Lower cognitive reappraisal capacity is related to impairments in attachment and personality structure in poly-drug use: an fMRI study.

Insecure attachment, impaired personality structure and impaired emotion regulation figure prominently in substance use disorders. While negative emotions can trigger drug-use and relapse, cognitive reappraisal may reduce emotional strain by promoting changes in perspective. In the present study, we explored behavioral and neural correlates of cognitive reappraisal in poly-drug use disorder by testing individuals' capability to generate cognitive reappraisals for aversive events (Reappraisal Inventiveness Test). 18 inpatients with poly-drug use disorder and 16 controls completed the Adult Attachment Scale, the Emotion Regulation Questionnaire, the Brief Symptom Inventory, the Wonderlic Personnel Test, and the Operationalized Psychodynamic Diagnosis Structure Questionnaire, as well as two versions of the Reappraisal Inventiveness Test (during fMRI and outside the lab). Compared to controls, polydrug inpatients reported impaired personality structure, attachment and emotion regulation abilities. In the Reappraisal Inventiveness Test, poly-drug inpatients were less flexible and fluent in generating reappraisals for anger-eliciting situations. Corresponding to previous brain imaging evidence, cognitive reappraisal efforts of both groups were reflected in activation of left frontal regions, particularly left superior and middle frontal gyri and left supplemental motor areas. However, no group differences in neural activation patterns emerged. This suggests that despite cognitive reappraisal impairments on a behavioral level, neural reflections of these deficits in poly-drug use disorder might be more complex.

Pinpointing Neural Correlates of Attachment in Poly-Drug Use: A Diffusion Tensor Imaging Study.

An increasing amount of evidence indicates the significance of attachment in the etiology of poly-drug use disorder (PUD). The aim of this study was to investigate associations between PUD and adult attachment in particular, with a focus on white matter (WM) fiber tract integrity. For this purpose, we selected several regions-of-interest based on previous findings which were examined for their role in PUD and estimated whole-brain associations between adult attachment and WM integrity. A total sample of 144 right-handed males were investigated (Age: M = 27; SD = 4.66). This included a group of patients diagnosed with PUD (n = 70) and a group of healthy controls (HC; n = 74). The Adult Attachment Scales (AAS) was applied to assess attachment attitudes in participants. Diffusion Tensor Imaging was used to investigate differences in WM integrity. The findings suggest substantially less attachment security in PUD patients compared to HC. Furthermore, PUD patients exhibited reduced integrity in WM fiber tracts, most pronounced in the bilateral corticospinal tract, the fronto-occipital fasciculus, and the right inferior longitudinal fasciculus. However, these results were not controlled for comorbid depressiveness. With regard to associations between adult attachment and WM integrity, the results for PUD patients indicate a negative relationship between "Comfort with Closeness" and the structural integrity of a cluster comprising parts of the right anterior thalamic radiation, the inferior fronto-occipital fasciculus and the uncinate fasciculus. Despite being limited by the cross-sectional design of this study, the results emphasize the significance of attachment in PUD etiology, both at a behavioral and a neurological level. Largely in line with previous research, the findings revealed tentative links between adult attachment and WM fiber tracts related to cognitive and affective functions in PUD patients.

The relationship between "Eyes Reading" ability and verbal memory in bipolar disorder.

In psychiatric disorders, neurocognitive impairments are prevalent and have been associated with poor outcome. Deficits in Theory of Mind (ToM, "mentalising") have also been observed in bipolar disorder (BD); however, the literature shows inconsistent data. The aim of this study was to explore ToM performance in a well-characterized sample of euthymic individuals with BD and its relationship with neurocognitive function. One hundred sixteen euthymic patients with BD between 18 and 74 years (mean age = 42.4, SD = 13.8) and 79 healthy controls (mean age = 39.8, SD = 16.5) were investigated with an extensive neurocognitive test battery (Trail Making Test A/B, d2 Test of Attention, Stroop Color-Word Test, California Verbal Learning Test, Multiple Choice Vocabulary Test). Additionally, all participants were given the Reading the Mind in the Eyes Test (RMET) to measure affective ToM, the ability to make assumptions about other people´s feelings. Overall, "Eyes Reading" performance was not impaired in individuals with BD compared with controls. However, a significant relationship between RMET and verbal memory in BD was shown, particularly in males. Data showed worse RMET performance in patients with memory deficits compared to patients without memory deficits and controls. Due to cross-sectional data, no conclusions can be made with respect to cause and effect.

White matter integrity in polydrug users in relation to attachment and personality: a controlled diffusion tensor imaging study.

The relationship between substance use disorders (SUD) and brain deficits has been studied extensively. However, there is still a lack of research focusing on the structural neural connectivity in long-term polydrug use disorder (PUD). Since a deficiency in white matter integrity has been reported as being related to various parameters of increased psychopathology, it might be considered an aggravating factor in the treatment of SUD. In this study we compared two groups of PUD inpatients (abstinent: n = 18, in maintenance treatment: n = 15) to healthy controls (n = 16) with respect to neural connectivity in white matter, and their relation to behavioral parameters of personality factors/organization and attachment styles. Diffusion Tensor Imaging was used to investigate white matter structure. Compared with healthy controls, the PUD patients showed reduced fractional anisotropy (FA) and increased radial diffusivity (RD) mainly in the superior fasciculus longitudinalis and the superior corona radiata. These findings suggest diminished neural connectivity as a result of myelin pathology in PUD patients. In line with our assumptions, we observed FA in the biggest cluster as negatively correlated with anxious attachment (r = 0.36, p < 0.05), personality dysfunctioning (r = -0.41; p < 0.01) as well positively correlated with personality factors Openness (r = 0.34; p < 0.05) and Agreeableness (r = 0.28; p < 0.05). Correspondingly these findings were inversely mirrored by RD. Further research employing enhanced samples and addressing longitudinally neuronal plastic effects of SUD treatment in relation to changes in personality and attachment is recommended.

Abdominal obesity is associated with impaired cognitive function in euthymic bipolar individuals.

OBJECTIVES: Overweight/obesity has been implicated to play a role in cognitive deficits in bipolar disorder (BD). This study aims to identify the relationship between body fat distribution and different domains of cognition in BD during euthymia. METHODS: A sample of 100 euthymic individuals with BD was measured with a cognitive test battery (i.e., Trail Making Test-A-B/TM-A/B, d2 Test of Attention, Stroop test, California Verbal Learning Test/CVLT) and an anthropometric measures set (body mass index, waist circumference, hip circumference, waist-to-hip-ratio, waist-to-height-ratio, and lipometry). Patient data were compared with a healthy control group (n = 64). RESULTS: Results show that overweight patients with BD exhibit lower performance in the TMT-A/B as well as in the free recall performance of the CVLT compared to normal-weight patients with BD and controls. In bipolar individuals, (abdominal) obesity was significantly associated with a poor cognitive performance. In bipolar females, associations with measures of verbal learning and memory were found; in bipolar males, associations with poor performance in the TMT-A/B and in the Stroop interference task were demonstrated. In controls, no associations were found. CONCLUSIONS: There are several possible pathways moderating the association between obesity and cognition in BD. Anthropometric and lipometry data underline the substantial mediating impact of body fat distribution on cognition in BD.

Serial position effects in patients with mild cognitive impairment and early and moderate Alzheimer's disease compared with healthy comparison subjects.

BACKGROUND/AIMS: This study aimed to investigate whether the serial position effects in memory can differentiate patients with different subtypes of mild cognitive impairment (MCI) from healthy controls and patients with different stages of Alzheimer's disease (AD). METHODS: The serial position effects was tested with the CERAD word list task in 184 persons (39 healthy control subjects, 15 amnestic MCI single domain subjects, 23 amnestic MCI multiple domain subjects, 31 nonamnestic MCI subjects, 45 early or mild AD patients, and 31 moderate AD patients). RESULTS: With progression of dementia, memory deficits increased and the impairment in the primacy effect during the learning trials advanced, whereas the recall of recent items was less impaired. The serial position profile of nonamnestic MCI patients resembled that of healthy control subjects, whereas amnestic MCI patients showed poorer performance in all 3 positions but no significant difference as a function of serial word position. CONCLUSION: Analyses of the serial position effect may be a useful complement to clinical neuropsychological measures for distinguishing amnestic MCI patients from normal aging and patients with different stages of dementia.

Induction of abscopal anti-tumor immunity and immunogenic tumor cell death by ionizing irradiation - implications for cancer therapies.

Although cancer progression is primarily driven by the expansion of tumor cells, the tumor microenvironment and anti-tumor immunity also play important roles. Herein, we consider how tumors can become established by escaping immune surveillance and also how cancer cells can be rendered visible to the immune system by standard therapies such as radiotherapy or chemotherapy, either alone or in combination with additional immune stimulators. Although local radiotherapy results in DNA damage (targeted effects), it is also capable of inducing immunogenic forms of tumor cell death which are associated with a release of immune activating danger signals (non-targeted effects), such as necrosis. Necrotic tumor cells may result from continued exposure to death stimuli and/or an impaired phosphatidylserine (PS) dependent clearance of the dying tumor cells. In such circumstances, mature dendritic cells take up tumor antigen and mediate the induction of adaptive and innate anti-tumor immunity. Locally-triggered, systemic immune activation can also lead to a spontaneous regression of tumors or metastases that are outside the radiation field - an effect which is termed abscopal. Preclinical studies have demonstrated that combining radiotherapy with immune stimulation can induce anti-tumor immunity. Given that it takes time for immunity to develop following exposure to immunogenic tumor cells, we propose practical combination therapies that should be considered as a basis for future research and clinical practice. It is essential that radiation oncologists become more aware of the importance of the immune system to the success of cancer therapy.

High hydrostatic pressure treatment generates inactivated mammalian tumor cells with immunogeneic features.

Most of the classical therapies for solid tumors have limitations in achieving long-lasting anti-tumor responses. Therefore, treatment of cancer requires additional and multimodal therapeutic strategies. One option is based on the vaccination of cancer patients with autologous inactivated intact tumor cells. The master requirements of cell-based therapeutic tumor vaccines are the: (a) complete inactivation of the tumor cells; (b) preservation of their immunogenicity; and (c) need to remain in accordance with statutory provisions. Physical treatments like freeze-thawing and chemotherapeutics are currently used to inactivate tumor cells for vaccination purposes, but these techniques have methodological, therapeutic, or legal restrictions. For this reason, we have proposed the use of a high hydrostatic pressure (HHP) treatment (p >or= 100 MPa) as an alternative method for the inactivation of tumor cells. HHP is a technique that has been known for more than 100 years to successfully inactivate micro-organisms and to alter biomolecules. In the studies here, we show that the treatment of MCF7, B16-F10, and CT26 tumor cells with HHP >or= 300 MPa results in mainly necrotic tumor cell death forms displaying degraded DNA. Only CT26 cells yielded a notable amount of apoptotic cells after the application of HHP. All tumor cells treated with >or= 200 MPa lost their ability to form colonies in vitro. Furthermore, the pressure-inactivated cells retained their immunogenicity, as tested in a xenogeneic as well as syngeneic mouse models. We conclude that the complete tumor cell inactivation, the degradation of the cell's nuclei, and the retention of the immunogeneic potential of these dead tumor cells induced by HHP favor the use of this technique as a powerful and low-cost technique for the inactivation of tumor cells to be used as a vaccine.

Trimer stability of YadA is critical for virulence of Yersinia enterocolitica.

Yersinia adhesin A (YadA) is a trimeric autotransporter adhesin with multiple functions in host-pathogen interactions. The aim of this study was to dissect the virulence functions promoted by YadA in vitro and in vivo. To accomplish this, we generated Yersinia enterocolitica O:8 mutants expressing point mutations in YadA G389, a highly conserved residue in the membrane anchor of YadA, and analyzed their impact on YadA expression and virulence functions. We found that point mutations of YadA G389 led to impaired transport, stability, and surface display of YadA. YadA G389A and G389S mutants showed comparable YadA surface expression, autoagglutination, and adhesion to those of wild-type YadA but displayed reduced trimer stability and complement resistance in vitro and were 10- to 1,000-fold attenuated in experimental Y. enterocolitica infection in mice. The G389T, G389N, and G389H mutants lost trimer stability, exhibited strongly reduced surface display, autoagglutination, adhesion properties, and complement resistance, and were avirulent (>10,000-fold attenuation) in mice. Our data demonstrate that G389 is a critical residue of YadA, required for optimal trimer stability, transport, surface display, and serum resistance. We also show that stable trimeric YadA protein is essential for virulence of Y. enterocolitica.

[Differences between men and women in side effects of second-generation antipsychotics]. / Neuere Antipsychotika. Unterschiede im Nebenwirkungsprofil bei Frauen und Männern.

In this review we investigate whether sex differences exist for side effects of second-generation antipsychotics. Results are based on a MEDLINE search for the years 1974 through 2005. Even if pharmacokinetics differ between females and males, significantly higher plasma levels for women have been demonstrated only for olanzapine and clozapine. Hyperprolactinaemia is mainly induced by treatment with risperidone and amisulpride, and there is evidence for more pronounced prolactin levels in females. Most studies reviewed indicate that clozapine and olanzapine are associated with more body weight gain, once more especially in female patients. Furthermore, the few published studies indicate that metabolic syndrome is more frequent in females and there are likely no gender-specific differences between the new antipsychotic medications concerning frequency and degree of acute or chronic movement disturbance. The risk of QT prolongation with torsades de pointes arrhythmia is again higher in females. In conclusion, there is some evidence of sex differences in the side effects of second-generation antipsychotics. For better understanding of the basic mechanisms in sex differences, future studies with a primary focus on this topic are required. More specific data will help to determine how these differences shall affect clinical management.

[Gender differences in cognitive functions]. / Geschlechtsunterschiede kognitiver Leistungen -- populärwissenschaftliche Stereotypien oder evidenzbasierte Studienergebnisse?

Gender differences in neuropsychological functioning of patients with psychiatric disorders have been studied extensively in the last years. The available studies provide conflicting results, which can be attributed to the complexity of variables influencing cognitive sex differences. In this article we review the literature about gender differences in cognitive functions in healthy men and women and discuss the relevance of hormones, socio-cultural factors, educational factors and training on the occurrence of these sex differences. Furthermore we summarize the results from functional MRI experiments, which is a useful tool for noninvasively localizing areas in the brain involved in specific cognitive functions.

Brain activation pattern during a verbal fluency test in healthy male and female volunteers: a functional magnetic resonance imaging study.

Sex differences in executive speech tasks, favoring women, have been noted in behavioral studies and functional imaging studies. In the present study ten female and ten male volunteers underwent functional magnetic resonance imaging in a conventional block design. All subjects were selected on the basis of high performance on the verbal fluency task. Regions of activation were detected after performance of a covert lexical verbal fluency task inside the scanner. Men and women who did not differ significantly in verbal fluency task performance showed a very similar pattern of brain activation. Our data argue against genuine between-sex differences in cerebral activation patterns during lexical verbal fluency activities when confounding factors like performance differences are excluded.

[The unmasking of secondary adrenal insufficiency and central diabetes insipidus by a highly febrile acute Hantaan virus infection]. / Demaskierung einer sekundären Nebennierenrindeninsuffizienz und eines Diabetes insipidus centralis durch eine hochfieberhafte akute Hantaan-Virus-Infektion.

CASE REPORT: A 32-year-old obese patient was admitted to our hospital as an emergency with very severe abdominal pain. Routine examinations initially failed to establish a diagnosis. The patient then went on to develop a high fever that was associated with polydipsia and polyuria. Serological studies revealed an acute infection with the Hantaan virus. Laboratory investigations showed hypofunction of the anterior and posterior lobes of the pituitary, with complete absence of ACTH, which was caused by two germinomas located intracranially. CONCLUSION: The clinical symptoms had thus been the result of acute secondary insufficiency of the adrenal cortex, which was unmasked by the acute, highly febrile Hantaan viral infection.

Ventilatory responses to cooling the ventrolateral medullary surface of awake and anesthetized goats.

The ventrolateral medulla (VLM) has been reported to be important as a source of tonic facilitation of dorsal respiratory neurons and as a site critical for respiratory rhythmogenesis. We investigated these theories in awake and anesthetized goats (n = 13) by using chronically implanted thermodes to create reversible neuronal dysfunction at superficial VLM sites between the first hypoglossal rootlet and the pontomedullary junction (area M (rostral) and area S). During halothane anesthesia (arterial PCO2 = 57.4 +/- 4.5 Torr), bilateral cooling (thermode temperature = 20 degrees C) of 60-100% of areas M and S for 30 s produced a sustained apnea (46 +/- 4 s) that lasted beyond the period of cooling. While the animals were awake (arterial PCO2 = 36.0 +/- 1.9 Torr), cooling the identical region in the same goats resulted in a decrease (approximately 50%) in pulmonary ventilation, with a brief apnea seen only in one goat. Reductions in both tidal volume and frequency were observed. Qualitatively similar responses were obtained when cooling caudal area M-rostral area S and rostral area M, but the responses were less pronounced. Minimal effects were seen in response to cooling caudal area S. During anesthesia, breathing is critically dependent on superficial VLM neurons, whereas in the awake state these neurons are not essential for the maintenance of respiratory rhythm. Our data are consistent with these superficial VLM neuronal regions providing tonic facilitation to more dorsal respiratory neurons in both the anesthetized and awake states.

Ectopic ACTH secretion due to a bronchopulmonary carcinoid localized by somatostatin receptor scintigraphy.

We present the case of a 65-year-old woman with an adrenocorticotropic hormone (ACTH) secreting bronchopulmonary carcinoid. This patient showed the typical long history of Cushing's syndrome, including hypokaliemia, impaired glucose tolerance, high levels of ACTH and beta-endorphin, and coproduction of other peptides. At the onset of clinical symptoms in 1979 an adrenal adenoma was suspected, and left-sided adrenalectomy was performed. The symptoms soon recurred, and the diagnosis of ACTH-dependent Cushing's syndrome was made. As no ACTH-secreting tumor was found, the right adrenal was resected, and the patient was followed up regularly. Fourteen years later chest roentgenography and computed tomography revealed a para-aortic pulmonary lesion, which was suspicious for a bronchopulmonary carcinoid. ACTH and beta-endorphin were excessively, pancreatic polypeptide slightly elevated at that time. The final diagnosis was made using somatostatin receptor scintigraphy which confirmed the hormonal activity of the suspicious lesion; no additional focus was found. This method turned out to be not only a useful additional localization technique but also a promising tool for characterization and staging of a suspected ACTH-producing carcinoid. The tumor was resected curatively, and the diagnosis was confirmed histologically.

Unrecognized cognitive impairment in cardiac rehabilitation patients.

To determine the prevalence of unrecognized brain dysfunction accompanying chronic severe cardiac disease, we examined 20 clinically stable consecutive admissions to a cardiac rehabilitation service who were free of known stroke or dementia. Age range was 47 to 85 years (mean +/- SEM, 72.5 +/- 2.1 years), the male: female ratio was 10:10. Multiple cognitive deficits including significant memory impairment and disorientation were present in eight patients (40%), and seven of these eight patients were unable to administer their own medications reliably. An additional six patients (30%) showed milder impairments. One patient was found to be normal after neurological examination, four showed evidence of a single brain lesion, and 15 of 20 (75%) had multiple neurological abnormalities suggesting multifocal brain disease. The mechanism of cognitive deficits in cardiac patients is unclear, and it may be related to multiple infarcts, or acute or chronic hypoxic damage secondary to arrhythmias, cardiac failure, or small vessel disease of the brain. The term "circulatory dementia" is proposed to describe patients with vascular disease and non-Alzheimer type dementia. Patients with cardiac disease should undergo cognitive screening, as early identification of patients at risk of progressive intellectual loss may allow early use of preventive therapy.