The occurrence of stress and anxiety disorders has been closely associated with alterations of the amygdala GABAergic system. In these disorders, dysregulation of the serotonergic system, a very important modulator of the amygdala GABAergic system, is also well recognized. The present study, utilizing a learned helplessness stress rat model, was designed to determine whether stress is capable of altering serotonergic modulation of the amygdala GABAergic system. In control rats, administration of 5-HT or a-methyl-5-HT, a 5-HT 2 receptor agonist, to basolateral amygdala (BLA) slices dramatically enhanced frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). This effect was blocked by selective 5-HT 2A receptor antagonists while a selective 5-HT 2B receptor agonist and a selective 5-HT 2C receptor agonist were without effect on sIPSCs. Double immunofluorescence labeling demonstrated that the 5-HT 2A receptor is primarily localized to parvalbumin-containing BLA interneurons. Thus, serotonin primarily acts via 5-HT 2A receptors to facilitate BLA GABAergic inhibition. In stressed rats, the 5-HT 2A receptor-mediated facilitative actions were severely impaired. Quantitative RT-PCR and western blot analysis showed that the impairment of 5-HT 2A receptor signaling primarily resulted from receptor downregulation. The stress-induced effect appeared to be specific to 5-HT 2A receptors because stress had no significant impact on other serotonin receptors, as well as histamine H 3 receptor and a 2 adrenoceptor signaling in the BLA. This severe impairment of 5-HT 2A receptor-mediated facilitation of BLA GABAergic inhibition might result in an amygdala circuitry with hyperexcitability, and a lower threshold of activation, and thus be an important mechanism underlying the emergence of stress-associated psychiatric symptoms.

Objective: To estimate whole-brain microinfarct burden from microinfarct counts in routine postmortem examination.Methods: We developed a simple mathematical method to estimate the total number of cerebral microinfarcts from counts obtained in the small amount of tissue routinely examined in brain autopsies. We derived estimates of total microinfarct burden from autopsy brain specimens from 648 older participants in 2 community-based clinical-pathologic cohort studies of aging and dementia.Results: Our results indicate that observing 1 or 2 microinfarcts in 9 routine neuropathologic specimens implies a maximum-likelihood estimate of 552 or 1,104 microinfarcts throughout the brain. Similar estimates were obtained when validating in larger sampled brain volumes. Conclusions:The substantial whole-brain burden of cerebral microinfarcts suggested by even a few microinfarcts on routine pathologic sampling suggests a potential mechanism by which these lesions could cause neurologic dysfunction in individuals with small-vessel disease. The estimation framework developed here may generalize to clinicopathologic correlations of other imaging-negative micropathologies. Neurology Cerebral microinfarcts are defined as ischemic infarctions, located anywhere in the brain, identifiable by microscopic but not visual inspection.1-3 In practice, these "invisible" lesions are typically less than 1-2 mm in diameter, and therefore smaller than the 3-15 mm diameters characteristic of lacunar infarcts.4,5 As a result, microinfarcts cannot be seen by either conventional structural neuroimaging or gross evaluation of brain slices. They are instead most commonly detected by microscopic examination of routinely selected brain sections, 2,6 or possibly as small acute infarcts on diffusion-weighted imaging (DWI) MRI. 7,8 Despite their small size, microinfarcts appear to be associated with dementia even after controlling for other neuropathologies (including macroscopic infarcts), 2,6 suggesting that microinfarct burden may be an important link between small-vessel disease and cognitive impairment.A crucial step in assessing the mechanism by which microinfarcts impact neurologic function is to determine their total burden in the brain. Microscopic sampling of the entire brain is not feasible, however. As a step toward overcoming this limitation, we present a simple method for estimating the total number of microinfarcts in the brain based on lesion counts obtained from routinely selected autopsy sections. Our findings suggest that the presence of even 1 or 2 microinfarcts in limited samples of brain tissue indicates a likely overall burden of hundreds of these small lesions.METHODS Data for this study were obtained from brain samples of 648 deceased and autopsied participants of the Rush Religious Orders Study and Memory and Aging project, 2 community-based clinical-pathologic cohort studies of aging and dementia (mean age at death 5 88.3 years, SD 5 6.6; 222 men, 426 women).9 Details of recruitment, clinical evaluation, cognitive tes...

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The association between antemortem [ 11 C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with LB (DLB). 76-year-old man presenting with a clinical diagnosis of DLB had undergone PiB-positron emission tomography (PET), 18 F FDG-PET and MRI 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ density and PiB retention in the 17 corresponding ROIs (r=0.899; p<0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques; whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r=0.13; p=0.66); nor between NFT density and PiB retention (r=−0.36; p=0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.

Candida albicans is a common microorganism in the intestine. However, invasive C. albicans infection has emerged as a life-threatening disease in recent years. The mortality rate of invasive candidiasis is high in critically ill hosts. C. albicans can switch from the yeast to the hyphal morphology, and take advantage of the impaired intestinal mucosal barrier and insufficient immunity of the host to facilitate its colonization and penetration. Despite the availability of potent new antifungal drugs in recent years, the treatment of severe candidiasis, especially candidaemia, has not been substantially improved. In this review, the virulence factors of C. albicans, as well as the antagonistic role of the intestinal mucosal barrier will be discussed to illuminate the mechanisms of C. albicans enterogenic infections.

BackgroundThis randomized controlled trial aimed to evaluate whether the serum procalcitonin (PCT) level can be utilized to guide the use of antibiotics in the treatment of acute exacerbations of asthma.MethodsA total of 293 consecutive patients with suspected asthma attacks from February 2005 to July 2010 participated in this study. 225 patients completed the study. Serum PCT levels, and other inflammatory biomarkers of all patients were measured. In addition to the standard treatment, the control group received antibiotics according to the attending physicians’ discretions, while the patients in the PCT group were treated with antibiotics according to serum PCT concentrations. Antibiotics usage was strongly discouraged when the PCT concentration was below 0.1 μg/L; discouraged when the PCT concentration was between 0.1 μg/L and 0.25 μg/L; or encouraged when the PCT concentration was above 0.25 μg/L. The primary endpoint was the determination of antibiotics usage. The second endpoints included the diagnostic accuracy of PCT and other laboratory biomarkers the effectiveness of asthma control, secondary ED visits, hospital re-admissions, repeated needs for steroids or dosage increase, needs for antibiotics, WBC count, PCT levels and FEV1%.ResultsAt baseline, two groups were identical regarding clinical, laboratory and symptom score. Probability of the antibiotics usage in the PCT group (46.1%) was lower than that in the control group (74.8%) (χ2 = 21.97, p < 0.001. RR = 0.561, 95% CI 0.441-0.713). PCT and IL-6 showed good diagnostic significance for bacterial asthma (r = 0.705, p = 0.003). The degrees of asthma control in patients were categorized to three levels and were comparable between the two groups at the six weeks follow-up period (χ2 = 1.62, p = 0.45). There were no significant difference regarding other secondary outcomes (p > 0.05).ConclusionsThe serum PCT concentration can be used to effectively determine whether the acute asthma patients have bacterial infections in the respiratory tract, and to guide the use of antibiotics in the treatment of acute asthma exacerbations, which may substantially reduce unnecessary antibiotic use without compromising the therapeutic outcomes.Trial registrationICTRP ChiCTR-TRC-12002534

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Background:Antimicrobial de-escalation refers to starting the antimicrobial treatment with broad-spectrum antibiotics, followed by narrowing the drug spectrum according to culture results. The present study evaluated the effect of de-escalation on ventilator-associated pneumonia (VAP) in trauma patients.Methods:This retrospective study was conducted on trauma patients with VAP, who received de-escalation therapy (de-escalation group) or non-de-escalation therapy (non-de-escalation group). Propensity score matching method was used to balance the baseline characteristics between both groups. The 28-day mortality, length of hospitalization and Intensive Care Unit stay, and expense of antibiotics and hospitalization between both groups were compared. Multivariable analysis explored the factors that influenced the 28-day mortality and implementation of de-escalation.Results:Among the 156 patients, 62 patients received de-escalation therapy and 94 patients received non-de-escalation therapy. No significant difference was observed in 28-day mortality between both groups (28.6% vs. 23.8%, P = 0.620). The duration of antibiotics treatment in the de-escalation group was shorter than that in the non-de-escalation group (11 [8–13] vs. 14 [8–19] days, P = 0.045). The expenses of antibiotics and hospitalization in de-escalation group were significantly lower than that in the non-de-escalation group (6430 ± 2730 vs. 7618 ± 2568 RMB Yuan, P = 0.043 and 19,173 ± 16,861 vs. 24,184 ± 12,039 RMB Yuan, P = 0.024, respectively). Multivariate analysis showed that high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, high injury severity score, multi-drug resistant (MDR) infection, and inappropriate initial antibiotics were associated with patients' 28-day mortality, while high APACHE II score, MDR infection and inappropriate initial antibiotics were independent factors that prevented the implementation of de-escalation.Conclusions:De-escalation strategy in the treatment of trauma patients with VAP could reduce the duration of antibiotics treatments and expense of hospitalization, without increasing the 28-day mortality and MDR infection.