[Research Status of and Recommendations for Prevention and Control of Sleep Disorders in China].

The quality of sleep, a key physiological factor that regulates information, memory, decision making, and other vital brain functions, can affect important physiological functions of the human body. According to disease classification systems, sleep disorders can be categorized into more than 90 types, including sleep apnea, insomnia, and hypersomnia. It may cause a variety of adverse consequences, such as depression, anxiety and other emotional disorders, as well as physical diseases such as hypertension, diabetes and stroke. In addition, the relevant cardiovascular and cerebrovascular diseases and cognitive impairment not only harm physical health, but also are associated with workplace accidents and safety problems, constituting public safety hazards. Sleep disorders have become a major social and scientific problem that impacts on the national economy and the livelihood of the people. Research on sleep disorders should be given more attention by researchers and policy makers. Herein, we mainly discussed the latest findings and difficulties concerning research on the prevention and intervention of sleep disorders and proposed strategies and suggestions accordingly.

Ischemic neurons recruit natural killer cells that accelerate brain infarction.

Brain ischemia and reperfusion activate the immune system. The abrupt development of brain ischemic lesions suggests that innate immune cells may shape the outcome of stroke. Natural killer (NK) cells are innate lymphocytes that can be swiftly mobilized during the earliest phases of immune responses, but their role during stroke remains unknown. Herein, we found that NK cells infiltrated the ischemic lesions of the human brain. In a mouse model of cerebral ischemia, ischemic neuron-derived fractalkine recruited NK cells, which subsequently determined the size of brain lesions in a T and B cell-independent manner. NK cell-mediated exacerbation of brain infarction occurred rapidly after ischemia via the disruption of NK cell tolerance, augmenting local inflammation and neuronal hyperactivity. Therefore, NK cells catalyzed neuronal death in the ischemic brain.

CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke.

BACKGROUND: Chemokine (C-X3-C motif) ligand 1 (CX3CL1)/ CX3C chemokine receptor 1 (CX3CR1) signaling is important in modulating the communication between neurons and resident microglia/migrated macrophages in the central nervous system (CNS). Although CX3CR1 deficiency is associated with an improved outcome following ischemic brain injury, the mechanism of this observation is largely unknown. The aim of this study was to investigate how CX3CR1 deficiency influences microglia/macrophage functions in the context of its protection following brain ischemia. METHODS: Wild-type (WT) and CX3CR1-deficient (CX3CR1⁻/⁻) mice were subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion. The ischemic brain damage was monitored by rodent high-field magnetic resonance imaging. Neurological deficit was assessed daily. Neuronal apoptotic death and reactive oxygen species (ROS) production were analyzed by immunostaining and live imaging. Activation/inflammatory response of microglia/macrophage were assessed using immunohistochemistry, flow cytometry, 5-bromo-2-deoxyuridine labeling, cytokine ELISA, and real-time PCR. RESULTS: CX3CR1⁻/⁻ mice displayed significantly smaller infarcts and less severe neurological deficits compared to WT controls, following MCAO. In addition, CX3CR1⁻/⁻ MCAO mice displayed fewer apoptotic neurons and reduced ROS levels. Impaired CX3CR1 signaling abrogated the recruitment of monocyte-derived macrophages from the periphery, suppressed the proliferation of CNS microglia and infiltrated macrophage, facilitated the alternative activation (M2 state) of microglia/macrophages, and attenuated their ability to synthesize and release inflammatory cytokines. CONCLUSION: Our results suggest that inhibition of CX3CR1 signaling could function as a therapeutic modality in ischemic brain injury, by reducing recruitment of peripheral macrophages and expansion/activation of CNS microglia and macrophages, resulting in protection of neurological function.

Impact of Cold Ischemic Time and Freeze-Thaw Cycles on RNA, DNA and Protein Quality in Colorectal Cancer Tissues Biobanking.

Tissue-derived RNA, DNA and protein samples become more and more crucial for molecular detection in clinical research, personalized and targeted cancer therapy. This study evaluated how to biobanking colorectal tissues through examining the influences of cold ischemic time and freeze-thaw cycles on RNA, DNA and protein integrity. Here, 144 pairs of tumor and normal colorectal tissues were used to investigate the impact of cold ischemic times (0-48h) on RNA, DNA and protein integrity at on ice or room temperature conditions. Additionally, 45 pairs of tissues experienced 0-9 freeze-thaw cycles, and then the RNA, DNA and protein quality were analyzed. On ice, RNA, DNA and protein from colorectal tumor and normal tissues were all stable up to 48h after surgery. At room temperature, RNA in colorectal tumor and normal tissues began to degrade at 8h and 24h, respectively. Meanwhile, the tumor tissues DNA degradation occurred at 24h after surgery at room temperature. Similarly, the protein expression level of tumor and normal tissues began to change at 24h after the surgery at room temperature. Interestingly, tissue RNA and DNA remained stable even after 9 freeze-thaw cycles, whereas the proteins levels were remarkably changed after 7 freeze-thaw cycles. This study provided a useful evidence on how to store human colorectal tissues for biobanking. Preserving the surgical colorectal tissue on ice was an effective way to prevent RNA, DNA and protein degradation. Importantly, more than 7 repeated freeze-thaw cycles were not recommended for colorectal tissues.

[Study of modified Biejiajian pill on pathological immune hepatic fibrosis model induced by albumin in rats].

OBJECTIVE: To quantitatively analyze the effect of modified Biejiajian Pill (BJJP) on the pathological change and degree of albumin induced immune hepatic fibrosis in rats. METHODS: Rats were immunized by multiple subcutaneous injections of human serum albumin (8 g/L) , and were medicated in groups respectively after antibody producing, BJJP high-dose (13 g/kg) group, medium-dose (6.5 g/kg) group, low-dose (3.25 g/kg) group, the model group, colchicines (1.0 mg/kg) group, and Ganpikang (22.23 mg/kg) group. Then, caudal vein injection of albumin was given 40 min after medication to induce liver fibrosis. Animals were sacrificed finally to observe the pathological change, and the distribution and content of collagen and plastin were determined quantitatively with HE and Masson stain. RESULTS: BJJP high-, medium-, and low-dose groups could obviously improve the pathological change of the hepatic fibrosis rats (decreasing rate of the total score was 62.50%, 40.75%, and 8.33%, respectively), and the content of collagen reduced markedly (P<0.05, P<0.01). CONCLUSION: BJJP can effectively prevent and reduce the pathological change of albumin induced immune hepatic fibrosis in rats.

[Guiding principles of clinical research on mild cognitive impairment (protocol)].

Mild cognitive impairment (MCI), as a nosological entity referring to elderly people with MCI but without dementia, was proposed as a warning signal of dementia occurrence and a novel therapeutic target. MCI clinical criteria and diagnostic procedure from the MCI Working Group of the European Alzheimer's Disease Consortium (EADC) may better reflect the heterogeneity of MCI syndrome. Beijing United Study Group on MCI funded by the Capital Foundation of Medical Developments (CFMD) proposed the guiding principles of clinical research on MCI. The diagnostic methods include clinical, neuropsychological, functional, neuroimaging and genetic measures. The diagnostic procedure includes three stages. Firstly, MCI syndrome must be defined, which should correspond to: (1) cognitive complaints coming from the patients or their families; (2) reporting of a relative decline in cognitive functioning during the past year by the patient or informant; (3) cognitive disorders evidenced by clinical evaluation; (4) activities of daily living preserved and complex instrumental functions either intact or minimally impaired; and (5) absence of dementia. Secondly, subtypes of MCI have to be recognized as amnestic MCI (aMCI), single non-memory MCI (snmMCI) and multiple-domains MCI (mdMCI). Finally, the subtype causes could be identified commonly as Alzheimer disease (AD), vascular dementia (VaD), and other degenerative diseases such as frontal-temporal dementia (FTD), Lewy body disease (LBD), semantic dementia (SM), as well as trauma, infection, toxicity and nutrition deficiency. The recommended special tests include serum vitamin B12 and folic acid, plasma insulin, insulin-degrading enzyme, Abeta40, Abeta42, inflammatory factors. Computed tomography (or preferentially magnetic resonance imaging, when available) is mandatory. As measurable therapeutic outcomes, the primary outcome should be the probability of progression to dementia, the secondary outcomes should be cognition and function, and the supplement outcome should be the syndrome defined by traditional Chinese medicine. And for APOE epsilon4 carrier, influence of the carrier status on progression rate to dementia and the effect of treatment should be evaluated.

[An explanation on "guiding principles of clinical research on mild cognitive impairment (protocol)"].

In order to provide the "guiding principles of clinical research on mild cognitive impairment (MCI) (protocol)" edited by Beijing United Study Group on MCI of the Capital Foundation of Medical Developments (CFMD) with evidence support, clinical criteria, subtypes, inclusion and exclusion of MCI, and use of rating scales were reviewed. The authors suggested that MCI clinical criteria and new diagnosis procedure from the MCI Working Group of the European Alzheimer's disease Consortium (EADC) may better reflect the heterogeneity of MCI syndrome. Diagnostic rating scales including Clinical Dementia Rating (CDR), Global Deterioration Scale (GDS), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and Instrumental Activities of Daily Living (IADL) are very useful in definition of MCI but can not replace its clinical criteria. Absence of major repercussions on daily life in patients with MCI was emphasized, but the patients may have minimal impairment in complex IADL. According to their previous research, the authors concluded that highly recommendable neuropsychological scales with cut-off scores in the screening of MCI cases should include Mini-Mental State Examination (MMSE), logistic memory test such as Delayed Story Recall (DSR), executive function test such as Clock Draw Test (CDT), language test such as Verbal Category Fluency Test (VCFT), etc. And finally, the detection of biological and neuroimaging changes, including atrophy in hippocampus or medial temporal lobe in patients with MCI, was introduced.

Hippocampal synaptic and neural network deficits in young mice carrying the human APOE4 gene.

INTRODUCTION: Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset sporadic Alzheimer disease. Emerging evidence demonstrates a hippocampus-associated learning and memory deficit in aged APOE4 human carriers and also in aged mice carrying human APOE4 gene. This suggests that either exogenous APOE4 or endogenous APOE4 alters the cognitive profile and hippocampal structure and function. However, little is known regarding how Apoe4 modulates hippocampal dendritic morphology, synaptic function, and neural network activity in young mice. AIM: In this study, we compared hippocampal dendritic and spine morphology and synaptic function of young (4 months) mice with transgenic expression of the human APOE4 and APOE3 genes. METHODS: Hippocampal dendritic and spine morphology and synaptic function were assessed by neuronal imaging and electrophysiological approaches. RESULTS: Morphology results showed that shortened dendritic length and reduced spine density occurred at hippocampal CA1 neurons in Apoe4 mice compared to Apoe3 mice. Electrophysiological results demonstrated that in the hippocampal CA3-CA1 synapses of young Apoe4 mice, basic synaptic transmission, and paired-pulse facilitation were enhanced but long-term potentiation and carbachol-induced hippocampal theta oscillations were impaired compared to young Apoe3 mice. However, both Apoe genotypes responded similarly to persistent stimulations (4, 10, and 40 Hz for 4 seconds). CONCLUSION: Our results suggest significant alterations in hippocampal dendritic structure and synaptic function in Apoe4 mice, even at an early age.

[Affection of Bushen Shengjing pill on NO and NOS in testicle and ante-oxidization of rat with spermatogenic cell injury].

OBJECTIVE: Discuss the functional mechanism of treating male infertility with Bushen Shengjing pill (BS). METHOD: Fill the SD rat with adenine so as to injure the germ cell which will produce the model rat with kidney yang deficiency. Measure the activity of SOD and NOS, the amount of NO and MDA in the testicle. RESULT: BS can promote the activity of SOD, reduce the activity of NOS and the amount of NO and MDA. CONCLUSION: BS has the function of protecting the germ cell which is closely related to the function that the pill can promote the activity of SOD, reduce the activity of NOS and the amount of NO and MDA.

[A clinical study on a randomized, double-blind control of Chinese medicine granules in treatment of vascular dementia].

OBJECTIVE: To evaluate the effectiveness of Chinese medicine granules (Compound Chinese extract from herbs) in the treatment on senile vascular dementia. METHOD: One hundred and twenty patients meeting criteria for vascular dementia were selected from patients in Dongzhimen Hospital and were randomly assigned into a treatment group (n = 70 cases), given 1 package of Chinese medicine granules with 1 placebo tablets, and a positive control group (n = 50 cases), given 1 tablets of Duxil with 1 package of placebo. All subjects took this medication 3 times a day for 2 months. Double-blind and double-moulding control were used in this study. At a baseline and end (two months later), all subjects were assessed using a battery consisting of MMSE and Blessed behavior measuring scale. RESULT: Both Chinese medicine granules and Duxil could remarkably increase the score of cognition and activity (P < 0.01). They had Similarly effectiveness and there was no statistical difference between the two groups in effectiveness of increasing memory scores. Chinese medicine granules was better than Duxil in increasing the scores of behavior (P < 0.05). CONCLUSION: Chinese medicine granules has certain effects on vascular dementia. And it has remarkable effectiveness in ameliorating the status of total body. And it can relieve the symptoms in vascular dementia.

[Influence of Chinese herbal extract complex on expression of corticotropin-releasing factor and protein kinasec protein in hippocampus of middle cerebral artery occlusion rats].

OBJECTIVE: To explore the influence of one Chinese herbal extract complex (GETO) on the expression of corticotropin-releasing factor(CRF) and protein kinasec(PKC) proteins of the hippocampus in middle cerebral artery orilusion(MCAO) rats. METHOD: All rats were subjected to MCAO by nylon thread, except the sham-group rats. Rats were divied into four groups: sham-group, cerebral ischemia model-group, GETO-group(6. 1 g x kg(-1) x d(-1) )and Duxil-group (7.3 mg x kg(-1) x d(-1)). Using immunohistochemistry technique we measured the expression quantity of CRF and PKC protein in hippocampus of MCAO rats at 2 h,6 h and 24 h after reperfusion, contrasted to Duxil. RESULT: CRF: There were lots of positive and deeper dyeing neurons in hippocampus of model-group rats, while there were a few of positive and lighter dyeing neurons in sham-group, GETO-group and Duxil-group. The positive expression areas of CRF protein in hippocampus of model-group was significantly bigger than that of sham-group, GETO -group and Duxil-group respectively( P <0. 01). PKC: There were a great number of denser positive granules in hippocampus of model-group rats, while there were a few of scattered positive granules in sham-group, GETO-group and Duxil-group. The positive expression areas of CRF protein in hippocampus of model-group was significantly bigger than that of sham-group, GETO-group and Duxil-group respectively( P < 0. 01). At the same time there was not significant difference about the expression of CRF and PKC protein between GETO group and Duxil-group. CONCLUSION: The high expression of CRF and PKC induced by cerebral ischemia may be one important factor that resulted in the delayed neuronal death in hippocampus. GETO can down-regulate the expression of CRF and PKC induced by cerebral ischemia, which may be one of the mechanisms that the Chinese herbal extract complex, protect cerebral ischemic injury.

[Research of kingsbrain on improving the learning and memory ability of MCAO rats].

OBJECTIVE: To explore the influence of Kingsbrain (GETO) on the learning memory impairment of rats with cerebral ischemia. METHOD: Rats with cerebral ischemia were administered GETO orally once a day for one month. The ability of spatial-learning memory of rats was evaluated by Morris Water Maze (MWM). Duxil was used as a positive control. RESULT: the results of place navigation of MWM showed that at the 3rd time of swimming training, the escape latency of rats of the GETO group, Duxil group and Sham group were shorter than that of model group. The escape latency were (54.1 +/- 43.94), (55.9 +/- 43.49), (50.4 +/- 34.99) and (85.4 +/- 42.8) s, respectively; but there was no significantly difference. After the 6th time of swimming training, the escape latency of rats of the GETO group (37.8 +/- 38.69) s, the Duxil group (37.4 +/- 38.03) s and the sham group (26.9 +/- 21.63) s were significantly shorter than that of model rats (77.5 +/- 47.59) s, P < 0.05, respectively. Comparison of the swimming distance among groups were similar to the escape latency among groups. In the test of spatial probe, results of the ratio of the swimming time of platform quadrant (tP) vs the total swimming time (tT) and the ratio of the swimming distance of platform quadrant (dP) vs the total swimming distance (dT) indicated that the ratios of the GETO group (0.347 +/- 0.0662, 0.344 +/-0.055 1), the Duxil group (0.345 +/- 0.0984, 0.34 +/- 0.0934) and the sham group (0.35 +/- 0.0662, 0.349 +/- 0.0589) were significantly higher than those of the Model group (0.261 +/- 0.0689, 0.274 +/- 0.0544), P < 0.05, respectively. CONCLUSION: GETO can significantly improve the spatial learning and memory ability of rats with cerebral ischemia, which provides the pharmacodynamics evidence for its clinical application of improveing the learning and memory ability in poststroke patients.

Ketones block amyloid entry and improve cognition in an Alzheimer's model.

Sporadic Alzheimer's disease (AD) is responsible for 60%-80% of dementia cases, and the most opportune time for preventive intervention is in the earliest stage of its preclinical phase. As traditional mitochondrial energy substrates, ketone bodies (ketones, for short), beta-hydroxybutyrate, and acetoacetate, have been reported to provide symptomatic improvement and disease-modifying activity in epilepsy and neurodegenerative disorders. Recently, ketones are thought as more than just metabolites and also as endogenous factors protecting against AD. In this study, we discovered a novel neuroprotective mechanism of ketones in which they blocked amyloid-ß 42, a pathologic hallmark protein of AD, entry into neurons. The suppression of intracellular amyloid-ß 42 accumulation rescued mitochondrial complex I activity, reduced oxidative stress, and improved synaptic plasticity. Most importantly, we show that peripheral administration of ketones significantly reduced amyloid burden and greatly improved learning and memory ability in a symptomatic mouse model of AD. These observations provide us insights to understand and to establish a novel therapeutic use of ketones in AD prevention.

[An experiment study of protection and treatment of Kudan granule on rats of pulmonary fibrosis induced by pinyangmycin].

OBJECTIVE: To explore the protection and treatment effects of Kudan granule on rats of pulmonary fibrosis induced by pinyangmycin. METHOD: In asepsis condition, rat was anaesthetized by 3.5% chloral hydrate, inserted the needle above the bifurcation of trachea and injecting 5 mg x kg(-1) pinyangmycin normal saline solution. RESULT: For model-group rats, after injecting pinyangmycin at 7, 14, 28, 56 days, there were mass inflammation cell infiltration at pulmonary alveoli and interstitial, the pulmonary alveolar wall and interstitial thickened obviously, and the pulmonary interval broadened distinctly. The structure of collagen fiber was destroyed, and the pulmonary alveoli disappeared. By Masson dyeing, there were hunk collagen fiber and the consolidation of lung had come into being. Compared with the model group, the rats of Kudan granule big-dose group, at 7, 14, 28, 56 days after injecting pinyangmycin, there were still much inflammation cell infiltration at pulmonary alveoli and interstitial, pulmonary interstitial edema and spotty necrosis, thickened alveolar wall, broadened pulmonary interval, and much collagen fiber in pulmonary interstitial, but there was not bunk the consolidation of lung. The curative effect of Kudan granule small-dose group was not better than that of Kudan granule big-dose group, because there were still bunk collagen fiber and the consolidation of lung in pulmonary interstitial. Although the destroyed area was more than 50%, it was better than that of the model-group. CONCLUSION: The big-dose Kudan granule show the better function of protection and treatment for pulmonary fibrosis of rats induced by pinyangmycin.

[The influence of CGE on expression of IL-1beta and c-fos protein in the hippocampus region in rats following cerebral ischemia-reperfusion].

OBJECTIVE: To observe inhibiting effect of CGE (compound ginseng extract) on increased expression of IL-1beta and c-fos protein following cerebral ischemia-reperfusion. METHOD: The vascular dementia model was made by middle cerebral artery occlusion for 2 hours. Expression of IL-1beta and c-fos were determined by immunohistochemistry in the hippocampus regions in brain tissue at the 0.5 h-7 d after reperfusion. CGE was diluted by CMC and poured into the stomach by 0.7 mL x (100 g)(-1) with a high dosage (19.34 x 10(3) g x L(-1) row herbs), a middle dosage (9.67 x 10(3) g x L(-1)), a low dosage (4.83 x 10(3) g x L(-1)). There were an IL-1ra (rhIL-1ra 20 microg injected into the left cerebral ventricle), a sham operation (NaCl 20 microL injected into the left cerebral ventricle) and a model as control. RESULT: Compared with control group, three dose groups (low, middle and high) in CGE showed significant inhibiting effects on the expression of c-fos protein at 2, 3, 4, 12 hours and 3 day following cerebral ischaemic-reperfusion. The level of the inhibiting effects in small and middle groups were lower at all time points than that in IL-1ra group (P < 0.05 to P < 0.01). CGE inhibited the expression of hippocampus IL-1beta protein, taking effect from the 2 h after reperfusion. Both HD group (531 +/- 151.1) and MD group (589.3 +/- 78.6) showed more obvious effect which lasted until the 72 h compared with the model group (687.6 +/- 116.7) (P < 0.01 and 0.05). Large dose group (81.3 +/- 16.1) showed the same level of the inhibiting effect on expression of c-fos protein as IL-1ra group (67.2 +/- 25.7) from 4 hour on following cerebral ischaemic reperfusion (P > 0.05). CONCLUSION: CGE with function of Yiqi Bushen, Huoxue Huatan has effect of inhibiting up-regulated expression of IL-1beta and c-fos protein following cerebral ischemia-reperfusion. However, this effect of CGE starts relatively later than that of IL-1ra. The effect of CGE is associated with its dosage, i.e. a larger dosage has a better effect on expression of c-fos protein in post-stroke dementia.

Pertussis toxin modulates microglia and T cell profile to protect experimental autoimmune encephalomyelitis.

Pertussis toxin (PTx) has various effects in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study was designed to explore the protective effects of PTx of different doses and subunits. EAE model was induced with myelin oligodendrocyte glycoprotein (MOG35-55, 200 ug) plus complete Freund's adjuvant in 6-7 week-old female C57BL/6 mice. PTx reduced clinical deficits of EAE by 91.3%. This reduction in clinical deficits was achieved by attenuating demyelination by 75.5%. Furthermore, PTx reduced the lymphocyte infiltration, deactivated microglia activation and changed T cell profile by increasing T helper (type 1 and 2) and T regulatory cells.

Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor.

We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective. However, the effect of PTx on VEGF has never been studied. We investigated whether PTx modulates neuronal VEGF expression and how it affects the pathogenesis of EAE. EAE was induced by injecting myelin oligodendrocyte glycoprotein 35-55 peptides with adjuvants into C57BL/6 mice. Clinical scores of EAE were evaluated daily for 19 days. Brain and spinal cord samples were collected and assessed for inflammation and demyelination. VEGF, NeuN for neurons, and Caspase-3 for apoptosis were stained for localization using immunohistochemistry techniques, followed by western blot analysis for quantification. Primary neurons were cultured to assess the direct effect of PTx on neuronal VEGF expression. PTx treatment increases neuronal VEGF expression by up to ∼75% in vitro and ∼60% in vivo, preventing neurons from apoptosis. This leads to resolution in inflammation and remyelination and amendment in motor deficits. Our findings suggest that upregulation of endogenous neuronal VEGF by PTx protects motor deficits in EAE and it is a potential therapeutic option for multiple sclerosis.

Deficits in spatial learning and memory is associated with hippocampal volume loss in aged apolipoprotein E4 mice.

Apolipoprotein E ε4 (ApoE4) has been implicated as a potential genetic risk factor for dementia. In this study, we investigate the effect of ApoE4 on learning and memory, changes in brain volume and neuroinflammatory responses in brain of ApoE4 transgenic mice. Four groups of male mice with ApoE4 and age-matched wild type (WT) (6-, 12-, 18- and 24-month) were studied. Spatial learning and retaining of mice was examined in the Morris Water Maze (MWM). Changes in brain volume (including the whole brain, hippocampus, cortex, total ventricles, and caudate putamen) were assessed by using 7T small animal MRI. Neuroinflammatory responses were analyzed by measuring the levels of microglia (Iba-1), iNOS, TNFα, and IL-6 quantitatively. In the MWM, ApoE4 mice showed longer escape latency (p < 0.05) and swim distance (p < 0.05) at age 12 month and older, comparing with the WT mice. They also demonstrated poor memory retention in the probe test (p < 0.05). Brain atrophy was significant in ApoE4 mice than age-matched WT mice (18 months: 0.079 ± 0.004 versus 0.086 ± 0.003, p = 0.018; and 24 months: 0.074 ± 0.005 versus 0.084 ± 0.006, p = 0.008). The expression of Iba-1, iNOS, and TNFα in hippocampus and cortex were significantly higher in ApoE4 mice than in WT mice at 12 months and older. These data suggest that ApoE4 plays an important role in learning and memory impairment. These deficits are associated with neuroinflammatory responses that may in turn lead to atrophy in hippocampus and cortex.

Centrally administered pertussis toxin inhibits microglia migration to the spinal cord and prevents dissemination of disease in an EAE mouse model.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) models are important vehicles for studying the effect of infectious elements such as Pertussis toxin (PTx) on disease processes related to acute demyelinating encephalomyelitis (ADEM) or multiple sclerosis (MS). PTx has pleotropic effects on the immune system. This study was designed to investigate the effects of PTx administered intracerebroventricularly (icv) in preventing downstream immune cell infiltration and demyelination of the spinal cord. METHODS AND FINDINGS: EAE was induced in C57BL/6 mice with MOG(35-55). PTx icv at seven days post MOG immunization resulted in mitigation of clinical motor symptoms, minimal T cell infiltration, and the marked absence of axonal loss and demyelination of the spinal cord. Integrity of the blood brain barrier was compromised in the brain whereas spinal cord BBB integrity remained intact. PTx icv markedly increased microglia numbers in the brain preventing their migration to the spinal cord. An in vitro transwell study demonstrated that PTx inhibited migration of microglia. CONCLUSION: Centrally administered PTx abrogated migration of microglia in EAE mice, limiting the inflammatory cytokine milieu to the brain and prevented dissemination of demyelination. The effects of PTx icv warrants further investigation and provides an attractive template for further study regarding the pleotropic effects of infectious elements such as PTx in the pathogenesis of autoimmune disorders.

Comparison of glucose-insulin-potassium and insulin-glucose as adjunctive therapy in acute myocardial infarction: a contemporary meta-analysis of randomised controlled trials.

BACKGROUND: There is conflicting evidence regarding two different insulin regimens for acute myocardial infarction (AMI), one focusing on delivering insulin ('insulin focus', glucose-insulin-potassium (GIK)) and one focusing on tight glycaemic control ('glycaemia focus', insulin-glucose). A longstanding controversy has focused on which strategy provides the greatest reduction in mortality. The aim of this study was to perform a meta-analysis of randomised controlled trials (RCTs) comparing GIK or insulin-glucose therapy versus standard therapy for AMI in the reperfusion era. METHODS: A MEDLINE/EMBASE/CENTRAL search was conducted of RCTs evaluating GIK or insulin-glucose as adjunctive therapy for AMI. The primary endpoint was all-cause mortality. The data were analysed with a random effect model. RESULTS: A total of 11 studies (including 23 864 patients) were identified, eight evaluating insulin focus with GIK and three evaluating glycaemia focus with insulin-glucose. Overall, insulin focus with GIK was not associated with a statistically significant effect on mortality (RR 1.07, 95% CI 0.89 to 1.29, p=0.487). Before the use of reperfusion, GIK also had no clear impact on mortality (RR 0.92, 95% CI 0.70 to 1.20, p=0.522). Pooled data from the three studies evaluating glycaemia focus showed that insulin-glucose did not reduce mortality in the absence of glycaemia control in patients with AMI with diabetes (RR 1.07, 95% CI 0.85 to 1.36, p=0.547). CONCLUSIONS: Current evidence suggests that GIK with insulin does not reduce mortality in patients with AMI. However, studies of glycaemia are inconclusive and it remains possible that glycaemic control is beneficial.