New insights into aging in LiNiO2 cathodes from high resolution paramagnetic NMR spectroscopy.

Bulk degradation processes are examined in the LiNiO2 cathode using high resolution solid-state NMR, combined with magnetometry and X-ray diffraction. Capacity decay is correlated with bulk heterogeneity, whereby multiple structural domains coexist in the charged state, and the Li content and electrochemical activity of these domains is unraveled for the first time.

Adaptive short-term plasticity in the typical reading network.

The left temporo-parietal cortex (TPC) is crucial for phonological decoding, i.e., for learning and retaining sound-letter mappings, and appears hypoactive in dyslexia. Here, we tested the causal contribution of this area for reading in typical readers with transcranial magnetic stimulation (TMS) and explored the reading network's response with fMRI. By investigating the underlying neural correlates of stimulation-induced modulations of the reading network, we can help improve targeted interventions for individuals with dyslexia. 28 typical adult readers overtly read simple and complex words and pseudowords during fMRI after effective and sham TMS over the left TPC. To explore differences in functional activation and effective connectivity within the reading network, we performed univariate and multivariate analyses, as well as dynamic causal modeling. While TMS-induced effects on reading performance and brain activation showed large individual variability, multivariate analyses revealed a shift in activation in the left inferior frontal cortex for pseudoword reading after effective TMS. Furthermore, TMS increased effective connectivity from the left ventral occipito-temporal cortex to the left TPC. In the absence of effects on reading performance, the observed changes in task-related activity and the increase in functional coupling between the two core reading nodes suggest successful short-term compensatory reorganization in the reading network following TMS-induced disruption. This study is the first to explore neurophysiological changes induced by TMS to a core reading node in typical readers while performing an overt reading task. We provide evidence for remote stimulation effects and emphasize the relevance of functional interactions in the reading network.

Effect of zinc, copper and resveratrol supplementation on the urinary level of 15-hydroxyeicosatetraenoic acid at the early stage of breast cancer in rats.

The aim of the present study was to assess the effect of zinc and copper, separately or in combination with resveratrol, on the concentration of 15-hydroxyeicosatetraenoic acid (15-HETE) in urine of rats with mammary cancer (adenocarcinoma) induced with 7,12- dimethyl-1,2-benz[a]anthracene (+ DMBA). The research focused on the kinetics of alterations in urinary 15-HETE at the early stage of carcinogenesis, as well as on the influence of dietary factors on the process. The content of 15-hydroxyeicosatetraenoic acid in the rats' urine was determined by enzyme-linked immunosorbent assay (ELISA). The 15-HETE level was standardized by conversion to the creatinine level. Regardless of the diet (standard, Zn, Zn+resveratrol, Cu, Cu+resveratrol), DMBA-induced breast carcinogenesis was not inhibited. On the contrary, in the Zn+resveratrol supplemented group, tumorigenesis developed at a considerably faster rate. It was found that the supplementation of the rats' diet with zinc only or zinc plus resveratrol resulted in a reduction of the 15-HETE level in urine of rats with mammry cancer (+ DMBA) as compared with control rats (- DMBA). A statistically lower concentration of 15-HETE was found in urine of rats supplemented with zinc or copper with resveratrol when compared with the animals that received only zinc or copper (p=0.02; p=0.0001). Summing up the obtained results, it can be concluded that the level of 15-HETE in urine of the examined animals depended on the applied supplementation.

Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington's disease.

AIMS: Quantitative estimation of cortical neurone loss in cases with chorea-acanthocytosis (ChAc) and its impact on laminar composition. METHODS: We used unbiased stereological tools to estimate the degree of cortical pathology in serial gallocyanin-stained brain sections through the complete hemispheres of three subjects with genetically verified ChAc and a range of disease durations. We compared these results with our previous data of five Huntington's disease (HD) and five control cases. Pathoarchitectonic changes were exemplarily documented in TE1 of a 61-year-old female HD-, a 60-year-old female control case, and ChAc3. RESULTS: Macroscopically, the cortical volume of our ChAc cases (ChAc1-3) remained close to normal. However, the average number of neurones was reduced by 46% in ChAc and by 33% in HD (P = 0.03 for ChAc & HD vs. controls; P = 0.64 for ChAc vs. HD). Terminal HD cases featured selective laminar neurone loss with pallor of layers III, V and VIa, a high density of small, pale, closely packed radial fibres in deep cortical layers VI and V, shrinkage, and chromophilia of subcortical white matter. In ChAc, pronounced diffuse astrogliosis blurred the laminar borders, thus masking the complete and partial loss of pyramidal cells in layer IIIc and of neurones in layers III, V and VI. CONCLUSION: ChAc is a neurodegenerative disease with distinct cortical neurodegeneration. The hypertrophy of the peripheral neuropil space of minicolumns with coarse vertical striation was characteristic of ChAc. The role of astroglia in the pathogenesis of this disorder remains to be elucidated.

Heart rate, respiratory rate, apnoeas and peripheral arterial oxygen saturation in healthy term neonates during quiet sleep.

AIM: This study compiled percentiles for cardiorespiratory parameters in healthy term neonates during quiet sleep. METHODS: We enrolled 215 healthy term neonates born at Hannover Medical School, Germany, between October 2011 and March 2013. They were prospectively observed on the maternity ward at a median age of two days using six-hour recordings of pulse oximeter plethysmography, oxygen saturation, thoracic breathing movements and electrocardiogram during sleep in a supine position. We examined their heart rate, respiratory rate and oxygen saturation during quiet sleep, plus bradycardias, apnoeas lasting at least four-seconds and desaturations below 85%. RESULTS: The 3rd, 50th and 97th percentiles were calculated as follows: heart rate 87, 112 and 133 beats per minute, respiratory rate 32, 44 and 57 per minute and oxygen saturation 94, 98 and 100%. Desaturations, apnoeas and bradycardias below 80 beats per minute were common and recorded in 54%, 98% and 30% of participants. In contrast, only 7% experienced bradycardias of less than two-thirds of the baseline heart rate and 5% experienced apnoeas exceeding 15 seconds. CONCLUSION: Our results will facilitate the evidence-based valuation of cardiorespiratory parameters in term neonates and help validate the significance of cardiorespiratory events in preterm infants at discharge.

A review of monopolar motor mapping and a comprehensive guide to continuous dynamic motor mapping for resection of motor eloquent brain tumors.

Monopolar mapping of motor function differs from the most commonly used method of intraoperative mapping, i.e. bipolar direct electrical stimulation at 50-60Hz (Penfield technique mapping). Most importantly, the monopolar probe emits a radial, homogenous electrical field different to the more focused inter-tip bipolar electrical field. Most users combine monopolar stimulation with the short train technique, also called high frequency stimulation, or train-of-five techniques. It consists of trains of four to nine monopolar rectangular electrical pulses of 200-500µs pulse length with an inter stimulus interval of 2-4msec. High frequency short train stimulation triggers a time-locked motor-evoked potential response, which has a defined latency and an easily quantifiable amplitude. In this way, motor thresholds might be used to evaluate a current-to-distance relation. The homogeneous electrical field and the current-to-distance approximation provide the surgeon with an estimate of the remaining distance to the corticospinal tract, enabling the surgeon to adjust the speed of resection as the corticospinal tract is approached. Furthermore, this stimulation paradigm is associated with a lower incidence of intraoperative seizures, allowing continuous stimulation. Hence, monopolar mapping is increasingly used as part of a strategy of continuous dynamic mapping: ergonomically integrated into the surgeon's tools, the monopolar probe reliably provides continuous/uninterrupted feedback on motor function. As part of this strategy, motor mapping is not any longer a time consuming interruption of resection but rather a radar-like, real-time information system on the spatial relationship of the current resection site to eloquent motor structures.

Huntington's disease (HD): the neuropathology of a multisystem neurodegenerative disorder of the human brain.

Huntington's disease (HD) is an autosomal dominantly inherited, and currently untreatable, neuropsychiatric disorder. This progressive and ultimately fatal disease is named after the American physician George Huntington and according to the underlying molecular biological mechanisms is assigned to the human polyglutamine or CAG-repeat diseases. In the present article we give an overview of the currently known neurodegenerative hallmarks of the brains of HD patients. Subsequent to recent pathoanatomical studies the prevailing reductionistic concept of HD as a human neurodegenerative disease, which is primarily and more or less exclusively confined to the striatum (ie, caudate nucleus and putamen) has been abandoned. Many recent studies have improved our neuropathological knowledge of HD; many of the early groundbreaking findings of neuropathological HD research have been rediscovered and confirmed. The results of this investigation have led to the stepwise revision of the simplified pathoanatomical and pathophysiological HD concept and culminated in the implementation of the current concept of HD as a multisystem degenerative disease of the human brain. The multisystem character of the neuropathology of HD is emphasized by a brain distribution pattern of neurodegeneration (i) which apart from the striatum includes the cerebral neo-and allocortex, thalamus, pallidum, brainstem and cerebellum, and which (ii) therefore, shares more similarities with polyglutamine spinocerebellar ataxias than previously thought.

Polyglutamine aggregation in Huntington's disease and spinocerebellar ataxia type 3: similar mechanisms in aggregate formation.

AIMS: Polyglutamine (polyQ) diseases are characterized by the expansion of a polymorphic glutamine sequence in disease-specific proteins and exhibit aggregation of these proteins. This is combated by the cellular protein quality control (PQC) system, consisting of chaperone-mediated refolding as well as proteasomal and lysosomal degradation pathways. Our recent study in the polyQ disease spinocerebellar ataxia type 3 (SCA3) suggested a distinct pattern of protein aggregation and PQC dysregulation. METHODS: To corroborate these findings we have investigated immunohistochemically stained 5 µm sections from different brain areas of Huntington's disease (HD) and SCA3 patients. RESULTS: Irrespective of disease and brain region, we observed peri- and intranuclear polyQ protein aggregates. A subset of neurones with intranuclear inclusions bodies exhibited signs of proteasomal dysfunction, up-regulation of HSPA1A and re-distribution of DNAJB1. The extent of the observed effects varied depending on brain area and disease protein. CONCLUSIONS: Our results suggest a common sequence, in which formation of cytoplasmic and nuclear inclusions precede proteasomal impairment and induction of the cellular stress response. Clearly, impairment of the PQC is not the primary cause for inclusion formation, but rather a consequence that might contribute to neuronal dysfunction and death. Notably, the inclusion pathology is not directly correlated to the severity of the degeneration in different areas, implying that different populations of neurones respond to polyQ aggregation with varying efficacy and that protein aggregation outside the neuronal perikaryon (e.g. axonal aggregates) or other effects of polyQ aggregation, which are more difficult to visualize, may contribute to neurodegeneration.

Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation.

Acute kidney injury (AKI) is common after hematopoietic cell transplant (HCT). The etiology of AKI is unknown because biopsies are rarely performed. The pathophysiology of injury is inferred from clinical data. Thrombotic microangiopathy (TMA) is often invoked as the cause of renal injury. Patients >2 years old undergoing their first HCT at Fred Hutchinson Cancer Research Center participated in this study. We prospectively measured plasma markers of coagulation activation, (PAI-1 and tPA) and fibrinolyis (D-dimer) weekly in 149 patients during the first 100 days post transplant. Cox proportional hazards modeling was used to determine associations between these markers and AKI (doubling of baseline serum creatinine). Kruskal-Wallis test was used to determine the associations between day 100 urinary albumin to creatinine ratios and these markers. Thirty one percent of patients developed AKI. Though elevations in these markers occurred frequently, neither PAI-1 nor tPA were associated with the development of AKI. D-dimer was associated with a slightly increased risk of AKI (relative risk=1.76; P-value 0.04). None of these markers were associated with micro- or macroalbuminuria at day 100. The lack of an association with AKI suggests that endothelial injury in the form of TMA is not a common cause of AKI early after transplant.

Male infertility in long-term survivors of pediatric cancer: a report from the childhood cancer survivor study.

PURPOSE: The purpose of this study was to assess the prevalence of male infertility and treatment-related risk factors in childhood cancer survivors. METHODS: Within the Childhood Cancer Survivor Study, 1,622 survivors and 274 siblings completed the Male Health Questionnaire. The analysis was restricted to survivors (938/1,622; 57.8 %) and siblings (174/274; 63.5 %) who tried to become pregnant. Relative risks (RR) and 95 % confidence intervals (CI) for the prevalence of self-reported infertility were calculated using generalized linear models for demographic variables and treatment-related factors to account for correlation among survivors and siblings of the same family. All statistical tests were two-sided. RESULTS: Among those who provided self-report data, the prevalence of infertility was 46.0 % in survivors versus 17.5 % in siblings (RR = 2.64, 95 % CI 1.88-3.70, p < 0.001). Of survivors who met the definition for infertility, 37 % had reported at least one pregnancy with a female partner that resulted in a live birth. In a multivariable analysis, risk factors for infertility included an alkylating agent dose (AAD) score ≥3 (RR = 2.13, 95 % CI 1.69-2.68 for AAD ≥3 versus AAD <3), surgical excision of any organ of the genital tract (RR = 1.63, 95 % CI 1.20-2.21), testicular radiation ≥4 Gy (RR = 1.99, 95 % CI 1.52-2.61), and exposure to bleomycin (RR = 1.55, 95 % CI 1.20-2.01). CONCLUSION: Many survivors who experience infertility father their own children, suggesting episodes of both fertility and infertility. This and the novel association of infertility with bleomycin warrant further investigation. IMPLICATIONS FOR CANCER SURVIVORS: Though infertility is common, male survivors reporting infertility often father their own children. Bleomycin may pose some fertility risk.

Involvement of the cholinergic basal forebrain nuclei in spinocerebellar ataxia type 2 (SCA2).

AIMS: Spinocerebellar ataxia type 2 (SCA2) belongs to the CAG repeat or polyglutamine diseases. Along with a large variety of motor, behavioural and neuropsychological symptoms the clinical picture of patients suffering from this autosomal dominantly inherited ataxia may also include deficits of attention, impairments of memory, as well as frontal-executive and visuospatial dysfunctions. As the possible morphological correlates of these cognitive SCA2 deficits are unclear we examined the cholinergic basal forebrain nuclei, which are believed to be crucial for several aspects of normal cognition and may contribute to impairments of cognitive functions under pathological conditions. METHODS: We studied pigment-Nissl-stained thick tissue sections through the cholinergic basal forebrain nuclei (that is, medial septal nucleus, nuclei of the diagonal band of Broca, basal nucleus of Meynert) of four clinically diagnosed and genetically confirmed SCA2 patients and of 13 control individuals according to the pathoanatomical approach. The pathoanatomical results were confirmed by additional quantitative investigations of these nuclei in the SCA2 patients and four age- and gender-matched controls. RESULTS: Our study revealed a severe and consistent neuronal loss in all of the cholinergic basal forebrain nuclei (medial septal nucleus: 72%; vertical nucleus of the diagonal band of Broca: 74%; horizontal limb of the diagonal band of Broca: 72%; basal nucleus of Meynert: 86%) of the SCA2 patients studied. Damage to the basal forebrain nuclei was associated with everyday relevant cognitive deficits only in our SCA2 patient with an additional Braak and Braak stage V Alzheimer's disease (AD)-related tau pathology. CONCLUSIONS: The findings of the present study: (1) indicate that the mutation and pathological process underlying SCA2 play a causative role for this severe degeneration of the cholinergic basal forebrain nuclei and (2) may suggest that degeneration of the cholinergic basal forebrain nuclei per se is not sufficient to cause profound and global dementia detrimental to everyday practice and activities of daily living.

Spinocerebellar ataxia type 1 (SCA1): new pathoanatomical and clinico-pathological insights.

AIMS: Spinocerebellar ataxia type 1 (SCA1) represents the first molecular genetically characterized autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG-repeat or polyglutamine diseases. Owing to limited knowledge about SCA1 neuropathology, appropriate pathoanatomical correlates of a large variety of SCA1 disease symptoms are missing and the neuropathological basis for further morphological and experimental SCA1 studies is still fragmentary. METHODS: In the present study, we investigated for the first time serial tissue sections through the complete brains of clinically diagnosed and genetically confirmed SCA1 patients. RESULTS: Brain damage in the three SCA1 patients studied went beyond the well-known brain predilection sites of the underlying pathological process. Along with neuronal loss in the primary motor cortex, it included widespread degeneration of gray components of the basal forebrain, thalamus, brainstem and cerebellum, as well as of white matter components in the cerebellum and brainstem. It involved the motor cerebellothalamocortical and basal ganglia-thalamocortical circuits, the visual, auditory, somatosensory, oculomotor, vestibular, ingestion-related, precerebellar, basal forebrain cholinergic and midbrain dopaminergic systems. CONCLUSIONS: These findings show for the first time that the extent and severity of brain damage in SCA1 is very similar to that of clinically closely related spinocerebellar ataxias (that is, SCA2, SCA3 and SCA7). They offer suitable explanations for poorly understood SCA1 disease symptoms and will facilitate the interpretation of further morphological and experimental SCA1 studies.

Cellular protein quality control and the evolution of aggregates in spinocerebellar ataxia type 3 (SCA3).

AIMS: A characteristic of polyglutamine diseases is the increased propensity of disease proteins to aggregate, which is thought to be a major contributing factor to the underlying neurodegeneration. Healthy cells contain mechanisms for handling protein damage, the protein quality control, which must be impaired or inefficient to permit proteotoxicity under pathological conditions. METHODS: We used a quantitative analysis of immunohistochemistry of the pons of eight patients with the polyglutamine disorder spinocerebellar ataxia type 3. We employed the anti-polyglutamine antibody 1C2, antibodies against p62 that is involved in delivering ubiquitinated protein aggregates to autophagosomes, antibodies against the chaperones HSPA1A and DNAJB1 and the proteasomal stress marker UBB⁺¹. RESULTS: The 1C2 antibody stained neuronal nuclear inclusions (NNIs), diffuse nuclear staining (DNS), granular cytoplasmic staining (GCS) and combinations, with reproducible distribution. P62 always co-localized with 1C2 in NNI. DNS and GCS co-stained with a lower frequency. UBB⁺¹ was present in a subset of neurones with NNI. A subset of UBB⁺¹-containing neurones displayed increased levels of HSPA1A, while DNAJB1 was sequestered into the NNI. CONCLUSION: Based on our results, we propose a model for the aggregation-associated pathology of spinocerebellar ataxia type 3: GCS and DNS aggregation likely represents early stages of pathology, which progresses towards formation of p62-positive NNI. A fraction of NNI exhibits UBB⁺¹ staining, implying proteasomal overload at a later stage. Subsequently, the stress-inducible HSPA1A is elevated while DNAJB1 is recruited into NNIs. This indicates that the stress response is only induced late when all endogenous protein quality control systems have failed.

The HSPB8-BAG3 chaperone complex is upregulated in astrocytes in the human brain affected by protein aggregation diseases.

AIMS: HSPB8 is a small heat shock protein that forms a complex with the co-chaperone BAG3. Overexpression of the HSPB8-BAG3 complex in cells stimulates autophagy and facilitates the clearance of mutated aggregation-prone proteins, whose accumulation is a hallmark of many neurodegenerative disorders. HSPB8-BAG3 could thus play a protective role in protein aggregation diseases and might be specifically upregulated in response to aggregate-prone protein-mediated toxicity. Here we analysed HSPB8-BAG3 expression levels in post-mortem human brain tissue from patients suffering of the following protein conformation disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3 (SCA3). METHODS: Western blotting and immunohistochemistry techniques were used to analyse HSPB8 and BAG3 expression levels in fibroblasts from SCA3 patients and post-mortem brain tissues, respectively. RESULTS: In all diseases investigated, we observed a strong upregulation of HSPB8 and a moderate upregulation of BAG3 specifically in astrocytes in the cerebral areas affected by neuronal damage and degeneration. Intriguingly, no significant change in the HSPB8-BAG3 expression levels was observed within neurones, irrespective of their localization or of the presence of proteinaceous aggregates. CONCLUSIONS: We propose that the upregulation of HSPB8 and BAG3 may enhance the ability of astrocytes to clear aggregated proteins released from neurones and cellular debris, maintain the local tissue homeostasis and/or participate in the cytoskeletal remodelling that astrocytes undergo during astrogliosis.

Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3).

The cerebellum is one of the well-known targets of the pathological processes underlying spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Despite its pivotal role for the clinical pictures of these polyglutamine ataxias, no pathoanatomical studies of serial tissue sections through the cerebellum have been performed in SCA2 and SCA3 so far. Detailed pathoanatomical data are an important prerequisite for the identification of the initial events of the underlying disease processes of SCA2 and SCA3 and the reconstruction of its spread through the brain. In the present study, we performed a pathoanatomical investigation of serial thick tissue sections through the cerebellum of clinically diagnosed and genetically confirmed SCA2 and SCA3 patients. This study demonstrates that the cerebellar Purkinje cell layer and all four deep cerebellar nuclei consistently undergo considerable neuronal loss in SCA2 and SCA3. These cerebellar findings contribute substantially to the pathogenesis of clinical symptoms (i.e., dysarthria, intention tremor, oculomotor dysfunctions) of SCA2 and SCA3 patients and may facilitate the identification of the initial pathological alterations of the pathological processes of SCA2 and SCA3 and reconstruction of its spread through the brain.

Paternal deprivation affects the development of corticotrophin-releasing factor-expressing neurones in prefrontal cortex, amygdala and hippocampus of the biparental Octodon degus.

Although the critical role of maternal care on the development of brain and behaviour of the offspring has been extensively studied, knowledge about the importance of paternal care is comparatively scarce. In biparental species, paternal care significantly contributes to a stimulating socio-emotional family environment, which most likely also includes protection from stressful events. In the biparental caviomorph rodent Octodon degus, we analysed the impact of paternal care on the development of neurones in prefrontal-limbic brain regions, which express corticotrophin-releasing factor (CRF). CRF is a polypeptidergic hormone that is expressed and released by a neuronal subpopulation in the brain, and which not only is essential for regulating stress and emotionality, but also is critically involved in cognitive functions. At weaning age [postnatal day (P)21], paternal deprivation resulted in an elevated density of CRF-containing neurones in the orbitofrontal cortex and in the basolateral amygdala of male degus, whereas a reduced density of CRF-expressing neurones was measured in the dentate gyrus and stratum pyramidale of the hippocampal CA1 region at this age. With the exception of the CA1 region, the deprivation-induced changes were no longer evident in adulthood (P90), which suggests a transient change that, in later life, might be normalised by other socio-emotional experience. The central amygdala, characterised by dense clusters of CRF-immunopositive neuropil, and the precentral medial, anterior cingulate, infralimbic and prelimbic cortices, were not affected by paternal deprivation. Taken together, this is the first evidence that paternal care interferes with the developmental expression pattern of CRF-expressing interneurones in an age- and region-specific manner.

Inner ear insult suppresses the respiratory response to carbon dioxide.

Compensated respiratory acidosis has been observed in a significant number of patients with active vestibular disease. We therefore hypothesized that the inner ear may play an unrecognized integral role in respiratory control. To test this premise, we investigated whether mice with induced inner ear injury demonstrated any alteration in their respiratory response to inhaled carbon dioxide (CO(2)). Experimental mice and control mice were included in two separate experiments. Intra-tympanic gentamycin injections were administered to induce inner ear damage in experimental animals. Hearing loss and vestibular dysfunction were tested 1-week after injections to confirm presence of inner ear insult, following which the animal's respiratory response to inhalation of 8% CO(2) was examined. Mice with inner ear injury (n=60) displayed a significantly diminished hypercapnic ventilatory response (HCVR). This contrasted with the normal HCVR seen in control mice that had not undergone tympanic injections (n=30), controls that received tympanic injections with saline (n=5), and controls that had gentamicin administered systemically (n=5). In response to inspired CO(2), the mean respiratory frequency of control mice increased by an average of 50% over their baseline values for both parts of the experiment. In contrast, the ear-damaged experimental group mean values increased by only three breaths per minute (bpm) (2%) in the first experiment and by 28 bpm (11%) in the second experiment. Inner ear damage significantly reduces the respiratory response to CO(2) inhalation. In addition to the established role of the inner ear organ in hearing and balance, this alludes to an unidentified function of the inner ear and its interconnecting neuronal pathways in respiratory regulation. This finding may offer valuable new clues for disease states with abnormal respiratory control where inner ear dysfunction may be present.

The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia type 6.

Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e., pathologically altered alpha-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system.

Paternal deprivation during infancy results in dendrite- and time-specific changes of dendritic development and spine formation in the orbitofrontal cortex of the biparental rodent Octodon degus.

The aim of this study in the biparental rodent Octodon degus was to assess the impact of paternal deprivation on neuronal and synaptic development in the orbitofrontal cortex, a prefrontal region which is essential for emotional and cognitive function. On the behavioral level the quantitative comparison of parental behaviors in biparental and single-mother families revealed that (i) degu fathers significantly participate in parental care and (ii) single-mothers do not increase their maternal care to compensate the lack of paternal care. On the brain structural level we show in three-week-old father-deprived animals that layer II/III pyramidal neurons in the orbitofrontal cortex displayed significantly lower spine densities on apical and basal dendrites. Whereas biparentally raised animals have reached adult spine density values at postnatal day 21, fatherless animals seem "to catch up" by a delayed increase of spine density until reaching similar values as biparentally raised animals in adulthood. However, in adulthood reduced apical spine numbers together with shorter apical dendrites were observed in father-deprived animals, which indicates that dendritic growth and synapse formation (seen in biparental animals between postnatal day 21 and adulthood) were significantly suppressed. These results demonstrate that paternal deprivation delays and partly suppresses the development of orbitofrontal circuits. The retarded dendritic and synaptic development of the apical dendrites of layer II/III pyramidal neurons in the orbitofrontal cortex of adult fatherless animals may reflect a reduced excitatory connectivity of this cortical subregion.

The central vestibular complex in dolphins and humans: functional implications of Deiters' nucleus.

Toothed whales (Odontocetes; e.g., dolphins) are well-known for efficient underwater locomotion and for their acrobatic capabilities. Nevertheless, in relation to other mammals including the human and with respect to body size, their vestibular apparatus is reduced, particularly the semicircular canals. Concomitantly, the vestibular nerve and most of the vestibular nuclei are thin and small, respectively, in comparison with those in terrestrial mammals. In contrast, the lateral (Deiters') vestibular nucleus is comparatively well developed in both coastal and pelagic dolphins. In the La Plata dolphin (Pontoporia blainvillei) and the Common dolphin (Delphinus delphis), all of the vestibular nuclei are present and their topographic relations are similar to those in humans. Quantitative analysis, however, revealed that in the dolphin most of the nuclei (superior, medial, descending nucleus) are minute both in absolute and relative terms. Here, the only exception is the lateral vestibular nucleus, which is of comparable size in humans and Pontoporia and decidedly more voluminous in Delphinus. While the small size of the majority of the dolphin's vestibular nuclei correlates well with miniaturization of the semicircular canals, the size of Deiters' nucleus seems to support its relative independence from the vestibular system and a close functional relationship with the cerebellum. In comparison with findings in humans and other terrestrial mammals, both of these aspects seem to be related to the physical conditions of aquatic life and locomotion in three dimensions.