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J Hein

Publications and source records attributed to J Hein.

At least 19 recordsLinked to original sources
PubMed2007

[Alcohol-related disorders: etiopathology and therapeutic considerations].

The scientific understanding of the neurobiological priniciples of alcoholism has made significant progress in recent years. Especially the effects of ethanol on the neurotransmitter-systems are well studied. Dopaminergic and GABAergic facilitation contribute to the stimulating effects of low doses of alcohol while many of its adverse effects are mediated by glutamatergic inhibition at higher doses. A reduced serotonine-metabolism was shown to be a risk factor for the development of an alcohol dependence. The historic success of absinthe is discussed in this context. Absinthe is a mixture of ethanol and thujone, a substance that leads to a GABAergic inhibition as well as a reduced serotonergic responsiveness. Many studies substantiate the role of cannabinoid as well as striatal opiate-receptors in alcohol-related disorders. Neuroimaging studies could prove the important role of the reward system in this connection. Genetic factors were shown to be predisposing, however biological and environmental factors have a regulatory effect on the gene expression. Disturbances of the hpa-axis (hypothalamus-pituitary gland-adrenal cortex) were also shown to play a role in alcohol dependence. The understanding of these neurobiological principles of alcohol-related disorders should contribute to enhance and improve their therapeutic options.

Alcohol-Related Disorders↗
PubMed2004

ParIS Genome Rearrangement server.

SUMMARY: ParIS Genome Rearrangement is a web server for a Bayesian analysis of unichromosomal genome pairs. The underlying model allows inversions, transpositions and inverted transpositions. The server generates a Markov chain using a Partial Importance Sampler technique, and samples trajectories of mutations from this chain. The user can specify several marginalizations to the posterior: the posterior distribution of number of mutations needed to transform one genome into another, length distribution of mutations, number of mutations that have occurred at a given site. Both text and graphical outputs are available. We provide a limited server, a downloadable unlimited server that can be installed locally on any linux/Unix operating system, and a database of mitochondrial gene orders.

Algorithms↗
PubMed2003

An efficient algorithm for statistical multiple alignment on arbitrary phylogenetic trees.

We present an efficient algorithm for statistical multiple alignment based on the TKF91 model of Thorne, Kishino, and Felsenstein (1991) on an arbitrary k-leaved phylogenetic tree. The existing algorithms use a hidden Markov model approach, which requires at least O( radical 5(k)) states and leads to a time complexity of O(5(k)L(k)), where L is the geometric mean sequence length. Using a combinatorial technique reminiscent of inclusion/exclusion, we are able to sum away the states, thus improving the time complexity to O(2(k)L(k)) and considerably reducing memory requirements. This makes statistical multiple alignment under the TKF91 model a definite practical possibility in the case of a phylogenetic tree with a modest number of leaves.

Algorithms↗
PubMed2001

A molecular clock dates the common ancestor of European-type porcine reproductive and respiratory syndrome virus at more than 10 years before the emergence of disease.

The disease caused by porcine reproductive and respiratory syndrome virus (PRRSV) emerged independently and almost simultaneously in Europe (1990) and North America (1987). The original reservoir of the virus and the date it entered the pig populations is not known. In this study, we demonstrate an accurate molecular clock for the European PRRSV ORF 3 gene, place the root in the genealogy, estimate the rate of nucleotide substitution, and date the most recent common viral ancestor of the data set to 1979; more than 10 years before the onset of the European epidemic. Based on these findings, we conclude that PRRSV virus most likely entered the pig population some time before the epidemic emergence of the virus, and hence, that emergence of European-type PRRSV is not the result of a recent species transmission event. Together, our results show that ORF3 sequencing is a valuable epidemiologic tool for examining the emergence and spread of PRRSV in Europe. As such, the panel of well-characterized and highly divergent ORF3 sequences described in this study provides a reference point for future molecular epidemiologic studies.

Animals↗
PubMed2001

Interleukin-12 and interleukin-18 are indispensable for protective immunity against enteropathogenic Yersinia.

Previous results have demonstrated an essential role of gamma interferon (IFN-gamma) in resistance against Yersinia enterocolitica. Hence, we investigated the course of Yersinia infection in mice deficient for the IFN-gamma-inducing cytokines interleukin-12 (IL-12 p40(-/-)) or interleukin-18 (IL-18(-/-)). The experiments described herein argue for a critical role of both cytokines in protective immune responses against this pathogen.

Animals↗
PubMed2001

Comparative efficacy of clarithromycin modified-release and clarithromycin immediate-release formulations in the treatment of lower respiratory tract infection.

BACKGROUND: A modified-release (MR) formulation of clarithromycin, distinct from the extended-release formulation, has recently been developed and has efficacy and tolerability similar to standard immediate-release (IR) clarithromycin, with the advantage of once-daily dosing. OBJECTIVE: The purpose of this study was to compare the efficacy (as measured by relief of clinical symptoms and eradication of specific pathogens) and tolerability of clarithromycin MR 500 mg administered once daily versus clarithromycin IR 250 mg administered twice daily for 5 days. METHODS: In this randomized, double-blind (with matching placebo), parallel-group. multicenter, controlled trial, patients with lower respiratory tract infection were randomized to 1 of 2 treatment regimens: clarithromycin MR 500 mg once daily plus clarithromycin IR 250 mg placebo twice daily or clarithromycin IR 250 mg BID plus clarithromycin MR 500 mg placebo once daily. RESULTS: Statistically equivalent clinical cure and success rates, overall symptomatic improvement, and bacteriologic responses were achieved with both treatments. In the clarithromycin MR group, the clinical cure rate was 72.5% (87/120), and the clinical success rate (cure plus symptomatic improvement) was 97.5% (117/120). Of the 124 patients treated with clarithromycin IR 250 mg BID, 98 (79.0%) achieved a clinical cure, and 120 (96.8%) achieved clinical success. There were no statistically significant between-group differences in clinical cure or success rates. More than 85% of patients in both study groups experienced improvement in dyspnea, cough, wheezing, chest discomfort, fatigue, and fever, and the visual appearance of sputum: these symptoms resolved completely in the majority of patients. Bacteriologic response (efficacy against specific pathogens), which was assessed as an objective efficacy criterion, was assessable for 40 patients treated with clarithromycin MR and 49 patients treated with clarithromycin IR. Bacteriologic eradication of the pretreatment target pathogen was achieved in 95.0% (38/40) of assessable patients treated with clarithromycin MR 500 mg once daily and 91.8% (45/49) of patients treated with clarithromycin IR 250 mg BID. Treatment-related adverse events were mild to moderate in all cases. Nausea (n = 9), diarrhea (n = 6), abdominal pain (n = 5), and gastric pain (n = 3) were the only study drug-related adverse events reported by > or = 1 patient in each treatment arm. Diarrhea was reported only in the clarithromycin IR group (n = 6) (P = 0.029 vs clarithromycin MR). CONCLUSIONS: Clarithromycin MR 500 mg administered once daily for 5 days is as effective and well tolerated as the IR formulation, with the advantage of once-daily dosing and fewer episodes of diarrhea.

Adolescent↗
PubMed2001

Quantification of murine IFN-gamma mRNA and protein expression: impact of real-time kinetic RT-PCR using SYBR green I dye.

Reliable quantification of cytokine mRNA expression is an important technique for analyzing immune responses. Up until now, little to no information has been available as to whether different mRNA quantification techniques lead to similar results. Recently, real time quantitative reverse transcriptase (RT)-PCR using SYBR Green I as a double stranded DNA specific dye has been introduced. This novel method enables simple and rapid measurement of PCR product accumulation during the log-linear reaction phase and obviates the need for expensive hybridization probes. Here, we analyzed murine gamma interferon (IFN)-gamma mRNA expression in splenocytes by this technique in comparison to semiquantitative noncompetitive RT-PCR, Northern blot analysis, and ELISA after stimulation of the cells with interleukin (IL)-12, IL-18 and a combination of both cytokines. The results clearly show that all of the techniques detect differences in the IFN-gamma gene expression induced by these distinctive stimuli qualitatively exactly in the same order. However, real-time kinetic RT-PCR offers several advantages, notably its high sensitivity that allows the detection of basal IFN-gamma mRNA expression in unstimulated samples. In addition it provides the lowest interassay variability of all techniques investigated. Finally, the gene expression measured by this method eliminates any post-PCR manipulations because the PCR product identification can be easily performed by melting curve analysis.

Animals↗
PubMed2001

Recombination, balancing selection and phylogenies in MHC and self-incompatibility genes.

Using a coalescent model of multiallelic balancing selection with recombination, the genealogical process as a function of recombinational distance from a site under selection is investigated. We find that the shape of the phylogenetic tree is independent of the distance to the site under selection. Only the timescale changes from the value predicted by Takahata's allelic genealogy at the site under selection, converging with increasing recombination to the timescale of the neutral coalescent. However, if nucleotide sequences are simulated over a recombining region containing a site under balancing selection, a phylogenetic tree constructed while ignoring such recombination is strongly affected. This is true even for small rates of recombination. Published studies of multiallelic balancing selection, i.e., the major histocompatibility complex (MHC) of vertebrates, gametophytic and sporophytic self-incompatibility of plants, and incompatibility of fungi, all observe allelic genealogies with unexpected shapes. We conclude that small absolute levels of recombination are compatible with these observed distortions of the shape of the allelic genealogy, suggesting a possible cause of these observations. Furthermore, we illustrate that the variance in the coalescent with recombination process makes it difficult to locate sites under selection and to estimate the selection coefficient from levels of variability.

Alleles↗
PubMed2001

A simulation study of the reliability of recombination detection methods.

There exist many methods to detect recombination or mosaic structure in a sample of DNA sequences. But how reliable are they? Four methods were investigated with respect to their power to detect recombination in simulated samples with different amounts of recombination and mutation. In addition, we investigated the impact of the shape of the underlying genealogy on their performances. We found that the methods detected far fewer recombinations than were theoretically possible and that methods based on the principle of incompatibility in general had more power than methods that did not make use of this principle explicitly. This seemed, in particular, to be the case for phylogenies generated under population expansion scenarios which result in long branches at the tips and small deep branches. In addition to the results obtained through simulations, a series of new theoretical results on recombination is presented.

Algorithms↗
PubMed2001

An algorithm for statistical alignment of sequences related by a binary tree.

An algorithm is presented that allows the calculation of the probability of a set of sequences related by a binary tree that has evolved according to the Thorne-Kishino-Felsenstein model (1991) for a fixed set of parameters. There are two ideas underlying this algorithm. Firstly, a markov chain is defined that generates ancestral sequences and their alignment at two neighboring nodes in a tree. Secondly, a stochastic walk on the binary tree, that defines a markov chain generating ancestral sequences and their alignment at the internal nodes in the tree is described. The running time of this algorithm is O(l2 kappa), where l is the geometric average of the sequence lengths and kappa the number of sequences--leaves at the binary tree. This could be improved to O(l kappa).

Algorithms↗
PubMed2000

Statistical alignment: computational properties, homology testing and goodness-of-fit.

The model of insertions and deletions in biological sequences, first formulated by Thorne, Kishino, and Felsenstein in 1991 (the TKF91 model), provides a basis for performing alignment within a statistical framework. Here we investigate this model.Firstly, we show how to accelerate the statistical alignment algorithms several orders of magnitude. The main innovations are to confine likelihood calculations to a band close to the similarity based alignment, to get good initial guesses of the evolutionary parameters and to apply an efficient numerical optimisation algorithm for finding the maximum likelihood estimate. In addition, the recursions originally presented by Thorne, Kishino and Felsenstein can be simplified. Two proteins, about 1500 amino acids long, can be analysed with this method in less than five seconds on a fast desktop computer, which makes this method practical for actual data analysis.Secondly, we propose a new homology test based on this model, where homology means that an ancestor to a sequence pair can be found finitely far back in time. This test has statistical advantages relative to the traditional shuffle test for proteins.Finally, we describe a goodness-of-fit test, that allows testing the proposed insertion-deletion (indel) process inherent to this model and find that real sequences (here globins) probably experience indels longer than one, contrary to what is assumed by the model.

Algorithms↗
PubMed2000

Are there specific disabilities of number processing in adolescent patients with Anorexia nervosa? Evidence from clinical and neuropsychological data when compared to morphometric measures from magnetic resonance imaging.

The cerebral effect of the loss of body weight in Anorexia nervosa (A.n.)--the so-called 'pseudoatrophy'-- is well known and confirmed by several neuroimaging studies. Another subject of intensive research has been whether A.n. leads to specific cognitive impairments, especially of intelligence. However, there are no previous studies on the relations between the cerebral changes, intelligence performance, and disorders of number processing in adolescent patients with A.n. We examined n = 18 inpatients with A.n. (means at admission: age 14.5 years, SD 1.59; BMI 14.9, SD 1.36), diagnosed according to ICD-10 criteria at three different timepoints: at admission to treatment (T1), with 50 % restoration of their normal weight (T2), and with normal weight (T3). At each timepoint, a cerebral MRI scan was obtained. Based on the MRI we determined the volume of the external and internal cerebrospinal fluid cavities, fissures of Sylvius, the surface of mesencephalon and pons, and surface and length of the Corpus callosum. At T1 and T3, a neuropsychological examination was conducted including tests of the general fluid ability and general cristallized ability of intelligence (CFT-20), as well as tests of vocabulary and number processing. The same instruments were given to a group of matched controls (means: age 15.8 years, SD 1.57; BMI 20.5, SD 2.3) at one timepoint. We could show a significant volume difference of the lateral ventricles and the fissure of Sylvius between patients at T, and controls, which abaded with the patient's weight restoration. But a significant surface deficit of the mesencephalon, and less pronounced in the pons, persisted to T3 in patients when compared to controls, suggesting a selectivity of the cerebral changes in A.n. The neuropsychological examinations revealed significant changes in test performance for both the general intelligence test and number processing. At T1 the number processing performance was significantly lower in patients when compared to controls. However, when the patients had restored their normal body weight, we found 2.02 % with a 'severe disorder of arithmetic skills' and 4.45 % with a 'functional disorder of arithmetic skills'. This combined prevalence of 6.47 % of patients with a subnormal arithmetic performance is analogous to that in the normal population.

Adolescent↗
PubMed2000

Neuropsychological differentiation of subnormal arithmetic abilities in children.

For the neuropsychological diagnosis of a Specific disorder of arithmetic skills the standard is defined worldwide by the diagnostic guidelines of the two major classification systems of psychiatric disorders, the ICD- 10 and the DSM-IV, both of which use the discrepancy criterion as the key feature of the diagnosis. It becomes clear that following such guidelines can only mean an extensive diagnostic assessment of patients with subnormal arithmetic abilities, including the social and previous medical history followed by the exclusion of a present disorder or disability, often necessitating laboratory, neuroimaging and neurophysiological tests. In the neuropsychological diagnosis of a Specific disorder of arithmetical skills we found a stepwise approach including previously obtained test results to be most practical and economical. The assessment instruments such as intelligence tests, neuropsychological test batteries, academic achievement tests, specific neuropsychological tests, test batteries for arithmetic abilities or error analysis are discussed. An overview of case studies in the literature is given; however, the overwhelming majority of case reports on patients with arithmetic disabilities are casuistics of adult patients with an acquired loss of arithmetic abilities. The importance of a differentiated neuropsychological diagnosis is demonstrated by four of our own cases: of borderline deficient intelligence, a combined disorder of academic skills, congenital brain dysfunction, and a specific disorder of arithmetic skills. Especially the new quality in assessing arithmetic abilities with the NUCALC battery is demonstrated; diagnostic and therapeutic consequences are discussed.

Adolescent↗
PubMed2000

The specific disorder of arithmetic skills. Prevalence studies in a rural and an urban population sample and their clinico-neuropsychological validation.

There is an often noted lack of research in the field of disorders of arithmetic skills. The present study assessed the prevalence in both an urban and a rural population sample of German schoolchildren, using standardized academic achievement tests. Eight school classes of third graders in each area were examined (n = 181,182; respectively). We found that 6.6 % (n = 12) of the rural and 6.59 % (n = 12) of the urban school children performed significantly worse in arithmetic than in their spelling tests. Since the diagnostic criteria for the Specific disorder of arithmetical skills and their significance are widely discussed, we attempted in a second step of the study to validate the diagnosis of the Specific disorder of arithmetical skills from a neuropsychological and medical viewpoint. For the validation we assessed clinical data, imaging and neurophysiologic studies as well as a neuropsychological test battery. Nine and five of the children, respectively, were available for this further evaluation. Although the majority of these probands (n = 10) had distinct arithmetic deficits, only three of them met the full diagnostic criteria of the ICD-10 for a Specific disorder of arithmetic skills. In a last step, we compared the data of both studies. Our data strongly support a thorough cliniconeurological, neuropsychological and academic assessment of students with a suspected Specific disorder of arithmetic skills. The current diagnostic criteria should be reconsidered and possibly modified towards a more psychopathologic definition. We stress the need that the condition becomes better known among all professions concerned with the care of children, as difficulties with acquiring arithmetic skills should be detected and approached appropriately as early as possible. The imperative demand of future empiric research is emphasized.

Brain↗
PubMed2000

The coalescent with gene conversion.

In this article we develop a coalescent model with intralocus gene conversion. The distribution of the tract length is geometric in concordance with results published in the literature. We derive a simulation scheme and deduce a number of analytical results for this coalescent with gene conversion. We compare patterns of variability in samples simulated according to the coalescent with recombination with similar patterns simulated according to the coalescent with gene conversion alone. Further, an expression for the expected number of topology shifts in a sample of present-day sequences caused by gene conversion events is derived.

Gene Conversion↗
PubMed2000

Consequences of recombination on traditional phylogenetic analysis.

We investigate the shape of a phylogenetic tree reconstructed from sequences evolving under the coalescent with recombination. The motivation is that evolutionary inferences are often made from phylogenetic trees reconstructed from population data even though recombination may well occur (mtDNA or viral sequences) or does occur (nuclear sequences). We investigate the size and direction of biases when a single tree is reconstructed ignoring recombination. Standard software (PHYLIP) was used to construct the best phylogenetic tree from sequences simulated under the coalescent with recombination. With recombination present, the length of terminal branches and the total branch length are larger, and the time to the most recent common ancestor smaller, than for a tree reconstructed from sequences evolving with no recombination. The effects are pronounced even for small levels of recombination that may not be immediately detectable in a data set. The phylogenies when recombination is present superficially resemble phylogenies for sequences from an exponentially growing population. However, exponential growth has a different effect on statistics such as Tajima's D. Furthermore, ignoring recombination leads to a large overestimation of the substitution rate heterogeneity and the loss of the molecular clock. These results are discussed in relation to viral and mtDNA data sets.

Artifacts↗
PubMed2000

Interferon consensus sequence binding protein confers resistance against Yersinia enterocolitica.

Interferon consensus sequence binding protein (ICSBP)-deficient mice display enhanced susceptibility to intracellular pathogens. At least two distinct immunoregulatory defects are responsible for this phenotype. First, diminished production of reactive oxygen intermediates in macrophages results in impaired intracellular killing of microorganisms. Second, defective early interleukin-12 (IL-12) production upon microbial challenge leads to a failure in gamma interferon (IFN-gamma) induction and subsequently in T helper 1 immune responses. Here, we investigated the role of ICSBP in resistance against the extracellular bacterium Yersinia enterocolitica. ICSBP(-/-) mice failed to produce IL-12 and IFN-gamma, but also IL-4, after Yersinia challenge. In addition, granuloma formation was highly disturbed in infected ICSBP(-/-) mice, leading to multiple necrotic abscesses in affected organs. Consequently, ICSBP(-/-) mice rapidly succumbed to acute Yersinia infection. In vitro treatment of spleen cells from ICSBP(-/-) mice with recombinant IL-12 (rIL-12) or rIL-18 in combination with a second stimulus resulted in IFN-gamma induction. In experimental therapy of infected ICSBP(-/-) mice, we observed that administration of rIL-12 induced IFN-gamma production which was associated with improved resistance to Yersinia. In contrast, treatment with rIL-18 failed to enhance endogenous IFN-gamma production but nevertheless reduced bacterial burden in ICSBP(-/-) mice. Although cytokine therapy with rIL-12 or rIL-18 ameliorated the course of Yersinia infection in ICSBP(-/-) mice, both cytokines failed to completely restore impaired immunity. Taken together, the results indicate that the transcription factor ICSBP is essential for efficient host immune defense against Yersinia. These results are important for understanding the complex host immune responses in bacterial infections.

Animals↗