Endothelial Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference

OBJECTIVES To review, analyze, and synthesize the literature on endothelial dysfunction in critically ill children with multiple organ dysfunction syndrome and to develop a consensus biomarker-based definition and diagnostic criteria. DATA SOURCES Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, using a combination of medical subject heading terms and key words to define concepts of endothelial dysfunction, pediatric critical illness, and outcomes. STUDY SELECTION Studies were included if they evaluated critically ill children with endothelial dysfunction, evaluated performance characteristics of assessment/scoring tools to screen for endothelial dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants (≤36 weeks gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and non-English language studies with the inability to determine eligibility criteria were excluded. DATA EXTRACTION Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment. DATA SYNTHESIS We identified 62 studies involving 84 assessments of endothelial derived biomarkers indirectly linked to endothelial functions including leukocyte recruitment, inflammation, coagulation, and permeability. Nearly all biomarkers studied lacked specificity for vascular segment and organ systems. Quality assessment scores for the collected literature were low. CONCLUSIONS The Endothelial Subgroup concludes that there exists no single or combination of biomarkers to diagnose endothelial dysfunction in pediatric multiple organ dysfunction syndrome. Future research should focus on biomarkers more directly linked to endothelial functions and with specificity for vascular segment and organ systems

PRNP P39L variant is a rare cause of frontotemporal dementia in Iialian population

The missense P39L variant in the prion protein gene (PRNP) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may be an extremely rare cause of FTD (0.13%)

A National Point‐of‐Care Ultrasound Competition for Medical Students

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146850/1/jum14670_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146850/2/jum14670.pd

Perforated carcinoma of the caecum presenting as necrotising fasciitis of the abdominal wall, the key to early diagnosis and management

BACKGROUND: Necrotising Fasciitis is a life threatening soft tissue infection which requires aggressive, early surgical management. CASE PRESENTATION: We present a rare case of a retroperitoneal perforation of a carcinoma of the caecum presenting as a necrotising fasciitis of the anterior abdominal wall. CONCLUSION: This case highlights the importance of early aggressive debridement to healthy tissue limits, the consideration of a rare underlying cause, and the scope for plastic surgical reconstruction in order that aggressive initial surgery can be adequately performed

Using Line Profiles to Test the Fraternity of Type Ia Supernovae at High and Low Redshifts

Using archival data of low-redshift (z < 0.01) Type Ia supernovae (SN Ia) and recent observations of high-redshift (0.16 < z <0.64; Matheson et al. 2005) SN Ia, we study the "uniformity'' of the spectroscopic properties of nearby and distant SN Ia. We find no difference in the measures we describe here. In this paper, we base our analysis solely on line-profile morphology, focusing on measurements of the velocity location of maximum absorption (vabs) and peak emission (vpeak). We find that the evolution of vabs and vpeak for our sample lines (Ca II 3945, Si II 6355, and S II 5454, 5640) is similar for both the low- and high-redshift samples. We find that vabs for the weak S II 5454, 5640 lines, and vpeak for S II 5454, can be used to identify fast-declining [dm15 > 1.7] SN Ia, which are also subluminous. In addition, we give the first direct evidence in two high-z SN Ia spectra of a double-absorption feature in Ca II 3945, an event also observed, though infrequently, in low-redshift SN Ia spectra (6/22 SN Ia in our local sample). We report for the first time the unambiguous and systematic intrinsic blueshift of peak emission of optical P-Cygni line profiles in Type Ia spectra, by as much as 8000 km/s. All the high-z SN Ia analyzed in this paper were discovered and followed up by the ESSENCE collaboration, and are now publicly available.Comment: 28 pages (emulateapj), 15 figures; accepted for publication in A

Quantifying myosin light chain phosphorylation in single adherent cells with automated fluorescence microscopy

<p>Abstract</p> <p>Background</p> <p>In anchorage dependent cells, myosin generated contractile forces affect events closely associated with adhesion such as the formation of stress fibers and focal adhesions, and temporally distal events such as entry of the cell into S-phase. As occurs in many signaling pathways, a phosphorylation reaction (in this case, phosphorylation of myosin light chain) is directly responsible for cell response. Western blotting has been useful in measuring intracellular phosphorylation events, but cells are lysed in the process of sample preparation for western blotting, and spatial information such as morphology, localization of the phosphorylated species, and the distribution of individual cell responses across the population is lost. We report here a reliable automated microscopy method for quantitative measurement of myosin light chain phosphorylation in adherent cells. This method allows us to concurrently examine cell morphology, cell-cell contact, and myosin light chain diphosphorylation in vascular smooth muscle cells.</p> <p>Results</p> <p>Paraformaldehyde fixation and Triton X-100 permeabilization preserved cell morphology and myosin light chain phosphorylation better than the alternative fixation/permeabilization methods tested. We utilized automated microscopy methods to acquire three color images, determine cell spread area, and quantify the intensity of staining within each cell with anti-phospho-MLC antibody. Our results indicate that A10 rat aortic smooth muscle cells exhibit a re producible non-Gaussian distribution of MLC phosphorylation across a population of unsynchronized genetically identical cells. Adding an inhibitor of Rho kinase, Y27632, or plating cells on a low density of fibronectin, reduced phospho-myosin light chain signal as expected. On the other hand, adding calyculin A, an activator of contractility, increased myosin light chain phosphorylation. The IC₅₀for myosin light chain phosphorylation using Y27632 was determined to be 2.1 ± 0.6 micrometers. We observed a positive linear relationship between cell area and myosin light chain diphosphorylation, which is consistent with what has been reported in the literature using other methods.</p> <p>Conclusion</p> <p>Our results show that using proper specimen fixation techniques and background subtraction methods, imaging cytometry can be used to reliably measure relative myosin light chain phosphorylation in individual adherent cells. Importantly, the ability to make this measurement in adherent cells allows for simultaneous measurement of and correlation with other parameters of cellular topography such as morphology and cell-cell proximity. This assay has potential application in screening for drug development.</p

Incidence and Correlates of HIV-1 RNA Detection in the Breast Milk of Women Receiving HAART for the Prevention of HIV-1 Transmission

The incidence and correlates of breast milk HIV-1 RNA detection were determined in intensively sampled women receiving highly active antiretroviral therapy (HAART) for the prevention of mother-to-child HIV-1 transmission.Women initiated HAART at 34 weeks of pregnancy. Breast milk was collected every 2-5 days during 1 month postpartum for measurements of cell-associated HIV DNA and cell-free HIV RNA. Plasma and breast milk were also collected at 2 weeks, 1, 3 and 6 months for concurrent HIV-1 RNA and DNA measurements. Regression was used to identify cofactors for breast milk HIV-1 RNA detection.Of 259 breast milk specimens from 25 women receiving HAART, 34 had detectable HIV-1 RNA (13%, incidence 1.4 episodes/100 person-days 95% CI = 0.97-1.9). Fourteen of 25 (56%) women had detectable breast milk HIV-1 RNA [mean 2.5 log(10) copies/ml (range 2.0-3.9)] at least once. HIV-1 DNA was consistently detected in breast milk cells despite HAART, and increased slowly over time, at a rate of approximately 1 copy/10(6) cells per day (p = 0.02). Baseline CD4, plasma viral load, HAART duration, and frequency of breast problems were similar in women with and without detectable breast milk HIV-1 RNA. Women with detectable breast milk HIV-1 RNA were more likely to be primiparous than women without (36% vs 0%, p = 0.05). Plasma HIV-1 RNA detection (OR = 9.0, 95%CI = 1.8-44) and plasma HIV-1 RNA levels (OR = 12, 95% CI = 2.5-56) were strongly associated with concurrent detection of breast milk HIV-1 RNA. However, no association was found between breast milk HIV-1 DNA level and concurrent breast milk HIV-1 RNA detection (OR = 0.96, 95%CI = 0.54-1.7).The majority of women on HAART had episodic detection of breast milk HIV-1 RNA. Breast milk HIV-1 RNA detection was associated with systemic viral burden rather than breast milk HIV-1 DNA

Predictive rules of efflux inhibition and avoidance in Pseudomonas aeruginosa

Antibiotic-resistant bacteria rapidly spread in clinical and natural environments and challenge our modern lifestyle. A major component of defense against antibiotics in Gram-negative bacteria is a drug permeation barrier created by active efflux across the outer membrane. We identified molecular determinants defining the propensity of small peptidomimetic molecules to avoid and inhibit efflux pumps in Pseudomonas aeruginosa, a human pathogen notorious for its antibiotic resistance.Combining experimental and computational protocols, we mapped the fate of the compounds from structure-activity relationships through their dynamic behavior in solution, permeation across both the inner and outer membranes, and interaction with MexB, the major efflux transporter of P. aeruginosa. We identified predictors of efflux avoidance and inhibition and demonstrated their power by using a library of traditional antibiotics and compound series and by generating new inhibitors of MexB. The identified predictors will enable the discovery and optimization of anti-bacterial agents suitable for treatment of P. aeruginosa infections