Iron(II) Complexes of P3 -Chain Ligands: Structural Diversity.

Iron(II) complexes containing ligands with a R2 P-P-PR2 unit were synthesized by metathesis reactions. With R=tBu, a mixture of two isomers is formed; in one of them, the terminal phosphorus binds to the Fe center (ylidic structure), while in the other one, the central P atom is linked to Fe. Starting from differently functionalized parent triphosphanes and corresponding functionalized Fe complexes, the ratio of isomers does not change. The outcome of the reaction and therefore the binding modes of the triphosphane ligands in the resulting compounds can be influenced by the size of the substituents. In the case of R=iPr a chelate complex is formed (both terminal P atoms are linked to the Fe center). Applying the mixed-substituted triphosphane, the ylidic structure of the resulting complex is preferred. The new compounds were characterized by NMR spectroscopy in solution and single-crystal X-ray diffraction in solid-state. The synthetic work was supported by DFT calculations.

The adolescent pattern of sleep spindle development revealed by HD-EEG.

Sleep spindles are developmentally relevant cortical oscillatory patterns; however, they have mostly been studied by considering the entire spindle frequency range (11-15 Hz) without a distinction between the functionally and topographically different slow and fast spindles, using relatively few electrodes and analysing wide age-ranges. Here, we employ high-density night sleep electroencephalography in three age-groups between 12 and 20 years of age (30 females and 30 males) and analyse the adolescent developmental pattern of the four major parameters of slow and fast sleep spindles. Most of our findings corroborate those very few previous studies that also make a distinction between slow and fast spindles in their developmental analysis. We find spindle frequency increasing with age. A spindle density change is not obvious in our study. We confirm the declining tendencies for amplitude and duration, although within narrower, more specific age-windows than previously determined. Spindle frequency seems to be higher in females in the oldest age-group. Based on the pattern of our findings, we suggest that high-density electroencephalography, specifically targeting slow and fast spindle ranges and relatively narrow age-ranges would advance the understanding of both adolescent cortical maturation and development and the functional relevance of sleep spindles in general.

Sleep-spindle frequency: Overnight dynamics, afternoon nap effects, and possible circadian modulation.

Homeostatic and circadian processes play a pivotal role in determining sleep structure, timing, and quality. In sharp contrast with the wide accessibility of the electroencephalogram (EEG) index of sleep homeostasis, an electrophysiological measure of the circadian modulation of sleep is still unavailable. Evidence suggests that sleep-spindle frequencies decelerate during biological night. In order to test the feasibility of measuring this marker in common polysomnographic protocols, the Budapest-Munich database of sleep records (N = 251 healthy subjects, 122 females, age range: 4-69 years), as well as an afternoon nap sleep record database (N = 112 healthy subjects, 30 females, age range: 18-30 years) were analysed by the individual adjustment method of sleep-spindle analysis. Slow and fast sleep-spindle frequencies were characterised by U-shaped overnight dynamics, with highest values in the first and the fourth-to-fifth sleep cycle and the lowest values in the middle of the sleeping period (cycles two to three). Age-related attenuation of sleep-spindle deceleration was evident. Estimated phases of the nadirs in sleep-spindle frequencies were advanced in children as compared to other age groups. Additionally, nap sleep spindles were faster than night sleep spindles (0.57 and 0.39 Hz difference for slow and fast types, respectively). The fine frequency resolution analysis of sleep spindles is a feasible method of measuring the assumed circadian modulation of sleep. Moreover, age-related attenuation of circadian sleep modulation might be measurable by assessing the overnight dynamics in sleep-spindle frequency. Phase of the minimal sleep-spindle frequency is a putative biomarker of chronotype.

Maturation-dependent vulnerability of emotion regulation as a response to COVID-19 related stress in adolescents.

BACKGROUND: The COVID-19 pandemic created unpredictable circumstances resulting in increased psychological strain. Here we investigate pandemic-related alterations in emotion regulation in adolescents assessed before and during the pandemic. We also take biological age into account in the response to the pandemic. METHODS: Mann-Whitney U tests were conducted to compare baseline data on the Difficulties in Emotion Regulation Scale (DERS) total scores of a pre-pandemic adolescent cohort (n = 241) with those obtained during the second wave of the pandemic (n = 266). We estimated biological age based on an ultrasonic boneage assessment procedure in a subgroup of males, including grammar school and vocational school students in the 9th and 10th grades, and analyzed their data independently. FINDINGS: There is a gender difference in the timing of vulnerability for pandemic-related stress in grammar school students: females are affected a year earlier than males. Vocational school male students mature faster than grammar school male students, and the timing of emotional vulnerability also precedes that of the grammar school students'. DISCUSSION: We interpret our findings within a developmental model suggesting that there might be a window of highest vulnerability in adolescent emotion regulation. The timing of the window is determined by both chronological and biological age, and it is different for females and males. APPLICATION TO PRACTICE: Defining the exact temporal windows of vulnerability for different adolescent cohorts allows for the timely integration of preventive actions into adolescent care to protect mental health during future chronic stressful situations.

Mesoporous Aerogel Microparticles Injected into the Abdominal Cavity of Mice Accumulate in Parathymic Lymph Nodes.

Mesoporous aerogel microparticles are promising drug delivery systems. However, their in vivo biodistribution pathways and health effects are unknown. Suspensions of fluorescein-labeled silica-gelatin hybrid aerogel microparticles were injected into the peritoneum (abdominal cavity) of healthy mice in concentrations of 52 and 104 mg kg-1 in a 3-week-long acute toxicity experiment. No physiological dysfunctions were detected, and all mice were healthy. An autopsy revealed that the aerogel microparticles were not present at the site of injection in the abdominal cavity at the end of the experiment. The histological study of the liver, spleen, kidneys, thymus and lymphatic tissues showed no signs of toxicity. The localization of the aerogel microparticles in the organs was studied by fluorescence microscopy. Aerogel microparticles were not detected in any of the abdominal organs, but they were clearly visible in the cortical part of the parathymic lymph nodes, where they accumulated. The accumulation of aerogel microparticles in parathymic lymph nodes in combination with their absence in the reticuloendothelial system organs, such as the liver or spleen, suggests that the microparticles entered the lymphatic circulation. This biodistribution pathway could be exploited to design passive targeting drug delivery systems for flooding metastatic pathways of abdominal cancers that spread via the lymphatic circulation.

The paradox of rapid eye movement sleep in the light of oscillatory activity and cortical synchronization during phasic and tonic microstates.

Rapid Eye Movement (REM) sleep is a peculiar neural state showing a combination of muscle atonia and intense cortical activity. REM sleep is usually considered as a unitary state in neuroscientific research; however, it is composed of two different microstates: phasic and tonic REM. These differ in awakening thresholds, sensory processing, and cortical oscillations. Nevertheless, studies examining cortical oscillations during REM microstates are scarce, and used low spatial sampling. Here, we analyzed the data of 18 healthy individuals assessed by high-density sleep EEG recordings. We systematically contrasted phasic and tonic REM periods in terms of topographical distribution, source localization, as well as local, global and long-range synchronization of frequency-specific cortical activity. Tonic periods showed relatively increased high alpha and beta power over frontocentral derivations. In addition, higher frequency components of beta power exhibited increased global synchronization during tonic compared to phasic states. In contrast, in phasic periods we found increased power and synchronization of low frequency oscillations coexisting with increased and synchronized gamma activity. Source localization revealed several multimodal, higher-order associative, as well as sensorimotor areas as potential sources of increased high alpha/beta power during tonic compared to phasic REM. Increased gamma power in phasic REM was attributed to medial prefrontal and right lateralized temporal areas associated with emotional processing. Our findings emphasize the heterogeneous nature of REM sleep, expressed in two microstates with remarkably different neural activity. Considering the microarchitecture of REM sleep may provide new insights into the mechanisms of REM sleep in health and disease.

In Vivo Applicability of Neosartorya fischeri Antifungal Protein 2 (NFAP2) in Treatment of Vulvovaginal Candidiasis.

As a consequence of emerging numbers of vulvovaginitis cases caused by azole-resistant and biofilm-forming Candida species, fast and efficient treatment of this infection has become challenging. The problem is further exacerbated by the severe side effects of azoles as long-term-use medications in the recurrent form. There is therefore an increasing demand for novel and safely applicable effective antifungal therapeutic strategies. The small, cysteine-rich, and cationic antifungal proteins from filamentous ascomycetes are potential candidates, as they inhibit the growth of several Candida spp. in vitro; however, no information is available about their in vivo antifungal potency against yeasts. In the present study, we investigated the possible therapeutic application of one of their representatives in the treatment of vulvovaginal candidiasis, Neosartorya fischeri antifungal protein 2 (NFAP2). NFAP2 inhibited the growth of a fluconazole (FLC)-resistant Candida albicans strain isolated from a vulvovaginal infection, and it was effective against both planktonic cells and biofilm in vitro We observed that the fungal cell-killing activity of NFAP2 is connected to its pore-forming ability in the cell membrane. NFAP2 did not exert cytotoxic effects on primary human keratinocytes and dermal fibroblasts at the MIC in vitro. In vivo murine vulvovaginitis model experiments showed that NFAP2 significantly decreases the number of FLC-resistant C. albicans cells, and combined application with FLC enhances the efficacy. These results suggest that NFAP2 provides a feasible base for the development of a fundamental new, safely applicable mono- or polytherapeutic topical agent for the treatment of superficial candidiasis.

Perceptual reversals in binocular rivalry: Improved detection from OKN.

When binocular rivalry is induced by opponent motion displays, perceptual reversals are often associated with changed oculomotor behavior (Frässle, Sommer, Jansen, Naber, & Einhäuser, 2014; Fujiwara et al., 2017). Specifically, the direction of smooth pursuit phases in optokinetic nystagmus typically corresponds to the direction of motion that dominates perceptual appearance at any given time. Here we report an improved analysis that continuously estimates perceived motion in terms of "cumulative smooth pursuit." In essence, smooth pursuit segments are identified, interpolated where necessary, and joined probabilistically into a continuous record of cumulative smooth pursuit (i.e., probability of eye position disregarding blinks, saccades, signal losses, and artefacts). The analysis is fully automated and robust in healthy, developmental, and patient populations. To validate reliability, we compare volitional reports of perceptual reversals in rivalry displays, and of physical reversals in nonrivalrous control displays. Cumulative smooth pursuit detects physical reversals and estimates eye velocity more accurately than existing methods do (Frässle et al., 2014). It also appears to distinguish dominant and transitional perceptual states, detecting changes with a precision of ±100 ms. We conclude that cumulative smooth pursuit significantly improves the monitoring of binocular rivalry by means of recording optokinetic nystagmus.

PRMT1 and PRMT8 regulate retinoic acid-dependent neuronal differentiation with implications to neuropathology.

Retinoids are morphogens and have been implicated in cell fate commitment of embryonic stem cells (ESCs) to neurons. Their effects are mediated by RAR and RXR nuclear receptors. However, transcriptional cofactors required for cell and gene-specific retinoid signaling are not known. Here we show that protein arginine methyl transferase (PRMT) 1 and 8 have key roles in determining retinoid regulated gene expression and cellular specification in a multistage neuronal differentiation model of murine ESCs. PRMT1 acts as a selective modulator, providing the cells with a mechanism to reduce the potency of retinoid signals on regulatory "hotspots." PRMT8 is a retinoid receptor target gene itself and acts as a cell type specific transcriptional coactivator of retinoid signaling at later stages of differentiation. Lack of either of them leads to reduced nuclear arginine methylation, dysregulated neuronal gene expression, and altered neuronal activity. Importantly, depletion of PRMT8 results in altered expression of a distinct set of genes, including markers of gliomagenesis. PRMT8 is almost entirely absent in human glioblastoma tissues. We propose that PRMT1 and PRMT8 serve as a rheostat of retinoid signaling to determine neuronal cell specification in a context-dependent manner and might also be relevant in the development of human brain malignancy.

Immune-mediated Skin Inflammation is Similar in Severe Atopic Dermatitis Patients With or Without Filaggrin Mutation.

Inflammatory cytokines can impair the skin barrier, but the question as to whether barrier alterations affect keratinocyte immune responses remains unanswered. The aim of this study was to investigate whether immune-mediated skin inflammation differs between severe atopic dermatitis patients with or without filaggrin mutation. The levels of filaggrin, inflammatory T helper 2 polarizing cytokines (thymic stromal lymphopoietin (TSLP) and interleukin 33 (IL-33)) and chemokine (C-C motif) ligand 27 (CCL27), histological severity markers, T and dendritic cell counts in biopsies from lesional skin of severe atopic dermatitis patients with and without filaggrin mutation and healthy skin were quantified by immunohistochemistry. The results were confirmed by quantitative PCR analyses. No significant differences were found between the 2 patient groups. Expression of atopic dermatitis-specific cytokines showed significant correlation with histological severity. These findings suggest that the immune-mediated skin inflammation (represented by keratinocyte-derived factors, T cell and dendritic cell counts) is similar in the 2 patient groups with severe atopic dermatitis, and that immune activation is connected to the severity of the disease rather than to the origin of barrier alterations.

[Pathological diagnosis, work-up and reporting of breast cancer. Recommendations of the 3rd Hungarian Consensus Conference on Breast Cancer]. / Az emlõrák patológiai diagnosztikája, feldolgozása és kórszövettani leletezése. Szakmai útmutatás a III. Emlõrák Konszenzus Konferencia alapján.

There have been relevant changes in the diagnosis and treatment of breast cancer to implement the updating of the 2010 recommendations made during the 2nd national consensus conference on the disease. Following a wide interdisciplinary consultation, the present recommendations have been finalized after their public discussion at the 3rd Hungarian Consensus Conference on Breast Cancer. The recommendations cover non-operative and intraoperative diagnostics, the work-up of operative specimens, the determination of prognostic and predictive markers and the content of the cytology and histology reports. Furthermore, it touches some special issues such as the current status of multigene molecular markers, the role of pathologists in clinical trials and prerequisites for their involvement, some relevant points about the future.

Protein kinase Cδ promotes proliferation and induces malignant transformation in skeletal muscle.

In this paper, we investigated the isoform-specific roles of certain protein kinase C (PKC) isoforms in the regulation of skeletal muscle growth. Here, we provide the first intriguing functional evidence that nPKCδ (originally described as an inhibitor of proliferation in various cells types) is a key player in promoting both in vitro and in vivo skeletal muscle growth. Recombinant overexpression of a constitutively active nPKCδ in C2C12 myoblast increased proliferation and inhibited differentiation. Conversely, overexpression of kinase-negative mutant of nPKCδ (DN-nPKCδ) markedly inhibited cell growth. Moreover, overexpression of nPKCδ also stimulated in vivo tumour growth and induced malignant transformation in immunodeficient (SCID) mice whereas that of DN-nPKCδ suppressed tumour formation. The role of nPKCδ in the formation of rhabdomyosarcoma was also investigated where recombinant overexpression of nPKCδ in human rhabdomyosarcoma RD cells also increased cell proliferation and enhanced tumour formation in mouse xenografts. The other isoforms investigated (PKCα, ß, ε) exerted only minor (mostly growth-inhibitory) effects in skeletal muscle cells. Collectively, our data introduce nPKCδ as a novel growth-promoting molecule in skeletal muscles and invite further trials to exploit its therapeutic potential in the treatment of skeletal muscle malignancies.

Early-onset binocularity in preterm infants reveals experience-dependent visual development in humans.

Although there is a great deal of knowledge regarding the phylo- and ontogenetic plasticity of the neocortex, the precise nature of environmental impact on the newborn human brain is still one of the most controversial issues of neuroscience. The leading model-system of experience-dependent brain development is binocular vision, also called stereopsis. Here, we show that extra postnatal visual experience in preterm human neonates leads to a change in the developmental timing of binocular vision. The onset age of binocular function, as measured by the visual evoked response to dynamic random dot correlograms (DRDC-VEP), appears to be at around the same time after birth in preterm (4.07 mo) and full-term (3.78 mo) infants. To assess the integrity of the visual pathway in the studied infants, we also measured the latency of the visual-evoked response to pattern reversal stimuli (PR-VEP). PR-VEP latency is not affected by premature birth, demonstrating that the maturation of the visual pathway follows a preprogrammed developmental course. Despite the immaturity of the visual pathway, clearly demonstrated by the PR-VEP latencies, our DRCD-VEP data show that the visual cortex is remarkably ready to accept environmental stimulation right after birth. This early plasticity makes full use of the available extra stimulation time in preterm human infants and results in an early onset of cortical binocularity. According to our data, the developmental processes preceding the onset of binocular function are not preprogrammed, and the mechanisms turning on stereopsis are extremely experience-dependent in humans.

Function of RasGRP3 in the formation and progression of human breast cancer.

INTRODUCTION: Ras guanine nucleotide exchange factors (RasGEFs) mediate the activation of the Ras signaling pathway that is over activated in many human cancers. The RasGRP3, an activator of H-Ras and R-Ras protein exerts oncogenic effects and the overexpression of the protein is observed in numerous malignant cancer types. Here, we investigated the putative alteration of expression and potential function of RasGRP3 in the formation and progression of human breast cancer. METHODS: The RasGRP3 and phosphoRasGRP3 expressions were examined in human invasive ductal adenocarcinoma derived samples and cell lines (BT-474, JIMT-1, MCF7, SK-BR-3, MDA-MB-453, T-47D) both in mRNA (Q-PCR) and protein (Western blot; immunohistochemistry) levels. To explore the biological function of the protein, RasGRP3 knockdown cultures were established. To assess the role of RasGRP3 in the viability of cells, annexin-V/PI staining and MitoProbe™ DilC1 (5) assay were performed. To clarify the function of the protein in cell proliferation and in the development of chemotherapeutic resistance, CyQuant assay was performed. To observe the RasGRP3 function in tumor formation, the Severe combined immunodeficiency (SCID) mouse model was used. To investigate the role of the protein in Ras-related signaling Q-PCR and Western blot experiments were performed. RESULTS: RasGRP3 expression was elevated in human breast tumor tissue samples as well as in multiple human breast cancer cell lines. Down-regulation of RasGRP3 expression in breast cancer cells decreased cell proliferation, induced apoptosis in MCF7 cells, and sensitized T-47D cells to the action of drugs Tamoxifen and trastuzumab (Herceptin). Gene silencing of RasGRP3 reduced tumor formation in mouse xenografts as well. Inhibition of RasGRP3 expression also reduced Akt, ERK1/2 and estrogen receptor alpha phosphorylation downstream from IGF-I insulin like growth factor-I (IGF-I) or epidermal growth factor (EGF) stimulation confirming the functional role of RasGRP3 in the altered behavior of these cells. CONCLUSIONS: Taken together, our results suggest that the Ras activator RasGRP3 may have a role in the pathological behavior of breast cancer cells and may constitute a therapeutic target for human breast cancer.

Sleep-EEG in dizygotic twins discordant for Williams syndrome.

BACKGROUND AND PURPOSE: Reports on twin pairs concordant and discordant for Williams syndrome were published before, but no study unravelled sleep physiology in these cases yet. We aim to fill this gap by analyzing sleep records of a twin pair discordant for Williams syndrome extending our focus on presleep wakefulness and sleep spindling. METHODS: We performed multiplex ligation-dependent probe amplification of the 7q11.23 region of a 17 years old dizygotic opposite-sex twin pair discordant for Williams syndrome. Polysomnography of laboratory sleep at this age was analyzed and followed-up after 1.5 years by ambulatory polysomnography. Sleep stages scoring, EEG power spectra and sleep spindle analyses were carried out. RESULTS: The twin brother showed reduced levels of amplification for all of the probes in the 7q11.23 region indicating a typical deletion spanning at least 1.038 Mb between FKBP6 and CLIP2. The results of the twin sister showed normal copy numbers in the investigated region. Lower sleep times and efficiencies, as well as higher slow wave sleep percents of the twin brother were evident during both recordings. Roughly equal NREM, Stage 2 and REM sleep percents were found. EEG analyses revealed state and derivation-independent decreases in alpha power, lack of an alpha spectral peak in presleep wakefulness, as well as higher NREM sleep sigma peak frequency in the twin brother. Faster sleep spindles with lower amplitude and shorter duration characterized the records of the twin brother. Spectra show a striking reliability and correspondence between the two situations (laboratory vs. home records). CONCLUSION: Alterations in sleep and specific neural oscillations including the alpha/sigma waves are inherent aspects of Williams syndrome.

Navigating Pubertal Goldilocks: The Optimal Pace for Hierarchical Brain Organization.

Adolescence is a timed process with an onset, tempo, and duration. Nevertheless, the temporal dimension, especially the pace of maturation, remains an insufficiently studied aspect of developmental progression. The primary objective is to estimate the precise influence of pubertal maturational tempo on the configuration of associative brain regions. To this end, the connection between maturational stages and the level of hierarchical organization of large-scale brain networks in 12-13-year-old females is analyzed. Skeletal maturity is used as a proxy for pubertal progress. The degree of maturity is defined by the difference between bone age and chronological age. To assess the level of hierarchical organization in the brain, the temporal dynamic of closed eye resting state high-density electroencephalography (EEG) in the alpha frequency range is analyzed. Different levels of hierarchical order are captured by the measured asymmetry in the directionality of information flow between different regions. The calculated EEG-based entropy production of participant groups is then compared with accelerated, average, and decelerated maturity. Results indicate that an average maturational trajectory optimally aligns with cerebral hierarchical order, and both accelerated and decelerated timelines result in diminished cortical organization. This suggests that a "Goldilocks rule" of brain development is favoring a particular maturational tempo.

In vivo application of a small molecular weight antifungal protein of Penicillium chrysogenum (PAF).

The antifungal protein of Penicillium chrysogenum (PAF) inhibits the growth of important pathogenic filamentous fungi, including members of the Aspergillus family and some dermatophytes. Furthermore, PAF was proven to have no toxic effects on mammalian cells in vitro. To prove that PAF could be safely used in therapy, experiments were carried out to investigate its in vivo effects. Adult mice were inoculated with PAF intranasally in different concentrations, up to 2700 µg·kg⁻¹ daily, for 2 weeks. Even at the highest concentration--a concentration highly toxic in vitro for all affected molds used, animals neither died due to the treatment nor were any side effects observed. Histological examinations did not find pathological reactions in the liver, in the kidney, and in the lungs. Mass spectrometry confirmed that a measurable amount of PAF was accumulated in the lungs after the treatment. Lung tissue extracts from PAF treated mice exerted significant antifungal activity. Small-animal positron emission tomography revealed that neither the application of physiological saline nor that of PAF induced any inflammation while the positive control lipopolysaccharide did. The effect of the drug on the skin was examined in an irritative dermatitis model where the change in the thickness of the ears following PAF application was found to be the same as in control and significantly less than when treated with phorbol-12-myristate-13-acetate used as positive control. Since no toxic effects of PAF were found in intranasal application, our result is the first step for introducing PAF as potential antifungal drug in therapy.

PARP2 promotes inflammation in psoriasis by modulating estradiol biosynthesis in keratinocytes.

Poly(ADP-ribose) polymerase 2 (PARP2) alongside PARP1 are responsible for the bulk of cellular PARP activity, and they were first described as DNA repair factors. However, research in past decades implicated PARPs in biological functions as diverse as the regulation of cellular energetics, lipid homeostasis, cell death, and inflammation. PARP activation was described in Th2-mediated inflammatory processes, but studies focused on the role of PARP1, while we have little information on PARP2 in inflammatory regulation. In this study, we assessed the role of PARP2 in a Th17-mediated inflammatory skin condition, psoriasis. We found that PARP2 mRNA expression is increased in human psoriatic lesions. Therefore, we studied the functional consequence of decreased PARP2 expression in murine and cellular human models of psoriasis. We observed that the deletion of PARP2 attenuated the imiquimod-induced psoriasis-like dermatitis in mice. Silencing of PARP2 in human keratinocytes prevented their hyperproliferation, maintained their terminal differentiation, and reduced their production of inflammatory mediators after treatment with psoriasis-mimicking cytokines IL17A and TNFα. Underlying these observations, we found that aromatase was induced in the epidermis of PARP2 knock-out mice and in PARP2-deficient human keratinocytes, and the resulting higher estradiol production suppressed NF-κB activation, and hence, inflammation in keratinocytes. Steroidogenic alterations have previously been described in psoriasis, and we extend these observations by showing that aromatase expression is reduced in psoriatic lesions. Collectively, our data identify PARP2 as a modulator of estrogen biosynthesis by epidermal keratinocytes that may be relevant in Th17 type inflammation. KEY MESSAGES : PARP2 mRNA expression is increased in lesional skin of psoriasis patients. PARP2 deletion in mice attenuated IMQ-induced psoriasis-like dermatitis. NF-κB activation is suppressed in PARP2-deficient human keratinocytes. Higher estradiol in PARP2-deficient keratinocytes conveys anti-inflammatory effect.

Fluvastatin-induced alterations of skeletal muscle function in hypercholesterolaemic rats.

Although statins, the most widely used drugs in the treatment of hyperlipidaemia, are generally accepted as efficient and safe drugs their side-effects on skeletal muscle have been reported with increasing frequency. The lack of an animal model in which these side effects would consistently be observed is one of the important drawbacks in studying statin associated myopathy. To overcome this and enable the studying of the effects of fluvastatin on skeletal muscles an animal model with high blood cholesterol levels was developed. In these animals cholesterol levels rose more than seven fold (from 1.5 ± 0.1 to 10.7 ± 2.0 mmol/l; n = 15 and 16) with a dramatic increase in low density lipoprotein/high density lipoprotein ratio (from 0.29 ± 0.02 to 1.56 ± 0.17). While the latter was reversed by statin treatment, an elevation in blood creatine kinase (CK) level indicated the presence of muscle wasting. Fibers from m. extensor digitorum longus (EDL) showed significant reduction in cross sectional area in the statin treated groups. Statin treatment also decreased the proliferation and fusion of skeletal myotubes in culture. In line with this, resting intracellular calcium concentration ([Ca(2+)](i)) was reduced in statin treated satellite cells and myotubes. On the other hand, in adult skeletal muscle fibers statin treatment increased resting [Ca(2+)](i) (116 ± 4 nM vs. 151 ± 5 nM; n = 33 and 34) and decreased both twitch and tetanic force both in EDL and m. soleus. In addition, in m. soleus the duration of twitch and tetanic force was shortened. These results clearly indicate that statin administration in these animals results in a myopathy characterized by decreased muscle force and elevated plasma CK level.

The spatial range of contour integration deficits in schizophrenia.

Contour integration (CI) refers to the process that represents spatially separated elements as a unified edge or closed shape. Schizophrenia is a psychiatric disorder characterized by symptoms such as hallucinations, delusions, disorganized thinking, inappropriate affect, and social withdrawal. Persons with schizophrenia are impaired at CI, but the specific mechanisms underlying the deficit are still not clear. Here, we explored the hypothesis that poor patient performance owes to reduced feedback or impaired longer-range lateral connectivity within early visual cortex--functionally similar to that found in 5- to 6-year old children. This hypothesis predicts that as target element spacing increases from .7 to 1.4° of visual angle, patient impairments will become more pronounced. As a test of the prediction, 25 healthy controls and 36 clinically stable, asymptomatic persons with schizophrenia completed a CI task that involved determining whether a subset of Gabor elements formed a leftward or rightward pointing shape. Adjacent shape elements were spaced at either .7 or 1.4° of visual angle. Difficulty in each spacing condition depended on the number of noise elements present. Patients performed worse than controls overall, both groups performed worse with the larger spacing, and the magnitude of the between-group difference was not amplified at the larger spacing. These results show that CI deficits in schizophrenia cannot be explained in terms of a reduced spatial range of integration, at least not when the shape elements are spaced within 1.5°. Later-developing, low-level integrative mechanisms of lateral connectivity and feedback appear not to be differentially impaired in the illness.