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Biomedical subjects

P Franke

Publications and source records attributed to P Franke.

At least 19 recordsLinked to original sources
PubMed2006

Rgs 2 gene polymorphisms as modulators of anxiety in humans?

Rgs2 (regulator of G-protein signalling 2) gene recently was reported as a quantitative trait gene for anxious behaviour in mice and male Rgs2 knockout mice have been shown to be more anxious than wildtype mice. Therefore we investigated four non-coding single nucleotide polymorphisms in a sample of 173 patients with panic disorder and 173 matched controls of German descent. At the genotype level all four SNPs were associated with panic disorder (p = 0.02-0.05). At the haplotype level the strongest association was observed for a haplotype containing SNP3 and SNP 4 (subgroup men and men with agoraphobia: p = 0.01 and 0.03). This points towards a functional polymorphism at the 3' end of the gene. Our results support the hypothesis that variations of the Rgs2 gene play a role also for the development of anxiety in humans.

Agoraphobia↗
PubMed2004

Genetic analysis of the biosynthesis of non-ribosomal peptide- and polyketide-like antibiotics, iron uptake and biofilm formation by Bacillus subtilis A1/3.

The Bacillus subtilis strain A1/3 shows exceptionally diverse antibiotic capacities compared to other B. subtilis strains. To analyze this phenomenon, mutants for the putative pantotheinyltransferase gene (pptS), and for several genes involved in non-ribosomal peptide synthesis and polyketide synthesis were constructed and characterized, using bioassays with blood cells, bacterial and fungal cells, and mass spectrometry. Among at least nine distinct bioactive compounds, five antibiotics and one siderophore activity were identified. The anti-fungal and hemolytic activities of strain A1/3 could be eliminated by mutation of the fen and srf genes essential for the synthesis of fengycins and surfactins. Both pptS- and dhb -type mutants were defective in iron uptake, indicating an inability to produce a 2,3-dihydroxybenzoate-type iron siderophore. Transposon mutants in the malonyl CoA transacylase gene resulted in the loss of hemolytic and anti-fungal activities due to the inhibition of bacillomycin L synthesis, and this led to the discovery of bmyLD-LA-LB* genes. In mutants bearing disruption mutations in polyketide (pksM- and/or pksR -like) genes, the biosynthesis of bacillaene and difficidins, respectively, was inactivated and was accompanied by the loss of discrete antibacterial activities. The formation of biofilms (pellicles) was shown to require the production of surfactins, but no other lipopeptides, indicating that surfactins serve specific developmental functions.

Acyl-Carrier Protein S-Malonyltransferase↗
PubMed2004

Association study of serotonin-2A receptor gene polymorphism and panic disorder in patients from Canada and Germany.

The T102C serotonin-2A (5-HT2A) receptor gene polymorphism has been studied extensively in a number of complex psychiatric conditions with mixed results. Recently a genetic association has been described between this polymorphism and panic disorder in a Japanese sample. To evaluate the impact of the T102C polymorphism in panic disorder we genotyped triad families (panic disorder patient and parents), and cases with controls in Canadian and German samples. No significant transmission disequilibrium was observed between the alleles of the T102C 5-HT2A receptor gene polymorphism and panic disorder, nor was a significant excess of either allele found in the case control analysis. Our data suggest thus that this polymorphism is unlikely to play a major role in the pathogenesis of panic disorder.

Alleles↗
PubMed2004

Cholecystokinin- and cholecystokinin-B-receptor gene polymorphisms in panic disorder.

Panic disorder like other neuropsychiatric disorders is believed to be caused by multiple psychosocial and biological factors. Several lines of evidence point to a role for the peptide neurotransmitter cholecystokinin in the pathogenesis of panic disorder. We therefore determined the allele and genotype frequencies of a single nucleotide polymorphism in the CCK gene (-36C>T) and one CT repeat polymorphism in the CCK-B-receptor gene in a German panic disorder sample (n = 115 for CCK gene polymorphism, n = 111 for CCK-B-receptor polymorphism) and compared them with gender and age matched controls. The length of the polymorphic CT repeat alleles varies between 146 bp and 180 bp. We first analysed the results by a permutation test which provided evidence for heterogeneity between patients and controls (p=0.002). We then analysed the data as a di-allelic polymorphism with a short (146-162bp) and a long (164-180bp) allele and as a tetra-allelic polymorphism with 4 alleles (146-154bp, 156-162bp, 164-170bp, 172-180bp). In the di-allelic analysis as well as in the tetra-allelic analysis there was an excess of the longer allele (p = 0.001) or the two longer alleles (p = 0.041) respectively in patients with panic disorder. No difference between groups was observed for the -36C > T polymorphism. Our findings are consistent with the notion that genetic variation in the CCK neurotransmitter system contributes to the pathogenesis of panic disorder.

Adult↗
PubMed2003

Human nuclear transcription factor gene CREM: genomic organization, mutation screening, and association analysis in panic disorder.

Panic disorder is an anxiety disorder with an estimated heritability of 48%. Variation in the gene of the nuclear transcription factor "cAMP-responsive element modulator" (CREM) might contribute to its pathogenesis. CREM knock-out mice exhibit significantly less anxiety behavior than wild-type mice and the alternative CREM gene product "inducible cAMP early repressor" (ICER) plays a pivotal role in the hypothalamo-pituitary-adrenal (HPA) axis, which is disturbed in panic disorder. We characterized the genomic organization of the human CREM gene and performed a systematic mutation screening by means of single stranded conformational analysis (SSCA) in a sample of 40 German patients with panic disorder (DSM-III-R). Four novel single nucleotide polymorphisms in CREM promoters P 1 and P 4, one trinucleotide (ATT)-repeat polymorphism in CREM promoter P 2-generating the ICER isoform-and a rare amino acid substitution in CREM exon glut 2 were identified. Association analysis in an extended sample of German patients (n = 88) revealed a significant excess of the shorter CREM P 2 promoter eight-repeat trinucleotide allele and of genotypes containing the eight-repeat trinucleotide allele in panic disorder (P = 0.02), in particular in panic disorder without agoraphobia (P = 0.001). A replication study in independent Italian (n = 76) and Spanish (n = 62) samples, however, failed to confirm this observation. This suggests that the CREM P 2 promoter trinucleotide polymorphism is not a major susceptibility factor in the pathogenesis of panic disorder. Functional analysis of the observed CREM P 2 promoter polymorphism as well as studies in independent panic disorder samples are necessary.

Agoraphobia↗
PubMed2003

[Psychiatric comorbidity in risk groups of opioid addiction: a comparison between opioid dependent and non-opioid dependent prisoners (in jail due to the German narcotics law)].

Individuals who do not develop opioid dependence although they have access to opioids might differ with regard to psychiatric risk factors from opioid-exposed subjects who developed opioid dependence. To test this assumption, the present investigation compared individuals who were in jail due to the German "Dangerous Drugs Act" (i. e. particular risk group due to facilitated opioid availability) according to presence or absence of opioid dependence and psychiatric comorbidity in each group. This study design is in line with the assumption that in addition to the (postulated) environmental risk factor of facilitated availability of opioids, psychiatric risk factors enhance the likelihood for the development of opioid dependence. Opioid addicts represent a risk group, not only for other forms of substance dependence, but also psychiatric disorders like anxiety disorders, suicide attempts and specific forms of personality disorders. However the difference between opioid dependent subjects and non-opioid dependent controls was less marked than initially postulated. Alcoholism of non-opioid dependent prisoners also was associated with depressive episodes, anxiety disorders as well as cocaine dependence. Despite the high frequency of life-time psychiatric comorbidity in the opioid dependent sample, this increased comorbidity was not paralleled by psychiatric treatment. In general, the sample of prisoners investigated here, was characterized by a high frequency of psychiatric disorders including substance dependence.

Adult↗
PubMed2002

Norepinephrine transporter gene (NET) variants in patients with panic disorder.

Several lines of evidence suggest that catecholamines, especially norepinephrine, are implicated in the etiology and/or symptomatology of panic disorder (PD). At the cellular level, functional noradrenergic neurotransmission depends on synaptic reuptake of norepinephrine as mediated by the norepinephrine transporter (NET). A pharmacological target of agents with an established anti-panic efficacy, e.g. tricyclic antidepressants, the NET is of particular interest in PD. We investigated the NET gene for the presence of 6 naturally occurring exonic sequence variants, 5 of which give rise to amino acid substitutions (Val69Ile, Thr99Ile, Val245Ile, Val449Ile and Gly478Ser) in a population of 87 patients with PD and 89 healthy controls. Except for a silent substitution (G1287A), overall frequencies of variant alleles were low (< or =0.016). None of the variants under study was found to be associated with PD regardless of an additional diagnosis of agoraphobia.

Amino Acid Substitution↗
PubMed2002

Phenylacetylene macrocycles with two opposing bipyridine donor sites: syntheses, X-ray structure determinations, and Ru complexation.

Reaction of the known macrocycle 1a, which contains two bipyridine units in opposing sides, with two equivalents of [Ru(bipy)2Cl2] furnishes the doubly exocyclically complexed macrocycle 8a in 55% yield. Synthesis of the shape-persistent macrocycle 1c by Hagihara-Sonogashira cross-coupling chemistry of suitably functionalized building blocks is reported. This macrocycle was also converted into a Ru complex (8c). X-ray analysis of single crystals of 1b and 1c shows a layered structure that contains "channels" filled with solvent molecules and parts of the flexible chains, with which the cycle is decorated for solubility reasons.

Journal Article↗
PubMed2002

Unsteady near wall residence times and shear exposure in model distal arterial bypass grafts.

Building on previous studies of unsteady flow within model distal bypass grafts we analyse the near wall residence times and shear exposure in a 45 degrees anastomosis under symmetrical and symmetry breaking geometric configurations. We define residence time as the minimum time for a particle to exit a spherical region and shear exposure as a temporal integral of the Huber-Henky-von-Mises criterion along a particle path over a fixed time interval. Decomposing the pulsatile cycle into four equal intervals we find that the interval of peak residence time in the host vessel is from mid-deceleration to peak diastole and peak diastole to mid-acceleration. The asymmetric model is shown to have a significantly lower residence time during these intervals. Considering the shear exposure prior to the residence time evaluation we determine that a higher average shear exposure exists in the asymmetric model associated with the upstream geometry modification. Analysis of the regions of high residence time and shear exposure suggests that the "toe" region and the interface between the "heel" and bulk flow are more significant than the bed and heel region. Although the asymmetric model considered in this study reduces residence times in the host artery, the product of the measure of shear exposure and residence time is not found to be preferable. If shear exposure were to be considered as an important factor in particle activation, the findings imply that for junction optimisation, greater consideration needs to be given both to the local junction asymmetry and upstream influence on the shear history.

Algorithms↗
PubMed2001

Regulation of glutamate dehydrogenase by reversible ADP-ribosylation in mitochondria.

Mitochondrial ADP-ribosylation leads to modification of two proteins of approximately 26 and 53 kDA: The nature of these proteins and, hence, the physiological consequences of their modification have remained unknown. Here, a 55 kDa protein, glutamate dehydrogenase (GDH), was established as a specific acceptor for enzymatic, cysteine-specific ADP-ribosylation in mitochondria. The modified protein was isolated from the mitochondrial preparation and identified as GDH by N-terminal sequencing and mass spectrometric analyses of tryptic digests. Incubation of human hepatoma cells with [14C]adenine demonstrated the occurrence of the modification in vivo. Purified GDH was ADP-ribosylated in a cysteine residue in the presence of the mitochondrial activity that transferred the ADP-ribose from NAD+ onto the acceptor site. ADP- ribosylation of GDH led to substantial inhibition of its catalytic activity. The stoichiometry between incorporated ADP-ribose and GDH subunits suggests that modification of one subunit per catalytically active homohexamer causes the inactivation of the enzyme. Isolated, ADP-ribosylated GDH was reactivated by an Mg2+-dependent mitochondrial ADP-ribosylcysteine hydrolase. GDH, a highly regulated enzyme, is the first mitochondrial protein identified whose activity may be modulated by ADP-ribosylation.

Adenosine Diphosphate↗
PubMed2001

Nonreplication of association between mu-opioid-receptor gene (OPRM1) A118G polymorphism and substance dependence.

In the present investigation we hypothesized the A118G (Asn40Asp) polymorphism of the mu-opioid receptor gene (OPRM1) as a particular vulnerability factor for heroin and alcohol dependence. Therefore, we tested this hypothesis in two independent large samples by two different methods: a case-control sample (comprising n = 287 heroin and n = 221 alcohol study subjects versus n = 365 nondependent controls) and a family-controlled sample of 111 parent-offspring trios of heroin-dependent study subjects and 75 parent-offspring trios of alcohol-dependent study subjects to avoid stratification artifacts. In both patient samples and by both methods we were unable to corroborate the hypothesis of OPRM1 A118G polymorphism as a particular risk factor for any kind of substance dependence including opioid addiction. In addition, there was no significant association between the endophenotype of the individuals under study (e.g., comorbidity, severity of illness) and a particular genotype of OPRM1.

Adenine↗
PubMed2001

First tryptophan-containing weak neurotoxin from cobra venom.

With the purpose of studying structure-function relationships among weak neurotoxins (called so because of their low toxicity), we have isolated a toxin (WTX) from the venom of cobra Naja kaouthia using a combination of gel-filtration and ion-exchange chromatography. The amino acid sequence of the isolated toxin was determined by means of Edman degradation and MALDI mass spectrometry, the primary structure obtained being confirmed by 1H-NMR in the course of spatial structure analysis. The WTX sequence differs slightly from that of the toxin CM-9a isolated earlier from the same venom (Joubert and Taljaard, Hoppe-Seyler's Z. Physiol. Chem., 361 (1980) 425). The differences include an extra residue (Trp36) between Ser35 and Arg37 as well as interchanging of two residues (Tyr52 and Lys50) in the C-terminal part of the toxin molecule. These changes improve the alignment that can be made with other weak neurotoxin sequences. An extended sequence comparison reveals that WTX is the first case of a tryptophan-containing weak neurotoxin isolated from cobra venom. WTX was found to compete with radioiodinated alpha-bungarotoxin for binding to the membrane-bound nicotinic acetylcholine receptor from Torpedo californica.

Amino Acid Sequence↗
PubMed2001

Association study of the low-activity allele of catechol-O-methyltransferase and alcoholism using a family-based approach.

Catechol-O-methyltransferase (COMT) is a major component of the metabolic pathways of neurotransmitters such as dopamine, adrenaline, and noradrenaline. The activity of COMT is known to vary within the population; it exists in common high- and low-activity forms that are determined by a Val --> Met polymorphism at amino acid position 108/158 (in soluble or membrane-bound COMT). Recently, the low-activity allele was reported to contribute to the development of late-onset alcoholism in men. The present study extends this study by utilizing a family-based association approach, and by including individuals with early-onset alcoholism. Although no significant transmission disequilibrium was found in the overall sample of 70 parent/offspring trios (TDT = 1.43, P = 0.23), we observed a preferential transmission of the low-activity allele to patients with an early onset of disease (n = 32, TDT = 4.83, P = 0.028). Our results provide further evidence for an involvement of the COMT low-activity allele in the development of alcoholism and demonstrate the need for further studies in large samples of alcoholic patients.

Adult↗
PubMed2001

Subcortical correlates of craving in recently abstinent alcoholic patients.

OBJECTIVE: This study investigated functional cerebral correlates of craving in alcoholic patients and examined the state/trait characteristics of the regional cerebral network implicated in craving. METHOD: Functional magnetic resonance imaging (fMRI) was used to map cerebral response elicited by ethanol odor in 10 male patients with alcohol dependence who had undergone detoxification and 10 matched nonpatients. After 3 weeks, during which the patients underwent standardized behavioral therapy with psychopharmacological intervention, all subjects were studied a second time with fMRI to evaluate the effects of therapy on the functional cerebral correlates of craving. RESULTS: In the alcoholic patients, cue-induced craving before treatment elicited activation primarily in the subcortical-limbic region of the right amygdala/hippocampal area and in the cerebellum. After treatment, activation was found in the superior temporal sulcus, while subcortical or cerebellar participation was no longer present. Comparison subjects showed no comparable amygdala or cerebellar activation during ethanol stimulation and demonstrated no change in activation pattern between measurements. CONCLUSIONS: This investigation points to state-dependent neurobiological correlates of cue-induced craving in alcoholic patients and suggests that these correlates can be influenced by therapeutic interventions. The presence of emotional aspects of craving is suggested by amygdala activation.

Adult↗
PubMed2000

Pharmacogenomics and addiction to opiates.

The risk of initiating and maintaining the use of opiates up to the point of abuse and dependence is to a large degree genetically transmitted and is separate from genetic risk factors for addiction to other drugs of abuse. Pharmacogenetic studies have so far focused on obvious candidate genes that are expected to be involved either in the pharmacokinetics or in the pharmacodynamics of opioids in the mesolimbic reward system of the brain. The few findings of a positive allelic association rarely withstand replication in independent case-control or less stratification-prone family-based association samples. A pharmacogenomic approach in the best sense of the word, however, involves an unbiased, genome-wide, parallel search for risk genes and gene expression patterns. So far, only quantitative trait loci mapping studies of inbred rodent strains and differential expression studies using high-density DNA microarrays fulfill these requirements. The present state of pharmacogenomic and pharmacogenetic studies in animals and humans with respect to opiate addiction is reviewed in this paper.

Animals↗