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PubMed2025

Clinical impact of obsessive-compulsive disorder comorbidity in bipolar disorder: a systematic review and meta-analysis.

BACKGROUND: Bipolar disorder (BD) is commonly comorbid with other psychiatric conditions, such as obsessive-compulsive disorder (OCD). Despite increasing interest in this comorbidity, quantitative data on its clinical characteristics remain limited. This systematic review and meta-analysis aimed to evaluate the clinical impact of OCD comorbidity in BD by comparing individuals with BD and OCD (BD-OCD) to those with BD without OCD. METHODS: We systematically searched the PubMed/MEDLINE, Scopus, PsycINFO, and Web of Science databases up to April 15, 2024. Meta-analyses were conducted to compare BD-OCD and BD without OCD groups across multiple clinical domains. RESULTS: From 11,959 initial records screened, 26 studies were included in the qualitative synthesis, with 22 eligible for meta-analysis. Individuals with BD-OCD showed higher odds of experiencing chronic mood episodes (OR = 9.42; 95%CI = 2.23, 39.9), rapid cycling (OR = 1.92; 95%CI = 1.04, 3.53), comorbid eating disorders (OR = 3.37; 95%CI = 1.99, 5.7), panic disorder (OR = 3.3; 95%CI = 2.11, 5.2), substance use disorders (OR = 1.39; 95%CI = 1.02, 1.89), and lifetime suicide attempts (OR = 1.85; 95%CI = 1.21, 2.84). Additionally, they presented earlier onset of BD (SMD = -0.27; 95%CI = -0.52, -0.01) and reduced functioning (SMD = -0.42; 95%CI = -0.59, -0.24). Most data were derived from adult populations, limiting the evidence available for children and adolescents. CONCLUSIONS: BD-OCD presents a more severe and complex clinical profile, requiring specialized assessment and integrated treatment approaches. Identifying these features may support earlier recognition and inform personalized interventions for this population.

Humans↗
PubMed2003

A geographic information system for characterizing exposure to Agent Orange and other herbicides in Vietnam.

Between 1961 and 1971, U.S. military forces dispersed more than 19 million gallons of phenoxy and other herbicidal agents in the Republic of Vietnam, including more than 12 million gallons of dioxin-contaminated Agent Orange, yet only comparatively limited epidemiologic and environmental research has been carried out on the distribution and health effects of this contamination. As part of a response to a National Academy of Sciences' request for development of exposure methodologies for carrying out epidemiologic research, a conceptual framework for estimating exposure opportunity to herbicides and a geographic information system (GIS) have been developed. The GIS is based on a relational database system that integrates extensive data resources on dispersal of herbicides (e.g., HERBS records of Ranch Hand aircraft flight paths, gallonage, and chemical agent), locations of military units and bases, dynamic movement of combat troops in Vietnam, and locations of civilian population centers. The GIS can provide a variety of proximity counts for exposure to 9,141 herbicide application missions. In addition, the GIS can be used to generate a quantitative exposure opportunity index that accounts for quantity of herbicide sprayed, distance, and environmental decay of a toxic factor such as dioxin, and is flexible enough to permit substitution of other mathematical exposure models by the user. The GIS thus provides a basis for estimation of herbicide exposure for use in large-scale epidemiologic studies. To facilitate widespread use of the GIS, a user-friendly software package was developed to permit researchers to assign exposure opportunity indexes to troops, locations, or individuals.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed2006

The tmRDB and SRPDB resources.

Maintained at the University of Texas Health Science Center at Tyler, Texas, the tmRNA database (tmRDB) is accessible at the URL http://psyche.uthct.edu/dbs/tmRDB/tmRDB.html with mirror sites located at Auburn University, Auburn, Alabama (http://www.ag.auburn.edu/mirror/tmRDB/) and the Royal Veterinary and Agricultural University, Denmark (http://tmrdb.kvl.dk/). The signal recognition particle database (SRPDB) at http://psyche.uthct.edu/dbs/SRPDB/SRPDB.html is mirrored at http://srpdb.kvl.dk/ and the University of Goteborg (http://bio.lundberg.gu.se/dbs/SRPDB/SRPDB.html). The databases assist in investigations of the tmRNP (a ribonucleoprotein complex which liberates stalled bacterial ribosomes) and the SRP (a particle which recognizes signal sequences and directs secretory proteins to cell membranes). The curated tmRNA and SRP RNA alignments consider base pairs supported by comparative sequence analysis. Also shown are alignments of the tmRNA-associated proteins SmpB, ribosomal protein S1, alanyl-tRNA synthetase and Elongation Factor Tu, as well as the SRP proteins SRP9, SRP14, SRP19, SRP21, SRP54 (Ffh), SRP68, SRP72, cpSRP43, Flhf, SRP receptor (alpha) and SRP receptor (beta). All alignments can be easily examined using a new exploratory browser. The databases provide links to high-resolution structures and serve as depositories for structures obtained by molecular modeling.

Amino Acid Sequence↗
PubMed2026

Genomic Medicine Sweden: Advancing precision medicine at the national level.

High-throughput sequencing has transformed clinical diagnostics of rare diseases (RD), cancer and infectious diseases by enabling the identification of disease-causing genetic alterations and facilitating individualised treatment and care. In response to these advances, Genomic Medicine Sweden (GMS) was established in 2017 as a national collaborative effort to accelerate implementation of genomics-based precision medicine within Sweden's regionally organized, publicly funded healthcare system. GMS brings together the seven university healthcare regions and their associated medical faculties, in collaboration with healthcare regions across Sweden, Science for Life Laboratory, patient organizations, industry and governmental agencies. Activities are coordinated through national disease-specific expert groups, supported by cross-cutting functions in bioinformatics, health economics, ethics, education and patient engagement. At the operational level, seven Genomic Medicine Centres, embedded at university hospitals, develop and deliver harmonised genomic diagnostics nationwide. The National Genomics Platform provides secure infrastructure for large-scale data storage, analysis, and national and international data sharing. Following initial project-based funding, GMS now receives long-term governmental support. This review describes the national implementation of genomic-based precision diagnostics, discusses challenges and lessons learnt, and highlights key milestones across disease areas, including whole-genome sequencing in RD and paediatric cancer, comprehensive genomic profiling of haematological malignancies and solid tumours, pathogen genomics in microbiology, pharmacogenomic testing and emerging applications of polygenic risk scores in complex diseases. Collectively, these efforts have contributed to more than 500,000 genomic tests being performed within Swedish healthcare between 2017 and 2025. Finally, we outline future diagnostic needs and priority areas to ensure sustainable, scalable and equitable access to precision medicine.

Precision Medicine↗
PubMed2002

Navigation and image-guided HBP surgery: a review and preview.

Image-guided surgery and navigation have resulted from convergent developments in radiology, teletransmission, and computer science. Patient selection and preoperative planning in hepatobiliary-pancreatic (HBP) surgery rely on preoperative imaging. The operative procedure is finally led by the fusion of additional information gained by the palpating hand and intraoperative ultrasound. Despite advances in reducing morbidity and mortality, decisions are often hardly quantifiable and are restricted to super-specialists in HBP surgery. New developments in computed tomography (CT) and magnetic resonance imaging (MRI) technology have led to the possibility of the volumetric prediction of liver resections. These data can be shared via telemedicine and used for simulation and training. Three-dimensional (3D) reconstructions have led to a better topologic understanding of tumor-vascular tree relations in the individual patient. With the increasing use of ablative procedures and laparoscopy, intraoperative imaging and navigation will hold increasing significance for the HBP surgeon. Flat screen monitors adjacent to the surgical field present computer-generated 3D virtual liver resection proposals which can be transferred into the real liver. The main obstacles in HBP navigation are the flexibility and mobility of the target organ. Intrahepatic and surface markers seem to be mandatory for computer-navigated surgery. The first feasibility studies are promising.

Bile Ducts↗
PubMed2006

Accurate determination of allelic frequencies in mitochondrial DNA mixtures by electrospray ionization time-of-flight mass spectrometry.

The mitochondrial locus 16519T/C was used as a model for the evaluation of the benefits of ion-pair reversed-phase high-performance liquid chromatography on-line hyphenated to electrospray ionization time-of-flight mass spectrometry (ICEMS assay) for the determination of allelic frequencies of single nucleotide polymorphisms. This marker has gained interest in forensic science owing to its ability to increase the discrimination power of mitochondrial DNA testing as a consequence of its high variability across various populations. In a first set of experiments, artificial mitochondrial DNA mixtures prepared from all four theoretically possible 16519 alleles served as samples. Any allele occurring at a frequency of as low as 1-5% was unequivocally detectable irrespective of the kind of allelic mixture. Measured and expected allelic frequencies correlated well following correction of observed experimental bias, which was most probably attributable to differential PCR amplification and/or preferential ionization. For thirteen different T/C mixtures with C contents in the range 1.0-99.0%, an average error of 1.2% and a maximum error of 2.2% were observed. Furthermore, ICEMS was applied to the quantitative genotyping of eight selected individuals of which four were heteroplasmic with C contents in the range 1.9-34.1%. To check the reliability of these results, allelic proportions were additionally determined by a cloning assay. The results of the two assays correlated well (R (2)=0.9971). In all cases, deviations were obtained that were smaller than 5.4%. The overall observed assay performance suggests that the described mass spectrometric technique represents one of the most powerful assays for the determination of allelic frequencies available today.

DNA, Mitochondrial↗
PubMed1980

[The search for "od." Karl Ludwig Freiheer von Reichenbach (1788-1869) and Karl Wilhelm Mayrhofer (1806-1853), two joined against Justus von Liebig].

The author describes the controversy between Justus von Liebig on one side and Reichenbach and Mayrhofer on the other side. It is a controversy about problems of science and medicine which are characteristic for the late 18th and the first half of the 19th century, when Mesmerism and similar ideas of occultic and comparative phenomenona were discussed and often refused as being "not scientific". Justus von Liebig and Karl Ludwig Freiherr von Reichenbach were both chemists, both interested in scientific progress and working in this field. They were friends in the years 1830 to 1848. But later on this friendship ended when Reichenbach--who in the mean time moved to Vienna--became more and more interested in phenomenons seen by sensitive persons concerning effects of light. Although Reichenbach himself was not able to recognize the phenomenons he was sure that other persons had this ability. He had the impression that there is a special force floating through the universe, and this force he called "od". Liebig, who was not able to follow this theory and rejected it has speculation, turned against Reichenbach in 1852-3. So the controversy began and their old friendship came to an end. Reichenbach's theory of the "od", characteristic for the time of the romanticism and leading back to Mesmerism was accepted and supported by the Austrian physician Dr. Karl Wilhelm Mayrhofer who had aroused his interest by describing similar phenomenos some of this patients had. The letters of both men, the chemist and the doctor, which are well preserved (Technical Museum of Vienna) and discussed here, give a good impression of Reichenbach's ideas concerning his theory of the "od" and his philosophical ideas. As Reichenbach tried to find a philosophy corresponding to his theory and as he meant to have found this in the philosophy of Friedrich Eduard Beneke his remarks in those letters give a good information about Beneke's discussion of Reichenbach's theory. Mayrhofer, on the other hand, following Reichenbach's theory of the "od", rejected Beneke's philosophy because he himself joined another philisophy on the basis of the christian religion. However, when Reichenbach's latest book on these problems appeared in 1854, Beneke and Mayrhofer had died shortly before and no further discussion was possible. But Reichenbach's theory, based on the ideas of Mesmerism, and the controversial discussion about new explanations of the phenomenona seen by sensitive persons are characteristic for this time and also for our time as such perceptions are not entirely denied but thought over in a new way.

Austria↗
PubMed2005

Biomarkers for toxicodynamic monitoring of immunosuppressants: NMR-based quantitative metabonomics of the blood.

Metabonomics is the latest "omics" science and provides metabolic endpoints of drug toxicity, drug efficacy, and pathophysiology. With high-resolution 'H-NMR (nuclear magnetic resonance)spectroscopy on body fluids (eg, urine, blood samples) used in combination with statistical tools, metabolic biomarkers of drug toxicity can be distinguished and validated. For 2 decades, immuno-suppressant cyclosporine (CsA) has been used in transplantation medicine as a potent calcineurin inhibitor with well-known nephrotoxic side effects. The combination of CsA with novel macrolide immunosuppressants-sirolimus (SRL) or everolimus (RAD)-has proved to have a beneficial synergistic immunosuppressive effect but may also possess an increased nephrotoxic potential. 1H-NMR spectroscopy was performed on the blood from CsA-, SRL-, and RAD (alone and in combination)-treated rats to predict metabolic toxicity and to identify and quantify specific metabolic biomarkers. After 6 days of treatment with 10 mg/kg CsA, a significant increase in blood glucose, hydroxybutyrate, creatine+creatinine, trimethylamine-N-oxide (TMAO), and cholesterol as well as a decrease in total glutathione concentrations were observed. SRL (3 mg/kg) enhanced the magnitude of CsA metabolic changes (enhanced toxicity),whereas combination with RAD (3 mg/kg) partly curtailed them. Together with pharmacokinetic studies, quantitative NMR-based metabonomics represents a powerful tool for pharmacokinetic-pharmacodynamic-toxicodynamic evaluation in drug research.

Animals↗
PubMed1995

Self-reported alcohol intake and cognition in aging twins.

OBJECTIVE: To determine the relationship between long-term alcohol intake and cognitive functioning in aging Caucasian men. METHOD: A retrospective cohort and co-twin-control study of self-reported alcohol intake and cognitive testing using the National Academy of Sciences-National Research Council (NAS-NRC) Twin Panel of U.S. veterans (born between 1917 and 1927). The study included 4,739 twins with two self-reported drinking histories (1970s and 1980s) and a telephone mental status interview (1990 and 1991) that also included 145 individuals with a diagnosis of alcoholism. RESULTS: Age and education adjusted cognitive scores were lower (p < .05) in diagnosed alcoholics than in the remainder of the subjects. To compare age and education adjusted cognitive scores in alcohol intake, the 4,739 twins were divided, based upon questionnaire data, into nondrinkers and 5 quintiles of drinkers by average reported drinks of alcohol weekly (< 1.0, 1-3.3, 3.4-8.1, 8.2-16.0, > 16.0). Past drinkers had scores lower (p < .05) than nondrinkers and all but quintiles 1 and 5 of the drinkers. The light drinkers in quintile 1 and the heavy drinkers in quintile 5 scored lower (p < .05) than the moderate drinkers in quintile 4. Monozygotic twins in quintile 4 scored higher (p < .05) than their co-twins in quintiles 1-3. CONCLUSIONS: No evidence was found to indicate an association between moderate long-term alcohol intake and lower cognitive scores in aging individuals. There was a suggestion of a small protective effect of past moderate alcohol intake on cognitive function with aging.

Aged↗
PubMed2006

Nobel laureates at the Stazione Zoologica Anton Dohrn: phenomenology and paths to discovery in neuroscience.

The practice of science usually involves more than a solitary genius in a solitary room, coping with the problem of her/his life. From the second half of the 19th century onwards, scientific research, especially in the field of the Natural Sciences, has grown into a more and more complex practice, which often entangles very special needs, in terms of research objects, techniques, sources, and perspectives. A few special places, such as the Stazione Zoologica di Napoli, have represented in this period the focal points of an ever growing international scientific network, promoting independent research, exchange and diffusion of novel practices and techniques and unrestricted confrontation. The so-called "Naples experience" has been cited by a large number of renowned scientists of the last two centuries as a key moment in their scientific life. Here we have tried to test it against the experience of three great scientists par excellence, i.e. three Nobel laureates (T. H. Morgan, Otto Warburg, J. D. Watson). The different experiences they have had at Naples represent, in our view, three different moments of the professional life of almost every scientist. Therefore, we have chosen to present them as a phenomenology. The final section is dedicated to a survey of the Zoological Station's contribution to neurosciences, especially to the Naples experience of the Nobel Prize winner Sir Bernard Katz and his assistant Ricardo Miledi, between 1965 and 1970. Their work on the squid at Naples allowed probing and quantitative refinement of results already obtained on different animals and contributed to reinforce the long lasting neurophysiological tradition of the institute.

Academies and Institutes↗
PubMed2002

DXYS156: a multi-purpose short tandem repeat locus for determination of sex, paternal and maternal geographic origins and DNA fingerprinting.

In forensic science and in legal medicine Y chromosomal typing is indispensable for sex determination, for paternity testing in the absence of the father and for distinguishing males in multiple rape cases. Another potential application is the estimation of paternal geographic origin or family name from a crime stain to narrow down the range of suspects and thus reduce costs of mass screenings. However, Y typing alone cannot provide a sufficiently resolved DNA fingerprint as required for court convictions. Thus, there is a dilemma whether or not to sacrifice valuable material for the sake of extensive Y chromosomal investigations when stain DNA is limited (typically allowing only few PCR amplifications). We here describe a Y-chromosome-specific nucleotide insertion in the duplicate short tandem repeat (STR) locus DXYS156 which allows us to distinguish males from females as does the commonly used amelogenin system, but with the advantage that this locus is multi-allelic, thus substantially contributing towards DNA fingerprinting of a sample and furthermore enabling the detection of sample contamination. Yet another bonus is that both the X and the Y copies of DXYS156 have alleles specific to different parts of the world, offering separate estimates of maternal and paternal descent of that sample. We therefore recommend the inclusion of DXYS156 in standard multiplexing kits for forensic, archaeological and genealogical applications.

Base Sequence↗
PubMed2005

Incidence of drug-induced liver injury in medical inpatients.

OBJECTIVES: Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemiology in inpatients are sparse. METHODS: To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chemistry laboratory liver parameters (CIOMS laboratory criteria) and the exclusion of any disease-related causes for the liver injury. Thus, only cases with probable or certain causality according to the World Health Organization criteria were included. RESULTS: Among a total of 6383 patients, liver parameters were determined in 4610, and 489 among them fulfilled the CIOMS laboratory criteria. However, 401 patients had to be excluded because of disease-related liver injury and, thus, the study cohort consisted of 4209 patients at risk for DILI. Among a total of 88 DILI cases, 31 had no documented normal baseline liver parameters and, thus, represented prevalent cases. The remaining 57 represented incident DILI cases. Thus, the incidence of DILI was 1.4% (95% CI 1.0, 1.7). The drug classes most frequently causing DILI were heparins, antibacterials, tuberculostatics and antineoplastic agents. Among those, antineoplastic agents and tuberculostatics showed the highest incidence. Liver injury was not mentioned among the diagnoses or in the physician's discharge letter in about 52-68% of all cases. CONCLUSION: Approximately 1 in 100 patients develops DILI during hospitalisation in a department of medicine. Incidences of DILI were highest for antineoplastic agents and tuberculostatics. DILI is frequently missed and, therefore, DILI detection by diagnoses will result in misleadingly low incidence rates.

Anti-Bacterial Agents↗
PubMed2001

The contemporary failure of nerve and the crisis in psychoanalysis.

The American Academy of Psychoanalysis is undergoing an identity crisis at this time, which is at least to a large extent a function of the whole current identity crisis in the field of psychoanalysis itself. In order to better understand this crisis, in this article I have first reviewed a similar situation which occurred in the history of classical Greece. Plato's famous Academy underwent a progressive deterioration and disintegration and fragmentation, until it ended up merely the handmaiden of another discipline, Christian theology, for a thousand years. I then propose that the identity crisis in psychoanalysis today has to do with our failure of nerve in the teeth of the abusive behavior of insurance companies regarding the payment for psychoanalysis and the current cultural ambience demanding "fast-fast-fast" relief. I call in this article for a return to Freud's basic principles as a focus for our identity. Of course we cannot ignore new discoveries in neurobiology if they are well established, or what we learn from the study of enactments in the here-and-how of the analytic procedure. Certainly the findings of Freud that are contradicted by firmly accepted empirical findings in neurobiology and other disciplines call for revision of some of his ideas, as do his mistaken views on the psychology of women and on certain other topics such as art, religion, and evolutionary biology. But this should not be permitted to blur our continuing focus on the fundamental principles of the clinical practice of psychoanalysis as Freud developed them over his lifetime. In this article I briefly reviewed those basic principles and proposed that we employ them as the basis for our identity as psychoanalysts and psychoanalytic psychiatrists. It represents a failure of nerve to drift this way and that with current fads and with the continuously deteriorating ambiance of our culture as the world slides into rampant global capitalism. Franz Alexander said years ago that psychoanalytic psychotherapy is one of the last remnants of the humanistic ideal, focussing on the individual unique person and his or her transcendent possibilities as well as maladaptive pathology. This article represents a clarion call for a debate on the identity of the American Academy of Psychoanalysis and what it stands for, which can only be clarified if we have a sharp focus on what we basically mean by "psychoanalysis." As Saul Bellow puts it (Atlas, 2000) in discussing the disappointing current situation for the arts and the humanistic disciplines, the intelligent public is waiting to hear from these disciplines what it cannot hear from pure science: Out of the struggle at the center has come an immense, painful longing for a broader, more flexible, fuller, more coherent, more comprehensive account of what we human beings are, who we are, and what this life is for...the individual struggles with dehumanization for the possession of his soul, (p.462). Below points out, in talking about writers, and in a discussion equally applicable to psychoanalysts, that if we do not "come again into the center it will not be because the center is preempted. It is not. [We] are free to enter if [we] so wish" (p.462).

Adult↗
PubMed1998

Ethical considerations for residents.

To help residents understand the moral obligations they have undertaken by becoming doctors, the author presents an overview of the ethical landscape of medical practice. She begins by stating that doctors' primary obligation is to use the knowledge of science in working together with others for the good of their patients. This involves (1) relying on the scientific method (and thus eschewing nonscientific alternatives) and supporting or conducting scientific research; (2) embracing the cooperative model (i.e., when appropriate, working cooperatively with other physicians and other health care providers); and (3) working for the good of the patient to preserve life, cure disease, restore or preserve function, educate, and alleviate suffering. In order to fulfill this complex obligation physicians must be professionally competent, they must respect their colleagues and patients, and they must genuinely care about their patients' well-being. The author then discusses the moral complexity of common encounters in medical practice. She explains the ethical conflicts that underlie issues of paternalism, justice, the use of patients for teaching, and end-of-life care. Since new moral problems are introduced with new technology and since medicine is confronting an increasing demand for services in the face of shrinking resources, she maintains that, more than ever, physicians must be aware of the ethical dimensions of their work and be able to organize their understanding of the issues. To meet the complex and demanding commitments of medical practice and to successfully navigate the ethical challenges that they will encounter, physicians must mold themselves not only to be knowledge and skilled professionals but also to be respectful and compassionate human beings.

Adult↗
PubMed2005

Experimental analysis of nature-nurture interactions.

The presumed opposition of nature and nurture has been a major concern of western civilization since its beginnings. Christian theologians interpreted Adam and Eve's eating of the forbidden fruit as the origin of an inherited 'original sin'. Saint Augustine explicitly applied the concept to human mental development, arguing that, because of original sin, children are inclined toward evil and education requires physical punishment. For centuries, it was considered parents' moral and religious obligation, not to nurture their children, in our current sense of that word, but to beat the willfulness out of them. 16thC humanists fought back, arguing that "schools have become torture chambers" while it is adults "who corrupt young minds with evil". Locke's (1690) statement that children are born as a 'white paper' was crucial in rejecting the dogma of an inborn (and sinful) nature. The original sin vs. white paper argument merged with another ancient dichotomy: inborn instinct (which controls animal behavior) vs. the reason and free will which humans have. Darwin made the concept of inherited instinct, common to both man and animals, one cornerstone of his theory of evolution. The 20(th)C saw scientists recast the debate as instinct vs. learning, bitterly argued between behaviorists and ethologists. Laboratory experimentation and field observation showed that behavior could develop without learning but also that conditioning paradigms could powerfully mold behavior. The progress of genetics and neurobiology has led to the modern synthesis that neural development, and hence behavior, results from the interdependent action of both heredity and environment.

Acculturation↗
PubMed2006

Excited-state hydrogen-atom transfer along solvent wires: water molecules stop the transfer.

Excited-state hydrogen-atom transfer (ESHAT) along a hydrogen-bonded solvent wire occurs for the supersonically cooled n = 3 ammonia-wire cluster attached to the scaffold molecule 7-hydroxyquinoline (7HQ) [Tanner, C.; et al. Science 2003, 302, 1736]. Here, we study the analogous three-membered solvent-wire clusters 7HQ.(NH3)n.(H2O)m, n + m = 3, using resonant two-photon ionization (R2PI) and UV-UV hole-burning spectroscopies. Substitution of H2O for NH3 has a dramatic effect on the excited-state H-atom transfer: The threshold for the ESHAT reaction is approximately 200 cm(-1) for 7HQ.(NH3)3, approximately 350 cm(-1) for both isomers of the 7HQ.(NH3)2.H2O cluster, and approximately 600 cm(-1) for 7HQ.NH3.(H2O)2 but increases to approximately 2000 cm(-1) for the pure 7HQ.(H2O)3 water-wire cluster. To understand the effect of the chemical composition of the solvent wire on the H-atom transfer, the reaction profiles of the low-lying electronic excited states of the n = 3 pure and mixed solvent-wire clusters are calculated with the configuration interaction singles (CIS) method. For those solvent wires with an NH3 molecule at the first position, injection of the H atom into the wire can occur by tunneling. However, further H-atom transfer is blocked by a high barrier at the first (and second) H2O molecule along the solvent wire. H-atom transfer along the entire length of the solvent wire, leading to formation of the 7-ketoquinoline (7KQ) tautomer, cannot occur for any of the H2O-containing clusters, in agreement with experimentally observed absence of 7KQ fluorescence.

Hydrogen↗
PubMed2004

Models for angiogenesis in gliomas.

During the last decades a lot of attention has been focussed on mechanisms of glioma vascularization, particularly in terms of investigating vascular growth factors and receptors. Recently, these efforts resulted in various approaches for antiangiogenic treatment strategies using in vitro cell culture systems as well as experimental orthotopic and non-orthotopic brain tumors. These basic science and preclinical trials need an assortment of models, which should allow investigating a variety of questions. Several objectives concerning basic endothelial cell (EC) characteristics can adequately be studied in vitro using EC monolayer assays. Three-dimensional spheroid techniques respect the more complex cell-cell and cell-environment interplay within a 3-dimensional culture. Recent advances in molecular genetic techniques offer a wide access to the genome of EC. Using these micro array or chip methods differences between micro- and macromolecular EC as well as variations within the gene pool of different organ specific EC can be assessed. To optimize the imitation of the crucial interaction of human gliomas with host endothelial cells, immunological cells and extracellular matrix, animal models are mandatory. An essential rule is to utilize an orthotopic model, since tumor-host-interaction is organ specific. To avoid alloimmunogenic responses, it is desirable to use weak or non-immunogenic glioma grafts, which is best accomplished in a syngeneic model. However, since rat gliomas poorly resemble human glioma growth patterns, human glioma xenografting into immunocompromized animals should be considered. In vivo-monitoring techniques like videoscopy via a cranial window or magnetic resonance imaging (MRI) allow for functional studies and improve the validity of the model employed. Finally, it is essentially to recognize the limitations of each model considered and to select that model which seems to be most appropriate for the objectives to be investigated.

Animals↗
PubMed2006

Molecular validation of LpxC as an antibacterial drug target in Pseudomonas aeruginosa.

LpxC [UDP-3-O-(R-3-hydroxymyristoyl)-GlcNAc deacetylase] is a metalloamidase that catalyzes the first committed step in the biosynthesis of the lipid A component of lipopolysaccharide. A previous study (H. R. Onishi, B. A. Pelak, L. S. Gerckens, L. L. Silver, F. M. Kahan, M. H. Chen, A. A. Patchett, S. M. Galloway, S. A. Hyland, M. S. Anderson, and C. R. H. Raetz, Science 274:980-982, 1996) identified a series of synthetic LpxC-inhibitory molecules that were bactericidal for Escherichia coli. These molecules did not inhibit the growth of Pseudomonas aeruginosa and were therefore not developed further as antibacterial drugs. The inactivity of the LpxC inhibitors for P. aeruginosa raised the possibility that LpxC activity might not be essential for all gram-negative bacteria. By placing the lpxC gene of P. aeruginosa under tight control of an arabinose-inducible promoter, we demonstrated the essentiality of LpxC activity for P. aeruginosa. It was found that compound L-161,240, the most potent inhibitor from the previous study, was active against a P. aeruginosa construct in which the endogenous lpxC gene was inactivated and in which LpxC activity was supplied by the lpxC gene from E. coli. Conversely, an E. coli construct in which growth was dependent on the P. aeruginosa lpxC gene was resistant to the compound. The differential activities of L-161,240 against the two bacterial species are thus the result primarily of greater potency toward the E. coli enzyme rather than of differences in the intrinsic resistance of the bacteria toward antibacterial compounds due to permeability or efflux. These data validate P. aeruginosa LpxC as a target for novel antibiotic drugs and should help direct the design of inhibitors against clinically important gram-negative bacteria.

Amidohydrolases↗