TNFα-induced DLK activation contributes to apoptosis in the beta-cell line HIT.

Reduction in beta-cell mass and function contributes to the pathogenesis of diabetes mellitus type 2. The proinflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1ß have been implicated in the pathogenesis of this disease. Overexpression of the dual leucine zipper kinase (DLK) inhibits beta-cell function and induces apoptosis in the beta-cell line HIT. In the present study, it was investigated whether TNFα or IL-1ß stimulates DLK enzymatic activity. Immunoblot analysis, transient transfection with luciferase reporter gene assays, and immunofluorescence were used. In contrast to IL-1ß, TNFα stimulated DLK kinase activity, which was dependent on the c-Jun N-terminal kinase (JNK). Furthermore, DLK contributed to TNFα-induced JNK phosphorylation. The phosphorylation of DLK on Ser-302 within the activation loop was required for DLK to stimulate JNK and to inhibit CREB-dependent gene transcription. TNFα induced apoptosis in a time- and concentration-dependent manner and inhibited CREB-directed gene transcription in HIT cells. The reduction of endogenous DLK by small interfering or small hairpin RNA attenuated TNFα's effects on apoptosis and CREB-dependent transcription. These data suggest that TNFα induces beta-cell apoptosis through activation of DLK thereby inhibiting the beta-cell protective transcription factor CREB. Furthermore, activation of DLK by a well-known diabetic risk factor supports the role of DLK in the pathogenesis of diabetes mellitus. Thus, the inhibition of DLK might prevent or retard the pathogenesis of diabetes mellitus type 2.

The influence of object height on maximum grip aperture in empirical and modeled data.

During a grasping movement, the maximum grip aperture (MGA) is almost linearly scaled to the dimension of the target along which it is grasped. There is still a surprising uncertainty concerning the influence of the other target dimensions on the MGA. We asked healthy participants to grasp cuboids always along the object's width with their thumb and index finger. Independent from variations of object width, we systematically varied height and depth of these target objects. We found that taller objects were generally grasped with a larger MGA. At the same time, the slope of the regression of MGA on object width decreased with increasing target height. In contrast, we found no effect of varying target depth on the MGA. Simulating these movements with a grasping model in which the objective to avoid contact of the digits with the target object at positions other than the goal positions was implemented yielded larger effects of target height than of target depth on MGA. We concluded that MGA does not only depend on the dimension of the target object along which it is grasped. Furthermore, the effects of the other 2 dimensions are considerably different. This pattern of results can partially be explained by the aim to avoid contacting the target object at positions other than the goal positions.

Limb apraxia in acute ischemic stroke: a neglected clinical challenge?

Symptoms of limb apraxia and executive dysfunctions are currently not explicitly considered by the National Institutes of Health Stroke Scale and, thus, not routinely tested by clinicians in the acute care of patients with suspected stroke. Neuropsychological testing, clinical examination, MRI, and functional magnetic resonance imaging (fMRI) were performed in a right-handed patient with acute onset of left-sided sensorimotor hemiparesis due to a right hemisphere ischemic stroke. Deficits in the execution of meaningless and meaningful gestures were not detected properly on initial clinical examination but were revealed later on through neuropsychological testing. Instead, the patient's inability to respond to specific instructions in the acute care setting was mistaken to reflect severe deficits in auditory comprehension. fMRI revealed right-hemispheric localization of language in the right-handed patient. We suggest including a bedside test for limb apraxia symptoms in acute clinical care of stroke patients. The distinction between deficits in limb praxis and impairments of language can be complicated owing to the common hemispheric co-localization of the two functions.

Routine clinical testing underestimates proprioceptive deficits in Friedreich's ataxia.

Friedreich's ataxia (FA) is the most common recessive ataxia in the Western world with degeneration of dorsal root ganglia neurons as its major neuropathological hallmark. The sensitivity of clinical tools commonly used for the assessment of the proprioceptive component of FA is currently unknown. We hypothesised that current clinical testing underestimates proprioceptive deficits in FA patients. Such an underestimation would hamper our understanding of the components of FA, the monitoring of disease progression, and the detection of deficits in the current advent of drug trials. We compared clinical tests for joint position sense (JPS) and vibration sense (VS) to a test of spatial position sense (SPS) that examines localisation of both hands across a horizontal 2D space. We tested 22 healthy controls to derive a cut-off for the SPS. Eleven patients with genetically confirmed FA participated in this study. All 11 FA patients were impaired in the SPS test. Two patients showed unimpaired JPS and VS. Two additional patients showed unimpaired JPS, while two other patients unimpaired VS. The SPS test was more sensitive and revealed deficits potentially earlier than clinical screening tests. Only the SPS showed a positive correlation with ataxia severity. The SPS was more sensitive than the commonly used JPS and VS. Thus, our results indicate that proprioceptive deficits in FA start earlier and are more severe than indicated by routine standard clinical testing. The contribution of proprioceptive deficits to the impairment of FA patients might therefore indeed be underestimated today.

Guidelines and quality measures for the diagnosis of optic ataxia.

Since the first description of a systematic mis-reaching by Bálint in 1909, a reasonable number of patients showing a similar phenomenology, later termed optic ataxia (OA), has been described. However, there is surprising inconsistency regarding the behavioral measures that are used to detect OA in experimental and clinical reports, if the respective measures are reported at all. A typical screening method that was presumably used by most researchers and clinicians, reaching for a target object in the peripheral visual space, has never been evaluated. We developed a set of instructions and evaluation criteria for the scoring of a semi-standardized version of this reaching task. We tested 36 healthy participants, a group of 52 acute and chronic stroke patients, and 24 patients suffering from cerebellar ataxia. We found a high interrater reliability and a moderate test-retest reliability comparable to other clinical instruments in the stroke sample. The calculation of cut-off thresholds based on healthy control and cerebellar patient data showed an unexpected high number of false positives in these samples due to individual outliers that made a considerable number of errors in peripheral reaching. This study provides first empirical data from large control and patient groups for a screening procedure that seems to be widely used but rarely explicitly reported and prepares the grounds for its use as a standard tool for the description of patients who are included in single case or group studies addressing optic ataxia similar to the use of neglect, extinction, or apraxia screening tools.

Effects of pictorial cues on reaching depend on the distinctiveness of target objects.

There is an ongoing debate under what conditions learned object sizes influence visuomotor control under preserved stereovision. Using meaningful objects (matchboxes of locally well-known brands in the UK) a previous study has nicely shown that the recognition of these objects influences action programming by means of reach amplitude and grasp pre-shaping even under binocular vision. Using the same paradigm, we demonstrated that short-term learning of colour-size associations was not sufficient to induce any visuomotor effects under binocular viewing conditions. Now we used the same matchboxes, for which the familiarity effect was shown in the UK, with German participants who have never seen these objects before. We addressed the question whether simply a high degree of distinctness, or whether instead actual prior familiarity of these objects, are required to affect motor computations. We found that under monocular and binocular viewing conditions the learned size and location influenced the amplitude of the reaching component significantly. In contrast, the maximum grip aperture remained unaffected for binocular vision. We conclude that visual distinctness is sufficient to form reliable associations in short-term learning to influence reaching even for preserved stereovision. Grasp pre-shaping instead seems to be less susceptible to such perceptual effects.

The recognition of everyday objects changes grasp scaling.

Current concepts of action and perception emphasise a dissociation between conscious visual recognition and visual action control. These models do not expect an effect of the recognisable identity of an object on the kinematic parameterisation of grasping movements under binocular viewing conditions without pre-test learning periods. We performed two experiments presenting participants with familiar everyday objects or neutral geometrical objects. The participants grasped either with full vision or without visual feedback after movement onset without an explicit training phase before the experiment. In general, the familiarity of objects increased the sensitivity to physical object size changes measured by the slope of the maximal grip aperture relative to object size. We conclude that associations between object identity and a particular size, presumably encoded in long-term memory, are integrated in the parameterisation of grasping movements upon the identification of individual objects.

Eye proprioception used for visual localization only if in conflict with the oculomotor plan.

Both the corollary discharge of the oculomotor command and eye muscle proprioception provide eye position information to the brain. Two contradictory models have been suggested about how these two sources contribute to visual localization: (1) only the efference copy is used whereas proprioception is a slow recalibrator of the forward model, and (2) both signals are used together as a weighted average. We had the opportunity to test these hypotheses in a patient (R.W.) with a circumscribed lesion of the right postcentral gyrus that overlapped the human eye proprioceptive representation. R.W. was as accurate and precise as the control group (n = 19) in locating a lit LED that she viewed through the eye contralateral to the lesion. However, when the task was preceded by a brief (<1 s), gentle push to the closed eye, which perturbed eye position and stimulated eye proprioceptors in the absence of a motor command, R.W.'s accuracy significantly decreased compared with both her own baseline and the healthy control group. The data suggest that in normal conditions, eye proprioception is not used for visual localization. Eye proprioception is, however, continuously monitored to be incorporated into the eye position estimate when a mismatch with the efference copy of the motor command is detected. Our result thus supports the first model and, furthermore, identifies the limits for its operation.

Direct electrical stimulation of human cortex - the gold standard for mapping brain functions?

Despite its clinical relevance, direct electrical stimulation (DES) of the human brain is surprisingly poorly understood. Although we understand several aspects of electrical stimulation at the cellular level, surface DES evokes a complex summation effect in a large volume of brain tissue, and the effect is difficult to predict as it depends on many local and remote physiological and morphological factors. The complex stimulation effects are reflected in the heterogeneity of behavioural effects that are induced by DES, which range from evocation to inhibition of responses - sometimes even when DES is applied at the same cortical site. Thus, it is a misconception that DES - in contrast to other neuroscience techniques - allows us to draw unequivocal conclusions about the role of stimulated brain areas.

Bilateral hand representations in human primary proprioceptive areas.

Sensory representations in the postcentral gyrus are supposed to be strictly lateralised and to provide spatially unbiased representations of limb positions. However, electrophysiological and behavioural measurements in humans and non-human primates tentatively suggested some degree of bilateral processing even in early somatosensory areas. We report a patient who suffered a small and confined lesion of the hand area in the postcentral gyrus that resulted in a proprioceptive deficit without any concomitant primary motor impairment. We performed a finger position-matching task with target locations being defined proprioceptively. Without visual feedback of either hand, the patient demonstrated a significant leftward shift of perceived locations when reaching with the ipsilesional right hand to her contralesional left hand and an opposite rightward shift when reaching with the left hand to the position of the right hand. Although these directional errors improved when vision of the active hand was allowed, errors were still significantly larger than those of age-matched healthy controls with unconstrained view of the active contralesional hand. Reaching to visual targets without visual online feedback the patient revealed comparable errors with both hands. Reaching to visual targets with full visual feedback, she was as accurate as controls with either hand. In summary, our data demonstrate an effect of the right postcentral lesion on proprioceptive information processing for both hands. The results suggest an integration of contralateral and ipsilateral proprioceptive information already at this early processing stage possibly mediated by callosal connections.

Visual action control does not rely on strangers--effects of pictorial cues under monocular and binocular vision.

Fast goal-directed actions are supposed to be controlled almost exclusively by bottom-up visual control. This mode of processing has been identified with the so-called dorsal visual stream. It is generally accepted that object recognition, mediated by the ventral stream, must be important for deciding what action to execute depending on the specific object to be grasped and the particular purpose. In contrast, the kinematic parameters of the actual movement itself are supposed to be unaffected by recognition processes. This view was recently challenged by the demonstration of a significant impact of object familiarity on grasping kinematics under binocular visual control (McIntosh & Lashley, 2008). This effect was observed for very well known everyday objects. However, it remained unclear whether the effect was really due to long-term, everyday familiarity of the target objects or whether it was simply mediated by short-term learning during the experiment. Therefore, we examined whether the same effect could also be found with objects that were geometrically identical to the ones used by McIntosh and Lashley (2008) and could be distinguished by a pictorial cue but were not associated with long-term, everyday experience. We only found an effect of familiarity under monocular but not under binocular control. Our observation suggests that indeed familiarity exerts an effect on movements under binocular control only if explicit knowledge about the objects is very stable and salient, e.g. after long-term experience.

Comment on "Movement intention after parietal cortex stimulation in humans".

Desmurget et al. (Reports, 8 May 2009, p. 811) applied direct electrical stimulation (DES) to the human cortex to study the origin of movement intention. Their interpretation assumed that DES causes cortical activation, whereas it is possible that it actually evokes deactivation. The lack of certain knowledge about the true effects of DES limits its use for validation of cognitive models.

Activation of the dual-leucine-zipper-bearing kinase and induction of beta-cell apoptosis by the immunosuppressive drug cyclosporin A.

Post-transplant diabetes is an untoward effect often observed under immunosuppressive therapy with cyclosporin A. Besides the development of peripheral insulin resistance and a decrease in insulin gene transcription, a beta-cell toxic effect has been described. However, its molecular mechanism remains unknown. In the present study, the effect of cyclosporin A and the dual leucine-zipper-bearing kinase (DLK) on beta-cell survival was investigated. Cyclosporin A decreased the viability of the insulin-producing pancreatic islet cell line HIT in a time- and concentration-dependent manner. Upon exposure to the immunosuppressant fragmentation of DNA, the activation of the effector caspase-3 and a decrease of full-length caspase-3 and Bcl(XL) were observed in HIT cells and in primary mature murine islets, respectively. Cyclosporin A and tacrolimus, both potent inhibitors of the calcium/calmodulin-dependent phosphatase calcineurin, stimulated the enzymatic activity of cellular DLK in an in vitro kinase assay. Immunocytochemistry revealed that the overexpression of DLK but not its kinase-dead mutant induced apoptosis and enhanced cyclosporin A-induced apoptosis to a higher extent than the drug alone. Moreover, in the presence of DLK, the effective concentration for cyclosporin A-caused apoptosis was similar to its known IC(50) value for the inhibition of calcineurin activity in beta cells. These data suggest that cyclosporin A through inhibition of calcineurin activates DLK, thereby leading to beta-cell apoptosis. This action may thus be a novel mechanism through which cyclosporin A precipitates post-transplant diabetes.