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1.
2.
To gain insight into the contribution of d-serine to impaired cognitive aging, we compared the metabolic pathway and content of the amino acid as well as d-serine-dependent synaptic transmission and plasticity in the hippocampus of young and old rats of the Wistar and Lou/C/Jall strains. Wistar rats display cognitive impairments with aging that are not found in the latter strain, which is therefore considered a model of healthy aging. Both mRNA and protein levels of serine racemase, the d-serine synthesizing enzyme, were decreased in the hippocampus but not in the cerebral cortex or cerebellum of aged Wistar rats, whereas the expression of d-amino acid oxidase, which degrades the amino acid, was not affected. Consequently, hippocampal levels of endogenous d-serine were significantly lower. In contrast, serine racemase expression and d-serine levels were not altered in the hippocampus of aged Lou/C/Jall rats. Ex vivo electrophysiological recordings in hippocampal slices showed a marked reduction in N-methyl-d-aspartate-receptor (NMDA-R)-mediated synaptic potentials and theta-burst-induced long-term potentiation (LTP) in the CA1 area of aged Wistar rats, which were restored by exogenous d-serine. In contrast, NMDA-R activation, LTP induction and responses to d-serine were not altered in aged Lou/C/Jall rats.These results further strengthen the notion that the serine racemase-dependent pathway is a prime target of hippocampus-dependent cognitive deficits with aging. Understanding the processes that specifically affect serine racemase during aging could thus provide key insights into the treatment of memory deficits in the elderly.  相似文献   

3.
The present studies employed a novel microelectrode array recording technology to study glutamate release and uptake in the dentate gyrus, CA3 and CA1 hippocampal subregions in anesthetized young, late-middle aged and aged male Fischer 344 rats. The mossy fiber terminals in CA3 showed a significantly decreased amount of KCl-evoked glutamate release in aged rats compared to both young and late-middle-aged rats. Significantly more KCl-evoked glutamate release was seen from perforant path terminals in the DG of late-middle-aged rats compared young and aged rats. The DG of aged rats developed an increased glutamate uptake rate compared to the DG of young animals, indicating a possible age-related change in glutamate regulation to deal with increased glutamate release that occurred in late-middle age. No age-related changes in resting levels of glutamate were observed in the DG, CA3 and CA1. Taken together, these data support dynamic changes to glutamate regulation during aging in subregions of the mammalian hippocampus that are critical for learning and memory.  相似文献   

4.

Introduction

Age associated cognitive impairment is associated with low levels of IGF-1, oxidative stress, and neuronal loss in the hippocampus. Ames dwarf mice are long-lived animals that exhibit peripheral IGF-1 deficiency. Hippocampal-based spatial memory (a homolog of cognitive function) has not been evaluated in these long-living mice.

Materials and methods

We evaluated the hippocampal-based spatial memory in 3-, 12- and 24-month-old Ames dwarf and wild type mice using the Barnes maze and the T-maze. We also examined the effect of a hippocampal-specific toxin, kainic acid (KA), on spatial memory to determine whether Ames mice were resistant to the cognitive impairment induced by this compound.

Results

We found that Ames dwarf mice exhibit enhanced learning, making fewer errors and using less time to solve both the Barnes and T-mazes. Dwarf mice also have significantly better short-term memory as compared to wild type mice. Both genotypes exhibited neuronal loss in the CA1 and CA3 areas of the hippocampus following KA, but Ames dwarf mice retained their spatial memory.

Discussion

Our results show that Ames dwarf mice retained their spatial memory despite neurodegeneration when compared to wild type mice at an “equiseizure” dose of KA.  相似文献   

5.
The atypical amino acid d-aspartate (d-Asp) occurs at considerable amounts in the developing brain of mammals. However, during postnatal life, d-Asp levels diminish following the expression of d-aspartate oxidase (DDO) enzyme. The strict control of DDO over its substrate d-Asp is particularly evident in the hippocampus, a brain region crucially involved in memory, and highly vulnerable to age-related deterioration processes. Herein, we explored the influence of deregulated higher d-Asp brain content on hippocampus-related functions during aging of mice lacking DDO (Ddo−/−). Strikingly, we demonstrated that the enhancement of hippocampal synaptic plasticity and cognition in 4/5-month-old Ddo−/− mice is followed by an accelerated decay of basal glutamatergic transmission, NMDAR-dependent LTP and hippocampus-related reference memory at 13/14 months of age. Therefore, the precocious deterioration of hippocampal functions observed in mutants highlights for the first time a role for DDO enzyme in controlling the rate of brain aging process in mammals.  相似文献   

6.

Objective

To compare the effectiveness of a group-based rehabilitation programme with an individual counselling programme at improving glycaemic control and cardiovascular risk factors among patients with type 2 diabetes.

Methods

We randomised 143 adult type 2 diabetes patients to either a 6-month multidisciplinary group-based rehabilitation programme or a 6-month individual counselling programme. Outcome measures included glycated haemoglobin (HbA1c), blood pressure, lipid profile, weight, and waist circumference.

Results

Mean HbA1c decreased 0.3%-point (95% confidence interval [CI] = −0.5, −0.1) in the rehabilitation group and 0.6%-point (95% CI = −0.8, −0.4) among individual counselling participants (p < 0.05). Within both groups, equal reductions occurred in body weight, waist circumference, systolic blood pressure and diastolic blood pressure, but no significant between-group differences between occurred for any of the cardiovascular outcomes. The group-based rehabilitation programme consumed twice as many personnel resources.

Conclusion

The group-based rehabilitation programme resulted in changes in glycaemic control and cardiovascular risk factor reduction that were equivalent or inferior to those of an individual counselling programme.

Practice implications

The group-based rehabilitation programme, tested in the current design, did not offer additionally improved outcomes and consumed more personnel resources than the individual counselling programme; its broad implementation is not supported by this study.Trial registration Clinicaltrials.gov NCT00284609.  相似文献   

7.
Continuous low-dose injection of d-galactose induces changes in mice that resemble accelerated aging. As such, these mice have been used as models to study mechanisms of aging. Here, we examined whether repeated (daily, for 60 days) subcutaneous injections (at 50?mg d-galactose/kg) into young adult (i.e., 2-month-old) mice induced changes in key immune system organs that were on par with those associated with aging. The results showed that galactose-treated mice develop histologic changes in their thymic cortical and medullary regions; immunohistochemical analysis revealed unorganized distributions of keratin-5 and keratin-8 proteins in the thymus of these hosts. These histological changes in the thymus of d-galactose-treated mice were also observed in the organs of aged (i.e., 24-month-old control mice); however, in this latter group, these changes were accompanied by a strong infiltration of adipose cells. Galactose-treated mice also evinced alterations within their splenic white and red pulp. Further, ultrastructural analyses of the thymus and spleen of the treated mice revealed increases in irregularly shaped lymphocytes bearing visible pyknosis. It was also seen that levels of autophagy within thymic epithelial cells were greatly decreased in the tissues of the galactose-treated mice, an outcome also seen in aged mice. Lastly, the level of memory T-lymphocytes and percentage of IgM-B220-B-lymphocytes in spleens of the galactose-treated mice were both increased (albeit insignificantly so) relative to values among splenocytes of age-matched control; however, these levels were not clealy as elevated as would be expected in “elderly” mice. Taken together, our results strongly suggest that d-galactose treatment can induce structural changes in the thymus and spleen, and some changes in organ-associated cell phenotypes, that are similar to several effects seen with aging. However, the fact that many endpoints do not appear to be truly reflective of what should be seen in immune system organs/cells of “elderly” mice now calls into question the appropriateness of the use of d-galactose (i.e., is it histologically/immunotoxicologically-proper?) to create age-mimicry in mice.  相似文献   

8.
The rescue of cognitive function through environmental enrichment (EE) during aging has been extensively documented. However, the age at onset, the duration of EE, and the cerebral mechanisms required to obtain the greatest benefits still remain to be determined. We have recently shown that EE applied for 3 mo after the median lifespan, i.e., the age at which 50% of the population is still alive (from 17 to 20 mo in NMRI mice), failed to prevent cognitive deficits in senescent animals. In the present study, mice were exposed to EE prior to the median lifespan, and for a longer total duration (from 14 to 20 mo), before the assessment of memory performance and the electrophysiological properties of hippocampal neuronal networks. The EE prevented memory deficits and reduced anxiety as the animal aged. Moreover, EE attenuated the age-related impairment of basal glutamatergic neurotransmission in CA1 hippocampal slices, and reversed the decrease in isolated N-methyl-D-Aspartate receptor (NMDA-R)-dependent synaptic potentials. Surprisingly, EE did not prevent the age-related alteration of theta-burst-induced long-term potentiation (LTP). This study therefore suggests that EE needs to be initiated before the age corresponding to the median lifespan and/or required long duration (> 3 mo) to have an effect on cognitive aging. In addition, we show that EE probably acts through theta-burst-independent mechanisms of synaptic plasticity.  相似文献   

9.
Possible involvement of nitric oxide (NO) in lipoprivic feeding was investigated in nondeprived male ICR mice adapted to a high-fat diet in a within-subjects design. Lipoprivation was induced by blocking fatty acid oxidation with Na-mercaptoacetate (MA), which produces a short-term increase in feeding in mice and rats. Food intake, measured at 1, 2, and 4 h following injection of 70 mg/kg of MA, was attenuated in a dose related manner with increasing pretreatment dose (1,10, 25 and 50 mg/kg sc) of the NO-synthase (NOS) inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), reaching statistical significance at 10 mg/kg of L-NAME at h1 when compared to vehicle control condition. The inactive isomer, D-NAME, was ineffective, thereby supporting stereospecific drug action and directly implicating NO. A control experiment measured general locomotor activity (grid crossings and rears) in an open arena under 10-50 mg/kg of L-NAME in the same mice; both measures were significantly different from vehicle condition only at the highest dose. These findings support involvement of NO in lipoprivic hyperphagia; they are consistent with and extend research linking NO and ingestive behaviors through use of NOS inhibitors. Possible influences of confounds were discussed.  相似文献   

10.

Rationale

The remote measurement of body temperature with radiotelemetry provides a minimally invasive and robust method for larger experimental animals such as Old World monkeys. Existing literature encompasses data using intraperitoneal (IP) and subcutaneous (SC) implantation locations which may affect inferences about body temperature.

Methods

The body temperatures of four adult male rhesus monkeys were monitored with radiotelemetry devices implanted both IP and SC in each subject. Animals were recorded at 5 min intervals for 5 months with the two transmitters being used in sequence on a weekly basis. Additional challenge with d-methamphetamine (0.32 mg/kg; i.m.) was conducted to compare the magnitude of the hyperthermic response measured IP and SC.

Results

Normal daily temperatures differed by about 0.5-0.8 °C across implant locations with IP temperature consistently higher. The difference was consistent across the circadian cycle and when compared 1, 3 or 5 months after surgical implantation. The magnitude of the hyperthermia response to methamphetamine was about 0.75 °C when measured with either IP or SC implants.

Conclusions

The study shows that data derived from the two major implantation locations used in existing literature are likely to be comparable.  相似文献   

11.

Background

Conventional techniques for diagnosing influenza based on viral cell culture or disease serology have limitations, and molecular assays, such as real-time polymerase chain reaction (rtPCR) are increasingly used.

Objectives

To evaluate the use of rtPCR as a diagnostic tool for the determination of influenza virus infection.

Study design

This prospective, double-blind, placebo-controlled, randomised efficacy study was conducted in persons aged 18-64 years. Cases of influenza-like-illness (ILI), defined as at least one systemic symptom [fever ≥37.8 °C and/or myalgia] and at least one respiratory symptom [cough and/or sore throat] were identified by active and passive surveillance. For each case of suspected ILI, nasal and throat swabs were collected and analysed by viral culture and rtPCR.

Results

227 ILI cases were positive by rtPCR while 64% (145/227) were positive by both rtPCR and culture. For both assays, the maximum percentage of swabs that tested positive was on Day 0, thereafter positive samples by rtPCR remained constant until Day 5 but decreased progressively by culture. All rtPCR positive cases with a viral load of below 4.5 log10 copies/sample were negative by culture. There were however culture negative cases with high viral loads. Vaccine efficacy for influenza was estimated as 54.7% by rtPCR (culture positive or negative) and 61.6% by culture irrespective of match to vaccine strain. Clinical severity was not significantly different between culture positive cases and culture negative but rtPCR positive cases.

Conclusions

rtPCR is a sensitive and specific diagnostic tool for influenza vaccine efficacy studies.  相似文献   

12.

Background

An outbreak of acute hemorrhagic conjunctivitis occurred in Cuba in 2008 and 2009.

Objective

To determinate the etiological agent associated with the Cuban outbreaks of acute hemorrhagic conjunctivitis during 2008 and 2009.

Study design

Conjunctival swabs and/or faecal samples from 382 patients with clinical diagnosis suggestive of acute hemorrhagic conjunctivitis were subject to viral culture in HEp-2 human laryngeal epidermoid carcinoma cells. Positive samples were identified by a specific Coxsackievirus A24 variant PCR and the 3C protease region of 16 isolates was sequenced for phylogenetic analysis.

Results

Enterovirus cytopathic effect was observed in 138 cases (36%). A higher percent of CA24v was recovered from faecal samples, 19 out of 45 cases (42.2%), than from conjunctival swabs, 127 out of 355 samples (35.8%). All isolates were identified as Coxsackievirus A24 variant. Phylogenetic analysis revealed that 2008 and 2009 Cuban outbreaks were caused by the same virus strains and that isolates were closely related to those from Taiwan (2006-2007), China (2007-2008) and Singapore (2005) with a bootstrap value of 71%.

Conclusions

Outbreaks of acute hemorrhagic conjunctivitis occurred in Cuba in 2008 and 2009 were caused by Coxsackievirus A24 variant. The faecal-oral route is another mode of transmission of CA24v in the acute hemorrhagic conjunctivitis outbreaks. Phylogenetic analysis of Cuban CA24v strains involved in an acute hemorrhagic conjunctivitis outbreak in 2008 and 2009 confirms a new introduction of the CA24 variant into the Americas from South-east Asia.  相似文献   

13.

Objective

Although shared decision making (SDM) has become increasingly important in bioethical discussions and clinical practice, it is not clear in which treatment situations SDM is suitable. We address this question by investigating social norms on the appropriateness of SDM in different situations.

Methods

We conducted qualitative expert interviews with patients, general practitioners, and health administration and research professionals.

Results

SDM was considered to be most important in severe illness and chronic condition. Furthermore, SDM was indicated to be required if there is more than one therapeutic option, especially if it is not clear which option is best. Interviewees classified end-of-life decisions and decisions about prevention as those that primarily should be made by informed patients. On the other hand a paternalistic decision was considered most appropriate in emergency situations and when the patient does not want to participate in decision making.

Conclusion

This study demonstrates that multiple situational factors and their interactions must be considered regarding the scope of SDM in medical consultation.

Practice implications

Research addressing this question will help physicians adjust their consultation style and allow implementations of SDM and decision aids to be tailored more appropriately to complex treatment situations.  相似文献   

14.

Background

Increased physical activity may have beneficial effects on cognitive outcomes; a role of brain-derived neurotrophic factor (BDNF) has been suggested in animal models but not yet tested in humans. This study investigated modification by BDNF val66met polymorphism of the association between physical activity, incident dementia and other cognitive outcomes.

Methods

Of 732 community elders, 107 had dementia at baseline, and 518 (83%) of the remainder were followed over 2.4 years. Cognitive impairment and decline were defined from Mini-Mental State Examination scores. Self-reported level of physical activity was recorded on a 4-point scale. BDNF val66met and apolipoprotein E genotypes were ascertained. Covariates included age, sex, education, depression, vascular risk factors, and instrumental activities of daily living.

Results

Baseline lower physical activity was significantly associated with incident dementia as well as with baseline dementia and cognitive impairment and incident cognitive decline. BDNF val66met polymorphism itself was not associated with any cognitive outcome. However, the strength of association between lower activity and all cognitive outcomes increased incrementally with the number of met alleles, and was strongest in those with the met/met genotype. BDNF × activity interaction terms were stronger for prospective outcomes (incident dementia, cognitive decline) compared to cross-sectional outcomes (prevalent dementia, cognitive impairment no dementia).

Conclusions

This study supports a previously suggested neurobiological basis for the effects of physical activity on dementia involving the BDNF system since the met allele is recognised to be associated with lower activity-dependent secretion of BDNF.  相似文献   

15.
We have investigated long-term synaptic depression in the CA1 region of rat hippocampal slices. Prolonged low-frequency stimulation (LFS; 900 stimuli delivered at 2 Hz) of the Schaffer collateral-commissural pathway in naïve slices did not induce long-term depression (LTD) of synaptic transmission. However, if long-term potentiation (LTP) was firstly induced in the pathway then LFS generated an LTD-like effect (i.e. depotentiation of LTP). Depotentiation could be induced 2 h (the longest time studied) after the induction of LTP and was stable for the duration of the experiment (followed for up to 40 min). The induction of depotentiation was not blocked by the N-methyl-d-aspartate receptor antagonist d-2-amino-5-phosphonopentanoate, the L-type voltage-gated Ca2+ channel blocker nimodipine or the nitric oxide synthase inhibitor N-nitro-l-arginine. However, the magnitude of depotentiation was reversibly reduced, in a stereoselective manner, by the specific metabotropic glutamate receptor (mGluR) antagonist (+)--methyl-4-carboxyphenylglycine. These results show that prolonged low frequency stimulation can result in an mGluR-dependent depotentiation of LTP.  相似文献   

16.

Background

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common long-chain fatty acid oxidation defect presenting with heterogeneous clinical phenotypes. Dietary fat plays a crucial role in disease pathogenesis and fat restriction is a common treatment measure. We here investigate the hepatic and muscular effects of a fat-enriched and a fat-restricted diet.

Methods

VLCAD knock-out (KO) and wild-type (WT) mice are subjected to a fat-rich (10.6%), a fat-reduced (2.6%) or a regular mouse diet (5.1%) for 5 weeks. Analyses are performed at rest and after one hour exercise on a treadmill. Acylcarnitines in muscle as well as lipid and glycogen content in muscle and liver are quantified. Expression of genes involved in lipogenesis is measured by Real-Time-PCR.

Results

At rest, VLCAD KO mice develop no clinical phenotype with all three diets, but importantly VLCAD KO mice cannot perform one hour exercise as compared to WT, this is especially apparent in mice with a fat-reduced diet. Moreover, changes in dietary fat content induce a significant increase in muscular long-chain acylcarnitines and hepatic lipid content in VLCAD KO mice after exercise. A fat-reduced diet up-regulates hepatic lipogenesis at rest. At the same time, muscular glycogen is significantly lower than in WT.

Conclusions

We here demonstrate that a fat-reduced and carbohydrate-enriched diet does not prevent the myopathic phenotype in VLCAD KO mice. An increase in dietary fat is safe at rest with respect to the muscle but results in a significant muscular acylcarnitine increase after exercise.  相似文献   

17.
《Journal of neurogenetics》2013,27(1-2):43-58
Postsynaptic membrane rafts are believed to play important roles in synaptic signaling, plasticity, and maintenance. We recently demonstrated the presence, at the electron microscopic level, of complexes consisting of membrane rafts and postsynaptic densities (PSDs) in detergent-resistant membranes (DRMs) prepared from synaptic plasma membranes (SPMs) (, J Neurochem, 119, 64–77). To further explore these complexes, here we investigated the nature of the binding between purified SPM-DRMs and PSDs in vitro. In binding experiments, we used SPM-DRMs prepared after treating SPMs with n-octyl-β-d-glucoside, because at concentrations of 1.0% or higher it completely separates SPM-DRMs and PSDs, providing substantially PSD-free unique SPM-DRMs as well as DRM-free PSDs. PSD binding to PSD-free DRMs was identified by mass spectrometry, Western blotting, and electron microscopy. PSD proteins were not incorporated into SPMs, and significantly less PSD proteins were incorporated into DRMs prepared from liver membranes, providing in vitro evidence that binding of PSDs to DRMs is specific and suggestion of the presence of specific interacting molecules. These specific interactions may have important roles in synaptic development, function, and plasticity in vivo. In addition, the binding system we developed may be a good tool to search for binding molecules and binding mechanisms between PSDs and rafts.  相似文献   

18.

Objective

To examine physiological and health-related quality of life (HRQOL) outcomes in community living adults attending a 12-week combined lifestyle wellness program.

Methods

A sample of overweight and obese adults (n = 319) and a subgroup who also had diabetes (n = 46 of 319) were studied. The program focuses on dietary, physical activity, and behavioral strategies to promote cardiovascular health. Baseline and 12-week measures were obtained.

Results

In the total sample, all physiological and HRQOL outcomes improved (p < .05), except HDL. High attendance was associated with the highest weight loss. In the diabetic subgroup, weight, steps/day, low density lipoprotein, and most aspects of HRQOL improved significantly.

Conclusion

Physiological and HRQOL benefits can be gained from a 12-week combined lifestyle program; greater benefits were obtained with higher attendance. Although the diabetic subgroup was not large, positive outcomes were realized.

Practice implications

The 12-week combined lifestyle program shows promise for improving outcomes in community living overweight and obese adults who may also be diabetic. By attending class, participants are reminded about strategies they are to apply during the 12-week program and, by program end, they are equipped with a tool kit of strategies for use in everyday life.  相似文献   

19.

Objective

To investigate the course of PTSD, depression, and current quality of life among adolescents 32-months after the 1999 Parnitha earthquake in Greece.

Methods

The follow-up was conducted among 511 adolescents originally evaluated at 3-months post-earthquake using the UCLA PTSD Reaction Index (PTSD-RI), Depression Self-Rating Scale (DSRS), and Quality of Life Questionnaire (QOLQ).

Results

Mean PTSD scores for the whole sample had subsided to mild levels; however, 8.8% were still experiencing moderate to severe levels of symptoms, and 13.6% met criteria for clinical depression. Frequency of experiencing reminders of the earthquake in the past month best explained the variance (15%) in PTSD severity, followed by depression at 3-months (8%). The QOLQ domain scores were negatively correlated with PTSD and depression. Depression at 3-months was the best predictor of QOLQ at 32-months, explaining 16% of the variance.

Limitations

Self-report instruments were used; hence the responses may have been over- or under-estimated; also, the findings may not be generalizable to other ethnic groups.

Conclusion

Ongoing screening is recommended after disaster to identify adolescents who continue to experience moderate to severe levels of PTSD and depressive symptoms. Specific interventions to reduce reactivity to earthquake-related reminders should be a component of post-disaster recovery programs. A quality of life measure can provide important information in addition to traditional scales for monitoring the course of recovery among adolescents after disasters.  相似文献   

20.

Introduction

The epidemiology of Staphylococcus aureus has changed radically since 1999, in particular, methicillin-resistant S. aureus (MRSA), originally restricted to hospital, has emerged as a significant pathogen in the community, and true community-acquired MRSA (CA-MRSA) infections have been reported in patients with no clear risk factors. CA-MRSA strains frequently produce Panton-Valentine leukocidin (PVL).

Objectives

The objectives of this study were: (i) to monitor the prevalence of PVL and toxic shock syndrome toxin-1 (TSST-1) isolates MRSA; (ii) to identify the staphylococcal cassette chromosome (SCCmec) types of MRSA isolates.

Material and methods

Sixty-four isolates, collected between 2005 and 2007 in Didouche Mourad hospital of Algeria. The isolates were identified by conventional methods. The antibiotic susceptibility of the isolates was performed using the disk diffusion method and automat Vitek2. The presence of gene mecA, the genes encoding SCCmec type, PVL and TSST-1 toxins were investigated by real-time PCR.

Results

All strains were gene mecA positives, 32 (50%) harboured SCCmec IV type, 28 (43.75%) harboured SCCmec V type. 19 (29.68%) have been identified positive for the leukocidin toxin (PVL), they harboured SCCmec type IV. The virulence factor TSST-1 was not present among these isolates.

Conclusion

These results show a high prevalence of PVL-positive H-MRSA in our wards.  相似文献   

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