Struck By Lightning Twice

INTRODUCTION: ANCA-associated vasculitides (AAV) refer to a group of disorders causing inflammation of small vessels which include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). Here I present a case of MPA vasculitis in a patient with alpha-1-antitrypsin (AAT) deficiency, and describe a proposed causal link between these two rare disease processes. CASE REPORT: • 43-year-old man with history of newly-diagnosed AAT deficiency liver disease. • Chief complaint of subacute shortness of breath associated with hemoptysis and fever for 5 months. • Symptoms had been progressively worsening despite multiple courses of antibiotics and inhalers. • Pulmonary CT angiogram (CTPA) was negative for pulmonary embolism but showed “multifocal pulmonary infiltrates for whichpneumonia andseptic emboli could not be excluded”. • Infectious workup negative. • Positive myeloperoxidase (MPO) antibodies and findings on thoracoscopic lung biopsy most consistent with MPA. • Managed with steroids and rituximab. DISCUSSION: • AAT is an acute-phase protein that inhibits the serine proteases of inflammatory cells, including proteinase 3 (PR3), to protect tissues from damage. •Mutations in the AAT-encoding gene SERPINA1 result in a structural change in AAT that inhibits its release into the bloodstream, leading to higher levels of proteases in the blood that can then cause excessive tissue damage. •Because increased levels of PR3 is a major component in the pathogenesis of ANCA vasculitis, a causal link between AAT deficiency and ANCA vasculitis has been proposed. There are many case reports describing this association, but the level of detail is variable based on the tests available at the time of the report. •Even though ANCA vasculitis is relatively rare, it is worth considering and pushed closer to the top of the differential list when a concurrent history of AAT deficiency is present.https://digitalcommons.psjhealth.org/psv_internal/1009/thumbnail.jp

The influence of culture and self-esteem on social media use

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Neuroinflammation mediates noise-induced synaptic imbalance and tinnitus in rodent models

Hearing loss is a major risk factor for tinnitus, hyperacusis, and central auditory processing disorder. Although recent studies indicate that hearing loss causes neuroinflammation in the auditory pathway, the mechanisms underlying hearing loss-related pathologies are still poorly understood. We examined neuroinflammation in the auditory cortex following noise-induced hearing loss (NIHL) and its role in tinnitus in rodent models. Our results indicate that NIHL is associated with elevated expression of proinflammatory cytokines and microglial activation-two defining features of neuroinflammatory responses-in the primary auditory cortex (AI). Genetic knockout of tumor necrosis factor alpha (TNF-alpha) or pharmacologically blocking TNF-alpha expression prevented neuroinflammation and ameliorated the behavioral phenotype associated with tinnitus in mice with NIHL. Conversely, infusion of TNF-alpha into AI resulted in behavioral signs of tinnitus in both wild-type and TNF-alpha knockout mice with normal hearing. Pharmacological depletion of microglia also prevented tinnitus in mice with NIHL. At the synaptic level, the frequency of miniature excitatory synaptic currents (mEPSCs) increased and that of miniature inhibitory synaptic currents (mIPSCs) decreased in AI pyramidal neurons in animals with NIHL. This excitatory-to-inhibitory synaptic imbalance was completely prevented by pharmacological blockade of TNF-alpha expression. These results implicate neuroinflammation as a therapeutic target for treating tinnitus and other hearing loss-related disorders.National Institute of Health [DC009259, DC014335]; Department of Defense [W81XWH-15-1-0028, W81XWH-15-1-0356, W81XWH-15-1-0357]; Food and Health Bureau of Hong Kong Special Administrative Region Government [04150076]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Treating triple negative breast cancer cells with erlotinib plus a select antioxidant overcomes drug resistance by targeting cancer cell heterogeneity

Among breast cancer patients, those diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst prog-nosis. TNBC does not express estrogen receptor-alpha, progesterone receptor, or the HER2 oncogene; therefore, TNBC lacks targets for molecularly-guided therapies. The concept that EGFR oncogene inhibitor drugs could be used as targeted treatment against TNBC has been put forth based on estimates that 30-60% of TNBC express high levels of EGFR. However, results from clinical trials testing EGFR inhibitors, alone or in combination with cytotoxic chemotherapy, did not improve patient outcomes. Results herein offer an explanation as to why EGFR inhibitors failed TNBC patients and support how combining a select antioxidant and an EGFR-specific small molecule kinase inhibitor (SMKI) could be an effective, novel therapeutic strategy. Treatment with CAT-SKL-a re-engineered protein form of the antioxidant enzyme catalase-inhibited cancer stem-like cells (CSCs), and treatment with the EGFR-specific SMKI erlotinib inhibited non-CSCs. Thus, combining the antioxidant CAT-SKL with erlotinib targeted both CSCs and bulk cancer cells in cultures of EGFR-expressing TNBC-derived cells. We also report evidence that the mechanism for CAT-SKL inhibition of CSCs may depend on antioxidant-induced downregulation of a short alternative mRNA splicing variant of the methyl-CpG binding domain 2 gene, isoform MBD2c

Continental carbonate facies of a Neoproterozoic panglaciation, north-east Svalbard

The Marinoan panglaciation (ca 650 to 635 Ma) is represented in north-east Svalbard by the 130 to 175 m thick Wilsonbreen Formation which contains syn-glacial carbonates in its upper 100 m. These sediments are now known to have been deposited under a CO2-rich atmosphere, late in the glaciation, and global climate models facilitate testing of proposed analogues. Precipitated carbonates occur in four of the seven facies associations identified: Fluvial Channel (including stromatolitic and intraclastic limestones in ephemeral stream deposits); Dolomitic Floodplain (dolomite-cemented sand and siltstones, and microbial dolomites); Calcareous Lake Margin (intraclastic dolomite and wave-rippled or aeolian siliciclastic facies); and Calcareous Lake (slump-folded and locally re-sedimented rhythmic/stromatolitic limestones and dolomites associated with ice-rafted sediment). There is no strong cyclicity, and modern analogues suggest that sudden changes in lake level may exert a strong control on facies geometry. Both calcite and dolomite in stromatolites and rhythmites display either primary or early diagenetic replacive growth. Oxygen isotope values (−12 to +15‰VPDB) broadly covary with δ13C. High δ13C values of +3·5 to +4·5‰ correspond to equilibration with an atmosphere dominated by volcanically degassed CO2 with δ13C of −6 to −7‰. Limestones have consistently negative δ18O values, while rhythmic and playa dolomites preserve intermediate compositions, and dolocretes possess slightly negative to strongly positive δ18O signatures, reflecting significant evaporation under hyperarid conditions. Inferred meltwater compositions (−8 to −15·5‰) could reflect smaller Rayleigh fractionation related to more limited cooling than in modern polar regions. A common pseudomorph morphology is interpreted as a replacement of ikaite (CaCO3·H2O), which may also have been the precursor for widespread replacive calcite mosaics. Local dolomitization of lacustrine facies is interpreted to reflect microenvironments with fluctuating redox conditions. Although differing in (palaeo)latitude and carbonate abundance, the Wilsonbreen carbonates provide strong parallels with the McMurdo Dry Valleys of Antarctica

A cross scale investigation of galena oxidation and controls on mobilization of lead in mine waste rock.

Abstract Galena and Pb-bearing secondary phases are the main sources of Pb in the terrestrial environment. Oxidative dissolution of galena releases aqueous Pb and SO4 to the surficial environment and commonly causes the formation of anglesite (in acidic environments) or cerussite (in alkaline environments). However, conditions prevalent in weathering environments are diverse and different reaction mechanisms reflect this variability at various scales. Here we applied complementary techniques across a range of scales, from nanometers to 10 s of meters, to study the oxidation of galena and accumulation of secondary phases that influence the release and mobilization of Pb within a sulfide-bearing waste-rock pile. Within the neutral-pH pore-water environment, the oxidation of galena releases Pb ions resulting in the formation of secondary Pb-bearing carbonate precipitates. Cerussite is the dominant phase and shannonite is a possible minor phase. Dissolved Cu from the pore water reacts at the surface of galena, forming covellite at the interface. Nanometer scale characterization suggests that secondary covellite is intergrown with secondary Pb-bearing carbonates at the interface. A small amount of the S derived from galena is sequestered with the secondary covellite, but the majority of the S is oxidized to sulfate and released to the pore water

Orbitally forced ice sheet fluctuations during the Marinoan Snowball Earth glaciation

Two global glaciations occurred during the Neoproterozoic. Snowball Earth theory posits that these were terminated after millions of years of frigidity when initial warming from rising atmospheric CO2 concentrations was amplified by the reduction of ice cover and hence a reduction in planetary albedo. This scenario implies that most of the geological record of ice cover was deposited in a brief period of melt-back. However, deposits in low palaeo-latitudes show evidence of glacial–interglacial cycles. Here we analyse the sedimentology and oxygen and sulphur isotopic signatures of Marinoan Snowball glaciation deposits from Svalbard, in the Norwegian High Arctic. The deposits preserve a record of oscillations in glacier extent and hydrologic conditions under uniformly high atmospheric CO2 concentrations. We use simulations from a coupled three-dimensional ice sheet and atmospheric general circulation model to show that such oscillations can be explained by orbital forcing in the late stages of a Snowball glaciation. The simulations suggest that while atmospheric CO2 concentrations were rising, but not yet at the threshold required for complete melt-back, the ice sheets would have been sensitive to orbital forcing. We conclude that a similar dynamic can potentially explain the complex successions observed at other localities

Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium

Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (< 2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data