About some symmetries of negation

This paper deals with some structural properties of the sequent calculus and describes strong symmetries between cut-free derivations and derivations, which do not make use of identity axioms. Both of them are discussed from a semantic and syntactic point of view. Identity axioms and cuts are closely related to the treatment of negation in the sequent calculus, so the results of this article explain some nice symmetries of negatio

Prävention von Frühgeburten

Zusammenfassung: Die Frühgeburt stellt heute, obwohl große Fortschritte im medizinisch-technischen Bereich gemacht wurden, immer noch eine Hauptursache der perinatalen Mortalität und Morbidität dar. Trotz intensiver Bemühungen im therapeutischen Bereich ist die Rate der Frühgeburten in den westlichen Ländern stabil oder - wie in den USA - sogar ansteigend. Präventive Maßnahmen rücken deswegen immer stärker in den Blickpunkt. In der vorliegenden Übersichtsarbeit werden basierend auf randomisierten oder Beobachtungsstudien die aktuellen Strategien zur Prävention diskutiert. Nach den derzeit vorliegenden Metaanalysen wird die perinatale Morbidität durch präventive Maßnahmen nicht verbessert, wohl aber das Gestationsalter verlängert. Was dies an Vorteilen für das Neugeborene bringt, bleibt zu kläre

A Quantitative Phenytoin GC-MS Method and its Validation for Samples from Human ex situ Brain Microdialysis, Blood and Saliva Using Solid-Phase Extraction

This study describes the development and validation of a gas chromatography-mass spectrometry (GC-MS) method to identify and quantitate phenytoin in brain microdialysate, saliva and blood from human samples. A solid-phase extraction (SPE) was performed with a nonpolar C8-SCX column. The eluate was evaporated with nitrogen (50°C) and derivatized with trimethylsulfonium hydroxide before GC-MS analysis. As the internal standard, 5-(p-methylphenyl)-5-phenylhydantoin was used. The MS was run in scan mode and the identification was made with three ion fragment masses. All peaks were identified with MassLib. Spiked phenytoin samples showed recovery after SPE of ≥94%. The calibration curve (phenytoin 50 to 1,200 ng/mL, n = 6, at six concentration levels) showed good linearity and correlation (r2 > 0.998). The limit of detection was 15 ng/mL; the limit of quantification was 50 ng/mL. Dried extracted samples were stable within a 15% deviation range for ≥4 weeks at room temperature. The method met International Organization for Standardization standards and was able to detect and quantify phenytoin in different biological matrices and patient samples. The GC-MS method with SPE is specific, sensitive, robust and well reproducible, and is therefore an appropriate candidate for the pharmacokinetic assessment of phenytoin concentrations in different human biological sample

Advances in therapeutic drug monitoring with a focus on phenytoin analysis

With the growing demand for a therapeutic drug monitoring (TDM) in clinical laboratories the development of appropriate and improved analytical methods to monitor drug concentrations and optimize patient care has become imperative. This dissertation contributes in this regard by developing sensitive, specific, and reliable GC-MS and LC-MS/MS methods to measure drug concentrations and validating them according to the FDA Guidance for Industry. The methods are performed based on the example of the critical dose drug phenytoin (PHT), which has characteristics – such as a small therapeutic range, nonlinear pharmacokinetics, interactions with other drugs, inter-individual genetic differences in the metabolism, and long-term therapy – that render it a highly suitable model substance and a reliable standard for the development and application of analytical methods to measure concentrations also of other medications. Both methods allow the measurement of low drug concentrations in different body compartments (i.e., blood, saliva, and samples from brain tissue microdialysis with relatively small sample volumes) and therefore could be used to measure drug concentrations in the compartment of interest for various other drugs. By systematically comparing the two methods, the dissertation concludes that although GC-MS is a sensitive and suitable method (e.g., for the measurement of volatile and thermally stable substitutes in a sample), the LC-MS/MS method offers significant advantages (in terms of its sensitivity, LOD/LOQ, needed sample volume, sample preparation, analysis time, and costs), which make it highly suitable for larger sample numbers as in pharmacokinetic/pharmacodynamic studies as well as for bedside and routine analyses. While these findings are based on the model substance PHT, other promising drugs for TDM are, for example, Midazolam, Ceftriaxon, Morphine, and Levatiracitam, which are often administered concomitantly in neurosurgery. In the future, the routinely used matrices (i.e., blood or urine) for TDM will be expanded with other sample sources like tissue biopsies, dried blood spots, and oral fluids. LC-MS/MS methods provide the advantage of drug quantification in such matrices which are easier to handle. Thus, the dissertation concludes that LC-MS/MS methods are the current gold standard for TDM. Furthermore, in this dissertation also a theoretical estimation method to calculate free drug concentrations has been tested, which could be used in the absence of corresponding lab methods or data – not every hospital or institution is able to afford a LC-MS/MS or a GC-MS instrument. The dissertation tested the usefulness of the Sheiner-Tozer algorithm for the correct estimation of the free PHT concentrations in hypoalbuminemic patients and compared the estimated with the measured free PHT levels. There were no statistically significant differences between the two methods and the estimated values highly correlated with the measured free PHT values. The results support the usefulness of the Sheiner-Tozer formula to calculate free PHT concentrations from the total PHT and the serum albumin value of a patient. These findings are of interest for all drugs with a high albumin binding such as immunosuppressants, antibiotics, or anticancer drugs

Identification of antenatal depression in obstetric care

Purpose: Detection rates of depression in obstetric care are generally low, and many women remain undiagnosed and do not receive adequate support. In many obstetric settings, screening tools for depression are not applied routinely and there is a great need to sensitize health care professionals for the patient at risk for enhanced levels of depression. The present study aimed at identifying commonly assessed patient characteristics that are associated with antenatal depression. Methods: One hundred and thirty seven women were screened using the Edinburgh Postnatal Depression Scale (EPDS) at the beginning of the second trimester at the outpatient department of a Tertiary University Hospital. Women were identified as at high risk for depression if scores were above a cut-off score of twelve. Obstetric history and outcome were extracted from patient files after delivery. Results: Twenty one percent of the sample screened as depression positive. Logistic regression with backwards elimination showed that the triad of nausea during pregnancy, reports of (premature) contractions and consumption of analgesics during pregnancy significantly predicted high depression scores with a positive predictive value of 84.3%. The relative risk for a depressed pregnant woman to regularly take analgesics during pregnancy was fourfold higher than for non-depressed women. Conclusions: If depression screening is not part of routine prenatal care, systematic assessment of depression should be targeted for patients presenting with the markers identified in this stud

Hyvä huutoääni - Eliittiäänenkäyttäjien huutostrategiat ja niiden perkeptuaalinen arviointi

Tutkimuksen tarkoituksena oli selvittää hyvän huutoäänen piirteet tutkimalla eliittiäänenkäyttäjien huutoäänen akustisia piirteitä sekä äänihuulivärähtelyn laatua. Lisäksi pyrittiin selvittämään, miten instrumentaaliset mittaustulokset korreloivat perkeptuaalisesti hyväksi arvioidun huutoäänen kanssa. Koehenkilöinä oli viisi miestä ja viisi naista, jotka olivat kaikki eliittiäänenkäyttäjiä eli koulutukseltaan joko näyttelijöitä tai laulajia. Koehenkilöiltä mitattiin matalin mahdollinen ääni sekä puheäänenkuvaajaa varten hiljainen, normaali, voimistettu ja huutoääni [pa:]-äännettä käyttäen. Perkeptuaalista arviointia varten äänitettiin erillinen huudon luentanäyte, joka oli katkelma Shakespearen Kuningas Lear -näytelmästä. Näytteistä mitattiin EGG-signaali ja tehtiin akustiset analyysit (F0, SPL, alfa-ratio) sekä LTAS-spektrit. Hyvän huutoäänen perkeptuaalisten piirteiden selvittämiseksi järjestettiin kuuntelukoe 11 hengen asiantuntijaraadille. Kuuntelijat arvioivat äänestä 12 piirrettä, joissa arvioitiin yleistä äänivaikutelmaa, äänihuulitason toimintaa sekä tarkoituksenmukaista äänenkäyttöä. Arvioista laskettiin keskiarvot ja näytteet laitettiin paremmuusjärjestykseen kokonaislaatupisteiden perusteella. Pisteiden perusteella tutkittiin instrumentaalisten tutkimustulosten korrelointia kuuntelija-arvioiden kanssa. Miesäänten spektrimuodoilla oli yhtä näytettä lukuun ottamatta havaittavissa yhtenäinen trendi, jossa esiintyi formanttien yhteensulautumista 2-3,5 kHz:n alueella ja tämän jälkeen voimakas pudotus. Kyseinen ilmiö näkyi erityisen selvästi parhaimmassa miesääninäytteessä. Naisten parhaimpien näytteiden spektreissä esiintyi formanttien voimistumista noin 2,8 kHz:ssä ja 4 kHz:ssä (laulajan- ja puhujanformantit). F0-keskiarvo korreloi molemmilla sukupuolilla alfa-ration kanssa (p < 0,01) eli äänenkorkeuden noustessa spektrin kaltevuus väheni. Alfa-ratio vaikutti pelkästään naisäänten perkeptuaalisiin arvioihin. Korkeammat kuin -2,5 dB olevat alfa-ratiot luokiteltiin liian kirkkaiksi ja korkeiksi, ja niiden tiiviys-, metallisuus- sekä työläysvaikutelmat lisääntyivät, mikä heikensi kokonaislaatupisteitä. CQ:lla oli yhteys molemmilla sukupuolilla hyvän huutoäänen muodostumiseen. Raja-arvona oli 60 %, jonka ylittyessä mm. äänenkorkeus-, tiiviys- ja työläysvaikutelmat lisääntyivät, mikä heikensi kokonaislaatupisteitä. Naisäänten perustaajuus oli myös yhteydessä pidentyneeseen äänihuulten kontaktiaikaan: huudossa F0 korreloi naisilla positiivisesti CQ:n kanssa (p < 0,05), mikä vahvisti aiempia tutkimustuloksia. SPL ei korreloinut minkään toisen akustisen piirteen kanssa, mikä voi viitata siihen, että äänen voimistamisessa on käytetty muita strategioita kuin äänenpainetason nostamista: mahdollisesti äänenkorkeuden nostoa tai formanttituunausta. Perkeptuaalisista arvioista SPL oli yhteydessä molemmilla sukupuolilla perturbaatioihin ja lisäksi miehillä hälypitoisuuteen. Kuuntelija-arvioissa hälypitoisuutta ja perturbaatioita ei aina koettu äänenlaatua huonontavina seikkoina, vaan myös draamallisina tehokeinoina. Naisilla SPL ja F0-keskiarvo korreloivat positiivisesti perkeptuaalisen kuuluvuuden kanssa, miehillä SPL ei korreloinut lainkaan kuuluvuuden kanssa. Kuuluvuuden merkitys hyvän huutoäänen muodostumiseen jäi tässä tutkimuksessa kyseenalaiseksi heikon inter-rater-reliabiliteetin takia. Molemmilla sukupuolilla hyvän huutoäänen tärkeimpiä perkeptuaalisia piirteitä olivat riittävän tumma äänenväri, äänen sijoitus, joka ei ole liian etinen sekä riittävän matala äänenkorkeus. Nämä vaikuttivat useisiin muihin äänenpiirteisiin. Akustisten ja perkeptuaalisten korrelaatioiden perusteella voidaan päätellä, että erityisesti CQ on yhteydessä hyvän huutoäänen muodostumiseen. Myös LTAS-spektrien perusteella oli havaittavissa tietynlaista suuntausta, mutta tämän tutkimuksen perusteella ei voida vielä tehdä lopullisia päätelmiä. Koska huutoääntä tarvitaan useissa ammateissa, eikä aihetta ole tutkittu paljon huutoäänen estetiikan kannalta, aiheesta olisi hyvä tehdä lisää tutkimuksia huutoäänen koulutuksen kehittämiseksi. Potentiaalisia jatkotutkimusaiheita ovat virtauksen ja subglottaalisen paineen vaikutus hyvään huutoääneen, äänenkorkeuden nostaminen voimistusstrategiana sekä ääniväylän erilaiset asetukset huudossa ja niiden viestinnälliset merkitykset

Determination of fetal chromosome aberrations from fetal DNA in maternal blood: has the challenge finally been met?

The analysis of cell-free fetal nucleic acids in maternal blood for prenatal diagnosis has been transformed by several recent profound technology developments. The most noteworthy of these are ‘digital PCR' and ‘next-generation sequencing' (NGS), which might finally deliver the long-sought goal of noninvasive detection of fetal aneuploidy. Recent data, however, indicate that NGS might even be able to offer a much more detailed appraisal of the fetal genome, including paternal and maternal inheritance of point mutations for mendelian disorders such as β-thalassaemia. Although these developments are very exciting, in their current form they are still too complex and costly, and will need to be simplified considerably for their optimal translation to the clinic. In this regard, targeted NGS does appear to be a step in the right direction, although this should be seen in the context of ongoing progress with the isolation of fetal cells and with proteomic screening marker

Role of omega 3-fatty acids and multivitamins in gestation

There is a rising interest in a balanced and varied women's diet not only preconceptionally but also during pregnancy and in the breastfeeding period in order to reduce fetal, neonatal, and maternal risks. A decreased intake of omega 3-fatty acids (FA) or deficiencies of micronutrients are a global health problem, not only in developing countries, where micronutrient-rich food and fortified aliments are often not available, and also in the industrialized world. In contrast to data about the daily periconceptionally intake of folate acid that has been shown to reduce substantially the occurrence and recurrence of neural tube defects (NTD), the benefit of other micronutrients is less determinant. Deficiencies of omega 3-FA may be a contributing factor for severe complications in pregnancy and postpartum. A meta-analysis for the role of omega 3-FA in preeclampsia and maternal postpartum depression is less consistent, some meta-view's results differ substantially or are even contradictory to large observational studies. Further well-designed studies are warranted. A personal interview and counseling concerning the daily diet should be integrated in the preconceptional and in the antenatal care and an individual supplementation should be offered, if indicate

Inhibitory postsynaptic actions of taurine, GABA and other amino acids on motoneurons of the isolated frog spinal cord

The actions of glycine, GABA, α-alanine, β-alanine and taurine were studied by intracellular recordings from lumbar motoneurons of the isolated spinal cord of the frog. All amino acids tested produced a reduction in the amplitude of postsynaptic potentials, a blockade of the antidromic action potential and an increase of membrane conductance. Furthermore, membrane polarizations occurred, which were always in the same direction as the IPSP. All these effects indicate a postsynaptic inhibitory action of these amino acids. When the relative strength of different amino acids was compared, taurine had the strongest inhibitory potency, followed by β-alanine, α α-alanine, GABA and glycine. Topically applied strychnine and picrotoxin induced different changes of postsynaptic potentials, indicating that distinct inhibitory systems might be influenced by these two convulsants. Interactions with amino acids showed that picrotoxin selectively diminished the postsynaptic actions of GABA, while strychnine reduced the effects of taurine, glycine, α- and β-alanine. But differences in the susceptibility of these amino acid actions to strychnine could be detected: the action of taurine was more sensitively blocked by strychnine compared with glycine, α- and β-alanine. With regard to these results the importance of taurine and GABA as transmitters of postsynaptic inhibition on motoneurons in the spinal cord of the frog is discussed