Comparison of gluteus medius muscle activity in Haflinger and Noriker horses with polysaccharide storage myopathy.

Type 1 polysaccharide storage myopathy caused by genetic mutation in the glycogen synthase 1 gene is present in many breeds including the Noriker and Haflinger horses. In humans, EMG has already been used to document changes in the muscle activity patterns of patients affected by human glycogen storage disorders. Therefore, the aim of the present study was to describe gluteus muscle activity with surface electromyography (sEMG) in Haflinger and Noriker horses with known GYS1 mutation status during walk and trot. Thirty-two horses (11 Haflinger and 21 Noriker horses) with homozygous non-affected (GG), heterozygous affected (GA) and homozygous affected (AA) status of GYS1 mutation without overt clinical signs of any myopathy were selected for the current study. Using surface electromyography gluteus medius muscle activity at walk and at trot was measured, and muscle activity was described in relation to the maximum observed value at the same sensor and the same gait. In order to further describe the signals in detail comprising both frequencies and amplitudes, the crossings through the baseline and the 25, 50 and 75 percentile lines were determined. The result of the relative muscle activity did not show a consistent difference between affected and non-affected horses. Genetically affected (GA and AA) horses showed significantly less density of muscle activity for both gaits and horse breeds except for the crossings per second at the baseline and 75 percentile at walk in the Haflinger horses and 75 percentile at trot in the Noriker horses. The medians of all calculated density values were significantly lower in the GA Haflingers compared to the GG Haflingers (p = 0.012) and also in the AA Norikers compared to the GG Norikers (p = 0.011). Results indicate that the GYS1 mutation reduces the number of functional muscle fibres detected by sEMG measurements even in the absence of overt clinical signs.

From Colonial Research Spirit to Global Commitment: Bayer and African Sleeping Sickness in the Mirror of History.

In the early 20th century, a series of epidemics across equatorial Africa brought African sleeping sickness (human African trypanosomiasis, HAT) to the attention of the European colonial administrations. This disease presented an exciting challenge for microbiologists across Europe to study the disease, discover the pathogen and search for an effective treatment. In 1923, the first "remedy for tropical diseases"-Suramin-manufactured by Bayer AG came onto the market under the brand name "Germanin." The development and life cycle of this product-which today is still the medicine of choice for Trypanosoma brucei (T.b), hodesiense infections-reflect medical progress as well as the successes and failures in fighting the disease in the context of historic political changes over the last 100 years.

Long term consistency and location specificity of equine gluteus medius muscle activity during locomotion on the treadmill.

BACKGROUND: The equine m. gluteus medius (GM) is the largest muscle of the horse, its main movement function is the extension of the hip joint. The objective of the present study was to measure equine GM activity in three adjacent locations on GM during walk and trot on a treadmill, in order to document potential differences. Fourteen Haflinger mares were measured using surface electromyography and kinematic markers to identify the motion cycles on three occasions over 16 weeks. The electrodes were placed on left and right gluteus medius muscle over the middle of its widest part and 5 cm lateral and medial of it. For data processing, electrical activity was normalised to its maximum value and timing was normalised to the motion cycle. A Gaussian distribution approach was used to determine up to 10 modes of focussed activity, and results were analysed separately for stance and swing phase of the ipsilateral hindlimb. RESULTS: Fair reliability was found for mean mode values (Cronbach's alpha = 0.66) and good reliability was found for mean mode locations (Cronbach's alpha = 0.71) over the three data collection days. The magnitude of muscle activity identified as mean mode value was much larger at trot than at walk, and mean mode value was significantly different between stance phases of walk and trot for all electrode positions (p < 0.01). The pattern of muscle activity identified as mean mode location was significantly different for walk and trot at all electrode positions, both during stance and swing phases (p < 0.001). This indicates the different timing pattern between the gaits. Results of the three electrode positions on the same muscle during each gait were not significantly different when comparing the same measurement. CONCLUSIONS: The middle of the equine GM does not show any indication of functional differentiation during walk and trot on a treadmill; this might be due to lack of segmentation as such, or due to lack of need for segmented use for these very basic main tasks of the muscle. The reliability of the sEMG measurements over several weeks was fair to good, an indication for the robustness of the methodology.

Fractalkine (CX3CL1)- and interleukin-2-enriched neuroblastoma microenvironment induces eradication of metastases mediated by T cells and natural killer cells.

Fractalkine (FKN) is a unique CX3C chemokine (CX3CL1) known to induce both adhesion and migration of leukocytes mediated by a membrane-bound and a soluble form, respectively. Its function is mediated through CX3C receptor (CX3CR), which is expressed by T(H)1 immune cells including T cells and natural killer (NK) cells. FKN was shown to be expressed in >90% of 68 neuroblastoma samples as determined by cDNA microarray analysis. Here, we characterized the effect of FKN in the neuroblastoma microenvironment using a syngeneic model genetically engineered to secrete FKN. We show FKN-mediated migration, adhesion, and IFN-gamma secretion of immune effector cells, but limited antineuroblastoma activity, in vitro and in vivo. Therefore, we tested the hypothesis that a combined increase of FKN and interleukin-2 (IL-2) in the neuroblastoma microenvironment induces an effective antitumor immune response. For this purpose, IL-2 was targeted to ganglioside GD2, which is highly expressed on neuroblastoma tissue, using an anti-GD2 antibody IL-2 immunocytokine (ch14.18-IL-2). Only mice bearing FKN- and IL-2-enriched neuroblastoma tumors exhibited a reduction in primary tumor growth and a complete eradication of experimental liver metastases. The depletion of T cells and NK cells in vivo abrogated the effect, and these effector cells showed the highest cytolytic activity in vitro. Finally, only the FKN- and IL-2-enriched neuroblastoma microenvironment resulted in T-cell activation and the release of proinflammatory cytokines. In summary, we showed for the first time the immunologic mechanisms by which targeted IL-2 treatment of neuroblastoma with an FKN-rich microenvironment induces an effective antitumor response.

Pulmonary hypertension in a case of Hb-Mainz hemolytic anemia.

The development of pulmonary arterial hypertension (PAH) is the leading cause of mortality in patients with thalassemia and sickle cell anemia and was reported to occur in hemolytic anemias such as hereditary stomatocytosis, and paroxysmal nocturnal hemoglobinuria. Here, we report for the first time on the development of PAH in a patient with Hb-Mainz hemolytic anemia. Hb-Mainz is an unstable hemoglobin variant resulting from mutations at codon 98 of the beta chain gene (Val>Glu) characterized by severe chronic hemolytic anemia. The development of PAH in this patient further supports the contention that there is a clinical syndrome of hemolysis-associated development of PAH.

Partly dissociable neural substrates for recognizing basic emotions: a critical review.

Facial expressions are powerful non-verbal displays of emotion which signal valence information to others and constitute an important communicative element in social interaction. Six basic emotional expressions (fear, disgust, anger, surprise, happiness, and sadness) have been shown to be universal in their performance and perception. Recently, a growing number of clinical and functional imaging studies have aimed at identifying partly dissociable neural subsystems for recognizing basic emotions. Convincing results have been obtained for fearful and disgusted facial expressions only. Empirical evidence for a specialized neural representation of anger, surprise, sadness, or happiness is more limited, primarily due to lack of clinical cases with selective impairments in recognizing these emotions. In functional imaging research, the detection of dissociable neural responses requires direct comparisons of signal changes associated with the perception of different emotions, which are often not provided. Only recently has evidence been obtained that the recruitment of emotion-specific neural subsystems may be closely linked to characteristic facial features of single expressions such as the eye region for fearful faces. Investigations into the neural systems underlying the processing of such diagnostic cues for each of the six basic emotions may be helpful to further elucidate their neural representation.

A common neural basis for receptive and expressive communication of pleasant facial affect.

There is accumulating evidence suggesting that the visual representation of facial affect is closely linked to its motor representation. To examine whether perception of pleasant facial affect involves neural circuitries associated with its production, we performed an fMRI experiment with 'compressed image acquisition' where subjects smiled and observed movies depicting other people smiling within scan-free time intervals between the acquisition of each image volume. Overlaps between the brain activation during observation and execution of smile expressions were located in the right premotor cortex and pars opercularis of the inferior frontal gyrus, right parietal operculum (SII) and left anterior insula. Observation of smile expressions further yielded signal increases within the posterior superior temporal sulcus (STS), fusiform gyrus and ventral amygdala. The results show that perceiving and expressing pleasant facial affect share a common neural basis in areas concerned with motor as well as somato- and limbic-sensory processing. In concert with temporal regions serving the visual analysis of facial expressive features, a mapping of the observed expressions onto neural circuitries associated with the production of these expressions and its somatosensory consequences could provide a description of what the expression would feel like if produced in the observer. Such a mechanism is suggested to be important for empathic understanding of others' feelings.

Functional neuroanatomy of perceiving surprised faces.

Surprise is one of six emotions having a specific and universally recognized facial expression. Functional imaging and neuropsychologic studies have uncovered partly separable neural substrates for perceiving different facial expressions; however, the functional neuroanatomy of perceiving surprised faces has not yet been investigated. Using functional magnetic resonance imaging (fMRI), we aimed to identify the neural substrate of surprise perception from facial expressions. Based on the assumption of unexpectedness and novelty as elicitors of facial surprise reactions, we hypothesized recruitment of medial temporal lobe structures implicated in novelty detection during the perception of surprise in others. Healthy subjects were scanned while they were presented with surprised faces. As a control, they viewed faces depicting neutral or disgust expressions. Activations during the emotional conditions were contrasted with each other and with the neutral face condition. Compared to both control conditions, perception of surprised facial expressions yielded consistently increased signals in the parahippocampal region, an area associated previously with novelty detection. Our findings therefore suggest a close relation between perceiving surprise in others and the response to novel events. Additionally, we confirmed activation of the insula during perception of disgust expressions.

Subthalamic nucleus stimulation affects a frontotemporal network: a PET study.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become an effective strategy in the treatment of motor symptoms in advanced Parkinson's disease. However, clinical studies have shown that DBS can affect verbal fluency. Seven Parkinson's disease patients with bilateral DBS of the STN were studied with positron emission tomography (PET) to investigate the effects of STN stimulation on regional cerebral blood flow during a verbal fluency task. Activation of the right orbitofrontal cortex and verbal fluency-associated activation within a left-sided frontotemporal network were decreased during STN stimulation compared with the OFF state. Our results offer an explanation for the commonest neuropsychological side effect of STN stimulation and show that STN stimulation affects a frontotemporal network during a fluency task.

Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia.

Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor antitumor efficacy, systemic toxicity, and the induction of drug resistance. Here, we provide the first evidence that hydrolytically activated prodrugs may overcome these problems. For this purpose, VP16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate 2 novel prodrugs of VP16. First, we established a more than 3-log higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug-resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced multidrug resistance-1 gene (MDR-1)-mediated multidrug resistance in vitro in a newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1-mediated efflux. Third, in vivo studies showed a maximum tolerated dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only the mice treated with this prodrug revealed a complete and long-lasting regression of established, drug-resistant leukemia. In summary, the hydrolytically activated etoposide prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro and in vivo and provide proof of concept for a highly promising new strategy for the treatment of MDR-1 drug-resistant malignancies.