The perils of debt deflation in the Euro area - a multi regime model

Academic research and policy makers in the Euro area are currently concerned with the threat of debt deflation and secular stagnation in Europe. Empirical evidence seems to suggest that secular stagnation and debt deflation in the Euro area may be rather slowly developing. Yet what appears as major peril is that debt deflation with a lack of economic growth, rising real interest rates and further rising debt may trigger household defaults, defaults of firms and banks, rise of risk premia, and default risk of certain sectors of the economy or sovereign defaults. It is this rising default and financial risk then that may lead to a regime change to a slowly moving debt crisis with high financial risk and high financial stress. In order to explore those issues, a macro policy model of Svensson type is introduced, exhibiting a regime of low and high financial stress. Then, a four dimensional multi-regime VAR is employed to an Euro area data set to support the theoretical model and the claim that in particular Southern Euro area countries are affected by debt deflation and financial market stress

Acoustic Pressure Pipette Aspiration Method Combined with Finite Element Analysis for Isotropic Materials

A measurement setup combined with a numerical simulation by a linear finite element analysis is presented as a method to determine the elastic modulus of both artificial and real tissue as a function of frequency. At the end, the future goal is to develop and validate the method to measure the elastic modulus of in-vivo human vocal folds over the human phonation frequency range. In the present study, a miniaturized acoustic pressure pipette aspiration technique is developed to measure the material characteristics of an isotropic silicone specimen with similar characteristics as human vocal folds. In previous studies, friction and compression force effects of the pipette tip wall on the surface of the sample and the radius of the pipette were not investigated. Moreover, the large scale of the measurement setups made them impossible to use for clinical applications. Therefore, two different pipette sample cross-section boundary conditions and two different pipette radii were used. With the aim of ensuring reliable results, we tested our method with pipettes of two different radii on four silicone samples with different consistencies over a frequency range of 50–500 Hz. The simulation verified the measurement results in which the strong dependency of the elastic modulus on the excitation frequency, radius of the pipette, the pipette tip compression force and friction was revealed. By the simulation results, two different frequency dependent equations were developed for calculating elastic modulus of the silicone mixtures in the two cross-section boundary conditions. It was concluded that using a very small gap in between the pipette tip and the specimen can cancel the impact of the pipette tip force and friction which are the major cause of uncertainty. However, if a connection between the pipette and the surface is unpreventable, the contact force should be restricted to be absolutely zero

Long-term neuromuscular sequelae of critical illness

In this observational study, we analyzed the long-term neuromuscular deficits of survivors of critical illness. Intensive care unit-acquired muscular weakness (ICU-AW) is a very common complication of critical illness. Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are two main contributors to ICU-AW. ICU-AW is associated with an increased mortality and leads to rehabilitation problems. However, the long-term outcome of ICU-AW and factors influencing it are not well known. We analyzed the medical records of 490 survivors of critical illness, aged 18-75years and located in the area of the study center. Intensive care unit (ICU) survivors with comorbidities that might influence neuromuscular follow-up examinations, muscle strength, or results of nerve conduction studies, such as renal or hepatic insufficiency, diabetes mellitus, or vitamin deficiency were excluded. A total of 51 patients were finally included in the study. Six to 24months after discharge from the ICU, we measured the Medical Research Council (MRC) sum score, the Overall Disability Sum score (ODSS), and also performed nerve conduction studies and EMG. For all ICU survivors, the median MRC sum score was 60 (range 47-60) and the median ODSS score was 0 (range 0-8). CIP was diagnosed in 21 patients (41%). No patient was diagnosed with CIM. Patients with diagnosis of CIP showed a higher median ODSS scores 1 (range 0-8) versus 0 (range 0-5); p<0.001 and lower median MRC sum scores 56 (range 47-60) versus 60 (range 58-60); p<0.001. The three main outcome variables MRC sum score, ODSS score and diagnosis of CIP were not related to age, gender, or diagnosis of sepsis. The MRC sum score (r=−0.33; p=0.02) and the ODSS score (r=0.31; p=0.029) were correlated with the APACHE score. There was a trend for an increased APACHE score in patients with diagnosis of CIP 19 (range 6-33) versus 16.5 (range 6-28); p=0.065. Patients with the diagnosis of CIP had more days of ICU treatment 11days (range 2-74) versus 4days (range 1-61); p=0.015, and had more days of ventilator support 8days (range 1-59) versus 2days (range 1-46); p=0.006. The MRC sum score and the ODSS score were correlated with the days of ICU treatment and with the days of ventilator support. The neuromuscular long-term consequences of critical illness were not severe in our study population. As patients with concomitant diseases and old patients were excluded from this study the result of an overall favorable prognosis of ICU-acquired weakness may not be true for other patient's case-mix. Risk factors for the development of long-term critical illness neuropathy are duration of ICU treatment, duration of ventilator support, and a high APACHE score, but not diagnosis of sepsis. Although ICU-AW can be serious complication of ICU treatment, this should not influence therapeutic decisions, given its favorable long-term prognosis, at least in relatively young patients with no concomitant disease

Haplotype analysis of the 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C (E429A) polymorphism

BACKGROUND: The polymorphism 5,10-methylenetetrahydrofolate reductase (MTHFR) c.1298A>C is associated with various diseases. 45 DNA samples homozygous for the A allele and 40 DNA samples homozygous for the C allele were taken from healthy German subjects of white Caucasian origin to analyze the haplotype of the two MTHFR c.1298A>C alleles. Samples were genotyped for the polymorphism MTHFR c.677C>T and for the silent polymorphisms MTHFR c.129C>T, IVS2 533G>A, c.1068C>T and IVS10 262C>G. FINDINGS: Haplotype construction revealed that the C-allele of MTHFR c.1298A>C was more frequently observed in cis with c.129T, IVS2 533A, c.677C, c.1068T, and IVS10 262G than expected from a normal distribution. Estimation of the most recent common ancestor with the DMLE + 2.3 program resulted in an estimated age of approximately 36,660 years of the MTHFR c.1298C allele. CONCLUSION: Given that the era from 30,000 to 40,000 years ago is characterised by the spread of modern humans in Europe and that the prevalence of the MTHFR c.1298C allele is significantly higher in Central Europe in comparison to African populations, a selective advantage of MTHFR c.1298C could be assumed, e. g. by adaption to changes in the nutritional environment. The known founder ancestry of the T allele of MTHFR c.677C>T allele, together with the present data suggests that the MTHFR mutant alleles c.677T and 1298C arose from two independent ancestral alleles, that both confer a selective advantage

Homocysteine plasma levels in patients treated with antiepileptic drugs depend on folate and vitamin B12 serum levels, but not on genetic variants of homocysteine metabolism

Background: Antiepileptic drugs (AEDs) are commonly used in the treatment of epilepsy, psychiatric diseases and pain disorders. Several of these drugs influence blood levels of folate and vitamin B12 and, consequently, homocysteine. This may be relevant for AED effects and side effects. However, not only folate and vitamin B12, but also genetic variants modify homocysteine metabolism. Here, we aimed to determine whether there is a pharmacogenetic interaction between folate, vitamin B12 and genetic variants and homocysteine plasma level in AED-treated patients. Methods: In this mono-center study, we measured homocysteine, folate and vitamin B12 plasma levels in a population of 498 AED-treated adult patients with epilepsy. In addition, we analyzed the genotypes of seven common genetic variants of homocysteine metabolism: methylenetetrahydrofolate reductase (MTHFR) c.677C>T and c.1298A>C, methionine synthase (MTR) c.2756A>G, dihydrofolate reductase (DHFR) c.594+59del19bp, cystathionine β-synthase (CBS) c.844_855ins68, transcobalamin 2 (TC2) c.776C>G and methionine synthase reductase (MTRR) c.66G>A. Results: On multivariate logistic regression, folate and vitamin B12 levels, but none of the genetic variants, were predictive for homocysteine levels. Conclusions: These data suggest that, in AED-treated patients, folate and vitamin B12 play important roles in the development of hyperhomocysteinemia, whereas genetic variants of homocysteine metabolism do not and thus do not contribute to the risk of developing hyperhomocysteinemia during AED treatmen

Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample

X-linked adrenoleukodystrophy (X-ALD) is the most common inherited leukodystrophy. Nevertheless, no genotype-phenotype correlation has been established so far. Unidentified modifier genes or other cofactors are suspected to modulate phenotype and prognosis. We recently described polymorphisms of methionine metabolism as possible disease modifiers in X-ALD. To retest these findings, we analyzed 172 new DNA samples of X-ALD patients from different populations (France, Germany, USA, China) by genotyping eight genetic variants of methionine metabolism, including DHFR c.594+59del19bp, CBS c.844_855ins68, MTR c.2756A>G, MTHFR c.677C>T and c.1298A>C, MTRR c.60A>G, RFC1 c.80G>A, and Tc2 c.776C>G. We compared three X-ALD phenotypes: childhood-onset cerebral demyelinating inflammatory type (CCALD; n=82), adulthood onset with focal cerebral demyelination (ACALD; n=38), and adulthood onset without cerebral demyelination (AMN; n=52). The association of genotypes and phenotypes was analyzed with univariate two-sided Pearson's χ 2. In the comparison between AMN and CCALD, the G allele of Tc2 c.776C>G was associated with X-ALD phenotypes (χ 2=6.1; P=0.048). The prevalence of the GG genotype of Tc2 c.776C>G was higher in patients with CNS demyelination compared to those without CNS demyelination (χ 2=4.42; P=0.036). The GG genotype was also more frequent in CCALD compared to AMN (χ 2=4.7; P=0.031). The other polymorphisms did not show any significant associations in this study sample. Whereas the influence of other polymorphisms of methionine metabolism was not confirmed, the present study supports the previously made observation that the Tc2 genotype contributes to X-ALD phenotype generatio

Methionine metabolism in an animal model of sepsis

Background: Sepsis is a disease with high incidence and lethality and is accompanied by profound metabolic disturbances. In mammalian methionine metabolism, S-adenosylmethionine (SAM) is produced, which is important in the synthesis of neurotransmitters and glutathione and as an anti-inflammatory agent. The degradation product and antagonist of SAM is S-adenosylhomocysteine (SAH). In this study, we investigated changes in methionine metabolism in a rodent model of sepsis. Methods: Sepsis was induced in male Wistar rats (n=21) by intraperitoneal injection of bacterial lipopolysaccharide (10mg/kg). Controls (n=18) received vehicle only. Blood was collected by cardiac puncture 24h later. Puncture of the suboccipital fossa was performed to collect cerebrospinal fluid (CSF). Methionine metabolites were measured using stable isotope dilution tandem mass spectrometry. Plasma total homocysteine and cysteine were measured by HPLC using fluorescence detection. Glutathione was assayed using a modified enzymatic microtiter plate assay. Results: We observed significantly higher plasma levels of SAM (p<0.001) and SAM/SAH ratio (p=0.004) in septic animals. In CSF, there was also a trend for higher levels of SAM in septic animals (p=0.067). Oxidative stress was reflected by an increase in the ratio of oxidized/reduced glutathione in septic animals (p=0.001). Conclusions: Sepsis is associated with an increase in SAM/SAH ratio in plasma and CSF in rodents. This indicates an altered methylation potential during sepsis, which may be relevant for sepsis-associated impairment of transmethylation reactions, circulation and defense against oxidative stress. If verified in humans, such findings could lead to novel strategies for supportive treatment of sepsis, as methionine metabolism can easily be manipulated by dietary strategies. Clin Chem Lab Med 2008;46:1398-40

Dynamic Biomechanical Analysis of Vocal Folds Using Pipette Aspiration Technique

The voice producing process is a complex interplay between glottal pressure, vocal folds, their elasticity and tension. The material properties of vocal folds are still insufficiently studied, because the determination of material properties in soft tissues is often difficult and connected to extensive experimental setups. To shed light on this less researched area, in this work, a dynamic pipette aspiration technique is utilized to measure the elasticity in a frequency range of 100–1000 Hz. The complex elasticity could be assessed with the phase shift between exciting pressure and tissue movement. The dynamic pipette aspiration setup has been miniaturized with regard to a future in-vivo application. The techniques were applied on 3 different porcine larynges 4 h and 1 d postmortem, in order to investigate the deterioration of the tissue over time and analyze correlation in elasticity values between vocal fold pairs. It was found that vocal fold pairs do have different absolute elasticity values but similar trends. This leads to the assumption that those trends are more important for phonation than having same absolute values