Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer.

Breast cancer is the most common cancer among females. Approximately 30% of cancer patients develop depression or depressive adaptation disorder within 5 years post diagnosis. Low grade inflammation and subsequent changes in neurotransmitter levels could be the pathophysiological link. In the current study we investigated the association of neurotransmitter precursor amino acids with a diagnosis of depression or state anxiety in 154 subjects suffering from breast cancer (BCA(+)), depression (DPR(+)), both or neither. Sociodemographic parameters, severity of depressive symptoms, and state anxiety (ANX) were recorded. Neopterin, kynurenine/tryptophan and phenylalanine/tyrosine were analysed by HPLC or ELISA. Significantly higher serum neopterin values were found in DPR(+) patients (p = 0.034) and in ANX(+) subjects (p = 0.008), as a marker of Th1-related inflammation. The phenylalanine/tyrosine ratio (index of the catecholamine pathway) was associated with the factors "breast cancer" and "depression" and their interaction (all p < 0.001); it was highest in the DPR(+)BCA(+) group. The kynurenine/tryptophan ratio (index of the serotonin pathway) was significantly associated with the factors "breast cancer" and "state anxiety" and their interaction (p < 0.001, p = 0.026, p = 0.02, respectively); it was highest in the ANX(+)BCA(+) group. In BCA(+) patients kynurenine/tryptophan ratios correlated with severity of state anxiety (r = 0.226, p = 0.048, uncorrected) and phenylalanine/tyrosine ratios with severity of depressive symptoms (r = 0.376, p < 0.05, corrected). In conclusion, levels of neurotransmitter precursor amino acids correlate with mental health, an effect which was much more pronounced in BCA(+) patients than in BCA(-) subjects. Aside from identifying underlying pathophysiological mechanisms, these results could be the basis for future treatment studies: in BCA(+) patients with depression the use of serotonin-noradrenaline reuptake inhibitors might be recommended while in those with predominant anxiety selective serotonin reuptake inhibitors might be the treatment of choice.

[Delirium in patients with neurological diseases: diagnosis, management and prognosis]. / Delir in der Neurologie : Diagnose, Behandlung und Prognose.

Delirium is a common acute neuropsychiatric syndrome. It is characterized by concurrent disturbances of consciousness and attention, perception, reasoning, memory, emotionality, the sleep-wake cycle as well as psychomotor symptoms. Delirium caused by alcohol or medication withdrawal is not the subject of the current review. Specific predisposing and precipitating factors have been identified in delirium which converge in a common final pathway of global brain dysfunction. The major predisposing factors are older age, cognitive impairment or dementia, sensory deficits, multimorbidity and polypharmacy. Delirium is always caused by one or more underlying pathologies which need to be identified. In neurology both primary triggers of delirium, such as stroke or epileptic seizures and also secondary triggers, such as metabolic factors or medication side effects play a major role. Nonpharmacological interventions are important in the prevention of delirium and lead to an improvement in prognosis. Delirium is associated with increased mortality and in the long term the development of cognitive deficits and functional impairment.

Differential effects of eyes open or closed in darkness on brain activation patterns in blind subjects.

In functional brain imaging, specific task conditions can be compared to a reference condition which is often eyes-open or eyes-closed in darkness without the execution of a specific task. Previous fMRI studies in sighted subjects have shown that eyes-open in darkness, without visual stimulation, increases the relative activity in cortical ocular motor and attentional areas ("exteroceptive" state; contrast OPEN>CLOSED). By contrast, eyes-closed causes a relative signal increase in sensory systems ("interoceptive" state; contrast CLOSED>OPEN). In the present study we used fMRI to determine whether these differential brain activity states can also be found in congenitally blind subjects: there were intragroup differences between the OPEN and CLOSED conditions. These differences were, however, less pronounced and occurred in other areas than in sighted controls. The contrast OPEN>CLOSED revealed a relative signal increase in the left frontal eye field, the middle occipital gyrus bilaterally and in the anterior cingulum. Relative signal increases in occipital cortex areas and the anterior cingulum were also apparent for this contrast in the intergroup comparison (congenitally totally blind subjects vs. sighted controls). They reflect the increased attentional load or arousal during the eyes-open condition and could be indicative of a functional reorganization of the occipital cortex in the blind. The contrast CLOSED>OPEN in the congenitally totally blind subjects lead to relative activations in the somatosensory cortex bilaterally, the middle temporal gyrus on the left and the frontal gyri on the right. These activations are residues of the "interoceptive" state found in sighted controls.

Vestibular paroxysmia: diagnostic features and medical treatment.

BACKGROUND: Vestibular paroxysmia (VP), which is attributed to neurovascular cross-compression (NVCC), leads to vertiginous spells. Although VP was described more than 30 years ago by Jannetta and colleagues, we still need more reliable data on its diagnostic features and the efficacy of medical treatment. METHODS: A follow-up study of 32 patients with recurrent short spells of vertigo and with diagnosis of VP by published criteria was performed using medical records and patient consultation (mean follow-up time 31.3 months). RESULTS: In 28% of patients the attacks occurred exclusively when at rest, whereas in 22% they were regularly precipitated by a certain action, most frequently a head turn (60%). The most common accompanying symptom was unsteadiness of stance or gait (75%). Constructive interference in steady state magnetic resonance imaging (n = 23) demonstrated at least one site of NVCC in all but one patient. Caloric testing disclosed a mild increase in vestibular deficit over time, and a hyperventilation-induced nystagmus was found in 70% of the tested patients (n = 23). The majority of patients were treated with carbamazepine (mean dose 568 mg/d) or oxcarbazepine (mean dose 870 mg/d). Treatment led to a significant reduction in the attack frequency to 10% of baseline (95% CI 6.69-14.96%), in attack intensity to 15% (95% CI 11.57-19.63%), and a reduction in attack duration to 11% (95% CI 6.72-17.40), after adjusting for time effects. CONCLUSION: This follow-up proves the usefulness of the diagnostic criteria, especially constructive interference in steady state magnetic resonance imaging, and the therapeutic efficacy of medical treatment.

Differences in saccade-evoked brain activation patterns with eyes open or eyes closed in complete darkness.

In this study we attempted to differentiate distinct components of the saccade network, namely cortical ocular motor centers and parieto-occipital brain regions, by means of a "minimal design" approach. Using a blocked design fMRI paradigm we evaluated the BOLD changes in a 2 x 2 factorial design experiment which was performed in complete darkness: while looking straight ahead with eyes open (OPEN) or closed (CLOSED) as well as during the execution of self-initiated horizontal to-and-fro saccades with the eyes open (SACCopen) or closed (SACCclosed). Eye movements were monitored outside the scanner via electro-oculography and during scanning using video-oculography. Unintentional eye-drifts did not differ during OPEN and CLOSED and saccade frequencies, and amplitudes did not vary significantly between the two saccade conditions. The main findings of the functional imaging study were as follows: (1) Saccades with eyes open or closed in complete darkness lead to distinct differences in brain activation patterns. (2) A parieto-occipital brain region including the precuneus, superior parietal lobule, posterior part of the intraparietal sulcus (IPS), and cuneus was relatively deactivated during saccades performed with eyes closed but not during saccades with eyes open or when looking straight ahead. This could indicate a preparatory state for updating spatial information, which is active during saccades with eyes open even without actual visual input. The preparatory state is suppressed when the eyes are closed during the saccades. (3) Selected ocular motor areas, not including the parietal eye field (PEF), show a stronger activation during SACCclosed than during SACCopen. The increased effort involved in performing saccades with eyes closed, perhaps due to the unusualness of the task, may be the cause of this increased activation.

Structural and functional MRIs disclose cerebellar pathologies in idiopathic downbeat nystagmus.

BACKGROUND: Neurologic disorders in which the etiology and pathogenesis are not yet understood are termed idiopathic. Downbeat nystagmus (DBN) is a frequent eye movement disorder that clinically manifests with oscillopsia and postural instability. Forty percent of patients with DBN are classified as having idiopathic DBN, because no underlying pathology can be demonstrated by conventional MRI or laboratory tests. METHODS: We evaluated gray matter brain volumes of 11 patients with idiopathic DBN and compared them to those of healthy controls using voxel-based morphometry. In a second, functional MRI experiment, patients and controls performed downward smooth pursuit eye movements (DOWN), which were then compared with straight-ahead fixation of a stationary target (MID). RESULTS: Small areas of localized gray matter atrophy were detected in the lateral cerebellar hemispheres (lobule VI) and ocular motor vermis of patients with idiopathic DBN, but not in the flocculus and paraflocculus. The functional imaging data, however, revealed reduced activation in the parafloccular lobule and in the ponto-medullary brainstem of the patients when they performed smooth pursuit eye movements downwards. CONCLUSIONS: The applied specialized imaging and data analysis techniques disclosed pathologies in an idiopathic eye movement disorder. The focal atrophy found in the vermal and lateral cerebellar regions in downbeat nystagmus (DBN) may lead to deficits in smooth pursuit eye movement initiation, which in turn causes hypofunction of the parafloccular lobe, associated with DBN. Our data are in line with experiments in primates showing that ablation of the floccular and parafloccular lobes disrupts smooth pursuit and causes DBN.

Detection of floccular hypometabolism in downbeat nystagmus by fMRI.

The authors evaluated floccular activity with fMRI during the performance of vertical smooth pursuit eye movements in four patients with downbeat nystagmus (DBN) due to cerebellar degeneration and in 16 healthy controls. Region of interest analysis revealed a significantly diminished activation of both floccular lobes during downward but not upward pursuit in DBN. These imaging data support the view that a functional deficiency of the flocculi in downward pursuit causes DBN.

The verprolin-like central (vc) region of Wiskott-Aldrich syndrome protein induces Arp2/3 complex-dependent actin nucleation.

Wiskott-Aldrich Syndrome protein (WASp) and related proteins stimulate actin filament nucleation by Arp2/3 complex. The isolated C-terminal VCA domain of WASp (containing Verprolin-like, Central and Acidic regions) is constitutively active but autoinhibited in the full-length protein. This study compared the ability of parts of VCA fused to the C terminus of glutathione S-transferase (GST) to bind actin and Arp2/3 complex in vitro and to activate actin polymerization in vitro and in cells. Fluorescence anisotropy measurements showed that GST-CA and GST-A bound Arp2/3 complex with K(d) values of 0.11 microm and 1.0 microm, respectively, whereas GST-VC displayed almost undetectable binding (K(d) > 1 mm). However, GST-VC activated actin nucleation through Arp2/3 complex in vitro, though requiring 70-fold higher concentration than GST-VCA while neither GST-CA nor GST-A activated Arp2/3 complex in vitro, though both GST-CA and GST-A inhibited Arp2/3 complex activation by WASp VCA. None of these constructs bound WASp from macrophage lysates. Both GST-VC and GST-CA induced actin accumulations when microinjected into primary human macrophages or human endothelial vein cells. However, only microinjection of GST-VC led to a significant increase of cellular polymerized actin. Additionally, endogenous Arp2/3 complex, but not WASp, colocalized with these GST-VC-induced actin accumulations. These data suggest that WASp constructs lacking the A region, previously thought to be indispensable for actin nucleation, are able to bind and activate Arp2/3 complex in vitro and in vivo.

Microtubule-dependent formation of podosomal adhesion structures in primary human macrophages.

Podosomes are unique actin-rich adhesion structures of monocyte-derived cells such as macrophages and osteoclasts. They clearly differ from other substratum-contacting organelles like focal adhesions in morphological and functional regards. Formation of podosomes has been shown to be dependent on the small GTPase CDC42Hs and its effector Wiskott-Aldrich syndrome protein (WASp). In this study, we investigated the functional relation between podosomes and the microtubule system in primary human macrophages. We demonstrate that, in contrast to focal adhesions, assembly of podosomes in macrophages and their monocytic precursors is dependent on an intact microtubule system. In contrast, experiments using Wiskott-Aldrich syndrome (WAS) macrophages indicate that the microtubule system is not reciprocally dependent on podosomes. A potential linker between podosomes and microtubules may be WASp itself, considering that microinjection of the WASp polyproline domain prevents podosome reassembly. This polyproline domain is thought to link WASp to microtubules via CDC42 interacting protein 4 (CIP4). Consistently, macrophages microinjected with CIP4 constructs deficient in either the microtubule- or the WASp-binding domain also fail to reassemble podosomes. In sum, our findings show that microtubules are essential for podosome formation in primary human macrophages and that WASp and CIP4 may be involved in this phenomenon.

The polarization defect of Wiskott-Aldrich syndrome macrophages is linked to dislocalization of the Arp2/3 complex.

Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder originally characterized by the clinical triad eczema, thrombocytopenia, and severe immunodeficieny, with recurrent bacterial and viral infections, indicating a profound immune cell defect. Such altered immune cells include monocytes, macrophages, and dendritic cells, which were reported to display disturbed cell polarization or chemotaxis. WAS is caused by mutations in the WAS protein (WASp), which is thought to organize the actin cytoskeleton through the Arp2/3 complex. Here we show that the Arp2/3 complex is an integral part of podosomes, actin-rich adhesion structures of macrophages, and that WAS macrophages fail to organize the Arp2/3 complex into podosomes. We also demonstrate that microinjection of a C-terminal acidic stretch of WASp into normal macrophages displaces Arp2/3 from podosomes and, in combination with chemoattractant stimulation of cells, induces a phenotype resembling the polarization-defective phenotype of stimulated WAS macrophages. These findings point to an important role of the Arp2/3 complex in polarization and migration of immune cells.