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1.  Single-cell resolution mapping of neuronal damage in acute focal cerebral ischemia using thallium autometallography 
Neuronal damage shortly after onset or after brief episodes of cerebral ischemia has remained difficult to assess with clinical and preclinical imaging techniques as well as with microscopical methods. We here show, in rodent models of middle cerebral artery occlusion (MCAO), that neuronal damage in acute focal cerebral ischemia can be mapped with single-cell resolution using thallium autometallography (TlAMG), a histochemical technique for the detection of the K+-probe thallium (Tl+) in the brain. We intravenously injected rats and mice with thallium diethyldithiocarbamate (TlDDC), a lipophilic chelate complex that releases Tl+ after crossing the blood–brain barrier. We found, within the territories of the affected arteries, areas of markedly reduced neuronal Tl+ uptake in all animals at all time points studied ranging from 15 minutes to 24 hours after MCAO. In large lesions at early time points, areas with neuronal and astrocytic Tl+ uptake below thresholds of detection were surrounded by putative penumbral zones with preserved but diminished Tl+ uptake. At 24 hours, the areas of reduced Tl+uptake matched with areas delineated by established markers of neuronal damage. The results suggest the use of 201TlDDC for preclinical and clinical single-photon emission computed tomography (SPECT) imaging of hyperacute alterations in brain K+ metabolism and prediction of tissue viability in cerebral ischemia.
PMCID: PMC3887354  PMID: 24129748
cerebral ischemia; diethyldithiocarbamate; histochemistry; potassium; stroke; thallium
2.  Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME 
Godoy, Patricio | Hewitt, Nicola J. | Albrecht, Ute | Andersen, Melvin E. | Ansari, Nariman | Bhattacharya, Sudin | Bode, Johannes Georg | Bolleyn, Jennifer | Borner, Christoph | Böttger, Jan | Braeuning, Albert | Budinsky, Robert A. | Burkhardt, Britta | Cameron, Neil R. | Camussi, Giovanni | Cho, Chong-Su | Choi, Yun-Jaie | Craig Rowlands, J. | Dahmen, Uta | Damm, Georg | Dirsch, Olaf | Donato, María Teresa | Dong, Jian | Dooley, Steven | Drasdo, Dirk | Eakins, Rowena | Ferreira, Karine Sá | Fonsato, Valentina | Fraczek, Joanna | Gebhardt, Rolf | Gibson, Andrew | Glanemann, Matthias | Goldring, Chris E. P. | Gómez-Lechón, María José | Groothuis, Geny M. M. | Gustavsson, Lena | Guyot, Christelle | Hallifax, David | Hammad, Seddik | Hayward, Adam | Häussinger, Dieter | Hellerbrand, Claus | Hewitt, Philip | Hoehme, Stefan | Holzhütter, Hermann-Georg | Houston, J. Brian | Hrach, Jens | Ito, Kiyomi | Jaeschke, Hartmut | Keitel, Verena | Kelm, Jens M. | Kevin Park, B. | Kordes, Claus | Kullak-Ublick, Gerd A. | LeCluyse, Edward L. | Lu, Peng | Luebke-Wheeler, Jennifer | Lutz, Anna | Maltman, Daniel J. | Matz-Soja, Madlen | McMullen, Patrick | Merfort, Irmgard | Messner, Simon | Meyer, Christoph | Mwinyi, Jessica | Naisbitt, Dean J. | Nussler, Andreas K. | Olinga, Peter | Pampaloni, Francesco | Pi, Jingbo | Pluta, Linda | Przyborski, Stefan A. | Ramachandran, Anup | Rogiers, Vera | Rowe, Cliff | Schelcher, Celine | Schmich, Kathrin | Schwarz, Michael | Singh, Bijay | Stelzer, Ernst H. K. | Stieger, Bruno | Stöber, Regina | Sugiyama, Yuichi | Tetta, Ciro | Thasler, Wolfgang E. | Vanhaecke, Tamara | Vinken, Mathieu | Weiss, Thomas S. | Widera, Agata | Woods, Courtney G. | Xu, Jinghai James | Yarborough, Kathy M. | Hengstler, Jan G.
Archives of Toxicology  2013;87(8):1315-1530.
This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
Electronic supplementary material
The online version of this article (doi:10.1007/s00204-013-1078-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3753504  PMID: 23974980
Non-parenchymal cells; Mechanisms of gene regulation; DILI; 3D Models; Cryopreservation; Clearance; Mathematical modeling
3.  Copy number variants in a sample of patients with psychotic disorders: is standard screening relevant for actual clinical practice? 
With the introduction of new genetic techniques such as genome-wide array comparative genomic hybridization, studies on the putative genetic etiology of schizophrenia have focused on the detection of copy number variants (CNVs), ie, microdeletions and/or microduplications, that are estimated to be present in up to 3% of patients with schizophrenia. In this study, out of a sample of 100 patients with psychotic disorders, 80 were investigated by array for the presence of CNVs. The assessment of the severity of psychiatric symptoms was performed using standardized instruments and ICD-10 was applied for diagnostic classification. In three patients, a submicroscopic CNV was demonstrated, one with a loss in 1q21.1 and two with a gain in 1p13.3 and 7q11.2, respectively. The association between these or other CNVs and schizophrenia or schizophrenia-like psychoses and their clinical implications still remain equivocal. While the CNV affected genes may enhance the vulnerability for psychiatric disorders via effects on neuronal architecture, these insights have not resulted in major changes in clinical practice as yet. Therefore, genome-wide array analysis should presently be restricted to those patients in whom psychotic symptoms are paired with other signs, particularly dysmorphisms and intellectual impairment.
PMCID: PMC3404708  PMID: 22848183
schizophrenia; psychotic disorders; microarray; copy number variants; 1q21; 7q11.2; 1p13.3
4.  Stacking faults and superstructures in a layered brownmillerite 
Stacking faults in Ca4Fe2Mn0.5Ti0.5O9 have been examined using X-ray diffraction and high-resolution transmission electron microscopy. Electron diffraction revealed two superstructures with ordered stacking sequences.
Single crystals of Ca4Fe2Mn0.5Ti0.5O9 have been synthesized using a flux method. The structural characterization using single-crystal X-ray diffraction revealed the space group Amma and unit-cell dimensions of a = 5.3510 (6), b = 26.669 (3), c = 5.4914 (6) Å. The structure is isotypic with Sr3NdFe3O9 [Barrier et al. (2005 ▶). Chem. Mater. 17, 6619–6623] and exhibits separated brownmillerite-type layers. One-dimensional diffuse scattering shows that the unit cell is doubled along c by alternating the intra-layer order of tetrahedral chains, causing stacking faults along the b direction. A computer simulation was performed, proving that the observed intensity variations along the diffuse scattering rods originates from two different local structures depending on the configuration of the tetrahedral chains. Selected-area electron diffraction experiments exhibit well ordered regions characterized by satellite reflections corresponding to two different superstructures. Both superstructures can be described using the superspace group A21/m(0βγ)0s, with γ = 0.5 and β ≃ 0.27 or β = 0.
PMCID: PMC3222140  PMID: 22101537
layered brownmillerite; diffuse scattering; stacking faults; modulated structure
5.  Is Ankyrin a genetic risk factor for psychiatric phenotypes? 
BMC Psychiatry  2011;11:103.
Genome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression.
We genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes.
We found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification.
Our results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.
PMCID: PMC3143918  PMID: 21702894
6.  The DAOA/G30 locus and affective disorders: haplotype based association study in a polydiagnostic approach 
BMC Psychiatry  2010;10:59.
The DAOA/G30 (D-amino acid oxidase activator) gene complex at chromosomal region 13q32-33 is one of the most intriguing susceptibility loci for the major psychiatric disorders, although there is no consensus about the specific risk alleles or haplotypes across studies.
In a case-control sample of German descent (affective psychosis: n = 248; controls: n = 188) we examined seven single nucleotide polymorphisms (SNPs) around DAOA/G30 (rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, and rs9558575) for genetic association in a polydiagnostic approach (ICD 10; Leonhard's classification).
No single marker showed evidence of overall association with affective disorder neither in ICD10 nor Leonhard's classification. Haplotype analysis revealed no association with recurrent unipolar depression or bipolar disorder according to ICD10, within Leonhard's classification manic-depression was associated with a 3-locus haplotype (rs2391191, rs1935062, and rs3916966; P = 0.022) and monopolar depression with a 5-locus combination at the DAOA/G30 core region (P = 0.036).
Our data revealed potential evidence for partially overlapping risk haplotypes at the DAOA/G30 locus in Leonhard's affective psychoses, but do not support a common genetic contribution of the DAOA/G30 gene complex to the pathogenesis of affective disorders.
PMCID: PMC2921107  PMID: 20667145
7.  Dental indications for the instrumental functional analysis in additional consideration of health-economic aspects 
Besides clinical and radiological examination instrumental functional analyses are performed as diagnostic procedures for craniomandibular dysfunctions. Instrumental functional analyses cause substantial costs and shows a considerable variability between individual dentist practices.
On the basis of published scientific evidence the validity of the instrumental functional analysis for the diagnosis of craniomandibular dysfunctions compared to clinical diagnostic procedures; the difference of the various forms of the instrumental functional analysis; the existence of a dependency on additional other factors and the need for further research are determined in this report. In addition, the cost effectiveness of the instrumental functional analysis is analysed in a health-policy context, and social, legal and ethical aspects are considered.
A literature search is performed in over 27 databases and by hand. Relevant companies and institutions are contacted concerning unpublished studies. The inclusion criteria for publications are (i) diagnostic studies with the indication “craniomandibular malfunction”, (ii) a comparison between clinical and instrumental functional analysis, (iii) publications since 1990, (iv) publications in English or German. The identified literature is evaluated by two scientists regarding the relevance of content and methodical quality.
The systematic database search resulted in 962 hits. 187 medical and economic complete publications are evaluated. Since the evaluated studies are not relevant enough to answer the medical or health economic questions no study is included.
The inconsistent terminology concerning craniomandibular dysfunctions and instrumental functional analyses results in a broad literature search in databases and an extensive search by hand. Since no relevant results concerning the validity of the instrumental functional analysis in comparison to the clinical functional analysis are found, it is impossible to make relevant statements concerning the underlying research questions.
Studies comparing the instrumental functional analysis to the clinical functional analysis for the diagnosis of craniomandibular dysfunctions are missing. So far the instrumental functional analysis is not systematically and independently validated in comparison to the clinical functional analysis as the reference standard. It is uncertain, whether conducting an instrumental functional analysis with a clinical functional analysis for the diagnostics of craniomandibular dysfunctions is recommendable. Further research is strongly recommended.
PMCID: PMC3010889  PMID: 21289879
craniomandibular dysfunction; instrumental functional analysis; clinical functional analysis; oral medicine; odontology; dentistry; cost-effectiveness; functional analysis; jawborne; dentofacial; mandibular joint; health economics; orthodontics; instruments; diagnosis; mouth
8.  A Recombination Hotspot in a Schizophrenia-Associated Region of GABRB2 
PLoS ONE  2010;5(3):e9547.
Schizophrenia is a major disorder with complex genetic mechanisms. Earlier, population genetic studies revealed the occurrence of strong positive selection in the GABRB2 gene encoding the β2 subunit of GABAA receptors, within a segment of 3,551 bp harboring twenty-nine single nucleotide polymorphisms (SNPs) and containing schizophrenia-associated SNPs and haplotypes.
Methodology/Principal Findings
In the present study, the possible occurrence of recombination in this ‘S1–S29’ segment was assessed. The occurrence of hotspot recombination was indicated by high resolution recombination rate estimation, haplotype diversity, abundance of rare haplotypes, recurrent mutations and torsos in haplotype networks, and experimental haplotyping of somatic and sperm DNA. The sub-segment distribution of relative recombination strength, measured by the ratio of haplotype diversity (Hd) over mutation rate (θ), was indicative of a human specific Alu-Yi6 insertion serving as a central recombining sequence facilitating homologous recombination. Local anomalous DNA conformation attributable to the Alu-Yi6 element, as suggested by enhanced DNase I sensitivity and obstruction to DNA sequencing, could be a contributing factor of the increased sequence diversity. Linkage disequilibrium (LD) analysis yielded prominent low LD points that supported ongoing recombination. LD contrast revealed significant dissimilarity between control and schizophrenic cohorts. Among the large array of inferred haplotypes, H26 and H73 were identified to be protective, and H19 and H81 risk-conferring, toward the development of schizophrenia.
The co-occurrence of hotspot recombination and positive selection in the S1–S29 segment of GABRB2 has provided a plausible contribution to the molecular genetics mechanisms for schizophrenia. The present findings therefore suggest that genome regions characterized by the co-occurrence of positive selection and hotspot recombination, two interacting factors both affecting genetic diversity, merit close scrutiny with respect to the etiology of common complex disorders.
PMCID: PMC2833194  PMID: 20221451
9.  Evaluation of medical and health economic effectiveness of bariatric surgery (obesity surgery) versus conservative strategies in adult patients with morbid obesity 
Obesity with its associated medical, psychological, social, and economic complications is considered a chronic, multifactorial disorder. Given the magnitude of the challenge obesity, there is a clear need for preventive as well as therapeutic measures and strategies on an individual and a public health level.
The goal of this health technology assessment (HTA)-report is to summarise the current literature on bariatric surgery, to evaluate their medical effectiveness/efficacy and cost-effectiveness as well as the ethical, social and legal implications of these procedures in comparison to conventional therapies and compared to each other.
Relevant publications are identified by means of a structured search of databases accessed on 13.11.2006 and an update conducted on 12.11.2007. In addition, a manual search of identified reference lists is conducted. The present report includes German and English literature published since 2001 and targeting adult subjects with morbid obesity (body mass index (BMI) >=40 kg/m² or BMI >=35 kg/m² with severe comorbidities). The methodological quality of studies included is assessed according to pre-defined quality criteria by two independent scientists.
Among 5910 retrieved publications, 25 medical articles, as well as seven health economic studies meet the inclusion criteria. The medical studies show a superior weight loss following bariatric surgery compared to conventional therapy. Malabsorptive procedures lead to a more profound weight loss than purely restrictive procedures. Weight reduction in general is accompanied by a reduced frequency of comorbidities (mostly diabetes type 2). The evidence is not sufficient to quantify these effects for individual procedures or to assess long-term outcomes. However, recent studies show a profound survival benefit for surgically treated patients up to a period of eleven years. The economic studies illustrate that bariatric surgery is cost-effective compared to no treatment or conservative treatment. The comparison between surgical therapies does not allow to draw any conclusions on cost-effectiveness. Appropriate studies/surveys, which are concerned with ethical, legal and social aspects, are not available.
Concerning clinical outcomes as well as cost-effectiveness, there is a lack of high quality studies. Clinical effectiveness and safety as well as cost-effectiveness of bariatric procedures in the short- and medium-term course are agreed on, but long-term evaluations that focus not exclusively on weight loss, but also on comorbidities and patient relevant outcomes such as quality of life, are needed. Also within the economic views are missing long-term evaluation particularly for the German health care system.
Based upon the available literature the short- and medium-term effectiveness of bariatric procedures on weight loss, comorbidities, e. g. diabetes, and mortality can be assumed and also seems to be cost-effective. No recommendation can be given with respect to the choice of a certain bariatric procedure or to the selection of particular groups of patients.
PMCID: PMC3011303  PMID: 21289912
10.  Positive Selection within the Schizophrenia-Associated GABAA Receptor β2 Gene 
PLoS ONE  2007;2(5):e462.
The gamma-aminobutyric acid type-A (GABAA) receptor plays a major role in inhibitory neurotransmissions. Intronic SNPs and haplotypes in GABRB2, the gene for GABAA receptor β2 subunit, are associated with schizophrenia and correlated with the expression of two alternatively spliced β2 isoforms. In the present study, using chimpanzee as an ancestral reference, high frequencies were observed for the derived (D) alleles of the four SNPs rs6556547, rs187269, rs1816071 and rs1816072 in GABRB2, suggesting the occurrence of positive selection for these derived alleles. Coalescence-based simulation showed that the population frequency spectra and the frequencies of H56, the haplotype having all four D alleles, significantly deviated from neutral-evolution expectation in various demographic models. Haplotypes containing the derived allele of rs1816072 displayed significantly less diversity compared to haplotypes containing its ancestral allele, further supporting positive selection. The variations in DD-genotype frequencies in five human populations provided a snapshot of the evolutionary history, which suggested that the positive selections of the D alleles are recent and likely ongoing. The divergence between the DD-genotype profiles of schizophrenic and control samples pointed to the schizophrenia-relevance of positive selections, with the schizophrenic samples showing weakened selections compared to the controls. These DD-genotypes were previously found to increase the expression of β2, especially its long isoform. Electrophysiological analysis showed that this long β2 isoform favored by the positive selections is more sensitive than the short isoform to the inhibition of GABAA receptor function by energy depletion. These findings represent the first demonstration of positive selection in a schizophrenia-associated gene.
PMCID: PMC1866178  PMID: 17520021
11.  Systematic mutation analysis of KIAA0767 and KIAA1646 in chromosome 22q-linked periodic catatonia 
BMC Psychiatry  2005;5:36.
Periodic catatonia is a familial subtype of schizophrenia characterized by hyperkinetic and akinetic episodes, followed by a catatonic residual syndrome. The phenotype has been evaluated in two independent genome-wide linkage scans with evidence for a major locus on chromosome 15q15, and a second independent locus on chromosome 22qtel.
In the positional and brain-expressed candidate genes KIAA0767 and KIAA1646, we searched for variants in the complete exons and adjacent splice-junctions as well as in parts of the 5'- and 3'-untranslated regions by means of a systematic mutation screening in individuals from chromosome 22q-linked pedigrees.
The mutation scan revealed 24 single nucleotide polymorphisms, among them two rare codon variants (KIAA0767: S159I; KIAA1646: V338G). However, both were neither found segregating with the disease in the respective pedigree nor found at a significant frequency in a case-control association sample.
Starting from linkage signals at chromosome22qtel in periodic catatonia, we screened two positional brain-expressed candidate genes for genetic variation. Our study excludes genetic variations in the coding and putative promoter regions of KIAA0767 and KIAA1646 as causative factors for periodic catatonia.
PMCID: PMC1274336  PMID: 16225677
12.  ZDHHC8 as a candidate gene for schizophrenia: Analysis of a putative functional intronic marker in case-control and family-based association studies 
BMC Psychiatry  2005;5:35.
The chromosome 22q11 region is proposed as a major candidate locus for susceptibility genes to schizophrenia. Recently, the gene ZDHHC8 encoding a putative palmitoyltransferase at 22q11 was proposed to increase liability to schizophrenia based on both animal models and human association studies by significant over-transmission of allele rs175174A in female, but not male subjects with schizophrenia.
Given the genetic complexity of schizophrenia and the potential genetic heterogeneity in different populations, we examined rs175174 in 204 German proband-parent triads and in an independent case-control study (schizophrenic cases: n = 433; controls: n = 186).
In the triads heterozygous parents transmitted allele G preferentially to females, and allele A to males (heterogeneity χ2 = 4.43; p = 0.035). The case-control sample provided no further evidence for overall or gender-specific effects regarding allele and genotype frequency distributions.
The findings on rs175174 at ZDHHC8 are still far from being conclusive, but evidence for sexual dimorphism is moderate, and our data do not support a significant genetic contribution of rs175174 to the aetiopathogenesis of schizophrenia.
PMCID: PMC1274335  PMID: 16225675
13.  Carcinogenicity of airborne combustion products observed in subcutaneous tissue and lungs of laboratory rodents. 
Most air pollution in West Germany is caused by combustion products. Particulate organic matter released by incomplete combustion is suspected to contribute to the "urban factor" of lung cancer frequency in urban-industrial centers. The carcinogenic potential of single components, groups of compounds and total source emissions of combustion processes was investigated in laboratory animals by subcutaneous injection, intratracheal instillation or inhalation. Tests by subcutaneous injection of condensates of automobile exhaust, extracts of coal furnace emissions and of airborne particles and different fractions of these extracts showed that the polycyclic aromatic hydrocarbons (PAH) with four to six benzene rings have the strongest experimental carcinogenicity. However, polar compounds (heterocyclic nitrogen-containing PAH, phenols, and others) also show remarkable carcinogenic potency. There were large differences between the dose-response relationships of several PAHs. In the subcutaneous tissue, benzo(a)pyrene and dibenz(a,h)anthracene are the most carcinogenic of the tested airborne PAHs. Furthermore, they can induce high tumor rates in the lung after subcutaneous injection in newborn mice and after intratracheal instillation of mice or hamsters. The tumor rate of benzo(a)pyrene did not further increase after simultaneous instillation of carbon black, but lead chloride may have a promoting effect. Far more than 100 PAHs are found in the urban atmosphere. However, because of the remarkable similarity of the PAH profiles in the examined samples, it may be sufficient to measure just a few stable PAHs in the urban air in order to facilitate an assessment of the carcinogenic potency of the PAH content in the atmosphere. To examine the carcinogenic or cocarcinogenic effects of gas and vapor emissions, studies with a two-phase model were carried out: phase 1 relates to the induction of a basic tumor rate in the lung by a well known carcinogen, while phase 2 is characterized by an inhalation of the substance under investigation. In an experiment with mice, the inhalation of a mixture of SO2 and NO2 seemed to increase the basic tumor rate induced by dibenz(a,h)anthracene. In a similar two-phase experiment conducted with hamsters, the inhalation of diesel exhaust (total exhaust as well as exhaust without particles) increased a basic tumor rate induced by diethyl nitrosamine. These experiments deserve confirmation before a detailed interpretation is attempted.
PMCID: PMC1569415  PMID: 6186480

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