Shifting networks and mixing metals: Changing metal trade routes to Scandinavia correlate with Neolithic and Bronze Age transformations.

Based on 550 metal analyses, this study sheds decisive light on how the Nordic Bronze Age was founded on metal imports from shifting ore sources associated with altered trade routes. On-and-off presence of copper characterised the Neolithic. At 2100-2000 BC, a continuous rise in the flow of metals to southern Scandinavia begins. First to arrive via the central German Únetician hubs was high-impurity metal from the Austrian Inn Valley and Slovakia; this was complemented by high-tin British metal, enabling early local production of tin bronzes. Increased metal use locally fuelled the leadership competitions visible in the metal-led material culture. The Únetice downfall c.1600 BC resulted for a short period in a raw materials shortage, visible in the reuse of existing stocks, but stimulated direct Nordic access to the Carpathian basin. This new access expedited innovations in metalwork with reliance on chalcopyrite from Slovakia, as well as opening new sources in the eastern Alps, along an eastern route that also conveyed Baltic amber as far as the Aegean. British metal plays a central role during this period. Finally, from c.1500 BC, when British copper imports ceased, the predominance of novel northern Italian copper coincides with the full establishment of the NBA and highlights a western route, connecting the NBA with the southern German Tumulus culture and the first transalpine amber traffic.

Correction: On the trail of Scandinavia's early metallurgy: Provenance, transfer and mixing.

[This corrects the article DOI: 10.1371/journal.pone.0219574.].

On the trail of Scandinavia's early metallurgy: Provenance, transfer and mixing.

The rich and long-lasting Nordic Bronze Age was dependent throughout on incoming flows of copper and tin. The crucial turning point for the development of the NBA can be pinpointed as the second phase of the Late Neolithic (LN II, c. 2000-1700 BC) precisely because the availability and use of metal increased markedly at this time. But the precise provenance of copper reaching Scandinavia in the early second millennium is still unclear and our knowledge about the driving force leading to the establishment of the Bronze Age in southern Scandinavia is fragmentary and incomplete. This study, drawing on a large data set of 210 samples representing almost 50% of all existing metal objects known from this period in Denmark, uses trace element (EDXRF) and isotope analyses (MC-ICP-MS) of copper-based artifacts in combination with substantial typological knowledge to profoundly illuminate the contact directions, networks and routes of the earliest metal supplies. It also presents the first investigation of local recycling or mixing of metals originating from different ore regions. Both continuity and change emerge clearly in the metal-trading networks of the Late Neolithic to the first Bronze Age period. Artifacts in LN II consist mainly of high-impurity copper (so-called fahlore type copper), with the clear exception of British imports. Targeted reuse of foreign artifacts in local production is demonstrated by the presence of British metal in local-style axes. The much smaller range of lead isotope ratios among locally crafted compared to imported artifacts is also likely due to mixing. In the latter half of Nordic LN II (1800-1700 BC), the first signs emerge of a new and distinct type of copper with low impurity levels, which gains enormously in importance later in NBA IA.

[Cerebral amyloid angiopathy associated with inflammation]. / Zerebrale Amyloidangiopathie assoziiert mit Inflammation.

Cerebral amyloid angiopathy (CAA) associated with inflammation is a rare form of a potentially reversible encephalopathy in a subgroup of patients with CAA. The cerebral amyloid deposition can in isolated cases induce an inflammation predominantly of the cerebral blood vessels and a multifocal edema of the cerebral white matter. The courses can occur as monophasic, relapsing remitting and primarily progressive forms. We present seven cases with different courses of the disease and give an overview of the pathophysiology, clinical aspects and treatment of the disease with reference to the current literature. The cases presented show a very different and often difficult differential diagnostic clinical picture and all showed a significant improvement under steroid medication without signs of recurrence of the disease during the course. The recognition and early consistent treatment of inflammatory forms of CAA with and without direct inflammatory involvement of vessels can be decisive for successful treatment.

[Non-heart-beating donors are ineligible]. / "Non-heart-beating donors" sind nicht geeignet.

The death of the donor is a mandatory prerequisite for organ transplantation (dead donor rule) worldwide. It is a medical, legal and ethical consensus to accept the concept of brain death, as first proposed in 1968 by the ad hoc committee of the Harvard Medical School, as a certain criterion of death. In isolated cases where the diagnosis of brain death was claimed to be wrong, it could be demonstrated that the diagnostic procedure for brain death had not been correctly performed. In March 2014 a joint statement by the German neuromedical societies emphasized that 1) the diagnosis of brain death is one of the safest diagnoses in medicine if performed according to accepted medical standards and criteria and 2) the concept of non-heart-beating donors (NHBD, i. e. organ donation after an arbitrarily defined duration of circulatory and cardiac arrest) practiced in some European countries must be absolutely rejected because it implicates a high risk of diagnostic error. According to the current literature it is unclear at what time cardiac and circulatory arrest is irreversible and leads to irreversible cessation of all functions of the entire brain including the brainstem, even though clinical signs of cessation of brain functions are always found after 10 min. Furthermore, is it often an arbitrary decision to exactly define the duration of cardiac arrest if continuous echocardiographic monitoring has not been carried out from the very beginning. Last but not least there are ethical concerns against the concept of NHBD because it might influence therapeutic efforts to resuscitate a patient with cardiac arrest. Therefore, the German Medical Council (BÄK) has repeatedly rejected the concept of NHBD for organ transplantation since 1995.

Diagnostic accuracy and cost-effectiveness of dermoscopy in primary care: a cluster randomized clinical trial.

OBJECTIVES: To determine the DA and cost-effectiveness of the dermoscope in primary care for skin lesions suspected of malignancy. METHODS: In a cluster randomized clinical trial, 48 Dutch general practices were randomized to either intervention group using a dermoscope or control group using only naked-eye examination. A total of 194 lesions from 170 patients in the intervention group and 222 lesions from 211 patients in the control group were analysed for DA and cost-effectiveness. RESULTS: The percentage of correctly diagnosed lesions in intervention group and control group was 50.5% and 40.5% respectively. This was 61.5% and 22.2% for melanomas. In the intervention group, three malignancies were treated with the expectative treatment option compared to none in the control group. The odds ratio (OR) of a correct diagnosis in the intervention group, compared to control group, was 1.51 (95% CI: 0.96­2.37) P = 0.07. Consequently, the relative risk was 1.25. The incremental cost-effectiveness ratio was €89 (95% CI −€60 to €598), indicating that using a dermoscope costs an additional €89 for one additional correctly diagnosed patient. Additional analyses showed better effects of dermoscopy compared to the control group for 98% of the bootstrap resamples. CONCLUSIONS: The probability of a correct diagnosis was 1.25 times higher using a dermoscope than without a dermoscope. Although this difference is marginally not statistically significant, dermoscopy in general practice appears to be cost effective. We therefore think that GPs should be trained to use a dermoscope, although they should realize that even with the use of a dermoscope not all lesions will be diagnosed correctly.

Eye movement disorders are different in Parkin-linked and idiopathic early-onset PD.

OBJECTIVES: Parkin gene mutations are the most common cause of early-onset parkinsonism. Patients with Parkin mutations may be clinically indistinguishable from patients with idiopathic early-onset Parkinson disease (EOPD) without Parkin mutations. Eye movement disorders have been shown to differentiate parkinsonian syndromes, but have never been systematically studied in Parkin mutation carriers. METHODS: Eye movements were recorded in symptomatic (n = 9) and asymptomatic Parkin mutation carriers (n = 13), patients with idiopathic EOPD (n = 14), and age-matched control subjects (n = 27) during established oculomotor tasks. RESULTS: Both patients with EOPD and symptomatic Parkin mutation carriers showed hypometric prosaccades toward visual stimuli, as well as deficits in suppressing reflexive saccades toward unintended targets (antisaccade task). When directing gaze toward memorized target positions, patients with EOPD exhibited hypometric saccades, whereas symptomatic Parkin mutation carriers showed normal saccades. In contrast to patients with EOPD, the symptomatic Parkin mutation carriers showed impaired tracking of a moving target (reduced smooth pursuit gain). The asymptomatic Parkin mutation carriers did not differ from healthy control subjects in any of the tasks. CONCLUSIONS: Although clinically similarly affected, symptomatic Parkin mutation carriers and patients with idiopathic EOPD differed in several oculomotor tasks. This finding may point to distinct anatomic structures underlying either condition: dysfunctions of cortical areas involved in smooth pursuit (V5, frontal eye field) in Parkin-linked parkinsonism vs greater impairment of basal ganglia circuits in idiopathic Parkinson disease.

Distributed representations of the "preparatory set" in the frontal oculomotor system: a TMS study.

BACKGROUND: The generation of saccades is influenced by the level of "preparatory set activity" in cortical oculomotor areas. This preparatory activity can be examined using the gap-paradigm in which a temporal gap is introduced between the disappearance of a central fixation target and the appearance of an eccentric target. METHODS: Ten healthy subjects made horizontal pro- or antisaccades in response to lateralized cues after a gap period of 200 ms. Single-pulse transcranial magnetic stimulation (TMS) was applied to the dorsolateral prefrontal cortex (DLPFC), frontal eye field (FEF), or supplementary eye field (SEF) of the right hemisphere 100 or 200 ms after the disappearance of the fixation point. Saccade latencies were measured to probe the disruptive effect of TMS on saccade preparation. In six individuals, we gave realistic sham TMS during the gap period to mimic auditory and somatosensory stimulation without stimulating the cortex. RESULTS: TMS to DLPFC, FEF, or SEF increased the latencies of contraversive pro- and antisaccades. This TMS-induced delay of saccade initiation was particularly evident in conditions with a relatively high level of preparatory set activity: The increase in saccade latency was more pronounced at the end of the gap period and when participants prepared for prosaccades rather than antisaccades. Although the "lesion effect" of TMS was stronger with prefrontal TMS, TMS to FEF or SEF also interfered with the initiation of saccades. The delay in saccade onset induced by real TMS was not caused by non-specific effects because sham stimulation shortened the latencies of contra- and ipsiversive anti-saccades, presumably due to intersensory facilitation. CONCLUSION: Our results are compatible with the view that the "preparatory set" for contraversive saccades is represented in a distributed cortical network, including the contralateral DLPFC, FEF and SEF.

Functional dissociation of saccade and hand reaching control with bilateral lesions of the medial wall of the intraparietal sulcus: implications for optic ataxia.

The posterior parietal cortex (PPC) is essential for the integration of visuomotor information during visually guided reaching. Studies in macaque monkeys have demonstrated a functional specialisation around the intraparietal sulcus (IPS) with a more medial representation of hand movements ("parietal reach region") and a more lateral representation of saccadic eye movements (lateral intraparietal area, LIP). Here we present evidence for the validity of this concept with respect to the human parietal cortex. We recorded isolated and combined goal-directed eye-hand movements in normal control subjects and in a patient with bilateral parieto-occipital lesions and incomplete Balint's syndrome including severe optic ataxia (misreaching to visual targets). Brain lesions in the patient were caused by acute posterior leucoencephalopathy in association with aortic surgery because of Takayasu's arteritis. MRI scans showed bilateral line-shaped hemorrhagic lesions, restricted to the cortex at the medial banks of the intraparietal sulcus, but leaving its lateral banks largely intact. In the patient visually guided reaching was significantly dysmetric, whereas the metrics of visually guided saccades were within normal limits. Dysmetria was more pronounced for the right visual field, with a gross hypermetria. Variability of the movement improved when a delay of 5 or 10 s was introduced between target presentation and movement execution. Lesion data support the concept of a functional specialisation around the human IPS: The cortex medial to the IPS predominantly controls rapid goal-directed reaching movements, comparable to the parietal reach region in monkeys, whereas saccadic eye movements appear to be controlled rather by the cortex lateral to the IPS.

Three-dimensional cytoarchitectonic analysis of the posterior bank of the human precentral sulcus.

Studies employing functional magnetic resonance imaging have identified the human frontal eye field as being in the anterior and partly in the posterior wall, as well as at the base of the precentral sulcus. Moreover, it is known that the frontal eye field extends rostrally to the superior frontal sulcus. According to Brodmann's cytoarchitectonic map, this region belongs to the dysgranular Brodmann area 6 of the premotor cortex. However, the frontal eye field in non-human primates has been located within the arcuate sulcus in Brodmann area 8, generating considerable debate about where to locate exactly the frontal eye field in humans. Functional studies of the primate frontal eye field have revealed a principal homology of voluntary saccadic control systems in human and old-world monkeys, especially the macaque. But these homologies seem to be contradicted by the reported topographic localization at the cytoarchitectonic level. Therefore, we studied the cytoarchitectonic structure of the posterior bank of the precentral sulcus of a human brain, employing newly developed spatial mapping techniques to provide data about whether or not this region should be considered cytoarchitecturally homogeneous or heterogeneous. We used functional magnetic resonance imaging results, as an initial guide in localizing a region which is activated by saccadic tasks. A maximum of activation was detected around the junction of the superior frontal sulcus and the precentral sulcus extending 1.5 cm along the precentral sulcus in direction of the lateral sulcus. Here, one human brain has been analyzed to obtain preliminary data about the cytoarchitectonical changes of a part of area 6. Statistical analysis of the three-dimensional architectonic data from this region allowed us to identify a zone at the posterior bank, which in other studies has been associated with a functional region that controls pursuit eye movements and performs sensory-to-motor transformations. We found two significant sectors along the ventral part of the posterior bank of the precentral sulcus. The caudal transition region coincides partly with a region that integrates retinal and eye position signals for target location, arm, and axial movements. The second more ventrally located region is attributed to process oral-facial movements. The caudal transition region coincides with our functional magnetic resonance imaging investigation. It was revealed that this region lies at the inferior frontal eye field, where a pronounced activation over a larger region can be stimulated. Currently, more studies are needed to combine functional magnetic resonance imaging data of maximal activation with data from whole histologic brain sections of more individuals and to quantify the variability of this region and its sub-regions by means of a standardized brain atlas.

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.

Smooth pursuit deficits in schizophrenia, affective disorder and obsessive-compulsive disorder.

BACKGROUND: In schizophrenia, affective disorders, and obsessive-compulsive disorder (OCD) dysfunction of frontal neuronal circuits has been suggested. Such impairments imply corresponding oculomotor deficits. METHOD: Eye movement response to foveofugal and foveopetal step-ramp stimuli was recorded within the same study design in patients with schizophrenia (N= 16), affective disorder (N= 15), and OCD (N= 18) and compared with controls (N=23) using infra-red reflection oculography. RESULTS: In the foveofugal task steady-state velocity was lower in all patient groups compared with controls. Post-saccadic eye velocity was also decreased in patients with schizophrenia and affective disorder. In the foveopetal stimulus steady-state velocity was reduced in schizophrenic patients, only. Changes of saccadic latencies or position errors were not found in any of the patient groups. Also, pursuit latency was unchanged and initial eye acceleration was not decreased. CONCLUSIONS: Unaltered saccadic parameters indicate intact motion perception in cortical visual area V5. Therefore, the observed deficit of pursuit maintenance implies a dysfunction of frontal networks in all patient groups including the pursuit region of the frontal eye field (FEF). In patients with schizophrenia and affective disorder reduced post-saccadic pursuit initiation may indicate an impaired interaction between the pursuit and the saccadic system.

[Spatial neglect]. / Räumlicher Neglect.

Unilateral spatial (hemi-)neglect or (hemi-)inattention are clinical terms used to describe a number of different clinical symptoms which have in common the patient's failure to attend to, respond adequately to, or orient voluntarily to people or objects in the contralesional space. Unilateral spatial neglect is most often observed following brain lesions affecting the right hemisphere, and in particular the right inferior parietal cortex (angular and supramarginal gyrus) and right temporoparietal junction. Importantly, the term hemineglect cannot be meaningfully used if the target behavior is explained by primary sensory or motor deficits only. Typically the patient's deficit is supramodal: patients with hemineglect fail to respond to novel or meaningful stimuli irrespective of whether they are presented in the visual, auditory, and somesthetic (somatosensory) domain. As adequate perception and spatial representation of both the body and the outside world are mandatory for almost all activities of daily living, hemineglect is known to limit the degree of active participation in rehabilitation programs and is thus commonly associated with poor functional recovery and less successful social reintegration. A number of new promising behavioral and pharmacological treatments may help to ameliorate neglect in the future.

EFNS task force--therapy of nystagmus and oscillopsia.

An overview of possible treatment options for oculomotor disorders that prevent clear vision is given. Downbeat nystagmus, upbeat nystagmus, seesaw nystagmus, periodic alternating nystagmus, acquired pendular nystagmus, and saccadic oscillations such as opsoclonus/ocular flutter are discussed. In addition, superior oblique myokymia and vestibular paroxysmia are reviewed. All treatment recommendations available in the literature are classified as class C only. In general, only some of the patients benefit from the treatment.

Horizontal canal benign paroxysmal positioning vertigo with ipsilateral hearing loss.

The etiology of benign paroxysmal positioning vertigo (h-BPPV) of the horizontal semicircular is unknown. Insight was obtained from two patients with h-BPPV and associated hearing impairment. Based on the different inner ear lesion patterns in neurolabyrinthitis contrary to ischemic labyrinthine infarction we assessed multiple vestibulo-cochlear functions for the first time in two patients who suffered from h-BPPV with sudden unilateral hearing loss. While in patient no. 1 the lesion pattern (posterior canal paresis in addition to the sudden hearing loss) could possibly be caused by ischemia of the common cochlear artery, the lesion pattern of patient no. 2 (hearing loss and ipsilateral paresis of the posterior and horizontal semicircular canal) exceeds the typical vascular labyrinthine territories and may indicate viral neurolabyrinthitis.

Eye movement abnormalities in essential tremor may indicate cerebellar dysfunction.

Experimental and clinical data indicate that the cerebellum is involved in the pathophysiology of advanced stages of essential tremor (ET). The aim of this study was to determine whether a dysfunction also affects cerebellar structures involved in eye movement control. Eye movements of 14 patients with ET and 11 age-matched control subjects were recorded using the scleral search-coil technique. Vestibular function was assessed by electro-oculography. Eight ET patients had clinical evidence of intention tremor (ET(IT)); six had a predominantly postural tremor (ET(PT)) without intention tremor. ET patients showed two major deficits that may indicate cerebellar dysfunction: (i) an impaired smooth pursuit initiation; and (ii) pathological suppression of the vestibulo-ocular reflex (VOR) time constant by head tilts ('otolith dumping'). In the step ramp smooth pursuit paradigm, the initial eye acceleration in the first 60 ms of pursuit generation was significantly reduced in ET patients, particularly in ET(IT) patients, by approximately 44% (mean 23.4 degrees/s(2)) compared with that of control subjects (mean 41.3 degrees/s(2)). Subsequent steady-state pursuit velocity and sinusoidal pursuit gain (e.g. 0.4 Hz: 0.90 versus 0.78) were also significantly decreased in ET patients, whereas pursuit latency was unaffected. The intention tremor score correlated with the pursuit deficit, e.g. ET(IT) patients were significantly more affected than ET(PT) patients. Gain and time constant (tau) of horizontal VOR were normal, but suppression of the VOR time constant by head tilt ('otolith dumping') was pathological in 41% of ET patients, particularly in ET(IT) patients. Saccades and gaze-holding function were not impaired. The deficit of pursuit initiation, its correlation with the intensity of intention tremor, and the pathological VOR dumping provide additional evidence of a cerebellar dysfunction in the advanced stage of ET, when intention tremor becomes part of the clinical symptoms, and point to a common pathomechanism. The oculomotor deficits may indicate an impairment of the caudal vermis in ET.

Visual search in patients with left visual hemineglect.

In patients with hemi-spatial neglect eye movement patterns during visual search reflect not only inattention for the contralesional hemi-field, but interacting deficits of multiple visuo-spatial and cognitive functions, even in the ipsilesional hemi-field. Evidence for these deficits is presented from the literature and from saccadic scan-path analysis during feature and conjunction search in 10 healthy subjects and in 10 patients with manifest or recovered left visual neglect due to right-hemispheric stroke. Deficits include (1) a rightward shift of spatial representation, (2) deficient spatial working memory and failure of systematic search strategies, leading to multiple re-fixations, more after frontal lesions, and (3) a reduced spotlight of attention and a deficient pop-out effect of color, more after temporo-parietal lesions.