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Doria JW, Forgacs PB
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Incidence, Implications, and Management of Seizures Following Ischemic and Hemorrhagic Stroke

Purpose of ReviewIn this review, we summarize the recent literature regarding the incidence and treatment of seizures arising after ischemic and hemorrhagic strokes. Additionally, we identify open questions in guidelines and standard clinical care to aid future studies aiming to improve management of seizures in post-stroke patients.Recent FindingsStudies demonstrate an increasing prevalence of seizures following strokes, probably a consequence of advances in post-stroke management and expanding use of continuous EEG monitoring. Post-stroke seizures are associated with longer hospitalization and increased mortality; therefore, prevention and timely treatment of seizures are important. The standard of care is to treat recurrent seizures with anti-epileptic drugs (AEDs) regardless of the etiology. However, there are no established guidelines currently for prophylactic use of AEDs following a stroke.SummaryThe prevalence of post-stroke seizures is increasing. Further studies are needed to determine the risk factors for recurrent seizures and epilepsy after strokes and optimal treatment strategies.
Estrogens receptors (ER) are involved in several sociosexual behaviors and fear responses. In particular, the ER alpha is important for sexual behaviors, whereas ER beta modulates anxiolytic responses. Using shRNA directed either against the ER alpha or the ER beta RNAs (or containing luciferase control) encoded within an adeno-associated viral vector, we silenced these receptors in the ventromedial nucleus of the hypothalamus (VMN) and the central amygdala (CeA). We exposed ovariectomized female rats, sequentially treated with estradiol benzoate and progesterone, to five stimuli, previously reported to elicit positive and negative affect. The subjects were housed in groups of 4 females and 3 males in a seminatural environment for several days before hormone treatment. We analyzed the frequency of a large number of behavior patterns. In addition, we performed analyses of co-occurrence in order to detect changes in the structure of behavior after infusion of the vectors. Silencing the ER alpha in the VMN disrupted lordosis and showed some anxiolytic properties in aversive situations, whereas silencing of the ER beta in this structure had no effect. This was also the case after silencing the ER alpha in the CeA. Silencing of the ER beta in this structure increased risk assessment, an expression of anxiety, and increased olfactory exploration of the environment. We hypothesize that the ER beta in the CeA has an important role in the well-established anxiolytic effects of estrogens, and that it may modulate arousal level. Furthermore, it seems that the ER alpha in the VMN is anxiogenic in aversive or threatening situations, in agreement with other studies.
Farfara D, Feierman E, Richards A, Revenko AS, MacLeod RA, Norris EH, Strickland S
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Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

GLIA 2019 JUL; 67(7):1359-1373
The cross-talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein-kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood-brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild-type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long-term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro-inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive-like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.
Castner J, Mammen MJ, Jungquist CR, Licata O, Pender JJ, Wilding GE, Sethi S
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Validation of fitness tracker for sleep measures in women with asthma

JOURNAL OF ASTHMA 2019 JUL 3; 56(7):719-730
Objective: Nighttime wakening with asthma symptoms is a key to assessment and therapy decisions, with no gold standard objective measure. The study aims were to (1) determine the feasibility, (2) explore equivalence, and (3) test concordance of a consumer-based accelerometer with standard actigraphy for measurement of sleep patterns in women with asthma as an adjunct to self-report. Methods: Panel study design of women with poorly controlled asthma from a university-affiliated primary care clinic system was used. We assessed sensitivity and specificity, equivalence and concordance of sleep time, sleep efficiency, and wake counts between the consumer-based accelerometer Fitbit Charge (TM) and Actigraph wGT3X+. We linked data between devices for comparison both automatically by 24-hour period and manually by sleep segment. Results: Analysis included 424 938 minutes, 738 nights, and 833 unique sleep segments from 47 women. The fitness tracker demonstrated 97% sensitivity and 40% specificity to identify sleep. Between device equivalence for total sleep time (15 and 42-minute threshold) was demonstrated by sleep segment. Concordance improved for wake counts and sleep efficiency when adjusting for a linear trend. Conclusions: There were important differences in total sleep time, efficiency, and wake count measures when comparing individual sleep segments versus 24-hour measures of sleep. Fitbit overestimates sleep efficiency and underestimates wake counts in this population compared to actigraphy. Low levels of systematic bias indicate the potential for raw measurements from the devices to achieve equivalence and concordance with additional processing, algorithm modification, and modeling. Fitness trackers offer an accessible and inexpensive method to quantify sleep patterns in the home environment as an adjunct to subjective reports, and require further informatics development.
Varble A, Marraffini LA
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Three New Cs for CRISPR: Collateral, Communicate, Cooperate

TRENDS IN GENETICS 2019 JUN; 35(6):446-456
Clustered regularly interspaced short palindromic repeats (CRISPR) loci and their associated (cas) genes provide protection against invading phages and plasmids in prokaryotes. Typically, short sequences are captured from the genome of the invader, integrated into the CRISPR locus, and transcribed into short RNAs that direct RNA-guided Cas nucleases to the nucleic acids of the invader for their degradation. Recent work in the field has revealed unexpected features of the CRISPR-Cas mechanism: (i) collateral, nonspecific, cleavage of host nucleic acids; (ii) secondary messengers that amplify the immune response; and (iii) immunosuppression of CRISPR targeting by phage-encoded inhibitors. Here, we review these new and exciting findings.
Varble A, Meaden S, Barrangou R, Westra ER, Marraffini LA
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Recombination between phages and CRISPR-cas loci facilitates horizontal gene transfer in staphylococci

NATURE MICROBIOLOGY 2019 JUN; 4(6):956-963
CRISPR (clustered regularly interspaced short palindromic repeats) loci and their associated (cas) genes encode an adaptive immune system that protects prokaryotes from viral(1) and plasmid(2) invaders. Following viral (phage) infection, a small fraction of the prokaryotic cells are able to integrate a small sequence of the invader's genome into the CRISPR array(1). These sequences, known as spacers, are transcribed and processed into small CRISPR RNA guides(3-5) that associate with Cas nucleases to specify a viral target for destruction(6-9). Although CRISPR-cas loci are widely distributed throughout microbial genomes and often display hallmarks of horizontal gene transfer(10)(-12), the drivers of CRISPR dissemination remain unclear. Here, we show that spacers can recombine with phage target sequences to mediate a form of specialized transduction of CRISPR elements. Phage targets in phage 85, Phi NM1, Phi NM4 and Phi 12 can recombine with spacers in either chromosomal or plasmid-borne CRISPR loci in Staphylococcus, leading to either the transfer of CRISPR-adjacent genes or the propagation of acquired immunity to other bacteria in the population, respectively. Our data demonstrate that spacer sequences not only specify the targets of Cas nucleases but also can promote horizontal gene transfer.
Frew JW
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Hidradenitis suppurativa and diabetes: big data bias masks a true association

Galea S, Vaughan R
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Socioeconomic Status, Principles, and Pragmatism: A Public Health of Consequence, June 2019

Hart EM, O'Connell A, Tang K, Wzorek JS, Grabowicz M, Kahne D, Silhavy TJ
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Fine-Tuning of sigma(E) Activation Suppresses Multiple Assembly-Defective Mutations in Escherichia coli

JOURNAL OF BACTERIOLOGY 2019 JUN; 201(11):? Article e00745
The Gram-negative outer membrane (OM) is a selectively permeable asymmetric bilayer that allows vital nutrients to diffuse into the cell but prevents toxins and hydrophobic molecules from entering. Functionally and structurally diverse a-barrel outer membrane proteins (OMPs) build and maintain the permeability barrier, making the assembly of OMPs crucial for cell viability. In this work, we characterize an assembly-defective mutant of the maltoporin LamB, LamB(G439D). We show that the folding defect of LaMBG439D results in an accumulation of unfolded substrate that is toxic to the cell when the periplasmic protease DegP is removed. Selection for suppressors of this toxicity identified the novel mutant degS(A323t) allele. The mutant DegS(A323E) protein contains an amino acid substitution at the PDZ/protease domain interface that results in a partially activated conformation of this protein. This activation increases basal levels of downstream sigma(E) stress response signaling. Furthermore, the enhanced sigma(E) activity of DegS(A323E) suppresses a number of other assembly-defective conditions without exhibiting the toxicity associated with high levels of sigma(E) activity. We propose that the increased basal levels of sigma(E) signaling primes the cell to respond to envelope stress before OMP assembly defects threaten cell viability. This finding addresses the importance of envelope stress responses in monitoring the OMP assembly process and underpins the critical balance between envelope defects and stress response activation. IMPORTANCE Gram negative bacteria, such as Escherichia coli, inhabit a natural environment that is prone to flux. In order to cope with shifting growth conditions and the changing availability of nutrients, cells must be capable of quickly responding to stress. Stress response pathways allow cells to rapidly shift gene expression profiles to ensure survival in this unpredictable environment. Here we describe a mutant that partially activates the sigma(E) stress response pathway. The elevated basal level of this stress response allows the cell to quickly respond to overwhelming stress to ensure cell survival.
Xu M, Kolding J, Cohen JE
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Sequential analysis and design of fixed-precision sampling of Lake Kariba fishes using Taylor's power law

Taylor's power law (TPL), which states that the variance of abundance is a power function of mean abundance, has been used to design sampling of agricultural pests and fish species. We show that TPL holds for means and variances of abundance of accumulated fish samples in the fished and unfished areas separately of Lake Kariba (between Zambia and Zimbabwe), measuring abundance indices by number and weight separately. We use TPL parameters estimated from sequentially accumulated samples to update a stopping line of fixed precision 0.1 after each new sample from a sampling day. In these Lake Kariba data, depending on the sampling area and abundance measure, our updated stopping-line method requires 21% to 41% of the number of sampling days and 19% to 40% of the number of samples that are planned a priori and performed under systematic sampling. Our novel method yields mean abundance estimates similar to those from systematic sampling and provides a conservative approach to reaching a fixed sampling precision level with reduced sampling labor and time. Using mixed-effect modeling for cumulative means and variances with either number or weight from both fished and unfished areas, we find that fishing increases the slope of TPL. This study provides the conceptual framework and an empirical case study for implementing a sequential sampling method for fish assemblages of an inland lake. The possible limitations and applications of our method for sampling in other environments are discussed.