Publications by authors named "David Prince"

99 Publications

A relative study on energy and exergy analysis between conventional single slope and novel stepped absorbable plate solar stills.

Environ Sci Pollut Res Int 2021 Jun 5. Epub 2021 Jun 5.

Ingenium Research Group, Universidad Castilla-La Mancha, Ciudad Real, Spain.

The innovation of novel absorbing materials using composite materials and nanotechnology is of new trends for many researches. Here, the present study is concerning to enhance the distilled water productivity of a proposed solar still (PSS) using novel absorbing materials. The absorbing material is composed of chitosan (obtained from waste shrimp shells), ethylene diamine tetraacetic acid (EDTA), and Chrysopogon zizaniodes (Vetiver). The combination of these materials is coined as CHEDZ, and it acts as a super absorbent polymer that is coated on the stepped solar still. Evaporation rate increases due to this absorbent, which further increases the yield of the still. In this present study, the PSS is compared with the conventional solar still (CSS) for the use of assessing the yield of freshwater in the same atmospheric circumstance. The experimental setup was performed through the period from December to February 2020 in the Indian climatic condition. The freshwater productivity was improved to 3.05 L/day while the yield of the CSS is 2.47 L/day. The increase in efficiency obtained from a PSS is 39.71% more than the productivity attained from the CSS. The energy efficiency of the PSS is 18.34% and the exergy efficiency is 0.45%.
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http://dx.doi.org/10.1007/s11356-021-14640-9DOI Listing
June 2021

COVID-19 pandemic and its impact on dental students: A multi-institutional survey.

J Dent Educ 2021 Mar 27. Epub 2021 Mar 27.

Universidade de São Paulo, Brazil.

Purpose/objectives: To investigate dental students' perceptions and concerns regarding the COVID-19 pandemic, their coping strategies and support resources, and their perceived stress levels.

Methods: A customized 19-item survey and the perceived stress scale (PSS) were applied to undergraduate dental students from the US, Spain, Ireland, Chile, India, and Brazil between April 10 and July 5, 2020. Linear modeling and mediation analysis were used to explore the relationships among demographics, stressors, coping mechanisms, social support, and stress RESULTS: A total of 4475 students responded to the survey. The majority (72.4%) were women, and 52.3% had no COVID-19 training at the time of the survey. The students reported that they had to accommodate to changes in patient care (96.6%) and didactic learning (95.2%) activities, while 88.5% of the respondents indicated at least one of their courses moved online. Transition to online courses went "smoothly with some troubles" for 51.8% of the respondents, and 48.3% perceived the faculty as prepared for the online transition; however, 45.9% reported feeling extremely concerned about the impact of COVID-19 on their education. The average PSS score was 21.9 of 40 (moderate stress). Multivariate models were built for participants with full data (n = 3899). Being male, having completed more dental coursework, and perceiving a smoother transition were associated with lower PSS scores; more concern about academic progress was associated with higher PSS. Faculty support mediated the relationship between a smoothness of transition and concern about academic progress and PSS scores CONCLUSION: Stress caused by the pandemic may be alleviated by smoother transition and good faculty support.
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http://dx.doi.org/10.1002/jdd.12597DOI Listing
March 2021

The accuracy of laser fluorescence (DIAGNOdent) in assessing caries lesion activity on root surfaces, around crown margins, and in furcations in older adults.

BDJ Open 2021 Mar 23;7(1):14. Epub 2021 Mar 23.

Roseman University of Health Sciences, College of Dental Medicine, South Jordan, UT, USA.

The authors conducted a case series to assess accuracy of DIAGNOdent (DD) in assessment of activity of dental caries lesions in root surfaces and in furcations and at crown margins. The study was a prospective, single center case series. The patients were 123 adults (age ≥ 55 years). To be included, a patient needed to have at least one active root caries lesion. The study was conducted at the Roseman College of Dental Medicine in South Jordan, Utah, USA and at area nursing homes. Lesions were rinsed and dried with air, and DD readings were obtained. Lesions were then isolated and 38% silver diamine fluoride was applied repeatedly for two minutes with a microbrush. DD readings and treatments were repeated every six months. Mean DD values were significantly different between active (unarrested) and inactive (arrested) caries for all comparisons, p-value < 0.0001. The optimal cut-off values for DD were between 20 and 35 except optimal cut-offs were higher for furcation and crown margin surfaces, particularly in the posterior (optimal cut-offs 40-45). This study demonstrates DD is a potentially valuable tool for assessing lesion activity in root surfaces, at restoration margins, and in furcations.
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http://dx.doi.org/10.1038/s41405-021-00069-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988107PMC
March 2021

BP in Young Adults with CKD and Associations with Cardiovascular Events and Decline in Kidney Function.

J Am Soc Nephrol 2021 May 10;32(5):1200-1209. Epub 2021 Mar 10.

Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, Washington.

Background: BP is an important modifiable risk factor for cardiovascular events and CKD progression in middle-aged or older adults with CKD. However, studies describing the relationship between BP with outcomes in young adults with CKD are limited.

Methods: In an observational study, we focused on 317 young adults (aged 21-40 years) with mild to moderate CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Exposures included baseline systolic BP evaluated continuously (per 10 mm Hg increase) and in categories (<120, 120-129, and ≥130 mm Hg). Primary outcomes included cardiovascular events (heart failure, myocardial infarction, stroke, or all-cause death) and CKD progression (50% decline of eGFR or ESKD). We used Cox proportional hazard models to test associations between baseline systolic BP with cardiovascular events and CKD progression.

Results: Cardiovascular events occurred in 52 participants and 161 had CKD progression during median follow-up times of 11.3 years and 4.1 years, respectively. Among those with baseline systolic BP ≥130 mm Hg, 3%/yr developed heart failure, 20%/yr had CKD progression, and 2%/yr died. In fully adjusted models, baseline systolic BP ≥130 mm Hg (versus systolic BP<120 mm Hg) was significantly associated with cardiovascular events or death (hazard ratio [HR], 2.13; 95% confidence interval [95% CI], 1.05 to 4.32) and CKD progression (HR, 1.68; 95% CI, 1.10 to 2.58).

Conclusions: Among young adults with CKD, higher systolic BP is significantly associated with a greater risk of cardiovascular events and CKD progression. Trials of BP management are needed to test targets and treatment strategies specifically in young adults with CKD.
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http://dx.doi.org/10.1681/ASN.2020081156DOI Listing
May 2021

Investigation on the performance enhancement of single-slope solar still using green fibre insulation derived from Artocarpus heterophyllus rags reinforced with Azadirachta indica gum.

Environ Sci Pollut Res Int 2021 Feb 25. Epub 2021 Feb 25.

Department of Mechanical Engineering, KPR Institute of Engineering and Technology, Arasur, Coimbatore, Tamil Nadu, 641 407, India.

The fruits and vegetable waste has become the highest compared with the production rate. These types of wastes had reached up to 70% by 2019-2020 as estimated by Food and Agriculture Organization (FAO). Improvisation of the performance of still using fibre insulation (Artocarpus heterophyllus rags and Azadirachta indica gum (AHRAIG)) has been carried out in this study. Potable water demand in arid areas is a vast problem where fresh water is very expensive. The proposed solar still (PSS) retains the basin temperature and raises the rate of evaporation. Rags are latex-like filament extracted from the waste of the jackfruit peels and an adhesive agent from Azadirachta indica tree. A comparison is made among still without insulation (SWI), still with polystyrene insulation (SPI) and still with fibre insulation (SFI) in producing the fresh water under same ambient conditions. The experiments result a promising yield of 9.3% rate of rise of potable water produced using AHRAIG insulation related to conventional still. The energy efficiency is premeditated as 26.45%, while the exergy efficiency is 4.07%. The production of the potable water reached 2.58 L/m for still with polystyrene insulation, 3.26 L/m for fibre insulation and 1.93 L/m for still without insulation, respectively.
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http://dx.doi.org/10.1007/s11356-021-13062-xDOI Listing
February 2021

The Multi-Ethnic Study of Atherosclerosis individual response to vitamin D trial: Building a randomized clinical trial into an observational cohort study.

Contemp Clin Trials 2021 Apr 12;103:106318. Epub 2021 Feb 12.

Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA, United States of America.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.
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http://dx.doi.org/10.1016/j.cct.2021.106318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089051PMC
April 2021

Silver diamine fluoride treatment of active root caries lesions in older adults: A case series.

J Dent 2021 02 24;105:103561. Epub 2020 Dec 24.

Roseman University of Health Sciences, College of Dental Medicine, 10894 S. River Front Parkway, South Jordan, UT, 84095, USA. Electronic address:

Objective: The authors conducted a case series to determine arrest of root surface caries lesions in older adults when teeth were treated topically with 38 % silver diamine fluoride (SDF).

Methods: The study was a prospective, single center case series. The patients were 62 older adults (age ≥55 years) who sought treatment at a dental school clinic. To be included, a patient needed to have at least one active root caries lesion. Lesions were rinsed and then dried with air, isolated, and then 38 % SDF was applied for two minutes with a microbrush. Treated lesions were re-evaluated at 2-3 weeks. Treatment was repeated every six months. Survival analysis methods for clustered data were used to estimate the caries lesion arrest probability over time separately for root surfaces and at crown margins.

Results: Fifty-five participants returned for follow-up (44 % female, mean age (SD) 79.8 (7.4)). The probability of a lesion arresting with treatment ranged from 82.9 to 91.6%. Arrest rates at 18 months were slightly higher in root surfaces than around crown margins, 91.6 % (95 % CI 69.1-97.1) versus 89.8 % (95 % CI 71.6-96.3). All furcal lesions (n = 7) were arrested by 6 months, 100 % (95 % CI 59-100).

Conclusion And Clinical Significance: Repeated application of 38 % SDF at 6-month intervals was effective in arresting decay of root surface lesions and lesions around crowns in older adults. Study outcomes support SDF treatment for older adult patients who are frail and residing in nursing homes or dependent living facilities.
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http://dx.doi.org/10.1016/j.jdent.2020.103561DOI Listing
February 2021

Adrenal Insufficiency in Cirrhosis: Don't Forget the Hypothalamus.

Clin Gastroenterol Hepatol 2021 May 26;19(5):1074. Epub 2020 Nov 26.

AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia; The Centenary Institute, Sydney, New South Wales, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1016/j.cgh.2020.06.007DOI Listing
May 2021

Gene expression during larval caste determination and differentiation in intermediately eusocial bumblebees, and a comparative analysis with advanced eusocial honeybees.

Mol Ecol 2021 02 7;30(3):718-735. Epub 2021 Jan 7.

School of Biological Sciences, University of East Anglia, Norwich, UK.

The queen-worker caste system of eusocial insects represents a prime example of developmental polyphenism (environmentally-induced phenotypic polymorphism) and is intrinsic to the evolution of advanced eusociality. However, the comparative molecular basis of larval caste determination and subsequent differentiation in the eusocial Hymenoptera remains poorly known. To address this issue within bees, we profiled caste-associated gene expression in female larvae of the intermediately eusocial bumblebee Bombus terrestris. In B. terrestris, female larvae experience a queen-dependent period during which their caste fate as adults is determined followed by a nutrition-sensitive period also potentially affecting caste fate but for which the evidence is weaker. We used mRNA-seq and qRT-PCR validation to isolate genes differentially expressed between each caste pathway in larvae at developmental stages before and after each of these periods. We show that differences in gene expression between caste pathways are small in totipotent larvae, then peak after the queen-dependent period. Relatively few novel (i.e., taxonomically-restricted) genes were differentially expressed between castes, though novel genes were significantly enriched in late-instar larvae in the worker pathway. We compared sets of caste-associated genes in B. terrestris with those reported from the advanced eusocial honeybee, Apis mellifera, and found significant but relatively low levels of overlap of gene lists between the two species. These results suggest both the existence of low numbers of shared toolkit genes and substantial divergence in caste-associated genes between Bombus and the advanced eusocial Apis since their last common eusocial ancestor.
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http://dx.doi.org/10.1111/mec.15752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898649PMC
February 2021

Management of patients with intermediate stage hepatocellular carcinoma.

Ther Adv Med Oncol 2020 5;12:1758835920970840. Epub 2020 Nov 5.

Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, The Fifth Affiliated Hospital of Wenzhou Medical University/Affiliated Lishui Hospital of Zhejiang University/The Central Hospital of Zhejiang Lishui, Lishui 323000, China.

Hepatocellular carcinoma (HCC) causes a significant health burden globally and its impact is expected to increase in the coming years. Intermediate stage HCC, as defined by the Barcelona Clinic Liver Cancer (BCLC) system stage B, represents up to 30% of patients at diagnosis and encompasses a broad spectrum of tumor burden. Several attempts have been made to further subclassify this heterogenous group. The current standard of care recommended by BCLC for intermediate stage HCC patients is transarterial chemoembolization (TACE), with modest outcomes reported. While refinements have been made to TACE technique and patient selection, it remains non-curative. In the real-world setting, only 60% of patients with intermediate stage HCC receive TACE, with the remainder deviating to a range of other therapies that have shown promise in select patient subgroups. These include curative treatments (resection, ablation, and liver transplantation), radiotherapy (stereotactic and radioembolization), systemic therapies, and their combination. In this review, we summarize the classifications and current management for patients with intermediate stage HCC as well as highlight recent key developments in this space.
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http://dx.doi.org/10.1177/1758835920970840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649909PMC
November 2020

Exploring the Intersection between Social Determinants of Health and Unmet Dental Care Needs Using Deep Learning.

Int J Environ Res Public Health 2020 10 6;17(19). Epub 2020 Oct 6.

College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA.

The goals of this study were to develop a risk prediction model in unmet dental care needs and to explore the intersection between social determinants of health and unmet dental care needs in the United States. Data from the 2016 Medical Expenditure Panel Survey were used for this study. A chi-squared test was used to examine the difference in social determinants of health between those with and without unmet dental needs. Machine learning was used to determine top predictors of unmet dental care needs and to build a risk prediction model to identify those with unmet dental care needs. Age was the most important predictor of unmet dental care needs. Other important predictors included income, family size, educational level, unmet medical needs, and emergency room visit charges. The risk prediction model of unmet dental care needs attained an accuracy of 82.6%, sensitivity of 77.8%, specificity of 87.4%, precision of 82.9%, and area under the curve of 0.918. Social determinants of health have a strong relationship with unmet dental care needs. The application of deep learning in artificial intelligence represents a significant innovation in dentistry and enables a major advancement in our understanding of unmet dental care needs on an individual level that has never been done before. This study presents promising findings and the results are expected to be useful in risk assessment of unmet dental care needs and can guide targeted intervention in the general population of the United States.
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http://dx.doi.org/10.3390/ijerph17197286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579108PMC
October 2020

Screening Emergency Admissions at Risk of Chronic Hepatitis C (SEARCH) to diagnose or 're-diagnose' infections is effective in Australia.

J Viral Hepat 2021 01 21;28(1):121-128. Epub 2020 Sep 21.

Liverpool Hospital, Sydney, NSW, Australia.

The World Health Organization has set ambitious viral hepatitis elimination targets; however, difficulties in identifying and engaging patients remain. The emergency visit is an opportunity for enhanced linkage to care (LTC). We assessed the effectiveness of an automated Emergency Department (ED) screening service in identifying patients with hepatitis C (HCV) and achieving LTC. A retrospective evaluation was undertaken, analysing the first 5000 patients screened through an automatic Australian service termed 'Screening Emergency Admissions at Risk of Chronic Hepatitis' (SEARCH). Screening was performed for those recommended in the Australian national testing policy, specifically overseas born (OB) and Aboriginal or Torres Strait Islanders (ATSI). Healthcare worker education, patient information materials and opt-out informed consent were used to test sera already collected for biochemistry assays. 5000 of 5801 (86.2%) consecutive eligible patients were screened (OB: 4778, ATSI: 222) from 14 093 ED presentations. HCV antibody was positive in 181 patients (3.6%); 51 (1.0%) were HCV RNA positive. Of 51 HCV RNA-positive patients, 12 were new diagnoses, 32 were 're-diagnoses' (aware but lost to follow-up [LTFU]), and 7 were previously known but treatment contraindicated. LTC was successful in 38 viraemic patients (7 deceased, 4 LTFU, 1 treatment ineligible and 1 declined). Of RNA-negative patients, 75 were previously treated and 49 had presumed spontaneous clearance. Opt-out consent was acceptable to all patients and staff involved. ED screening can lead to additional diagnosing and 're-diagnosing' of HCV, with high rates of LTC. Opt-out consent and automation removed major obstacles to testing.
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http://dx.doi.org/10.1111/jvh.13393DOI Listing
January 2021

Investigation of performance enhancement of solar still incorporated with Gallus gallus domesticus cascara as sensible heat storage material.

Environ Sci Pollut Res Int 2021 Jan 20;28(1):611-624. Epub 2020 Aug 20.

Department of Automobile Engineering, Hindustan Institute of Technology and Science, Chennai, Tamil Nadu, 603 103, India.

In this research work, the conventional single slope still (CSS) with egg shells of breed Gallus gallus domesticus cascara as sensible heat storage (SHS) material are studied experimentally to enhance the yield. In this experimental investigation, the proposed single slope still (PSS) with SHS material was made in comparison with the CSS to evaluate the productivity of fresh water under the same ambient conditions. Comparatively, this PSS has higher thermal conductivity than the CSS. The yield obtained from the PSS is 2.46 L/m, while the yield from the CSS is 2.07 L/m. The average rate at which the rise of output fresh water obtained from the PSS is 18% more than the fresh water output obtained from the CSS. The daily energy efficiency of the PSS is 26.07%, and for the CSS, it is only 22.25%. The daily exergy efficiency of the PSS is 2.36%, and for the CSS, it is only 1.67%. Since using the egg shell will employ as organic waste management and modification in this still is economical, less initial, and maintenance cost.
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http://dx.doi.org/10.1007/s11356-020-10470-3DOI Listing
January 2021

Assessment of knowledge and perception about silver diamine fluoride (SDF) for treating older adults among graduating dental students.

J Dent Educ 2020 Nov 27;84(11):1210-1218. Epub 2020 Jun 27.

Preventive and Community Dentistry, University of Iowa College of Dentistry, Iowa City, Iowa, USA.

Purpose/objectives: Silver diamine fluoride (SDF) is a promising therapy for arresting and preventing caries in difficult to treat, high-risk populations, including institutionalized older adults. This study investigates the knowledge and perceptions about SDF of graduating dental students in multiple U.S. dental schools, as well as their willingness to use SDF in their practices.

Methods: A survey was designed consisting of 21 total questions: 6 questions regarding students' demographic information and their SDF content exposure contextualization, 8 questions tailored to investigate 2 domains regarding students' knowledge about SDF (properties and indication), and 7 questions aiming to investigate 3 domains regarding students' perceptions about SDF (SDF usefulness, appropriateness of using SDF, and willingness to use SDF when in private practice). The survey was then distributed to graduating dental students at 7 U.S. dental schools.

Results: A total of 386 surveys (response rate of 55%) was collected from 7 schools in the Spring of 2019. The median score resulting from the SDF content exposure questions was 3 (SD = 1.43) from a range of 0-5. The median score from knowledge about SDF properties was 4 (SD = 1.18) from a range of 0 to 6. In the multivariate analysis, a linear model found that the covariates "SDF Usefulness", "SDF Appropriateness" and "SDF Patient Willingness to Use" were significantly associated with higher student willingness to use SDF (R = 0.395).

Conclusion: The results indicated that the graduating students have a positive perception of SDF regarding its usefulness and appropriateness. Graduating students appear inclined to utilize SDF upon entering private practice.
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http://dx.doi.org/10.1002/jdd.12261DOI Listing
November 2020

Health and dental care expenditures in the United States from 1996 to 2016.

PLoS One 2020 11;15(6):e0234459. Epub 2020 Jun 11.

Roseman University of Health Sciences College of Dental Medicine, South Jordan, UT, United States of America.

Introduction: As total health and dental care expenditures in the United States continue to rise, healthcare disparities for low to middle-income Americans creates an imperative to analyze existing expenditures. This study examined health and dental care expenditures in the United States from 1996 to 2016 and explored trends in spending across various population subgroups.

Methods: Using data collected by the Medical Expenditure Panel Survey, this study examined health and dental care expenditures in the United States from 1996 to 2016. Trends in spending were displayed graphically and spending across subgroups examined. All expenditures were adjusted for inflation or deflation to the 2016 dollar.

Results: Both total health and dental expenditures increased between 1996 and 2016 with total healthcare expenditures increasing from $838.33 billion in 1996 to $1.62 trillion in 2016, a 1.9-fold increase. Despite an overall increase, total expenditures slowed between 2004 and 2012 with the exception of the older adult population. Over the study period, expenditures increased across all groups with the greatest increases seen in older adult health and dental care. The per capita geriatric dental care expenditure increased 59% while the per capita geriatric healthcare expenditure increased 50% across the two decades. For the overall US population, the per capita dental care expenditure increased 27% while the per capita healthcare expenditure increased 60% over the two decades. All groups except the uninsured experienced increased dental care expenditure over the study period.

Conclusions: Healthcare spending is not inherently bad since it brings benefits while exacting costs. Our findings indicate that while there were increases in both health and dental care expenditures from 1996 to 2016, these increases were non-uniform both across population subgroups and time. Further research to understand these trends in detail will be helpful to develop strategies to address health and dental care disparities and to maximize resource utilization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234459PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289437PMC
August 2020

Partial Activation of TrkB Receptors Corrects Interneuronal Calcium Channel Dysfunction and Reduces Epileptogenic Activity in Neocortex following Injury.

Cereb Cortex 2020 07;30(9):5180-5189

Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5122, USA.

Decreased GABAergic inhibition due to dysfunction of inhibitory interneurons plays an important role in post-traumatic epileptogenesis. Reduced N-current Ca2+ channel function in GABAergic terminals contributes to interneuronal abnormalities and neural circuit hyperexcitability in the partial neocortical isolation (undercut, UC) model of post-traumatic epileptogenesis. Because brain-derived neurotrophic factor (BDNF) supports the development and maintenance of interneurons, we hypothesized that the activation of BDNF tropomyosin kinase B (TrkB) receptors by a small molecule, TrkB partial agonist, PTX BD4-3 (BD), would correct N channel abnormalities and enhance inhibitory synaptic transmission in UC cortex. Immunocytochemistry (ICC) and western blots were used to quantify N- and P/Q-type channels. We recorded evoked (e)IPSCs and responses to N and P/Q channel blockers to determine the effects of BD on channel function. Field potential recordings were used to determine the effects of BD on circuit hyperexcitability. Chronic BD treatment 1) upregulated N and P/Q channel immunoreactivity in GABAergic terminals; 2) increased the effects of N or P/Q channel blockade on evoked inhibitory postsynaptic currents (eIPSCs); 3) increased GABA release probability and the frequency of sIPSCs; and 4) reduced the incidence of epileptiform discharges in UC cortex. The results suggest that chronic TrkB activation is a promising approach for rescuing injury-induced calcium channel abnormalities in inhibitory terminals, thereby improving interneuronal function and suppressing circuit hyperexcitability.
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http://dx.doi.org/10.1093/cercor/bhz254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391412PMC
July 2020

Prolonged prophylactic effects of gabapentin on status epilepticus-induced neocortical injury.

Neurobiol Dis 2020 08 19;142:104949. Epub 2020 May 19.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address:

Long-term consequences of status epilepticus (SE) occur in a significant proportion of those who survive the acute episode. We developed an in vivo model of acute focal neocortical SE (FSE) to study long-term effects on local cortical structure and function and potential strategies to mitigate adverse consequences of SE. An acute 2 h episode of FSE was induced in anesthetized mice by epidural application of gabazine +4-aminopyridine over sensorimotor neocortex. Ten and 30 days later, the morphological and functional consequences of this single episode of FSE were studied using immunocytochemical and electrophysiological techniques. Results, focused on cortical layer V, showed astrogliosis, microgliosis, decreased neuronal density, and increased excitatory synapses, along with increased immunoreactivity for thrombospondin 2 (TSP2) and α2δ-1 proteins. In addition, neocortical slices, obtained from the area of prior focal seizure activity, showed abnormal epileptiform burst discharges along with increases in the frequency of miniature and spontaneous excitatory postsynaptic currents in layer V pyramidal cells, together with decreases in both parvalbumin immunoreactivity (PV-IR) and the frequency of miniature inhibitory postsynaptic currents in layer V pyramidal cells. Treatment with an approved drug, gabapentin (GBP) (ip 100 mg/kg/day 3×/day for 7 days following the FSE episode), prevented the gliosis, the enhanced TSP2- and α2δ-1- IR and the increased excitatory synaptic density in the affected neocortex. This model provides an approach for assessing adverse effects of FSE on neocortical structure and function and potential prophylactic treatments.
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http://dx.doi.org/10.1016/j.nbd.2020.104949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083016PMC
August 2020

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Epilepsia 2020 03;61(3):359-386

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany.

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.
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http://dx.doi.org/10.1111/epi.16450DOI Listing
March 2020

Improvising the efficiency of single-sloped solar still using thermally conductive nano-ferric oxide.

Environ Sci Pollut Res Int 2020 Sep 11;27(26):32191-32204. Epub 2019 Nov 11.

Department of Automobile Engineering, Hindustan Institute of Technology and Science, Chennai, Tamil Nadu, 603103, India.

The world is facing a severe shortage of freshwater, and so we are in urge to fetch new technologies to resolve water scarcity. To desalinate saline water, the single-sloped solar still (SSSS) has proven to be a viable option with much affordability. This research work concentrates on the usage of nanomaterial on the absorbent layer to improve the thermal conductivity of the basin area and thus the distillate produced per hour. The micro-coated and nano-FeO particles were employed and analyzed. The experiment proved that the implementation of this idea had a better productivity rate. The nanoparticles and microparticles were added at weight proportions of 10%. The experiment was conducted on two consecutive days. On the first day, the saline water was maintained at 0.5 cm depth, while on the next day, the saline water level was maintained at 1 cm. The cumulative yield for micro absorbent layer solar still (MALSS) was 3.23 kg/m and nanoabsorbent layer solar still (NALSS) was 4.39 kg/m.
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http://dx.doi.org/10.1007/s11356-019-06661-2DOI Listing
September 2020

Faecal calprotectin testing for identifying patients with organic gastrointestinal disease: systematic review and meta-analysis.

Med J Aust 2019 11 3;211(10):461-467. Epub 2019 Nov 3.

Mater Hospital Brisbane, Brisbane, QLD.

Objectives: To assess the clinical effectiveness of faecal calprotectin (FC) testing for distinguishing between organic gastrointestinal diseases (organic GID), such as inflammatory bowel disease (IBD), and functional gastrointestinal disorders (functional GIDs).

Study Design: Studies that assessed the accuracy of FC testing for differentiating between IBD or organic GID and functional GIDs were reviewed. Articles published in English during January 1998 - June 2018 that compared diagnostic FC testing in primary care and outpatient hospital settings with a reference test and employed the standard enzyme-linked immunosorbent FC assay method with a cut-off of 50 or 100 μg/g faeces were included. Study quality was assessed with QUADAS-2, an evidence-based quality assessment tool for diagnostic accuracy studies.

Data Sources: MEDLINE and EMBASE; reference lists of screened articles.

Data Synthesis: Eighteen relevant studies were identified. For distinguishing patients with organic GID (including IBD) from those with functional GIDs (16 studies), the estimated sensitivity of FC testing was 81% (95% CI, 74-86%), the specificity 81% (95% CI, 71-88%); area under the curve (AUC) was 0.87. For distinguishing IBD from functional GIDs (ten studies), sensitivity was 88% (95% CI, 80-93%), specificity 72% (95% CI, 59-82%), and AUC 0.89. Assuming a population prevalence of organic GID of 1%, the positive predictive value was 4.2%, the negative predictive value 100%. The difference in sensitivity and specificity between FC testing cut-offs of 50 μg/g and 100 μg/g faeces was not statistically significant (P = 0.77).

Conclusions: FC testing is clinically useful for distinguishing organic GID (including IBD) from functional GIDs, and its incorporation into clinical practice for evaluating patients with lower gastrointestinal symptoms could lead to fewer patients with functional GIDs undergoing colonoscopy, reducing costs for both patients and the health system.

Prospero Registration: CRD4201810507.
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http://dx.doi.org/10.5694/mja2.50384DOI Listing
November 2019

Enhancement of PV/T-integrated single slope solar desalination still productivity using water film cooling and hybrid composite insulation.

Environ Sci Pollut Res Int 2020 Sep 23;27(26):32179-32190. Epub 2019 Aug 23.

Department of Automobile Engineering, Hindustan Institute of Technology and Science, Chennai, Tamil Nadu, 603103, India.

This context is about enhancing the freshwater production of a single slope solar desalination still (SSSDS) using water film cooling over the glass cover and using hybrid natural fibre composite (HNFC) insulation. In contrast to the conventional insulations, we proposed the HNFC insulation; this composite was made of natural fibre Pharsalus vulgaris (6 %) and nano-silica (1 %) with unsaturated polyester resin. In this study, conventional SSSDS and proposed SSSDS with enhanced evaporation and condensation have been designed. The same was built with native materials. A conventional and proposed type SSSDS was subjected to the same experimental condition. The experimental result showed that using water film cooling over glass cover and HNFC insulation at 0.5 cm depth caused a 35% increase in the amount of distilled water when compared with the conventional type SSSDS with polystyrene-Styrofoam (thermocol) insulation. Water film cooling over glass cover and HNFC insulation at 1 cm depth caused a 21% increase in the amount of distilled water when compared with the conventional type SSSDS with thermocol insulation. The conventional type solar desalination still with thermocol insulation at 0.5 and 1 cm depth yields are 1.665 and 1.171 l/m/day, respectively, and the proposed solar desalination still with water film cooling over glass cover and HNFC insulation at 0.5 and 1 cm depth yields are 2.253 and 1.420 l/m/day, respectively.
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http://dx.doi.org/10.1007/s11356-019-06131-9DOI Listing
September 2020

Heterozygosity for the Alpha-1-Antitrypsin Z Allele in Cirrhosis Is Associated With More Advanced Disease.

Liver Transpl 2019 08 25;25(8):1285-1286. Epub 2019 Jun 25.

A. W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia.

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http://dx.doi.org/10.1002/lt.25487DOI Listing
August 2019

Staged Implementation of Awakening and Breathing, Coordination, Delirium Monitoring and Management, and Early Mobilization Bundle Improves Patient Outcomes and Reduces Hospital Costs.

Crit Care Med 2019 07;47(7):885-893

Division of Critical Care Medicine, Department of Medicine, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.

Objectives: To measure the impact of staged implementation of full versus partial ABCDE bundle on mechanical ventilation duration, ICU and hospital lengths of stay, and cost.

Design: Prospective cohort study.

Setting: Two medical ICUs within Montefiore Healthcare Center (Bronx, NY).

Patients: One thousand eight hundred fifty-five mechanically ventilated patients admitted to ICUs between July 2011 and July 2014.

Interventions: At baseline, spontaneous (B)reathing trials (B) were ongoing in both ICUs; in period 1, (A)wakening and (D)elirium (AD) were implemented in both full and partial bundle ICUs; in period 2, (E)arly mobilization and structured bundle (C)oordination (EC) were implemented in the full bundle (B-AD-EC) but not the partial bundle ICU (B-AD).

Measurements And Main Results: In the full bundle ICU, 95% patient days were spent in bed before EC (period 1). After EC was implemented (period 2), 65% of patients stood, 54% walked at least once during their ICU stay, and ICU-acquired pressure ulcers and physical restraint use decreased (period 1 vs 2: 39% vs 23% of patients; 30% vs 26% patient days, respectively; p < 0.001 for both). After adjustment for patient-level covariates, implementation of the full (B-AD-EC) versus partial (B-AD) bundle was associated with reduced mechanical ventilation duration (-22.3%; 95% CI, -22.5% to -22.0%; p < 0.001), ICU length of stay (-10.3%; 95% CI, -15.6% to -4.7%; p = 0.028), and hospital length of stay (-7.8%; 95% CI, -8.7% to -6.9%; p = 0.006). Total ICU and hospital cost were also reduced by 24.2% (95% CI, -41.4% to -2.0%; p = 0.03) and 30.2% (95% CI, -46.1% to -9.5%; p = 0.007), respectively.

Conclusions: In a clinical practice setting, the addition of (E)arly mobilization and structured (C)oordination of ABCDE bundle components to a spontaneous (B)reathing, (A)wakening, and (D) elirium management background led to substantial reductions in the duration of mechanical ventilation, length of stay, and cost.
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http://dx.doi.org/10.1097/CCM.0000000000003765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579661PMC
July 2019

Transgressive segregation reveals mechanisms of immunity to -infecting races of white rust ().

Proc Natl Acad Sci U S A 2019 02 28;116(7):2767-2773. Epub 2019 Jan 28.

The Sainsbury Laboratory, University of East Anglia, Norwich Research Park, NR4 7UH Norwich, United Kingdom;

accessions are universally resistant at the adult leaf stage to white rust () races that infect the crop species and We used transgressive segregation in recombinant inbred lines to test if this apparent species-wide (nonhost) resistance in is due to natural pyramiding of multiple () genes. We screened 593 inbred lines from an multiparent advanced generation intercross (MAGIC) mapping population, derived from 19 resistant parental accessions, and identified two transgressive segregants that are susceptible to the pathogen. These were crossed to each MAGIC parent, and analysis of resulting F progeny followed by positional cloning showed that resistance to an isolate of race 2 (Ac2V) can be explained in each accession by at least one of four genes encoding nucleotide-binding, leucine-rich repeat (NLR) immune receptors. An additional gene was identified that confers resistance to an isolate of race 9 (AcBoT) that infects Thus, effector-triggered immunity conferred by distinct NLR-encoding genes in multiple accessions provides species-wide resistance to these crop pathogens.
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http://dx.doi.org/10.1073/pnas.1812911116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377460PMC
February 2019

Partial TrkB receptor activation suppresses cortical epileptogenesis through actions on parvalbumin interneurons.

Neurobiol Dis 2018 05 2;113:45-58. Epub 2018 Feb 2.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, United States. Electronic address:

Post-traumatic epilepsy is one of the most common and difficult to treat forms of acquired epilepsy worldwide. Currently, there is no effective way to prevent post-traumatic epileptogenesis. It is known that abnormalities of interneurons, particularly parvalbumin-containing interneurons, play a critical role in epileptogenesis following traumatic brain injury. Thus, enhancing the function of existing parvalbumin interneurons might provide a logical therapeutic approach to prevention of post-traumatic epilepsy. The known positive effects of brain-derived neurotrophic factor on interneuronal growth and function through activation of its receptor tropomyosin receptor kinase B, and its decrease after traumatic brain injury, led us to hypothesize that enhancing trophic support might improve parvalbumin interneuronal function and decrease epileptogenesis. To test this hypothesis, we used the partial neocortical isolation ('undercut', UC) model of posttraumatic epileptogenesis in mature rats that were treated for 2 weeks, beginning on the day of injury, with LM22A-4, a newly designed partial agonist at the tropomyosin receptor kinase B. Effects of treatment were assessed with Western blots to measure pAKT/AKT; immunocytochemistry and whole cell patch clamp recordings to examine functional and structural properties of GABAergic interneurons; field potential recordings of epileptiform discharges in vitro; and video-EEG recordings of PTZ-induced seizures in vivo. Results showed that LM22A-4 treatment 1) increased pyramidal cell perisomatic immunoreactivity for VGAT, GAD65 and parvalbumin; 2) increased the density of close appositions of VGAT/gephyrin immunoreactive puncta (putative inhibitory synapses) on pyramidal cell somata; 3) increased the frequency of mIPSCs in pyramidal cells; and 4) decreased the incidence of spontaneous and evoked epileptiform discharges in vitro. 5) Treatment of rats with PTX BD4-3, another partial TrkB receptor agonist, reduced the incidence of bicuculline-induced ictal episodes in vitro and PTZ induced electrographic and behavioral ictal episodes in vivo. 6) Inactivation of TrkB receptors in undercut TrkB mice with 1NMPP1 abolished both LM22A-4-induced effects on mIPSCs and on increased perisomatic VGAT-IR. Results indicate that chronic activation of the tropomyosin receptor kinase B by a partial agonist after cortical injury can enhance structural and functional measures of GABAergic inhibition and suppress posttraumatic epileptogenesis. Although the full agonist effects of brain-derived neurotrophic factor and tropomyosin receptor kinase B activation in epilepsy models have been controversial, the present results indicate that such trophic activation by a partial agonist may potentially serve as an effective therapeutic option for prophylactic treatment of posttraumatic epileptogenesis, and treatment of other neurological and psychiatric disorders whose pathogenesis involves impaired parvalbumin interneuronal function.
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http://dx.doi.org/10.1016/j.nbd.2018.01.018DOI Listing
May 2018

Post-resuscitation arterial oxygen and carbon dioxide and outcomes after out-of-hospital cardiac arrest.

Resuscitation 2017 11 21;120:113-118. Epub 2017 Sep 21.

The Clinical Trials Center, Department of Biostatistics, University of Washington, Seattle, WA, United States.

Objective: To determine if arterial oxygen and carbon dioxide abnormalities in the first 24h after return of spontaneous circulation (ROSC) are associated with increased mortality in adult out-of-hospital cardiac arrest (OHCA).

Methods: We used data from the Resuscitation Outcomes Consortium (ROC), including adult OHCA with sustained ROSC ≥1h after Emergency Department arrival and at least one arterial blood gas (ABG) measurement. Among ABGs measured during the first 24h of hospitalization, we identified the presence of hyperoxemia (PaO2≥300mmHg), hypoxemia (PaO2<60mmHg), hypercarbia (PaCO2>50mmHg) and hypocarbia (PaCO2<30mmHg). We evaluated the associations between oxygen and carbon dioxide abnormalities and hospital mortality, adjusting for confounders.

Results: Among 9186 OHCA included in the analysis, hospital mortality was 67.3%. Hyperoxemia, hypoxemia, hypercarbia, and hypocarbia occurred in 26.5%, 19.0%, 51.0% and 30.6%, respectively. Initial hyperoxemia only was not associated with hospital mortality (adjusted OR 1.10; 95% CI: 0.97-1.26). However, final and any hyperoxemia (1.25; 1.11-1.41) were associated with increased hospital mortality. Initial (1.58; 1.30-1.92), final (3.06; 2.42-3.86) and any (1.76; 1.54-2.02) hypoxemia (PaO2<60mmHg) were associated with increased hospital mortality. Initial (1.89; 1.70-2.10); final (2.57; 2.18-3.04) and any (1.85; 1.67-2.05) hypercarbia (PaCO2>50mmHg) were associated with increased hospital mortality. Initial (1.13; 0.90-1.41), final (1.19; 1.04-1.37) and any (1.01; 0.91-1.12) hypocarbia (PaCO2<30mmHg) were not associated with hospital mortality.

Conclusions: In the first 24h after ROSC, abnormal post-arrest oxygen and carbon dioxide tensions are associated with increased out of-hospital cardiac arrest mortality.
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http://dx.doi.org/10.1016/j.resuscitation.2017.08.244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5660655PMC
November 2017

Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis.

Neurobiol Dis 2017 Dec 18;108:100-114. Epub 2017 Aug 18.

Epilepsy Research Laboratories, Stanford Univ. Sch. of Medicine, United States. Electronic address:

Electrophysiological experiments in the partial cortical isolation ("undercut" or "UC") model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) there were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and -67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and -mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition.

Significance: Injury to cortical structures is a major cause of epilepsy, accounting for about 20% of cases in the general population, with an incidence as high as ~50% among brain-injured personnel in wartime. Loss of GABAergic inhibitory interneurons is a significant pathophysiological factor associated with epileptogenesis following brain trauma and other etiologies. Results of these experiments show that the largest population of cortical interneurons, the parvalbumin-containing fast-spiking (FS) interneurons, are preserved in the partial neocortical isolation model of partial epilepsy. However, axonal terminals of these cells are structurally abnormal, have decreased content of GABA synthetic enzymes and vesicular GABA transporter and make fewer synapses onto pyramidal neurons. These structural abnormalities underlie defects in GABAergic neurotransmission that are a key pathophysiological factor in epileptogenesis found in electrophysiological experiments. BDNF, and its TrkB receptor, key factors for maintenance of interneurons and pyramidal neurons, are decreased in the injured cortex. Results suggest that supplying BDNF to the injured epileptogenic brain may reverse the structural and functional abnormalities in the parvalbumin FS interneurons and provide an antiepileptogenic therapy.
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http://dx.doi.org/10.1016/j.nbd.2017.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927780PMC
December 2017

TGFβ signaling is associated with changes in inflammatory gene expression and perineuronal net degradation around inhibitory neurons following various neurological insults.

Sci Rep 2017 08 9;7(1):7711. Epub 2017 Aug 9.

Department of Integrative Biology, University of California Berkeley, Berkeley, CA, 94720, USA.

Brain damage due to stroke or traumatic brain injury (TBI), both leading causes of serious long-term disability, often leads to the development of epilepsy. Patients who develop post-injury epilepsy tend to have poor functional outcomes. Emerging evidence highlights a potential role for blood-brain barrier (BBB) dysfunction in the development of post-injury epilepsy. However, common mechanisms underlying the pathological hyperexcitability are largely unknown. Here, we show that comparative transcriptome analyses predict remodeling of extracellular matrix (ECM) as a common response to different types of injuries. ECM-related transcriptional changes were induced by the serum protein albumin via TGFβ signaling in primary astrocytes. In accordance with transcriptional responses, we found persistent degradation of protective ECM structures called perineuronal nets (PNNs) around fast-spiking inhibitory interneurons, in a rat model of TBI as well as in brains of human epileptic patients. Exposure of a naïve brain to albumin was sufficient to induce the transcriptional and translational upregulation of molecules related to ECM remodeling and the persistent breakdown of PNNs around fast-spiking inhibitory interneurons, which was contingent on TGFβ signaling activation. Our findings provide insights on how albumin extravasation that occurs upon BBB dysfunction in various brain injuries can predispose neural circuitry to the development of chronic inhibition deficits.
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http://dx.doi.org/10.1038/s41598-017-07394-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550510PMC
August 2017

Albugo-imposed changes to tryptophan-derived antimicrobial metabolite biosynthesis may contribute to suppression of non-host resistance to Phytophthora infestans in Arabidopsis thaliana.

BMC Biol 2017 03 20;15(1):20. Epub 2017 Mar 20.

The Sainsbury Laboratory, Norwich Research Park, Norwich, NR4 7UH, United Kingdom.

Background: Plants are exposed to diverse pathogens and pests, yet most plants are resistant to most plant pathogens. Non-host resistance describes the ability of all members of a plant species to successfully prevent colonization by any given member of a pathogen species. White blister rust caused by Albugo species can overcome non-host resistance and enable secondary infection and reproduction of usually non-virulent pathogens, including the potato late blight pathogen Phytophthora infestans on Arabidopsis thaliana. However, the molecular basis of host defense suppression in this complex plant-microbe interaction is unclear. Here, we investigate specific defense mechanisms in Arabidopsis that are suppressed by Albugo infection.

Results: Gene expression profiling revealed that two species of Albugo upregulate genes associated with tryptophan-derived antimicrobial metabolites in Arabidopsis. Albugo laibachii-infected tissue has altered levels of these metabolites, with lower indol-3-yl methylglucosinolate and higher camalexin accumulation than uninfected tissue. We investigated the contribution of these Albugo-imposed phenotypes to suppression of non-host resistance to P. infestans. Absence of tryptophan-derived antimicrobial compounds enables P. infestans colonization of Arabidopsis, although to a lesser extent than Albugo-infected tissue. A. laibachii also suppresses a subset of genes regulated by salicylic acid; however, salicylic acid plays only a minor role in non-host resistance to P. infestans.

Conclusions: Albugo sp. alter tryptophan-derived metabolites and suppress elements of the responses to salicylic acid in Arabidopsis. Albugo sp. imposed alterations in tryptophan-derived metabolites may play a role in Arabidopsis non-host resistance to P. infestans. Understanding the basis of non-host resistance to pathogens such as P. infestans could assist in development of strategies to elevate food security.
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http://dx.doi.org/10.1186/s12915-017-0360-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358052PMC
March 2017

Epileptiform activity and behavioral arrests in mice overexpressing the calcium channel subunit α2δ-1.

Neurobiol Dis 2017 Jun 11;102:70-80. Epub 2017 Feb 11.

Department of Neurology and Neurological Sciences, Stanford University, School of Medicine, Stanford, CA 94305, USA. Electronic address:

The alpha2delta-1 subunit (α2δ-1) of voltage-gated calcium channels is a receptor for astrocyte-secreted thrombospondins that promote developmental synaptogenesis. Alpha2delta-1 receptors are upregulated in models of injury-induced peripheral pain and epileptogenic neocortical trauma associated with an enhancement of excitatory synaptic connectivity. These results lead to the hypothesis that overexpression of α2δ-1 alone in neocortex of uninjured transgenic (TG) mice might result in increased excitatory connectivity and consequent cortical hyperexcitability and epileptiform activity. Whole cell recordings from layer V pyramidal neurons in somatosensory cortical slices of TG mice showed increased frequency and amplitude of miniature and spontaneous EPSCs and prolonged bursts of polysynaptic EPSCs. Epileptiform field potentials were evoked in layers II/III and V of brain slices from TG mice, but not controls. Dual immunoreactivity for Vglut-2 and PSD95 showed increased density of close appositions in TG mice compared to controls, suggesting an increased number of excitatory synapses. Video-EEG monitoring showed that 13/13 implanted TG mice aged >P21, but not controls, had frequent abnormal spontaneous epileptiform events, consisting of variable duration, high amplitude bi-hemispheric irregular bursts of delta activity, spikes and sharp waves lasting many seconds, with a variable peak frequency of ~1-3Hz, associated with behavioral arrest. The epileptiform EEG abnormalities and behavioral arrests were reversibly eliminated by treatment with i.p. ethosuximide. Behavioral seizures, consisting of ~15-30s duration episodes of rigid arched tail and head and body extension, followed by loss of balance and falling, frequently occurred in adult TG mice during recovery from isoflurane-induced anesthesia, but were rare in WT mice. Results show that over-expression of α2δ-1 subunits increases cortical excitatory connectivity and leads to neocortical hyperexcitability and epileptiform activity associated with behavioral arrests in adult TG mice. Similar increases in expression of α2δ-1 in models of cortical injury may play an important role in epileptogenesis.

Significance: Binding of astrocytic-secreted thrombospondins to their α2δ-1 receptor facilitates excitatory synapse formation and excitatory transmission during cortical development and after injury. Upregulation of α2δ-1 is present in models of injury-induced pain and epileptogenic cortical trauma, along with many other molecular alterations. Here we show that overexpression of α2δ-1 alone in TG mice can enhance excitatory connectivity in neocortex and lead to neural circuit hyperexcitability and episodes of electrographic epileptiform activity, associated with behavioral arrests in transgenic mice. α2δ-1 is the high-affinity receptor for gabapentinoids and a potential target for prophylactic treatment of posttraumatic epilepsy and other disorders in which excessive aberrant excitatory connectivity is a pathophysiological feature.
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http://dx.doi.org/10.1016/j.nbd.2017.01.009DOI Listing
June 2017