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Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10−8) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10−7). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

This work was partially supported by intramural funds of the University of Pisa, DKFZ, and University Hospital of Southern Jutland, Denmark, and by a grant of the French National Cancer Institute (INCA). The authors wish to thank Dr. Dominic Edelmann (Division of Biostatistics, DKFZ) for helpful advice about data analysis., There is overwhelming epidemiologic evidence that the risk of multiple myeloma (MM) has a solid genetic background. Genome-wide association studies (GWAS) have identified 23 risk loci that contribute to the genetic susceptibility of MM, but have low individual penetrance. Combining the SNPs in a polygenic risk score (PRS) is a possible approach to improve their usefulness. Using 2361 MM cases and 1415 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, we computed a weighted and an unweighted PRS. We observed associations with MM risk with OR = 3.44, 95% CI 2.53-4.69, p = 3.55 x 10(-15) for the highest vs. lowest quintile of the weighted score, and OR = 3.18, 95% CI 2.1 = 34-4.33, p = 1.62 x 10(-13) for the highest vs. lowest quintile of the unweighted score. We found a convincing association of a PRS generated with 23 SNPs and risk of MM. Our work provides additional validation of previously discovered MM risk variants and of their combination into a PRS, which is a first step towards the use of genetics for risk stratification in the general population., University of Pisa, DKFZ, University Hospital of Southern Jutland, Denmark, Institut National du Cancer (INCA) France

From March through December 2020, 100 autopsies were performed (Semmelweis University, Budapest, Hungary), with chart review, of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection demonstrated by real-time reverse-transcription polymerase chain reaction testing (mean age, 74.73 years, range 40–102 years; 50 males, mean age 71.96 years, and 50 females, mean age 77.5 years). Classified by the date of death, 21 cases were from the pandemic’s “first wave” (March through July) and 79 from the “second wave” (August through December). Three mortality categories were defined by relevance of SARS-CoV-2 infection: (1) “strong” association (n=57), in which COVID-19 was primary responsible for death; (2) “contributive” association (n=27), in which a pre-existing condition independent of COVID-19 was primary responsible for death, albeit with substantial COVID-19 co-morbidity; (3) “weak” association (n=16), in which COVID-19 was minimally or not at all responsible for death. Distributions among categories differed between the first wave, in which the “contributive” association cases dominated (strong: 24%, contributive: 48%, weak: 28%), and the second wave, in which the “strong” association cases dominated (strong: 66%, contributive: 21%, weak: 13%). Charted co-morbidities included hypertension (85 %), cardiovascular diseases (71 %), diabetes (40 %), cerebrovascular diseases (31 %), chronic respiratory diseases (30 %), malignant tumors (20 %), renal diseases (19 %), diseases of the central nervous system (15 %), and liver diseases (6 %). Autopsy evaluation analyzed alterations on macroscopy as well as findings on microscopy of scanned and scored sections of formalin-fixed, paraffin-embedded tissue samples (50–80 blocks/case). Severity of histological abnormalities in the lung differed significantly between “strong” and “contributive” (pp

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Approximately 50% of AD patients show anxiety and depressive symptoms, which may contribute to cognitive decline. We aimed to investigate whether the triple-transgenic mouse (3xTg-AD) is a good preclinical model of this co-morbidity. The characteristic histological hallmarks are known to appear around 6-month; thus, 4- and 8-month-old male mice were compared with age-matched controls. A behavioral test battery was used to examine anxiety- (open field (OF), elevated plus maze, light-dark box, novelty suppressed feeding, and social interaction (SI) tests), and depression-like symptoms (forced swim test, tail suspension test, sucrose preference test, splash test, and learned helplessness) as well as the cognitive decline (Morris water maze (MWM) and social discrimination (SD) tests). Acetylcholinesterase histochemistry visualized cholinergic fibers in the cortex. Dexamethasone-test evaluated the glucocorticoid non-suppression. In the MWM, the 3xTg-AD mice found the platform later than controls in the 8-month-old cohort. The SD abilities of the 3xTg-AD mice were missing at both ages. In OF, both age groups of 3xTg-AD mice moved significantly less than the controls. During SI, 8-month-old 3xTg-AD animals spent less time with friendly social behavior than the controls. In the splash test, 3xTg-AD mice groomed themselves significantly less than controls of both ages. Cortical fiber density was lower in 8-month-old 3xTg-AD mice compared to the control. Dexamethasone non-suppression was detectable in the 4-month-old group. All in all, some anxiety- and depressive-like symptoms were present in 3xTg-AD mice. Although this strain was not generally more anxious or depressed, some aspects of comorbidity might be studied in selected tests, which may help to develop new possible treatments.

"Introduction: Many studies demonstrated that psychological factors play an important role in the development and course of diabetes mellitus. Objective: The focus of our research, among the first in a Hungarian sample, was to examine depression and anxiety levels and diabetes-specific quality of life in people with type 2 diabetes, to explore gender differences, and to analyze the relationship of depression and anxiety with diabetes-specific quality of life. Method: 157 people diagnosed with type 2 diabetes (women: 58.6%, men: 40.1%) were assessed for levels of depression Center for Epidemiologic Studies Depression Scale – Hungarian version), anxiety (Spielberger’s Trait Anxiety Questionnaire) and diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life – Hungarian version). Results: 65% of subjects did not show depressive symptoms, but 56.1% showed moderate trait anxiety. More severe depressive symptoms (U = 1625, p0.001) and higher trait anxiety (U = 1556, p0.001) were significantly more frequent in women compared to men. Depressive symptom severity and trait anxiety were inversely and weakly correlated with diabetes-specific quality of life. Discussion: In summary, the results suggest that the psychological state (depressive symptoms and anxiety) in patients with type 2 diabetes is associated with their diabetes-specific quality of life. Women with diabetes also have higher levels of depression and anxiety compared to men with diabetes. Conclusion: Psychological assessment of patients’ depressive and anxiety symptoms and quality of life is recommended in the care of diabetic patients, and appropriate treatment is recommended as needed. This may improve patients’ quality of life, therapeutic cooperation and disease prognosis."Bevezetés: Számos kutatási eredmény igazolja, hogy a diabetes mellitus kialakulásában és lefolyásában a pszichológiai tényezőknek is jelentős szerepük van. Célkitűzés: Kutatásunk középpontjában, hazai mintán az elsők között, a 2-es típusú diabetesszel élők depresszió- és szorongásszintjének és diabetesspecifikus életminőségének vizsgálata, valamint a nemi eltérések feltárása állt, továbbá elemeztük a depresszió és a szorongás kapcsolatát a diabetesspecifikus életminőséggel. Módszer: 157 fő, 2-es típusú diabetesszel diagnosztizált személy (nők: 58,6%, férfiak: 40,1%). depresszió- (a „10-item Center for Epidemiologic Studies Depression Scale” magyar változata), szorongás- (Spielberger Vonásszorongás Kérdőív) és diabetesspecifikus életminőségszintjét (az „Audit of Diabetes-Dependent Quality of Life” magyar változata) vizsgáltuk. Eredmények: A vizsgálati személyek 65%-ában depresszív tünetek nem mutatkoztak, 56,1%-ukban azonban közepes vonásszorongás volt kimutatható. Súlyosabb depressziós tünetek (U = 1625, p0,001) és nagyobb vonásszorongás (U = 1556, p0,001) szignifikánsan gyakrabban fordult elő a nők körében a férfiakhoz viszonyítva. A depresszív tünetek súlyossága és a vonásszorongás fordított irányú, gyenge korrelációs kapcsolatban állt a diabetesspecifikus életminőséggel. Megbeszélés: A 2-es típusú cukorbetegek depresszív tünetei és szorongásra való hajlama fordított irányú kapcsolatban áll a betegek diabetesspecifikus életminőségével. A cukorbeteg nők depresszió- és szorongásszintje magasabb a férfi diabetesesekhez képest. Következtetés: A cukorbetegek gondozása során javasolt a betegek depressziós, szorongásos tüneteinek és életminőségének pszichológiai vizsgálata, valamint szükség szerint adekvát kezelése. Ezáltal javulhat a betegek életminősége, terápiás együttműködése és a betegség prognózisa. Orv Hetil. 2022; 163(45): 1789–1797.

After months of restrictive containment efforts to fight the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemic, European countries are planning to reopen. To support the process, we conducted a cross-sectional survey among the Hungarian population to estimate the prevalence of infectious cases and prior SARS-CoV-2 exposure. A representative sample (n = 17,787) for the Hungarian population of 14 years or older living in private households (n = 8,283,810) was selected. The study was performed within 16 days after 50 days of restrictions, when the number of confirmed cases was stable low. Naso- and oropharyngeal smears and blood samples were collected for PCR and antibody testing. The testing was accompanied by a questionnaire about symptoms, comorbidities, and contacts. Design-based prevalence estimates were calculated. In total, 10,474 individuals (67.7% taken into account a sample frame error of 2315) of the selected sample participated in the survey. Of the tested individuals, 3 had positive PCR and 69 had positive serological test. Population estimate of the number of SARS-CoV-2 infection and seropositivity were 2421 and 56,439, respectively, thus active infection rate (2.9/10,000) and the prevalence of prior SARS-CoV-2 exposure (68/10,000) was low. Self-reported loss of smell or taste and body aches were significantly more frequent among those with SARS-CoV-2. In this representative, cross-sectional survey of the Hungarian population with a high participation rate, the overall active infection rate was low in sync with the prevalence of prior SARS-CoV-2 exposure. We demonstrated a potential success of containment efforts, supporting an exit strategy. NCT04370067, 30.04.2020.

In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels

IntroductionThe prevalence of neuropathic lesions in young patients with type 1 diabetes mellitus (T1DM) at the time of transition from pediatric care to adult-oriented diabetes care is poorly studied. A comparative study with healthy volunteers to assess the possible neuropathic condition of this special population and to identify the potential early screening needs has not been performed yet. The results may provide important feedback to pediatric diabetes care and a remarkable baseline reference point for further follow up in adult diabetes care.Patients and MethodsTwenty-nine young patients with T1DM [age: 22.4 ± 2.9 years; HbA1c: 8.5 ± 2.1%, diabetes duration: 12.2 ± 5.8 years; (mean ± SD)] and 30 healthy volunteers (age: 21.5 ± 1.6 years; HbA1c: 5.3 ± 0.3%) were involved in the study. Autonomic function was assessed by standard cardiovascular reflex tests. Complex peripheral neuropathic testing was performed by Neurometer®, Neuropad®-test, Tiptherm®, Monofilament®, and Rydel-Seiffer tuning fork tests.ResultsT1DM patients had significantly higher diastolic blood pressure than controls (80 ± 9 vs. 74 ± 8 mmHg, p < 0.01), but there was no significant difference in systolic blood pressure (127 ± 26 vs. 121 ± 13 mmHg). Cardiovascular reflex tests had not revealed any significant differences between the T1DM patients and controls. No significant differences with Neurometer®, Neuropad®-test, and Monofilament® were detected between the two groups. The vibrational sensing on the radius on both sides was significantly impaired in the T1DM group compared to the controls with Rydel-Seiffer tuning fork test (right: 7.5 ± 1.0 vs. 7.9 ± 0.3; left: 7.5 ± 0.9 vs. 7.9 ± 0.3, p < 0.05). The Tiptherm®-test also identified a significant impairment in T1DM patients (11 sensing failures vs. 1, p < 0.001). In addition, the neuropathic complaints were significantly more frequently present in the T1DM patient group than in the controls (9 vs. 0, p < 0.01).ConclusionIn this young T1DM population, cardiovascular autonomic neuropathy and cardiac morphological alterations could not be found. However, Rydel-Seiffer tuning fork and Tiptherm®-tests revealed peripheral sensory neurological impairments in young T1DM patients at the time of their transition to adult diabetes care.

The earliest signs of cognitive decline include deficits in temporal (time-based) speech characteristics. Type 2 diabetes mellitus (T2DM) patients are more prone to mild cognitive impairment (MCI). The aim of this study was to compare the temporal speech characteristics of elderly (above 50 y) T2DM patients with age-matched nondiabetic subjects.A total of 160 individuals were screened, 100 of whom were eligible (T2DM: n=51; nondiabetic: n=49). Participants were classified either as having healthy cognition (HC) or showing signs of MCI. Speech recordings were collected through a phone call. Based on automatic speech recognition, 15 temporal parameters were calculated.The HC with T2DM group showed significantly shorter utterance length, higher duration rate of silent pause and total pause, and higher average duration of silent pause and total pause compared with the HC without T2DM group. Regarding the MCI participants, parameters were similar between the T2DM and the nondiabetic subgroups.Temporal speech characteristics of T2DM patients showed early signs of altered cognitive functioning, whereas neuropsychological tests did not detect deterioration. This method is useful for identifying the T2DM patients most at risk for manifest MCI, and could serve as a remote cognitive screening tool.

D.C., F.C., and M.G. conceived and designed the study. A.M. and M.G. performed labwork. A.M., F.C., D.C., and M.G. drafted the manuscript. A.M., F.C., D.C., and M.G. performed data quality control and statistical analyses. All other authors provided samples and data. All authors critically read, commented, and approved the manuscript., Telomere length measured in leukocyte (LTL) has been found to be associated with the risk of developing several cancer types, including myeloproliferative neoplasms (MPNs). LTL is genetically determined by, at least, 11 SNPs previously shown to influence LTL. Their combination in a score has been used as a genetic instrument to measure LTL and evaluate the causative association between LTL and the risk of several cancer types. We tested, for the first time, the “teloscore” in 480 MPN patients and 909 healthy controls in a European multi-center case–control study. We found an increased risk to develop MPNs with longer genetically determined telomeres (OR = 1.82, 95% CI 1.24–2.68, P = 2.21 × 10−3, comparing the highest with the lowest quintile of the teloscore distribution). Analyzing the SNPs individually we confirm the association between TERT-rs2736100-C allele and increased risk of developing MPNs and we report a novel association of the OBFC1-rs9420907-C variant with higher MPN risk (ORallelic= 1.43; 95% CI 1.15–1.77; P = 1.35 × 10−3). Consistently with the results obtained with the teloscore, both risk alleles are also associated with longer LTL. In conclusion, our results suggest that genetically determined longer telomeres could be a risk marker for MPN development

Összefoglaló. Az új típusú koronavírus-fertőzés (COVID-19) nagy terhet ró az egészségügyi ellátórendszerre és a társadalomra. A betegségnek három nagy szakasza van, melyek alapvetően meghatározzák a kezelést. Az I-IIA fázisban az antivirális, míg a IIB-III. fázisban a gyulladásgátló kezelés áll előtérben, melyhez intenzív terápiás, szupportív kezelés csatlakozik. A jelen ajánlás kizárólag a gyógyszeres kezelésre vonatkozik, és a rendelkezésre álló bizonyítékok alapján foglalja össze a terápiás lehetőségeket. Emellett egy javasolt kezelési algoritmust is tartalmaz. Orv Hetil. 2021; 162(17): 643-651. Summary. The novel coronavirus infection (COVID-19) places a heavy burden on the health care system and our society. There are three major stages in the disease that fundamentally determine treatment approaches. Phases I-IIA require primarily antiviral treatment. In phases IIB-III, anti-inflammatory treatment is needed accompanied by intensive and supportive care. This recommendation applies only to pharmacotherapy and summarizes the therapeutic options based on the available evidence. It also includes a proposed treatment algorithm. Orv Hetil. 2021; 162(17): 643-651.

Theranostics 11(1), 292-303 (2021). doi:10.7150/thno.51872, Published by Ivyspring, Wyoming, NSW

Contains fulltext : 232394.pdf (Publisher’s version ) (Closed access) We evaluated the association between germline genetic variants located within the 3'-untranlsated region (polymorphic 3'UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3'-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

This work was partially supported by intramural funds of Univerity of Pisa and DKFZ; by Fondo de Investigaciones Sanitarias (Madrid, Spain) [PI12/02688 to J. S., PI17/02276 to J.S.]; by Instituto de Salud Carlos III, co-funded by FEDER funds —a way to build Europe—[PI14-00613 to V.M.] and by Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) [2017SGR723 to V.M.]. Open Access funding enabled and organized by Projekt DEAL., Telomeres are involved in processes like cellular growth, chromosomal stability, and proper segregation to daughter cells. Telomere length measured in leukocytes (LTL) has been investigated in different cancer types, including multiple myeloma (MM). However, LTL measurement is prone to heterogeneity due to sample handling and study design (retrospective vs. prospective). LTL is genetically determined; genome-wide association studies identified 11 SNPs that, combined in a score, can be used as a genetic instrument to measure LTL and evaluate its association with MM risk. This approach has been already successfully attempted in various cancer types but never in MM. We tested the "teloscore" in 2407 MM patients and 1741 controls from the International Multiple Myeloma rESEarch (IMMeNSE) consortium. We observed an increased risk for longer genetically determined telomere length (gdTL) (OR = 1.69; 95% CI 1.36-2.11; P = 2.97 x 10(-6) for highest vs. lowest quintile of the score). Furthermore, in a subset of 1376 MM patients we tested the relationship between the teloscore and MM patients survival, observing a better prognosis for longer gdTL compared with shorter gdTL (HR = 0.93; 95% CI 0.86-0.99; P = 0.049). In conclusion, we report convincing evidence that longer gdTL is a risk marker for MM risk, and that it is potentially involved in increasing MM survival., Univerity of Pisa, Helmholtz Association, Instituto de Salud Carlos III PI12/02688 PI17/02276, Instituto de Salud Carlos III, European Commission, FEDER funds-a way to build Europe PI14-00613, Agency for Management of University and Research Grants (AGAUR) of the Catalan Government (Barcelona, Spain) 2017SGR723, Projekt DEAL

Canadian Institutes of Health Research, Grant/ Award Number: 81274; Huntsman Cancer Institute Pilot Funds; Leukemia Lymphoma Society, Grant/Award Number: 6067-09; the National Institute of Health/National Cancer Institute, Grant/Award Numbers: P30 CA016672, P30 CA042014, P30 CA13148, P50 CA186781, R01 CA107476, R01 CA134674, R01 CA168762, R01 CA186646, R01 CA235026, R21 CA155951, R25 CA092049, R25 CA47888, U54 CA118948; Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah; VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council, Grant/Award Numbers: 1074383, 209057, 396414; Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database; Mayo Clinic Cancer Center; University of Pisa and DKFZ, The authors thank all site investigators that contributed to the studies within the Multiple Myeloma Working Group (Interlymph Consortium), staff involved at each site and, most importantly, the study participants for their contributions that made our study possible. This work was partially supported by intramural funds of University of Pisa and DKFZ. This work was supported in part by the National Institute of Health/National Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30 CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30 CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01 CA168762, P50 CA186781 and the NCI Intramural Research Program), Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute Pilot Funds, Utah PopulationDatabase, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah StateDepartment of Health, University of Utah, Canadian Institutes of Health Research (Grant number 81274), VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council (Grants 209057, 396414, 1074383), Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database and the Mayo Clinic Cancer Center.Open Access funding enabled and organized by ProjektDEAL., The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions., Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10(-7) either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients., Canadian Institutes of Health Research (CIHR) 81274, Huntsman Cancer Institute Pilot Funds, Leukemia and Lymphoma Society 6067-09, United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Cancer Institute (NCI) P30 CA016672 P30 CA042014 P30 CA13148 P50 CA186781 R01 CA107476 R01 CA134674 R01 CA168762 R01 CA186646 R01 CA235026 R21 CA155951 R25 CA092049 R25 CA47888 U54 CA118948, Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah, VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council 1074383 209057 396414, Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database, Mayo Clinic Cancer Center, University of Pisa, Helmholtz Association

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future. (C) 2019 American Academy of Allergy, Asthma & Immunology

Background Philadelphia negative myeloproliferative neoplasms (MPNs) are characterized by frequent mutations of driver genes including JAK2, CALR and MPL. While the influence of JAK2 V617F mutant allele burden on the clinical phenotype of MPN patients is well-described, the impact of CALR mutant allele burden on clinical features needs further investigation. Patients and methods Quantitative assessment of JAK2 and CALR mutations was performed on diagnostic DNA samples from 425 essential thrombocythemia (ET) and 227 primary myelofibrosis patients using real-time quantitative PCR and fragment length analysis. Characterization of CALR mutations and detection of MPL mutations were performed by Sanger sequencing. Results Twelve novel CALR mutations have been identified. ET patients with CALRmut load exceeding the median value exhibited lower hemoglobin values (12.0 vs. 13.6 g/dL), higher LDH levels (510 vs. 351 IU/L) and higher rate of myelofibrotic transformation (19% vs. 5%). The CALRmut load was higher among ET patients presenting with splenomegaly compared to those without splenomegaly (50.0% vs. 43.5%). Conclusion Our study confirms the clinical significance of driver mutational status and JAK2mut load in MPNs; in addition, unravels a novel clinical association between high CALRmut load and a more proliferative phenotype in ET.

Myeloproliferative neoplasms (MPNs) are a group of diseases that cause myeloid hematopoietic cells to overproliferate. Epidemiological and familial studies suggest that genetic factors contribute to the risk of developing MPN, but the genetic susceptibility of MPN is still not well known. Indeed, only few loci are known to have a clear role in the predisposition to this disease. Some studies reported a diagnosis of MPNs and multiple myeloma (MM) in the same patients, but the biological causes are still unclear. We tested the hypothesis that the two diseases share at least partly the same genetic risk loci. In the context of a European multicenter study with 460 cases and 880 controls, we analyzed the effect of the known MM risk loci, individually and in a polygenic risk score (PRS). The most significant result was obtained among patients with chronic myeloid leukemia (CML) for PS0RS1C1-rs2285803, which showed to be associated with an increased risk (OR = 3.28, 95% CI 1.79-6.02, P = .00012, P = .00276 when taking into account multiple testing). Additionally, the PRS showed an association with MPN risk when comparing the last with the first quartile of the PRS (OR = 2.39, 95% CI 1.64-3.48, P = 5.98 × 10-6 ). In conclusion, our results suggest a potential common genetic background between MPN and MM, which needs to be further investigated.

Background: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients. Methods: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated. Findings: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P =.67). Overall survival (Kaplan-Meier survival estimates, P =.46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P =.04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group. Interpretation: The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality. Trial registration: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012., SCOPUS: ar.j, info:eu-repo/semantics/published

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5 × 109/l), and 3.1% hypereosinophilia (HE; >1.5 × 109/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p

Genetic variants in genes acting during the maturation process of immature B-cell to differentiated plasma cell could influence the risk of developing multiple myeloma (MM). During B-cell maturation, several programmed genetic rearrangements occur to increase the variation of the immunoglobulin chains. Class switch recombination (CSR) is one of the most important among these mechanisms. Germline polymorphisms altering even subtly this process could play a role in the etiology and outcome of MM. We performed an association study of 30 genetic variants in the key CSR genes, using 2632 MM patients and 2848 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the Heidelberg MM Group and the ESTHER cohort. We found an association between LIG4-rs1555902 and decreased MM risk, which approached statistical significance, as well as significant associations between AICDA-rs3794318 and better outcome. Our results add to our knowledge on the genetic component of MM risk and survival., Partially supported by intramural funds of DKFZ, by grants PI12/02688 and PI17/02276 from Fondo de Investigaciones Sanitarias (Madrid, Spain), Instituto de Salud Carlos III, co-funded by FEDER funds –a way to build Europe– grant PI14-00613 and Agency for Management of University and Research Grants (AGAUR) of the Catalan Government grant 2017SGR723. The ESTHER study was funded by grants from the Baden-Württemberg state Ministry of Science, Research and Arts (Stuttgart, Germany), the Federal Ministry of Education and Research (Berlin, Germany), the Federal Ministry of Family Affairs, Senior Citizens, Women and Youth (Berlin, Germany) and the Saarland Ministry of Social Affairs, Health, Women and Family (Saarbrücken, Germany)

BACKGROUND Following kidney transplantation (KT), new-onset diabetes mellitus (NODM) is one of the most common complications. NODM usually occurs early after KT, and is diagnosed according to the general guidelines relevant for general diabetes mellitus patients. Arterial stiffness is a surrogate marker of cardiovascular risk. According to the literature, a successful KT has only limited and late beneficial effects on aortic elastic properties. The present study aimed to assess whether NODM has any additive value on the worsening of echocardiography-derived aortic elastic properties in transplanted patients. METHODS We have included 28 nondiabetic post-KT patients in the study, older than 18 years (mean age: 48.2 ± 6.9 years; 13 men, 15 women). After an oral glucose tolerance test, 8 patients were diagnosed with NODM, and their results were compared to 23 age-, sex-, and risk factor-matched controls (mean age: 54.9 ± 11.0 years; 9 men, 14 women). All post-KT patients and matched controls underwent a complete transthoracic 2-dimensional Doppler echocardiography, together with an assessment of echocardiographic aortic elastic properties. The assessments included aortic strain, aortic distensibility, and aortic stiffness index. RESULTS Aortic elastic properties showed alterations in post-KT patients compared to matched controls (aortic strain: .084 ± .039 vs .057 ± .032, P < .05; aortic distensibility: 2.36 ± 1.09 cm2/dynes 10-6 vs 1.83 ± 1.18 cm2/dynes 10-6, P = .07; aortic stiffness index: 7.15 ± 3.58 vs 11.2 ± 6.1, P

French National Cancer Institute (INCA) and the Fondation Francaise pour la Recherche contre le Myelome et les Gammapathies (FFMRG), the Intergroupe Francophone du Myelome (IFM), NCI R01 NCI CA167824 and a generous donation from Matthew Bell. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank the Association des Malades du Myelome Multiple (AF3M) for their continued support and participation. Where authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization

Increase of liver function is one of the most common complications after kidney transplantation due to the use of immunosuppressive therapy and hyperlipidemia in addition to hepatitis C virus (HCV) infection.Following the selection criteria (n = 59), the study is based on applied immunosuppressive therapy, baseline data of patients, further correlation between HCV and liver function deterioration. Patients were subjected to fasting laboratory examination to monitor serum electrolytes, uric acid and albumin levels. We looked at the effects of immunosuppressive therapy on the lipids (TG, TC, HDL, LDL) and liver enzymes (GOT, GPT, ALP, GGT). The analysis of the relationship between lipids and liver enzymes was also included in our study.The data basics were not significantly different between the tacrolimus and the cyclosporine groups. In the laboratory results, Mg levels were significantly different between the two groups (p = 0.044). The impact of HCV on the liver function was significantly different on GGT (p = 0.008). We examed the lipids and liver function level between the tacrolimus and the patients receiving cyclosporine-based immunosuppression and the total cholesterol (p = 0.005) and GOT (p = 0.05) were significantly different between the two groups. Hyperlipidemia was associated with 26% of patients taking tacrolimus-based immunosuppression, and 89% of those receiving cyclosporine; the difference was significant (p = 0.002). Regarding the effect of hyperlipidemia on liver enzymes, ALP (p = 0.006) and GGT (p = 0.0001) were significantly higher.Increases in hepatic enzymes, ALT and GGT indicate the damage to hepatocytes. Beside the increase of liver function, which is the main risk factor in hepatitis on HCV soil, the applied immunosuppressive therapy and hyperlipidemia lead to degradation of allograft function and long-term graft loss. Orv hetil. 2019; 160(5): 186-190.Absztrakt: Bevezetés: A vesetranszplantáció utáni májfunkcióromlás az egyik leggyakoribb szövődmény, melynek oka a hepatitis C-vírus (HCV)-fertőzés mellett az alkalmazott immunszuppresszív terápia és hyperlipidaemia. Módszer: A beválasztási kritériumokat követően (n = 59) vizsgáltuk az alkalmazott immunszuppresszív terápiát, a betegek alapadatait, további a HCV és a májfunkció romlása közötti összefüggést. A betegeknél éhomi laboratóriumi vizsgálat történt, melynek során néztük a szérumionokat, húgysav-, albuminszintet. Az immunszuppresszív terápia lipidekre (TG, TC, HDL, LDL), valamint májenzimekre (GOT, GPT, ALP, GGT) gyakorolt hatását néztük. Vizsgálatunk részét képezte a lipidek és a májenzimek közötti kapcsolat elemzése is. Eredmények: A betegek alapadatait vizsgálva a takrolimuszt (n = 50) és a ciklosporint (n = 9) szedők körében szignifikáns különbséget nem találtunk. A laboratóriumi eredmények tekintetében a Mg-szint szignifikánsan eltért a két csoport között (p = 0,044). A HCV-fertőzés májenzimekre gyakorolt hatását nézve a GGT (p = 0,008) szignifikánsan különbözött. A lipideket vizsgálva a takrolimusz- és a ciklosporinalapú immunszuppresszióban részesülő betegek között az összkoleszterin (p = 0,005), valamint a májenzimek közül a GOT (p = 0,05) szignifikánsan eltért a két betegcsoport között. A hyperlipidaemia a takrolimuszalapú immunszuppressziót szedők körében 26%-ban, míg a ciklosporint szedőknél 89%-ban fordult elő, melyek között a különbség szignifikáns volt (p = 0,002). A hyperlipidaemia májenzimekre gyakorolt hatását nézve az ALP (p = 0,006) és a GGT (p = 0,0001) szignifikánsan magasabb volt. Következtetés: A májenzimek, az ALT és a GGT emelkedése utal a májsejtek sérülésére. A májfunkció romlásának a legfőbb rizikófaktora a HCV talaján kialakult hepatitis mellett az alkalmazott immunszuppresszív terápia és a hyperlipidaemia, mely az allograftfunkció romlásához és hosszú távon graftvesztéshez vezet. Orv Hetil. 2019; 160(5): 186–190.

Background For patients with type 2 diabetes (T2D), cardiovascular disease (CVD) is the single most common cause of mortality. In 2008 and 2012, the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) respectively mandated cardiovascular outcomes trials (CVOTs) on all new anti-diabetic agents, as prospective trials statistically powered to rule out excess cardiovascular risk in patients with T2D. Unexpectedly, some of these CVOTs have demonstrated not only cardiovascular safety, but also cardioprotective effects, as was first shown for the SGLT2 inhibitor empagliflozin in EMPA-REG OUTCOME. Expert opinion To debate newly available CVOT data and to put them into context, we convened as a group of medical experts from the Central and Eastern European Region. Here we describe our discussions, focusing on the conclusions we can draw from EMPA-REG OUTCOME and other SGLT2 inhibitor CVOTs, including when considered alongside real-world evidence. Conclusion CVOTs investigating SGLT2 inhibitors have suggested benefits beyond glucose lowering that have been confirmed in real-world evidence studies.

Transfer is a planned movement of patients and their medical records from one provider to another. Only a few data are available from real life in inflammatory bowel disease patients in this topic.Our aim was to retrospectively evaluate the results of the transfer of our patients without longitudinal transition.Data of the transferred patients at the University of Szeged were analysed. Patients were diagnosed in paediatric care. Transfer strategy at our departments was detailed medical summary.59 patients were enrolled in this study. 28.8% of the patients had mild to moderate disease activity and 71.2% was in remission at the time of transfer. Steroid therapy was initiated in 58% of the patients within an average of 9.1 months after the transfer. Anti-tumor necrosis factor therapy was given to 24% of the patients during the paediatric care and to an additional 23% in the adult care within an average of 28 months. Almost 70% of the patients received immunosuppressive therapy during paediatric and adult care. Surgery was required in 17% of the patients within an average 10.7 months after the transfer.Our results revealed that one-third of the paediatric patients have been transferred to adult care in active stage of disease. Shortly after the transfer 58% of the patients required corticosteroids and 17% surgery. Every fifth patient needed biological therapy to be initiated after the transfer. Longitudinal transition may have a potential to decrease the need for therapeutic change and the relatively high rate of surgery. Orv Hetil. 2018; 159(44): 1789-1793.Absztrakt: Bevezetés: A gyulladásos bélbetegségek gyakran serdülőkorban manifesztálódnak. A transzfer a betegek gyermekgyógyászati szakrendelésről történő átadását kísérő folyamatnak, a tranzíciónak az utolsó lépése, melynek kimenetelével ez idáig kisszámú tanulmány foglalkozott. Célkitűzés: Felmérni az általunk alkalmazott transzfer eredményességét gyermekszakrendelésről felnőttszakrendelésre átkerülő betegeink körében. Módszer: A Szegedi Tudományegyetem, I. Belgyógyászati Klinikára átkerült és gondozott betegek demográfiai és klinikai adatait elemeztük retrospektív módon. Az általunk vizsgált betegeknél a gyulladásos bélbetegség diagnózisa a gyermekgyógyászati ellátásban került felállításra. Klinikánkon a betegek transzferje során részletes egészségügyi dokumentáció elkészítése és átadása történt. Eredmények: 59 gyulladásos bélbeteg adatait elemeztük. Huszonhét esetben (45,7%) történt endoszkópia a transzferhez kötötten. A transzfer idejében a betegek 28,8%-ánál enyhe, illetve közepesen súlyos volt a betegség aktivitása, míg 71,2%-uk remisszióban volt. A betegek 58%-ánál kortikoszteroid indult, átlagosan 9,1 hónap után. Anti-tumornekrózisfaktor-terápia a gyermekgyógyászati ellátás alatt a betegek 24%-ánál lett bevezetve, és a betegek további 23%-ánál történt meg a felnőttellátás során, a transzfert követően átlagosan 28 hónapon belül. A betegek 70%-a részesült immunszuppresszív kezelésben a transzfer körüli időszakban. Sebészeti beavatkozásra 17%-ban volt szükség a transzfer után átlagosan 10,7 hónapon belül. Következtetés: Betegeink egyharmada aktív állapotban került át a felnőttellátásba. Fiatal betegeink 58%-a igényelt kortikoszteroidterápiát és 17%-a sebészeti beavatkozást a transzfert követő kevesebb, mint egy éven belül. Minden ötödik betegnél biológiai terápia indult a felnőttellátásban. A longitudinális tranzíció folyamatát alkalmazva valószínűleg volna esélyünk csökkenteni az átadásközeli terápiaeszkalációk számát és a relatíve magas sebészeti beavatkozási arányt. Orv Hetil. 2018; 159(44): 1789–1793.

The authors summarize the medical history of a patient with impaired healing of a wound in the sole of foot. The 63-year-old male patient had a second-degree burn in the sole of the left foot as he stepped on the hot concrete after taking off his slipper. On admission to our department, local wound management had already been started, his wound showed no healing tendency. Bilateral X-ray was performed of his left leg, osteomyelitis was not confirmed, soft tissue drainage was applied, and bacterial culture from the wound confirmed methicillin-resistant Staphylococcus aureus infection. After soaking the leg in water, phlegmon developed on the dorsal part of the foot and the patient had septic fever. X-ray was repeated, and osteomyelitis was confirmed. Enucleation of the hallux of the left foot and metatarsal resection were performed. Wound dressing was exchanged and wound toilette was applied daily, insulin therapy was modified after consultation with a diabetologist. 7 months after the surgery, the wound was completely healed, carbohydrate metabolism of the patient was controlled. Our case draws attention to the importance of informing the patients of potential complications - in this case of the diabetic foot and its proper care. Treatment of ulcer of the lower leg requires multidisciplinary care, which means that the diabetologist and the surgeon has to cooperate in the care of these patients, carbohydrate metabolism should be balanced and regular wound care is necessary. Orv Hetil. 2018; 159(42): 1727-1730.Absztrakt: A szerzők esettanulmányukban egy nem gyógyuló talpi seb kórtörténetét foglalják össze. A 63 éves férfi beteg papucs levételét követően forró betonra lépett, és a bal talpán II. fokú égési sérüléseket szenvedett. Klinikánkra történő felvételekor már lokális kezelésben részesült, de a kezelés hatására a seb gyógyhajlamot nem mutatott. A lábról kétirányú röntgenfelvétel készült, mely osteomyelitist nem igazolt. Ekkor lágyrész-drenázs történt, a sebből a tenyésztés során methicillinrezisztens Staphylococcus aureus tenyészett. A láb vízben való áztatását követően lábháti phlegmone és septicus lázmenet alakult ki. Ismételt röntgenvizsgálat után az osteomyelitis igazolódott. A bal láb I. ujjának enucleatióját és metatarsusreszekciót végeztünk. Naponkénti kötéscseréket végeztünk, sebtoilettel. Inzulinját diabetológus segítségével módosítottuk. A műtétet követő 7. hónapban a seb teljes gyógyulását értük el, a beteg szénhidrát-anyagcseréje rendeződött. Esetünk bizonyítja, hogy kiemelten fontos felhívni a beteg figyelmét a lehetséges szövődményekre (diabeteses láb és annak megfelelő ápolása). A lábszárfekély kezelése multidiszciplináris összefogást igényel. A kezelés a diabetológus és a sebész együttes munkáját jelenti, szükséges a szénhidrát-anyagcsere egyensúlyban tartása, valamint a seb rendszeres ellátása. Orv Hetil. 2018; 159(42): 1727–1730.

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.

Objective: To assess the utility of visual electrophysiological methods, visual evoked potentials (VEPs) and pattern electroretinograms (PERGs) were recorded for the detection of subclinical optic nerve and retinal involvement in patients with diabetes mellitus. Subjects and Methods: The data of 63 patients (126 eyes) with no vascular retinopathy or optic neuropathy were retrospectively analyzed. The patients were divided into polyneuropathic/nonpolyneuropathic groups to differentiate between early and late subclinical stages. The recorded parameters were compared with local reference values. Results: 116 eyes (92%) had VEP and 76 (60%) had PERG abnormalities. The most frequent alteration was latency delay, but waveform and amplitude irregularities were also observed. The simultaneous use of the two methods allowed us to differentiate abnormal VEPs of purely optic nerve origin from those reflecting retinal involvement. Conclusions: We suggest that regular electrophysiological screening should receive more attention in the ophthalmological care of diabetic patients.

Objective: Changes in left atrial (LA) function can be observed in type 1 diabetes mellitus (T1DM). Three-dimensional (3-D) speckle tracking echocardiography (STE) seems to be a promising tool for volumetric and functional evaluation of LA. The objective of the present study was to compare 3DSTE-derived LA volumetric and strain parameters between T1DM patients and matched healthy controls. Methods: This prospective study consists of 17 subcutaneous insulin pump-treated non-obese patients with T1DM (mean age: 33.5±8.2 years, 8 males). To exclude possible cardiovascular disease, patients with complaints of chest pain, dyspnea, or signs of cerebrovascular disease or peripheral artery disease were not included. Their results were compared with 20 age-matched and gender-matched healthy controls (mean age: 36.9±11.0 years, 9 males). Independent sample Student t-test and Fisher’s exact test were used for comparisons. Bland–Altman method was used for evaluating intraobserver and interobserver correlations. Results: Anemia and impaired renal function were not confirmed in T1DM patients. Calculated LA maximum and minimum volumes and LA volume before atrial contraction were significantly increased in T1DM patients. Total atrial stroke volume was increased (23.6±6.9 mL vs. 19.6±4.6 mL, p=0.04), whereas mean segmental circumferential peak strain was decreased (28.9%±11.4% vs. 37.3%±12.5%, p=0.04). Segmental basal longitudinal and area strains were increased, whereas segmental superior circumferential and area strains and midatrial 3-D strain were decreased in T1DM. Conclusion: Both 3DSTE-derived volumetric and strain analysis confirmed alterations in LA function, suggesting early LA remodeling in patients with T1DM. (Anatol J Cardiol 2016; 16: 587-93)

Authors report on a case of a male patient of systemic mastocytosis that was associated with extensive cutaneous lesions. Chronic diarrhoea worsening his quality of life was well managed by the administration of antihistamines. The pleural fluid recurrence soon after drainage has been controlled by the administration of alpha interferon. 40 years after the onset of the first skin signs progression has been manifested in the development of "B" (bone marrow infiltration rate30%, dysmyelopoiesis, serum tryptase20 μg/L, hepato- and splenomegaly) and "C" symptoms (liver function test abnormalities, cytopenia, malabsorption, osteoporosis). The patient died at age of 87. The authors' aim was to attract attention on this rare disease and emphasize that symptomatic therapy with antihistamines and drugs available based on customised rights by the National Health Insurance Fund might provide good quality of life. Orv Hetil. 2018; 159(5): 192-196.

Seriously ill patients with influenza may be unable to take oral medication. The safety of intravenous oseltamivir was evaluated in adults and adolescents. This prospective, part-randomized study enrolled hospitalized patients aged ≥13 years with clinical or laboratory-confirmed influenza, who started study medication within 144 h of illness onset. Patients with normal renal function received oseltamivir 100 or 200 mg every 12 h for 5 days by slow intravenous infusion. Patients with renal impairment received lower doses, appropriate to the degree of impairment. Blood samples were taken for pharmacokinetics, and nasal swabs were taken to monitor viral shedding and resistance [reverse transcription polymerase chain reaction (RT-PCR) and culture]. Adverse events (AEs) were monitored for 30 days from treatment initiation. Of the 118 patients enrolled, 103 had normal renal function. On day 1, 64 patients had laboratory-confirmed influenza. Ninety-four (80 %) patients completed 5 days of oseltamivir treatment (32 intravenous only). Sixty-eight and 13 patients reported on-treatment AEs and serious AEs (SAEs), respectively (62 and nine during intravenous dosing, respectively). For 33 and six patients, these AEs and SAEs were considered treatment-related (31 and five during intravenous dosing, respectively); 11 patients had AEs causing treatment withdrawal. Five patients died. Adequate systemic exposure to oseltamivir carboxylate (OC) was achieved at the intravenous doses tested. Oseltamivir-resistant viruses (H275Y) were detected in two patients. In seriously ill, hospitalized patients with/without renal impairment, intravenous oseltamivir was not associated with adverse safety findings at the dosages tested and achieved systemic OC exposures at least as high as the approved oral dose.

Irregular vascular dilatation in the antrum or the cardia of the stomach can be the cause of severe gastrointestinal bleeding. The first term for it - in the beginning of the 50's of the previous century - was GAVE (Gastric Antral Vascular Ectasia) since at that time no similar phenomenon had been registered before. A quarter of a century later, after publishing a few cases, a witty internist described it as "watermelon stomach" because the macroscopic picture is similarly looking as the aforesaid fruit's appearing. This rare condition occured in one of our patient with many comorbid diseases.

The authors review current advances in the therapy of diabetic neuropathy. The role of glycemic control and management of cardiovascular risk factors in the prevention and treatment of neuropathic complications are discussed. As further options of pathogenetically oriented treatment, recent knowledge on benfotiamine and alpha-lipoic acid is comprehensively reviewed. Alpha-lipoic acid is a powerful antioxidant and clinical trials have proven its efficacy in ameliorating neuropathic signs and symptoms. Benfotiamine acts via the activation of transketolase and thereby inhibits alternative pathways triggered by uncontrolled glucose influx in the cells comprising polyol, hexosamine, protein-kinase-C pathways and formation of advanced glycation end products. Beyond additional forms of causal treatment, choices of symptomatic treatment will be summarized. The latter is mostly represented by the anticonvulsive agents pregabalin and gabapentin as well as duloxetine widely acknowledged as antidepressant. Finally, non-pharmacological therapeutic alternatives are summarized. The authors conclude that combination therapy should be more often suggested to our patients; especially the combination of pathogenetic and symptomatic agents.

Background New-onset diabetes after transplantation (NODAT) is one of the most common complications after kidney transplantation. Methods Patients were randomly assigned to receive cyclosporine A–based or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following 3 groups, on the basis of the results: normal, impaired fasting glucose/impaired glucose tolerance, or NODAT. NODAT developed in 14% of patients receiving cyclosporine A–based immunosuppression and in 26% of patients taking tacrolimus ( P = .0002). Results Albumin levels were similar, but uric acid level ( P = .002) and the age of the recipient ( P = .003) were significantly different between the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection and interstitial fibrosis/tubular atrophy were significantly different in the NODAT group. Changes in the Banff score provided significant difference regarding tubulitis and interstitial inflammation ( P = .05). Conclusions The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

Mastocytosis is a clonal mast cell proliferative disease, divided into cutaneous and systemic forms. The characteristic symptoms are caused by neoplastic mast cell infiltrations in different organs and/or the release of mediators.The aim of the authors was to summarize their clinical observations in patients with mastocytosis.22 adult patients diagnosed consecutively with mastocytosis were enrolled in the study. Skin and bone marrow biopsies were taken to establish the diagnosis and perform c-KIT mutation (D816V) analysis.One of the 22 patients had teleangiectasia macularis eruptiva perstans, while 20/22 patients had urticaria pigmentosa. All patients had cutaneous lesions. In 12 patients iliac crest biopsy was performed and 9 of them had bone marrow involvement, classified as indolent systemic mastocytosis. The c-kit mutation D816V was found in one subject both in skin and bone marrow samples. The patients were treated with antihistamine, PUVA, interferon-α or imatinib.The authors draw attention to this rare disease in order to help recognition of relevant signs and symptoms and establish an early diagnosis.Bevezetés: A mastocytosis a hízósejtek (mastocyták) felszaporodásával járó ritka megbetegedés, amely a WHO-besorolás szerint cutan és szisztémás formákra osztható. A klinikai tünetekhez a hízósejtek szöveti infiltrációja és/vagy a mediátorfelszabadulás vezet. Célkitűzés: A szerzők a Semmelweis Egyetem Mastocytosis Hálózat részeként a jellegzetes bőrtüneteket mutató betegek kivizsgálásával szerzett tapasztalatainak összefoglalását tűzték ki célul. Módszer: Összesen 22 mastocytosisos felnőtt beteget vizsgáltak. A diagnózis felállítása bőrszövettani vizsgálat, csontvelővizsgálat, D816V szomatikus c-KIT-mutációanalízis alapján történt. Eredmények: Húsz beteg esetében urticaria pigmentosát, egy esetben teleangiectasia macularis eruptiva perstanst észleltek. A bőr szövettani vizsgálata minden esetben igazolta a klinikai diagnózist. Cristabiopsziával 9/12 esetben a csontvelői részvétel alapján indolens szisztémás mastocytosis diagnózisa volt felállítható. c-KIT-mutációt (D816V) egy betegben igazoltak mind a csontvelőben, mind a bőrben. A betegek a klinikum függvényében antihisztamin, PUVA, a c-kit-szekvenálás eredménye alapján alfa-interferon vagy tirozinkináz-gátló terápiában részesültek. Következtetések: A mastocytosis diagnózisának felállításában a bőrgyógyász szerepe kiemelten fontos, de a betegség kiterjedtségének tisztázására a csontvelő vizsgálatát minden esetben tanácsos elvégezni. Orv. Hetil., 2013, 154, 1469–1475.

Preeclampsia is characterized by maternal systemic anti-angiogenic and pro-inflammatory states. Syndecan-1 is a cell surface proteoglycan expressed by the syncytiotrophoblast, which plays an important role in angiogenesis and resolution of inflammation. Our aim was to examine placental syndecan-1 expression in preeclampsia with or without hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome. Placentas were obtained from women in the following groups: (1) late-onset preeclampsia (n = 8); (2) early-onset preeclampsia without (n = 7) and (3) with HELLP syndrome (n = 8); (4) preterm controls (n = 5); and (5) term controls (n = 9). Tissue microarrays (TMAs) were constructed from paraffin-embedded placentas. TMA slides were immunostained for syndecan-1 and evaluated using microscopy, virtual microscopy, and semi-automated image analysis. Maternal sera from patients with preeclampsia (n = 49) and controls (n = 32) were immunoassayed for syndecan-1. BeWo cells were treated with Forskolin or Latrunculin B or kept in ischemic conditions. SDC1 expression and syndecan-1 production were investigated with qRT-PCR, confocal microscopy, and immunoassays. Syndecan-1 was localized to the syncytiotrophoblast apical membrane in normal placentas. Syndecan-1 immunoscores were higher in late-onset preeclampsia (p = 0.0001) and early-onset preeclampsia with or without HELLP syndrome (p = 0.02 for both) than in controls. Maternal serum syndecan-1 concentration was lower in preeclampsia (median, 673 ng/ml; interquartile range, 459-1,161 ng/ml) than in controls (1,158 ng/ml; 622-1,480 ng/ml). SDC1 expression and syndecan-1 immunostainings in BeWo cells and syndecan-1 concentrations in supernatants increased during cell differentiation. Disruption of the actin cytoskeleton with Latrunculin B decreased syndecan-1 release, while ischemic conditions increased it. Syncytiotrophoblastic syndecan-1 expression depends on the differentiation of villous trophoblasts, and trophoblastic syndecan-1 release is decreased in preeclampsia and HELLP syndrome. This phenomenon may be related to the disturbed syncytiotrophoblastic cortical actin cytoskeleton and associated with maternal anti-angiogenic and pro-inflammatory states in these syndromes.

Myelodysplastic syndromes (MDS) often transform into acute leukemia (AL-MDS), although its prognostic details have not been examined thoroughly. We retrospectively analyzed the prognosis of 189 AL-MDS patients. Ninety-four patients received best supportive care (BSC), and 94 patients received disease-modifying therapies (DMT) that included chemotherapy (CHT) for 65 patients, allogeneic stem-cell transplantation (allo-SCT) for 21 patients, and other therapies for 8 patients. The median survival time was 142 days. In patients treated with BSC, platelet count alone was an independent prognostic factor. In younger patients treated with DMT (

Paroxysmal nocturnal hemoglobinuria is a rare hematological disease. It is associated with increased maternal and fetal complications to such an extent that pregnancy has been considered relatively contraindicated in woman with paroxysmal nocturnal haemoglobinuria. Recently, eculizumab, a monoclonal antibody, has been shown to decrease complications during pregnancies. The highest risk is thromboembolic complication and, therefore, anticoagulant is a standard therapy during pregnancy. In the presented case, a 29-year-old woman with a 5-year history of paroxysmal nocturnal haemoglobinuria had a pregnancy. It was her first pregnancy and was complicated by a sinus thrombosis at the 11th gestational week. After the introduction of eculizumab treatment, the remaining period of pregnancy and delivery were uncomplicated. There are only a few cases in the literature about pregnancy in woman with paroxysmal nocturnal hemoglobinuria who are treated with eculizumab. This monoclonal antibody seems to be safe and it likely prevents many of the complications otherwise observed.

Correspondence.-- et al.

Background The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease. Methods This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV ( n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days ( n=30) or placebo/200 mg of IDX320 twice-daily for 3 days ( n=8). Results In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log10 IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log10 in the placebo group. Conclusions Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.

The aim of this study was to evaluate the effectivity and safety of insulin therapy in patients with DM secondary to underlying chronic pancreatitis with initially inappropriate glycemic control.Pancreatic DM patients treated with oral antidiabetics (OAD) or pre-mixed insulin (PMI) with HbA1c ≥7.0% were recruited. Intensive conservative insulin treatment (ICT) (Group A, n = 16) or PMI (Group B, n = 8) was introduced instead of OAD, or the initial PMI therapy was switched to ICT (Group C, n = 10). The changes in HbA1c, fasting plasma glucose, body weight and hypoglycemic events from baseline to 2 years were followed.The patients in Group A and B had been treated with oral antidiabetics for 55 ± 68 months before switching to insulin therapy. The level of HbA1c had worsened from 8.3 ± 1.5% to 9.8 ± 1.7% during this period. The ICT had reduced HbA1c significantly from 9.7 ± 1.8% to 7.6 ± 1.4% after 12 weeks, in Group A, and five patients had HbA1c7.0%. The introduction of PMI in Group B reduced HbA1c from 10.0 ± 1.4% to 9.0 ± 0.6% by 12 weeks. None of the patients had HbA1c7.0%. By 12 weeks, the introduction of ICT in Group C had reduced the level of HbA1c from 8.8 ± 1.7% to 7.7 ± 1.2%. Two patients reached HbA1c7.0%. There were two severe hypoglycemic episodes during the 2 years, one-one case in Group A and B.Oral medication becomes insufficient early in pancreatic DM. Long-term improvement of glycemic control can be achieved through intensified insulin therapy and in selected cases through PMI with a low risk of hypoglycemia.

Multiple myeloma (MM) is a heterogeneous disease group regarding prognosis, clinical course, and response to therapeutic interventions. Numerous prognostic factors have been identified however there was no consensus about the best prognostic indicators or the proper staging systems. In a previous study the A/M ratio containing albumin (A) and monoclonal component (M) emerged as reliable predictor of survival duration in patients treated with conventional chemotherapy. In the current retrospective study authors evaluated the prognostic role of this fraction in the era of novel agents. They assessed the A/M ratio prior treatment in 56 newly diagnosed MM patients from the aspect of the survival time. According to the results the A/M being

The prevalence of adult-type hypolactasia varies ethnically and geographically among populations. A C/T(-13910) single nucleotide polymorphism (SNP), upstream of the lactase gene, is known to be associated with lactase non-persistence. The aim of this study was to determine the prevalence of lactase-persistent and non-persistent genotypes in the Hungarian population, the age at onset and the applicability of the lactose H2 breath test in comparison with genetic screening. The prevalence of the C/C(-13910) genotype among adults was 37%. Hypolactasia starts to appear at around 5 years of age. Over the age of 12 years, almost all of those with a C/C(-13910) genotype have lactase non-persistence. The C/C(-13910) genotype was closely associated with a positive lactose H2 breath test in symptomatic children, whereas the lactase-persistent genotypes correlated better with a negative H2 test in a control group. In conclusion, supplementary non-invasive breath and genotyping tests furnish a perfect clinical diagnosis.

Udgivelsesdato: 2008-Nov BACKGROUND AND AIMS: Somatosensory hyperalgesia in the referred pain area (RPA) in patients with acute or chronic abdominal pain syndromes may result from the convergence of nerve fibers from visceral and somatic tissues at the spinal and supraspinal levels. Chronic biliary pain in patients with the postcholecystectomy syndrome (i.e., biliary hypersensitivity) may be explained by persistent hyperexcitability of neurons in the central nervous system (CNS). The aim of this study was to evaluate the cutaneous neural sensory perception in the RPA in patients with chronic postcholecystectomy biliary pain and a sphincter of Oddi (SO) dysfunction (SOD). METHODS: Forty-two patients with persistent biliary pain and suspected SOD, 27 age-matched healthy volunteers, and 18 age-matched asymptomatic cholecystectomized controls were prospectively investigated by quantitative sensory testing (Neurometer CPT). The biliary symptoms and the severity of pain were classified on a visual analog pain severity scale system via a previously validated and standardized questionnaire. The patients helped the doctors locate the RPA in the right upper quadrant. The sensory detection threshold was determined noninvasively (Neurometer CPT) with transcutaneous electrical stimulation at 5, 250, and 2,000 Hz, and different current intensities (range from 0.01 to 9.99 mA) applied in a single (patient) blinded method. These three frequencies selectively excite small unmyelinated (C fibers), small myelinated (A-delta), and large myelinated (A-beta) fibers, which transmit dull pain, sharp pain, and touch, respectively. The contralateral region of the abdomen left upper quadrant served as the control area. The sensory current perception threshold ratio (SCPTR) of the data measured in the contralateral area and the RPA was calculated. RESULTS: The SCPTRs in the definite SOD patients with biliary pain, healthy volunteers, the asymptomatic cholecystectomized controls, and the symptomatic cholecystectomized patients but without SOD were 2.32 +/- 1.4 versus 1.06 +/- 0.24 versus 0.97 +/- 0.16 versus 0.83 +/- 0.35 at 2,000 Hz; 2.19 +/- 1.0 versus 1.01 +/- 0.26 versus 1.02 +/- 0.25 versus 0.88 +/- 0.35 at 250 Hz; and 2.19 +/- 1.1 versus 1.12 +/- 0.26 versus 0.99 +/- 0.37 versus 0.84 +/- 0.32 at 5 Hz, respectively. Significant hypersensitivity was detected in the RPA at different stimulation frequencies in the SOD patients with biliary pain versus the cholecystectomized controls: at 5 Hz: P = 0.00001; at 250 Hz: P = 0.00001; and at 2,000 Hz: P = 0.0001, respectively. CONCLUSION: Continuous visceral pain (biliary pain) caused by local inflammatory/sensitizing processes or a CNS malfunction could lead to significant hypersensitivity of the peripheral nociceptive nerve fibers in SOD patients. Postcholecystectomy pain may be explained by persistent hyperexcitability of the nociceptive neurons in the CNS with or without objective motility disorders of the SO.

Allelic distribution of −308 G > A (TNF 1/2) polymorphism of the TNF-alpha, and the +252 A > G promoter polymorphism of the LT-alpha gene, the 1267 A > G polymorphism of the HSP70-2 gene as well as the −429 T > C promoter polymorphism of the RAGE gene were tested in 94 MM cases and 141 controls. Significantly less MM patients than controls carried the TNF2 allele (p = 0.018) and the TNF2-LTA 252G haplotype (p = 0.025). The difference was, however, restricted to the females, as well as the relatively young (

Background The vascular endothelial growth factor (VEGF) has a critical role in vasculogenesis and vascular permeability in several diseases including preeclampsia. There are at least 30 single nucleotide polymorphic (SNP) places on this gene. VEGF G+405C , C−2578A and C−460T SNPs are known to be related to VEGF production. VEGF polymorphisms were studied in preeclampsia, but not in HELLP syndrome. Therefore, we decided to determine the allele and genotype frequencies of VEGF G+405C , C−460T and C−2578A SNPs in healthy pregnant women and HELLP syndrome patients. Methods The authors introduced a quantitative real-time PCR method for the determination of the three VEGF SNPs. Blood samples were collected from 71 HELLP syndrome patients and 93 healthy controls. DNA was isolated by using silica adsorption method. The SNPs were determined by quantitative real-time PCR and melting curve analysis using LightCycler. Results There were significant differences in the allele and genotype frequencies of VEGF C−460T SNP between the two study groups. The T allele was present in 71.1% in the HELLP group, while in 53.8% in the controls ( p = 0.0014). The TT genotype occurred significantly more frequently in the HELLP group than in the control group (45.1% vs. 21.5%; p (for genotype frequencies) = 0.0011). The TT genotype carriers had an increased risk of HELLP syndrome, which was independent of maternal age and primiparity (adjusted odds ratio (OR) = 3.03, 95% confidence interval (CI) = 1.51–6.08; p = 0.002). Although the VEGF G+405C allele and genotype distributions did not differ significantly between the two groups, the CC genotype carriers were also found to have an increased risk for HELLP syndrome after adjustment for maternal age and primiparity (adjusted OR = 3.67, 95% CI = 1.05–12.75; p = 0.041). The VEGF C−2578A SNP was not associated with HELLP syndrome. Conclusions The quantitative real-time PCR combined with melting curve analyses is a fast and reliable method for the determination of VEGF SNPs. We found that the VEGF −460TT and +405CC genotype carriers have an increased risk of HELLP syndrome. As these two SNPs were previously observed to be related to production of the VEGF protein, we suppose that these VEGF polymorphisms – interacting with other genetic and environmental factors – could play a role in the development of HELLP syndrome.

Dysregulation of the Notch-pathway has been implicated in the pathogenesis of chronic lymphocytic leukaemia (B-CLL). We characterized the mRNA expression of Notch pathway elements in circulating normal B- and B-CLL cells, and compared expression profiles with clinical and prognostic data. Similar expression profiles were found in normal B-cells and B-CLL cells, however, most B-CLL samples showed lower Hairy/Enhancer of Split-1 expression than normal B-cells, which suggests that the pathway is not over-activated in B-CLL. The expression of Notch-pathway genes did not correlate with other prognostic factors of B-CLL. The importance of Notch-signalling in CLL cells in lymphatic tissue microenvironments remains to be determined.