Torsional control of eye-head saccades

Under natural conditions the head and the eye are both free to rotate about three mutuall orthogonal axes each (horizontal, vertical and torsional). Theoretically, these six degrees of freedom would allow any two-dimensional direction of the line of sight to be obtained by infinitely many torsional head and eye orientations. Yet, for any one gaze direction our brain chooses specific angles of torsion for the head and the eye. For steady fixation of distant targets with the head fixed and upright this observation is known as Donders' law (1847). It has been shown to hold independently of the direction of the rapid gaze shift (saccade) preceding a fixation. Surprisingly, despite considerable research on head and eye coordination the full implications of Donders' law still have not been analyzed for head-unrestrained gaze shifts. It has merely been studied whether torsional constraints hold, when gaze is returned repeatedly to the targets from single initial positions. The aim of this study was to see whether Donders' law holds after head-unrestrained saccades, independently of the saccade direction. Secondary objectives were to analyze whether the neural controls of the eye and the head are dependent or independent during this task and to collect and present control data for comparison with patient recordings in clinical context. Therefore, seven healthy human subjects made large head-unrestrained gaze shifts to a single set of visual targets during two separate conditions: 1) Repeated saccades to individual target positions from the same direction respectively (Star paradigm). 2) Repeated saccades to every target position from several different directions (Diamond paradigm). Three-dimensional orientations of head and eye were measured simultaneously with the magnetic search coil technique and consecutively plotted in three-dimensional space so that those orientations obeying Donders' law formed a surface. For each of the three body units the static orientations formed subspaces that resembled surfaces in the shape of twisted double saddles. Surfaces of head orientations had the most pronounced twist, eye in head surfaces were the most planar and surfaces of gaze orientations showed intermediate twist. The standard deviation of torsional residuals of the approximated surfaces (torsional thickness) was bigger for gaze than for the eye and smallest for the head. Head and eye torsion, as averaged over individual fixations, were correlated differently within every subject, but between subjects there was no correlation. In summary, neither surface shapes nor torsional thickness of gaze, head or eye differed between the two conditions (Star/Diamond). With this it is shown for the first time that Donders' law of torsional control holds true for gaze, head and eye orientations independently of the direction of the preceding saccade. The absence of correlation between head and eye torsion can be explained by independent controllers of head and eye movements. This yields a new, further argument supporting recent models of neuronal gaze control that are based on the assumption of independent head and eye controllers. Studies with patients carrying lesions in possible target structures of such neuronal controllers are needed to further investigate these models. Finally, clinically-diagnostic relevance of this study arises from the comparison to results of studies on gaze coordination after midbrain lesions where patients exhibit an altered form of Donders' law.Unter natürlichen Bedingungen sind Rotationen von Kopf und Auge um jeweils drei voneinander unabhängige Raumachsen (Quer-, Hoch- und Längsachse) möglich. Diese sechs Freiheitsgrade würden beim Blick in jede zweidimensionale Richtung beliebige Drehungen um die Längsachse (Torsion) sowohl des Kopfes als auch des Auges erlauben. Unser Gehirn wählt jedoch in jeder Blickrichtung je einen spezifischen Torsionswinkel für Kopf und Auge. Für die Fixation entfernter Blickziele bei aufrechtem, unbewegtem Kopf wurde diese Tatsache als Donders' Law (1847) bekannt. Das Gesetz gilt unabhängig von der Richtung der der Fixation vorhergehenden raschen Blickbewegung (Sakkade). Überraschenderweise wurde trotz zahlreicher Untersuchungen zur Kopf- und Augenkoordination die vollständige Gültigkeit von Donders' Law bei Blickbewegungen mit bewegtem Kopf noch nicht gezeigt. Es wurde lediglich untersucht, ob die resultierenden Torsionsbeschränkungen weiter gelten, wenn der Blick wiederholt von denselben Ausgangspositionen auf verschiedene Punkte gerichtet wird. Hauptziel dieser Arbeit war zu prüfen, ob Donders' Law nach Sakkaden mit bewegtem Kopf unabhängig von der Sakkadenrichtung gilt. Zudem wurde analysiert, ob Kopf und Auge dabei einer gemeinsamen oder separaten neuronalen Kontrolle unterliegen, und es wurden Kontrolldaten zum Vergleich mit Patientenmessungen im klinischen Kontext gesammelt. Dazu führten sieben gesunde menschliche Probanden Sakkaden mit bewegtem Kopf zwischen einer Anordnung visueller Blickziele unter zwei Versuchsbedingungen durch: 1) Wiederholte Sakkaden auf jedes Ziel aus der jeweils gleichen Richtung (Star Paradigma). 2) Wiederholte Sakkaden auf jedes Ziel aus mehreren verschiedenen Richtungen (Diamond Paradigma). Die dreidimensionalen Kopf- und Augenbewegungen wurden simultan mit der magnetischen Search-Coil-Technik gemessen und zur Analyse räumlich dargestellt, so dass Positionen, die Donders' Law entsprechen, eine Fläche bilden. Für jede der drei Körpereinheiten lagen die statischen Positionen in Unterräumen, die Flächen in Form verdrehter (getwisteter) Doppelsättel ähnelten. Die Flächen der Kopfpositionen wiesen den deutlichsten Twist auf, die der Auge-im-Kopf Positionen waren nahezu eben und die Flächen der Blickpositionen zeigten einen mittleren Twist. Die Standardabweichung der Torsionsresiduen der genäherten Flächen (Torsionsdicke) war größer für den Blick als für das Auge und am kleinsten für den Kopf. Kopf- und Augentorsion, gemittelt über die Einzelfixationen, waren für jeden einzelnen Probanden unterschiedlich korreliert; über alle Probanden ergab sich jedoch keine signifikante Korrelation. Zusammenfassend unterschieden sich weder Flächenform noch Torsionsdicke von Blick, Kopf oder Auge zwischen den beiden Bedingungen (Star/ Diamond). Damit ist zum ersten Mal gezeigt, dass Donders' Law für Blick-, Kopf- und Augenpositionen unabhängig von der Richtung der vorangegangenen Sakkade gilt. Die fehlende Korrelation der Kopf- und Augentorsion ist auf eine unabhängige Kontrolle von Kopf- und Augenbewegungen zurückzuführen. Dies ist ein neues, weiteres Argument zur Bestätigung aktueller Modelle der neuronalen Kontrolle von Blickbewegungen, die von der Annahme unabhängiger Kopf- und Augencontroller ausgehen. Studien mit Patienten, die Läsionen in möglichen Zielstrukturen für solche neuronalen Controller tragen, sind zur weiteren Untersuchung dieser Modelle nötig. Abschließend ergibt sich klinisch-diagnostische Relevanz der Arbeit aus dem Vergleich mit Studiendaten zur Blickkoordination nach Mittelhirnläsionen, bei denen Patienten eine veränderte Form von Donders' Law aufweisen

Translation of stable hepadnaviral mRNA cleavage fragments induced by the action of phosphorothioate-modified antisense oligodeoxynucleotides

Phosphorothioate-modified antisense oligodeoxynucleotides (ASOs) are used to suppress gene expression by inducing RNase H-mediated cleavage with subsequent degradation of the target mRNA. However, previous observations suggest that ASO/RNase H can also result in the generation of stable mRNA cleavage fragments and expression of truncated proteins. Here, we addressed the underlying translational mechanisms in more detail using hepadnavirus-transfected hepatoma cells as a model system of antisense therapy. Generation of stable mRNA cleavage fragments was restricted to the ASO/RNase H pathway and not observed upon cotransfection of isosequential small interfering RNA or RNase H-incompetent oligonucleotides. Furthermore, direct evidence for translation of mRNA fragments was established by polysome analysis. Polysome-associated RNA contained cleavage fragments devoid of a 5′ cap structure indicating that translation was, at least in part, cap-independent. Further analysis of the uncapped cleavage fragments revealed that their 5′ terminus and initiation codon were only separated by a few nucleotides suggesting a 5′ end-dependent mode of translation, whereas internal initiation could be ruled out. However, the efficiency of translation was moderate compared to uncleaved mRNA and amounted to 13–24% depending on the ASO used. These findings provide a rationale for understanding the translation of mRNA fragments generated by ASO/RNase H mechanistically

Heterophoria: Vergence stability and visual acuity after asymmetric saccades

Many patients with heterophoria report on symptoms related to impaired vision. To investigate whether these symptoms are provoked by saccades this study examines whether in heterophoria effects on intrasaccadic and postsaccadic vergence movements are linked to effects on visual performance. Visual acuity was measured in 35 healthy subjects during fixation and immediately after asymmetric diverging saccades. Binocular position traces were recorded by video-oculography. Subjects with exophoria showed larger intrasaccadic divergence amplitudes, which in turn led to smaller postsaccadic divergence amplitudes. Visual acuity did not depend on heterophoria or vergence amplitudes. The results suggest that compensating for exophoria requires increased convergence activity as compared to orthophoria or compensated esophoria. Visual acuity seemed relatively robust with respect to postsaccadic vergence movements

Isolation and characterisation of metallothionein from the clam Ruditapes decussatus

Metallothioneins (MT) were obtained after purification from metal-exposed clams (Ruditapes decussatus) using gel-permeation and ion-exchange chromatography. Four cadmium-metallothioneins (CdMTs) were resolved by ion-exchange chromatography and they all had similar molecular weights, high cadmium content and an absorption spectra indicative of the presence of characteristic Cd-S aggregates. The NH2-terminal sequence suggests the presence of at least two class I clam MT isoforms. For the other two putative clam CdMTs isolated, the results of the amino acid determination were inconclusive. One was slightly contaminated and the other one had a blocked NH2-terminal. These clam metalothioneins contain glycine, which seems to be a common feature of molluscan MT family and exhibited more similarity to oysters than to mussels. Further investigation on the inducibility of these isoforms will be necessary if clams are to be used as biomarkers of metal exposure

Resonant Raman scattering by collective modes of the one-dimensional electron gas

We show that the low-energy peak in the polarized resonant Raman spectra of quantum wires, which is commonly associated with ``single particle excitations'', can be interpreted as signature of intra-band collective spin excitations. A broad maximum in the resonant depolarized spectra is predicted to exist above the frequency of the spin density excitation, due to simultaneous but independent propagation of spin- and charge-density modes.Comment: 4 pages, accepted for publication in Phys. Rev. Let

RESH. Rechnernetze als Supercomputer und Hochleistungsdatenbanken. Zwischenbericht Oktober 1998

Dieser Zwischenbericht stellt die Ergebnisse der Forschergruppe RESH im Zusammenhang dar, die in den ersten neun Monaten der Projektlaufzeit erarbeitet wurden. Dargestellt werden die Ergebnisse der einzelnen Teilprojekte sowie Ausblicke auf geplante weitere Arbeitseinheiten. Am 6. Oktober 1998 wurden diese Zwischenergebnisse in Kurzvorträgen vorgestellt, um die Aktivitäten der einzelnen Teilprojekte besser auf einander abzustimmen. Ebenfalls im Bericht enthalten sind die Poster, mit denen die Forschergruppe RESH anläßlich des Tags der Informatik am 6. November 1998 ihre Arbeit der interessierten Öffentlichkeit vorstellte

Cathodal tDCS Over Motor Cortex Does Not Improve Tourette Syndrome: Lessons Learned From a Case Series

Introduction: Current pathophysiological hypotheses of Gilles de la Tourette Syndrome (GTS) refer to temporally abnormal neuronal activation in cortico-striato-thalamo-cortical (CSTC) networks. Modifying cortical activity by non-invasive brain-stimulation appears to be a new treatment option in GTS. Background: Previous studies suggested therapeutic effects of cathodal transcranial direct current stimulation (tDCS) to pre-supplementary motor areas (SMA), however, treatment modalities concerning electrode placement, current intensity and stimulation-rate have not been systematically explored. Aim of this study was to assess efficacy of an alternative stimulation regime on GTS symptoms in a pilot study. To test a treatment protocol with tDCS twice a day, we administered 10 sessions over 5 days of bilateral cathodal tDCS (30 min, 2 mA) over the pre-SMA in three patients with severe GTS. Tic severity as well as obsessive-compulsive (OC) symptoms and affective scales were rated before and after tDCS treatment. Discussion: Only one out of three patients showed a 34.5% reduction in tic severity. The two other patients showed an increase in tic severity. All patients showed a mild increase in positive affect and a reduction in negative affect, OC symptom changes were heterogeneous. Our results do not support earlier findings of extensive therapeutic effects of cathodal tDCS on tics in patients with GTS and show that prediction of stimulation effects on a targeted brain area remains inaccurate. Concluding Remarks: Future research will have to focus on the determination of most effective stimulation modes regarding site, polarity and frequency of tDCS in GTS patients

Efficacy, safety, and dose of Pafuramidine, a new oral drug for treatment of first stage sleeping sickness, in a phase 2a clinical study and phase 2b randomized clinical studies

Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.; The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.; Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3

Determinants of completion of advance directives: a cross-sectional comparison of 649 outpatients from private practices versus 2158 outpatients from a university clinic

Objectives To compare outpatients from private practices and outpatients from a university clinic regarding the determinants of completion of advance directives (AD) in order to generalise results of studies from one setting to the other. Five determinants of completion of AD were studied: familiarity with AD, source of information about AD, prior experiences with own life-threatening diseases or family members in need of care and motives in favour and against completion of AD.Design Observational cross-sectional study.Setting Private practices and a university clinic in Germany in 2012.Participants 649 outpatients from private practices and 2158 outpatients from 10 departments of a university clinic.Outcome measures Completion of AD, familiarity with AD, sources of information about AD (consultation), prior experiences (with own life-threatening disease and family members in need of care), motives in favour of or against completion of AD, sociodemographic data.Results Determinants of completion of AD did not differ between outpatients from private practices versus university clinic outpatients. Prior experience with severe disease led to a significantly higher rate of completion of AD (33%/36% with vs 24%/24% without prior experience). Participants with completion of AD had more often received legal than medical consultation before completion, but participants without completion of AD are rather aiming for medical consultation. The motives in favour of or against completion of AD indicated inconsistent patterns.Conclusions Determinants of completion of AD are comparable in outpatients from private practices and outpatients from a university clinic. Generalisations from university clinic samples towards a broader context thus seem to be legitimate. Only one-third of patients with prior experience with own life-threatening diseases or family members in need of care had completed an AD as expression of their autonomous volition. The participants’ motives for or against completion of AD indicate that ADs are considered a kind of ‘negative autonomy’ as instruments to prevent particular forms of therapy. Interactive, repeated and situation-based AD discussions might reach a higher percentage of patients and concurrently enable personal volitions and thereby strengthen individual ‘positive autonomy’.</p