OBJECTIVES::
Measurements of extravascular lung water (EVLW) correlate to the degree of pulmonary edema and have substantial prognostic information in critically ill patients. Prior studies using single indicator thermodilution have reported that 21% to 35% of patients with clinical acute respiratory distress syndrome (ARDS) have normal EVLW (<10 mL/kg). Given that lung size is independent of actual body weight, we sought to determine whether indexing EVLW to predicted or adjusted body weight affects the frequency of increased EVLW in patients with ARDS. DESIGN:: Prospective, observational cohort study. SETTING:: Medical and surgical intensive care units at two academic hospitals. PATIENTS:: Thirty patients within 72 hrs of meeting American-European Consensus Conference definition of ARDS and 14 severe sepsis patients without ARDS. INTERVENTIONS:: None. MEASUREMENT AND MAIN RESULTS:: EVLW was measured for 7 days by PiCCO transpulmonary thermodilution; 225 measurements of EVLW indexed to actual body weight (ActBW) were compared with EVLW indexed to predicted body weight (PBW) and adjusted body weight (AdjBW). Mean EVLW indexed to ActBW was 12.7 mg/kg for ARDS patients and 7.8 mg/kg for non-ARDS sepsis patients (p < .0001). In all patients, EVLW increased an average of 1.1 ± 2.1 mL/kg when indexed to AdjBW and 2.0 ± 4.1 mL/kg when indexed to PBW. Indexing EVLW to PBW or AdjBW increased the proportion of ARDS patients with elevated EVLW (each p < .05) without increasing the frequency of elevated EVLW in non-ARDS patients. EVLW indexed to PBW had a stronger correlation to Lung Injury Score (r = .39 vs. r = .17) and Pao2/Fio2 ratio (r = .25 vs. r = .10) than did EVLW indexed to ActBW. CONCLUSIONS:: Indexing EVLW to PBW or AdjBW reduces the number of ARDS patients with normal EVLW and correlates better to Lung Injury Score and oxygenation than using ActBW. Studies are needed to confirm the presumed superiority of this method for diagnosing ARDS and to determine the clinical treatment implications.
Endometriosis is a nonmalignant, but potentially metastatic, gynecological condition manifested by the extrauterine growth of inflammatory endometrial implants. Ten percent of reproductive-age women are affected and commonly suffer pelvic pain and/or infertility. The theories of endometriosis histogenesis remain controversial, but retrograde menstruation and metaplasia each infer mechanisms that explain the immune cell responses observed around the ectopic lesions. Recent findings from our laboratories and others suggest that retinoic acid metabolism and action are fundamentally flawed in endometriotic tissues and even generically in women with endometriosis. The focus of our ongoing research is to develop medical therapies as adjuvants or alternatives to the surgical excision of these lesions. On the basis of concepts put forward in this review, we predict that the pharmacological actions and anticipated low side-effect profiles of retinoid supplementation might provide a new treatment option for the long-term management of this chronic and debilitating gynecological disease.
The repeated failures of amyloid-targeting therapies have challenged our narrow understanding of Alzheimer’s disease (AD) pathogenesis and inspired wide-ranging investigations into the underlying mechanisms of disease. Increasing evidence indicates that AD develops from an intricate web of biochemical and cellular processes that extend far beyond amyloid and tau accumulation. This growing recognition surrounding the diversity of AD pathophysiology underscores the need for holistic systems-based approaches to explore AD pathogenesis. Here we describe how network-based proteomics has emerged as a powerful tool and how its application to the AD brain has provided an informative framework for the complex protein pathophysiology underlying the disease. Furthermore, we outline how the AD brain network proteome can be leveraged to advance additional scientific and translational efforts, including the discovery of novel protein biomarkers of disease.
Neurofilament light (NFL) proteins in cerebrospinal fluid (CSF) are a marker of neuronal damage, especially subcortical axonal injury and white matter disease. Subjects with Alzheimer's disease (AD) have shown elevated levels of CSF NFL as compared to controls. However, the presence of the APOE ε4 allele, an established risk factor for AD, was not found to associate with higher CSF NFL concentrations. We examined whether TOMM40 variants, which have been reported to influence age of onset of AD and are in linkage disequilibrium with APOE, have an effect on CSF NFL levels, in 47 healthy, cognitively intact individuals with or without APOE ε4. Our results show that the presence of APOE ε4 alone does not affect CSF NFL levels significantly; however APOE and TOMM40 appear to interact. Subjects with APOE ε4 have higher CSF NFL levels than non-ε4 carriers, only when they do not carry a short poly-T variant of TOMM40, which is associated with later age of onset of AD, and may act as protective against the dose effect of ε4.
Extracorporeal membrane oxygenation (ECMO) is a lifesaving procedure used in neonates, children, and adults with severe, reversible, cardiopulmonary failure.On the basis of single-center studies, the incidence of AKI occurs in 70%-85% of ECMO patients. Those with AKI and those who require renal replacement therapy (RRT) are at high risk for mortality, independent of potentially confounding variables. Fluid overload is common in ECMO patients, and is one of the main indications for RRT. RRT to maintain fluid balance and metabolic control is common in some but not all centers. RRT on ECMO can be performed via an in-line hemofilter or by incorporating a standard continuous renal replacement machine into the ECMO circuit. Both of these methods require specific technical considerations to provide safe and effective RRT. This reviewsummarizes available epidemiologic data and how they apply to our understanding of AKI pathophysiology during ECMO, identifies indications for RRT while on ECMO, reviews technical elements for RRT application in the setting of ECMO, and finally identifies specific researchfocused questions that need to be addressed to improve outcomes in this at-risk population.
Norovirus infection is the most common cause of acute gastroenteritis in developed countries. Developing an assay based on a non-invasive biomarker for detecting incident norovirus infections could improve disease surveillance and epidemiological investigations. This project involved analysis of IgA and IgG norovirus-specific antibody responses in saliva samples from a Norwalk virus (Genogroup I, genotype 1 norovirus) challenge study involving infected and symptomatic, and non-infected asymptomatic individuals. Saliva was collected at the challenge, and two weeks and 40. days post-challenge. Samples were analyzed using the Luminex fluorometric and Meso Scale Discovery (MSD) electrochemiluminescence immunoassays. Recombinant P domains of Norwalk virus capsid protein, as well as similar recombinant proteins of two genogroup II noroviruses (VA387 and VA207) were used as antigens. Immunoconversions were defined as >. 4-fold increase in antibody responses to the norovirus antigens. Various sample pre-treatment options, buffers, saliva dilution ratios, and data adjustment approaches to control for sample-to-sample variability in saliva composition were compared using the Luminex assay. The results suggest that adjusting responses to the norovirus antigens for responses to the protein purification tag, glutathione-S-transferase (GST), significantly improved the odds of producing a correct immunoconversion test result. IgG-based tests were more accurate compared to IgA-based tests. At optimal conditions, both Luminex and MSD assays for Norwalk-specific IgG antibodies correctly identified all infected and non-infected individuals. There was no evidence of cross-reactivity of anti-Norwalk virus antibodies with genogroup II noroviruses. These results suggest that salivary antibody responses can be used for the detection of incident infections with Norwalk virus in prospective surveys.
We examined the relationship between CSF immune cells and neurocognition and neuronal damage in HIV+ individuals before and after initiating antiretroviral therapy. Multivariate analysis at baseline indicated that greater CD4+ T cell abundance was associated with better cognition (p =.017), while higher CSF HIV RNA was associated with increased neuronal damage (p =.014). Following 24 weeks of antiretroviral therapy, CD8+ T cells, HLA-DR expressing CD4+ and CD8+ T cells, B cells, NK cells, and non-classical monocyte percentage decreased in CSF. Female gender was negatively associated with cognitive performance over time, as was higher percentage of HLA-DR expressing CD8+ T cells at baseline.
Background: A clinical study comparing the hemodynamic outcomes of transcatheter mitral valve replacement (TMVR) with vs. without Laceration of the Anterior Mitral leaflet to Prevent Outflow Obstruction (LAMPOON) has never been designed nor conducted. Aims: To quantify the hemodynamic impact of LAMPOON in TMVR using patient-specific computational (in silico) models. Materials: Eight subjects from the LAMPOON investigational device exemption trial were included who had acceptable computed tomography (CT) data for analysis. All subjects were anticipated to be at prohibitive risk of left ventricular outflow tract (LVOT) obstruction from TMVR, and underwent successful LAMPOON immediately followed by TMVR. Using post-procedure CT scans, two 3D anatomical models were created for each subject: (1) TMVR with LAMPOON (performed procedure), and (2) TMVR without LAMPOON (virtual control). A validated computational fluid dynamics (CFD) paradigm was then used to simulate the hemodynamic outcomes for each condition. Results: LAMPOON exposed on average 2 ± 0.6 transcatheter valve cells (70 ± 20 mm2 total increase in outflow area) which provided an additional pathway for flow into the LVOT. As compared to TMVR without LAMPOON, TMVR with LAMPOON resulted in lower peak LVOT velocity, lower peak LVOT gradient, and higher peak LVOT effective orifice area by 0.4 ± 0.3 m/s (14 ± 7% improvement, p = 0.006), 7.6 ± 10.9 mmHg (31 ± 17% improvement, p = 0.01), and 0.2 ± 0.1 cm2 (17 ± 9% improvement, p = 0.002), respectively. Conclusion: This was the first study to permit a quantitative, patient-specific comparison of LVOT hemodynamics following TMVR with and without LAMPOON. The LAMPOON procedure achieved a critical increment in outflow area which was effective for improving LVOT hemodynamics, particularly for subjects with a small neo-left ventricular outflow tract (neo-LVOT).
Secretion of melatonin, a natural hormone whose receptors are present in the ciliary epithelium, displays diurnal variation in the aqueous humor (AH), potentially contributing to the regulation of intraocular pressure. This study aimed to determine the effects of melatonin on AH secretion in porcine ciliary epithelium. The addition of 100 µM melatonin to both sides of the epithelium significantly increased the short-circuit current (Isc) by ~40%. Stromal administration alone had no effect on the Isc, but aqueous application triggered a 40% increase in Isc, similar to that of bilateral application without additive effect. Pre-treatment with niflumic acid abolished melatonin-induced Isc stimulation. More importantly, melatonin stimulated the fluid secretion across the intact ciliary epithelium by ~80% and elicited a sustained increase (~50–60%) in gap junctional permeability between pigmented ciliary epithelial (PE) cells and non-pigmented ciliary epithelial (NPE) cells. The expression of MT3 receptor was found to be >10-fold higher than that of MT1 and MT2 in porcine ciliary epithelium. Aqueous pre-treatment with MT1/MT2 antagonist luzindole failed to inhibit the melatonin-induced Isc response, while MT3 antagonist prazosin pre-treatment abolished the Isc stimulation. We conclude that melatonin facilitates Cl− and fluid movement from PE to NPE cells, thereby stimulating AH secretion via NPE-cell MT3 receptors.