Publications by authors named "Łukasz Pawliński"

10 Publications

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MiRNA Expression in Patients with Gaucher Disease Treated with Enzyme Replacement Therapy.

Life (Basel) 2020 Dec 22;11(1). Epub 2020 Dec 22.

Clinical Department of Metabolic Diseases and Diabetology, University Hospital in Krakow, 30-688 Kraków, Poland.

Aims: The aim of the work was to establish potential biomarkers or drug targets by analysing changes in miRNA concentration among patients with Gaucher disease (GD) compared to in healthy subjects.

Methods: This study was an observational, cross-sectional analysis of 30 adult participants: 10 controls and 20 adults with GD type 1. Patients with GD type 1 were treated with enzyme replacement therapy (ERT) for at least two years. The control group was composed of healthy volunteers, unrelated to the patients, adjusted with age, sex and body mass index (BMI). The miRNA alteration between these groups was examined. After obtaining preliminary results on a group of six GD patients by the high-output method (TaqMan low-density array (TLDA)), potential miRNAs were selected for confirming the results by using the qRT-PCR method. With Diane Tools, we analysed miRNAs of which differential expression is most significant and their potential role in GD pathophysiology. We also determined the essential pathways these miRNAs are involved in.

Results: 266 dysregulated miRNAs were found among 753 tested. Seventy-eight miRNAs were downregulated, and 188 were upregulated. Thirty miRNAs were significantly altered; all of them were upregulated. The analysis of pathways regulated by the selected miRNAs showed an effect on bone development, inflammation or regulation of axonal transmission in association with Parkinson's disease.

Conclusions: We revealed few miRNAs, like miR-26-5p, which are highly altered and fit the GD pathophysiological model, might be considered as novel biomarkers of disease progression but need further evaluation.
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http://dx.doi.org/10.3390/life11010002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822051PMC
December 2020

Proteomic biomarkers in Gaucher disease.

J Clin Pathol 2021 Jan 14;74(1):25-29. Epub 2020 May 14.

Metabolic Diseases and Diabetology Department, Szpital Uniwersytecki w Krakowie, Kraków, małopolskie, Poland

Aims: The research work was conducted to find new biomarkers and potential drug targets in Gaucher disease type 1 (GDt1) by analysing the serum proteins.

Methods: This study was an observational, cross-sectional analysis of a group of 12 adult participants: six Gaucher disease (GD) patients and six healthy control. Fasting venous blood underwent proteomics analysis and molecular tests. Over 400 proteins were analysed, and in case of significantly different concentrations between the study and control group, we checked corresponding genes to confirm changes in their expression and consistency with protein alteration.

Results: We found 31 proteins that significantly differed in concentration between GDt1 patients and a control group. These were mostly proteins involved in the regulation of the inflammatory processes and haemostasis. The levels of proteins such as alpha-1-acid glycoprotein 2, S100-A8/A9, adenyl cyclase-associated protein 1, haptoglobin or translationally controlled tumour protein related to inflammation process were significantly higher in GD patients than in control group, whereas the levels of some proteins such as heavy constant mu and gamma 4 or complement C3/C4 complex involved in humoral response like immunoglobulins were significantly decreased in GD patients. Alteration in two proteins concentration was confirmed in RNA analysis.

Conclusions: The work revealed few new targets for further investigation which may be useful in clinical practice for diagnosis, treatment and monitoring GDt1 patients.
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http://dx.doi.org/10.1136/jclinpath-2020-206580DOI Listing
January 2021

Case report of endoprosthesis -Y implantation in severe respiratory failure in the MPSII patient; comparison with literature data.

BMC Pulm Med 2020 Apr 20;20(1):99. Epub 2020 Apr 20.

Clinical Department of Metabolic Diseases, University Hospital, Krakow, Poland.

Background: The tracheobronchomalacia is a life-threatening complication of mucopolysaccharidosis (MPS) without known effective, optimal treatment. The severe expiratory collapse of the trachea and bronchi is one of causes of the high rate of deaths in the course of airway impairment in MPSII patients.

Case Presentation: Due to the adynamic tracheobronchomalacia despite of enzymatic treatment (ERT) in our MPSII patient, a life-saving tracheal bifurcated type-Y endoprosthesis (a self-expanding, metal stent for the prosthesis of tracheal and bronchial stenosis) was implanted. In the followed months, the breathing efficiency improved, but then gradual worsening, progression of bronchi occlusion at the stent border resulted in patient's death.

Conclusion: The Y-stent implantation appears to be a short-term, life-saving solution without satisfactory long-term effects due to the progress of peripheral bronchomalacia and increased tissue proliferation and granulation, that arises during the illness' course.
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http://dx.doi.org/10.1186/s12890-020-1143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171830PMC
April 2020

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

J Inherit Metab Dis 2020 07 21;43(4):671-693. Epub 2020 Apr 21.

Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.
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http://dx.doi.org/10.1002/jimd.12241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574589PMC
July 2020

Specific gene expression in type 1 diabetic patients with and without cardiac autonomic neuropathy.

Sci Rep 2020 03 27;10(1):5554. Epub 2020 Mar 27.

Department of Metabolic Diseases, University Hospital, Krakow, Poland.

We hypothesized that some molecular pathways might interact to initiate the process of nervous tissue destruction, promoting cardiac autonomic neuropathy (CAN) in the course of diabetes type 1 (T1D). The study group consisted of 60 T1D patients (58.33% women/41.67% men), on standard therapy. The control group consisted of twenty healthy volunteers recruited in accordance with age, gender and body weight. The presence of CAN was documented by the Ewing test method (ProSciCard apparatus). A microarray data analysis was performed using Gene Spring version 13. The microarray results for selected genes were confirmed by real-time PCR (qRT-PCR), using specific TaqMan Gene Expression Assays. Plasma IL-6 content was measured by an enzyme-linked immunosorbent assay (ELISA). The p < 0.05 value was considered as statistically significant. The microarray analysis, confirmed by qRTPCR, showed significant up-regulation of autophagy, quantity of mitochondria, quality regulatory genes (mTOR, GABARAPL2) apoptosis, ER-stress and inflammation (NFKB1, IL1b, IL1R1, SOD1), in T1D when compared to the control group. A significantly higher IL-6 protein level was observed in T1D patients, in comparison to the control group. We concluded that the observed changes in gene expression and activation of intracellular pathways give a coherent picture of the important role of oxidative stress in inflammation and the activation of apoptosis in the pathomechanism of DM. The significance of the inflammatory process, confirmed by the increased level of the inflammation biomarker IL-6 in the pathomechanisms of CAN was shown even in patients with properly treated T1D.
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http://dx.doi.org/10.1038/s41598-020-62498-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101413PMC
March 2020

Dual-action ambroxol in treatment of chronic pain in Gaucher Disease.

Eur J Pain 2020 05 9;24(5):992-996. Epub 2020 Mar 9.

Clinical Department of Metabolic Diseases, University Hospital in Krakow, Krakow, Poland.

A significant number of patients with Gaucher disease (GD) suffer from chronic or acute pain that reduces their quality of life. A mutation in lysosomal enzyme β-glucosidase (GCase) leads to an accumulation of glucocerebroside in the macrophage-lineage cells, causing the development of clinical symptoms. Novel studies have revealed that ambroxol (trans-4-(2-amino-3,5-dibromobenzylamino)-cyclohexanol), the well-known mucolytic drug, acts as a chaperone for the mutant, misfolded enzyme. In addition, as has recently been shown, ambroxol is a Na 1.8 channel blocker in Aβ, Aδ and unmyelinated C fibres, and therefore reduces the transmission of sensory stimuli from the primary afferent neurons to the dorsal spinal cord. In this way, it can act analgetically. Thus, in addition to broncholytic properties, ambroxol combines two other important functions: it enhances enzyme replacement therapy (ERT) and pain management in patients with GD. We present a 38-year-old female patient with type 3 GD who had reported permanent bone pain in the lumbar-sacral part of the spine for over a year without any pathology evidenced in the undertaken, recommended diagnostic tests. The pain was partly controlled with standard analgesics, that is, paracetamol and tramadol. Ambroxol was introduced at a dose of 150mg/d without a noticeable effect. However, when the dose was increased up to 450mg/d, the intensity of pain diminished and subsided within the following months. Two of three attempts to reduce the dose of ambroxol resulted in a pain relapse within a week, which subsided after resetting the previous, higher dose. This observation of the effects of ambroxol in a GD patient is worth considering for other GD patients with chronic pain.
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http://dx.doi.org/10.1002/ejp.1538DOI Listing
May 2020

[Cardiovascular autonomic neuropathy in the course of diabetes - the review of actual knowledge.]

Postepy Biochem 2019 Dec 30;65(4):306-312. Epub 2019 Dec 30.

Szpital Uniwersytecki w Krakowie, Katedra Chorób Metabolicznych, Collegium Medicum Uniwersytetu Jagiellońskiego.

Diabetic neuropathy, including autonomic cardiovascular neuropathy, is the most common chronic complication of diabetes. It causes serious health and social consequences, leading to a significant reduction of life expectancy in DM patients. Its development is initially asymptomatic and therefore often underestimated, and only the early detection of diabetic neuropathy gives a real chance to stop its progression and prevent irreversible damage to the nerves. The optimal glycemic control is the most important factor preventing the development of neuropathy, inhibiting its occurrence and progression. In the advanced stage, however, only symptomatic treatment remains. The article provides an overview of current knowledge about etiopathogenesis, therapy, symptoms and the latest clinical trials on NSN and DM.
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http://dx.doi.org/10.18388/pb.2019_287DOI Listing
December 2019

Epigenetic mechanism in search for the pathomechanism of diabetic neuropathy development in diabetes mellitus type 1 (T1DM).

Endocrine 2020 04 4;68(1):235-240. Epub 2020 Jan 4.

University Hospital in Krakow, Kraków, Poland.

Objective: The aim of this study was to check the hypothesis concerning the crucial role of DNA methylation (one of the epigenetic mechanisms) within selected genes related to the destruction and regeneration of neural cells and its input in the pathogenesis of diabetic neuropathy, using a model of the DNA in peripheral blood cells.

Methods: A cross-sectional, case-control study was conducted, consisting of 24 adult Type 1 Diabetes Melitus (T1DM) patients with autonomic neuropathy (CAN), 25 T1DM patients without neuropathy and 25 matched, healthy adults acting as a control (Ctrl). The Ewing's tests, using the ProSciCard apparatus (Mewicon CATEEM-Tec GmbH), was employed to assess the severity of the patients' symptoms of autonomic neuropathy. For DNA methylation analysis, DNA material of each sample DNA after bisulfite conversion was used for the hybridization of BeadChips (Infinium Methylation EPIC Kit, Illumina), and imaged on the Illumina HiScan. The changes in the expression of selected genes were examined using real-time PCR. Probes were labeled using fluorescein amidite, FAM (Thermo Fisher Scientific). Amplification was performed using the continuous fluorescence detection 7900 HT Fast Real-Time PCR system (Thermo Fisher Scientific). The expression ratio of the target mRNA was normalized to the level of 18s RNA and compared with the control. Statistical analysis was performed using Statistica version 13.1. The statistically significant results were recognized, with a value of p < 0.05.

Results: Clinical analysis of the investigated groups revealed a significantly higher percentage of personal insulin pump users in the group without neuropathy. The glucose metabolic control, based on the HbA1c level analysis, was also significantly better in T1DM patients without CAN. The Bumphunter method for DNA methylation analysis showed statistically significant regions related to the genes involved in nerve regeneration ninjurin 2 (NINJ2) and functionality (BR serine/threonine kinase 2 BRSK2, claudin 4 CLDN4). When compared with T1DM patients without neuropathy, T1DM patients with neuropathy showed significantly increased methylation in the first NINJ2 axon, and a lower level of DNA methylation in the region of the first intron of BRSK2, as well as the CLDN4 5'UTR regions. The qRT-PCR results confirmed the decreased expression of NINJ2 and CLDN4 genes in patients with T1DM with CAN.

Conclusions: The different DNA methylation profiles, correlating with the expression of genes related to nervous tissue development and regeneration in patients with T1DM with autonomic neuropathy provide evidence for the role of epigenetic mechanisms promoting the development of CAN, a chronic complication of T1DM.
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http://dx.doi.org/10.1007/s12020-019-02172-9DOI Listing
April 2020

Is treatment of type 1 diabetes mellitus (insulin therapy, metabolic control) optimal for preventing cardiovascular autonomic neuropathy?

Endokrynol Pol 2019 7;70(4):323-329. Epub 2019 Mar 7.

Department of Metabolic Diseases, University Hospital, Krakow, Poland.

Introduction: Long-term poor metabolic control promotes the occurrence of microvascular complications, such as cardiovascular autonomic neuropathy (CAN) and atherogenic hyperlipidaemia, which translates into increased mortality in patients with type 1 diabetes mellitus (T1DM). The aim of the study was to assess the prevalence of CAN in patients with T1DM in relation to treatment method (continuous subcutaneous insulin infusion, CSII, versus multiple daily injections using pens, MDI) and metabolic control.

Material And Methods: The study group comprised 93 adults (60 women, 33 men), mean age 31 years, with T1DM being treated at a local clinical centre from 2011 to 2015. The presence of CAN, the results of laboratory tests, and anthropometric data were analysed. The subjects were divided into two groups according to treatment method (CSII, MDI).

Results: The median duration of diabetes was 16 years. 61% of the subjects used MDI and 39% used CSII. 41% of the subjects presented with CAN (confirmed with the Ewing test using ProSciCard apparatus), with a significantly lower prevalence in the group of patients treated with CSII (15.4% vs. 60.4%; p < 0.001). The mean HbA1c level in the CSII-treated group was noticeably lower (7.44 ± 1.67% vs.8.55 ± 1.1%, p < 0.001), and these patients also had lower triglyceride levels (0.71 vs. 1.32 mmol/L, p < 0.001). Regardless of the treatment method, 72% of all patients under 40 years of age achieved their therapeutic target of LDL cholesterol level < 2.6 mmol/L, whereas only 13% of all those over 40 years old achieved an LDL cholesterol level < 1.8 mmol/L.

Conclusions: The presented results draw attention to the high prevalence of CAN among T1DM patients. The study reveals the need for more intensive monitoring and treatment of hyperlipidaemia, despite good glycaemic control, especially in those over the age of 40 years.
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http://dx.doi.org/10.5603/EP.a2019.0011DOI Listing
February 2020

The additive effect on the antiepileptic treatment of ambroxol in type 3 Gaucher patient. The early observation.

Blood Cells Mol Dis 2018 02 11;68:192-193. Epub 2016 Dec 11.

Department of Metabolic Diseases University Hospital, Krakow, Poland. Electronic address:

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http://dx.doi.org/10.1016/j.bcmd.2016.12.001DOI Listing
February 2018