Publications by authors named "Rachel Thomas"

112 Publications

Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload.

BMC Biol 2021 Jul 30;19(1):154. Epub 2021 Jul 30.

Laboratory of Pediatrics, Systems Medicine of Metabolism and Signaling, University Medical Center Groningen, University of Groningen, Postbus 196, 9700, AD, Groningen, The Netherlands.

Background: The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD).

Results: As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet.

Conclusion: We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.
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http://dx.doi.org/10.1186/s12915-021-01082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323306PMC
July 2021

Modeling phenotypic heterogeneity of Glycogen Storage Disease type Ia liver disease in mice by somatic CRISPR/Cas9-mediated gene editing.

Hepatology 2021 Jun 22. Epub 2021 Jun 22.

Department of Pediatrics, University Medical Center Groningen, The Netherlands.

Patients with Glycogen Storage Disease type 1a (GSD Ia) primarily present with life-threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long-term complications still occur, amongst which liver tumor development. Variations in residual glucose-6-phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications, and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal healthcare and quality of life for GSD Ia patients. Currently available GSD Ia animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity, or the contribution of gene-gene interactions in the liver. To meet these needs, we generated and characterized a novel hepatocyte-specific GSD Ia mouse model using somatic CRISPR/Cas9-mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis, and increased liver tumor incidence. This approach was furthermore successful to simultaneously modulate hepatic G6PC and ChREBP, a transcription factor that is activated in GSD Ia and protects against hepatic steatosis under these conditions. Importantly, it also allowed to model a spectrum of GSD Ia phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and hepatic steatosis. In conclusion, we show that somatic CRISPR/Cas9-mediated gene editing allows to model a spectrum of hepatocyte-borne GSD Ia disease symptoms in mice, and to efficiently study gene-gene interactions in the liver. This approach opens new perspectives for translational research and will likely contribute to novel and personalized treatments for GSD Ia and other genetic liver diseases.
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http://dx.doi.org/10.1002/hep.32022DOI Listing
June 2021

Health and nutrition of loggerhead sea turtles (Caretta caretta) in the southeastern United States.

J Anim Physiol Anim Nutr (Berl) 2021 Jun 13. Epub 2021 Jun 13.

Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.

Loggerhead sea turtles (Caretta caretta) are opportunistic carnivores that feed primarily on benthic invertebrates and fish. Sea turtle rehabilitation requires provision of a species-specific, balanced diet that supplies nutrition similar to that of a wild diet; this can be challenging because free-ranging loggerheads' diets vary depending on their life stage and geographic location, with predominant prey species dictated by local availability. The goal of this study was to better understand the nutritional needs of subadult and adult loggerheads in rehabilitation. This was accomplished by conducting a retrospective survey of stomach contents identified during gross necropsy of 153 deceased loggerheads that stranded in coastal Georgia, USA. A total of 288 different forage items were identified; the most frequently observed prey items belong to the subphylum Crustacea (N = 131), followed by bony fish (Osteichthyes; N = 45), gastropod mollusks (N = 40), bivalve mollusks (N = 23), and Atlantic horseshoe crabs (Limulus polyphemus; N = 15). The proportions of certain prey items differed significantly with turtle size; adult turtles ate proportionately more gastropods (p = 0.001), and subadults ate proportionately more fish (p = 0.01). Stomach contents information was used to determine common local prey items (blue crab, cannonball jellyfish, horseshoe crab, whelk), which were evaluated for nutritional content. Additionally, we compared hematology and plasma biochemistry profiles (including proteins, trace minerals, and vitamins) between four cohorts of loggerhead turtles, including free-ranging subadults and adults, nesting females, and loggerheads undergoing rehabilitation. This information was applied to inform a regionally specific, formulated diet for tube feeding, and a supplement containing vitamins and minerals for captive loggerheads, to more closely approximate the nutritional content of their natural diet. Assessing the regional and temporal variability in loggerhead diets is an important component in their effective conservation because resultant data can be used to help understand the impacts of environmental perturbations on benthic food webs.
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http://dx.doi.org/10.1111/jpn.13575DOI Listing
June 2021

Lateral advection supports nitrogen export in the oligotrophic open-ocean Gulf of Mexico.

Nat Commun 2021 06 3;12(1):3325. Epub 2021 Jun 3.

Department of Earth, Ocean and Atmospheric Sciences, Florida State University, Tallahassee, FL, USA.

In contrast to its productive coastal margins, the open-ocean Gulf of Mexico (GoM) is notable for highly stratified surface waters with extremely low nutrient and chlorophyll concentrations. Field campaigns in 2017 and 2018 identified low rates of turbulent mixing, which combined with oligotrophic nutrient conditions, give very low estimates for diffusive flux of nitrate into the euphotic zone (< 1 µmol N m d). Estimates of local N-fixation are similarly low. In comparison, measured export rates of sinking particulate organic nitrogen (PON) from the euphotic zone are 2 - 3 orders of magnitude higher (i.e. 462 - 1144 µmol N m d). We reconcile these disparate findings with regional scale dynamics inferred independently from remote-sensing products and a regional biogeochemical model and find that laterally-sourced organic matter is sufficient to support >90% of open-ocean nitrogen export in the GoM. Results show that lateral transport needs to be closely considered in studies of biogeochemical balances, particularly for basins enclosed by productive coasts.
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http://dx.doi.org/10.1038/s41467-021-23678-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175579PMC
June 2021

Have we reached the limits in altruistic kidney donation?

Transpl Int 2021 07 19;34(7):1187-1197. Epub 2021 Jun 19.

Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Little France Crescent, Edinburgh, UK.

Altruistic donation (unspecified donation) is an important aspect of living donor kidney transplantation. Although donation to a stranger is lawful and supported in many countries, it remains uncommon and not actively promoted. Herein, we ask the question if we have reached the limit in altruistic donation. In doing so, we examine important ethical questions that define the limits of unspecified donation, such as the appropriate balance between autonomous decision-making and paternalistic protection of the donor, the extent of outcome uncertainty and risk-benefit analyses that donors should be allowed to accept. We also consider the scrutiny and acceptance of donor motives, the potential for commercialization, donation to particular categories of recipients (including those encountered through social media) and the ethical boundaries of active promotion of unspecified kidney donation. We conclude that there is scope to increase the number of living donation kidney transplants further by optimizing existing practices to support and promote unspecified donation. A number of strategies including optimization of the assessment process, innovative approaches to reach potential donors together with reimbursement of expenses and a more specific recognition of unspecified donation are likely to lead to a meaningful increase in this type of donation.
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http://dx.doi.org/10.1111/tri.13921DOI Listing
July 2021

Dermatomyositis Flare With Immune Checkpoint Inhibitor Therapy for Melanoma.

Cureus 2021 Apr 9;13(4):e14387. Epub 2021 Apr 9.

Rheumatology, Wright-Patterson Medical Center, Dayton, USA.

Immune checkpoint inhibitor (ICI) medications have seen expanded use in the management of numerous malignancies. These therapies encompass a unique spectrum of immune-related adverse events (irAEs). Rheumatological irAEs from ICIs have been described in various case reports; however, limited literature exists regarding the treatment of patients with pre-existing myositis. We describe a case of myositis flare after initiation of nivolumab for metastatic melanoma in a patient who had previously achieved remission of dermatomyositis.
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http://dx.doi.org/10.7759/cureus.14387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106943PMC
April 2021

Environmental DNA monitoring of oncogenic viral shedding and genomic profiling of sea turtle fibropapillomatosis reveals unusual viral dynamics.

Commun Biol 2021 05 12;4(1):565. Epub 2021 May 12.

The Whitney Laboratory for Marine Bioscience and Sea Turtle Hospital, University of Florida, St. Augustine, FL, USA.

Pathogen-induced cancers account for 15% of human tumors and are a growing concern for endangered wildlife. Fibropapillomatosis is an expanding virally and environmentally co-induced sea turtle tumor epizootic. Chelonid herpesvirus 5 (ChHV5) is implicated as a causative virus, but its transmission method and specific role in oncogenesis and progression is unclear. We applied environmental (e)DNA-based viral monitoring to assess viral shedding as a direct means of transmission, and the relationship between tumor burden, surgical resection and ChHV5 shedding. To elucidate the abundance and transcriptional status of ChHV5 across early, established, regrowth and internal tumors we conducted genomics and transcriptomics. We determined that ChHV5 is shed into the water column, representing a likely transmission route, and revealed novel temporal shedding dynamics and tumor burden correlations. ChHV5 was more abundant in the water column than in marine leeches. We also revealed that ChHV5 is latent in fibropapillomatosis, including early stage, regrowth and internal tumors; higher viral transcription is not indicative of poor patient outcome, and high ChHV5 loads predominantly arise from latent virus. These results expand our knowledge of the cellular and shedding dynamics of ChHV5 and can provide insights into temporal transmission dynamics and viral oncogenesis not readily investigable in tumors of terrestrial species.
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http://dx.doi.org/10.1038/s42003-021-02085-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115626PMC
May 2021

Thymic Aging May Be Associated with COVID-19 Pathophysiology in the Elderly.

Cells 2021 03 12;10(3). Epub 2021 Mar 12.

Department of Microbiology, Immunology & Genetics, University of North Texas Health Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global pandemic of coronavirus disease 2019 (COVID-19) and particularly exhibits severe symptoms and mortality in elderly individuals. Mounting evidence shows that the characteristics of the age-related clinical severity of COVID-19 are attributed to insufficient antiviral immune function and excessive self-damaging immune reaction, involving T cell immunity and associated with pre-existing basal inflammation in the elderly. Age-related changes to T cell immunosenescence is characterized by not only restricted T cell receptor (TCR) repertoire diversity, accumulation of exhausted and/or senescent memory T cells, but also by increased self-reactive T cell- and innate immune cell-induced chronic inflammation, and accumulated and functionally enhanced polyclonal regulatory T (Treg) cells. Many of these changes can be traced back to age-related thymic involution/degeneration. How these changes contribute to differences in COVID-19 disease severity between young and aged patients is an urgent area of investigation. Therefore, we attempt to connect various clues in this field by reviewing and discussing recent research on the role of the thymus and T cells in COVID-19 immunity during aging (a synergistic effect of diminished responses to pathogens and enhanced responses to self) impacting age-related clinical severity of COVID-19. We also address potential combinational strategies to rejuvenate multiple aging-impacted immune system checkpoints by revival of aged thymic function, boosting peripheral T cell responses, and alleviating chronic, basal inflammation to improve the efficiency of anti-SARS-CoV-2 immunity and vaccination in the elderly.
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http://dx.doi.org/10.3390/cells10030628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001029PMC
March 2021

Thymic atrophy creates holes in Treg-mediated immuno-regulation via impairment of an antigen-specific clone.

Immunology 2021 Aug 15;163(4):478-492. Epub 2021 Apr 15.

Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center, Fort Worth, TX, USA.

Age-related thymic atrophy results in reduced output of naïve conventional T (Tcon) cells. However, its impact on regulatory T (Treg) cells is insufficiently understood. Given evidence that thymic Treg (tTreg) cell generation is enhanced in the aged, atrophy thymus and that the aged periphery accumulates peripheral Treg (pTreg) cells, we asked why these Treg cells are unable to effectively attenuate increased autoreactivity-induced chronic inflammation in the elderly. We designed a mock-self-antigen chimera mouse model, in which membrane-bound ovalbumin (mOVA) transgenic mice, bearing a FoxN1-floxed gene for induction of conditional thymic atrophy, received OVA-specific (OT-II) T-cell receptor (TCR) transgenic progenitor cells. The chimeric mice with thymic atrophy exhibited a significant decrease in OVA-specific tTreg and pTreg cells but not polyclonal (pan)-Treg cells. These OVA-specific pTreg cells were significantly less able to suppress OVA-specific stimulation-induced proliferation in vitro and exhibited lower FoxP3 expression. Additionally, we conducted preliminary TCR repertoire diversity sequencing for Treg cells among recent thymic emigrants (RTEs) from Rag -FoxP3 dual-reporter mice and observed a trend for decreased diversity in mice with thymic atrophy compared to littermates with normal thymus. These data indicate that although the effects of age-related thymic atrophy do not affect pan-Treg generation, certain tissue-specific Treg clones may experience abnormal agonist selection. This, combined with enhanced pan-pTreg cells, may greatly contribute to age-related chronic inflammation, even in the absence of acute autoimmune disease in the elderly.
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http://dx.doi.org/10.1111/imm.13333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274191PMC
August 2021

A randomized trial of an online, coach-assisted self-management PTSD intervention tailored for women veterans.

J Consult Clin Psychol 2021 Feb;89(2):134-141

Department of Psychiatry & Behavioral Sciences.

Objective: Scalable, efficiently delivered treatments are needed to address the needs of women Veterans with PTSD. This randomized clinical trial compared an online, coach-assisted cognitive behavioral intervention tailored for women Veterans with PTSD to phone monitoring only.

Method: Women Veterans who met diagnostic criteria for PTSD were randomized to an 8-week web-based intervention, called DElivery of Self TRaining and Education for Stressful Situations (DESTRESS)-Women Veterans version (WV), or to phone monitoring only (N = 102). DESTRESS-WV consisted of online sessions and 15-min weekly phone calls from a study coach. Phone monitoring included 15-min weekly phone calls from a study coach to offer general support. PTSD symptom severity (PTSD Symptom-Checklist-Version 5 [PCL-5]) was evaluated pre and posttreatment, and at 3 and 6 months posttreatment.

Results: More participants completed phone monitoring than DESTRESS-WV (96% vs. 76%, p = 0.01), although treatment satisfaction was significantly greater in the DESTRESS-WV condition. We failed to confirm the superiority of DESTRESS-WV in intent-to-treat slope changes in PTSD symptom severity. Both treatments were associated with significant reductions in PTSD symptom severity over time. However, post hoc analyses of treatment completers and of those with baseline PCL ≥ 33 revealed that the DESTRESS-WV group had greater improvement in PTSD symptom severity relative to phone monitoring with significant differences at the 3-month follow-up assessment.

Conclusions: Both DESTRESS-WV and phone monitoring resulted in significant improvements in women Veterans' PTSD symptoms. DESTRESS-WV may be an appropriate care model for women Veterans who can engage in the demands of the treatment and have higher baseline symptoms. Future research should explore characteristics of and the methods of reliably identifying women Veterans who are most likely to benefit. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/ccp0000556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238393PMC
February 2021

Molecular characterization of a marine turtle tumor epizootic, profiling external, internal and postsurgical regrowth tumors.

Commun Biol 2021 02 1;4(1):152. Epub 2021 Feb 1.

The Whitney Laboratory for Marine Bioscience and Sea Turtle Hospital, University of Florida, St. Augustine, FL, 32080, USA.

Sea turtle populations are under threat from an epizootic tumor disease (animal epidemic) known as fibropapillomatosis. Fibropapillomatosis continues to spread geographically, with prevalence of the disease also growing at many longer-affected sites globally. However, we do not yet understand the precise environmental, mutational and viral events driving fibropapillomatosis tumor formation and progression.Here we perform transcriptomic and immunohistochemical profiling of five fibropapillomatosis tumor types: external new, established and postsurgical regrowth tumors, and internal lung and kidney tumors. We reveal that internal tumors are molecularly distinct from the more common external tumors. However, they have a small number of conserved potentially therapeutically targetable molecular vulnerabilities in common, such as the MAPK, Wnt, TGFβ and TNF oncogenic signaling pathways. These conserved oncogenic drivers recapitulate remarkably well the core pan-cancer drivers responsible for human cancers. Fibropapillomatosis has been considered benign, but metastatic-related transcriptional signatures are strongly activated in kidney and established external tumors. Tumors in turtles with poor outcomes (died/euthanized) have genes associated with apoptosis and immune function suppressed, with these genes providing putative predictive biomarkers.Together, these results offer an improved understanding of fibropapillomatosis tumorigenesis and provide insights into the origins, inter-tumor relationships, and therapeutic treatment for this wildlife epizootic.
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http://dx.doi.org/10.1038/s42003-021-01656-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851172PMC
February 2021

Rationale and design of the pragmatic randomized trial of icosapent ethyl for high cardiovascular risk adults (MITIGATE).

Am Heart J 2021 05 28;235:54-64. Epub 2021 Jan 28.

Division of Research, Kaiser Permanente Northern California, Oakland, CA; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA; Departments of Medicine (Nephrology), Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, CA; Department of Medicine (Nephrology), Stanford University, Palo Alto, CA.

Objective: The MITIGATE study aims to evaluate the real-world clinical effectiveness of pre-treatment with icosapent ethyl (IPE), compared with usual care, on laboratory-confirmed viral upper respiratory infection (URI)-related morbidity and mortality in adults with established atherosclerotic cardiovascular disease (ASCVD).

Background: IPE is a highly purified and stable omega-3 fatty acid prescription medication that is approved for cardiovascular risk reduction in high-risk adults on statin therapy with elevated triglycerides. Preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral URIs.

Methods: MITIGATE is a virtual, electronic health record-based, open-label, randomized, pragmatic clinical trial enrolling ∼16,500 participants within Kaiser Permanente Northern California - a fully integrated and learning health care delivery system with 21 hospitals and >255 ambulatory clinics serving ∼4.5 million members. Adults ≥50 years with established ASCVD and no prior history of coronavirus disease 2019 (COVID-19) will be prospectively identified and pre-randomized in a 1:10 allocation ratio (∼ 1,500 IPE: ∼15,000 usual care) stratified by age and previous respiratory health status to the intervention (IPE 2 grams by mouth twice daily with meals) vs the control group (usual care) for a minimum follow-up duration of 6 months. The co-primary endpoints are moderate-to-severe laboratory-confirmed viral URI and worst clinical status due to a viral URI at any point in time.

Conclusion: The MITIGATE study will inform clinical practice by providing evidence on the real-world clinical effectiveness of pretreatment with IPE to prevent and/or reduce the sequelae of laboratory-confirmed viral URIs in a high-risk cohort of patients with established ASCVD.
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http://dx.doi.org/10.1016/j.ahj.2021.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843090PMC
May 2021

Interventions for Tobacco Cessation in Adults, Including Pregnant Persons: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

JAMA 2021 01;325(3):280-298

Kaiser Permanente Evidence-based Practice Center, Center for Health Research, Kaiser Permanente, Portland, Oregon.

Importance: It has been estimated that in 2018 nearly 20% of adults in the US were currently using a tobacco product.

Objective: To systematically review the effectiveness and safety of pharmacotherapy, behavioral interventions, and electronic cigarettes for tobacco cessation among adults, including pregnant persons, to inform the US Preventive Services Task Force.

Data Sources: PubMed, PsycInfo, Database of Abstracts of Reviews of Effects, Cochrane Database of Systematic Reviews, Centre for Reviews and Dissemination of Health Technology Assessment; surveillance through September 25, 2020.

Study Selection: Systematic reviews of tobacco cessation interventions and randomized clinical trials that evaluated the effects of electronic cigarettes (e-cigarettes) or pharmacotherapy among pregnant persons.

Data Extraction And Synthesis: Independent critical appraisal and data abstraction; qualitative synthesis and random-effects meta-analyses.

Main Outcomes And Measures: Health outcomes, tobacco cessation at 6 months or more, and adverse events.

Results: Sixty-seven reviews addressing pharmacotherapy and behavioral interventions were included as well as 9 trials (N = 3942) addressing e-cigarettes for smoking cessation and 7 trials (N = 2285) of nicotine replacement therapy (NRT) use in pregnancy. Combined pharmacotherapy and behavioral interventions (pooled risk ratio [RR], 1.83 [95% CI, 1.68-1.98]), NRT (RR, 1.55 [95% CI, 1.49-1.61]), bupropion (RR, 1.64 [95% CI, 1.52-1.77]), varenicline (RR, 2.24 [95% CI, 2.06-2.43]), and behavioral interventions such as advice from clinicians (RR, 1.76 [95% CI, 1.58-1.96]) were all associated with increased quit rates compared with minimal support or placebo at 6 months or longer. None of the drugs were associated with serious adverse events. Five trials (n = 3117) reported inconsistent findings on the effectiveness of electronic cigarettes on smoking cessation at 6 to 12 months among smokers when compared with placebo or NRT, and none suggested higher rates of serious adverse events. Among pregnant persons, behavioral interventions were associated with greater smoking cessation during late pregnancy (RR, 1.35 [95% CI, 1.23-1.48]), compared with no intervention. Rates of validated cessation among pregnant women allocated to NRT compared with placebo were not significantly different (pooled RR, 1.11 [95% CI, 0.79-1.56], n = 2033).

Conclusions And Relevance: There is strong evidence that a range of pharmacologic and behavioral interventions, both individually and in combination, are effective in increasing smoking cessation in nonpregnant adults. In pregnancy, behavioral interventions are effective for smoking cessation, but data are limited on the use of pharmacotherapy for smoking cessation. Data on the effectiveness and safety of electronic cigarettes for smoking cessation among adults are also limited and results are inconsistent.
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http://dx.doi.org/10.1001/jama.2020.23541DOI Listing
January 2021

Identifying cell-enriched miRNAs in kidney injury and repair.

JCI Insight 2020 12 17;5(24). Epub 2020 Dec 17.

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom.

Small noncoding RNAs, miRNAs (miRNAs), are emerging as important modulators in the pathogenesis of kidney disease, with potential as biomarkers of kidney disease onset, progression, or therapeutic efficacy. Bulk tissue small RNA-sequencing (sRNA-Seq) and microarrays are widely used to identify dysregulated miRNA expression but are limited by the lack of precision regarding the cellular origin of the miRNA. In this study, we performed cell-specific sRNA-Seq on tubular cells, endothelial cells, PDGFR-β+ cells, and macrophages isolated from injured and repairing kidneys in the murine reversible unilateral ureteric obstruction model. We devised an unbiased bioinformatics pipeline to define the miRNA enrichment within these cell populations, constructing a miRNA catalog of injury and repair. Our analysis revealed that a significant proportion of cell-specific miRNAs in healthy animals were no longer specific following injury. We then applied this knowledge of the relative cell specificity of miRNAs to deconvolute bulk miRNA expression profiles in the renal cortex in murine models and human kidney disease. Finally, we used our data-driven approach to rationally select macrophage-enriched miR-16-5p and miR-18a-5p and demonstrate that they are promising urinary biomarkers of acute kidney injury in renal transplant recipients.
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http://dx.doi.org/10.1172/jci.insight.140399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819746PMC
December 2020

The Beneficial Effects of Apical Sodium-Dependent Bile Acid Transporter Inactivation Depend on Dietary Fat Composition.

Mol Nutr Food Res 2020 Oct 20:e2000750. Epub 2020 Oct 20.

Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands.

Scope: The apical sodium-dependent bile acid transporter (ASBT, SLC10A2) is important in the enterohepatic cycling of bile acids and thereby in the intestinal absorption of lipids. ASBT inhibition has been shown to improve aspects of the metabolic syndrome, but the underlying mechanisms have remained unclear. Here, the effect of ASBT inhibition on the uptake of specific fatty acids and its consequences for diet-induced obesity and non-alcoholic fatty liver disease (NAFLD) are investigated.

Methods: Intestinal fat absorption is determined in mice receiving an ASBT inhibitor and in Asbt mice. Metabolic disease development is determined in Asbt mice receiving a low-fat control diet (LFD) or high-fat diet (HFD) rich in saturated fatty acids (SFAs) or PUFAs.

Results: Both ASBT inhibition and Asbt gene inactivation reduce total fat absorption, particularly of SFAs. Asbt gene inactivation lowers bodyweight gain, improves insulin sensitivity, and decreases the NAFLD activity score upon feeding a HFD rich in SFAs, but not in PUFAs.

Conclusions: The beneficial metabolic effects of ASBT inactivation on diet-induced obesity depend on decreased intestinal absorption of SFAs, and thus on the dietary fatty acid composition. These findings highlight the importance of dietary fatty acid composition in the therapeutic effects of ASBT inhibition.
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http://dx.doi.org/10.1002/mnfr.202000750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757219PMC
October 2020

Facilitating Activity and Self-management for people with Arthritic knee, hip or lower back pain (FASA): A cluster randomised controlled trial.

Musculoskelet Sci Pract 2020 12 10;50:102271. Epub 2020 Oct 10.

Faculty for Health, Social Care and Education. St George's University of London & Kingston University, UK.

Background: Chronic musculoskeletal pain including osteoarthritis (OA) can significantly limit the functional independence of individuals. The spine and hip and knee are predominantly affected; management guidelines for each recommend exercise and education to support self-management.

Objectives: This study investigated the effectiveness of a generic exercise and self-management intervention for people over-50 with hip/knee OA and/or lower back pain compared to continued GP management.

Design: Single blind, cluster randomised controlled trial.

Method: Participants who had previously consulted with hip/knee OA and/or chronic lower back pain were recruited from 45 GP practices in SW England. Practices were randomly allocated to receive continued GP care (control) or continued GP care and a 6-week group exercise and self-management intervention facilitated by a physiotherapist and located in a community-based physiotherapy department. The primary outcome measure was the Dysfunction Index of the Short Musculoskeletal Functional Assessment (DI-SMFA) measured at six month post-rehabilitation.

Results: 349 participants were recruited and allocated to the intervention (n = 170) or control (n = 179) arms; the attrition rate was 13% at the 6 month primary end-point. One minor adverse event in the intervention group that required no medical input was reported. Intervention arm participants reported better function at 6 months compared with continued GP management alone (-3.01 difference in DI-SMFA [95%CI -5.25, -0.76], p = 0.01).

Conclusions: A generic exercise and self-management intervention resulted in statistically significant changes in function after six-months compared with GP management alone, but clinical significance of these findings is less clear. This may be an effective way of managing group interventions for lower limb OA and chronic lower back pain.
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http://dx.doi.org/10.1016/j.msksp.2020.102271DOI Listing
December 2020

The Heart Failure Readmission Intervention by Variable Early Follow-up (THRIVE) Study: A Pragmatic Randomized Trial.

Circ Cardiovasc Qual Outcomes 2020 10 24;13(10):e006553. Epub 2020 Sep 24.

Division of Research, Kaiser Permanente Northern California, Oakland, CA (K.K.L., R.C.T., T.C.T., T.K.L., A.S.G.).

Background: In-person clinic follow-up within 7 days after discharge from a heart failure hospitalization is associated with lower 30-day readmission. However, health systems and patients may find it difficult to complete an early postdischarge clinic visit, especially during the current pandemic. We evaluated the effect on 30-day readmission and death of follow-up within 7 days postdischarge guided by an initial structured nonphysician telephone visit compared with follow-up guided by an initial clinic visit with a physician.

Methods And Results: We conducted a pragmatic randomized trial in a large integrated healthcare delivery system. Adults being discharged home after hospitalization for heart failure were randomly assigned to either an initial telephone visit with a nurse or pharmacist to guide follow-up or an initial in-person clinic appointment with primary care physicians providing usual care within the first 7 days postdischarge. Telephone appointments included a structured protocol enabling medication titration, laboratory ordering, and booking urgent clinic visits as needed under physician supervision. Outcomes included 30-day readmissions and death and frequency and type of completed follow-up within 7 days of discharge. Among 2091 participants (mean age 78 years, 44% women), there were no significant differences in 30-day heart failure readmission (8.6% telephone, 10.6% clinic, =0.11), all-cause readmission (18.8% telephone, 20.6% clinic, =0.30), and all-cause death (4.0% telephone, 4.6% clinic, =0.49). Completed 7-day follow-up was higher in 1027 patients randomized to telephone follow-up (92%) compared with 1064 patients assigned to physician clinic follow-up (79%, <0.001). Overall frequency of clinic visits during the first 7 days postdischarge was lower in participants assigned to nonphysician telephone guided follow-up (48%) compared with physician clinic-guided follow-up (77%, <0.001).

Conclusions: Early, structured telephone follow-up after hospitalization for heart failure can increase 7-day follow-up and reduce in-person visits with comparable 30-day clinical outcomes within an integrated care delivery framework. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03524534.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.006553DOI Listing
October 2020

Spontaneous liver disease in wild-type C57BL/6JOlaHsd mice fed semisynthetic diet.

PLoS One 2020 21;15(9):e0232069. Epub 2020 Sep 21.

Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Mouse models are frequently used to study mechanisms of human diseases. Recently, we observed a spontaneous bimodal variation in liver weight in C57BL/6JOlaHsd mice fed a semisynthetic diet. We now characterized the spontaneous variation in liver weight and its relationship with parameters of hepatic lipid and bile acid (BA) metabolism. In male C57BL/6JOlaHsd mice fed AIN-93G from birth to postnatal day (PN)70, we measured plasma BA, lipids, Very low-density lipoprotein (VLDL)-triglyceride (TG) secretion, and hepatic mRNA expression patterns. Mice were sacrificed at PN21, PN42, PN63 and PN70. Liver weight distribution was bimodal at PN70. Mice could be subdivided into two nonoverlapping groups based on liver weight: 0.6 SD 0.1 g (approximately one-third of mice, small liver; SL), and 1.0 SD 0.1 g (normal liver; NL; p<0.05). Liver histology showed a higher steatosis grade, inflammation score, more mitotic figures and more fibrosis in the SL versus the NL group. Plasma BA concentration was 14-fold higher in SL (p<0.001). VLDL-TG secretion rate was lower in SL mice, both absolutely (-66%, p<0.001) and upon correction for liver weight (-44%, p<0.001). Mice that would later have the SL-phenotype showed lower food efficiency ratios during PN21-28, suggesting the cause of the SL phenotype is present at weaning (PN21). Our data show that approximately one-third of C57BL/6JOlaHsd mice fed semisynthetic diet develop spontaneous liver disease with aberrant histology and parameters of hepatic lipid, bile acid and lipoprotein metabolism. Study designs involving this mouse strain on semisynthetic diets need to take the SL phenotype into account. Plasma lipids may serve as markers for the identification of the SL phenotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232069PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505464PMC
October 2020

Thymic rejuvenation via FOXN1-reprogrammed embryonic fibroblasts (FREFs) to counteract age-related inflammation.

JCI Insight 2020 09 17;5(18). Epub 2020 Sep 17.

Age-associated systemic, chronic inflammation is partially attributed to increased self-autoreactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), whereas exogenous FOXN1 in TECs can partially rescue age-related thymic involution. TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule, and intrathymic injection of naturally young TECs can lead to middle-aged thymus regrowth. Therefore, as a thymic rejuvenation strategy, we extended these 2 findings by combining them with 2 types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated FOXN1-reprogrammed embryonic fibroblasts (FREFs). We engrafted these FREFs directly into the aged murine thymus. We found substantial regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and autoreactive T cell-mediated inflammation in old mice. Therefore, this approach has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to substantially, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in elderly people.
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http://dx.doi.org/10.1172/jci.insight.140313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526556PMC
September 2020

Provision of first contact physiotherapy in primary care across the UK: a survey of the service.

Physiotherapy 2020 09 27;108:2-9. Epub 2020 Apr 27.

Faculty of Health and Applied Sciences, University of the West of England, Glenside Campus, Blackberry Hill, Stapleton BS16 1DD, Bristol, UK. Electronic address:

Background: First Contact Physiotherapy (FCP) is an emerging model of care whereby a specialist physiotherapist located within general practice undertakes the first patient assessment, diagnosis and management without a prior GP consultation. Despite institutional and professional body support for this model and NHS commitment to its implementation, data regarding current FCP provision are limited.

Objectives: To identify current FCP service provision across the UK, including models of provision and key professional capabilities.

Design: Cross-sectional online survey, targeting physiotherapists and service managers involved in FCP.

Methods: Recruitment involved non-probability sampling targeting those involved in FCP service provision through emails to members of known clinical networks, snowballing and social media. The survey gathered data about respondents, FCP services and the role and scope of physiotherapists providing FCP.

Results: The authors received 102 responses; 32 from service managers and 70 working in FCP practice from England (n=60), Scotland (n=22), Wales (n=14), and Northern Ireland (n=2). Most practitioners were NHS band 7 or 8a (91%, n=63), with additional skills (e.g. requesting investigations, prescribing). 17% (12/70) worked 37.5hours/week; 37% (26/70) ≤10hours; most (71%, 50/70) used 20-minute appointments (range 10-30minutes); varying arrangements were reported for administration and follow-up. Services covered populations of 1200 to 600,000 (75% <100,000); access mostly involved combinations of self-booking and reception triage. Commissioning and funding arrangements varied widely; NHS sources provided 90% of services.

Conclusions: This survey provides new evidence regarding variation in FCP practice across the UK, indicating that evidence-informed, context specific guidance on optimal models of provision is required.
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http://dx.doi.org/10.1016/j.physio.2020.04.005DOI Listing
September 2020

Promoting engagement in physical activity in early rheumatoid arthritis: A proof-of-concept intervention study.

Musculoskeletal Care 2020 12 14;18(4):487-500. Epub 2020 Jul 14.

Faculty of Health and Applied Sciences, University of the West of England, Bristol, UK.

Objective(s): The aim of this study is to test the feasibility and acceptability of promoting engagement in physical activity in early rheumatoid arthritis (PEPA-RA) to inform a future trial.

Design: A 'proof of concept' study was carried out.

Setting: This study was conducted in community hospitals delivered by musculoskeletal primary care physiotherapists.

Participants: Participants were 12 adults with rheumatoid arthritis (RA) diagnosed 6-24 months previously (nine females, three males; mean age 58 years, range 23-79).

Intervention: The intervention consisted of five sessions, that is, four group sessions and one individual session facilitated by a physiotherapist over 12 weeks including patient education and support for behaviour change as well as supervised practical exercise.

Main Outcomes: The main outcomes were attendance, completion of outcome measures, adverse events, and participant and physiotherapist feedback views relating to the intervention.

Results: Overall attendance was 85%, with sessions missed due to illness or RA flare. Outcome measure completion ranged from 83% to 100%. There were no clinically meaningful changes in pain or function at 12 weeks, but mean 6-min walk distance improved from 394 to 440 m. No serious adverse events were reported, and participants were generally positive about the intervention. Suggested minor modifications for the group sessions included venue accessibility and ensuring that physical activity time was protected. Several participants indicated that they would have liked to receive the intervention earlier following diagnosis.

Conclusions: PEPA-RA and the outcomes appear feasible and acceptable. Overall, small beneficial effects were noted at 12 weeks for most outcomes. Challenges to recruitment resulted in a smaller than anticipated sample size, and the majority of participants were active at baseline indicating that future recruitment needs to target less active individuals.
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http://dx.doi.org/10.1002/msc.1493DOI Listing
December 2020

Primary repair of severely retracted nonchronic distal biceps tendon rupture using 2-incision anterior-approach repair.

JSES Int 2020 Jun 3;4(2):231-237. Epub 2020 Mar 3.

Department of Orthopaedic Surgery, University of Missouri, Columbia, MO, USA.

Background: Primary repair of a severely retracted distal biceps tendon can pose a technical challenge. We sought to describe the method and clinical outcomes of a surgical technique used as an adjunct to the conventional anterior single-incision repair for severely retracted biceps tendons. This technique involves a second anterior incision proximally to retrieve a severely retracted tendon followed by passing the tendon through a soft-tissue tunnel.

Methods: We identified 30 consecutive patients who had undergone a primary distal biceps tendon repair by an anterior-approach cortical-button technique. A phone survey was conducted for patient-reported outcomes. Patients returned for bilateral forearm supination strength testing in 2 positions (45º of pronation and 45º of supination). Outcomes were compared between patients who required a second incision and high elbow flexion (>60º) because of severe tendon retraction and those who did not require such interventions.

Results: No significant differences in elbow range of motion, supination strength, or patient-reported outcomes were found between the 2 groups of patients ( > .05). Regarding supination strength, the operated side was significantly weaker than the uninjured side in both pronated and supinated positions ( < .05). Both the operated and uninjured sides showed significantly higher torque in a pronated position than in a supinated position ( < .05).

Conclusions: Severely retracted distal biceps tendons can be successfully repaired using a second incision and high elbow flexion without negative effects on the outcomes. Supination strength was decreased following an anterior-approach cortical-button technique, but patient-reported outcomes were not affected negatively.
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http://dx.doi.org/10.1016/j.jseint.2020.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256892PMC
June 2020

Interventions to Prevent Illicit and Nonmedical Drug Use in Children, Adolescents, and Young Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

JAMA 2020 05;323(20):2067-2079

Kaiser Permanente Evidence-based Practice Center, Center for Health Research, Kaiser Permanente, Portland, Oregon.

Importance: Illicit and nonmedical (use in ways other than instructed) drug use is common in adolescents and young adults and increases the risk of harmful outcomes such as injuries, violence, and poorer academic performance.

Objective: To review the benefits and harms of interventions to prevent illicit and nonmedical drug use in children, adolescents, and young adults to inform the US Preventive Services Task Force.

Data Sources: MEDLINE, PubMED, PsycINFO, and the Cochrane Central Register of Controlled Trials (January 1, 2013, to January 31, 2019 [children and adolescents]; January 1, 1992, to January 31, 2019 [young adults <25 years]); surveillance through March 20, 2020.

Study Selection: Clinical trials of behavioral counseling interventions to prevent initiation of illicit and nonmedical drug use among young people.

Data Extraction And Synthesis: Critical appraisal was completed independently by 2 investigators. Data were extracted by 1 reviewer and checked by a second. Random-effects meta-analysis was used to estimate the effect sizes associated with the interventions.

Main Outcomes And Measures: Number of times illicit drugs were used; any illicit drug or any cannabis use.

Results: Twenty-nine trials (N = 18 353) met inclusion criteria. Health, social, or legal outcomes such as mental health symptoms, family functioning, consequences of drug use, and arrests were reported in 19 trials and most showed no group differences. The effects on illicit drug use in 26 trials among nonpregnant youth (n = 17 811) were highly variable; the pooled result did not show a clinically important or statistically significant association with illicit drug use (standardized mean difference, -0.08 [95% CI, -0.16 to 0.001]; 24 effects [from 23 studies]; n = 12 801; I2 = 57.0%). The percentage of participants using illicit drugs ranged from 2.3% to 38.6% in the control groups and 2.4% to 33.7% in the intervention groups at 3 to 32 months' follow-up. The median absolute risk difference between groups was -2.8%, favoring the intervention group (range, -11.5% to 14.8%). The remaining 3 trials provided a perinatal home-visiting intervention to pregnant Native American youth. One trial (n=322) found a reduction in illicit drug use at 38 months (eg, cannabis use in the previous month, 10.7% in the intervention group and 15.6% in the control group) but not at earlier follow-up assessments. Across all 29 trials, only 1 trial reported on harms and found no statistically significant group differences.

Conclusions And Relevance: The evidence for behavioral counseling interventions to prevent initiation of illicit and nonmedical drug use among adolescents and young adults was inconsistent and imprecise, with some interventions associated with reduction in use and others associated with no benefit or increased use. Health, social, and legal outcomes were sparsely reported, and few showed improvements.
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http://dx.doi.org/10.1001/jama.2020.1432DOI Listing
May 2020

Thymic Function Associated With Cancer Development, Relapse, and Antitumor Immunity - A Mini-Review.

Front Immunol 2020 30;11:773. Epub 2020 Apr 30.

Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, TX, United States.

The thymus is the central lymphoid organ for T cell development, a cradle of T cells, and for central tolerance establishment, an educator of T cells, maintaining homeostatic cellular immunity. T cell immunity is critical to control cancer occurrence, relapse, and antitumor immunity. Evidence on how aberrant thymic function influences cancer remains largely insufficient, however, there has been recent progress. For example, the involuted thymus results in reduced output of naïve T cells and a restricted T cell receptor (TCR) repertoire, inducing immunosenescence and potentially dampening immune surveillance of neoplasia. In addition, the involuted thymus relatively enhances regulatory T (Treg) cell generation. This coupled with age-related accumulation of Treg cells in the periphery, potentially provides a supportive microenvironment for tumors to escape T cell-mediated antitumor responses. Furthermore, acute thymic involution from chemotherapy can create a tumor reservoir, resulting from an inflammatory microenvironment in the thymus, which is suitable for disseminated tumor cells to hide, survive chemotherapy, and become dormant. This may eventually result in cancer metastatic relapse. On the other hand, if thymic involution is wisely taken advantage of, it may be potentially beneficial to antitumor immunity, since the involuted thymus increases output of self-reactive T cells, which may recognize certain tumor-associated self-antigens and enhance antitumor immunity, as demonstrated through depletion of autoimmune regulator () gene in the thymus. Herein, we briefly review recent research progression regarding how altered thymic function modifies T cell immunity against tumors.
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http://dx.doi.org/10.3389/fimmu.2020.00773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203483PMC
March 2021

Further analysis of modifications to the three-step guided compliance procedure to enhance compliance among children with autism.

J Appl Behav Anal 2020 09 8;53(4):2339-2348. Epub 2020 May 8.

School of Behavior Analysis, Florida Institute of Technology.

Three-step guided compliance (vocal prompt, vocal plus model prompt, vocal prompt plus physical guidance) is a commonly used procedure to increase compliance among children with intellectual disabilities. Previous research has suggested that under some conditions, slight modifications to the three-step procedure may enhance its effectiveness. These modifications include omitting the model prompt and decreasing the interprompt interval. In the current study, we evaluated another modification to the procedure: the delivery of a high-preference item contingent upon compliance with the first vocal prompt (i.e., differential reinforcement). For 2 participants with autism, compliance remained low when we implemented differential reinforcement and the guided compliance procedure in isolation. However, compliance improved when we combined differential reinforcement and the three-step guided procedure, suggesting that for at least some children, the combination of contingent access to a high-preference item and the guided compliance procedure is more effective than either intervention alone.
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http://dx.doi.org/10.1002/jaba.721DOI Listing
September 2020

The C291R Tau Variant Forms Different Types of Protofibrils.

Front Mol Neurosci 2020 18;13:39. Epub 2020 Mar 18.

School of Life Sciences, University of Warwick, Coventry, United Kingdom.

Mutations in the gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in native-state and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at ~210 nm compared with ~199 nm for tau-K18 WT. These data suggest mutation-enhanced β-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve β-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures.
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http://dx.doi.org/10.3389/fnmol.2020.00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093375PMC
March 2020

How to set up a clinical trial.

Postgrad Med J 2020 Sep 26;96(1139):564-569. Epub 2020 Mar 26.

The Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburgh, UK.

Clinical trials are considered the gold-standard method for the evaluation of healthcare interventions. However, randomised control trials are complex to perform and many researchers, especially those in the early stages of their career, can find it challenging to know where to start set up, contribute to or lead a trial. This guide provides an introduction to trials and also practical advice to help potential investigators complete their clinical trial to time and to budget by signposting the pathway through the complex regulatory landscape. The authors draw on their own recent experiences of running clinical trials and provide tips and tricks for troubleshooting common problems encountered including trial design and documentation.
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http://dx.doi.org/10.1136/postgradmedj-2019-137379DOI Listing
September 2020

Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.

Clin Sci (Lond) 2020 04;134(7):727-746

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.
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http://dx.doi.org/10.1042/CS20190124DOI Listing
April 2020
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