Synoptic operative reporting: assessing the completeness, accuracy, reliability, and efficiency of synoptic reporting for Roux-en-Y gastric bypass.

OBJECTIVE: Synoptic reporting (SR) is one solution to improve the quality of operative reports. However, SR has not been investigated in bariatric surgery despite an identified need by bariatric surgeons. SR for RYGB was developed using quality indicators (QIs) established by a national Delphi process. The objective of this study is to assess the completeness, accuracy, reliability, and efficiency of synoptic versus narrative operative reports (NR) in Roux-en-Y gastric bypass (RYGB). METHODS: A NR and SR were completed on 104 consecutive RYGBs. Two evaluators independently compared the reports to QIs. Completeness and accuracy measures were determined. Reliability was calculated using Bland-Altman plots and 95% limits of agreement (LOA). Time to complete SR and NR was also compared. RESULTS: The mean completion rate of SR was 99.8% (±SD 0.98%) compared to 64.0% (±SD 6.15%) for NR (t = 57.9, p < 0.001). All subsections of SR were >99% complete. This was significantly higher than for NR (p < 0.001) except for small bowel division details (p = 0.530). Accuracy was significantly higher for SR than NR (94.2% ± SD 4.31% vs. 53.6% ± SD 9.82%, respectively, p < 0.001). Rater agreement was excellent for both SR (0.11, 95% LOA -0.53 to 0.75) and NR (-0.26, 95% LOA -4.85 to 4.33) (p = 0.242), where 0 denotes perfect agreement. SR completion times were significantly shorter than NR (3:55 min ± SD 1:26 min and 4:50 min ± SD 0:50 min, respectively, p = 0.007). CONCLUSION: The RYGB SR is superior to NR for completeness and accuracy. This platform is also both reliable and efficient. This SR should be incorporated into clinical practice.

Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure.

Gulf War illness (GWI) is a currently untreatable multi-symptom disorder experienced by 1990-1991 Persian Gulf War (GW) veterans. The characteristic hallmarks of GWI include cognitive dysfunction, tremors, migraine, and psychological disturbances such as depression and anxiety. Meta-analyses of epidemiological studies have consistently linked these symptomatic profiles to the combined exposure of GW agents such as organophosphate-based and pyrethroid-based pesticides (e.g. chlorpyrifos (CPF) and permethrin (PER) respectively) and the prophylactic use of pyridostigmine bromide (PB) as a treatment against neurotoxins. Due to the multi-symptomatic presentation of this illness and the lack of available autopsy tissue from GWI patients, very little is currently known about the distinct early pathological profile implicated in GWI (including its influence on synaptic function and aspects of neurogenesis). In this study, we used preclinical models of GW agent exposure to investigate whether 6-month-old mice exposed to CPF alone, or a combined dose of CPF, PB and PER daily for 10 days, demonstrate any notable pathological changes in hippocampal, cortical (motor, piriform) or amygdalar morphometry. We report that at an acute post-exposure time point (after 3 days), both exposures resulted in the impairment of synaptic integrity (reducing synaptophysin levels) in the CA3 hippocampal region and altered neuronal differentiation in the dentate gyrus (DG), demonstrated by a significant reduction in doublecortin positive cells. Both exposures also significantly increased astrocytic GFAP immunoreactivity in the piriform cortex, motor cortex and the basolateral amygdala and this was accompanied by an increase in (basal) brain acetylcholine (ACh) levels. There was no evidence of microglial activation or structural deterioration of principal neurons in these regions following exposure to CPF alone or in combination with PB and PER. Evidence of subtle microvascular injury was demonstrated by the reduction of platelet endothelial cell adhesion molecule (PECAM)-1 levels in CPF+PB+PER exposed group compared to control. These data support early (subtle) neurotoxic effects on the brain following exposure to GW agents.

Selective antihypertensive dihydropyridines lower Aß accumulation by targeting both the production and the clearance of Aß across the blood-brain barrier.

Several large population-based or clinical trial studies have suggested that certain dihydropyridine (DHP) L-type calcium channel blockers (CCBs) used for the treatment of hypertension may confer protection against the development of Alzheimer disease (AD). However, other studies with drugs of the same class have shown no beneficial clinical effects. To determine whether certain DHPs are able to impact underlying disease processes in AD (specifically the accumulation of the Alzheimer Aß peptide), we investigated the effect of several antihypertensive DHPs and non-DHP CCBs on Aß production. Among the antihypertensive DHPs tested, a few, including nilvadipine, nitrendipine and amlodipine inhibited Aß production in vitro, whereas others had no effect or raised Aß levels. In vivo, nilvadipine and nitrendipine acutely reduced brain Aß levels in a transgenic mouse model of AD (Tg PS1/APPsw) and improved Aß clearance across the blood-brain barrier (BBB), whereas amlodipine and nifedipine were ineffective showing that the Aß-lowering activity of the DHPs is independent of their antihypertensive activity. Chronic oral treatment with nilvadipine decreased Aß burden in the brains of Tg APPsw (Tg2576) and Tg PS1/APPsw mice, and also improved learning abilities and spatial memory. Our data suggest that the clinical benefit conferred by certain antihypertensive DHPs against AD is unrelated to their antihypertensive activity, but rely on their ability to lower brain Aß accumulation by affecting both Aß production and Aß clearance across the BBB.

Epitope-dependent effects of Beta-amyloid antibodies on Beta-amyloid clearance in an in vitro model of the blood-brain barrier.

OBJECTIVE: To investigate the role of RAGE in the epitope-dependent effects of Aß antibodies used as a peripheral sink therapy in AD. METHODS: An in vitro model of the BBB was used to examine the effect of various Aß antibodies or Aß peptide fragments on Aß exchange across the BBB. RESULTS: An N-terminal Aß antibody significantly enhanced the basolateral-to-apical transcytosis of fluorescein-Aß(1-42) across the BBB model (41%), while no effect was apparent with a C-terminal Aß antibody. Interestingly, modulation of RAGE in the presence of a C-terminal Aß antibody resulted in a 65% increase in Aß clearance across the BBB model, suggesting the C-terminal antibody-Aß complex is susceptible to RAGE transport. Additionally, N-terminal peptide fragments of Aß attenuated the brain penetration of full length Aß in the BBB model, indicating the N-terminal region of Aß is required for brain uptake. CONCLUSIONS: Antibodies masking the N-terminal region of Aß increase Aß clearance across the BBB by preventing Aß from interacting with the RAGE transporter, whereas antibodies bound to the C-terminus of Aß are taken up by RAGE and, hence, do not influence the BBB clearance of Aß.

Induction of drug efflux protein expression by venlafaxine but not desvenlafaxine.

Venlafaxine and its metabolite desvenlafaxine are serotonin-norepinephrine reuptake inhibitors currently prescribed for the treatment of depression. Previously, it was reported that venlafaxine is an inducer of MDR1, the gene responsible for P-glycoprotein (P-gp). The present study expanded upon these findings by examining the effect of venlafaxine and desvenlafaxine on the expression of both P-gp and the breast cancer resistance protein (BCRP) in human brain endothelial cells (HBMEC), an in vitro model of the blood-brain barrier (BBB). The HBMEC were treated for 1 h with various concentrations (500 nM to 50 µM) of venlafaxine and desvenlafaxine. Western blot analysis revealed treatment with venlafaxine significantly induced the expression of P-gp (2-fold) and BCRP (1.75-fold) in a dose-dependent manner, while treatment with desvenlafaxine had no effect on drug efflux transporter expression. To determine the functional significance of this effect, the permeability of a known drug efflux probe, rhodamine 123, across the BBB model and Caco-2 cells, a model of intestinal absorption, were examined. Treatment with venlafaxine (1-50 µM) for 1 h significantly reduced the apical-to-basolateral permeability of R123 across the BBB model (30%) and Caco-2 cell monolayers (25%), indicative of increased drug efflux transporter expression at the apical membrane. Conversely, desvenlafaxine had no effect on R123 permeability in either cellular model. These studies indicate that venlafaxine, but not desvenlafaxine is an inducer of drug efflux transporter expression, which consequently increases the potential for clinical drug-drug interactions. Therefore, based on these preliminary results, caution should be taken when prescribing venlafaxine with other P-gp substrates.

Extended results of the Alzheimer's disease anti-inflammatory prevention trial.

BACKGROUND: Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimer's dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2,528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups. METHODS: We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aß(1-42.) RESULTS: Including 40 new events observed during follow-up of 2,071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairment--no dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration. CONCLUSIONS: These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies.

Reduction of beta-amyloid pathology by celastrol in a transgenic mouse model of Alzheimer's disease.

BACKGROUND: Abeta deposits represent a neuropathological hallmark of Alzheimer's disease (AD). Both soluble and insoluble Abeta species are considered to be responsible for initiating the pathological cascade that eventually leads to AD. Therefore, the identification of therapeutic approaches that can lower Abeta production or accumulation remains a priority. NFkappaB has been shown to regulate BACE-1 expression level, the rate limiting enzyme responsible for the production of Abeta. We therefore explored whether the known NFkappaB inhibitor celastrol could represent a suitable compound for decreasing Abeta production and accumulation in vivo. METHODS: The effect of celastrol on amyloid precursor protein (APP) processing, Abeta production and NFkappaB activation was investigated by western blotting and ELISAs using a cell line overexpressing APP. The impact of celastrol on brain Abeta accumulation was tested in a transgenic mouse model of AD overexpressing the human APP695sw mutation and the presenilin-1 mutation M146L (Tg PS1/APPsw) by immunostaining and ELISAs. An acute treatment with celastrol was investigated by administering celastrol intraperitoneally at a dosage of 1 mg/Kg in 35 week-old Tg PS1/APPsw for 4 consecutive days. In addition, a chronic treatment (32 days) with celastrol was tested using a matrix-driven delivery pellet system implanted subcutaneously in 5 month-old Tg PS1/APPsw to ensure a continuous daily release of 2.5 mg/Kg of celastrol. RESULTS: In vitro, celastrol dose dependently prevented NFkappaB activation and inhibited BACE-1 expression. Celastrol potently inhibited Abeta1-40 and Abeta1-42 production by reducing the beta-cleavage of APP, leading to decreased levels of APP-CTFbeta and APPsbeta. In vivo, celastrol appeared to reduce the levels of both soluble and insoluble Abeta1-38, Abeta1-40 and Abeta1-42. In addition, a reduction in Abeta plaque burden and microglial activation was observed in the brains of Tg PS1/APPsw following a chronic administration of celastrol. CONCLUSIONS: Overall our data suggest that celastrol is a potent Abeta lowering compound that acts as an indirect BACE-1 inhibitor possibly by regulating BACE-1 expression level via an NFkappaB dependent mechanism. Additional work is required to determine whether chronic administration of celastrol can be safely achieved with cognitive benefits in a transgenic mouse model of AD.

CD40/CD40L interaction induces Abeta production and increases gamma-secretase activity independently of tumor necrosis factor receptor associated factor (TRAF) signaling.

CD40, a member of tumor necrosis factor receptor superfamily, and its cognate ligand CD40L are both elevated in the brain of Alzheimer's disease (AD) patients compared to controls. We have shown that pharmacological or genetic interruption of CD40/CD40L interaction results in mitigation of AD-like pathology in vivo in transgenic AD mouse models, and in vitro. Recently, we showed that CD40L stimulation could increase Abeta levels via NFkappaB signaling, presumably through TRAFs. In the present work, using CD40 mutants, we show that CD40L can increase levels of Abeta(1-40), Abeta(1-42), sAPPbeta, sAPPalpha and CTFbeta independently of TRAF signaling. We report an increase in mature/immature APP ratio after CD40L treatment of CD40wt and CD40-mutant cells, reflecting alterations in APP trafficking. In addition, results from CD40L treatment of a neuroblastoma cell line over-expressing the C-99 APP fragment suggest that CD40L has an effect on gamma-secretase. Furthermore, inhibition of gamma-secretase activity significantly reduces sAPPbeta levels in the CD40L treated HEK/APPsw CD40wt and the CD40-mutant cells. The latter suggests CD40/CD40L interaction primarily acts on gamma-secretase and affects beta-secretase via a positive feedback mechanism. Taken together, our data suggest that CD40/CD40L interaction modulates APP processing independently of TRAF signaling.

The granulocyte macrophage colony stimulating factor (GM-CSF) regulates amyloid beta (Abeta) production.

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of amyloid beta (Abeta) plaques in the brain parenchyma. An inflammatory component to AD has been suggested in association with increased cytokine release. We have previously shown that CD40L stimulation of microglia induces increases in pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6, IL-8 and GM-CSF. We have also shown that CD40L stimulation increases Abeta levels in HEK-293 cells over-expressing both the amyloid precursor protein (APP) and CD40 (HEK/APPsw/CD40). In this study, we show that GM-CSF neutralizing antibodies mitigate the CD40L-induced production of Abeta in HEK/APPsw/CD40 cells. In addition, we demonstrate that treatment of these cells with recombinant GM-CSF significantly increases Abeta levels. Furthermore, we show that shRNA silencing of the GM-CSF receptor gene significantly reduces Abeta levels to below base line in non-stimulated HEK/APPsw/CD40 cells. Analysis of cell surface proteins revealed that silencing of the GM-CSF receptor also decreases APP endocytosis (therefore reducing the availability of APP to be cleaved in the endosomes). Taken together, our results suggest that GM-CSF operates downstream of CD40/CD40L interaction and that GM-CSF modulates Abeta production by influencing APP trafficking. GM-CSF signaling may be a suitable therapeutic target against Abeta production in AD.

Diagnostic utility of APOE, soluble CD40, CD40L, and Abeta1-40 levels in plasma in Alzheimer's disease.

A continuous inflammatory state is associated with Alzheimer's disease (AD) evidenced by an increase in proinflammatory cytokines around beta-amyloid (Abeta) deposits. In addition, functional loss of CD40L is shown to result in diminished Amyloid precursor proton (APP) processing and microglial activation, supporting a prominent role of CD40-CD40L in AD etiology. We therefore hypothesize that a peripheral increase in Abeta may result in corresponding increase of sCD40 and sCD40L further contributing to AD pathogenesis. We measured plasma Abeta, sCD40 and sCD40L levels in 73 AD patients and compared to 102 controls matched on general demographics. We demonstrated that Abeta(1-40), levels of sCD40 and sCD40L are increased in AD and declining MMSE scores correlated with increasing sCD40L, which in turn, correlated positively with Abeta(1-42). We then combined sCD40, sCD40L, Abeta and APOE and found that this biomarker panel has high sensitivity and specificity (>90%) as a predictor of clinical AD diagnosis. Given the imminent availability of potentially disease modifying therapies for AD, a great need exists for peripheral diagnostic markers of AD. Thus, we present preliminary evidence for potential usefulness for combination of plasma sCD40, sCD40L along with Abeta(1-40) and APOE epsilon4 in improving the clinical diagnosis of AD.

Role of CD40 ligand in amyloidosis in transgenic Alzheimer's mice.

We have shown that interaction of CD40 with CD40L enables microglial activation in response to amyloid-beta peptide (Abeta), which is associated with Alzheimer's disease (AD)-like neuronal tau hyperphosphorylation in vivo. Here we report that transgenic mice overproducing Abeta, but deficient in CD40L, showed decreased astrocytosis and microgliosis associated with diminished Abeta levels and beta-amyloid plaque load. Furthermore, in the PSAPP transgenic mouse model of AD, a depleting antibody against CD40L caused marked attenuation of Abeta/beta-amyloid pathology, which was associated with decreased amyloidogenic processing of amyloid precursor protein (APP) and increased circulating levels of Abeta. Conversely, in neuroblastoma cells overexpressing wild-type human APP, the CD40-CD40L interaction resulted in amyloidogenic APP processing. These findings suggest several possible mechanisms underlying mitigation of AD pathology in response to CD40L depletion, and validate the CD40-CD40L interaction as a target for therapeutic intervention in AD.

Femoral artery necrosis due to parenteral intravascular drug misuse: a case report and literature review.

Accidental intra-arterial injection as a consequence of drug misuse has been described in both the upper and lower limbs. We present a case in which a drug abuser injected heroin into his femoral artery. This resulted in necrosis of the femoral artery requiring an autologous graft. A life threatening haemorrhage necessitated ligation of the common femoral artery. His limb survived.

Cocaine-induced oxidative stress precedes cell death in human neuronal progenitor cells.

By 2003, an estimated 34 million Americans had used cocaine according to the National Survey on Drug Use & Health. About 5.9 million of those had used in the past 12 months. Chronic cocaine users often develop addiction, dependency and tolerance to the drug. The psychological and physical effects of cocaine are due to the disruption of the limbic system in the central nervous system (CNS). Increased oxidative stress reported in the frontal cortex and the striatum of rats exposed to cocaine suggests that oxidative damage plays a significant role in cocaine-induced disruption of the CNS. Although it is evident that cocaine induces oxidative stress in the CNS, little has been learned about whether such increased oxidative stress is also relevant to apoptosis in cocaine-exposed models. To gain insight into the role of cocaine-induced oxidative stress in apoptosis, we hypothesized that oxidative stress precedes cell death when cocaine is administrated. To test this hypothesis, we have monitored the oxidative stress and apoptotic effects of acute cocaine exposure in human neuronal progenitor cells (HNPC). We found that oxidative stress was significantly increased at 48h after a 30min cocaine exposure compared to control cells, and that this was followed by cell death at 72h. Using the same experimental paradigm we have previously shown that pro-inflammatory genes are up-regulated in cocaine-exposed HNPC at 24h. Therefore, we suggest that the increased oxidative stress (possibly mediated by inflammatory responses) precedes cell death in cocaine-exposed HNPC. This may have implications for the consequences of cocaine abuse in situations where antioxidant capacity is compromised, as in the aging brain.

Genomic analysis of response to traumatic brain injury in a mouse model of Alzheimer's disease (APPsw).

Numerous studies have shown that the beta-amyloid peptide (Abeta) or beta-amyloid deposits impact many processes that can contribute to neurodegeneration, ranging from immune and inflammatory processes to cell death and apoptosis, processes characteristic of both Alzheimer's disease and head injury. Human and animal studies of traumatic brain injury (TBI) have shown that Abeta production is increased acutely following injury, and there is evidence for increased amyloid deposition and risk for Alzheimer's disease following TBI. Given the poorer outcome after injury observed both in transgenic mice overproducing Abeta, as well as in humans subjected to repetitive head injury, one may conclude that the presence of elevated brain levels of Abeta, whether endogenous or as a consequence of previous injury, exacerbates many of the deleterious processes triggered by TBI. We sought to test this hypothesis by examining the genomic response to injury in wild-type mice and in transgenic mice (APPsw) overexpressing and accumulating cerebral Abeta/beta-amyloid. Gene expression was investigated by microarray 24 h after controlled cortical impact (CCI) injury or sham injury in aged APPsw transgenic mice and wild-type controls. Stringent statistical analysis revealed differential expression of a total of 129 genes in the transgenic TBI vs. sham comparison and 119 genes in the wild-type TBI vs. sham comparison. Of these, only 28 genes were common to both comparisons, suggesting considerable differences in response to injury in the Alzheimer models compared to wild-type mice. We focused our analyses by creating a "genotype-dependent" data set of response to injury which contained the genes that were uniquely altered in response to injury in either wild-type or APPsw mice, as well as those which were significantly differently modulated following TBI in one genotype compared to the other. The cellular functions predicted to be influenced by these changes in gene expression thus indicate the adverse pathways triggered by increased levels of Abeta, and the potentially favorable (recovery) pathways which are activated in wild-type mice but suppressed when Abeta levels are high. The results show that the cellular functions most influenced by the cerebral Abeta levels following TBI include inflammation, immune response, and cell death, which suggest a particular vulnerability to head injury in the Alzheimer brain.

Electronic synoptic reporting: assessing the completeness of synoptic and narrative reports for Roux-en-Y gastric bypass.

BACKGROUND: Operative reporting is the foundation of surgical communication. The quality indicators (QIs) contained in these reports can be used to document the performance of processes that affect patient care and may afford quality assurance with improvement in healthcare. OBJECTIVES: We assessed the degree to which the electronic synoptic report (SR) documents the operative QIs compared with narrative reports (NR) for Roux-en-Y gastric bypass (RYGB). The time to report availability on patient chart was also identified as a secondary measure. SETTING: Academic center, public hospital, Canada. METHODS: A total of 40 prospectively collected RYGB synoptic reports and 40 case-matched historical NRs were compared against checklist QIs that were established by a national Delphi process. These checklist QIs are validated and have high interrater agreement at our institution. Time from dictation to report availability on patient chart was measured. RESULTS: SR had a mean completion of 99.7% (±standard deviation [SD] 1.3%) compared with 64.0% (±SD 6.3%) for NR (t = 36.0, P<.0001). All subsections of SR were>99% complete and significantly higher than NR (P<.001). The mean time from NR dictation to report availability was 4.14 days (SD±3.17, range 0-10 d). All SRs were in the operative area after the procedure and were available immediately. CONCLUSION: The RYGB synoptic report is superior to the narrative report for inclusion of accepted quality indicators and time to availability. Important elements, including process of care, demographic characteristics, and anatomic-related data, were often missing from the NR. SR is a promising method for improving documentation for RYGB.

Inflammatory cytokine levels correlate with amyloid load in transgenic mouse models of Alzheimer's disease.

BACKGROUND: Inflammation is believed to play an important role in the pathology of Alzheimer's disease (AD) and cytokine production is a key pathologic event in the progression of inflammatory cascades. The current study characterizes the cytokine expression profile in the brain of two transgenic mouse models of AD (TgAPPsw and PS1/APPsw) and explores the correlations between cytokine production and the level of soluble and insoluble forms of Abeta. METHODS: Organotypic brain slice cultures from 15-month-old mice (TgAPPsw, PS1/APPsw and control littermates) were established and multiple cytokine levels were analyzed using the Bio-plex multiple cytokine assay system. Soluble and insoluble forms of Abeta were quantified and Abeta-cytokine relationships were analyzed. RESULTS: Compared to control littermates, transgenic mice showed a significant increase in the following pro-inflammatory cytokines: TNF-alpha, IL-6, IL-12p40, IL-1beta, IL-1alpha and GM-CSF. TNF-alpha, IL-6, IL-1alpha and GM-CSF showed a sequential increase from control to TgAPPsw to PS1/APPsw suggesting that the amplitude of this cytokine response is dependent on brain Abeta levels, since PS1/APPsw mouse brains accumulate more Abeta than TgAPPsw mouse brains. Quantification of Abeta levels in the same slices showed a wide range of Abeta soluble:insoluble ratio values across TgAPPsw and PS1/APPsw brain slices. Abeta-cytokine correlations revealed significant relationships between Abeta1-40, 1-42 (both soluble and insoluble) and all the above cytokines that changed in the brain slices. CONCLUSION: Our data confirm that the brains of transgenic APPsw and PS1/APPsw mice are under an active inflammatory stress, and that the levels of particular cytokines may be directly related to the amount of soluble and insoluble Abeta present in the brain suggesting that pathological accumulation of Abeta is a key driver of the neuroinflammatory response.

Gulf War agent exposure causes impairment of long-term memory formation and neuropathological changes in a mouse model of Gulf War Illness.

Gulf War Illness (GWI) is a chronic multisymptom illness with a central nervous system component such as memory deficits, neurological, and musculoskeletal problems. There are ample data that demonstrate that exposure to Gulf War (GW) agents, such as pyridostigmine bromide (PB) and pesticides such as permethrin (PER), were key contributors to the etiology of GWI post deployment to the Persian GW. In the current study, we examined the consequences of acute (10 days) exposure to PB and PER in C57BL6 mice. Learning and memory tests were performed at 18 days and at 5 months post-exposure. We investigated the relationship between the cognitive phenotype and neuropathological changes at short and long-term time points post-exposure. No cognitive deficits were observed at the short-term time point, and only minor neuropathological changes were detected. However, cognitive deficits emerged at the later time point and were associated with increased astrogliosis and reduction of synaptophysin staining in the hippocampi and cerebral cortices of exposed mice, 5 months post exposure. In summary, our findings in this mouse model of GW agent exposure are consistent with some GWI symptom manifestations, including delayed onset of symptoms and CNS disturbances observed in GWI veterans.

Amelioration of experimental autoimmune encephalomyelitis by anatabine.

Anatabine, a naturally occurring alkaloid, is becoming a commonly used human food supplement, taken for its claimed anti-inflammatory properties although this has not yet been reported in human clinical trials. We have previously shown that anatabine does display certain anti-inflammatory properties and readily crosses the blood-brain barrier suggesting it could represent an important compound for mitigating neuro-inflammatory conditions. The present study was designed to determine whether anatabine had beneficial effects on the development of experimental autoimmune encephalomyelitis (EAE) in mice and to precisely determine its underlying mechanism of action in this mouse model of multiple sclerosis (MS). We found that orally administered anatabine markedly suppressed neurological deficits associated with EAE. Analyses of cytokine production in the periphery of the animals revealed that anatabine significantly reduced Th1 and Th17 cytokines known to contribute to the development of EAE. Anatabine appears to significantly suppress STAT3 and p65 NFκB phosphorylation in the spleen and the brain of EAE mice. These two transcription factors regulate a large array of inflammatory genes including cytokines suggesting a mechanism by which anatabine antagonizes pro-inflammatory cytokine production. Additionally, we found that anatabine alleviated the infiltration of macrophages/microglia and astrogliosis and significantly prevented demyelination in the spinal cord of EAE mice. Altogether our data suggest that anatabine may be effective in the treatment of MS and should be piloted in clinical trials.

Plasma microRNA biomarkers for detection of mild cognitive impairment.

Early stages of many neurodegenerative diseases, such as Alzheimer's disease, vascular and frontotemporal dementia, and Parkinson's disease, are frequently associated with Mild Cognitive Impairment (MCI). A minimally invasive screening test for early detection of MCI may be used to select optimal patient groups in clinical trials, to monitor disease progression and response to treatment, and to better plan patient clinical care. Here, we examined the feasibility of using pairs of brain-enriched plasma microRNA (miRNA), at least one of which is enriched in synapses and neurites, as biomarkers that could differentiate patients with MCI from age-matched controls. The identified biomarker pairs fall into two sets: the "miR-132 family" (miR-128/miR-491-5p, miR-132/miR-491-5p and mir-874/miR-491-5p) and the "miR-134 family" (miR-134/miR-370, miR-323-3p/miR-370 and miR-382/miR-370). The area under the Receiver-Operating Characteristic curve for the differentiation of MCI from controls using these biomarker pairs is 0.91-0.95, with sensitivity and specificity at 79%-100% (miR-132 family) and 79%-95% (miR-134 family), and p〈0.001. In a separate longitudinal study, the identified miRNA biomarker pairs successfully detected MCI in majority of patients at asymptomatic stage 1-5 years prior to clinical diagnosis. The reported biomarker pairs also appear useful for detecting age-related brain changes. Further testing in a larger study is necessary for validation of these results.