Evaluating battery electric vehicle usage in the EU: A comparative study based on member state energy mixes.

The transport sector is undergoing a major transformation, as battery electric vehicles (BEV) are gaining ground. Therefore, assessing the sustainability aspects of their use is crucial to obtaining a clear picture of the sector. This article aims to meet this requirement by using European Union (EU) data for the period 2011 to 2021 and focuses not only on EU-27 aggregates but also on each member state separately. For the evaluation, a well-to-wheel (WTW) method was used to calculate two parameters: energy-specific CO2 emissions (ε) and total efficiency of energy conversions, transmission, and battery (ηtotal). For these values, the annual electricity mixes of the countries were tracked in 5 + 1 categories (combined cycle gas turbine (CCGT), thermal power plant, biofuels, nuclear power plant (NPP), renewables, and imports). The calculated results were illustrated by sustainability matrices describing the former and current positions of the countries. The EU-27 aggregate achieved a 0.04 increase (from 0.37 to 0.41) in total efficiency and a 29 gCO2/MJmotion decrease (from 113 to 84 gCO2/MJmotion) during the period. This ε value for 2021 was around half the world average. However, very significant differences were identified between member states, which are also assessed in the article with special emphases on the five most populated EU countries (Germany, France, Italy, Spain, and Poland).

Blood pressure in preterm infants with bronchopulmonary dysplasia in the first three months of life.

BACKGROUND: Neonatal hypertension is common in preterm infants with bronchopulmonary dysplasia (BPD). Our study aimed to examine blood pressure variation in the first three months of life in preterm BPD patients. METHODS: We conducted a retrospective, single-centre study at the Neonatal Intensive Care Unit of the University of Szeged, Hungary. We collected blood pressure data from 26 preterm infants (born at < 30 weeks gestation) with moderate or severe BPD over three years (2019-2021). We calculated the BPD group's daily average blood pressure values and used previously defined normal blood pressure values from a preterm patient group born at < 30 weeks gestation as a reference. We used 19,481 systolic, diastolic and mean blood pressure measurement data separately to calculate daily average blood pressures. RESULTS: We found a statistically significant correlation between the blood pressure values of the BPD patient group and the reference data. The difference between the blood pressure curve of the group with BPD and that of the reference group was also statistically significant. We also analysed individual patients' daily average blood pressure values and found that 11 patients (42%) had hypertensive blood pressure values for three or more days within the first 90 days of life. Within this group, our statistical analysis showed a 25% chance of acute kidney injury. CONCLUSION: The blood pressure of the BPD group not only correlated with but also significantly differed from the reference data. Hypertension lasting three or more days occurred more frequently in patients with acute kidney injury accompanied by BPD.

[Abdominal and cranial ultrasound screenings in our Neonatal Intensive Care Unit]. / Hasi és agyi ultrahang-szurovizsgálatok Neonatális Intenzív Centrumunkban.

INTRODUCTION: Previously, all admitted neonates to our tertiary Neonatal Unit, University of Szeged, had a cranial and abdominal ultrasound performed as part of their care. OBJECTIVE: To analyze the findings and to evaluate the effectiveness of the universal ultrasound screening. METHOD: Results of cranial and abdominal ultrasound imaging performed in our Unit between 1st January 2014 and 31st December 2015 were analyzed retrospectively. Abnormalities found during the screening scans were studied further and assessed until discharge and during the first 2 years. All imagings were performed by a radiologist. RESULTS: During the examined 2 years, 579 neonates were admitted (gestational age mean 34.2 weeks [23-41, SD ± 4.04]), abdominal ultrasound was performed in 562 (97%) and cranial ultrasound in 560 (97%) babies, on the 3.6th day of life at an average (0-18, SD ± 2.24). Of all abdominal ultrasound scans, 87% (n = 488) was carried out as screening, and the found abnormalities in 140 (29%) of the cases: renal pelvic dilatation (n = 67 [47.9%]), free abdominal fluid (n = 17 [12.1%]), echogenic kidneys (n = 13 [9.3%]), congenital abnormalities of the kidney and urinary tract (n = 9 [6.4%]), abnormalities of the liver, bile system, adrenal gland [n = 14 [10%]). The screening identified 4 (0.8%) neonates with renal abnormilaties requiring surgical correction. In regards of renal abnormalities, we observed male (p = 0.18) and left sided (p = 0.54) predominance. Screening cranial ultrasound was performed in 65% (n = 362) of all neonates, discovering 51 (14%) anomalies: plexus chorioideus cyst (n = 21 [41%]), plexus chorioideus hemorrhage (n = 9 [17.6%]), mild ventricular asymmetry (n = 8 [15.7%]), subependymal hemorrhage (n = 5 [9.8%]), abnormalities of the periventricular area (n = 4 [7.8%]), colpocephaly, hydrocephalus externus, echogenic meninx and thalamic nodule [n = 1-1 (1.9-1.9%)]. CONCLUSION: Abdominal ultrasound screening discovered renal abnormalities and umbilical line complications as clinically relevant findings. However, a small number of renal abnormalities identified by screening required surgical intervention. Further studies are needed to identify possible risk groups to develop more efficient screening strategy to decrease the number of screened babies for 1 relevant finding (number to screen). Cranial ultrasound screening did not identify any abnormalities that needed intervention. We can not recommend universal cranial ultrasound screening based on our results. Orv Hetil. 2023; 164(31): 1222-1230.

Oscillometric arterial blood pressure in haemodynamically stable neonates in the first 2 weeks of life.

BACKGROUND: We aimed to provide data on the normal blood pressure of haemodynamically stable neonates. Our study uses retrospective, real-life oscillometric blood pressure measurement values to determine the expected blood pressure in different gestational age, chronological age and birth weight groups. We also investigated the effect of antenatal steroid on neonatal blood pressure. METHODS: Our retrospective study (2019-2021) was carried out in the Neonatal Intensive Care Unit of the University of Szeged, Hungary. We involved 629 haemodynamically stable patients and analysed 134,938 blood pressure values. Data were collected from electronic hospital records of IntelliSpace Critical Care Anesthesia by Phillips. We used the PDAnalyser program for data handling and the IBM SPSS program for statistical analysis. RESULTS: We found a significant difference between the blood pressure of each gestational age group in the first 14 days of life. The systolic, diastolic and mean blood pressure rise are steeper in the preterm group than in the term group in the first 3 days of life. No significant blood pressure differences were found between the group with a complete antenatal steroid course and those who received incomplete steroid prophylaxis or did not receive antenatal steroids. CONCLUSION: We determined the average blood pressure of stable neonates and obtained normative data by percentiles. Our study provides additional data on how blood pressure varies with gestational age and birth weight. A higher resolution version of the Graphical abstract is available as Supplementary information.

Use of antibiotics in suspected early-onset neonatal sepsis / Antibiotikumhasználat korai szepszis gyanúja esetén újszülöttkorban.

Összefoglaló. Bevezetés: Az újszülöttkori szepszis ritka, de magas mortalitással járó állapot. Az Egészségügyi Szakmai Kollégium Neonatológiai Tagozata 2017-ben bevezette a korai szepszisrol szóló állásfoglalást, meghatározva a kezelés indikációját a túlzott mértéku antibiotikumadás elkerülése céljából. Célkituzés: Retrospektív analízissel vizsgáltuk az állásfoglalás elotti és utáni idoszak antibiotikumhasználatát klinikánk beteganyagán. Módszer: Az intézményünkben 2014. 01. 01. és 2018. 12. 31. között született, a 34. gestatiós hetet betöltött újszülöttek adatait vizsgáltuk a következo kimenetelekre koncentrálva: szepszisre utaló klinikai tünetek jelenléte, az antibiotikummal kezelt újszülöttek száma, koraiszepszis-incidencia, mortalitás. A statisztikai analízis az RStudio programmal történt (szignifikancia: p<0,05). Eredmények: A vizsgált 5 évben összesen 12 347 újszülött jött a világra, közülük antibiotikumot kapott 1502 (12,16%); évekre lebontva: 2014-ben 517 (21,10%), 2015-ben 401 (16,63%), 2016-ban 459 (17,96%), 2017-ben 61 (2,39%), 2018-ban 64 (2,69%). Az antibiotikumterápiában részesültek (n = 1502) közül 239 (15,91%) újszülöttnek volt fertozésre utaló tünete. A klinikai tüneteket mutató újszülöttek száma nem növekedett szignifikánsan (p = 0,285); 2014-ben 52 (2,12%), 2015-ben 42 (1,74%), 2016-ban 42 (1,64%), 2017-ben 46 (1,80%), 2018-ban 57 (2,40%). Hemokultúra-pozitív szepszis összesen: 4; koraiszepszis-incidencia: 0,324/1000. Szepszishez kötheto haláleset nem volt. Megbeszélés: A protokollváltást megelozoen az újszülöttek csupán rizikófaktorok alapján is részesültek antibiotikumterápiában, 2017 óta azonban elsosorban a fertozés klinikai tüneteit mutató újszülötteket kezeljük, ami az antibiotikumhasználat szignifikáns csökkenéséhez vezetett. A korábbi, rizikófaktorok alapján adott antibiotikumterápia megszüntetését követoen nem emelkedett a tünetet mutató szeptikus újszülöttek száma, sem a korai szepszis okozta mortalitás. Következtetés: A 34. gestatiós hetet betöltött újszülötteknél a korai szepszis gyanúja miatti antibiotikumhasználat biztonsággal csökkentheto volt, ezzel megelozve a felesleges antibiotikumkezelés rövid és hosszú távú mellékhatásait. Orv Hetil. 2022; 163(11): 431-437. INTRODUCTION: Early-onset neonatal sepsis is a rare, but life-threatening condition. In 2017, the Hungarian Neonatal Society issued a national guideline to rationalize the use of antibiotic use in neonatal sepsis. OBJECTIVE: To retrospectively determine the frequency of prescribed antibiotics before and after the introduction of national guidance. METHOD: Data of neonates (>34. gestational weeks) delivered in our hospital between 1st January 2014 and 31st December 2018 were analysed with focusing on signs of sepsis, number of neonates treated with antibiotics, incidence of early-onset neonatal sepsis, sepsis-related mortality. Statistical analysis was performed with RStudio software (significance: p<0.05). RESULTS: During the analysed time period, 12 347 neonates were born, 1502 (12.16%) neonates were given antibiotics, showing a significant decrease after 2017: 517 (21.10%) in 2014, 401 (16.63%) in 2015, 459 (17.96%) in 2016, 61 (2.39%) in 2017, 64 (2.69%) in 2018, respectively. Out of the group of neonates treated with antibiotics (n = 1502), only 239 (15.91%) neonates showed the clinical signs of sepsis. No significant change was observed in the number of symptomatic newborns during the study period: 52 (2.12%) in 2014, 42 (1.74%) in 2015, 42 (1.64%) in 2016, 46 (1.80%) in 2017, 57 (2.40%) in 2018, p = 0.285. Blood culture confirmed neonatal sepsis was observed in 4 babies, incidence of early-onset neonatal sepsis was 0.324/1000, sepsis-related mortality was zero. DISCUSSION: Before the introduction of the national guideline, most of the neonates were prescribed antibiotics based on risk factors. Since 2017, antibiotics have been mainly preserved for newborns with clinical signs of sepsis. Despite cessation of antiobiotic treatment indicated by risk factors, the number of symptomatic babies and sepsis-related mortality have not increased. CONCLUSION: The use of antibiotics for neonates >34th gestational week can be safely reduced, entailing a decrease in short- and long-term complications of early antibiotic use. Orv Hetil. 2022; 163(11): 431-437.

Vitamin D Deficiency Cause Gender Specific Alterations of Renal Arterial Function in a Rodent Model.

Vitamin D deficiency shows positive correlation to cardiovascular risk, which might be influenced by gender specific features. Our goal was to examine the effect of Vitamin D supplementation and Vitamin D deficiency in male and female rats on an important hypertension target organ, the renal artery. Female and male Wistar rats were fed with Vitamin D reduced chow for eight weeks to induce hypovitaminosis. Another group of animals received normal chow with further supplementation to reach optimal serum vitamin levels. Isolated renal arteries of Vitamin D deficient female rats showed increased phenylephrine-induced contraction. In all experimental groups, both indomethacin and selective cyclooxygenase-2 inhibition (NS398) decreased the phenylephrine-induced contraction. Angiotensin II-induced contraction was pronounced in Vitamin D supplemented males. In both Vitamin D deficient groups, acetylcholine-induced relaxation was impaired. In the female Vitamin D supplemented group NS398, in males the indomethacin caused reduced acetylcholine-induced relaxation. Increased elastic fiber density was observed in Vitamin D deficient females. The intensity of eNOS immunostaining was decreased in Vitamin D deficient females. The density of AT1R staining was the highest in the male Vitamin D deficient group. Although Vitamin D deficiency induced renal vascular dysfunction in both sexes, female rats developed more extensive impairment that was accompanied by enzymatic and structural changes.

[Clinical features and therapy of uveitis in childhood]. / A gyermekkori uveitis klinikai jellemzoi és terápiája.

Introduction: Uveitis is characterized by inflammation of the middle layer of the eye. Its overall incidence is low. Autoimmune diseases and infections are the most common underlying diseases. Out of the autoimmune diseases, juvenile idiopathic arthritis is associated most frequently with uveitis. The topical ophthalmological treatment may fail in a significant proportion of the patients and immunomodulatory therapy may be required. Aim and method: In a retrospective study, data of 33 children diagnosed and treated with uveitis at the Department of Pediatrics and Ophthalmology, University of Pécs during the last 5 years were collected and analyzed. Results: The mean age of the patients was 9.3 (0.3-17.8) years. Boys and girls were equally affected with an exception of patients with juvenile idiopathic arthritis where female predominance was found. An underlying disease could be identified in 60% of the cases (20/33). Uveitis was associated in 12 patients with juvenile idiopathic arthritis, in 2 patients with Behcet's disease and in a single case with inflammatory bowel disease. Infections have been proven in 5 patients. The autoimmune diseases caused an eye inflammation typically in anterior localization, in contrast to the infections that resulted in posterior uveitis. The majority of the patients required systemic treatment. 3 of them received systemic corticosteroid and 18 patients methotrexate as disease-modifying antirheumatic drug. 13 children with severe disease activity required biological therapy (adalimumab injection). Remission could be achieved in 1.45 (0.75-2.5) months. Conclusion: Pediatric uveitis is of great importance. Early diagnosis, adequate therapy and follow-up require multidisciplinary cooperation. Orv Hetil. 2019; 160(34): 1335-1339.

Inhibition of DNA methyltransferase leads to increased genomic 5-hydroxymethylcytosine levels in hematopoietic cells.

5-Hydroxymethylcytosine (5hmC) is produced from 5-methylcytosine (5mC) by Ten-eleven translocation (TET) dioxygenases. The epigenetic modification 5hmC has crucial roles in both cellular development and differentiation. The 5hmC level is particularly high in the brain. While 5mC is generally associated with gene silencing/reduced expression, 5hmC is a more permissive epigenetic mark. To understand its physiological function, an easy and accurate quantification method is required. Here, we have developed a novel LC-MS/MS-based approach to quantify both genomic 5mC and 5hmC contents. The method is based on the liberation of nucleobases by formic acid. Applying this method, we characterized the levels of DNA methylation and hydroxymethylation in mouse brain and liver, primary hepatocytes, and various cell lines. Using this approach, we confirm that the treatment of different cell lines with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine leads to a decrease in 5mC content. This decrease was accompanied by an increase in 5hmC levels in cell lines of hematopoietic origin. Finally, we showed that ascorbate elevates the levels of 5hmC and augments the effect of 5-aza-2'-deoxycytidine without significantly influencing 5mC levels.

The purchase sources of and price paid for cigarettes in six European countries: Findings from the EUREST-PLUS ITC Europe Surveys.

INTRODUCTION: Tobacco tax policies have been proven to be effective in reducing tobacco consumption, but their impact can be mitigated through price-minimizing behaviours among smokers. This study explored the purchase sources of tobacco products and the price paid for tobacco products in six EU member states. METHODS: Data from Wave 1 of the EUREST-PLUS ITC Europe Survey collected from nationally representative samples of adult smokers in Germany, Greece, Hungary, Poland, Romania and Spain (ITC 6E Survey) were used. The ITC 6E Survey sample, conducted in 2016, randomly sampled 6011 adult cigarette smokers aged 18 years or older. Information on purchase sources of tobacco was examined by country. The difference in reported purchase price by purchase location (store vs non-store/other) was analysed using linear regression for each country. RESULTS: Tobacco purchasing patterns and sources varied widely between countries. Non-store/other purchases were very rare in Hungary (0.1%) while these types of purchases were more common in Germany (5.1%) and Poland (8.6%). Reported prices of one standard pack of 20 cigarettes were highest in Germany (4.80€) and lowest in Hungary (2.45€). While non-store purchases were only made by a minority of smokers (>10% in all countries), the price differential was considerable between store and non-store/other sources, up to 2€ per pack in Greece and in Germany. CONCLUSIONS: The results suggest a huge variation of purchasing sources and price differentials between store and non-store purchasing sources across the six EU member states examined. While the cross-sectional data precludes any causal inference, supply chain control through licensing as introduced in Hungary and the lack of such measures in the other countries might nevertheless be a plausible explanation for the large differences in the frequency of non-store purchases observed in this study.

The transcriptional activity of hepatocyte nuclear factor 4 alpha is inhibited via phosphorylation by ERK1/2.

Hepatocyte nuclear factor 4 alpha (HNF4α) nuclear receptor is a master regulator of hepatocyte development, nutrient transport and metabolism. HNF4α is regulated both at the transcriptional and post-transcriptional levels by different mechanisms. Several kinases (PKA, PKC, AMPK) were shown to phosphorylate and decrease the activity of HNF4α. Activation of the ERK1/2 signalling pathway, inducing proliferation and survival, inhibits the expression of HNF4α. However, based on our previous results we hypothesized that HNF4α is also regulated at the post-transcriptional level by ERK1/2. Here we show that ERK1/2 is capable of directly phosphorylating HNF4α in vitro at several phosphorylation sites including residues previously shown to be targeted by other kinases, as well. Furthermore, we also demonstrate that phosphorylation of HNF4α leads to a reduced trans-activational capacity of the nuclear receptor in luciferase reporter gene assay. We confirm the functional relevance of these findings by demonstrating with ChIP-qPCR experiments that 30-minute activation of ERK1/2 leads to reduced chromatin binding of HNF4α. Accordingly, we have observed decreasing but not disappearing binding of HNF4α to the target genes. In addition, 24-hour activation of the pathway further decreased HNF4α chromatin binding to specific loci in ChIP-qPCR experiments, which confirms the previous reports on the decreased expression of the HNF4a gene due to ERK1/2 activation. Our data suggest that the ERK1/2 pathway plays an important role in the regulation of HNF4α-dependent hepatic gene expression.

Prolyl Hydroxylase 3 Attenuates MCL-1-Mediated ATP Production to Suppress the Metastatic Potential of Colorectal Cancer Cells.

Hypoxia is a common feature of solid tumors. Prolyl hydroxylase enzymes (PHD1-3) are molecular oxygen sensors that regulate hypoxia-inducible factor activity, but their functions in metastatic disease remain unclear. Here, we assessed the significance of PHD enzymes during the metastatic spread of colorectal cancer. PHD expression analysis in 124 colorectal cancer patients revealed that reduced tumoral expression of PHD3 correlated with increased frequency of distant metastases and poor outcome. Tumorigenicity and metastatic potential of colorectal tumor cells over and underexpressing PHD3 were investigated in orthotopic and heterotopic tumor models. PHD3 overexpression in a syngeneic tumor model resulted in fewer liver metastases, whereas PHD3 knockdown induced tumor spread. The migration of PHD3-overexpressing tumor cells was also attenuated in vitro Conversely, migratory potential and colony formation were enhanced in PHD3-deficient cells, and this phenotype was associated with enhanced mitochondrial ATP production. Furthermore, the effects of PHD3 deficiency were accompanied by increased mitochondrial expression of the BCL-2 family member, member myeloid cell leukemia sequence 1 (MCL-1), and could be reversed by simultaneous inhibition of MCL-1. MCL-1 protein expression was likewise enhanced in human colorectal tumors expressing low levels of PHD3. Therefore, we demonstrate that downregulation of PHD3 augments metastatic spread in human colorectal cancer and identify MCL-1 as a novel downstream effector of oxygen sensing. Importantly, these findings offer new insight into the possible, context-specific deleterious effects of pharmacologic PHD inhibition. Cancer Res; 76(8); 2219-30. ©2016 AACR.

Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma.

INTRODUCTION: Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Four subgroups with distinct genetic, epigenetic and clinical characteristics have been identified. Survival remains particularly poor in patients with Group 3 tumors harbouring a MYC amplification. We herein explore the molecular mechanisms and translational implications of class I histone deacetylase (HDAC) inhibition in MYC driven MBs. MATERIAL AND METHODS: Expression of HDACs in primary MB subgroups was compared to normal brain tissue. A panel of MB cell lines, including Group 3 MYC amplified cell lines, were used as model systems. Cells were treated with HDAC inhibitors (HDACi) selectively targeting class I or IIa HDACs. Depletion of HDAC2 was performed. Intracellular HDAC activity, cellular viability, metabolic activity, caspase activity, cell cycle progression, RNA and protein expression were analyzed. RESULTS: HDAC2 was found to be overexpressed in MB subgroups with poor prognosis (SHH, Group 3 and Group 4) compared to normal brain and the WNT subgroup. Inhibition of the enzymatic activity of the class I HDACs reduced metabolic activity, cell number, and viability in contrast to inhibition of class IIa HDACs. Increased sensitivity to HDACi was specifically observed in MYC amplified cells. Depletion of HDAC2 increased H4 acetylation and induced cell death. Simulation of clinical pharmacokinetics showed time-dependent on target activity that correlated with binding kinetics of HDACi compounds. CONCLUSIONS: We conclude that HDAC2 is a valid drug target in patients with MYC amplified MB. HDACi should cover HDAC2 in their inhibitory profile and timing and dosing regimen in clinical trials should take binding kinetics of compounds into consideration.

Successful postoperative treatment of a lumbosacral ulcer in a neonate after myelomeningocele.

Wound care in neonates demands special awareness of the anatomical and physiological characteristics of their skin, and the danger of adverse mechanical and toxicological events. Here, we present the case of a full-term neonate born with myelomeningocele. Following the closing surgery on the 3rd day of postuterine life, the operated region became inflamed, the sutures opened and a necrotic discharging ulcer developed. Besides parenteral antibiotic treatment based on the microbiological findings, intelligent hydrofiber dressings were applied to the wound with regard to the special characteristics of wound care in neonates. After 72 days, the ulcer had healed with a small residual scar, and the infant is currently demonstrating normal physical and mental development.

Deficiency of the oxygen sensor PHD1 augments liver regeneration after partial hepatectomy.

PURPOSE: Liver regeneration after partial hepatectomy (PH) occurs in conditions of reduced oxygen supply. HIF prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3) are oxygen sensors involved in adaptive response to hypoxia. Specific functions of these PHD enzymes in liver regeneration have, however, remained enigmatic. Here, we investigated the significance of PHD1 in liver regeneration following hepatectomy. METHODS: Liver regeneration was studied in PHD1-deficient (PHD1(-/-)) and wild type (WT) mice subjected to 80% hepatectomy. For in vitro analyses, hepatocytes were isolated from PHD1(-/-) and WT livers. Cell cycle progression was studied via FACS-based analysis of nuclear DNA profile. Transcription factor binding assays, qRT-PCR, and immunoblotting were applied to study the relevance of PHD1 downstream effectors during liver regeneration. RESULTS: Liver regeneration was significantly enhanced in PHD1(-/-) mice compared to WT littermates. This effect was due to enhanced proliferation rather than to hypertrophy of liver cells. Cell cycle progression was significantly enhanced, and transcriptional activity of the cell cycle regulator c-Myc was increased in PHD1-deficient hepatocytes. These changes coincided with increased expression of cyclin D2, a cell cycle-promoting c-Myc target, and decreased expression of the cell cycle-delaying c-Myc target p21. CONCLUSIONS: Loss of PHD1 enhances liver regeneration by boosting hepatocyte proliferation in a c-Myc-dependent fashion. PHD1 might, therefore, represent a potential target to facilitate liver regeneration after surgical resection.

Loss of the oxygen sensor PHD3 enhances the innate immune response to abdominal sepsis.

Hypoxia and HIFs (HIF-1α and HIF-2α) modulate innate immune responses in the setting of systemic inflammatory responses and sepsis. The HIF prolyl hydroxylase enzymes PHD1, PHD2 and PHD3 regulate the mammalian adaptive response to hypoxia; however, their significance in the innate immune response has not been elucidated. We demonstrate in this study that deficiency of PHD3 (PHD3(-/-)) specifically shortens the survival of mice subjected to various models of abdominal sepsis because of an overwhelming innate immune response, leading to premature organ dysfunction. By contrast, this phenotype was absent in mice deficient for PHD1 (PHD1(-/-)) or PHD2 (PHD2(+/-)). In vivo, plasma levels of proinflammatory cytokines were enhanced, and recruitment of macrophages to internal organs was increased in septic PHD3-deficient mice. Reciprocal bone marrow transplantation in sublethally irradiated mice revealed that enhanced susceptibility of PHD3-deficient mice to sepsis-related lethality was specifically caused by loss of PHD3 in myeloid cells. Several in vitro assays revealed enhanced cytokine production, migration, phagocytic capacity, and proinflammatory activation of PHD3-deficient macrophages. Increased proinflammatory activity of PHD3-deficient macrophages occurred concomitantly with enhanced HIF-1α protein stabilization and increased NF-κB activity, and interference with the expression of HIF-1α or the canonical NF-κB pathway blunted their proinflammatory phenotype. It is concluded that impairment of PHD3 enzyme function aggravates the clinical course of abdominal sepsis via HIF-1α- and NF-κB-mediated enhancement of the innate immune response.

Molecular oxygen sensing: implications for visceral surgery.

BACKGROUND: Since mammalian cells rely on the availability of oxygen, they have devised mechanisms to sense environmental oxygen tension, and to efficiently counteract oxygen deprivation (hypoxia). These adaptive responses to hypoxia are essentially mediated by hypoxia inducible transcription factors (HIFs). Three HIF prolyl hydroxylase enzymes (PHD1, PHD2 and PHD3) function as oxygen sensing enzymes, which regulate the activity of HIFs in normoxic and hypoxic conditions. Many of the compensatory functions exerted by the PHD-HIF system are of immediate surgical relevance since they regulate the biological response of ischemic tissues following ligation of blood vessels, of oxygen-deprived inflamed tissues, and of tumors outgrowing their vascular supply. PURPOSE: Here, we outline specific functions of PHD enzymes in surgically relevant pathological conditions, and discuss how these functions might be exploited in order to support the treatment of surgically relevant diseases.

[Beyond genetics--the emerging role of epigenetics and its clinical aspects]. / A genetikán is túl - Az epigenetika eloretörése és orvosi vonatkozásai.

Analysis of genomic sequences has clearly shown that the genomic differences among species do not explain the diversity of life. The genetic code itself serves as only a part of the dynamic complexity that results in the temporal and spatial changes in cell phenotypes during development. It has been concluded that the phenotype of a cell and of the organism as a whole is more influenced by environmentally-induced changes in gene activity than had been previously thought. The emerging field of epigenetics focuses on molecular marks on chromatin; called the epigenome, which serve as transmitters between the genome and the environment. These changes not only persist through multiple cell division cycles, but may also endure for multiple generations. Irregular alterations of the epigenome; called epimutations, may have a decisive role in the etiology of human pathologies such as malignancies and other complex human diseases. Epigenetics can provide the missing link between genetics, disease and the environment. Therefore, this field may have an increasing impact on future drug design and serve as a basis for new therapeutic/preventative approaches.

Prognostic impact of B-cell density in cutaneous melanoma.

Studies on the prognostic importance of tumor-infiltrating lymphocytes have mainly focused on T cells, while little is known about the role of tumor-infiltrating B lymphocytes. We investigated the prevalence of CD20(+) B cells by immunohistochemistry in primary melanoma samples of 106 patients and analyzed in relation to clinicopathological parameters and patients' survival. The majority of samples contained a significant amount of B lymphocytes, predominantly dispersed in the stroma surrounding tumor deposits (mean peritumoral and intratumoral densities: 178.7 ± 156.1 vs. 4.9 ± 6.9 cells/mm², respectively). B cells organized in follicle-like aggregates were also observed in 26% of the samples. B-cell density correlated with that of activated (CD25(+) or OX40(+)) T lymphocytes. Infiltration by CD20(+) lymphocytes did not correlate with tumor thickness, while the presence of B-cell aggregates was observed more frequently in thick melanomas. On the other hand, B-cell infiltration was more pronounced in nonmetastatic or lymph node metastatic tumors, compared to visceral metastatic ones. Accordingly, high number of these cells provided significant survival advantage (P = 0.0391 and P = 0.0136 for intra- and peritumoral infiltration, respectively). Furthermore, combination of peritumoral B-cell density with the number of activated T lymphocytes identified patient subgroups with different disease outcome, which was most favorable in the case of high density, while very poor in the case of low density of both cell types. Multivariate survival analysis identified tumor thickness and CD20(+)/OX40(+) cell density combination as significant independent prognostic factors. Taken together, our results show correlation between low number of CD20(+) B lymphocytes and melanoma progression, indicating a possible role of tumor-infiltrating B cells in antitumoral immune response. It was also reflected in better outcome of the disease since the density of B lymphocytes alone as well as in combination with that of activated T cells proved of prognostic importance in patients with malignant melanoma.

The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice.

Systemic iron homeostasis is mainly controlled by the liver through synthesis of the peptide hormone hepcidin (encoded by Hamp), the key regulator of duodenal iron absorption and macrophage iron release. Here we show that the liver-specific microRNA miR-122 is important for regulating Hamp mRNA expression and tissue iron levels. Efficient and specific depletion of miR-122 by injection of a locked-nucleic-acid-modified (LNA-modified) anti-miR into WT mice caused systemic iron deficiency, characterized by reduced plasma and liver iron levels, mildly impaired hematopoiesis, and increased extramedullary erythropoiesis in the spleen. Moreover, miR-122 inhibition increased the amount of mRNA transcribed by genes that control systemic iron levels, such as hemochromatosis (Hfe), hemojuvelin (Hjv), bone morphogenetic protein receptor type 1A (Bmpr1a), and Hamp. Importantly, miR-122 directly targeted the 3' untranslated region of 2 mRNAs that encode activators of hepcidin expression, Hfe and Hjv. These data help to explain the increased Hamp mRNA levels and subsequent iron deficiency in mice with reduced miR-122 levels and establish a direct mechanistic link between miR-122 and the regulation of systemic iron metabolism.