Neurite Orientation Dispersion and Density Imaging for Assessing Acute Inflammation and Lesion Evolution in MS.

BACKGROUND AND PURPOSE: MR imaging is essential for MS diagnosis and management, yet it has limitations in assessing axonal damage and remyelination. Gadolinium-based contrast agents add value by pinpointing acute inflammation and blood-brain barrier leakage, but with drawbacks in safety and cost. Neurite orientation dispersion and density imaging (NODDI) assesses microstructural features of neurites contributing to diffusion imaging signals. This approach may resolve the components of MS pathology, overcoming conventional MR imaging limitations. MATERIALS AND METHODS: Twenty-one subjects with MS underwent serial enhanced MRIs (12.6 ± 9 months apart) including NODDI, whose key metrics are the neurite density and orientation dispersion index. Twenty-one age- and sex-matched healthy controls underwent unenhanced MR imaging with the same protocol. Fifty-eight gadolinium-enhancing and non-gadolinium-enhancing lesions were semiautomatically segmented at baseline and follow-up. Normal-appearing WM masks were generated by subtracting lesions and dirty-appearing WM from the whole WM. RESULTS: The orientation dispersion index was higher in gadolinium-enhancing compared with non-gadolinium-enhancing lesions; logistic regression indicated discrimination, with an area under the curve of 0.73. At follow-up, in the 58 previously enhancing lesions, we identified 2 subgroups based on the neurite density index change across time: Type 1 lesions showed increased neurite density values, whereas type 2 lesions showed decreased values. Type 1 lesions showed greater reduction in size with time compared with type 2 lesions. CONCLUSIONS: NODDI is a promising tool with the potential to detect acute MS inflammation. The observed heterogeneity among lesions may correspond to gradients in severity and clinical recovery after the acute phase.

The association of cognitive distortions and the type of gambling in problematic and disordered gambling.

BACKGROUND: Previous studies have shown that particular types of gambling are related to the development of gambling-related problems. Further, gambling-related cognitive distortions contribute to the development of disordered gambling. The aim of the present study is to compare different gambling types with respect to cognitive distortions and the development of disordered gambling. METHODS: Based on a proactively screened sample of vocational school students (N = 6718), 309 students were selected to undergo an in-depth interview. We assessed the Gamblers-Belief-Questionnaire (GBQ) to measure gambling-related cognitive distortions and the Stinchfield questionnaire for assessing gambling-related problems. Associations between cognitive distortions, gambling-related symptoms, and types of gambling were analysed using logistic regression analyses. RESULTS: Higher scores on the GBQ subscale "belief in luck/perseverance" led to a significantly higher chance to be classified as a person with Gambling Disorder (Conditional Odds Ratio (COR) = 1.05, Confidence Interval (CI) = 1.02-1.08) as well as problematic gambling (COR = 1.04, CI = 1.01-1.06). Higher scores on the subscale "illusion of control" were also associated with problematic gambling (COR = 1.04, CI = 1.00-1.08). The multivariate analyses of the gambling types identified only sports betting as a predictor for problematic gambling (COR = 1.91, CI = 1.05-3.49). When controlling for cognitive distortions, sports betting was not significant anymore. With respect to disordered gambling, gambling on electronic gambling machines (EGMs) turned out to be a risk factor besides cognitive distortions (COR = 2.59, CI = 1.04-6.49). DISCUSSION: The present study confirmed the high relevance of cognitive distortions for problematic and disordered gambling especially for sports betting and gambling on EGMs. Preventive measures and psychotherapy should take these relationships into account.

[Migration Background and Pathological Gambling: Results of a Nationwide Epidemiological Study on the Impact of Region of Origin in Germany]. / Migrationshintergrund und pathologisches Glücksspielen: Befunde einer deutschlandweiten epidemiologischen Untersuchung zur Bedeutung der Herkunftsregion.

OBJECTIVE: To investigate the extent to which the presence and number of symptoms of pathological gambling (PG), distinguished by region of origin (RO), differ. METHODS: Data was obtained from a nationwide telephone survey of 15 023 individuals living in Germany and aged 14-64 years. They were categorized according to their RO and the number of symptoms of PG (0-10 DSM-IV-criteria). RESULTS: The lifetime prevalence of PG symptoms is 18.1% for people of the RO Turkey, 9.0% for those of the RO Yugoslavia and 6.8% for those without a migration background. Compared to the latter, the two-part count data regression method showed a higher chance of PG symptoms for the RO Turkey as well as a 70.3 and 87.2% increase in the number of symptoms for the RO Turkey and Yugoslavia, respectively. CONCLUSION: The RO could independently contribute to the presence and amount of symptoms of PG.

Genome-wide association study of pathological gambling.

BACKGROUND: Pathological gambling is a behavioural addiction with negative economic, social, and psychological consequences. Identification of contributing genes and pathways may improve understanding of aetiology and facilitate therapy and prevention. Here, we report the first genome-wide association study of pathological gambling. Our aims were to identify pathways involved in pathological gambling, and examine whether there is a genetic overlap between pathological gambling and alcohol dependence. METHODS: Four hundred and forty-five individuals with a diagnosis of pathological gambling according to the Diagnostic and Statistical Manual of Mental Disorders were recruited in Germany, and 986 controls were drawn from a German general population sample. A genome-wide association study of pathological gambling comprising single marker, gene-based, and pathway analyses, was performed. Polygenic risk scores were generated using data from a German genome-wide association study of alcohol dependence. RESULTS: No genome-wide significant association with pathological gambling was found for single markers or genes. Pathways for Huntington's disease (P-value=6.63×10(-3)); 5'-adenosine monophosphate-activated protein kinase signalling (P-value=9.57×10(-3)); and apoptosis (P-value=1.75×10(-2)) were significant. Polygenic risk score analysis of the alcohol dependence dataset yielded a one-sided nominal significant P-value in subjects with pathological gambling, irrespective of comorbid alcohol dependence status. CONCLUSIONS: The present results accord with previous quantitative formal genetic studies which showed genetic overlap between non-substance- and substance-related addictions. Furthermore, pathway analysis suggests shared pathology between Huntington's disease and pathological gambling. This finding is consistent with previous imaging studies.

Prevalence of suicide attempts in pathological gamblers in a nationwide Austrian treatment sample.

BACKGROUND: For pathological gambling (PG), a 12-month prevalence rate of up to 0.66% has been reported. Multiple financial, occupational and relationship problems and losses, humiliation of the person and the environment are possible side effects and may lead to hopelessness, suicidal ideation and suicidal behavior. Suicide attempt rates among pathological gamblers of between 4% and 40% and suicidal ideation of between 12% and 92% have been reported. AIM: This study aims at assessing the prevalence of suicide attempts in PG and at elucidating differences between the patients with and without suicide attempt history (SAH) in a large nationwide Austrian sample. METHODS: Between 2002 and 2011, the Austrian Society for the Research of Non-Substance Related Addiction collected 862 questionnaires of pathological gamblers undergoing outpatient and inpatient treatment for PG in Austria. RESULTS: (a) Of all pathological gamblers, 9.7% had an SAH. (b) The SAH group suffered significantly more from a comorbid disorder and was more often in previous inpatient treatments. (c) The SAH patients had a longer time of an abstinence period in their PG career. DISCUSSION: One in 10 pathological gamblers has an SAH, demonstrating the relevance of suicidality in this population. Significant differences for several parameters were found for PG with and without SAH. However, a regression analysis only explained 15% of the variance. This suggests that suicidality must be considered in pathological gamblers in general.

Simultaneous computed tomography-guided biopsy and radiofrequency ablation of solitary pulmonary malignancy in high-risk patients.

BACKGROUND: In recent years experience has been accumulated in percutaneous radiofrequency ablation (RFA) of lung malignancies in nonsurgical patients. OBJECTIVES: In this study, we retrospectively evaluated a simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions. METHODS: CT-guided transthoracic core needle biopsy of solitary pulmonary lesions suspicious for malignancy was performed and histology was proven based on immediate frozen sections. RFA probes were placed into the pulmonary tumors under CT guidance and the ablation was performed subsequently. The procedure-related morbidity was analyzed. Follow-up included a CT scan and pulmonary function parameters. RESULTS: A total of 33 CT-guided biopsies and subsequent RFA within a single procedure were performed. Morbidity of CT-guided biopsy included pulmonary hemorrhage (24%) and a mild pneumothorax (12%) without need for further interventions. The RFA procedure was not aggravated by the previous biopsy. The rate of pneumothorax requiring chest tube following RFA was 21%. Local tumor control was achieved in 77% with a median follow-up of 12 months. The morbidity of the CT-guided biopsy had no statistical impact on the local recurrence rate. CONCLUSIONS: The simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions is a safe procedure. The potential of this combined approach is to avoid unnecessary therapies and to perform adequate therapies based on histology. Taking the local control rate into account, this approach should only be performed in those patients who are unable to undergo or who refuse surgery.

Control of domain wall polarity by current pulses.

Direct observation of current-induced propagation of purely transverse magnetic domain walls with spin-polarized scanning electron microscopy is reported in Fe30Ni70 nanowires. After propagation, the domain walls keep their transverse nature but switch polarity in some cases. For uniform Ni70Fe30 wires, the effect is random and illustrates domain-wall propagation above the Walker threshold. In the case of Ni{70}Fe_{30}/Fe wires, the transverse magnetization component in the wall is entirely determined by the polarity of the current pulse, an effect that is not reconciled by present theories even when taking into account the nonuniform Oersted field generated by the current.

Expression of the glycodelin A gene and the detection of its protein in tissues and serum of ovarian carcinoma patients.

BACKGROUND: Glycodelin A (GdA), also known as placental protein 14 (PP14), has been detected in endometrial, cervical and ovarian carcinoma cells. It is suspected to be a marker of human ovarian cancer tissues. MATERIALS AND METHODS: We investigated serum, tissue and cyst fluid samples of patients with an ovarian carcinoma in contrast to patients with benign and malignant diseases such as uterine myoma, endometriosis, cervical, uterine and breast cancer, and metastases of bladder and colon carcinoma. Used methods were enzyme-immunoassay, immunohistochemistry (IHC) and polymerase chain reaction (PCR). RESULTS: In 81% of the control group the GdA-expression was negative, which was confirmed by IHC and PCR. Of the ovarian carcinoma group only 52% showed correspondence between IHC and PCR. CONCLUSION: These results indicate that determination of GdA is not sensitive or specific enough for use as a tumour marker.

Direct observation of domain-wall configurations transformed by spin currents.

Direct observations of current-induced domain-wall propagation by spin-polarized scanning electron microscopy are reported. Current pulses move head-to-head as well as tail-to-tail walls in submicrometer Fe20Ni80 wires in the direction of the electron flow, and a decay of the wall velocity with the number of injected current pulses is observed. High-resolution images of the domain walls reveal that the wall spin structure is transformed from a vortex to a transverse configuration with subsequent pulse injections. The change in spin structure is directly correlated with the decay of the velocity.

Activation of the dopaminergic system of medial prefrontal cortex of gerbils during formation of relevant associations for the avoidance strategy in the shuttle-box.

1. A detailed analysis of behavior is a prerequisite for identification of components of information processing during learning. 2. Components of shuttle-box learning like the signal detection and signal evaluation can be differentiated using behavioral events such as the attention response and the orienting response. 3. Chiefly during evaluation of signal meaning in the acquisition phase of the avoidance strategy the extracellular DA is increased in mPFC. 4. The kinetics of prefrontal dopaminergic activation from trial to trial depends on the stage of avoidance learning. 5. The increase of DA in mPFC can be an indicator for the involvement of working memory principles in signal evaluation stages of conditioning.

A semiautomatic method for adding behavioral data to videotape records in combination with the Noldus Observer system.

The Observer 3.0 (Noldus, 1991) was used as the base for a time-saving fine analysis of animal behavior. A PC controlled a shuttlebox and a shuttlebox control unit. Learning behavior was recorded on videotapes by an S-VHS camcorder with vertical interval time code (VITC), which was used to generate an observational data file (ODF). The observational system was enhanced by automatically recorded status signals from the PC as event markers on the soundtrack of the videotape. These signals were used to subdivide a training session into numbered trials during generation of the ODF. They were later used for a PC-aided fine analysis of behavioral events, such as attention responses (AR) and orienting responses (OR) during shuttlebox learning. In this way, a large number of both automatically inserted PC event markers and manually inserted, key-defined behavioral events were registered and analyzed effectively in a semiautomatic fashion. The system is illustrated with an analysis of shuttle-box avoidance data from gerbils (Meriones unguiculatus).

Stages of avoidance strategy formation in gerbils are correlated with dopaminergic transmission activity.

This detailed analysis of behavior is aimed at the differentiation of the components of information processing during associative conditioning. In gerbils, the influences of various acquired non-avoidance strategies as pre-experience were studied during the learning of a standard avoidance task in the same shuttle-box. Identical cue stimuli, frequency-modulated tones as conditioned stimuli and electric footshocks as unconditioned stimuli, were used in various behavioral tasks. In addition to common parameters such as avoidance performance and reaction times, behavioral events such as the attention response and the orienting response were quantified. Thereby, components of shuttle-box learning such as signal detection and signal evaluation were found to be affected by pre-experience-dependent dynamics. Using a microdialysis technique during avoidance learning in the shuttle-box, we found that only strategy formation was correlated with high dopamine levels in medial prefrontal cortex. The increase in dopamine in medial prefrontal cortex may be an indicator of the involvement of working memory principles in signal evaluation stages of conditioning.

The inhibitory influence of an acquired escape strategy on subsequent avoidance learning in gerbils.

In gerbils an acquired non-avoidance strategy as pre-experience in a shuttle-box was studied in its influence on the learning of a standard avoidance paradigm. Thereby the same cue stimuli, frequency modulated tones (CS) and electric footshocks (US) were used in different behavioral paradigms. In the preexperience sessions the interstimulus interval between CS and US and on the other hand the escapability or inescapability of the US was varied. It was found that the experience with a relatively long interstimulus interval led to a prolonged maintenance of an acquired escape strategy during subsequent standard avoidance learning. This effect increased with the preexperience of an inescapable US. Additional insights into the temporal inhibition of avoidance learning by the pre-experience were provided by behavioral events like attention responses and orienting responses reflecting components of information processing.

Autonomous induction of proliferation, JNK and NF-alphaB activation in primary resting T cells by mobilized CD28.

Induction of proliferation in primary resting T cells requires engagement of both the antigen-specific TCR and the co-stimulatory receptor CD28. Here we report that CD28 functions as an autonomous mitogenic receptor which is mobilized by TCR signaling through cytoskeletal rearrangement. Shortcutting of TCR-dependent CD28 recruitment by stimulation with monoclonal antibodies specific for mobilized CD28 results in maximum proliferation and IL-2 secretion in primary resting T cells without activation of ZAP-70, a central component of the TCR's signal transduction machinery. Engagement of mobilized CD28 fully activates the c-Jun N-terminal kinase cascade and translocation of NF-alphaB, two key targets of signal integration in co-stimulation. We propose a two-step activation model for co-stimulation in primary resting T cells in which antigen recognition recruits co-stimulatory receptors which then autonomously transduce signals promoting T cell proliferation.

Expression of T-cell receptor beta-chain mRNA and protein in gamma/delta T-cells from euthymic and athymic rats: implications for T-cell lineage divergence.

The relationship between alpha/beta and gamma/delta T-cell lineages was studied in rats using RT-PCR analysis of TCRbeta transcripts in gamma/delta T-cell hybridomas and an intracellular staining technique to detect TCRbeta protein in primary gamma/delta T-cells. We report the presence of functional TCRbeta transcripts in 2/9 gamma/delta T-cell hybridomas. About 15% of peripheral gamma/delta T-cells and thymocytes also express TCRbeta protein, giving a minimum estimate for successful Tcrb rearrangement based on ex vivo single cell analysis. In athymic rats, gamma/delta T-cells expressing intracellular beta protein are present but at a lower frequency than in euthymic controls, suggesting that in the thymus, more gamma/delta T-cell precursors pass through a stage where functional beta rearrangement has occurred than in extrathymic sites. Analysis of TCR expression in purified transitory immature CD4-8+ (iCD8SP) thymocytes and their spontaneously developing CD4+8+ (DP) progeny showed that TCRy mRNA is expressed in iCD8SP cells but not in their immediate DP progeny that reinitiate RAG-I transcription and commence alpha/betaTCR expression. We conclude that rat gamma/delta T cells can separate from the alpha/beta lineage after TCRbeta expression, but not after entry into the DP compartment.

Increase of extracellular dopamine in prefrontal cortex of gerbils during acquisition of the avoidance strategy in the shuttle-box.

We examined whether extracellular dopamine (DA) increase in medial prefrontal cortex is correlated with the establishment or with the retrieval of an auditory avoidance strategy in a shuttle-box. Using microdialysis from right medial prefrontal cortex (mPFC) in combination with behavioral measures, gerbils were trained on a tone-footshock combination in two sessions on two successive days. Sessions in each animal involving avoidance strategy formation and avoidance strategy retrieval were differentiated post hoc by using the percentage of conditioned responses (CR) and other behavioral measures of training sessions. It was found that exclusively strategy formation correlated with high DA levels in mPFC.

Opposite CD4/CD8 lineage decisions of CD4+8+ mouse and rat thymocytes to equivalent triggering signals: correlation with thymic expression of a truncated CD8 alpha chain in mice but not rats.

Unselected CD4+8+ rat thymocytes, generated in vitro from their direct precursors, are readily converted to functional TCRhigh T cells by stimulation with immobilized TCR-specific mAb plus IL-2. Lineage decision invariably occurs toward CD4-8+, regardless of the timing of TCR stimulation after entry into the CD4+8+ compartment or the concentration of TCR-specific mAb used for stimulation. CD4-specific mAb synergizes with suboptimal TCR-specific mAb in inducing T cell maturation, but lineage decision remains exclusively CD4-8+. These results contrast with those obtained in mice, in which Abs to the TCR complex were shown to promote CD4+8- T cell maturation from CD4+8+ thymocytes. Surprisingly, when rat and mouse CD4+8+ thymocytes were stimulated with PMA/ionomycin under identical conditions, the opposite lineage commitment was observed, i.e., mouse thymocytes responded with the generation of CD4+8- and rat thymocytes with the generation of CD4-8+ cells. It thus seems that CD4+8+ thymocytes of the two species respond with opposite lineage decisions to strong activating signals such as given by TCR-specific mAb or PMA/ionomycin. A possible key to this difference lies in the availability of p56lck for coreceptor. supported signaling. We show that in contrast to mouse CD4+8+ thymocytes, which express both a complete and a truncated CD8 alpha-chain (CD8 alpha') unable to bind p56lck, rat thymocytes only express full-length CD8 alpha molecules. Mice, but not rats, therefore may use CD8 alpha' as a "dominant negative" coreceptor chain to attenuate the CD8 signal, thereby facilitating MHC class II recognition through the higher amount of p56lck delivered, and rats may use a different mechanism for MHC class distinction during positive selection.

In vitro model for the nuclear transport of the hepadnavirus genome.

Hepadnaviruses contain a DNA genome, but they replicate via an RNA intermediate, synthesized by the cellular RNA polymerase II in the nucleus of the infected cell. Thus, nuclear transport of the viral DNA is required in the viral life cycle. Protein-free DNA is only poorly imported into the nucleus, so one or more of the viral proteins must be involved in the transport of the viral genome. In order to identify these viral proteins, we purified woodchuck hepadnavirus (WHV) core particles from infected woodchuck liver, isolated WHV DNA, and extracted the covalent complex of viral polymerase from the particles using urea. Intact core particles, the polymerase-DNA complex, or protein-free WHV DNA from core particles was added to digitonin-permeabilized HuH-7 cells, in which the cytosol was substituted by rabbit reticulocyte lysate (RRL) and an ATP-generating system. The distribution of the viral genome was analyzed by semiquantitative PCR or by hybridization in total nuclei, RRL, nuclear membranes, and nucleoplasm. The polymerase-DNA complex was efficiently transported into the nucleus, as indicated by the resistance of the nucleus-associated DNA to a short-term treatment with DNase I of the intact nuclei. The DNA within core particles stayed mainly in the cytosol and remained protected against DNase I. A minor part of the encapsidated DNA was bound to nuclei. It was protected against DNase I but became accessible after disruption of the nuclei. Deproteinized viral DNA completely remained in the cytosol. These data show that the viral polymerase is probably sufficient for mediating the transport of a hepadnavirus genome into the nucleus and that the viral core particles may release the genome at the nuclear membrane.