Effect of glucagon-like peptide-1 analogue; Exendin-4, on cognitive functions in type 2 diabetes mellitus; possible modulation of brain derived neurotrophic factor and brain Visfatin.

BACKGROUND: Brain derived neurotrophic factor (BDNF) is one of the most essential neurotrophic factors in the brain. BDNF is involved in learning, memory and locomotion suggesting it as a target in type 2 diabetes mellitus (T2DM) associated cognitive changes. Visfatin; an adipokine discovered to be expressed in the brain; was found to have multiple effects including its participation in keeping energy supply to the cell and is consequentially involved in cell survival. Its role in cognitive functions in T2DM was not studied before. Recent studies point to the possible neuro-protective mechanisms of glucagon-like peptide 1 analogue: Exendin-4 (Ex-4) in many cognitive disorders, but whether BDNF or Visfatin are involved or not in its neuro-protective mechanisms; is still unknown. AIMS: to study the changes in cognitive functions in T2DM, either not treated or treated with Glucagon-like peptide 1 (GLP-1) analogue: Ex-4, and to identify the possible underlying mechanisms of these changes and whether BDNF and brain Visfatin are involved. METHODS: A total of 36 adult male wistar albino rats were divided into 4 groups; Control, Exendin-4 control, Diabetic and Exendin-4 treated groups. At the end of the study, Y-maze and open field tests were done the day before scarification to assess spatial working memory and locomotion, respectively. Fasting glucose and insulin, lipid profile and tumor necrosis factor- alpha (TNF-α) were measured in the serum. Homeostasis model assessment insulin resistance was calculated. In the brain tissue, malondialdehyde (MDA) level, gene expression and protein levels of BDNF and Visfatin, area of degenerated neurons, area of glial cells and area % of synaptophysin immunoexpression were assessed. RESULTS: Compared with the control, the untreated diabetic rats showed insulin resistance, dyslipidemia and elevation of serum TNF-α. The brain tissue showed down-regulation of BDNF gene expression and reduction of its protein level, up-regulation of Visfatin gene expression and elevation of its protein level, increase in MDA, area of degenerated neurons and area of glial cells and reduction in area % of synaptophysin immunoexpression. These changes were paralleled with significant deterioration in spatial working memory and locomotion. Treatment of diabetic rats with Ex-4 reversed all these changes. CONCLUSION: T2DM has a negative impact on cognitive functions through different pathological and subcellular mechanisms. The current study provides evidence for involvement of BDNF and brain Visfatin in T2DM- associated cognitive dysfunction. BDNF and brain Visfatin were also found to contribute to the neuro-protective effect of Ex-4 via modulation of inflammation, oxidative stress, neuro-degeneration and synaptic function.

Reuse water: Exposure duration, seasonality and treatment affect tissue responses in a model fish.

Partially remediated gray (reuse) water will likely find increasing use in a variety of applications owing to the increasing scarcity of freshwater. We aimed to determine if a model fish, the goldfish, could sense reuse water using olfaction (smell), and if 30min or 7d (acute) and 60d (sub-chronic) exposures would affect their olfactory responses to natural odorants. We examined olfaction as previous studies have found that numerous chemicals can impair the olfactory sense, which is critical to carrying out numerous life-sustaining behaviors from feeding to mating. We also examined if fish olfactory and liver tissues would mount a response in terms of biotransformation enzyme gene expression, and whether treatment of reuse water with UV/H2O2 ameliorated adverse effects following reuse water exposure. We found that fish olfactory tissue responded to reuse water as it would to a natural odorant and that UV/H2O2 treatment had no influence on this. With acute exposures, olfactory impairment was apparent regardless of water type (e.g. responses of 23-55% of control), but in sub-chronic exposures, only the untreated reuse water caused olfactory impairment. The exposure of fish to reuse water increased the expression of one enzyme (CYP1A; >2.5-6.5 fold change) and reuse water treatment with UV/H2O2 reversed the effect. There was a seasonal effect that was likely due to changes in water quality (60d summer exposure impaired olfaction whereas spring and fall exposures did not). Overall, the data suggest that reuse water may be detected by olfaction, impair olfactory responses in fish receiving unavoidable exposures, and that exposure duration and season are important factors to consider regarding adverse effects.

Activation of migration of endogenous stem cells by erythropoietin as potential rescue for neurodegenerative diseases.

UNLABELLED: Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive cognitive dysfunction and memory loss. There is deposition of amyloid plaques in the brain and subsequent neuronal loss. Neuroinflammation plays a key role in the pathogenesis of AD. There is still no effective curative therapy for these patients. One promising strategy involves the stimulation of endogenous stem cells. This study investigated the therapeutic effect of erythropoietin (EPO) in neurogenesis, and proved its manipulation of the endogenous mesenchymal stem cells in model of lipopolysaccharide (LPS)-induced neuroinflammation. METHODS: Forty five adult male mice were divided equally into 3 groups: Group I (control), group II (LPS untreated group): mice were injected with single dose of lipopolysaccharide (LPS) 0.8 mg/kg intraperitoneally (ip) to induce neuroinflammation, group III (EPO treated group): in addition to (LPS) mice were further injected with EPO in dose of 40 µg/kg of body weight three times weekly for 5 consecutive weeks. Groups were tested for their locomotor activity and memory using open field test and Y-maze. Cerebral specimens were subjected to histological and morphometric studies. Glial fibrillary acidic protein (GFAP) and mesenchymal stem cell marker CD44 were assessed using immunostaining. Gene expression of brain derived neurotrophic factor (BDNF) was examined in brain tissue. RESULTS: LPS decreased locomotor activity and percentage of correct choices in Y-maze test. Cerebral sections of LPS treated mice showed increased percentage area of dark nuclei and amyloid plaques. Multiple GFAP positive astrocytes were detected in affected cerebral sections. In addition, decrease BDNF gene expression was noted. On the other hand, EPO treated group, showed improvement in locomotor and cognitive function. Examination of the cerebral sections showed multiple neurons exhibiting less dark nuclei and less amyloid plaques in comparison to the untreated group. GFAP positive astrocytes were also reduced. Cerebral sections of the EPO treated group showed multiple branched and spindle CD44 positive cells inside and around blood vessels more than in LPS group. This immunostaining was negative in the control group. EPO administration increased BDNF gene expression. CONCLUSION: This study proved that EPO provides excellent neuroprotective and neurotrophic effects in vivo model of LPS induced neuroinflammation. It enhances brain tissue regeneration via stimulation of endogenous mesenchymal stem cells proliferation and their migration to the site of inflammation. EPO also up regulates cerebral BDNF expression and production, which might contributes to EPO mediated neurogenesis. It also attenuates reactive gliosis thus reduces neuroinflammation. These encouraging results obtained with the use of EPO proved that it may be a promising candidate for future clinical application and treatment of neurodegenerative diseases.

Effectiveness of ozonation treatment in eliminating toxicity of oil sands process-affected water to Chironomus dilutus.

Water soluble organic compounds (OCs), including naphthenic acids (NAs), are potentially toxic constituents of oil sands process-affected water (OSPW) that is generated during extraction of bitumen from Alberta oil sands. Ozonation can decrease concentrations of OCs in OSPW. However, effects of ozonated-OSPW on multicellular organisms are unknown. A 10-day and a chronic exposure of Chironomus dilutus to OSPW were conducted to assess effects on survival, growth, development, and behavior. Two separate batches of OSPW were treated with 30 or 80 mg ozone (O(3))/L. Wet body masses of larvae exposed to OSPW were 64 to 77% less than their respective controls (p < 0.001). However, both levels of ozonation significantly attenuated effects of OSPW on growth. Similarly, chronic exposure to untreated OSPW resulted in significantly less pupation than in the controls, with 31% and 71% less pupation of larvae exposed to the two batches of OSPW (p < 0.05). Emergence was significantly less for larvae exposed to OSPW, with 13% and 8% of larvae emerging, compared to 81% in controls (p < 0.0001). Both levels of ozonation of OSPW attenuated effects on emergence. These results suggest that OCs degraded by ozonation causes toxicity of OSPW toward C. dilutus, and that ozonation attenuates toxicity of OSPW.

Mechanisms of vincristine-induced neurotoxicity: Possible reversal by erythropoietin.

Vincristine (VCR) is a potent anticancer drug, but neurotoxicity is one of its most important dose-limiting toxicities. In this study, we investigated the neurotoxic effect of VCR, the possible mechanisms and the role of erythropoietin (EPO) in the protection against VCR-induced neurotoxicity in a rat model. The neurotoxicity of VCR and protective effect of EPO were examined using the tail flick test and by recording electrophysiological characteristics in isolated sciatic nerve. To elucidate the underlying mechanisms, mRNA expression of N-methyl-D-aspartate (NMDA) receptor, an index of glutamate excitotoxicity, and calcitonin gene-related peptide (CGRP), an important regulator of vascular tone, were measured in both spinal cord and sciatic nerves using an RT-PCR method. After intraperitoneal injection at a dose of 150 µg/kg three times weekly for five consecutive weeks, VCR significantly decreased the latency of tail withdrawal reflex, the amplitude of maximum compound action potential (MCAP) and chronaxie, and prolonged the duration of action potential (AP) and relative refractory period (RRP), but it had no effect on conduction velocity. VCR increased NMDA receptor expression and decreased CGRP expression. Forty µg/kg of EPO improved all VCR-induced changes, except chronaxie, while a higher dose of 80 µg/kg reversed all parameters and its effect was more prominent on tail flick test latency and NMDA receptor expression. These results suggested that VCR might cause increased nerve excitability and induce a state of glutamate excitotoxicity through enhancing NMDA receptor expression and diminishing CGRP expression, thus resulting in axonal degeneration. EPO had an obvious neuroprotective effect probably through decreasing NMDA receptor expression and increasing CGRP expression both centrally and peripherally.

Neural networks modelling of streamflow, phosphorus, and suspended solids: application to the Canadian Boreal forest.

Sediment has long been identified as an important vector for the transport of nutrients and contaminants such as heavy metals and microorganisms. The respective nutrient loading to water bodies can potentially lead to dissolved oxygen depletion, cyanobacteria toxin production and ultimately eutrophication. This study proposed an artificial neural network (ANN) modelling algorithm that relies on low cost readily available meteorological data for simulating streamflow (Q), total suspended solids (TSS) concentration, and total phosphorus (TP) concentration. The models were applied to a 130-km2 watershed in the Canadian Boreal Plain. Our results demonstrated that through careful manipulation of time series analysis and rigorous optimization of ANN configuration, it is possible to simulate Q, TSS, and TP reasonably well. R2 values exceeding 0.89 were obtained for all modelled data cases. The proposed models can provide real time predictions of the modelled parameters, can answer questions related to the impact of climate change scenarios on water quantity and quality, and can be implemented in water resources management through Monte Carlo simulations.

Geostatistical mapping of precipitation: implications for rain gauge network design.

This study examined four univariate kriging techniques; simple kriging (SK), ordinary kriging (OK), multi-Gaussian kriging (MGC), and log-normal kriging (LNK); and two multivariate kriging algorithms; kriging with external drift (KED) using elevation and slope in two different models for the estimation of daily rainfall in a 250 m x 250 m grid over a 750 km2 area in the Canadian Boreal forest. Multivariate kriging did not enhance daily rainfall predictions. SK, OK, and LNK produced statistically comparative results with OK being slightly better. MGC was the worst univariate estimator, mainly due to the high percentage of data spikes. Sequential Gaussian simulation (SGS) was then implemented to produce 100 equiprobable maps of rainfall. A multi-objective approach; that is based on overlaying the map of the kriging variance, the DEM, and land use/land cover maps in a GIS framework to identify the areas of commonly favourable features; was proposed to identify potential future sampling locations.

Human development index adjusted for environmental indicators: case study in one Egyptian village.

The Egypt Human Development Report 2003 does not take account of the impact of the environment on human development indicators. A case study was made in one village in El-Montaza district, Alexandria governorate, Egypt. The environmental indicators used for calculating the human development index were access to safe water, access to sanitation and environment surrounding the house. The human development index for this village decreased from 0.622 to 0.595 after adjustment for environmental factors.

Ozonation of biologically treated landfill leachate: treatment efficiency and molecular size distribution analysis.

A wide range of ozone doses were used to oxidise biologically treated Clover Bar landfill leachate, and results were compared to those of a previous study that involved aged raw leachate. The COD, BOD5 and colour of the leachate were measured prior to and after ozonation. The molecular size distribution of each sample was also analysed. At an ozone dose of 2.6 g l(-1), COD and colour removal efficiencies were 47% and 91%, respectively, while BOD5 increased by 324%. The BOD5/COD ratio increased from 0.02 prior to ozonation to approximately 0.2 following an ozone dose of 5.5 g l(-1), indicating improvement in the leachate biodegradability. Ozonation was very effective in reducing the concentration of organic compounds with molecular weights larger than 300 Dalton. After ozonation, no new peaks representing small molecules were observed. Relationships representing ozone dose, COD, BOD5, and the BOD5/COD ratio, as functions of total peak area of molecular size distribution, were determined.

[Percutaneous radiofrequency ablation of hepatic metastases. Preliminary experience]. / Ablathermie percutanée des métastases hépatiques par radiofréquence. Expérience prélimniaire.

AIM: To evaluate the efficiency of percutaneous radiofrequency ablation in the treatment of liver metastases. METHODS: Eighteen patients with 31 liver metastases, mainly from colorectal cancer, 10 - 35 mm in diameter (m = 23), underwent 26 courses of percutaneous radiofrequency ablation. Fifteen patients had previously undergone hepatectomy, and 3 patients had contra-indications to surgery. Imaging guidance was ultrasound in 21 patients, CT in 4 (tumors not seen with ultrasound), and both in 1. A generator working at 450 KHz with a maximum output power of 150 W was used to treat each lesion for 18 - 20 min. Treatment was monitored with real time ultrasound. RESULTS: Among the 12 patients followed more than 3 months, only one of the 24 treated lesions recurred after a mean follow up of 259 ¿ 109 days. Liver disease was controlled in 8 of the 12 patients after 90 - 509 days (m = 306). Among these 8 patients, 3 were tumor free after 559, 378 and 90 days, respectively; 2 died tumor free of non-tumoral disease (pulmonary embolism, digestive bleeding); 3 developed lung metastases treated with chemotherapy (n = 2) or surgery (n = 1). Three of the 12 patients had widespread hepatic tumor occurrence, and one patient died of these metastases. Six patients experienced mild skin burns, but no major complication was observed. CONCLUSION: Radiofrequency ablation of hepatic metastases appears safe and promising in this preliminary experience. Further investigation is needed.

Involuntary action of the external anal sphincter. Manometric and electromyographic studies.

The changes in the rectal neck (anal canal) pressure and electromyography (EMG) of the external anal sphincter and levator ani muscle were studied in 20 dogs before and after internal anal sphincter excision by 2 weeks and monthly up to 10 months. The rectal neck pressure dropped to 41% of the preoperative level. It was then gradually elevated from the beginning of the 1st month following excision till it reached 88% of the level before excision at the 10th month. The external sphincter EMG basal activity after internal sphincterectomy by 2 weeks showed a decrease in the amplitude of the slow and high potential waves. From the 1st to the 7th month after excision, changes in the frequency and amplitude of the waves occurred, and by the 10th month, the external sphincter showed the characteristics of the EMG of both the internal and external anal sphincters. The basal activity of the levator ani muscle increased at the 10th month. As reported previously, the changes in the rectal neck pressure and in the EMG of the external anal sphincter after internal sphincterectomy seem to be due to the histological changes in the muscle and include striated and smooth muscle fiber hypertrophy and proliferation. These changes adapt the external sphincter to serve the function of not only voluntary but also involuntary continence.

A new concept of the anatomy of the anal sphincter mechanism and the physiology of defecation. The involuntary action of the external anal sphincter: histologic study.

The histologic changes in the external anal sphincter after internal anal sphincter excision were studied in 20 dogs. An external sphincter biopsy was taken before internal sphincterectomy and 2 weeks and monthly thereafter for 10 months. The excised material was studied microscopically after being stained with hematoxylin and eosin, Verhoeff-van Gieson and succinic dehydrogenase. 70% of external sphincter specimens before internal sphincter excision showed smooth muscle fibers scattered between the striated fibers. These smooth fibers could be responsible for the resting tone of the external sphincter. After internal sphincter excision, characteristic histologic changes could be identified in the external sphincter. From the 2nd week to the 5th month after excision, the external sphincter showed degenerative and hypertrophic changes. From the 6th to the 10th month, there were regeneration of the striated muscle fibers and increase in the number of smooth fibers so that by the 10th month a 'compound' muscle of striated and smooth fibers was identified. Two theories were put forward to explain the smooth fiber preponderance in the external sphincter after internal sphincter excision: mutant and replacement theories. The increased nonstriated element in the external sphincter seems to be a structural-functional adaptation so that the external sphincter takes on the involuntary function of the excised muscle.