Atorvastatin ameliorates cerebral vasospasm and early brain injury after subarachnoid hemorrhage and inhibits caspase-dependent apoptosis pathway

Backgroud  

Cerebral vasospasm (CVS) and early brain injury remain major causes of morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH). Hydroxymethylglutaryl coenzyme A reductase inhibitors, also known as statins, has the neuroprotective effects and ameliorating CVS after SAH. This study was designed to explore apoptosis inhibiting effects of atorvastatin and its potential apoptotic signal pathway after SAH.     

Investigating lung remodeling in Modul8-treated BALB/c asthmatic animals

Animal models of bronchial hyperresponsiveness have been successfully used to investigate the pathophysiology of asthma. When mice are sensitized and challenged with an allergen, such as OVA, they experience symptoms and processes similar to that of humans, and are therefore widely used as asthmatic animal models. In the current study the BALB/c murine asthmatic animal model was used to investigate the histological and ultrastructural changes that occur in the lungs of asthmatic animals that received no treatment, compared to two groups of asthmatic animals that were treated with a homeopathic immunodulator Modul8^® and hydrocortisone as positive control, respectively. Eosinophil counts in the bronchial lavage of the animals were also analyzed, since it is known that eosinophil counts are increased in the bronchial lavage in asthma. Results indicated that eosinophil counts were elevated in asthmatic animals compared to the controls, but were found to be significantly decreased in the treatment groups. Also, in the asthmatic, untreated animals, histological and ultrastructural changes, typically associated with the inflammatory process were found. Both treatment groups compared well to that of the control animals, indicating that the homeopathic product might be successfully used in the treatment of asthma.     

Use of focused ultrasound for stimulation of nerve structures

Pulsed focused ultrasound can stimulate the receptor and conductive nerve structures of humans and animals as well as the neurons of the central nervous system of invertebrates. The possibility of a wide practical use of this method in medicine and physiology is considered. For example, the stimulating ability of focused ultrasound is applied to the diagnosis of neurological diseases, to the study of skin and tissue sensitivity in man, to the diagnosis of hearing disorders, and to the introduction of auditory information to the deaf with certain forms of hearing pathology. The factors that affect focused ultrasound as a stimulus for the irritation of nerve structures are discussed.     

Design of a reverberant chamber for noise exposure experiments with small animals

Previous work on the acoustic design of small reverberant chambers for studies on laboratory animals has paid, in general, more attention to the frequency response at certain points in their interior. These designs aimed to provide a frequency response as flat as possible at the receivers, thus avoiding unpleasant spectral coloration effects. However, an equally important, and frequently neglected, aspect is to set an acoustic field as spatially uniform as possible inside the zone where the animals are to be placed during the exposure to noise. Here, an optimization procedure is described to calculate the proportions of the chamber dimensions that confers the highest sound level with the minimum mean squared deviation averaged in a given area inside the chamber. In addition, new stimuli have been designed with a high-pass filtering and linear with frequency gain. These stimuli were intended to adapt the characteristics of the exposing noise to the rodent hearing spectrum, displaced toward higher frequencies than the hearing frequency band of humans.     

Infrared dynamical thermovision of the biological objects

Dynamical infrared thermovision and applications for real time functional diagnostic of biological objects are reviewed. Experiments with humans and animals are described. It is shown that method is very promising for blood flow studies and brain research.     

Drug-anaesthetic interaction in phMRI: the case of the psychotomimetic agent phencyclidine

Pharmacological magnetic resonance imaging (phMRI) provides a powerful means to map the effects of drugs on brain activity, with important applications in pharmacological research. However, phMRI studies in preclinical species are often conducted under general anaesthesia as a means to avoid head motion and to minimise the stress induced by the procedure. Under these conditions, the phMRI response to the drug of interest may be affected by interactions with the anaesthetic agent, with consequences for the interpretation of the data. Here, we have investigated the phMRI response to phencyclidine (PCP), an NMDA receptor blocker, in the halothane-anaesthetised rat for varying levels of anaesthesia and different PCP challenge doses. PCP induces psychotic-like symptoms in humans and laboratory animals and is widely applied as a pharmacological model of schizophrenia. However, PCP possesses anaesthetic properties per se, and its interactions with halothane might result in significant effects on the phMRI activation patterns. We observed two qualitatively different patterns of phMRI response. At 0.5 mg/kg iv PCP and 0.8% halothane maintenance anaesthesia, the lowest doses explored, an activation of discrete cortico-limbo-thalamic structures was observed, consistent with neuroimaging studies in humans and 2-deoxyglucose functional mapping in conscious animal models. However, higher anaesthetic concentrations or higher PCP challenge doses resulted in complete abolition of the positive response and in a widespread cortical deactivation (negative response). In the intermediate regime, we observed a dichotomic behaviour, with individual subjects showing one pattern or the other. These findings indicate a dose-dependent drug-anaesthetic interaction, with a complete reversal of the effects of PCP at higher challenge doses or HT concentrations.     

Categorical perception of conspecific communication sounds by Japanese macaques, Macaca fuscata

Field studies indicate that Japanese macaque (Macaca fuscata) communication signals vary with the social situation in which they occur [S. Green, "Variation of vocal pattern with social situation in the Japanese monkey (Macaca fuscata): A field study," in Primate Behavior, edited by L. A. Rosenblum (Academic, New York, 1975), Vol. 4]. A significant acoustic property of the contact calls produced by these primates is the temporal position of a frequency peak within the vocalization, that is, an inflection from rising to falling frequency [May et al., "Significant features of Japanese macaque communication sounds: A psychophysical study," Anim. Behav. 36, 1432-1444 (1988)]. The experiments reported here are based on the hypothesis that Japanese macaques derive meaning from this temporally graded feature by parceling the acoustic variation inherent in natural contact calls into two functional categories, and thus exhibit behavior that is analogous to the categorical perception of speech sounds by humans. To test this hypothesis, Japanese macaques were trained to classify natural contact calls by performing operant responses that signified either an early or late frequency peak position. Then, the subjects were tested in a series of experiments that required them to generalize this behavior to synthetic calls representing a continuum of peak positions. Demonstration of the classical perceptual effects noted for human listeners suggests that categorical perception reflects a principle of auditory information processing that influences the perception of sounds in the communication systems not only of humans, but of animals as well.     

Sleep,aging, and lifespan in <Emphasis Type="Italic">Drosophila</Emphasis>

Background  

Epidemiological studies in humans suggest that a decrease in daily sleep duration is associated with reduced lifespan, but this issue remains controversial. Other studies in humans also show that both sleep quantity and sleep quality decrease with age. Drosophila melanogaster is a useful model to study aging and sleep, and inheriting mutations affecting the potassium current Shaker results in flies that sleep less and have a shorter lifespan. However, whether the link between short sleep and reduced longevity exists also in wild-type flies is unknown. Similarly, it is unknown whether such a link depends on sleep amount per se, rather than on other factors such as waking activity. Also, sleep quality has been shown to decrease in old flies, but it remains unclear whether aging-related sleep fragmentation is a generalized phenomenon.     

Calcium signals in the nucleus accumbens: Activation of astrocytes by ATP and succinate

Background

Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage (SAH) due to reduced cerebral blood flow (CBF) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells (SMC) via activation of mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK)1/2 signal pathway. We hypothesize that SAH initiates cerebrovascular ERK1/2 activation, resulting in receptor upregulation. The raf inhibitor will inhibit the molecular events upstream ERK1/2 and may provide a therapeutic window for treatment of cerebral ischemia after SAH.

Results

Here we demonstrate that SAH increases the phosphorylation level of ERK1/2 in cerebral vessels and reduces the neurology score in rats in additional with the CBF measured by an autoradiographic method. The intracisternal administration of SB-386023-b, a specific inhibitor of raf, given 6 h after SAH, aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h. This is accompanied by reduced phosphorylation of ERK1/2 in cerebrovascular SMC. SAH per se enhances contractile responses to endothelin-1 (ET-1), 5-carboxamidotryptamine (5-CT) and angiotensin II (Ang II), upregulates ET_B, 5-HT_1B and AT₁ receptor mRNA and protein levels. Treatment with SB-386023-b given as late as at 6 h but not at 12 h after the SAH significantly decreased the receptor upregulation, the reduction in CBF and the neurology score.

Conclusion

These results provide evidence for a role of the ERK1/2 pathway in regulation of expression of cerebrovascular SMC receptors. It is suggested that raf inhibition may reduce late cerebral ischemia after SAH and provides a realistic time window for therapy.     

Phoneme representation and classification in primary auditory cortex

A controversial issue in neurolinguistics is whether basic neural auditory representations found in many animals can account for human perception of speech. This question was addressed by examining how a population of neurons in the primary auditory cortex (A1) of the naive awake ferret encodes phonemes and whether this representation could account for the human ability to discriminate them. When neural responses were characterized and ordered by spectral tuning and dynamics, perceptually significant features including formant patterns in vowels and place and manner of articulation in consonants, were readily visualized by activity in distinct neural subpopulations. Furthermore, these responses faithfully encoded the similarity between the acoustic features of these phonemes. A simple classifier trained on the neural representation was able to simulate human phoneme confusion when tested with novel exemplars. These results suggest that A1 responses are sufficiently rich to encode and discriminate phoneme classes and that humans and animals may build upon the same general acoustic representations to learn boundaries for categorical and robust sound classification.     

Effects of caloric deprivation and satiety on sensitivity of the gustatory system

Background  

Sensitivity of the gustatory system could be modulated by a number of short-term and long-term factors such as body mass, gender, age, local and systemic diseases and pathological processes, excessive alcohol drinking, drug dependence, smoking, composition of oral fluid, state of oral hygiene, consumption of some foods among many others. A few studies have demonstrated the effects of hunger and caloric satiety on sensitivity of the gustatory system in obese humans and animals. The aim of the present study was to assess the effects of short-term caloric deprivation and satiety on recognition taste thresholds of healthy, non-smoking, non-drinking, non-obese young male subjects. The two-alternative forced-choice technique was used to measure taste threshold.     

Stimulus intensity and loudness recruitment: neural correlates

An abnormally rapid rate of loudness growth for given increments in stimulus intensity is seen both in patients with cochlear pathology and in normal listeners under conditions of wide-spectrum noise masking. The phenomenological similarity between these psychophysical observations raises the question of whether a single mechanism, or set of mechanisms, underlies them. Recent neurophysiological studies in animals have addressed the effects of cochlear pathology and noise masking on the neural correlates of stimulus intensity in the central auditory nervous system. A comparison of the data presented in those studies reveals that there are sequelae of cochlear pathology seen in the discharges of auditory-nerve fibers that might reasonably be expected to contribute to a steepened loudness function. These sequelae are not seen at the same locus in normal animals studied with noise masking paradigms. Noise masking, however, may have effects on the tonal sensitivity of more central neurons that mimic some of the sequelae of cochlear pathology seen in the auditory nerve. These data suggest that the mechanisms underlying the two manifestations of recruitment may be quite different, one having a uniquely cochlear site, while the other reflects purely central processes.     

Can in vitro assays substitute for in vivo studies in assessing the pulmonary hazards of fine and nanoscale materials?

Risk evaluations for nanomaterials require the generation of hazard data as well as exposure assessments. Most of the validated nanotoxicity studies have been conducted using in vivo experimental designs. It would be highly desirable to develop in vitro pulmonary hazard tests to assess the toxicity of fine and nanoscale particle-types. However, in vitro evaluations for pulmonary hazards are known to have limited predictive value for identifying in vivo lung toxicity effects. Accordingly, this study investigated the capacity of in vitro screening studies to predict in vivo pulmonary toxicity of several fine or nanoparticle-types following exposures in rats. Initially, complete physicochemical characterization of particulates was conducted, both in the dry and wet states. Second, rats were exposed by intratracheal instillation to 1 or 5 mg/kg of the following particle-types: carbonyl iron, crystalline silica, amorphous silica, nanoscale zinc oxide, or fine zinc oxide. Inflammation and cytotoxicity endpoints were measured at 24 h, 1 week, 1 month and 3 months post-instillation exposure. In addition, histopathological analyses of lung tissues were conducted at 3 months post-exposure. Pulmonary cell in vitro studies consisted of three different culture conditions at 4 different time periods. These included (1) rat L2 lung epithelial cells, (2) primary rat alveolar macrophages, and (3) alveolar macrophage—L2 lung epithelial cell co-cultures which were incubated with the same particles as tested in the in vivo study for 1, 4, 24, or 48 h. Cell culture fluids were evaluated for cytotoxicity endpoints and inflammatory cytokines at the different time periods in an attempt to match the biomarkers assessed in the in vivo study. Results of in vivo pulmonary toxicity studies demonstrated that instilled carbonyl iron particles produced little toxicity. Crystalline silica and amorphous silica particle exposures produced substantial inflammatory and cytotoxic effects initially, but only the crystalline silica variety produced sustained and progressive inflammatory and cytotoxic responses, leading to the development of pulmonary fibrosis. Exposures to nanoscale or fine-sized zinc oxide particles produced potent but typical “metal fume fever”-like reversible inflammation/cytotoxic effects which were resolved by 1-month postinstillation exposure. In contrast to the in vivo results, using cytotoxicity and inflammation endpoints, in vitro effects to the various particle-types were difficult to gauge, owing to the number of variables that were studied (i.e., cell-types, time-course, dose response (including particle overload doses)), and various endpoints (e.g., cytotoxicity = LDH, MTT; inflammation/cytokines = MIP-2). For instance, none of the in vitro endpoints could mimic a transient inflammatory/cytotoxic response—as was measured following exposures to amorphous silica, or fine or nanoscale zinc oxide particles. We conclude that current in vitro cell culture systems do not accurately forecast the pulmonary hazard responses of instilled particle-types. It seems clear that in vitro cellular systems will need to be further developed, standardized, and validated (relative to in vivo effects) in order to provide useful screening data on the relative toxicity of inhaled particles.     

Effect of laser radiation on living systems: Role of light coherence

The influence of spatial and temporal coherence, as well as speckle dynamics, on animal organisms is studied in detail. Our theoretical and experimental studies reveal no biophysical evidence of the influence of light coherence on living systems at any level, as well as no specific effects caused by laser radiation. The effects of laser therapy used for treatment of a wide range of diseases of humans require further detailed investigation and possibly a revision of the existing concept.     

Manganese-enhanced magnetic resonance imaging investigation of the interferon-α model of depression in rats

Therapeutic effects of interferon-α (IFN-α) are known to be associated with CNS toxicity in humans, and in particular with depression symptoms. Animal models of IFN-α-induced depression (sickness behaviour) have been developed in rodents using various preparations, dosing schedules or routes of administrations. In this work, Manganese Enhanced MRI (MEMRI) has been applied to investigate an experimental model of sickness behaviour induced by administration of IFN-α in rats. IFN-α (3.10⁵ U/kg), or vehicle, was daily administered i.p., for 7 days in rats (n = 20 IFN-α treated and n = 20 controls). After treatment, animals were assigned to behavioural (n = 10 treated, n = 10 control) or MRI (n = 10 treated and n = 10 control) studies. Animals assigned to the MRI study received two repeated i.p. injections of MnCl₂, before image acquisition. Images were acquired at 4.7 T using T₁ mapping for determination of Mn concentration in brain. After co-registration of T₁ maps to a digital brain atlas, differences between brains of treated and untreated animals were assessed pixel-to-pixel by statistical analysis.     

Alien Attack: A Non-Pharmaceutical Complement for ADHD Treatment

Mental health issues are among the most common health issues nowadays, with attention-deficit hyperactivity disorder (ADHD) being the most common neurobehavioral disorder affecting children and adolescents. ADHD is a heterogeneous disease affecting patients in various cognitive domains that play a key role in daily life, academic development, and social abilities. Furthermore, ADHD affects not only patients but also their families and their whole environment. Although the main treatment is based on pharmacotherapy, combined therapies including cognitive training and psychological therapy are often recommended. In this paper, we propose a user-centered application called Alien Attack for cognitive training of children with ADHD, based on working memory, inhibitory control, and reaction-time tasks, to be used as a non-pharmacological complement for ADHD treatment in order to potentiate the patients’ executive functions (EFs) and promote some beneficial effects of therapy.     

Overview-the role of NMR spectroscopy in epilepsy

Nuclear magnetic resonance (NMR) spectroscopy permits noninvasive, serial measurements of several metabolites with important neurobiologic roles in localized brain regions in vivo. Over the last decade, this technique has been applied to investigations of both animals and humans with epilepsy. Several nuclei that include specific proton, phosphorus, and carbon isotopes provide NMR signals that measure specific compounds in vivo. This paper reviews the studies that have used these multinuclear NMR techniques to investigate the role of these methods in the diagnosis and pathogenesis of epilepsy.     

Differential diagnosis of spasmodic dysphonia: A kinematic perspective

Although originally considered an hysterical functional disorder, spasmodic dysphonia (SD) appears to be a heterogeneic symptom complex that is associated with several neurological diseases. Perceptual, acoustic, and electromyographic studies have not clearly differentiated the underlying pathologies that result in spasmodic phonatory dysfunction. Kinematic analysis of documented laryngeal examinations during phonation and respiration indicates that particular different movement disorders affect laryngeal function and are associated with spasmodic phonatory characteristics. The particular features of dystonia, tremors, myoclonus, and progressive supranuclear pathology should be recognized, since they may present with disease focal to the laryngeal muscles. Other movement disorders may also be associated with spasmodic phonatory abnormalities, but are less likely to be focal. Treatment of SD signs and symptoms is more likely to be successful and assessments of treatment more likely to be meaningful if the underlying pathophysiology of spasmodic phonatory behavior is identified.     

In vivo assessment of blood-spinal cord barrier permeability: serial dynamic contrast enhanced MRI of spinal cord injury

Serial in vivo dynamic contrast enhanced (DCE) MRI studies were performed on spinal cord injured rats on post-injury Days 0, 10, 20 and 30 to determine the distribution of gadopentetate-dimeglumine (Gd) concentration in injured cord tissue. A two-compartment pharmacokinetic model was fitted to the time course of the concentration data at the epicenter of injury for each post-injury day. From these fits, the rates of the Gd transport between plasma and injured cord tissue were determined as a measure of blood-spinal cord barrier (BSCB) permeability. The results indicated that Gd transport rates decrease steadily with a concomitant improvement in motor functions of the rats with post-injury time. Specifically, the rates of Gd accumulation in injured SC tissue and its clearance correlated with the neurobehavioral scores with correlation coefficients of rho = -0.96 and -0.79, respectively, suggesting a significant link between the neurobehavioral function and the restoration of BSCB integrity as a result of the ongoing repair and recovery processes within the injured cords.