Correlation of selected serum protein levels with the degree of disability and NEDA-3 status in multiple sclerosis phenotypes.

OBJECTIVE: Multiple sclerosis (MS) is a multifactorial disease that begins in 80-85% of patients as a relapsing-remitting form (RRMS), and about 50% of patients gradually develop a secondary progressive form (SPMS). Approximately 10-20% of patients are affected primarily by the progressive form (PPMS) of this disease, which is characterised by a progressive course. This work focuses on the detection of potential protein biomarkers (CHI3L1, sNfL, CXCL13, MCP-1, MMP-2, and MMP-9) in the serum of patients with multiple sclerosis, divided according to phenotype. PATIENTS AND METHODS: We detected serum (RRMS: n=40, SPMS: n=25, PPMS: n=15) concentrations of selected markers of demyelination and inflammation using ELISA and zymographic determination for accurate and reproducible recognition of individual forms of MS, as well as a comparison of their levels with a worsening of no evidence of disease activity (NEDA-3) status and patients' disability. RESULTS: We detected that concentrations of sNfL in the blood of patients with PMS were higher than in those with RRMS (about 46%, p<0.001). The association with a worsening of NEDA-3 status was confirmed in the RRMS group by positive correlation of sNfL and the expanded disability status scale (EDSS) score (r=0.579, p<0.01). The levels of MCP-1 protein were not significantly different in patients with the RRMS to the progressive form of MS (r=0.58, p=0.02), while the levels of CHI3L1 in both the RRMS and PMS groups were significantly increased in groups with evidence of disease activity (RRMS about 76%, p<0.001 and PMS about 62%, p<0.001). CONCLUSIONS: Earlier and non-invasive detection of serum biomarkers and their correlations with neurological disability can help to recognise the transition from RRMS to progressive forms of MS and complement the results of clinical and radiological follow-up of the patient and potentially help in monitoring the patient's response to the treatment.

Expression of selected inflammatory proteins and metalloproteinases in periodontitis.

OBJECTIVE: Periodontitis is a chronic inflammatory disease caused by microbial dental plaque which leads to the destruction and loss of supporting tissues of the tooth. Microbial plaque alone, however, is not enough to cause the disease. The body's response plays an important role, in which an imbalance between the pro-inflammatory and anti-inflammatory effects of cytokines leads to an inflammatory reaction. PATIENTS AND METHODS: We detected changes in mRNA expression and protein levels of MIP-1α, and metalloproteinases (MMP-2, MMP-9) contributing to cascades in the initiation and progression of inflammatory bone resorption and destruction of periodontal soft tissues in patients with aggressive (AP) or chronic (CP) forms of periodontitis in comparison with healthy individuals (control). RESULTS: MIP-1α mRNA levels were highest in AP (280 ± 23% higher than the control) also in comparison with CP. The difference in protein level was less pronounced. MMP-2 mRNA expression values were similar (300 ± 12% higher in comparison with control), but protein levels were lower, also when compared to CP. Only in CP MMP-9 mRNA levels were significantly higher than the control (30 ± 8%), while protein levels were again higher in AP. Both AP and CP showed a positive correlation between the level of MIP-1a and MMP-2 (0.879, and 0.954 respectively). However, a strong positive correlation was only found between the levels of MMP-2 and MMP-9 in CP (0.812). CONCLUSIONS: MIP-1α, MMP-2 and MMP-9 mRNA expression, along with the concentration of proteins in saliva in patients with periodontal disease, is higher than in healthy individuals and correlates with the severity of the disease.

Thermal Waves and Heat Transfer Efficiency Enhancement in Harmonically Modulated Turbulent Thermal Convection.

We study turbulent Rayleigh-Bénard convection over four decades of Rayleigh numbers 4×10^{8}

Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study.

OBJECTIVES: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study. METHODS: ASCEND-1 was an open-label, multicentre, phase 1, dose-escalation and expansion study of ceritinib (fasted) in ALK inhibitor (ALKi)-naïve or ALKi-pretreated patients with locally advanced or metastatic ALK + NSCLC. Biopsies were assayed by next-generation sequencing (NGS) using a Foundation Medicine panel targeting 295 genes. Somatic alterations were correlated with clinical outcome (cut-off 14-Apr-2014). A total of 285 ALK + NSCLC patients were treated with ceritinib at doses ≥ 300 mg. RESULTS: NGS data were generated for 85 pts (ALKi-pretreated [n = 54]; ALKi-naïve [n = 31]), 57 were collected from patients before exposure to any ALKi. NGS did not detect ALK rearrangement in 14 of 85 patients; several of these ALK NGS negative cases harbored alternative drivers, e.g. EGFR mutation. Of the 71 biopsies with NGS confirmed ALK rearrangement, the most frequently detected rearrangements were EML4-ALK variant 1 (V1) and EML4-ALK V3 (36.6% [26/71] and 32.4% [23/71] respectively). Eight (six crizotinib-pretreated and two pretreated with crizotinib followed by alectinib) of the 21 ALKi-pretreated patients carried a point mutation of the ALK TKD, and had the biopsy collected between 1 and 14 days before ceritinib; with the exception of one patient with a G1202R point mutation, all patients derived clinical benefit from ceritinib treatment. Of the 14 ALKi-naïve patients, ceritinib was effective in almost all patients, including a patient carrying a concomitant ERBB4 and HGF amplification. CONCLUSIONS: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01283516. Registered January 26, 2011, https://clinicaltrials.gov/ct2/show/NCT01283516.

The fox tapeworm, Echinococcus multilocularis, in grey wolves and dogs in Slovakia: epidemiology and genetic analysis.

Echinococcus multilocularis, the causative agent of human alveolar echinococcosis, is an important emerging parasite in the northern hemisphere. In epidemiological studies, the highest attention is being paid to foxes as the main reservoir hosts responsible for geographic expansion from multiple focal populations and the invasion of urban habitats, but little information is available on the parasite distribution in other carnivores. Hence, the study was designed to obtain updated information about the occurrence and genetic diversity of E. multilocularis in grey wolves and dogs in Slovakia. Faecal samples of wolves were collected from three locations under a certain level of environmental protection in the central and eastern parts of the country, and the presence of the parasite DNA was detected in 35.7% of 112 samples, with the highest rate (51.2%) recorded in the Poloniny National Park in north-eastern Slovakia. Among 110 faecal dog samples, E. multilocularis was detected in three faeces from segregated Roma settlements in the eastern part of the country, which accounted for an overall positivity of 2.7%. Sequence analysis of two mitochondrial genes, 12S rRNA and NADH dehydrogenase subunit 1, revealed four haplotypes in 13 isolates from wolves and dogs originating from four sites in eastern and central Slovakia, with all samples bearing a European-type pattern of E. multilocularis. The more than one-third positivity rate of E. multilocularis in wolf faecal samples dispersed over a large part of the country has corroborated the extensive circulation of the parasite in wildlife and confirmed the need to improve intervention control strategies.

Thermal radiation in Rayleigh-Bénard convection experiments.

An important question in turbulent Rayleigh-Bénard convection (RBC) is the effectiveness of convective heat transport, which is conveniently described via the scaling of the Nusselt number (Nu) with the Rayleigh (Ra) and Prandtl (Pr) numbers. In RBC experiments, the heat supplied to the bottom plate is also partly transferred by thermal radiation. This heat transport channel, acting in parallel with the convective and conductive heat transport channels, is usually considered insignificant and thus neglected. Here we present a detailed analysis of conventional far-field as well as strongly enhanced near-field radiative heat transport occurring in various RBC experiments. A careful inclusion of the radiative transport appreciably changes the Nu=Nu(Ra) scaling inferred in turbulent RBC experiments near ambient temperature utilizing gaseous nitrogen and sulfur hexafluoride as working fluids. On the other hand, neither the conventional far-field radiation nor the strongly enhanced near-field radiative heat transport appreciably affects the heat transport law deduced in cryogenic helium RBC experiments.

3D bioprinting for orthopaedic applications: Current advances, challenges and regulatory considerations.

In the era of personalised medicine, novel therapeutic approaches raise increasing hopes to address currently unmet medical needs by developing patient-customised treatments. Three-dimensional (3D) bioprinting is rapidly evolving and has the potential to obtain personalised tissue constructs and overcome some limitations of standard tissue engineering approaches. Bioprinting could support a wide range of biomedical applications, such as drug testing, tissue repair or organ transplantation. There is a growing interest for 3D bioprinting in the orthopaedic field, with remarkable scientific and technical advances. However, the full exploitation of 3D bioprinting in medical applications still requires efforts to anticipate the upcoming challenges in translating bioprinted products from bench to bedside. In this review we summarised current trends, advances and challenges in the application of 3D bioprinting for bone and cartilage tissue engineering. Moreover, we provided a detailed analysis of the applicable regulations through the 3D bioprinting process and an overview of available standards covering bioprinting and additive manufacturing.

Molecular recognition of aortic valve stenosis and regurgitation.

OBJECTIVE: Aortic valve stenosis (AS) presents a disease during which there are changes of the aortic valve structure that modify the blood structure of patients. The aim of this study was to improve the effectiveness of differential diagnostics of aortic stenosis and aortic regurgitation using molecular techniques on both mRNA (RT-PCR) and protein (biochip protein). PATIENTS AND METHODS: An experimental group (n = 58) consisting of patients with aortic valve stenosis (n = 26) and aortic regurgitation (AR, n = 32) was compared with a control group (n = 35). Both blood serum and valve tissue samples were used for the determination of gene expression specific genes related to inflammatory response (CRP, IL6, IL2R, IL6R, TNFR1, and 2) as well as genes and proteins involved in remodeling of the extracellular matrix (MMP9, TIMP, Emilin-1). RESULTS: We found that hsCRP and IL6 plasma levels of patients with AS were higher than both controls and patients with AR (mean 5.6 ng/ml). The differences between AS and AR were detected only in mRNA levels of MMP9 and TIMP where increased levels characteristic for AS were found (about 74%, p < 0.01 and 87%, p < 0.001 higher than AR). CONCLUSIONS: The achieved results could contribute to the improvement of early diagnosis of selected cardiovascular disease in the future and improve the quality of patient's life.

Polypharmacy in Parkinson's disease: risks and benefits with little evidence.

Polypharmacy is common practice in Parkinson's disease. Medical treatment targeting the dopaminergic system alone may include up to five different compounds: L-DOPA (in combination with a DOPA decarboxylase inhibitor), a catechol-O-methyltransferase (COMT) and a monoamine oxidase (MAO-B) inhibitor and a dopamine agonist. Particular motor and non-motor symptoms may require additional specific therapeutics, such as drugs aimed at tremor control and to treat depression, dementia and orthostatic and autonomic dysfunction. No prospective studies have yet been performed with regard to the efficacy or the long-term benefit of combining such different treatments in Parkinson's disease and retrospective analyses are sparse. We thus tried to compile the available evidence for polypharmacy strategies in Parkinson's disease and devised an expert opinion statement.

Elusive transition to the ultimate regime of turbulent Rayleigh-Bénard convection.

By using cryogenic ^{4}He gas as the working fluid in a cylindrical cell 0.3 m in both height and diameter, we study the influence of non-Oberbeck-Boussinesq (NOB) effects on the heat transfer in turbulent Rayleigh-Bénard convection (RBC). We show that the NOB effects increase the heat transfer efficiency when the top plate temperature closely approaches the saturation vapor curve even far away from the critical point. Viewed in this light, our analysis points to the likelihood that the claim of having observed the transition to Kraichnan's ultimate regime, under nominally similar conditions in the experiments with SF_{6} [Phys. Rev. Lett. 108, 024502 (2012)PRLTAO0031-900710.1103/PhysRevLett.108.024502], is probably an NOB effect and the important issue of the transition to the ultimate state of RBC remains open.

Evaluation of molecular changes of distal organs after small bowel transplantation.

The ischemia and reperfusion of a jejunal graft during transplantation triggers the stress of endoplasmic reticulum thus inducing the synthesis of pro-inflammatory cytokines. Spreading of these signals stimulate immunological reactions in distal tissues, i.e. lung, liver and spleen. The aim of this study was to detect the molecular changes in liver and spleen induced by transplanted jejunal graft with one or six hours of reperfusion (group Tx1 and Tx6). Analysis of gene expression changes of inflammatory mediators (TNF-alpha, IL-10) and specific chaperones (Gadd153, Grp78) derived from endoplasmic reticulum (ER) was done and compared to control group. The qRT-PCR method was used for amplification of the specific genes. The levels of corresponding proteins were detected by Western blot with immunodetection. Protein TNF-alpha was in liver tissue significantly overexpressed in the experimental group Tx1 by 48 % (p<0.001). In the group Tx6 we found decreased levels of the same protein to the level of controls. However, the protein concentrations of TNF-alpha in spleen showed increased levels in group Tx1 by 31 % (p<0.001) but even higher levels in the group Tx6 by 115 % (p<0.001) in comparing to controls. Our data demonstrated that the spleen is more sensitive to post-transplantation inflammation than liver, with consequent stress of ER potentially inducing apoptosis and failure of basic functions of lymphoid tissue.

Demonstration of a 120° hybrid based simplified coherent receiver on SOI for high speed PON applications.

We demonstrate the first simplified coherent receiver using a 120° hybrid on silicon-on-insulator (SOI) for high speed PON applications. This coherent receiver integrates an inverse taper edge coupler for the received signal, a vertical grating coupler for the local oscillator input, a polarization splitter and rotator (PSR), a 120° hybrid based on a 3×3 multimode interference (MMI) coupler, and three germanium photodetectors. We achieved 25 Gbit/s two-level pulse amplitude modulation (PAM-2) transmission over 30 km standard single mode fiber (SMF) in the C-band without any digital signal processing (DSP) (e.g., pre-emphasis, pulse shaping, equalization, nonlinearity compensation) and dispersion compensation (e.g., optical or digital) either at the transmitter or at the receiver. The requirements for frequency and phase locking of the local oscillator (LO) were avoided due to the use of intensity modulated signals. Receiver sensitivities of -23.70 dBm, -20.30 dBm, and -15.10 dBm are achieved at a bit error rate (BER) below the hard-decision forward error correction (HD-FEC) threshold (i.e., 3.8 × 10-3) in back-to-back (B2B), after 21 km and 30 km, respectively. We also demonstrate 25 Gbit/s PAM-4 transmission achieving receiver sensitivities of -15.30 dBm, -13.90 dBm, and -9.50 dBm below the HD-FEC threshold in B2B, after 10.5 km and 21 km, respectively.

Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy.

PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.

Recurrent stenosis following carotid artery stenting treated with a drug-eluting balloon: a single-center retrospective analysis.

PURPOSE: Early in-stent restenosis after stent-protected angioplasty of the carotid artery (SPAC) is an infrequent, but potentially harmful condition for patients with carotid artery disease. METHODS: In our retrospective single-center analysis of 176 patients with carotid artery stenting between 2009 and 2015, using duplex ultrasound, we detected 9 patients with high-grade carotid artery in-stent restenosis. All restenosis patients were treated with a drug-eluting balloon (DEB) to prevent recurrent neointimal hyperplasia. One patient had bilateral carotid artery disease with bilateral in-stent restenosis, and 1 patient needed repeated DEB treatment 19 months after the first DEB intervention, so 11 DEB procedures, in total, were performed. RESULTS: The median time-interval between primary carotid artery stenting and first DEB-treatment was 9 months. In 3 of the 11 interventions, the DEB treatment was assisted by an additional stent. One repeat DEB treatment was necessary, and three DEB treatments were followed by a secondary stent. No peri-interventional complications (TIA, stroke, or death) were observed during or after DEB intervention. Therefore, in the entire group, the 1y event-free survival (EFS) was 100%, and the 2y/3y/5y EFS was 83%. CONCLUSION: DEB intervention seems to be an effective and safe treatment for patients with high-grade in-stent restenosis after SPAC.

[Myasthenia gravis should be considered in cases of Parkinson's disease and progressive dysphagia]. / Bei Morbus Parkinson und progredienter Dysphagie an Myasthenia gravis denken.

We report on four consecutive patients with Parkinson's disease, in whom anti-acetylcholine receptor (AChR) antibody positive bulbar myasthenia gravis (MG) turned out to be responsible for progressive dysphagia.

RADON CHAMBER IN THE CENTRAL MINING INSTITUTE-THE CALIBRATION FACILITY FOR RADON AND RADON PROGENY MONITORS.

The article presents the advantages of the radon chamber with volume of 17 m3, that belongs to Silesian Centre for Environmental Radioactivity and its applicability for calibration of equipment designed to measure the radon concentration and its short-lived decay products. The chamber can be operated under controlled conditions in the range from -20 to 60°C and relative humidity from 20 to 90%. There is also discussed the influence of aerosol concentration and their size distribution on the calibration results. When calibrating the measuring devices in an atmosphere with a large contribution of ultrafine particles that are defined as particles with diameter <0.1 µm, their sensitivity may decrease by tens of percent.

MEASUREMENTS OF AIRBORNE CONCENTRATIONS OF RADON AND THORON DECAY PRODUCTS.

Liquid scintillation counting (LSC) is a measuring technique, broadly applied in environmental monitoring of radionuclides. One of the possible applications of LSC is the measurement of radon and thoron decay products. But this method is suitable only for grab sampling. For long-term measurements a different technique can be applied-monitors of potential alpha energy concentration (PAEC) with thermoluminescent detectors (TLD). In these devices, called Alfa-2000 sampling probe, TL detectors (CaSO4:Dy) are applied for alpha particles counting. Three independent heads are placed over the membrane filter in a dust sampler's microcyclone. Such solution enables simultaneous measurements of PAEC and dust content. Moreover, the information which is stored in TLD chips is the energy of alpha particles, not the number of counted particles. Therefore, the readout of TL detector shows directly potential alpha energy, with no dependence on equilibrium factor, etc. This technique, which had been used only for radon decay products measurements, was modified by author to allow simultaneous measurements of radon and thoron PAEC. The LSC method can be used for calibration of portable radon decay products monitors. The LSC method has the advantage to be an absolute one, the TLD method to measure directly the (dose relevant) deposited energy.