Dagmara Mirowska-Guzel

Association of IL1A, IL1B, ILRN, IL6, IL10 and TNF-α polymorphisms with risk and clinical course of multiple sclerosis in a Polish population.

Single nucleotide polymorphisms in human pro- and anti-inflammatory genes, including IL1RN VNTR (rs315952), IL1A 4845G>T (rs17561), L1B-511C>T (rs16944), IL6-174G>C (rs1800795), IL10-1082 A>G (rs 1800896) and TNFα-308G>A (rs1800629) and their impact on multiple sclerosis risk and disease progression in a Polish population were investigated. Increased risk of MS was found for IL6-174 CC homozygotes (OR, 2.88; p<0.00001). In turn, IL1A 4845 TT genotype determined earlier appearance of MS onset whereas IL1B-511 TT genotype was associated with later occurrence of MS but faster disability progression.

A prospective study of the financial costs of multiple sclerosis at different stages of the disease

The aim of our study was to estimate the costs of multiple sclerosis (MS) in Poland according to severity of disease. Total, direct and indirect costs were compared in 148 patients divided into three groups categorized by disease severity: stage I Expanded Disability Status Scale (EDSS <3.5), stage II (EDSS 4.0–6.0) and stage III (EDSS >6.5). Cost evaluation was performed from the societal perspective and covered the 5‐month period. Simple sensitivity analysis was performed by varying the tariffs and valuing caregiving at 40% of the average wage. The mean total cost/patient for 5 months was estimated at 10 955, 15 603 and 18 464 PLN for stage I, II and III, respectively [exchange rate: 4 PLN = 1 EUR; purchasing power pariety: 1 EUR = 2.05 PLN] (P < 0.0001). Regardless of EDSS stage indirect costs exceeded direct costs. Both direct and indirect costs increased with MS progression. For indirect cost the main item was productivity loss. This study confirms that MS represents a high economic burden, with indirect costs greatly exceeding direct costs. As costs increase with disease progression, treatment efforts should focus on patients in the early stages of MS.

BDNF − 270 C>T polymorphisms might be associated with stroke type and BDNF − 196 G>A corresponds to early neurological deficit in hemorrhagic stroke

Genetic factors might be involved in stroke prognosis, however the role of brain-derived neurotrophic factor (BDNF) in stroke recovery is unknown. We have studied BDNF -196 G>A and -270 C>T polymorphisms in ischemic and hemorrhagic stroke and their impact on stroke prognosis. There was higher occurrence of BDNF -270 CC genotype in patients with hemorrhagic than ischemic stroke (96% versus 86%, p=0.0495). In hemorrhagic stroke BDNF -196 GG carriers scored better in NIHSS at admission (14.23 versus 21.00, p=0.0192) and after 7days (8.60 versus 15.00, p=0.0408) of onsets. None of the determined polymorphisms had any impact on 30-day early outcome in ischemic and hemorrhagic stroke.

TNF inhibitors – Mechanisms of action, approved and off-label indications

Tumor necrosis factor inhibitors (TNFi) belong to the group of biologic drugs, holding presently top positions on lists of most profitable products for pharmaceutical companies. Although current indications for TNFi include only selected diseases with an established role of immune dysfunction in their pathogenesis, studies on new indications are being carried out all over the world. The most important aspect of TNFi therapy is a targeted therapeutic approach, allowing to avoid a wide range of side effects associated with treatment with nonspecific immunosuppressive agents. Results of the trials on TNFi in the approved indications are widely accessible and analyzed elsewhere, both in primary publications as well as in systematic reviews and meta-analyses. Here we aim to discuss their mechanisms of action, and approved, as well as off-label indications of TNFi. In addition, we present comprehensive evidence on TNFi in treatment of rheumatoid arthritis (RA); the first authorized and probably most extensively developed indication for the majority of TNFi.

Association of MMP1, MMP3, MMP9, and MMP12 polymorphisms with risk and clinical course of multiple sclerosis in a Polish population

Single nucleotide polymorphisms in human MMP genes, including MMP1 (-1637 1G>2G), MMP3 (-1612 5A>6A), MMP9 (-1562 C>T), and MMP12 (-82 A>G), and their impact on multiple sclerosis risk and disease progression in a Polish population were investigated. Increased risk of MS was found among carriers of at least one T allele of MMP9 -1562 C>T (OR, 1.7; p=0.0030) and one G allele of MMP12 -82 A>G (OR, 3.9; p<0.00001). Additionally, an association between MMP9 genotype and MMP-9 levels in peripheral blood was detected. Our results suggest that MMP9 -1562 C>T and MMP12 -82 A>G polymorphisms affect susceptibility to multiple sclerosis.

The role of epidermal sphingolipids in dermatologic diseases.

Sphingolipids, a group of lipids containing the sphingoid base, have both structural and biological functions in human epidermis. Ceramides, as a part of extracellular lipids in the stratum corneum, are important elements of the skin barrier and are involved in the prevention of transepidermal water loss. In addition, ceramides regulate such processes as proliferation, differentiation and apoptosis of keratinocytes. Another important sphingolipid, sphingosine-1-phosphate (S1P), inhibits proliferation and induces differentiation of keratinocytes. A recent clinical study of the efficacy and safety of ponesimod (a selective modulator of the S1P receptor 1) suggested that sphingolipid metabolism may become a new target for the pharmacological treatment of psoriasis. The role of sphingolipids in some dermatologic diseases, including psoriasis, atopic dermatitis and ichthyoses was summarized in this article.

Association between BDNF-196 G>A and BDNF-270 C>T polymorphisms, BDNF concentration, and rTMS-supported long-term rehabilitation outcome after ischemic stroke.

BACKGROUND The efficacy of rehabilitation in ischemic stroke patients likely varies because of brain plasticity. One of the main neurotrophins in the central nervous system is brain-derived neurotrophic factor (BDNF). OBJECTIVES This study aimed to determine allelic and genotypic distribution of BDNF-196 G>A and -270 C>T polymorphisms, and to assess the impact of repetitive transcranial magnetic stimulation (rTMS) on serum BDNF concentrations measured before rehabilitation, after the first 6 h of rehabilitation, and after 3 weeks of rehabilitation. METHODS Twenty-six patients with hand paresis and 20 with aphasia were randomly assigned to treatment with rTMS or sham stimulation (placebo group). RESULTS In men with aphasia, after the first 6 h of rTMS-supported rehabilitation, BDNF concentration was lower among rTMS-treated patients than placebo-treated patients. A similar difference was observed in women with aphasia after 3 weeks of rTMS-supported rehabilitation. No significant differences in serum BDNF concentration were observed in patients with different BDNF-196 G>A or -270 C>T genotypes. During the observation period, BDNF concentration did not differ significantly between patients who improved and those who did not. DISCUSSION One possible explanation for the observed difference between rTMS-stimulated and sham-stimulated patients is the suppression of BDNF production by rTMS in the healthy brain hemisphere.

Impact of BDNF -196 G>A and BDNF -270 C>T Polymorphisms on Stroke Rehabilitation Outcome: Sex and Age Differences

Abstract Background: Genetic factors, including gene polymorphisms, are promising in determining stroke rehabilitation outcome. Brain-derived neurotrophic factor (BDNF) is one of the most attractive because of its role in neuroplasticity and brain repair. Objective: The aim of present study was to assess the role of BDNF -196 G>A (val66met) and -270 C>T on clinical parameters and functional outcome in patients with ischemic and hemorrhagic stroke. Additional analyses according to sex and age (≤55 and >55 years) were performed. Methods: Three hundred thirty-eight patients (287 with ischemic and 51 with hemorrhagic stroke) were evaluated in terms of neurological deficit (National Institute of Heath Stroke Scale [NIHSS]), activities of daily living (Barthel Index [BI]), and everyday functionality (Rankin score [RS]) before and after rehabilitation. BDNF polymorphism genotyping was performed by polymerase chain reaction restriction fragment length polymorphism analysis. Results: In multivariative analysis, unfavorable outcome of stroke rehabilitation (RS ≥2) was associated with independent factors: ischemic stroke (odds ratio [OR], 2.59; 95% CI, 1.03-6.47), female gender (OR, 2.80; 95% CI, 1.39-5.64), depression (OR, 4.24; 95% CI, 1.45-12.35), falls (OR, 2.61; 95% CI, 1.16-5.87), and BDNF -196 GG polymorphism (OR, 2.18; 95% CI, 1.09-4.35). The differences of functional parameters measured with BI and RS on admission and at discharge are apparent only for comparisons between patients ≤55 and >55 years old carrying BDNF -196 GA+AA genotypes but not in those carrying -196 GG genotype; the differences were evident in women but not in men. Conclusions:BDNF -196 G>A polymorphism might affect functional outcome of stroke rehabilitation, but this hypothesis needs further verification.

Are cognitive and behavioural deficits a part of the clinical picture in Kennedy's disease? A case study

Two years prior to diagnosis of Kennedys disease (KD), a 53-year-old man began experiencing neurological symptoms, including nasal speech, postural tremor, tremor in the upper extremities, and muscle weakness. Genetic analysis revealed 46 CAG repeats in the androgen receptor gene. The patients altered social conduct and complaints of forgetfulness led to a neuropsychological assessment. A mild impairment in visuospatial and visuoconstructive abilities, visual short-term memory, and a personality disorder were detected. Although cognition and behaviour in KD are typically normal, our findings suggest that the disease may cause mild cognitive and behavioural changes as part of the diseases clinical manifestation.

Mechanism of action of three newly registered drugs for multiple sclerosis treatment

Multiple sclerosis (MS) is a disease of suspected autoimmune origin leading to neurodegeneration. The disease pathomechanism is considered to be primarily based on neuroinflammation directed against myelin antigens caused by autoreactive T cells. MS etiology remains still unknown, which makes it difficult to create an efficient therapy, therefore, MS treatment targets mechanisms involved in disease pathology. In this review, we present the mechanism of action of three newly registered drugs for MS. Dimethyl fumarate (DMF) is an agent presenting a broad spectrum of action. Its main activity is based on activating the nuclear factor E2 dependent pathway leading to antioxidant enzyme synthesis. DMF in general suppresses the pro-inflammatory immune activity and exerts a neuroprotective action. Teriflunomide is a more focused drug, acting as an inhibitor of pyrimidines synthesis, important for rapidly dividing cells such as activated lymphocytes. Similarly, alemtuzumab, an anti-CD52 antibody, causes depletion of mainly lymphocytes. Since in MS pathology, T and B cells are involved, this mode of action is promising.