Levosimendan in Acute and Advanced Heart Failure: an Expert Perspective on Posology and Therapeutic Application.

Levosimendan, a calcium sensitizer and potassium channel-opener, is widely appreciated by many specialist heart failure practitioners for its effects on systemic and pulmonary hemodynamics and for the relief of symptoms of acute heart failure. The drug's impact on mortality in large randomized controlled trials has been inconsistent or inconclusive but, in contrast to conventional inotropes, there have been no indications of worsened survival and some signals of improved heart failure-related quality of life. For this reason, levosimendan has been proposed as a safer inodilator option than traditional agents in settings, such as advanced heart failure. Positive effects of levosimendan on renal function have also been described. At the HEART FAILURE 2018 congress of the Heart Failure Association of the European Society of Cardiology, safe and effective use levosimendan in acute and advanced heart failure was examined in a series of expert tutorials. The proceedings of those tutorials are summarized in this review, with special reference to advanced heart failure and heart failure with concomitant renal dysfunction. Meta-analysis of clinical trials data is supportive of a renal-protective effect of levosimendan, while physiological observations suggest that this effect is exerted at least in part via organ-specific effects that may include selective vasodilation of glomerular afferent arterioles and increased renal blood flow, with no compromise of renal oxygenation. These lines of evidence require further investigation and their clinical significance needs to be evaluated in specifically designed prospective trials.

Dose-dependent electrophysiological effects of the myosin activator omecamtiv mecarbil in canine ventricular cardiomyocytes.

Omecamtiv mecarbil (OM) is a myosin activator agent recently developed for treatment of heart failure. Although its action on extending systolic ejection time and increasing left ventricular ejection fraction is well documented, no data is available regarding its possible side-effects on cardiac ion channels. Therefore, the present study was designed to investigate the effects of OM on action potential morphology and the underlying ion currents in isolated canine ventricular myocytes using sharp microelectrodes, conventional patch clamp, and action potential voltage clamp techniques. OM displayed a concentration-dependent action on action potential configuration: 1 µM OM had no effect, while action potential duration and phase-1 repolarization were reduced and the plateau potential was depressed progressively at higher concentrations (10 - 100 µM; P < 0.05 compared to control). Accordingly, OM (10 µM) decreased the density of the transient outward K+ current (Ito), the L-type Ca2+ current (ICa) and the rapid delayed rectifier K+ current (IKr), but failed to modify the inward rectifier K+ current (IK1). It is concluded, that although the therapeutic concentrations of OM are not likely to influence cardiac ion currents significantly, alterations of the major cardiac ion currents can be anticipated at concentrations above those clinically tolerated.

Calcium sensitizers: What have we learned over the last 25 years?

The use of inotropes for correcting hemodynamic dysfunction in patients with congestive heart failure has been described over many decades. Drugs such as cardiac glycosides, cathecolamines, phosphodiestherase inhibitors, and calcium sensitizers have been in turn proposed. However, the number of new chemical entities in this therapeutic field has been surprisingly low, and the current selection of drugs is limited. One of the paradigm shifts in the discovery for new inotropes was to focus on 'calcium sensitizers' instead of 'calcium mobilizers'. This was designed to lead to the development of safer inotropes, devoid of the complications that arise due to increased intracellular calcium levels. However, only three such calcium sensitizers have been fully developed over the latest 30 years. Moreover, two of these, levosimendan and pimobendan, have multiple molecular targets and other pharmacologic effects in addition to inotropy, such as peripheral vasodilation. More recently, omecamtiv mecarbil was described, which is believed to have a pure inotropy action that is devoid of pleiotropic effects. When the clinical data of these three calcium sensitizers are compared, it appears that the less pure inotropes have the cutting edge over the purer inotrope, due to additional effects during the treatment of a complex syndrome such as acute congested heart failure. This review aims to answer the question whether calcium sensitization per se is a sufficient strategy for bringing required clinical benefits to patients with heart failure. This review is dedicated to the memory of Heimo Haikala, a true and passionate innovator in this challenging field.

The novel cardiac myosin activator omecamtiv mecarbil increases the calcium sensitivity of force production in isolated cardiomyocytes and skeletal muscle fibres of the rat.

BACKGROUND AND PURPOSE: Omecamtiv mecarbil (OM) is a novel cardiac myosin activator drug for inotropic support in systolic heart failure. Here we have assessed the concentration-dependent mechanical effects of OM in permeabilized cardiomyocyte-sized preparations and single skeletal muscle fibres of Wistar-Kyoto rats under isometric conditions. EXPERIMENTAL APPROACHES: Ca2+ -dependent active force production (Factive ), its Ca2+ sensitivity (pCa50 ), the kinetic characteristics of Ca2+ -regulated activation and relaxation, and Ca2+ -independent passive force (Fpassive ) were monitored in Triton X-100-skinned preparations with and without OM (3nM-10 µM). KEY RESULTS: In permeabilized cardiomyocytes, OM increased the Ca2+ sensitivity of force production (ΔpCa50 : 0.11 or 0.34 at 0.1 or 1 µM respectively). The concentration-response relationship of the Ca2+ sensitization was bell-shaped, with maximal effects at 0.3-1 µM OM (EC50 : 0.08 ± 0.01 µM). The kinetics of force development and relaxation slowed progressively with increasing OM concentration. Moreover, OM increased Fpassive in the cardiomyocytes with an apparent EC50 value of 0.26 ± 0.11 µM. OM-evoked effects in the diaphragm muscle fibres with intrinsically slow kinetics were largely similar to those in cardiomyocytes, while they were less apparent in muscle fibres with fast kinetics. CONCLUSIONS AND IMPLICATIONS: OM acted as a Ca2+ -sensitizing agent with a downstream mechanism of action in both cardiomyocytes and diaphragm muscle fibres. The mechanism of action of OM is connected to slowed activation-relaxation kinetics and at higher OM concentrations increased Fpassive production.

Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism.

Few studies have included subjects with the propensity to reach old age in good health, with the aim to disentangle mechanisms contributing to staying healthier for longer. The hypothalamic-pituitary-thyroid (HPT) axis maintains circulating levels of thyroid stimulating hormone (TSH) and thyroid hormone (TH) in an inverse relationship. Greater longevity has been associated with higher TSH and lower TH levels, but mechanisms underlying TSH/TH differences and longevity remain unknown. The HPT axis plays a pivotal role in growth, development and energy metabolism. We report that offspring of nonagenarians with at least one nonagenarian sibling have increased TSH secretion but similar bioactivity of TSH and similar TH levels compared to controls. Healthy offspring and spousal controls had similar resting metabolic rate and core body temperature. We propose that pleiotropic effects of the HPT axis may favour longevity without altering energy metabolism.

Myeloperoxidase evokes substantial vasomotor responses in isolated skeletal muscle arterioles of the rat.

AIMS: Myeloperoxidase (MPO) catalyses the formation of a wide variety of oxidants, including hypochlorous acid (HOCl), and contributes to cardiovascular disease progression. We hypothesized that during its action MPO evokes substantial vasomotor responses. METHODS: Following exposure to MPO (1.92 mU mL(-1)) in the presence of increasing concentrations of hydrogen peroxide (H2O2), changes in arteriolar diameter of isolated gracilis skeletal muscle arterioles (SMAs) and coronary arterioles (CAs) and in the isometric force in basilar arteries (BAs) of the rat were monitored. RESULTS: Myeloperoxidase increased vascular tone to different degrees in CAs, SMAs and BAs. The mechanism of increased vasoconstriction was studied in detail in SMAs. MPO-evoked vasoconstrictions were prevented by the MPO inhibitor 4-aminobenzhydrazide (50 µM), by endothelium removal in the SMAs. Surprisingly, the HOCl scavenger L-methionine (100 µM), the thromboxane A2 (TXA2) antagonist SQ-29548 (1 µM) or the non-specific cyclooxygenase (COX) antagonist indomethacin (1 µM) converted the MPO-evoked vasoconstrictions to pronounced vasodilations in SMAs, not seen in the presence of H2O2. In contrast to noradrenaline-induced vasoconstrictions, the MPO-evoked vasoconstrictions were not accompanied by significant increases in arteriolar [Ca(2+)] levels in SMAs. CONCLUSION: These data showed that H2O2 -derived HOCl to be a potent vasoconstrictor upon MPO application. HOCl activated the COX pathway, causing the synthesis and release of a TXA2-like substance to increase the Ca(2+) sensitivity of the contractile apparatus in vascular smooth muscle cells and thereby to augment H2 O2 -evoked vasoconstrictions. Nevertheless, inhibition of the HOCl-COX-TXA2 pathway unmasked the effects of additional MPO-derived radicals with a marked vasodilatory potential in SMAs.

Evolutionary origins of the placental expression of chromosome 19 cluster galectins and their complex dysregulation in preeclampsia.

INTRODUCTION: The dysregulation of maternal-fetal immune tolerance is one of the proposed mechanisms leading to preeclampsia. Galectins are key regulator proteins of the immune response in vertebrates and maternal-fetal immune tolerance in eutherian mammals. Previously we found that three genes in a Chr19 cluster encoding for human placental galectin-13 (PP13), galectin-14 and galectin-16 emerged during primate evolution and may confer immune tolerance to the semi-allogeneic fetus. MATERIALS AND METHODS: This study involved various methodologies for gene and protein expression profiling, genomic DNA methylation analyses, functional assays on differentiating trophoblasts including gene silencing, luciferase reporter and methylation assays. These methods were applied on placental specimens, umbilical cord blood cells, primary trophoblasts and BeWo cells. Genomic DNA sequences were analyzed for transposable elements, transcription factor binding sites and evolutionary conservation. RESULTS AND DISCUSSION: The villous trophoblastic expression of Chr19 cluster galectin genes is developmentally regulated by DNA methylation and induced by key transcription factors of villous placental development during trophoblast fusion and differentiation. This latter mechanism arose via the co-option of binding sites for these transcription factors through promoter evolution and the insertion of an anthropoid-specific L1PREC2 transposable element into the 5' untranslated region of an ancestral gene followed by gene duplication events. Among placental Chr19 cluster galectin genes, the expression of LGALS13 and LGALS14 is down-regulated in preterm severe preeclampsia associated with SGA. We reveal that this phenomenon is partly originated from the dysregulated expression of key transcription factors controlling trophoblastic functions and galectin gene expression. In addition, the differential DNA methylation of these genes was also observed in preterm preeclampsia irrespective of SGA. CONCLUSIONS: These findings reveal the evolutionary origins of the placental expression of Chr19 cluster galectins. The complex dysregulation of these genes in preeclampsia may alter immune tolerance mechanisms at the maternal-fetal interface.

Structure-activity relationships of vanilloid receptor agonists for arteriolar TRPV1.

BACKGROUND AND PURPOSE: The transient receptor potential vanilloid 1 (TRPV1) plays a role in the activation of sensory neurons by various painful stimuli and is a therapeutic target. However, functional TRPV1 that affect microvascular diameter are also expressed in peripheral arteries and we attempted to characterize this receptor. EXPERIMENTAL APPROACH: Sensory TRPV1 activation was measured in rats by use of an eye wiping assay. Arteriolar TRPV1-mediated smooth muscle specific responses (arteriolar diameter, changes in intracellular Ca(2+)) were determined in isolated, pressurized skeletal muscle arterioles obtained from the rat and wild-type or TRPV1(-/-) mice and in canine isolated smooth muscle cells. The vascular pharmacology of the TRPV1 agonists (potency, efficacy, kinetics of action and receptor desensitization) was determined in rat isolated skeletal muscle arteries. KEY RESULTS: Capsaicin evoked a constrictor response in isolated arteries similar to that mediated by noradrenaline, this was absent in arteries from TRPV1 knockout mice and competitively inhibited by TRPV1 antagonist AMG9810. Capsaicin increased intracellular Ca(2+) in the arteriolar wall and in isolated smooth muscle cells. The TRPV1 agonists evoked similar vascular constrictions (MSK-195 and JYL-79) or were without effect (resiniferatoxin and JYL-273), although all increased the number of responses (sensory activation) in the eye wiping assay. Maximal doses of all agonists induced complete desensitization (tachyphylaxis) of arteriolar TRPV1 (with the exception of capsaicin). Responses to the partial agonist JYL-1511 suggested 10% TRPV1 activation is sufficient to evoke vascular tachyphylaxis without sensory activation. CONCLUSIONS AND IMPLICATIONS: Arteriolar TRPV1 have different pharmacological properties from those located on sensory neurons in the rat.

Microarray profiling reveals that placental transcriptomes of early-onset HELLP syndrome and preeclampsia are similar.

BACKGROUND: The involvement of the placenta in the pathogenesis of preeclampsia and HELLP syndrome is well established, and placental lesions are also similar in these two syndromes. Here we aimed to examine the placental transcriptome and to identify candidate biomarkers in early-onset preeclampsia and HELLP syndrome. METHODS: Placental specimens were obtained at C-sections from women with early-onset preeclampsia and HELLP syndrome, and from controls who delivered preterm or at term. After histopathological examination, fresh-frozen placental specimens were used for microarray profiling and validation by qRT-PCR. Differential expression was analysed using log-linear models while adjusting for gestational age. Gene ontology and pathway analyses were used to interpret gene expression changes. Tissue microarrays were constructed from paraffin-embedded placental specimens and immunostained. RESULTS: Placental gene expression was gestational age-dependent among preterm and term controls. Out of the 350 differentially expressed genes in preeclampsia and 554 genes in HELLP syndrome, 224 genes (including LEP, CGB, LHB, INHA, SIGLEC6, PAPPA2, TREM1, and FLT1) changed in the same direction (elevated or reduced) in both syndromes. Many of these encode proteins that have been implicated as biomarkers for preeclampsia. Enrichment analyses revealed similar biological processes, cellular compartments and biological pathways enriched in early-onset preeclampsia and HELLP syndrome; however, some processes and pathways (e.g., cytokine-cytokine receptor interaction) were over-represented only in HELLP syndrome. CONCLUSION: High-throughput transcriptional and tissue microarray expression profiling revealed that placental transcriptomes of early-onset preeclampsia and HELLP syndrome largely overlap, underlying a potential common cause and pathophysiologic processes in these syndromes. However, gene expression changes may also suggest a more severe placental pathology and pronounced inflammatory response in HELLP syndrome than in preeclampsia.

Natural radioactivity in the soils of some eastern counties of Hungary.

Soil samples were collected from six East-Hungarian counties at 98 different sites and the radionuclides (238)U, (226)Ra, (232)Th and (40)K were determined in these samples by gamma spectrometry. The means and ranges of the activity concentrations obtained for the above isotopes were 33.3 (6-68), 29.7 (10-61), 32.1 (9-56) and 418 (218-670) Bq kg(-1) (dry mass), respectively. Significant differences between certain counties were revealed. (226)Ra/(238)U activity ratio <1 was found at near-river sites lying on the plain terrain. The results were compared with those of the only nationwide survey published for Hungary till now. The mean activity concentrations obtained in this work for the East-Hungarian counties were slightly lower than those resulted for the whole country in the nationwide survey. Its main reason is possibly the different average geological character of the two areas. The computed mean terrestrial absorbed dose rate in air in the East-Hungarian region is 41.0 nGy h(-1).

Incidence of chromosomal abnormalities in the presence of fetal subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops.

INTRODUCTION: The authors investigated the incidence of chromosomal abnormalities in subcutaneous oedema detected in the fetus by intrauterine ultrasonography. MATERIAL AND METHOD: In the 10-year period, intrauterine karyotyping was performed in pregnancies with positive ultrasound findings for subcutaneous oedema, such as nuchal oedema, cystic hygroma and non-immune hydrops. RESULTS: Intrauterine karyotyping in fetal subcutaneous oedema was carried out in 434 cases. The chromosomal investigation was made in nuchal oedema in 374 cases, in 120 patients the chromosomal examination was made in the first trimester because of nuchal translucency, and in 254 cases in the second trimester because of nuchal thickening. Cystic hygroma cases (27 patients), non-immune hydrops cases (20 patients), and combined cases of non-immune hydrops and cystic hygroma (13 patients) were investigated separately. In nuchal oedema, pathological karyotypes were detected in 8.33% in the first trimester and in 5.51% in the second trimester. Chromosomal abnormality was found in 48.15, 20, and 53.8% in cystic hygroma, non-immune hydrops, and combined occurrence of non-immune hydrops and cystic hygroma, respectively. Considering all of the changes accompanied by subcutaneous oedema, 50, 25 and 18.75% of the pathological karyotypes was X-monosomy, trisomy 18 and trisomy 21, respectively. DISCUSSION: It was important to distinguish nuchal oedema and cystic hygroma, and in the case of non-immune hydrops, it was also important to discuss cases with or without cystic hygroma separately. During the investigations, cases of non-immune hydrops with or without cystic hygroma were evaluated as separate categories. CONCLUSIONS: The authors emphasize the differentiation of the various types of subcutaneous oedema and the importance of precise information about the risks, provided during genetic counselling.

Whole blood chemiluminescence response in broiler chickens on different experimental diets and challenged with Clostridium perfringens.

UNLABELLED: 1. OBJECTIVES: To validate the whole blood chemiluminescence (WBCL) assay in chickens, a simple and rapid method of measuring production of reactive oxygen species by circulating polymorphonuclear (PMN) leukocytes. To determine the physiological response and innate immune response associated with oral challenge with Clostridium perfringens in broiler chickens under different nutritional conditions. 2. In Experiment 1, birds were orally challenged with C. perfringens 1. type A or sham-challenged saline on days 14-21 post-hatch and fed protein-balanced diets containing 160 or 180 g crude protein/kg and 0.98 or 1.75% glycine in a 2 x 2 x 2 factorial arrangement of treatments. 2. Challenged birds had higher WBCL responses and more severe intestinal lesions than unchallenged birds. Birds fed diets containing 1.75% glycine had more intestinal lesions than those fed 0.98% glycine. 3. In Experiment 2 birds were fed protein-balanced diets containing 0.76, 2.10, 3.43 or 4.77% glycine. The birds fed 0.76% glycine diet had lower WBCL responses compared to birds fed the other three diets. Intestinal lesions were worse in the birds fed the highest, 4.77% glycine diet than in those fed the 0.76 or 2.10% glycine diets. 4. We conclude that the WBCL assay is a practical and sensitive means of assessing innate immune function in birds. The results suggest that both bacterial challenge and glycine content of chickens' diet influence their lesion scores and innate immune function.

Analysis of perioperative morbidity according to whether the uterine cavity is opened or remains closed during abdominal myomectomy--results of 423 abdominal myomectomy cases.

UNLABELLED: For women who desire pregnancy or who wish to retain their uterus, myomectomy is the standard approach for the treatment of fibroids. Abdominal myomectomy seems to be the best choice when there are large subserosal or intramural fibroids (> 5-7 cm), or submucosal fibroids > 3 cm or when multiple fibroids (> 3) are to be removed. When submucosal myomas are present or multiple fibroids are to be removed, opening the uterine cavity during the surgical procedure is more likely to happen. There is lack of published evidence about whether there is any difference in perioperative morbidity and management of those cases where the uterine cavity is opened during the surgical procedure compared with those where the uterine cavity remains closed. METHODS: We undertook a retrospective review of 423 abdominal myomectomies via either an opened or closed uterine cavity. As a primary outcome we assessed the overall perioperative morbidity rate and as a secondary outcome we compared the necessity of pre and postoperative transfusions, intraoperative bleeding, febrile morbidity, unintended surgical interventions, life-threatening events, need for relaparotomies and duration of hospital stay between the opened and non opened uterine cavity groups. RESULTS: The overall perioperative morbidity rate was significantly higher in those cases where the uterine cavity was opened during surgery; however the difference was caused only by the increased risk of intraoperative bleeding. All the other variables, such as febrile morbidity, number of relaparotomies, unintended surgical procedures and life-threatening events did not differ between the two groups. CONCLUSION: Although there is an increased risk of intraoperative bleeding it seems that entering the uterine cavity during abdominal myomectomy can be considered as safe a procedure as in those cases where the uterine cavity remains closed.

Lean birds in the city: body size and condition of house sparrows along the urbanization gradient.

1. Urbanized habitats differ from natural ones in several ecological features, including climate, food availability, strength of predation and competition. Although the effects of urbanization on avian community composition are well known, there is much less information about how individual birds are affected by these human-generated habitat differences. 2. In this study we investigated the relationships between the morphological characteristics and the degree of habitat urbanization in house sparrows, Passer domesticus (Linne 1758) . We collected data for more than 1000 non-breeding adult birds in Hungary between 1997 and 2006, from seven sites including farmlands, suburban areas and city centres. 3. We found that the body mass, tarsus length and body condition of free-living sparrows differed among the sites: birds in more urbanized habitats were consistently smaller and in worse condition than birds in more rural habitats. A composite measure of habitat urbanization (based on building density, road density and vegetation cover) explained over 75% of variance between sites in the studied traits, after we controlled for the effects of sex, year, season and time of capture. 4. The difference in body mass between rural and urban sparrows was significant when birds were kept in aviaries under identical conditions, with constant ad libitum food availability. It is therefore unlikely that the reduced body size and condition of urban sparrows are a consequence of reduced access to food for adults (e.g. due to strong competition), or their short-term responses to high food predictability (e.g. by strategic mass regulation). 5. We suggest that habitat differences in nestling development or adaptive divergence of sparrow populations due to distinct environmental conditions (such as differing predation pressure) may account for the differences along the urbanization gradient.

Prenatal diagnosis of abnormal course of umbilical vein and absent ductus venosus--report of three cases.

An abnormal course of the umbilical vein is a rare anomaly. Its association with the congenital absence of the ductus venosus is common. We found 3 cases of an abnormal course of the umbilical vein and an absent ductus venosus. In 2 of these cases, the umbilical vein turned down and continued in the internal iliac vein, and no ductus venosus was found. One of these pregnancies was terminated. From the continued pregnancy a growth-retarded baby was born. At follow-up examinations, mild microcephaly, mildly elevated levels of ammonia, delayed speech and mild muscular hypotonia were found. In the third case, the umbilical vein turned up from the level of umbilical ring and the anterior of the liver above the diaphragma and connected directly into the right atrium. Associated complex congenital heart malformations - transposition of the great arteries, and ventricular septal defect - were diagnosed prenatally. In the umbilical vein from the placenta to the umbilical ring, the flow was low velocity continuous; from the umbilical ring to the right atrium, the flow was biphasic high velocity (90 cm/s). Such an elevated blood flow could be a sign of increased cardiac preload. The long-term neurological follow-up of babies with prenatally diagnosed venous malformations is necessary.

Variation of indoor radon progeny concentration and its role in dose assessment.

Instantaneous measurements of equilibrium equivalent concentration of radon (EEC(Rn)) were taken over a period of 1 year in 2004 in a typical house at Amritsar city, located in the northwest part of India. A method based on absolute beta counting subsequent to grab aerosol sampling was used. During that year, EEC(Rn) varied between 1.56B qm(-3) and 22.77B qm(-3) with average value of 8.76Bb qm(-3). EEC(Rn) decreased with the transition from winter to summer and vice versa, having a negative correlation with outdoor temperature. The use of mechanical ventilation, under normal living conditions during summer, caused an extra decrease in the concentrations. The variations with temperature and mechanical ventilation are discussed. Some major issues related to the uncertainties in dose calculations caused by the lack of knowledge of equilibrium factor and ignoring the effect of life style on the radon and its progeny concentrations are discussed.

Chlamydia trachomatis infection, Fallopian tube damage and a mannose-binding lectin codon 54 gene polymorphism.

BACKGROUND: Mannose-binding lectin (MBL), a component of the innate immune system, provides a first-line defense against invading microorganisms. Polymorphisms in the MBL gene have been associated with increased risk of infection. Chlamydia trachomatis genital tract infections are a major cause of Fallopian tube occlusion. Our objective was to test whether an MBL codon 54 polymorphism might contribute to development of C. trachomatis-associated tubal damage. METHODS: In a case-control study, 97 women with occluded and 104 women with patent Fallopian tubes were tested for a history of chlamydial infection by serology and for their MBL codon 54 genotype by PCR and restriction fragment length polymorphism analysis. Clinical data were blinded to those performing all laboratory analyses. RESULTS: Women with tubal occlusion who also had a positive chlamydial serology had the highest rate of variant MBL B allele carriage (P<0.001). Among women who were chlamydial antibody negative, allele B carriage was also more frequent in those with blocked, as opposed to patent, Fallopian tubes (P<0.01). CONCLUSIONS: Wild-type allele A homozygosity is protective against, while carriage of the variant allele B is a risk factor for, Fallopian tube occlusion in women who are seropositive or seronegative for C. trachomatis.

Natural origins of off-flavours in fish related to feeding habits.

The objective of our study was to survey the accumulated 2-methylisoborneol (MIB) and geosmin (GSM) in fillets of five important farmed fish species in Hungarian aquaculture in relation to MIB and GSM concentrations in water and sediment in the aquatic systems where they were raised: (the planktivorous silver carp (Hypophthalmichthys molitrix), the herbivorous grass carp (Ctenopharyngodon idella), the bottom-feeding omnivorous common carp (Cyprinus carpio), the omnivorous tilapia (Oreochromis niloticus) and the carnivorous African catfish (Clarias gariepinus)). Water, sediment and fish samples were collected from different experimental aquatic systems which included a combined aquaculture-algae (CAA) system, effluent-fed fishponds, a pond recycling system and a traditional fishpond. MIB and GSM contents were extracted with distillation-headspace solid-phase-microextraction (SPME) and extracts analysed by GC-MS. Results showed that off-flavour contents in fish fillets were related to the feeding habits of the studied fish species. Higher GSM concentrations were found in the fillet of bottom-feeding common carp than in the silver carp or African catfish in all studied aquatic systems. Usually, low GSM concentrations were detected in the water of fishponds but sometimes the levels of this odour compound in carp fillet were well above the limits of human detection. This suggests that the off-flavour tainting of common carp may originate from the sediment or benthic algallactinomycete sources. Negligible MIB levels were found in all samples in all of the studied aquatic systems.

Spinal anesthesia for cesarean section in a woman with Kartagener's syndrome and a twin pregnancy.

Kartagener's syndrome is an inherited disease characterized by a triad of symptoms: bronchiectasis, situs inversus and sinusitis resulting from defective cilial motility. There are few reports in the literature regarding the optimum anesthetic technique in patients with Kartagener's syndrome. The main anesthetic considerations are related to the respiratory system and increased risk of infection. We report the case of a woman with Kartagener's syndrome and a twin pregnancy conceived by in-vitro fertilization-embryo transfer, who underwent cesarean section under spinal anesthesia. Despite recurrent pulmonary problems, the twin pregnancy resulted in a successful outcome. This was facilitated by a close working relationship between the obstetrician, anesthesiologist and patient.

Mannose-binding lectin (MBL) codon 54 gene polymorphism protects against development of pre-eclampsia, HELLP syndrome and pre-eclampsia-associated intrauterine growth restriction.

Insufficient invasion of the spiral arteries by trophoblast cells is associated with the etiology of pre-eclampsia, the syndrome of hemolysis, elevated liver enzymes and low platelet counts (HELLP) and pre-eclampsia-associated intrauterine growth restriction (IUGR). Mannose-binding lectin (MBL) is a component of the innate immune system. MBL-mediated activation of the complement cascade is an important event in the destruction of invading trophoblasts. The gene coding for MBL is polymorphic, and variant alleles result in greatly reduced circulating MBL levels. The aim of this study was to test the association between an MBL polymorphism and pre-eclampsia, HELLP syndrome and IUGR. DNA was extracted from buccal swabs of 51 women with pre-eclampsia, 81 women with HELLP syndrome and 184 healthy pregnant controls. Aliquots were tested for a single nucleotide MBL gene polymorphism at codon 54 by PCR and endonuclease digestion. Homozygosity for the wild-type allele was more frequent in patients with pre-eclampsia (P = 0.04) and HELLP syndrome (P = 0.02) when compared with controls. The presence of the variant allele was more prevalent among controls than in women with pre-eclampsia (P = 0.02) or HELLP syndrome (P = 0.028). Twenty-two (55%) patients with pre-eclampsia and 43 (53%) women with HELLP syndrome delivered an IUGR neonate. MBL-54 heterozygosity was more frequent in controls (27.2%) than in pre-eclamptic women (4.5%, P = 0.025) and those with HELLP syndrome (11.7%, P = 0.05) who delivered an IUGR neonate. Genotype frequencies of neonates born to mothers in all study groups were similar. Carriage of the MBL codon 54 polymorphism protects against pre-eclampsia, HELLP syndrome and IUGR and implies that an MBL-mediated event might be involved in the pathogenesis of these disorders.