Expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 (KDR/Flk-1) in ischemic skeletal muscle and its regeneration

Vascular endothelial growth factor (VEGF) is a hypoxia-inducible endothelial cell mitogen and survival factor. Its receptor VEGFR-2 (KDR/Flk-1) mediates these effects. We studied the expression of VEGF and VEGFR-2 in ischemic human and rabbit skeletal muscle by immunohistochemistry and in situ hybridization. Human samples were obtained from eight lower limb amputations because of acute or chronic critical ischemia. In chronically ischemic human skeletal muscle VEGF and VEGFR-2 expression was restricted to atrophic and regenerating skeletal myocytes, whereas in acutely ischemic limbs VEGF and VEGFR-2 were expressed diffusely in the affected muscle. Hypoxia-inducible factor-1alpha was associated with VEGF and VEGFR-2 expression both in acute and chronic ischemia but not in regeneration. Hindlimb ischemia was induced in 20 New Zealand White rabbits by excising the femoral artery. Magnetic resonance imaging and histological sections revealed extensive ischemic damage in the thigh and leg muscles of ischemic rabbit hindlimbs with VEGF expression similar to acute human lower limb ischemia. After 1 and 3 weeks of ischemia VEGF expression was restricted to regenerating myotubes and by 6 weeks regeneration and expression of VEGF was diminished. VEGFR-2 expression was co-localized with VEGF expression in regenerating myotubes. Macrophages and an increased number of capillaries were associated with areas of ischemic muscle expressing VEGF and VEGFR-2. In conclusion, two patterns of VEGF and VEGFR-2 expression in human and rabbit ischemic skeletal muscle are demonstrated. In acute skeletal muscle ischemia VEGF and VEGFR-2 are expressed diffusely in the affected muscle. In chronic skeletal muscle ischemia and in skeletal muscle recovering from ischemia VEGF and VEGFR-2 expression are restricted to atrophic and regenerating muscle cells suggesting the operation of an autocrine pathway that may promote survival and regeneration of myocytes.     

In vitro electroretinogram for the study of the functionality of differentiated retinal pigment epithelium cells

The purpose of this study is to develop and test a method to reveal if the retinal pigment epithelium (RPE) cells differentiated from human embryonic stem cells (hESC) support the functions of photoreceptors. hESC-derived RPE (hESC–RPE) cells offer a potent cell source for cell replacement therapy that may be used to prevent certain eye diseases. Methods to assure the functionality of the RPE cells are well warranted. Electroretinograms (ERG) measure the electrophysiological response of the retina to light stimuli. A setup was developed that enables the measurement of ERG in vitro from mice retinas cultured together with hESC–RPE cells. The co-culture of RPE and retinas seems to be a viable tool to assess the functionality of RPE in vitro. However, owing to limited sample size results were somewhat mixed, and thus it was not possible to prove that hESC–RPE cells enhance the ERG response of a mouse retina in vitro. The long-term culturing of the retinas needs to be refined to acquire more conclusive evidence of the supporting role of the RPE and to explore the full potential of the co-culture and ERG methods in assessing RPE functionality.     

Shaker K+ channels contribute early nonlinear amplification to the light response in Drosophila photoreceptors

We describe the contribution of rapidly inactivating Shaker K+ channels to the dynamic membrane properties of Drosophila photoreceptors. Phototransduction was measured in wild-type and Shaker mutant (Sh14) Drosophila photoreceptors by stimulating with white noise-modulated light contrast and recording the resulting intracellular membrane potential fluctuations. A second-order Volterra kernel series was used to characterize the nonlinear dynamic properties of transduction in the two situations. First-order kernels were indistinguishable in wild-type and Sh14 photoreceptors, indicating that the basic light transduction machinery was always intact. However, second-order kernels of Shaker mutants lacked a large, early amplification, indicating a novel role for Shaker K+ channels in amplifying and accelerating the voltage response of wild-type photoreceptors. A cascade model of two nonlinear static components surrounding one linear dynamic component was able to partially reproduce the experimental responses. Parameters obtained by fitting the model to the experimental data supported the hypothesis that normal Shaker K+ channels contribute an early, positive nonlinearity that partially offsets a later attenuating nonlinearity caused by membrane shunting.     

Absence of association between an intercellular adhesion molecule 1 gene E469K polymorphism and Alzheimer's disease in Finnish patients

Increased expression of intercellular adhesion molecule 1 (ICAM1), a protein known to contribute to inflammatory responses, has been detected in the brain tissue of patients with Alzheimer's disease (AD) and animals modelled to mimic AD or Parkinson's disease (PD). ICAM1 may, thus, be implicated in the pathogenesis of these disorders. Our purpose was to investigate whether genetic variants of the ICAM1 gene have a role in causing susceptibility to AD and/or PD. We genotyped the E469K polymorphism of ICAM1 in 196 AD, 52 PD and 202 control patients of Finnish origin. The distributions of the genotype and allele frequencies of the polymorphism did not differ significantly between the AD, PD or the control patients. We therefore conclude that the E469K polymorphism of ICAM1 is not a risk factor for AD or PD.     

In situ pH within particle beds of bioactive glasses

The in vitro behavior of three bioactive glasses with seven particle size distributions was studied by measuring the in situ pH inside the particle beds for 48h in simulated body fluid (SBF). After immersion, the surface of the particles was characterized with a field emission scanning electron microscope equipped with an energy-dispersive X-ray analyzer. In addition, the results were compared with the reactions of the same glasses formed as plates. A similar trend in pH as a function of immersion time was observed for all systems. However, the pH inside the particle beds was markedly higher than that in the bulk SBF of the plates. The pH decreased as power functions with increasing particle size, i.e. with decreasing surface area. The in vitro reactivity expressed as layer formation strongly depended on the particle size and glass composition. The average thickness of the total reaction layer decreased with the increase in sample surface area. Well-developed silica and calcium phosphate layers typically observed on glass plates could be detected only on some particles freely exposed to the solution. No distinct reaction layers were observed on the finest particles, possibly because the layers spread out on the large surface area. Differences in the properties of the bulk SBF and the solution inside the particle bed were negligible for particles larger than 800mum. The results enhance our understanding of the in vitro reactions of bioactive glasses in various product forms and sizes.     

The Effect of Small Variation of the Frequent Auditory Stimulus on the Event-Related Brain Potential to the Infrequent Stimulus

We investigated whether the mismatch process between a rare stimulus and the trace of frequent stimulus, which generates the mismatch-negativity component of the event-related potential, can tolerate a small variation in the intensity of the frequent stimulus. Series of short tone pips were presented to 10 subjects while they were reading a book and ignoring the auditory stimuli. The intensity (mean 80dB) of the frequent stimulus (600 Hz) varied within a range that was different in different blocks. The probability of the infrequent stimuli which were, in different blocks, either intensity deviants (600 Hz/70dB) or frequency deviants (650 Hz/80dB) was 10%. Both deviant stimuli elicited mismatch negativity even when the intensity of the frequent stimulus varied, although the amplitude of this component decreased with the increasing variability of the frequent stimulus. These results show that the generator process of mismatch negativity tolerates some variation in the repetitive stimulus, thus indicating that this process is also activated in ecologically more valid conditions. This is crucial to the interpretation of the generator process of mismatch negativity as a biologically vital warning mechanism.     

Responses of the human auditory cortex to changes in one versus two stimulus features

Neuromagnetic responses were recorded with a 24 SQUID magnetometer in two oddball experiments to determine whether mismatch responses to changes in single stimulus features are additive. In experiment 1, the one feature deviants differed from standards in interstimulus interval (ISI) or frequency, and the two feature deviants in both ISI and frequence. In experiment 2, deviants differed in duration, frequency, or both. All deviants evoked a mismatch field (MMF) with sources close to each other in the supratemporal auditory cortex. Except for the ISI deviants, the MMF sources were about 1 cm anterior to the source of the 100ms response, N100m, to the standards. In the two experiments, MMFs obtained in response to the two feature deviants resembled closely the sum of MMFs in response to one feature deviants. The results suggest that the standards leave a multiple neuronal representation in the human auditory cortex. The particular neuronal traces of the representation react independently to changes in different features of sound stimuli.     

A prospective latent analyses study of psychiatric comorbidity of DSM‐IV bipolar I and II disorders

Mantere O, Isometsä E, Ketokivi M, Kiviruusu O, Suominen K, Valtonen HM, Arvilommi P, Leppämäki S. A prospective latent analyses study of psychiatric comorbidity of DSM‐IV bipolar I and II disorders.
Bipolar Disord 2010: 12: 271–284. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: To test two hypotheses of psychiatric comorbidity in bipolar disorder (BD): (i) comorbid disorders are independent of BD course, or (ii) comorbid disorders associate with mood. Methods: In the Jorvi Bipolar Study (JoBS), 191 secondary‐care outpatients and inpatients with DSM‐IV bipolar I disorder (BD‐I) or bipolar II disorder (BD‐II) were evaluated with the Structured Clinical Interview for DSM‐IV Disorders, with psychotic screen, plus symptom scales, at intake and at 6 and 18 months. Three evaluations of comorbidity were available for 144 subjects (65 BD‐I, 79 BD‐II; 76.6% of 188 living patients). Structural equation modeling (SEM) was used to examine correlations between mood symptoms and comorbidity. A latent change model (LCM) was used to examine intraindividual changes across time in depressive and anxiety symptoms. Current mood was modeled in terms of current illness phase, Beck Depression Inventory (BDI), Young Mania Rating Scale, and Hamilton Depression Rating Scale; comorbidity in terms of categorical DSM‐IV anxiety disorder diagnosis, Beck Anxiety Inventory (BAI) score, and DSM‐IV‐based scales of substance use and eating disorders. Results: In the SEM, depression and anxiety exhibited strong cross‐sectional and autoregressive correlation; high levels of depression were associated with high concurrent anxiety, both persisting over time. Substance use disorders covaried with manic symptoms (r = 0.16–0.20, p < 0.05), and eating disorders with depressive symptoms (r = 0.15–0.32, p < 0.05). In the LCM, longitudinal intraindividual improvements in BDI were associated with similar BAI improvement (r = 0.42, p < 0.001). Conclusions: Depression and anxiety covary strongly cross‐sectionally and longitudinally in BD. Substance use disorders are moderately associated with manic symptoms, and eating disorders with depressive mood.     

Nonlinear relationship between emotional valence and brain activity: Evidence of separate negative and positive valence dimensions

Emotion plays a significant role in goal‐directed behavior, yet its neural basis is yet poorly understood. In several psychological models the cardinal dimensions that characterize the emotion space are considered to be valence and arousal. Here 3T functional magnetic resonance imaging (fMRI) was used to reveal brain areas that show valence‐ and arousal‐dependent blood oxygen level dependent (BOLD) signal responses. Seventeen healthy adults viewed pictures from the International Affective Picture System (IAPS) for brief 100 ms periods in a block design paradigm. In many brain regions BOLD signals correlated significantly positively with valence ratings of unpleasant pictures. Interestingly, partly in the same regions but also in several other regions BOLD signals correlated negatively with valence ratings of pleasant pictures. Therefore, there were several areas where the correlation across all pictures was of inverted U‐shape. Such correlations were found bilaterally in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC) extending to anterior cingulate cortex (ACC), and insula. Self‐rated arousal of those pictures which were evaluated to be unpleasant correlated with BOLD signal in the ACC, whereas for pleasant pictures arousal correlated positively with the BOLD signal strength in the right substantia innominata. We interpret our results to suggest a major division of brain mechanisms underlying affective behavior to those evaluating stimuli to be pleasant or unpleasant. This is consistent with the basic division of behavior to approach and withdrawal, where differentiation of hostile and hospitable stimuli is crucial. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.