up. CSF GAP-43 concentration was significantly lower in progressive MS compared with HCs (p = 0.004) and RRMS (p =  < 0.001) and correlated negatively with disability (p = 0.026). However, DMTs did not alter CSF GAP-43. Interestingly, in RRMS CSF GAP-43 levels were higher in patients with signs of active inflammatory disease than in patients in remission (p = 0.042). According to CSF GAP-43 concentrations, regeneration seems reduced in progressive MS, increased during disease activity in RRMS but is unaffected by treatment of highly active DMTs.
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http://dx.doi.org/10.1038/s41598-019-54032-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872811PMC
November 2019

Neurofilament light for measuring the treatment efficacy in clinical practice: are we there yet?

Authors:
Lenka Novakova

J Neurol Neurosurg Psychiatry 2019 12 13;90(12):1305. Epub 2019 Oct 13.

Institute of Neuroscience and Physiology, University of Gothenburg Sahlgrenska Academy, Gothenburg, Sweden

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http://dx.doi.org/10.1136/jnnp-2019-321615DOI Listing
December 2019

Cerebrospinal fluid biomarkers in patients with neurological symptoms but without neurological diseases.

Acta Neurol Scand 2019 Sep 31;140(3):177-183. Epub 2019 May 31.

Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden.

Background: Elevated levels of the cerebrospinal fluid (CSF) neuronal injury markers (neurofilament light chain [NF-L] and total tau protein [t-tau]) and of the astroglial marker glial fibrillary acidic protein (GFAP) are found in etiologically different neurological disorders affecting the peripheral and the central nervous system.

Aims: To explore the role of CSF biomarkers in the clinical management of patients admitted for alarming neurological symptoms, but in whom neurological disorders could be excluded.

Methods: Study participants were patients seeking medical attention for neurological symptoms primarily considered to be caused by a neurological diagnosis and investigated according to clinical routine. Demographic, clinical, and CSF data were extracted retrospectively from medical records. Patients with a final neurological diagnosis were excluded.

Results: Out of 990 patients, 900 with a neurological diagnosis were excluded leaving 90 patients without a final neurological diagnosis. Sixty-eight (75.6%) were females. Median (range) age at lumbar puncture was 34.7 (16.9-65.1) years. Age-adjusted CSF-NF-L, CSF-t-tau, and CSF-GFAP concentrations were normal in 89 (98.9%), 86 (95.6%), and 87 (96.7%) patients, respectively.

Conclusion: In patients with significant neurological symptoms but in whom a neurological diagnosis could not be made, the CSF markers NF-L, t-tau, and GFAP did not indicate signs of neuronal or astroglial cell damage close to symptom onset. Consequently, increased levels of CSF markers are not expected in this patient group and, if present, should raise suspicion of underlying neurological disorders and motivate further investigations.
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http://dx.doi.org/10.1111/ane.13118DOI Listing
September 2019

Cerebrospinal fluid NCAM levels are modulated by disease-modifying therapies.

Acta Neurol Scand 2019 May 5;139(5):422-427. Epub 2019 Mar 5.

Department of Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, London, UK.

Background: Little is known about what leads to recovery between relapses in multiple sclerosis (MS), particularly following treatment. In the past, it has been demonstrated that soluble neural cell adhesion molecule (sNCAM), a putative biomarker of neuroplasticity, increased following steroid treatment in the Cerebrospinal fluid (CSF) of MS subjects undergoing acute relapses. Taking this a step further, we have evaluated the effect of disease-modifying treatment (DMTs) on CSF sNCAM levels in various subtypes of MS.

Methods: We measured CSF sNCAM levels at baseline and after 12-24 months of DMT in 69 patients, 49 relapsing-remitting MS (RRMS), 20 progressive MS(PMS), and 24 healthy controls (HC) using an in-house ELISA. Of this, 31 patients had received natalizumab, 17 mitoxantrone, and 21 fingolimod. Changes in disability were measured using EDSS and disease severity by MSSS. In conjunction, CSF NfL levels were also measured.

Results: At baseline, the mean sNCAM level was 268.7 ng/mL (SD: 109 ng/mL) in MS patients compared with 340.6 ng/ml (SD: 139 ng/mL) in HC, and PMS had significantly lower sNCAM (239.2 ng/mL, SD: 123.0, P = 0.019) compared to RRMS (269.4, SD: 127.4, P = 0.043). After natalizumab and mitoxantrone treatments, we observed an increase in mean sNCAM. However, in the fingolimod-treated group, mean sNCAM decreased. There was no correlation found with EDSS or MSSS, or NfL levels as a whole.

Conclusions: Cerebrospinal fluid sNCAM levels were found to be lower in MS than in HC and the lowest sNCAM levels were found in PMS. Following natalizumab and mitoxantrone treatments, we observed an elevation in sNCAM levels, an effect that was not observed following fingolimod treatment. These changes, however, did not appear to correlate with disability in the short-term or NfL levels.
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http://dx.doi.org/10.1111/ane.13069DOI Listing
May 2019

Sulfatide isoform pattern in cerebrospinal fluid discriminates progressive MS from relapsing-remitting MS.

J Neurochem 2018 08 3;146(3):322-332. Epub 2018 Jul 3.

Department of Clinical Chemistry and Transfusion Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Several biomarkers including proteins and lipids have been reported in MS cerebrospinal fluid (CSF), reflecting different aspects of the pathophysiology particularly of relapsing-remitting MS (RRMS). Sulfatide, abundant in the myelin sheath and a proposed target for autoimmune attack in MS, has been reported altered in MS CSF. Here, we investigated the potential of CSF sulfatide and its isoforms as biomarkers in MS. A highly sensitive and quantitative mass spectrometry method was employed to determine levels of sulfatide isoforms in CSF from RRMS and progressive MS (PMS) patients, and healthy donors (HD). We demonstrate that levels of total CSF sulfatide and C24:1, C26:1, and C26:1-OH isoforms were significantly increased in PMS compared with RRMS patients and HD, while C23:0-OH was significantly decreased in CSF from PMS patients compared to the other two groups. Multivariate discriminant analysis showed that CSF sulfatide isoform pattern in PMS patients was distinct and non-overlapping with that of RRMS patients and HD. Sulfatide levels did not correlate with tested biomarkers or clinical parameters. The results suggest that CSF sulfatide isoform levels may be used to discriminate the phenotype of MS and might play a role in the progression of the disease.
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http://dx.doi.org/10.1111/jnc.14452DOI Listing
August 2018

Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers.

PLoS One 2018 3;13(4):e0194828. Epub 2018 Apr 3.

Institute of Neuroscience and Physiology, Department of Clinical Neuroscience, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization.

Objective: This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course.

Methods: This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations ≥2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction.

Results: Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration.

Conclusions: In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194828PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882126PMC
July 2018

Monitoring disease activity in multiple sclerosis using serum neurofilament light protein.

Neurology 2017 Nov 27;89(22):2230-2237. Epub 2017 Oct 27.

From the Department of Clinical Neuroscience (L.N., M.A., C.M., J.L.) and Department of Psychiatry and Neurochemistry (H.Z., K.B.), Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg; Clinical Neurochemistry Laboratory (H.Z., K.B.), Sahlgrenska University Hospital, Mölndal, Sweden; Department of Molecular Neuroscience (H.Z.), UCL Institute of Neurology, London, UK; Department of Pharmacology and Clinical Neuroscience (P.S.), Umeå University; University Department of Clinical Neuroscience (M.K., T.O., F.P.), Neuroimmunology Unit, and Department of Clinical Sciences (A.S.), Danderyd Hospital, Karolinska Institutet, Stockholm; and Department of Neurology (M.G.), Faculty of Medicine and Health, Örebro University, Sweden.

Objective: To examine the effects of disease activity, disability, and disease-modifying therapies (DMTs) on serum neurofilament light (NFL) and the correlation between NFL concentrations in serum and CSF in multiple sclerosis (MS).

Methods: NFL concentrations were measured in paired serum and CSF samples (n = 521) from 373 participants: 286 had MS, 45 had other neurologic conditions, and 42 were healthy controls (HCs). In 138 patients with MS, the serum and CSF samples were obtained before and after DMT treatment with a median interval of 12 months. The CSF NFL concentration was measured with the UmanDiagnostics NF-light enzyme-linked immunosorbent assay. The serum NFL concentration was measured with an in-house ultrasensitive single-molecule array assay.

Results: In MS, the correlation between serum and CSF NFL was = 0.62 ( < 0.001). Serum concentrations were significantly higher in patients with relapsing-remitting MS (16.9 ng/L) and in patients with progressive MS (23 ng/L) than in HCs (10.5 ng/L, < 0.001 and < 0.001, respectively). Treatment with DMT reduced median serum NFL levels from 18.6 (interquartile range [IQR] 12.6-32.7) ng/L to 15.7 (IQR 9.6-22.7) ng/L ( < 0.001). Patients with relapse or with radiologic activity had significantly higher serum NFL levels than those in remission ( < 0.001) or those without new lesions on MRI ( < 0.001).

Conclusions: Serum and CSF NFL levels were highly correlated, indicating that blood sampling can replace CSF taps for this particular marker. Disease activity and DMT had similar effects on serum and CSF NFL concentrations. Repeated NFL determinations in peripheral blood for detecting axonal damage may represent new possibilities in MS monitoring.
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http://dx.doi.org/10.1212/WNL.0000000000004683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705244PMC
November 2017

Formaldehyde fixation is detrimental to actin cables in glucose-depleted cells.

Microb Cell 2016 Apr 12;3(5):206-214. Epub 2016 Apr 12.

Laboratory of Cell Reproduction, Institute of Microbiology of the CAS, v.v.i., Prague, Czech Republic.

Actin filaments form cortical patches and emanating cables in fermenting cells of . This pattern has been shown to be depolarized in glucose-depleted cells after formaldehyde fixation and staining with rhodamine-tagged phalloidin. Loss of actin cables in mother cells was remarkable. Here we extend our knowledge on actin in live glucose-depleted cells co-expressing the marker of actin patches (Abp1-RFP) with the marker of actin cables (Abp140-GFP). Glucose depletion resulted in appearance of actin patches also in mother cells. However, even after 80 min of glucose deprivation these cells showed a clear network of actin cables labeled with Abp140-GFP in contrast to previously published data. In live cells with a mitochondrial dysfunction (rho cells), glucose depletion resulted in almost immediate appearance of Abp140-GFP foci partially overlapping with Abp1-RFP patches in mother cells. Residual actin cables were clustered in patch-associated bundles. A similar overlapping "patchy" pattern of both actin markers was observed upon treatment of glucose-deprived rho cells with FCCP (the inhibitor of oxidative phosphorylation) and upon treatment with formaldehyde. While the formaldehyde-targeted process stays unknown, our results indicate that published data on yeast actin cytoskeleton obtained from glucose-depleted cells after fixation should be considered with caution.
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http://dx.doi.org/10.15698/mic2016.05.499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349148PMC
April 2016

High Interferon-γ Uniquely in Vδ1 T Cells Correlates with Markers of Inflammation and Axonal Damage in Early Multiple Sclerosis.

Front Immunol 2017 9;8:260. Epub 2017 Mar 9.

Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

We have identified a population of T lymphocytes in peripheral blood, Vδ1 TCRγδ T lymphocytes, which unexpectedly was uniquely expressing high production of interferon-γ in newly diagnosed, untreated multiple sclerosis (MS) patients. IFN-γ production in this population distinctly correlated to parameters of clinical disease activity, inflammation, and neuronal damage. These Vδ1 T lymphocytes belong to a population of innate T lymphocytes that recognize antigen in the context of CD1d/CD1c and which include reactivity to the myelin glycosphingolipid sulfatide. Importantly, patients treated with natalizumab, blocking leukocyte transmigration to central nervous system, had completely normalized levels of interferon-γ-producing Vδ1 T lymphocytes. A biomarker and early sign of demyelinating disease in MS is much warranted and would help identify immunopathogenesis and prognosis of disease as well as monitor success with adequate treatment. The present study identifies the Vδ1 T lymphocytes as an early marker of MS and a possible link to understanding the disease etiology.
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http://dx.doi.org/10.3389/fimmu.2017.00260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5343019PMC
March 2017

Cerebrospinal fluid biomarkers as a measure of disease activity and treatment efficacy in relapsing-remitting multiple sclerosis.

J Neurochem 2017 04 29;141(2):296-304. Epub 2016 Nov 29.

Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Cerebrospinal fluid (CSF) biomarkers can reflect different aspects of the pathophysiology of relapsing-remitting multiple sclerosis (RRMS). Understanding the impact of different disease modifying therapies on the CSF biomarker profile may increase their implementation in clinical practice and their appropriateness for monitoring treatment efficacy. This study investigated the influence of first-line (interferon beta) and second-line (natalizumab) therapies on seven CSF biomarkers in RRMS and their correlation with clinical and radiological outcomes. We included 59 RRMS patients and 39 healthy controls. The concentrations of C-X-C motif chemokine 13 (CXCL13), C-C motif chemokine ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein, neurofilament light protein (NFL), and neurogranin were determined by ELISA, and chitotriosidase (CHIT1) was analyzed by spectrofluorometry. RRMS patients had higher levels of NFL, CXCL13, CHI3L1, and CHIT1 than controls (p < 0.001). Subgroup analysis revealed higher NFL, CXCL13 and CHIT1 levels in patients treated with first-line therapy compared to second-line therapy (p = 0.008, p = 0.001 and p = 0.026, respectively). NFL and CHIT1 levels correlated with relapse status, and NFL and CXCL13 levels correlated with the formation of new magnetic resonance imaging lesions. Furthermore, we found an association between inflammatory and degenerative biomarkers. The results indicate that CSF levels of NFL, CXCL13, CHI3L1, and CHIT1 correlate with the clinical and/or radiological disease activity, providing additional dimensions in the assessment of treatment efficacy.
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http://dx.doi.org/10.1111/jnc.13881DOI Listing
April 2017

Rituximab in multiple sclerosis: A retrospective observational study on safety and efficacy.

Neurology 2016 Nov 19;87(20):2074-2081. Epub 2016 Oct 19.

From the Department of Pharmacology and Clinical Neuroscience (J.S., R.S., P.I.-J., M.V., P.S., A.S.), Umeå University; Departments of Clinical Neuroscience (R.S., P.A., A.B., K.F., F.P.) and Clinical Sciences, Danderyd Hospital (A.S.), Karolinska Institutet, Stockholm; and Department of Clinical Neuroscience (L.N., C.M., M.A., J.L.), Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.

Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS).

Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded.

Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected.

Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS.

Classification Of Evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.
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http://dx.doi.org/10.1212/WNL.0000000000003331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109942PMC
November 2016

Rituximab versus fingolimod after natalizumab in multiple sclerosis patients.

Ann Neurol 2016 Jun 20;79(6):950-8. Epub 2016 Apr 20.

Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden.

Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy.

Methods: We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umeå, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%).

Results: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center).

Interpretation: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns. Ann Neurol 2016;79:950-958.
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http://dx.doi.org/10.1002/ana.24651DOI Listing
June 2016

Cerebrospinal fluid biomarkers of inflammation and degeneration as measures of fingolimod efficacy in multiple sclerosis.

Mult Scler 2017 01 11;23(1):62-71. Epub 2016 Jul 11.

Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: The disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) vary in their mode of action and when therapies are changed, the consequences on inflammatory and degenerative processes are largely unknown.

Objective: We investigated the effect of switching from other DMTs to fingolimod on cerebrospinal fluid (CSF) biomarkers.

Methods: 43 RRMS patients were followed up after 4-12 months of fingolimod treatment. Concentrations of C-X-C motif chemokine 13 (CXCL13), chemokine (C-C motif) ligand 2 (CCL2), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), neurofilament light protein (NFL), and neurogranin (NGRN) were analyzed by enzyme-linked immunosorbent assay (ELISA), while chitotriosidase (CHIT1) was analyzed by spectrofluorometry.

Results: The levels of NFL, CXCL13, and CHI3L1 decreased ( p < 0.05) after fingolimod treatment. Subgroup analysis revealed a reduction in NFL ( p < 0.001), CXCL13 ( p = 0.001), CHI3L1 ( p < 0.001), and CHIT1 ( p = 0.002) in patients previously treated with first-line therapies. In contrast, the levels of all analyzed biomarkers were essentially unchanged in patients switching from natalizumab.

Conclusion: We found reduced inflammatory activity (CXCL13, CHI3L1, and CHIT1) and reduced axonal damage (NFL) in patients switching from first-line DMTs to fingolimod. Biomarker levels in patients switching from natalizumab indicate similar effects on inflammatory and degenerative processes. The CSF biomarkers provide an additional measure of treatment efficacy.
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http://dx.doi.org/10.1177/1352458516639384DOI Listing
January 2017

Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone.

Mult Scler 2016 10 11;22(12):1587-1595. Epub 2016 Jan 11.

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden/UCL Institute of Neurology, University College London (UCL), London, UK.

Background: Microglia-mediated proteolysis of the triggering receptor expressed on myeloid cells-2 (TREM-2) produces soluble TREM-2 (sTREM-2) that can be measured in cerebrospinal fluid (CSF) samples. Loss-of-function mutations in TREM2 or in the gene encoding its adaptor protein cause the rare Nasu-Hakola disease (NHD). Multiple sclerosis (MS) is an autoimmune disease that in common with NHD is characterized by demyelination and microglial activation.

Objective: To investigate the potential utility of sTREM-2 as a biomarker for MS and to follow treatment effects.

Methods: sTREM-2 was analyzed in CSF samples from subjects with MS (N = 59); relapsing-remitting MS (RRMS) (N = 36), secondary progressive MS (SPMS) (N = 20) and primary progressive MS (PPMS) (N = 3), and controls (N = 27). CSF levels of sTREM-2 were also assessed before and after treatment of patients with natalizumab or mitoxantrone.

Results: CSF levels of sTREM-2 were significantly increased in patients with RRMS, SPMS, and PPMS compared with controls. After natalizumab treatment, the levels of sTREM-2 were normalized to control levels. The levels of sTREM-2 were also reduced after mitoxantrone treatment.

Conclusion: Increased CSF levels of sTREM-2, a new marker of microglial activation, in MS and normalization upon treatment with either natalizumab or mitoxantrone support a role for microglial activation in active MS.
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http://dx.doi.org/10.1177/1352458515624558DOI Listing
October 2016

Reduced cerebrospinal fluid concentrations of oxysterols in response to natalizumab treatment of relapsing remitting multiple sclerosis.

J Neurol Sci 2015 Nov 29;358(1-2):201-6. Epub 2015 Aug 29.

Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: Natalizumab therapy reduces inflammation and degeneration of the CNS in relapsing-remitting multiple sclerosis (RRMS). In cerebrospinal fluid (CSF) the concentration of 24S-hydroxycholesterol (24OHC) reflect neurodegeneration, whereas 27-hydroxycholesterol (27OHC) is dependent on the integrity of the blood-brain barrier (BBB).

Objective: To measure the impact from natalizumab treatment on 24OHC and 27OHC concentrations in serum and CSF of RRMS.

Methods: In serum and CSF obtained from 31 patients before and following 12 months of natalizumab treatment, 24OHC and 27OHC were analyzed by isotope-dilution mass spectrometry.

Results: Natalizumab treatment reduced CSF-24OHC concentrations (p=0.002), CSF-27OHC concentrations (p=0.01) and serum-24OHC concentrations (p=0.029). There was no significant effect of the treatment on serum-27OHC concentrations. Serum concentrations of 24OHC correlated with Symbol Digit Modalities Test scores before (r=0.5, p=0.007) and after natalizumab treatment (r=0.403, p=0.033).

Conclusions: We showed for the first time that natalizumab treatment of RRMS reduced the concentrations of 24- and 27OHC in CSF, indicating reduced neurodegeneration and improved integrity of the BBB, respectively. Our results imply a role for serum 24OHC as a biomarker of cognition (visuo-spatial ability and processing speed) in RRMS.
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http://dx.doi.org/10.1016/j.jns.2015.08.1537DOI Listing
November 2015

Decoding of Baby Calls: Can Adult Humans Identify the Eliciting Situation from Emotional Vocalizations of Preverbal Infants?

PLoS One 2015 20;10(4):e0124317. Epub 2015 Apr 20.

Faculty of Humanities, Charles University, Prague, Czech Republic; National Institute of Mental Health, Klecany, Czech Republic.

Preverbal infants often vocalize in emotionally loaded situations, yet the communicative potential of these vocalizations is not well understood. The aim of our study was to assess how accurately adult listeners extract information about the eliciting situation from infant preverbal vocalizations. Vocalizations of 19 infants aged 5-10 months were recorded in 3 negative (Pain, Isolation, Demand for Food) and 3 positive (Play, Reunion, After Feeding) situations. The recordings were later rated by 333 adult listeners on the scales of emotional valence and intensity. Subsequently, the listeners assigned the eliciting situations in a forced choice task. Listeners were almost perfectly able to discriminate whether a recording came from a negative or a positive situation. Their discrimination may have been based on perceived valence as they consistently assigned higher valence when listening to positive, and lower valence when listening to negative, recordings. Ability to identify the particular situation within the negative or positive realm was substantially weaker, with only three of the six situations being discriminated above chance. The best discriminated situation, Play, was associated with high perceived intensity. The weak qualitative discrimination of negative situations seemed to be based on graded perception of negative recordings, from the most intense and unpleasant (assigned to Pain) to the least intense and least unpleasant (assigned to Demand for Food). Parenthood and younger age, but not gender of listeners, had weak positive effects on the accuracy of judgments. Our results indicate that adults almost flawlessly distinguish positive and negative infant sounds, but are rather inaccurate regarding identification of the specific needs of the infant and may normally employ other sensory channels to gain this information.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124317PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403804PMC
February 2016

Olfactory performance is predicted by individual sex-atypicality, but not sexual orientation.

PLoS One 2013 7;8(11):e80234. Epub 2013 Nov 7.

Department of Anthropology, Faculty of Humanities, Charles University, Prague, Czech Republic, United States of America.

Many previous studies have reported robust sex differences in olfactory perception. However, both men and women can be expected to vary in the degree to which they exhibit olfactory performance considered typical of their own or the opposite sex. Sex-atypicality is often described in terms of childhood gender nonconformity, which, however, is not a perfect correlate of non-heterosexual orientation. Here we explored intrasexual variability in psychophysical olfactory performance in a sample of 156 individuals (83 non-heterosexual) and found the lowest odor identification scores in heterosexual men. However, when childhood gender nonconformity was entered in the model along with sexual orientation, better odor identification scores were exhibited by gender-nonconforming men, and greater olfactory sensitivity by gender-conforming women, irrespective of their sexual orientation. Thus, sex-atypicality, but not sexual orientation predicts olfactory performance, and we propose that this might not be limited to olfaction, but represent a more general phenomenon.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080234PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3820642PMC
August 2014

Heat shock-induced accumulation of translation elongation and termination factors precedes assembly of stress granules in S. cerevisiae.

PLoS One 2013 25;8(2):e57083. Epub 2013 Feb 25.

Institute of Microbiology of AS CR, v.v.i., Prague, Czech Republic.

In response to severe environmental stresses eukaryotic cells shut down translation and accumulate components of the translational machinery in stress granules (SGs). Since they contain mainly mRNA, translation initiation factors and 40S ribosomal subunits, they have been referred to as dominant accumulations of stalled translation preinitiation complexes. Here we present evidence that the robust heat shock-induced SGs of S. cerevisiae also contain translation elongation factors eEF3 (Yef3p) and eEF1Bγ2 (Tef4p) as well as translation termination factors eRF1 (Sup45p) and eRF3 (Sup35p). Despite the presence of the yeast prion protein Sup35 in heat shock-induced SGs, we found out that its prion-like domain is not involved in the SGs assembly. Factors eEF3, eEF1Bγ2 and eRF1 were accumulated and co-localized with Dcp2 foci even upon a milder heat shock at 42°C independently of P-bodies scaffolding proteins. We also show that eEF3 accumulations at 42°C determine sites of the genuine SGs assembly at 46°C. We suggest that identification of translation elongation and termination factors in SGs might help to understand the mechanism of the eIF2α factor phosphorylation-independent repression of translation and SGs assembly.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057083PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3581570PMC
September 2013

Differential patterns of food appreciation during consumption of a simple food in congenitally anosmic individuals: an explorative study.

PLoS One 2012 18;7(4):e33921. Epub 2012 Apr 18.

Department of Anthropology, Faculty of Humanities, Charles University, Prague, Czech Republic.

Food is evaluated for various attributes. One of the key food evaluation domains is hedonicity. As food is consumed, its hedonic valence decreases (due to prolonged sensory stimulation) and hedonic habituation results. The aim of the present study was to investigate changes in food pleasantness ratings during consumption of a simple food by individuals without olfactory experience with food as compared to normosmics. 15 congenital anosmics and 15 normosmic controls were each presented with ten 10 g banana slices. Each was visually inspected, then smelled and chewed for ten seconds and subsequently rated for hedonicity on a 21-point scale. There was a significant difference in pleasantness ratings between congenital anosmics and controls (F(1, 26) = 6.71, p = .02) with the anosmics exhibiting higher ratings than the controls, a significant main repeated-measures effect on the ratings (F(1.85, 48) = 12.15, p<.001), which showed a decreasing trend over the course of consumption, as well as a significant portion*group interaction (F(1.85, 48) = 3.54, p = .04), with the anosmic participants experiencing a less pronounced decline. The results of the present explorative study suggest that over the course of consumption of a simple food, congenitally anosmic individuals experience differential patterns of appreciation of food as compared to normosmics. In this particular case, the decrease of hedonic valence was less pronounced in congenital anosmics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033921PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3329520PMC
November 2012

Learning about the functions of the olfactory system from people without a sense of smell.

PLoS One 2012 21;7(3):e33365. Epub 2012 Mar 21.

Smell and Taste Clinic, Department of Otorhinolaryngology, University of Dresden Medical School, Dresden, Germany.

The olfactory system provides numerous functions to humans, influencing ingestive behavior, awareness of environmental hazards and social communication. Approximately 1/5 of the general population exhibit an impaired sense of smell. However, in contrast to the many affected, only few patients complain of their impairment. So how important is it for humans to have an intact sense of smell? Or is it even dispensable, at least in the Western world? To investigate this, we compared 32 patients, who were born without a sense of smell (isolated congenital anosmia--ICA) with 36 age-matched controls. A broad questionnaire was used, containing domains relevant to olfaction in daily life, along with a questionnaire about social relationships and the BDI-questionnaire. ICA-patients differed only slightly from controls in functions of daily life related to olfaction. These differences included enhanced social insecurity, increased risk for depressive symptoms and increased risk for household accidents. In these domains the sense of olfaction seems to play a key role.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033365PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310072PMC
August 2012

Olfactory perception is positively linked to anxiety in young adults.

Perception 2012 ;41(10):1246-61

Department of Anthropology, Faculty of Humanities, Charles University, U Kríze 8, 158 00 Prague 5, Czech Republic.

Olfactory abilities show a high degree of inter-individual variability and this could be partly related to personality differences. Here, in two studies, we tested a potential link between personality dimensions and olfactory perception. Sixty-eight (study 1) and a hundred and fifty-six (study 2) young adults completed the Big Five questionnaire and performed the Sniffin' Sticks test for assessing odour threshold, identification, and (in study 2) discrimination. In neither study did we find a significant link between personality dimensions and olfactory identification scores. However, in study 1, we found a significant positive correlation between the neuroticism dimension and olfactory sensitivity. This was mainly due to the anxiety and self-consciousness subscales, which load onto the neuroticism dimension. In a follow-up study, we again found a significant association between anxiety and odour perception, specifically in odour discrimination. Our results indicate that variability in anxiety could partly explain the high inter-individual variation in olfactory perception.
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http://dx.doi.org/10.1068/p7244DOI Listing
April 2013

Robust heat shock induces eIF2alpha-phosphorylation-independent assembly of stress granules containing eIF3 and 40S ribosomal subunits in budding yeast, Saccharomyces cerevisiae.

J Cell Sci 2009 Jun 26;122(Pt 12):2078-88. Epub 2009 May 26.

Laboratory of Cell Reproduction, Institute of Microbiology of the AS CR, v.v.i., Prague, Czech Republic.

Environmental stresses inducing translation arrest are accompanied by the deposition of translational components into stress granules (SGs) serving as mRNA triage sites. It has recently been reported that, in Saccharomyces cerevisiae, formation of SGs occurs as a result of a prolonged glucose starvation. However, these SGs did not contain eIF3, one of hallmarks of mammalian SGs. We have analyzed the effect of robust heat shock on distribution of eIF3a/Tif32p/Rpg1p and showed that it results in the formation of eIF3a accumulations containing other eIF3 subunits, known yeast SG components and small but not large ribosomal subunits and eIF2alpha/Sui2p. Interestingly, under these conditions, Dcp2p and Dhh1p P-body markers also colocalized with eIF3a. Microscopic analyses of the edc3Deltalsm4DeltaC mutant demonstrated that different scaffolding proteins are required to induce SGs upon robust heat shock as opposed to glucose deprivation. Even though eIF2alpha became phosphorylated under these stress conditions, the decrease in polysomes and formation of SGs occurred independently of phosphorylation of eIF2alpha. We conclude that under specific stress conditions, such as robust heat shock, yeast SGs do contain eIF3 and 40S ribosomes and utilize alternative routes for their assembly.
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http://dx.doi.org/10.1242/jcs.045104DOI Listing
June 2009

Comparative study of non-invasive blood pressure measurement methods in elderly people.

Annu Int Conf IEEE Eng Med Biol Soc 2007 ;2007:612-5

Czech Technical University in Prague, Faculty of Electrical Engineering, Department of Cybernetics, Technicka 2, Prague 6, Czech Republic.

Results obtained by the modern automatic blood pressure (BP) monitors using oscillometric method [5] are highly dependent on conditions of cardiovascular system of the monitored person. Especially, with people who suffer from cardiovascular diseases (e.g. atherosclerosis) the resulting values differ significantly from those measured by the traditional auscultation method. A reasonable solution for improvement of quality of oscillometric method could be a sophisticated intelligent BP measuring system which applies for evaluation of BP more complex approach taking into account the monitored person's condition of patient cardiovascular system (CS) i.e. the hemodynamic parameters of CS (e.g. heart rate, stroke volume, total peripheral resistance, systemic arterial compliance, pulse wave velocity, augmentation index etc.). Such a system has to be based on appropriate models of the considered diseases which are validated on real life data. For that purpose, we have started to build a database of real-life oscillometric pulsations waveforms (OPW) complemented by the values of "auscultation" blood pressure measurements and additional relevant information about the considered patients (age, sex, etc.) as well as their diagnosis. This data collection requires a special HW device for measurement of the OPW--we have developed such a device and it has been validated in Czech Certified Metrological Centre. Our OPW monitor is connected through the T-pieces and tubes to the cuff, mercury sphygmomanometer and automatic "oscillometric" blood pressure monitor.
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http://dx.doi.org/10.1109/IEMBS.2007.4352364DOI Listing
March 2008