Activity and connectivity changes of central projection areas revealed by functional magnetic resonance imaging in NaV1.8-deficient mice upon cold signaling.

The voltage-gated sodium channel subtype NaV1.8 is expressed in the peripheral nervous system in primary afferent nociceptive C-fibers and is essential for noxious cold signaling. We utilized functional magnetic resonance imaging on NaV1.8-deficient (NaV1.8-/-) compared with wildtype (WT) mice to identify brain structures decoding noxious cold and/or heat signals. In NaV1.8-/- mice functional activity patterns, activated volumes and BOLD signal amplitudes are significantly reduced upon noxious cold stimulation whereas differences of noxious heat processing are less pronounced. Graph-theoretical analysis of the functional connectivity also shows dramatic alterations in noxious cold sensation in NaV1.8-/- mice and clearly reduced interactions between certain brain structures. In contrast, upon heat stimulation qualitatively quite the same functional connectivity pattern and consequently less prominent connectivity differences were observed between NaV1.8-/- and WT mice. Thus, the fact that NaV1.8-/- mice do not perceive nociceptive aspects of strong cooling in contrast to their WT littermates seems not only to be a pure peripheral phenomenon with diminished peripheral transmission, but also consists of upstream effects leading to altered subsequent nociceptive processing in the central nervous system and consequently altered connectivity between pain-relevant brain structures.

Coinheritance of hereditary spherocytosis and reversibility of cirrhosis in a young female patient with hereditary hemochromatosis.

Here we report a 33-years-old woman with hereditary spherocytosis and hemochromatosis due to homozygosity for the C282Y mutation of the HFE gene. The coinheritance of both conditions led to severe iron overload and liver cirrhosis at young age. The patient was treated by repeated phlebotomy, and reversibility of cirrhosis was documented by transient elastography. This report discusses the pathophysiology of iron accumulation in patients with hemolytic anemia combined with HFE C282Y homozygosity. The case indicates that patients with hematological disorders characterized by increased erythropoetic activity should be screened for HFE mutations.

Functional MRI reveals activation of a subcortical network in a 5-year-old girl with genetically confirmed myoclonus-dystonia.

We investigated a five-year-old girl suffering from genetically confirmed, action-induced myoclonus-dystonia (M-D) with functional magnetic resonance imaging (MRI). We compared the activation pattern by movements of her right hand as if drawing a picture, which elicited M-D, with simple snapping movements (without overt M-D). The drawing and snapping conditions resulted in activation of a motor network including the motor cortex, the putamen, and the cerebellar hemispheres. The direct comparison of the drawing condition with snapping as control revealed specific activations within the thalamus and the dentate nucleus. An age matched healthy control did not show significant activation within the thalamus or dentate nucleus.

Pharmacokinetic behaviour of levodopa and 3-O-methyldopa after repeat administration of levodopa/carbidopa with and without entacapone in patients with Parkinson's disease.

Addition of the catechol-O-methyltransferase (COMT) inhibitor entacapone (EN) prolongs plasma metabolism of levodopa (LD). Objectives were to determine the clinical response after EN addition and the plasma degradation of LD and 3-O-methyldopa [3-OMD]. Not optimum treated hospitalised patients with Parkinson's disease received the same LD dosage on the first day only with carbidopa (CD) and on the second day with CD and EN (t.i.d.) within a standardised setting. We scored motor symptoms and measured LD- and 3-OMD levels on both days at fixed moments. Motor impairment significant better improved probably due to significant higher maximum concentrations [C(max)] and computed area under the curve values of LD levels during the LD/CD/EN condition. Time to C(max) of LD was significantly delayed after the first two LD/CD/EN intakes. An impact of EN on 3-OMD levels appeared. A possibly augmented LD absorption and a prolonged LD metabolism after EN supplementation may contribute to a more continuous LD delivery to the brain.

Motor reorganization in asymptomatic carriers of a single mutant Parkin allele: a human model for presymptomatic parkinsonism.

Mutations in the Parkin gene are the most common known single cause of early-onset parkinsonism. It has been shown that asymptomatic carriers with a single mutant allele have latent presynaptic dopaminergic dysfunction in the striatum. Here we used functional MRI to map movement-related neuronal activity during internally selected or externally determined finger movements in 12 asymptomatic carriers of a Parkin mutation and 12 healthy non-carriers. Mean response times were 63 ms shorter during internally selected movements than during externally guided movements (P = 0.003). There were no differences in mean response times between groups (P > 0.2). Compared with externally determined movements, the internal selection of movements led to a stronger activation of rostral motor areas, including the rostral cingulate motor area (rCMA), rostral supplementary motor area, medial and dorsolateral prefrontal cortices. The genotype had a significant impact on movement-related activation patterns. Asymptomatic carriers showed a stronger increase in movement-related activity in the right rCMA and left dorsal premotor cortex, but only if movements relied on internal cues. In addition, synaptic activity in the rCMA had a stronger influence on activity in the basal ganglia in the context of internally selected movements in asymptomatic carriers relative to non-carriers. We infer that this reorganization of striatocortical motor loops reflects a compensatory effort to overcome latent nigrostriatal dysfunction.

The anterior cingulate cortex contains distinct areas dissociating external from self-administered painful stimulation: a parametric fMRI study.

The anterior cingulate cortex (ACC) has a pivotal role in human pain processing by integrating sensory, executive, attentional, emotional, and motivational components of pain. Cognitive modulation of pain-related ACC activation has been shown by hypnosis, illusion and anticipation. The expectation of a potentially noxious stimulus may not only differ as to when but also how the stimulus is applied. These combined properties led to our hypothesis that ACC is capable of distinguishing external from self-administered noxious tactile stimulation. Thermal contact stimuli with noxious and non-noxious temperatures were self-administered or externally applied at the resting right hand in a randomized order. Two additional conditions without any stimulus-eliciting movements served as control conditions to account for the certainty and uncertainty of the impending stimulus. Calculating the differences in the activation pattern between self-administered and externally generated stimuli revealed three distinct areas of activation that graded with perceived stimulus intensity: (i) in the posterior ACC with a linear increase during external but hardly any modulation for the self-administered stimulation, (ii) in the midcingulate cortex with activation patterns independent of the mode of application and (iii) in the perigenual ACC with increasing activation during self-administered but decreasing activation during externally applied stimulation. These data support the functional segregation of the human ACC: the posterior ACC may be involved in the prediction of the sensory consequences of pain-related action, the midcingulate cortex in pain intensity coding and the perigenual ACC is related to the onset uncertainty of the impending stimuli.

The cerebellum in the cerebro-cerebellar network for the control of eye and hand movements--an fMRI study.

The coordination of optical information and manipulation of objects in space by eye and hand movements is controlled by a cerebro-cerebellar network. The differential influence of prefrontal, motor, or parietal areas in combination with cerebellar areas, especially within the posterior hemispheres, on the control of eye and hand movements is not very well defined. Using fMRI we investigated the functional representation of isolated or combined eye and hand movements within the cerebellum and the impact of differential cognitive preload on the activation patterns. Each task consisted of the performance of saccades or hand movements triggered by a cue presented on a screen in front of the scanner. Saccades were tested for visually guided saccades, triple step saccades, and for visuospatial memory. Sequential finger opposition movements were tested for predictive and nonpredictive movements. Combined and isolated eye-hand reaching movements were tested toward a target presented in 5 different horizontal positions. Visually guided saccades activated the cerebellar vermis lobuli VI-VII, triple step saccades, including visuospatial memorization, in addition the cerebellar hemispheres lobuli VII-VIII. Sequential finger movements and reaching movements activated a cerebellar network consisting of the lobuli IV-VI, the vermis, and the lobuli VII-VIII with broader areas and additional regions especially within the lobus VII for more complex movements. The combined in contrast to the isolated performance of eye and hand movements demonstrated specialized activation foci within the cerebellar vermis and posterior hemispheres. We could demonstrate a differential representation of eye and hand movements within the cerebellum. Additional "cognitive" preload within a given task leads to additional activation of the posterior cerebellar hemispheres, with a subspecialization corresponding to premotor and parietal area connections.

Cerebellar neural responses related to actively and passively applied noxious thermal stimulation in human subjects: a parametric fMRI study.

Cerebellar activation is consistently found during noxious stimulation but little is known about its pain-related specificity. Under natural circumstances noxious stimuli are actively or passively delivered with concomitant tactile sensory stimulation. Using fMRI we therefore studied pain-related cerebellar activation with innocuous and noxious thermal stimuli in a parametric design taking motor execution as confounding factor into account. With respect to psychophysical pain ratings anterior vermal and ipsilateral hemispheric lobule VI activation was parametrically modulated for stimulus intensity in actively but not in passively elicited thermal stimulation. The cerebellum seems to be capable of distinguishing active from passive painful stimuli.

Cerebellar activation in opsoclonus: an fMRI study.

It is controversial whether opsoclonus is a cerebellar or brainstem disorder. Two patients whose opsoclonus largely disappeared on eye closure underwent fMRI. A comparison of these two states revealed neither vermal nor brainstem activation but rather a bilateral activation in the deep cerebellar nuclei in excess of what the authors found in healthy subjects. The results support a crucial role of the fastigial nucleus in opsoclonus.

Differential cerebellar activation related to perceived pain intensity during noxious thermal stimulation in humans: a functional magnetic resonance imaging study.

Little is known about the cerebellar involvement in pain processing in spite of the fact that the cerebellum probably plays a crucial role in pain-related behavior. Using functional magnetic resonance imaging we examined the differential cerebellar activation in 18 healthy subjects in relation to their perceived pain-intensity of noxious and non-noxious thermal stimuli. In contrast to non-noxious (40 degrees C) stimuli, noxious (48.5 degrees C) stimuli revealed activation in the deep cerebellar nuclei, anterior vermis and bilaterally in the cerebellar hemispheric lobule VI. With the same noxious stimulus (48.5 degrees C) there was differential cerebellar activation depending on the perceived pain intensity: high pain intensity ratings were associated with activation in ipsilateral hemispheric lobule III-VI, deep cerebellar nuclei and in the anterior vermis (lobule III). This differential cerebellar activation pattern probably reflects not only somatosensory processing but also perceived pain intensity that may be important for cerebellar modulation of nociceptive circuits.

Interindividual variation in CYP1A1 expression in breast tissue and the role of genetic polymorphism.

The cytochrome P4501A1 (CYP1A1) enzyme is regulated at the transcriptional level and its expression is influenced by genetic factors, polymorphisms in the structural and regulatory genes, and by environmental factors such as exposure to polycyclic aromatic hydrocarbons (PAHs). To investigate the role of CYP1A1 in breast cancer, we studied CYP1A1 expression in breast tissue, thereby taking all possible modifying factors into account. We measured CYP1A1 expression in 58 non-tumor breast tissue specimens from both breast cancer patients (n = 26) and cancer-free individuals (n = 32) using a newly developed reverse transcription-polymerase chain reaction assay. CYP1A1 expression varied between specimens approximately 400-fold and was independent of age. CYP1A1 expression was somewhat higher in tissue from breast cancer patients than in that from cancer-free individuals, but this difference was not statistically significant. Analysis for CYP1A1 genetic polymorphisms revealed eight variants, seven in the cancer-free group and one in the patient group. The variant genotype was not a good predictor of expression level. We conclude that high CYP1A1 expression could be a risk factor for breast cancer and that the known CYP1A1 polymorphisms are not good predictors of CYP1A1 expression.

Use of a collagen/elastin-membrane for the tissue engineering of dermis.

In an experimental model in rats, xenogeneic membranes consisting of processed native collagen and elastin were grafted to serve as a template for the formation of a neo-dermis, while in vitro-cultured autogeneic keratinocytes were applied on top of this to restore an epidermis. The process of tissue reconstruction and the digestion of the grafted membrane components were analysed by histological and immunohistochemical methods as well as electron microscopy. Approximately 3 weeks post grafting the membranes were completely vascularised and colonized by different types of cells. After 6 weeks, the collagenous fibres of the graft were mostly replaced by newly formed collagenous texture, whereas elastic membrane components were still present even after 20 weeks. In a second step, in vitro-cultured keratinocytes were applied onto the partially integrated membranes, resulting in an epithelial coverage of approximately 47% of the grafted area after 8-11 days. As early as on day 6 post application, a multilayered, partially differentiated epithelium, together with lymphocytes and Langerhans' cells, could be observed. After 10 days the formation of a basement membrane including anchoring fibrils appeared to be complete. This three-dimensional matrix structure offers a promising scaffold for a tissue engineering strategy to restore skin structure and function. Further experimental studies are in progress to test its applicability to human skin replacement.

Breast cancer detection: maps of 2 San Francisco Bay area counties.

OBJECTIVES: This study describes the incidence of late-stage and in situ breast cancer among White women, using specialized mapping techniques that reflect incidence adjusted for the population at risk, and applies these maps to characterize areas with high and low risk of breast cancer. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) database and the US Census Bureau were used to study the geographic distribution of breast cancer at the census-tract level in 2 San Francisco Bay Area counties for the years 1978 through 1982. Sociodemographic characteristics of areas with high and low incidence of the stage-specific disease were compared by means of a linear discriminant function. RESULTS: For late-stage breast cancer, the most important variables in discriminating high-risk from low-risk areas were college education, percentage of residents over age 65, and median income. The strongest ecologic indicators of high risk for in situ breast cancer were median income and percentage unemployed. CONCLUSIONS: This study demonstrates the usefulness of census tracts and sociodemographic measures of income and education in describing in situ and late-stage breast cancer.