[Health policy experiences of publicly financed laboratory services in Hungary with health insurance data analysis]. / A közfinanszírozott laboratóriumi szolgáltatások egészségpolitikai tapasztalatai Magyarországon egészségbiztosítási adatok elemzésével.

Introduction: In order to provide appropriate prevention, diagnosztics, decision on therapy and monitoring the results of medical treatment, there is an increasing need for laboratory examinations. Aim: The aim of our study is the health-ecnomics analysis of laboratory budget of the Hungarian Health Insurance Fund. Data and method: Data were derived from the financial database of the National Health Insurance Fund Administration. The analysis covered the period of 2002-2018. We analysed the annual budget for laboratory examinations, the number of patients and examinations, the market share of laboratory services providers according to their owner structure from the health insurance curative-preventive budget. Results: The budget available for financing the laboratory examinations (21-22 billion Hungarian forint (Ft)/év) did not change significantly between 2005 and 2015. There was a significant decrease in the number of both patients and examinations between 2006 and 2008. In the latest years, there were 14-15 million cases per year and 180 million examinations per year. The market share of for-profit companies decreased from 29.0% in 2010 to 10.6% in 2018, while the market share of governmental institutions increased from 27.1% in 2010 to 78.7% in 2018. Conclusion: The activity of laboratories was stabilized in the latest years. After the necessary correction of professional regulations and code maintenance, the laboratory budget can be increased towards the mainly public laboratory services providers. Orv Hetil. 2020; 161(12): 468-473.

The Usage of Pedicled or Free Muscle Flaps Represents a Beneficial Approach for Periprosthetic Infection After Knee Arthroplasty.

INTRODUCTION: Periprosthetic joint infection (PJI) is a severe complication after a total knee replacement that is primarily associated with soft tissue defects. Finding an appropriate therapy for PJI is a major challenge because of the lack of guidelines and research comparing treatment options. METHODS: In this study, we retrospectively compared 78 patients who had a knee prosthetic infection within a mean follow-up period of 24 months. Group A received a soft tissue coverage in addition to orthopedic surgical therapy with or without a component replacement (CR) of the prosthesis. Group B received the same orthopedic treatment without plastic surgery for soft tissue coverage. RESULTS: Only 21% of the patients in group A received a CR compared with 70% in group B (P = 0.0001). In group A, 83% did not have a recurrent infection, and in group B, 57% of the patients had no further infection and regained joint function (P = 0.0376). In group A, only 15% of the patients who received a CR had a significant complication within the follow-up period of 2 years, whereas in group B, 75% of patients exhibiting a major complication (P = 0.0048*). CONCLUSIONS: Soft tissue coverage improves the outcome after PJI of the knee with soft tissue defects. Patients who simultaneously needed plastic surgery for defect coverage and orthopedic surgery for CR had the lowest number of complications overall. Based on the results of this study, a therapy algorithm could be identified considering the soft tissue defect grade leading to the lowest major complication rates and maximizing the outcome of knee prosthesis infection therapies.

Three-dimensional assessment of lower limb alignment: Reference values and sex-related differences.

BACKGROUND: Three-dimensional (3D) preoperative planning and assisted surgery is increasingly popular in deformity surgery and arthroplasty. Reference ranges for 3D lower limb alignment are needed as a prerequisite for standardized analysis of alignment and preoperative planning in 3D, but are not yet established. METHODS: On 60 3D bone models of the lower limbs based on computed tomography data, fifteen parameters per leg were assessed by standardized validated 3D analysis. Distribution parameters and differences between sexes were evaluated. Reference values were generated by adding/subtracting one standard deviation from the mean. RESULTS: Women had a significantly lower mean mechanical lateral distal femoral angle compared with men (86.4 ±â€¯2.1° vs. 87.8 ±â€¯2.0°; P < .05) and significantly lower mean joint line convergence angle (-2.5 ±â€¯1.4° vs. -1.3 ±â€¯1.2; P < .01), but higher mean hip knee ankle angle (178.9 ±â€¯1.9° vs. 177.8 ±â€¯2.3°; P < .05) and mean femoral torsion (18.2 ±â€¯9.5° vs. 13.2 ±â€¯6.4°; P < .05), resulting in a tendency towards valgus alignment and vice versa for men. Differences in mean medial proximal tibial angle were not significant. The mean mechanical axis deviation from the tibial knee joint center was 6.9 ±â€¯7.3 mm medial and 1.4 ±â€¯16.1 mm ventral without significant differences between sexes. CONCLUSIONS: We describe total and sex-related reference ranges for all alignment relevant axes and joint angles of the lower limb. There are sex-related differences in certain alignment parameters, which should be considered in analysis and surgical planning.

Presence of varicella zoster virus in zosteriform leukaemia cutis.

Leukaemia cutis is a relatively rare manifestation in chronic lymphocytic leukaemia, characterized by a diverse morphology of skin lesions. We report two patients who developed zosteriform skin symptoms; however, the histological analysis revealed leukaemia infiltration as the cause of their symptoms. Contrary to previous reports, varicella zoster virus DNA was detectable in the lesions. These findings suggest that varicella zoster virus plays an active role in the development of zosteriform leukaemia cutis.

Three-dimensional assessment of lower limb alignment: Accuracy and reliability.

INTRODUCTION: Three-dimensional (3D) surgical planning and patient-specific implants are becoming increasingly popular in orthopedics and trauma surgery. In contrast to the established and standardized alignment assessment on two-dimensional (2D) long standing radiographs (LSRs) there is neither a standardized nor a validated protocol for the analysis of 3D bone models of the lower limb. This study aimed to create a prerequisite for pre-operative planning. METHODS: According to 2D analysis and after meticulous research, 24 landmarks were defined on 3D bone models obtained from computed axial tomography (CT) scans for a 3D alignment assessment. Three observers with different experience levels performed the test three different times on three specimens. Intraobserver and interobserver variability of the landmarks and the intraclass correlation coefficient (ICC) of the resulting axes and joint angles were evaluated. RESULTS: Overall, the intraobserver and interobserver variability was low, with a mean deviation <5 mm for all landmarks. The ICC of all joint angles and axis deviations was >0.8, except for tibial torsion (ICC = 0.69). All knee joint angles showed excellent ICC (>0.95). CONCLUSIONS: Using the defined landmarks, a standardized 3D alignment assessment with low intraobserver and interobserver variability and high ICC values for the knee joint angles can be performed regardless of examiner's experience. The described method serves as a reliable standardized protocol for a 3D malalignment test of the lower limb. Three-dimensional pre-operative analysis might enhance understanding of deformities and lead to a new focus in surgical planning.

Systemic lupus erythematosus in the light of the regulatory effects of galectin-1 on T-cell function.

Galectin-1 is an endogenous immunoregulatory lectin-type protein. Its most important effects are the inhibition of the differentiation and cytokine production of Th1 and Th17 cells, and the induction of apoptosis of activated T-cells. Galectin-1 has been identified as a key molecule in antitumor immune surveillance, and data are accumulating about the pathogenic role of its deficiency, and the beneficial effects of its administration in various autoimmune disease models. Initial animal and human studies strongly suggest deficiencies in both galectin-1 production and responsiveness in systemic lupus erythematosus (SLE) T-cells. Since lupus features widespread abnormalities in T-cell activation, differentiation and viability, in this review the authors wished to highlight potential points in T-cell signalling processes that may be influenced by galectin-1. These points include GM-1 ganglioside-mediated lipid raft aggregation, early activation signalling steps involving p56Lck, the exchange of the CD3 ζ-ZAP-70 to the FcRγ-Syk pathway, defective mitogen-activated protein kinase pathway activation, impaired regulatory T-cell function, the failure to suppress the activity of interleukin 17 (IL-17) producing T-cells, and decreased suppression of the PI3K-mTOR pathway by phosphatase and tensin homolog (PTEN). These findings place galectin-1 into the group of potential pathogenic molecules in SLE.

Pilot Study of the Occurrence of Somatic Mutations in Ciliary Signalling Pathways as a Contribution Factor to Autosomal Dominant Polycystic Kidney Development.

Autosomal-dominant polycystic kidney disease (ADPKD) is an inherited disease that results in multiple kidney cysts, and it is a common cause of end-stage renal disease. Recent studies have shown that disease progression can be slowed by simultaneous disruption of the primary cilium and polycystins. The exact genetic mechanism of this process is still unknown. The aim of the present study was to characterize the mutation profile of ciliary signalling pathways in the renal epithelial cells of ADPKD patients. In our study, we performed an analysis of 110 genes encoding the components of Sonic Hedgehog, Hippo, Notch, Wnt and planar cell polarity signalling (PCP) by targeted next-generation sequencing. We analysed 10 formalin-fixed, paraffinembedded (FFPE) tissue samples of patients with ADPKD. We identified a unique mutation profile in each of the analysed ADPKD samples, which was characterized by the presence of pathogenic variants in eight to 11 genes involved in different signalling pathways. Despite the significant genetic heterogeneity of ADPKD, we detected five genes whose genetic variants affected most ADPKD samples. The pathogenic variants in NCOR2 and LRP2 genes were present in all analysed samples of ADPKD. In addition, eight out of 10 samples showed a pathogenic variant in the MAML2 and FAT4 genes, and six out of 10 samples in the CELSR1 gene. In our study, we identified the signalling molecules that may contribute to the cystogenesis and may represent potential targets for the development of new ADPKD treatments.

New Mutations Associated with Rasopathies in a Central European Population and Genotype-Phenotype Correlations.

We performed the genetic analysis of Rasopathy syndromes in patients from Central European by direct sequencing followed by next generation sequencing of genes associated with Rasopathies. All 51 patients harboured the typical features of Rasopathy syndromes. Thirty-five mutations were identified in the examined patients (22 in PTPN11, two in SOS1, one in RIT1, one in SHOC2, two in HRAS, three in BRAF, two in MAP2K1 and two in the NF1 gene). Two of them (p.Gly392Glu in the BRAF gene and p.Gln164Lys in the MAP2K1 gene) were novel with a potentially pathogenic effect on the structure of these proteins. Statistically significant differences in the presence of pulmonary stenosis (63.64% vs. 23.81%, P = 0.013897) and cryptorchidism (76.47% vs. 30%, P = 0.040224) were identified as the result of comparison of the prevalence of phenotypic features in patients with the phenotype of Noonan syndrome and mutation in the PTPN11 gene, with the prevalence of the same features in patients without PTPN11 mutation. Cryptorchidism as a statistically significant feature in our patients with PTPN11 mutation was not reported as significant in other European countries (Germany, Italy and Greece). The majority of mutations were clustered in exons 3 (45.45%), 8 (22.73%), and 13 (22.73%) of the PTPN11 gene.

Quantitative impact of direct, personal feedback on hand hygiene technique.

This study investigated the effectiveness of targeting hand hygiene technique using a new training device that provides objective, personal and quantitative feedback. One hundred and thirty-six healthcare workers in three Hungarian hospitals participated in a repetitive hand hygiene technique assessment study. Ultraviolet (UV)-labelled hand rub was used at each event, and digital images of the hands were subsequently taken under UV light. Immediate objective visual feedback was given to participants, showing missed areas on their hands. The rate of inadequate hand rubbing reduced from 50% to 15% (P < 0.001). However, maintenance of this reduced rate is likely to require continuous use of the electronic equipment.

Trends in Major Lower Limb Amputation Related to Peripheral Arterial Disease in Hungary: A Nationwide Study (2004-2012).

OBJECTIVES: To assess the trends of peripheral arterial disease associated major lower limb amputation in Hungary over a 9 year period (2004-2012) in the whole Hungarian population. METHODS: This was a retrospective cohort study employing administrative health care data. Major amputations were identified in the entire Hungarian population during a 9 year period (2004-2012) using the health care administrative data. Direct standardization was used to eliminate the potential bias induced by the different age and sex structure of the compared populations. For external direct standardization, the ESP 2013 was chosen as reference. RESULTS: 76,798 lower limb amputations were performed. The number of major amputations was 38,200; these procedures affected 32,084 patients. According to case detection, 50.4% of the amputees were diabetic. The overall primary amputation rate was 71.5%. The annual crude and age adjusted major amputation rates exhibited no significant long-term pattern over the observation period. The major lower limb amputation incidence for the overall period was 42.3/10(5) in the total population and 317.9/10(5) in diabetic population. CONCLUSION: According to this whole population based study from Hungary, the incidence of lower limb major amputation is high with no change over the past 9 years. An explanation for this remains to be determined, as the traditional risk factors in Hungary do not account for it. The characteristics of major amputation (the rate of primary amputation, the ratio of below to above knee amputation and the age of the affected population) underline the importance of screening, early detection, improved vascular care and an optimal revascularization policy. Standardization and validation of amputation detection methods and reporting is essential.

The ultrastructure and flexibility of thylakoid membranes in leaves and isolated chloroplasts as revealed by small-angle neutron scattering.

We studied the periodicity of the multilamellar membrane system of granal chloroplasts in different isolated plant thylakoid membranes, using different suspension media, as well as on different detached leaves and isolated protoplasts-using small-angle neutron scattering. Freshly isolated thylakoid membranes suspended in isotonic or hypertonic media, containing sorbitol supplemented with cations, displayed Bragg peaks typically between 0.019 and 0.023Å(-1), corresponding to spatially and statistically averaged repeat distance values of about 275-330 Å⁻¹. Similar data obtained earlier led us in previous work to propose an origin from the periodicity of stroma thylakoid membranes. However, detached leaves, of eleven different species, infiltrated with or soaked in D2O in dim laboratory light or transpired with D2O prior to measurements, exhibited considerably smaller repeat distances, typically between 210 and 230 Å⁻¹, ruling out a stromal membrane origin. Similar values were obtained on isolated tobacco and spinach protoplasts. When NaCl was used as osmoticum, the Bragg peaks of isolated thylakoid membranes almost coincided with those in the same batch of leaves and the repeat distances were very close to the electron microscopically determined values in the grana. Although neutron scattering and electron microscopy yield somewhat different values, which is not fully understood, we can conclude that small-angle neutron scattering is a suitable technique to study the periodic organization of granal thylakoid membranes in intact leaves under physiological conditions and with a time resolution of minutes or shorter. We also show here, for the first time on leaves, that the periodicity of thylakoid membranes in situ responds dynamically to moderately strong illumination. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy.

Rasopathies - dysmorphic syndromes with short stature and risk of malignancy.

OBJECTIVES: The term ´Rasopathies´ represents a group of five neurodevelopmental syndromes (Noonan, LEOPARD, Costello, Cardio-facio-cutaneous, and Neurofibromatose-Noonan syndrome) caused by germline mutation in genes encoding proteins involved in RAS/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway. The RAS/MAPK signaling pathway participates in regulation of cell determination, proliferation, differentiation, migration, and senescence and dysregulation of this pathway can lead to the risk of tumorigenesis. In this review, we aim to summarize the current clinical and molecular genetic knowledge on Rasopathies with special attention for the risk of cancer. We propose also clinical and therapeutic approach for patients with malignancy. METHODS: We are reviewing the clinical and molecular basis of Rasopathies based on recent studies, clinical examination, and molecular diagnostics (mutation analysis of causal genes for Rasopathies) in Slovak pediatric patients. RESULTS: Some clinical features, such as short stature, a specific facial dysmorphology and cardiac abnormalities are common to all of Rasopathy syndromes. However, there are unique signs by which the syndromes can differ from each other, especially multiple lentigo in LEOPARD syndrome, increased risk of malignancy in Costello syndrome, dry hyperkeratotic skin in patients with cardio-facio-cutaneous syndrome, and neurofibromas and cafe-au-lait spots in neurofibromatosis-Noonan syndrome. CONCLUSION: Despite the overlapping clinical features, Rasopathy syndromes exhibit unique fenotypical features and the precise molecular diagnostics may lead to confirmation of each syndrome. The molecular diagnostics may allow the detection of pathogenic mutation associated with tumorigenesis.

Clustering of mutations in the 5' tertile of the NF1 gene in Slovakia patients with optic pathway glioma.

Optic pathway gliomas (OPG) occur in 15% of patients with neurofibromatosis type 1 (NF1; OMIM 162200). Genotype-phenotype correlations in patients with NF1 may help to determine the risk group for developing complications such as OPG in coincidence with other NF1.features. We evaluated 52 patients with NF1 (25 with OPG and 27 without OPG). All subjects underwent a clinical examination focused on neurofibromatosis type 1 and molecular diagnostics of NF1 gene using protocol based on RNA analysis confirming the diagnosis of NF1. In the group with OPG patients, there was a significantly higher incidence of freckling (P=0.017), neurofibromatosis bright objects (NBO) (P=0.0038), compared to the group without OPG. The differences between the groups with respect to Lisch nodules were on the borderline of statistical significance (P=0.088). The frequency of neurofibromas in the group with OPG was not significant (P=0.9). From all patients with the mutation localized in the first tertile of the NF1 gene majority (71%) had optic glioma compared to individuals who didn't have the OPG 29% (P=0.0049). Our results present the clustering of mutations in the 5'tertile of NF1 gene in patients with optic nerve glioma and suggest higher incidence of freckling and neurofibromatosis brain objects in these patients. Molecular analysis of NF1 gene is important part in complex management of NF1 patients and contributes to a better understanding of clinical picture of NF1 patients. .

Effect of natural polyphenols (Pycnogenol) on oxidative stress markers in children suffering from Crohn's disease--a pilot study.

Crohn's disease (CD) is a nonspecific, chronic inflammatory disease of the gastrointestinal tract. It is supposed that in etiopathogenesis oxidative stress (OS) plays a role. However, its precise role in the active and non-active states of disease is not known yet. We conducted a pilot study focusing on the relationship between OS of CD in remission and the possibility to influence clinical parameters and markers of OS by polyphenolic extract, Pycnogenol® (Pyc). Compared to 15 healthy controls 15 pediatric CD patients (all were in remission according to their disease activity index - PCDAI) had reduced the activity of Cu/Zn-superoxide dismutase (SOD) and increased the oxidative damage to proteins. We found negative correlations between markers of inflammation (calprotectin, CRP) as well as between PCDAI and total antioxidant capacity (TAC). Activities of antioxidant enzymes, SOD, and glutathione peroxidase (GPX) negatively correlated with calprotectin and PCDAI. Pyc (2 mg/kg) positively influenced the parameters of OS in CD patients after 10 weeks of administration.

[Clinical dysmorphic syndromes with tumorigenesis]. / Klinické dysmorfické syndrómy s tumorigenézou.

Genetic alterations cause predisposition to malignancy by increased cancer risk related to constitutional mutations in growth-regulating or DNA repair genes. Some pediatric malignancies are associated with dysmorphic features in several body areas. Through physical examination, we recognise characteristic signs of genetic dysmorphic disorders, such as somatic overgrowth, undergrowth, macrocephaly, microcephaly and dysmorphic changes of the face, eyes, mouth and lips, heart, gastrointestinal tract, urinary tract, genitalia and skeleton. Recognition of a cancer-associated dysmorphic syndrome allows intensive cancer screening and genetic counseling. Therefore, it is recommended that every child with cancer should be examined by a clinical geneticist. Molecular diagnostics of germinal mutations may very effectively detect families at high risk of malignancy and help provide primary prevention. This work presents clinical syndromes with genetic background and cancer screening recommendations for 18 syndromes with increased cancer risk.

Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene.

A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.