Morphological Degeneration Research Articles

Increased Müller Cell De-Differentiation After Grafting of Retinal Stem Cell in the Sub-Retinal Space of Royal College of Surgeons Rats

In several vertebrate classes, the Müller glia are capable of de-differentiating, proliferating, and acquiring a progenitor-like state in response to acute retinal injury or in response to exogenous growth factors. Our previous study has shown that Müller cells can be activated and de-differentiated into retinal progenitors during Royal College of Surgeons (RCS) rats' degeneration, although the limited proliferation cannot maintain retinal function. We now report that rat retinal stem cells (rSCs) transplanted into RCS rats slowed the progression of retinal morphological degeneration and prevented the functional disruption. Further, we found that retinal progenitor cells labeled with Chx10 were increased significantly after rSCs transplantation, and most of them are mainly from activated Müller cells. rSCs transplantation also enhances neurogenic potential by producing more recoverin-positive photoreceptors, which was proved coming from Müller glia-derived cells. These results provide evidence that stem cell-based therapy may offer a novel therapeutic approach for the treatment of retinal degeneration, and that Müller glia in mammalian retina can be activated and de-differentiated by rSC transplantation and may have therapeutic effects.

The effects of acrylamide on the frequency of megakaryocytic emperipolesis and the mitotic activity of rat bone marrow cells

Although the pathophysiological importance of emperipolesis is not known exactly, it has been reported to increase significantly in cases of various cancer types, different tumours and thrombosis disorders. In this study the effects of acrylamide on the frequency of megakaryocytic emperipolesis and the mitotic activity in rat bone marrow cells were determined. For this purpose, two separate experiments were performed with Sprague-Dawley rats gavaged with 0, 30, 45 and 60 mg acrylamide kg⁻¹ body weight (BW) for five consecutive days. In the second experiment, 3 mg colchicine kg⁻¹ BW was injected intraperitoneally 2 h before cervical dislocation. Bone marrow samples were taken 24 h after the last application in both experiments. It was found that only the highest dose of acrylamide significantly decreased the incidence of megakaryocytic emperipolesis and that the types of bone marrow cells engulfed by megakaryocytes were mostly neutrophil granulocytes. Neither megakaryocytes nor engulfed cells showed any morphological degeneration. In the mitotic activity experiment, doses of 45 and 60 mg acrylamide kg⁻¹ BW decreased the mitotic activity of bone marrow cells in comparison with the control group. It was concluded that the decrease in megakaryocytic emperipolesis frequency might be a consequence of the decrease in mitotic activity in bone marrow cells.

Randomisierte klinische Studie zur Wirksamkeit einer Kombination aus Matrix/Rhythmus-Therapie und multimodaler stationärer Schmerztherapie bei Patienten mit chronischen lumbalen Rückenschmerzen

PURPOSE: A randomized controlled clinical trial was implemented to evaluate the effectiveness of combined Matrix/Rhythmus therapy (rhythmic relaxation of muscle and connective tissue, 8-12 Hz) and multimodal indoor rehabilitation in patients suffering from chronic low back pain as well as of degenerative changes of the lumbal spine confirmed morphologically by x-ray and/or MR, when compared to the multimodal pain therapy combined with a sensoric stimulation by means of a massage ball. PATIENTS AND METHODS: A total of 73 patients was randomized onto the respective combined therapeutic schemes according to a block randomisation scheme. According to the trial's inclusion criteria all patients suffered from chronic low back pain and showed morphological degenerations. All patients received a 12 days indoor multimodal pain therapy, which was complemented with a five session schedule of the Matrix/Rhythmus therapy for the intervention group and a five session schedule of a sensomotoric therapy for the control group. On admission, two weeks later on withdrawal from the indoor rehabilitation, and three months afterwards the study patients were asked to undergo a questionnaire assessment including the Oswestry questionnaire. The change of the Oswestry total score [%] three months after vs. before therapy was defined as the primary clinical endpoint of the investigation. The patients in the control group showed a median age of 57 years vs. 54 years in the intervention group (47% vs. 49% females, respectively); 33% vs. 27% of the patients were classified stage III of chronicity staging according to MPSS. RESULTS: On admission, the control patients reported a median Oswestry index of 54%, on withdrawal of 63% and on recall of 61%. The intervention group showed respective median Oswestry estimates of 64%, 67% and 71%. The median three months increase in the Oswestry index was estimated 4% for both treatment groups (Wilcoxon p=0.469). CONCLUSION: When being combined with a multimodal lower back pain rehabilitation in patients showing morphological degenerations, the Matrix/Rhythmus therapy according to Randoll did neither demonstrate clinically relevant nor statistically significant benefit in comparison to the alternative treatment addendum of a sensomotoric massage. Further investigations are deemed necessary however, to quantify the clinical efficacy of the concept in patients suffering, for example, from acute lower back pain (in particular, in patients showing non-chronic stages in musculoskeletal disease development without morphological findings).

Texture analysis of cartilage T2 maps: individuals with risk factors for OA have higher and more heterogeneous knee cartilage MR T2 compared to normal controls - data from the osteoarthritis initiative

IntroductionThe goals of this study were (i) to compare the prevalence of focal knee abnormalities, the mean cartilage T2 relaxation time, and the spatial distribution of cartilage magnetic resonance (MR) T2 relaxation times between subjects with and without risk factors for Osteoarthritis (OA), (ii) to determine the relationship between MR cartilage T2 parameters, age and cartilage morphology as determined with whole-organ magnetic resonance imaging scores (WORMS) and (iii) to assess the reproducibility of WORMS scoring and T2 relaxation time measurements including the mean and grey level co-occurrence matrix (GLCM) texture parameters.MethodsSubjects with risk factors for OA (n = 92) and healthy controls (n = 53) were randomly selected from the Osteoarthritis Initiative (OAI) incidence and control cohorts, respectively. The specific inclusion criteria for this study were (1) age range 45-55 years, (2) body mass index (BMI) of 19-27 kg/m2, (3) Western Ontario and McMaster University (WOMAC) pain score of zero and (4) Kellgren Lawrence (KL) score of zero at baseline. 3.0 Tesla MR images of the right knee were analyzed using morphological gradings of cartilage, bone marrow and menisci (WORMS) as well as compartment specific cartilage T2 mean and heterogeneity. Regression models adjusted for age, gender, and BMI were used to determine the difference in cartilage parameters between groups.ResultsWhile there was no significant difference in the prevalence of knee abnormalities (cartilage lesions, bone marrow lesions, meniscus lesions) between controls and subjects at risk for OA, T2 parameters (mean T2, GLCM contrast, and GLCM variance) were significantly elevated in those at risk for OA. Additionally, a positive significant association between cartilage WORMS score and cartilage T2 parameters was evident.ConclusionsOverall, this study demonstrated that subjects at risk for OA have both higher and more heterogeneous cartilage T2 values than controls, and that T2 parameters are associated with morphologic degeneration.

Valeriana wallichii root extracts and fractions with activity against Leishmania spp

Leishmanial diseases, posing a public health problem worldwide, are caused by Leishmania parasites with a dimorphic life cycle alternating between the promastigote and amastigote forms. Promastigotes transmitted by the vector are transformed into amastigotes residing in the host tissue macrophages. Presently, new antiparasitic agents are needed against Leishmania donovani and Leishmania major, the respective organisms causing visceral and cutaneous leishmaniasis, since the available treatments are unsatisfactory due to toxicity, high cost, and emerging drug resistance. Over the years, traditional medicinal flora throughout the world enriched the modern pharmacopeia. Hence, roots of 'Indian Valerian' (Valeriana wallichii DC) were studied for its antileishmanial activity for the first time. The methanol and chloroform extracts showed activity against L. donovani promastigotes and both promastigotes and amastigotes of L. major. The most active fraction, F3, obtained from the chloroform extract, showed IC(50) at ∼ 3-7 μg/ml against both the promastigotes and 0.3 μg/ml against L. major amastigotes. On investigation of the mechanism of cytotoxicity in L. donovani promastigotes, the 'hall-mark' events of morphological degeneration, DNA fragmentation, externalization of phosphatidyl serine, and mitochondrial membrane depolarization indicated that F3 could induce apoptotic death in leishmanial cells. Therefore, the present study revealed a novel and unconventional property of V. wallichii root as a prospective source of effective antileishmanial agents.

An Omega-3 Fatty Acid-Enriched Diet Prevents Skeletal Muscle Lesions in a Hamster Model of Dystrophy

Currently, despite well-known mutational causes, a universal treatment for neuromuscular disorders is still lacking, and current therapeutic efforts are mainly restricted to symptomatic treatments. In the present study, δ-sarcoglycan-null dystrophic hamsters were fed a diet enriched in flaxseed-derived ω3 α-linolenic fatty acid from weaning until death. α-linolenic fatty acid precluded the dystrophic degeneration of muscle morphology and function. In fact, in dystrophic animals fed flaxseed-derived α-linolenic fatty acid, the histological appearance of the muscular tissue was improved, the proliferation of interstitial cells was decreased, and the myogenic differentiation originated new myocytes to repair the injured muscle. In addition, muscle myofibers were larger and cell membrane integrity was preserved, as witnessed by the correct localization of α-, β-, and γ-sarcoglycans and α-dystroglycan. Furthermore, the cytoplasmic accumulation of both β-catenin and caveolin-3 was abolished in dystrophic hamster muscle fed α-linolenic fatty acid versus control animals fed standard diet, while α-myosin heavy chain was expressed at nearly physiological levels. These findings, obtained by dietary intervention only, introduce a novel concept that provides evidence that the modulation of the plasmalemma lipid profile could represent an efficacious strategy to ameliorate human muscular dystrophy.

399 FACTORS ASSOCIATED WITH PREVALENT MAGNETIC RESONANCE IMAGING (MRI)-DETECTED MENISCAL EXTRUSION IN PERSONS WITH OR AT RISK FOR KNEE OSTEOARTHRITIS: THE MOST STUDY

Purpose: Semiquantitative (SQ) grading of the intervertebral disk is based on signal intensity, intervertebral disk height and differentiation of the nucleus and annulus. Shortcomings of SQ grading are insensitivity to change in longitudinal assessment. The T2 values of intervertebral disks are a reflection of hydration and proteoglycan content, of collagen structure and fibre texture. Hydration and consequently degeneration of the nucleus is directly correlated with T2 values. T2 mapping of the nucleus might potentially be applied as an additive surrogate marker of cross-sectional and longitudinal assessment of disk integrity. Aim of study was to asses T2 relaxation times of the nucleus pulposus of intervertebral disks of the lumbar spine by T2 mapping and correlate mean T2 values with a descriptive SQ classification of disk morphology. Secondary aim was interand intrareader evaluation of SQ grading and T2 mapping. Methods: Lumbar MRI was performed on volunteers without lumbar pain on a 1.5 T system (Magnetom Avanto, Siemens, Erlangen, Germany). The intervertebral disks of the L1/2 to the L5/S1 levels were assessed. The protocol for MR measurements consisted of a multi-echo T2 spin echo sequence (TR 1,200 ms, 11 echoes of 12.7 ms increments, Field of view 280×280 mm, 8 mm slice thickness). Total acquisition time was 13 min 22 sec. The intervertebral discs were SQ assessed according to their morphology using the Pfirrmann-classification of disk degeneration. T2 relaxation times were obtained using a pixel wise, monoexponential, non-negative least squares (NNLS) fit analysis. Circular-shaped regions of interest (ROI) were drawn manually in the center of the nucleus pulposus by two readers separately using OsiriX version 3.6.1 as DICOM-viewer. Descriptive statistics using the mean T2 values and 95% confidence intervals were applied for comparison between T2 maps and morphologic grading. Interand Intraobserver reliabilitiy for T2 mapping and morphologic grading were calculated by generalized estimation equations (GEE). Statistical analyses were performed using PASW statistics version 17.0.2 for mac (SPSS Institute, Chicago, IL, USA). Results: 21 volunteers were examined. Mean age was 26.6 years (range 24-31), mean BMI 21.9 (range19.0-26.2). 105 disks were analyzed. The distribution of morphologic grading was as follows: 10 grade 1, 52 grade 2, 26 grade 3, 10 grade 4 and 7 grade 5. Mean T2 values for each grade were 152ms (± 22,5), 118ms (± 24,5), 86ms (± 19,3), 56ms (± 13,4) and 52ms (± 8,0) respectively. Values for grades 1-4 showed significant differences (p<0.001), while the difference of mean T2 values for grades 4 and 5 did not reach statistical significance (p=0.25). Interand intraobserver reliability for SQ grading and T2 mapping was good. Conclusions: T2 values in the nucleus pulposus significantly decrease with increasing grades of morphologic degeneration. T2 mapping might be a promising complimentary tool to assess cross-sectional and longitudinal changes of disk degeneration or disk repair.

In vitro and in vivo antifungal activities of the essential oils of various plants against tomato grey mould disease agent Botrytis cinerea

The aim of this study was to find an alternative to synthetic fungicides currently used in the control of devastating fungal pathogen Botrytis cinerea, the causal agent of grey mould disease of tomato. Antifungal activities of essential oils obtained from aerial parts of aromatic plants, which belong to the Lamiacea family such as origanum ( Origanum syriacum L. var. bevanii), lavender ( Lavandula stoechas L. var. stoechas) and rosemary ( Rosmarinus officinalis L.), were investigated against B. cinerea. Contact and volatile phase effects of different concentrations of the essential oils were found to inhibit the growth of B. cinerea in a dose-dependent manner. Volatile phase effects of essential oils were consistently found to be more effective on fungal growth than contact phase effect. A volatile vapour of origanum oil at 0.2 μg/ml air was found to completely inhibit the growth of B. cinerea. Complete growth inhibition of pathogen by essential oil of lavender and rosemary was, however, observed at 1.6 μg/ml air concentrations. For the determination of the contact phase effects of the tested essential oils, origanum oil at 12.8 μg/ml was found to inhibit the growth of B. cinerea completely. Essential oils of rosemary and lavender were inhibitory at relatively higher concentrations (25.6 μg/ml). Spore germination and germ tube elongation were also inhibited by the essential oils tested. Light and scanning electron microscopic (SEM) observations revealed that the essential oils cause considerable morphological degenerations of the fungal hyphae such as cytoplasmic coagulation, vacuolations, hyphal shrivelling and protoplast leakage and loss of conidiation. In vivo assays with the origanum essential oil, being the most efficient essential oil, under greenhouse conditions using susceptible tomato plants resulted in good protection against grey mould severity especially as a curative treatment. This study has demonstrated that the essential oils are potential and promising antifungal agents which could be used as biofungicide in the protection of tomato against B. cinerea.

Age-related morphologic changes alter robustness of neuronal function

Aging and neurodegenerative disorders significantly alter both neuronal function and morphology. We have shown recently that, if uncompensated by altered ion channel distributions, morphologic changes in aging increase neuronal excitability [1]. Different combinations of active conductances can evoke similar firing patterns, giving rise to functional homeostasis. To elucidate possible mechanisms of homeostasis in the parameter space defined by ionic conductances, we recently utilized thermal random walks to identify regions (an ensemble) within which the functional output of a neuron is maintained. Typically a number of such regions, which are topologically disconnected from each other, are identified. The eigenvalues and eigenvectors of the ensemble covariance matrix serve as measures for its size and orientation, and the capacity for functional homeostasis or robustness is measured by the set of largest (robust) eigenvalues and corresponding eigenvectors. In this study, we explore how functional homeostasis might be affected by the kinds of morphologic changes that occur with aging or neurodegenerative disorders. To this end, we extract the change in orientation and extent of the ensembles found for the original model by subjecting it to three kinds of perturbations involving morphology and desired firing properties. First, we mimic age-related morphologic degeneration by reducing the number of spines in the original neuron. Second, we increase the number of spines in the original neuron, mimicking a younger one. The third perturbation also involves increased spines, however, the target firing rate is reduced so as to also mimic the electrophysiology of a younger neuron. We find that, for all the perturbations considered, the initial ensembles remain topologically disconnected, although they change in size and orientation. In particular, while the sensitive eigendirections remain unchanged, the robust eigendirections change in orientation, suggesting that functional robustness of a neuron is determined largely by its morphology. Consequently, possible homeostatic mechanisms, that enable a young neuron to maintain function, are able to do so less efficiently as the neuron undergoes age related morphologic changes .This is so because a homeostatic mechanism would be more effective if it were to orient itself along the robust eigendirections of the ensembles, and become less so as the robust directions change due to morphologic changes. Although morphologic perturbations drastically change robust eigendirections, preliminary evidence indicates that these directions may be restored through appropriate compensatory changes in functional output. In conclusion, the need to maintain functional robustness may be responsible for altered function as a neuron ages.

The Mitochondrial Fusion-Promoting Factor Mitofusin Is a Substrate of the PINK1/Parkin Pathway

Loss-of-function mutations in the PINK1 or parkin genes result in recessive heritable forms of parkinsonism. Genetic studies of Drosophila orthologs of PINK1 and parkin indicate that PINK1, a mitochondrially targeted serine/threonine kinase, acts upstream of Parkin, a cytosolic ubiquitin-protein ligase, to promote mitochondrial fragmentation, although the molecular mechanisms by which the PINK1/Parkin pathway promotes mitochondrial fragmentation are unknown. We tested the hypothesis that PINK1 and Parkin promote mitochondrial fragmentation by targeting core components of the mitochondrial morphogenesis machinery for ubiquitination. We report that the steady-state abundance of the mitochondrial fusion-promoting factor Mitofusin (dMfn) is inversely correlated with the activity of PINK1 and Parkin in Drosophila. We further report that dMfn is ubiquitinated in a PINK1- and Parkin-dependent fashion and that dMfn co-immunoprecipitates with Parkin. By contrast, perturbations of PINK1 or Parkin did not influence the steady-state abundance of the mitochondrial fission-promoting factor Drp1 or the mitochondrial fusion-promoting factor Opa1, or the subcellular distribution of Drp1. Our findings suggest that dMfn is a direct substrate of the PINK1/Parkin pathway and that the mitochondrial morphological alterations and tissue degeneration phenotypes that derive from mutations in PINK1 and parkin result at least in part from reduced ubiquitin-mediated turnover of dMfn.

Cellular characterization of an in-vitro cell culture model of seal-induced cardiac ischaemia.

The lack of a well-characterized in-vitro cell culture model of load-induced cardiac ischaemia has hampered investigations into the mechanism of ischemic injury. We therefore developed a new in-vitro model of cardiac ischaemia that mimics distinct features of ischaemic injury. Neonatal rat heart cells were cultured in a sealed flask for 24-72 h. In this environment, the cells were exposed to stresses of hypoxia, acidosis and stagnant incubation medium. The pO2 and pH of the medium gradually decreased during the ischaemic insult and ultimately fell to a level of 14 mmHg and pH 6.8, respectively. The model triggered severe cell injury, including morphological degeneration, CPK release, beating impairment and ATP depletion. Apoptosis occurred in some cardiomyocytes as early as 24 h after onset of seal-induced ischaemia. This was evidenced by positive nuclear staining using Hoechst 33258 and by the induction of caspase-3 mRNA. By 72 h, internucleosomal DNA fragmentation was observed in 45% of the myocytes; however, a non-myocyte preparation subjected to the same ischaemic insult exhibited no evidence of DNA fragmentation. These results demonstrate that neonatal cardiomyocytes subjected to the new simulated ischaemia model exhibit several similarities to cardiac ischaemia, including the simultaneous appearance of necrosis, breakdown of cellular ATP, beating cessation and apoptosis. The new model should prove useful in unravelling the molecular alterations underlying ischaemic injury and myocardial apoptosis.

Predominant cone photoreceptor dysfunction in a hyperglycaemic model of non-proliferative diabetic retinopathy

Approximately 2.5 million people worldwide are clinically blind because of diabetic retinopathy. In the non-proliferative stage, the pathophysiology of this ocular manifestation of diabetes presents as morphological and functional disruption of the retinal vasculature, and dysfunction of retinal neurons. However, it is uncertain whether the vascular and neuronal changes are interdependent or independent events. In addition, the identity of the retinal neurons that are most susceptible to the hyperglycaemia associated with diabetes is unclear. Here, we characterise a novel model of non-proliferative diabetic retinopathy in adult zebrafish, in which the zebrafish were subjected to oscillating hyperglycaemia for 30 days. Visual function is diminished in hyperglycaemic fish. Significantly, hyperglycaemia disrupts cone photoreceptor neurons the most, as evidenced by prominent morphological degeneration and dysfunctional cone-mediated electroretinograms. Disturbances in the morphological integrity of the blood-retinal barrier were also evident. However, we demonstrate that these early vascular changes are not sufficient to induce cone photoreceptor dysfunction, suggesting that the vascular and neuronal complications in diabetic retinopathy can arise independently. Current treatments for diabetic retinopathy target the vascular complications. Our data suggest that cone photoreceptor dysfunction is a clinical hallmark of diabetic retinopathy and that the debilitating blindness associated with diabetic retinopathy may be halted by neuroprotection of cones.

Molecular decay of the tooth gene Enamelin (ENAM) mirrors the loss of enamel in the fossil record of placental mammals.

Vestigial structures occur at both the anatomical and molecular levels, but studies documenting the co-occurrence of morphological degeneration in the fossil record and molecular decay in the genome are rare. Here, we use morphology, the fossil record, and phylogenetics to predict the occurrence of “molecular fossils” of the enamelin (ENAM) gene in four different orders of placental mammals (Tubulidentata, Pholidota, Cetacea, Xenarthra) with toothless and/or enamelless taxa. Our results support the “molecular fossil” hypothesis and demonstrate the occurrence of frameshift mutations and/or stop codons in all toothless and enamelless taxa. We then use a novel method based on selection intensity estimates for codons (ω) to calculate the timing of iterated enamel loss in the fossil record of aardvarks and pangolins, and further show that the molecular evolutionary history of ENAM predicts the occurrence of enamel in basal representatives of Xenarthra (sloths, anteaters, armadillos) even though frameshift mutations are ubiquitous in ENAM sequences of living xenarthrans. The molecular decay of ENAM parallels the morphological degeneration of enamel in the fossil record of placental mammals and provides manifest evidence for the predictive power of Darwin's theory.

Regeneration of static-load-degenerated articular cartilage extracellular matrix by vitamin C supplementation

The effect of a physiological dose of vitamin C (100 microg/ml) on goat articular cartilage chondrocytes cultured in an alginate matrix and subjected to static pressurization of 2.4 MPa was investigated. Biochemical analyses of DNA, glycosaminoglycan (GAG), collagen and protease activity were carried out in various matrix fractions, i.e. cellular matrix (CM) and further removed matrix (FRM), and in culture medium. The treatment of chondrocytes with vitamin C after static pressure increased the GAG content in both CM and FRM (P < 0.03) as compared with control or vitamin C/ static load alone. The collagen content of chondrocytes treated with vitamin C alone and vitamin C after static load also increased significantly in FRM (P < 0.003) as compared with control and static load alone. The specific activity of protease in CM and FRM decreased after vitamin C supplementation both with and without static pressure relative to control (P < 0.003). Transmission electron-microscopic images showed a mixed population of spherical and elliptical chondrocytes when vitamin C was added after static load as compared with static load alone where only elliptical cells were seen. Abundant pericellular and collagen fibrils were seen in this group of chondrocytes as compared with all other groups and the control. The results thus show that, in vitro, vitamin C supplementation of chondrocytes after static loading has the potential to reduce the morphological and biochemical degeneration of chondrocytes caused by static loading, thereby improving the cellular health and functioning of articular cartilage.

Network effects of age-related NMDA reduction in a model of working memory

Specific cognitive deficits in working memory tasks are associated with normal aging in humans and nonhuman primates, even in the absence of pathologies such as Alzheimer's disease. Because normal aging does not involve widespread neuron death or gross morphological degeneration, the cause of these deficits remains unclear, although subtle anatomical and physiological effects are likely to play a causal role [1]. NMDA glutamate receptors in spines mediate synaptic communication and are critical in long-term potentiation (LTP) and learning. NMDA's dependence on postsynaptic depolarization has been proposed to enhance network stability through synaptic bistability [2]. Reduced NMDA expression is associated with aging in macaque monkeys and rats [3].

Cardiac denervation and dysautonomia in Parkinson's disease: A review of screening techniques

Parkinson's disease (PD) has classically been characterized by features of motor dysfunction, but these may manifest only after the nigrostriatal system has incurred significant damage. However, recent evidence suggests that cardiac sympathetic denervation occurs early on in PD. This may trigger a shift in physicians' attention to features of cardiovascular dysautonomia and allow for the evolution of earlier screening techniques. MIBG and PET (6F-DA) scans have demonstrated the functional loss of postganglionic sympathetic cardiac neurons, while immunohistochemical stains have revealed signs of morphological degeneration. Given this information, various screening techniques have been proposed, though most are particular to PD patients with orthostatic hypotension (OH). This is a considerable drawback given that the prevalence of OH in PD patients is estimated to be 41%. We present the argument that a shift in focus is needed; investigators should look for other manners by which to screen patients that are not reliant upon blood pressure. In our point of view, the problem with using blood pressure as a measurement is that it can be affected by many other factors unrelated to cardiac denervation. This may be why many patients with PD cannot be detected using these techniques. In order to make further progress on this front, we believe that investigators should start looking for variables that are more purely dependent upon cardiac denervation. We give one possible example of such a variable in this paper using heart transplant patients as a model.

CHOLESTEROL EFFLUX AND THE EFFECT OF COMBINED TREATMENT WITH NIACIN AND CHROMIUM ON AORTA OF HYPERLIPIDEMIC RAT

Endothelial cells may play a potential role in cholesterol efflux from peripheral tissues to liver. Cholesterol efflux from cells is essential for activation of the reverse cholesterol transport pathway and cardiovascular health. One of the cholesterol transporters is steroidogenic acute regulatory protein (StAR) which promotes intramitochondrial delivery of cholesterol to the cholesterol side-chain cleavage system. The aim of the present study was to determine the effects of a niacin–chromium complex on aortas of hyperlipidemic rats and on the cholesterol efflux from aorta endothelial cells by examination under light and transmission electron microscopes and evaluating the StAR immunoreactivity, respectively. Aorta lipid peroxidation (LPO) and glutathione (GSH) levels were determined by spectrophotometric methods. After treating hyperlipidemic animals with the complex, the StAR immunoreactivity in endothelial cells increased to achieve cholesterol homeostasis and efflux. Combined treatment with niacin and chromium resulted in an inhibition in the mast cell secretion and a decrease in lipid vacuole size in unilocular adipose tissue surrounding aorta, as well as in a decrease in morphological degenerations observing in aorta of hyperlipidemic rats. Aorta LPO levels increased and GSH levels decreased in the hyperlipidemic group, whereas treatment with niacin and chromium reversed these effects. In conclusion, this study reveals that combined treatment with niacin and chromium prevents the morphological and biochemical changes observed in thoracic aorta of hyperlipidemic rats, and may regulate effectively cardiovascular diseases inducing an increase in StAR levels on endothelial cells.

Increased Tunel Positive Cells in CA1, CA2, and CA3 Subfields of Rat Hippocampus Due to Copper and Ethanol Co-Exposure

Copper (Cu) is an essential element for life. However, it is toxic at excessive doses, whereas exposure to ethanol (EtOH) has known to cause morphological changes, degeneration, and neuronal loss in central nervous system. A previous investigation by the authors’ group showed that Cu and EtOH co-treatment cause severe hippocampal neuronal loss in CA1, CA2, and CA3 subfields of rat hippocampus. This study was designed to analyze the possible mechanism(s) of action of this effect. In addition, the possible neurogenesis in response to a potent neurodegenerative treatment in rat hippocampus was analyzed. Results demonstrated that Cu and EtOH induced neuronal loss in rat hippocampus was in correlation with the increased cell death analyzed on the basis of TdT-mediated dUTP nick end labeling (TUNEL) assay. On the other hand, neuronal regenerative activity was detectable in analyzed CA1, CA2, and CA3 subfields of the rat hippocampus analyzed on the basis of 5-bromo-2′-deoxy-uridine (BrdU) labeling assay; however, this activity in treated group was not significantly different from that of control group.

Cholesterol efflux and the effect of combined treatment with niacin and chromium on aorta of hyperlipidemic rat

Endothelial cells may play a potential role in cholesterol efflux from peripheral tissues to liver. Cholesterol efflux from cells is essential for activation of the reverse cholesterol transport pathway and cardiovascular health. One of the cholesterol transporters is steroidogenic acute regulatory protein (StAR) which promotes intramitochondrial delivery of cholesterol to the cholesterol side-chain cleavage system. The aim of the present study was to determine the effects of a niacin-chromium complex on aortas of hyperlipidemic rats and on the cholesterol efflux from aorta endothelial cells by examination under light and transmission electron microscopes and evaluating the StAR immunoreactivity, respectively. Aorta lipid peroxidation (LPO) and glutathione (GSH) levels were determined by spectrophotometric methods. After treating hyperlipidemic animals with the complex, the StAR immunoreactivity in endothelial cells increased to achieve cholesterol homeostasis and efflux. Combined treatment with niacin and chromium resulted in an inhibition in the mast cell secretion and a decrease in lipid vacuole size in unilocular adipose tissue surrounding aorta, as well as in a decrease in morphological degenerations observing in aorta of hyperlipidemic rats. Aorta LPO levels increased and GSH levels decreased in the hyperlipidemic group, whereas treatment with niacin and chromium reversed these effects. In conclusion, this study reveals that combined treatment with niacin and chromium prevents the morphological and biochemical changes observed in thoracic aorta of hyperlipidemic rats, and may regulate effectively cardiovascular diseases inducing an increase in StAR levels on endothelial cells.

Age-related neuromorphological distortion affects stability and robustness in a simulated test of spatial working memory

Normal aging in humans and nonhuman primates is associated with cognitive decline, particularly in tasks involving working memory function that relies on the prefrontal cortex [1]. Because normal aging is not correlated with widespread neuron death or gross morphological degeneration, the biological substrate of these deficits remains unclear [2]. We have constructed a simulated network of model neurons with sufficient detail to model age-related perturbations to morphology and network connectivity, in order to investigate the extent to which these morphological changes in single neurons could explain the functional degradation. Spatial working memory can be modeled with a bump-style network of recurrently connected model neurons, characterized by a continuum of dynamical attractor states that provide an analogue of working memory of spatial orientation [3]. A bump-attractor network (Figure ​(Figure1)1) was constructed using branching compartmental models of layer 2/3 neocortical pyramidal neurons [4]. Spine number and density are reduced with age in this neuron type [5], a morphological perturbation that was modeled as a reduction in both recurrent network connectivity and equivalent dendritic surface area. Network function was quantified in terms of the dynamical stability of network attractor states during the delay period of a simulated memory task, as well as the robustness of task performance against perturbation of network parameters. Stability and robustness were compared between young and aged model neuron populations with the multi-dimensional stability manifold method, which has been used in a previous study to examine the dependence of network simulations on modeling methodology [6]. Figure 1 Bump attractor network model receiving input encoding the direction '315°' (green neuron), with fully interconnected populations of layer 2/3 pyramidal neurons and GABAergic interneurons. Neurons are arranged in direction-selective columns. ... By defining a stability manifold, we demonstrate how stability and robustness can be quantified as a function of biologically relevant perturbations to single cell morphology and network parameters. This provides a novel technique for evaluating the functional significance of local morphological changes, caused by age, disease or injury, upon cognition at the organism scale.