Publications by authors named "John Flanagan"

240 Publications

Monoclonal Antibodies to S and N SARS-CoV-2 Proteins as Probes to Assess Structural and Antigenic Properties of Coronaviruses.

Viruses 2021 09 22;13(10). Epub 2021 Sep 22.

Department of Microbiology & Immunology, Penn State College of Medicine, Hershey, PA 17033, USA.

Antibodies targeting the spike (S) and nucleocapsid (N) proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential tools. In addition to important roles in the treatment and diagnosis of infection, the availability of high-quality specific antibodies for the S and N proteins is essential to facilitate basic research of virus replication and in the characterization of mutations responsible for variants of concern. We have developed panels of mouse and rabbit monoclonal antibodies (mAbs) to the SARS-CoV-2 spike receptor-binding domain (S-RBD) and N protein for functional and antigenic analyses. The mAbs to the S-RBD were tested for neutralization of native SARS-CoV-2, with several exhibiting neutralizing activity. The panels of mAbs to the N protein were assessed for cross-reactivity with the SARS-CoV and Middle East respiratory syndrome (MERS)-CoV N proteins and could be subdivided into sets that showed unique specificity for SARS-CoV-2 N protein, cross-reactivity between SARS-CoV-2 and SARS-CoV N proteins only, or cross-reactivity to all three coronavirus N proteins tested. Partial mapping of N-reactive mAbs were conducted using truncated fragments of the SARS-CoV-2 N protein and revealed near complete coverage of the N protein. Collectively, these sets of mouse and rabbit monoclonal antibodies can be used to examine structure/function studies for N proteins and to define the surface location of virus neutralizing epitopes on the RBD of the S protein.
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http://dx.doi.org/10.3390/v13101899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537396PMC
September 2021

Baseline SARS-CoV-2 Viral Load is Associated With COVID-19 Disease Severity and Clinical Outcomes: Post-Hoc Analyses of a Phase 2/3 Trial.

J Infect Dis 2021 Sep 8. Epub 2021 Sep 8.

Regeneron Pharmaceuticals, Inc., Tarrytown, NY  USA.

Background: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding COVID-19.

Methods: SARS-CoV-2 levels were analyzed by quantitative real-time polymerase chain reaction (RT-qPCR) of nasopharyngeal or oropharyngeal swab specimens collected at baseline and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalized patients enrolled in a multicenter, randomized, placebo-controlled phase 2/3 trial of sarilumab for COVID-19 (NCT04315298).

Results: In post-hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold (Ct) and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time versus placebo.

Conclusions: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.
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http://dx.doi.org/10.1093/infdis/jiab445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8522400PMC
September 2021

False Positive Responses in Standard Automated Perimetry.

Am J Ophthalmol 2021 Jul 18;233:180-188. Epub 2021 Jul 18.

From Ophthalmology Research Unit, Department of Clinical Sciences Malmö, Lund University (A.H. and B.B.); Department of Ophthalmology, Skåne University Hospital, Malmö, Sweden (A.H.).

Purpose: To analyze the relationship between rates of false positive (FP) responses and standard automated perimetry results.

Design: Prospective multicenter cross-sectional study.

Methods: One hundred twenty-six patients with manifest or suspect glaucoma were tested with Swedish Interactive Thresholding Algorithm (SITA) Standard, SITA Fast, and SITA Faster at each of 2 visits. We calculated intervisit differences in mean deviation (MD), visual field index (VFI), and number of statistically significant test points as a function of FP rates and also as a function of general height (GH).

Results: Increasing FP values were associated with higher MD values for all 3 algorithms, but the effects were small, 0.3 dB to 0.6 dB, for an increase of 10 percentage points of FP rate, and for VFI even smaller (0.6%-1.4%). Only small parts of intervisit differences were explained by FP (r values 0.00-0.11). The effects of FP were larger in severe glaucoma, with MD increases of 1.1 dB to 2.0 dB per 10 percentage points of FP, and r values ranging from 0.04 to 0.33. The numbers of significantly depressed total deviation points were affected only slightly, and pattern deviation probability maps were generally unaffected. GH was much more strongly related to perimetric outcomes than FP.

Conclusions: Across 3 different standard automated perimetry thresholding algorithms, FP rates showed only weak associations with visual field test results, except in severe glaucoma. Current recommendations regarding acceptable FP ranges may require revision. GH or other analyses may be better suited than FP rates for identifying unreliable results in patients who frequently press the response button without having perceived stimuli.
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http://dx.doi.org/10.1016/j.ajo.2021.06.026DOI Listing
July 2021

2017 National Optometry Workforce Survey.

Optom Vis Sci 2021 05;98(5):500-511

School of Optometry and Vision Science Program, University of California, Berkeley, Berkeley, California.

Significance: Planning for the effective delivery of eye care, on all levels, depends on an accurate and detailed knowledge of the optometric workforce and an understanding of demographic/behavioral trends to meet future needs of the public.

Purpose: The purposes of this study were to assess the current and future supply of doctors of optometry and to examine in-depth trends related to (1) demographic shifts, (2) sex-based differences, (3) differences in practice behaviors in between self-employed and employed optometrists, and (4) the concept of additional capacity within the profession.

Methods: The 2017 National Optometry Workforce Survey (31 items) was distributed to 4050 optometrists, randomly sampled from a population of 45,033 currently licensed and practicing optometrists listed in the American Optometric Association's Optometry Master Data File. A stratified sampling method was applied to the population of optometrists using primary license state, age, and sex as variables to ensure a representative sample.

Results: With a response rate of 29% (1158 responses), the sample ensured a 95% confidence interval with a margin of error of <5%. Key results include finding no significant differences between men and women for hours worked (38.9 vs. 37.5), productivity (patient visits per hour, 2.0 vs. 1.9), or career options/professional growth satisfaction with 65% for both. The data indicate a likely range of additional patient capacity of 2.29 to 2.57 patients per week (5.05 to 5.65 million annually profession-wide).

Conclusions: The optometric workforce for the next decade is projected to grow 0.6 to 0.7% more annually than the U.S. population. The study found additional capacity for the profession more limited than previously suggested. Findings also illustrate an evolving/equitable workforce based on sex, in terms of both productivity and satisfaction. The trend toward employed versus self-employed was marked with 44% reporting they are employed, up from 29% in 2012.
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http://dx.doi.org/10.1097/OPX.0000000000001688DOI Listing
May 2021

Ophthalmic Physiol Opt 2021 05 20;41(3):632. Epub 2021 Mar 20.

State University of New York, New York, USA.

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http://dx.doi.org/10.1111/opo.12803DOI Listing
May 2021

An N-terminal conserved region in human Atg3 couples membrane curvature sensitivity to conjugase activity during autophagy.

Nat Commun 2021 01 14;12(1):374. Epub 2021 Jan 14.

Departments of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA, USA.

During autophagy the enzyme Atg3 catalyzes the covalent conjugation of LC3 to the amino group of phosphatidylethanolamine (PE) lipids, which is one of the key steps in autophagosome formation. Here, we have demonstrated that an N-terminal conserved region of human Atg3 (hAtg3) communicates information from the N-terminal membrane curvature-sensitive amphipathic helix (AH), which presumably targets the enzyme to the tip of phagophore, to the C-terminally located catalytic core for LC3-PE conjugation. Mutations in the putative communication region greatly reduce or abolish the ability of hAtg3 to catalyze this conjugation in vitro and in vivo, and alter the membrane-bound conformation of the wild-type protein, as reported by NMR. Collectively, our results demonstrate that the N-terminal conserved region of hAtg3 works in concert with its geometry-selective AH to promote LC3-PE conjugation only on the target membrane, and substantiate the concept that highly curved membranes drive spatial regulation of the autophagosome biogenesis during autophagy.
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http://dx.doi.org/10.1038/s41467-020-20607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809043PMC
January 2021

Association between birth weight and risk of overweight at adulthood in Labrador dogs.

PLoS One 2020 10;15(12):e0243820. Epub 2020 Dec 10.

NeoCare, Université de Toulouse, ENVT, Toulouse, France.

Several studies in humans indicate that low birth weight predisposes individuals to obesity in later life. Despite the constant increase in prevalence of obesity in the canine population and the major health consequences of this affection, few investigations have been carried out on the association between birth weight and the development of overweight in dogs. The purpose of the current study was to examine the association between birth weight and some other neonatal characteristics and overweight at adulthood in a population of purebred Labrador dogs. Information was collected about the sex, age, neuter status, birth weight, and growth rates (between 0-2 days and 2-15 days of age) in 93 Labrador dogs raised under similar environmental conditions until two months old. The body condition scores (BCS, scale of 1-9) of these dogs at adulthood were recorded, with BCS equal to or greater than 6 classified as overweight. Dogs were split into two groups based on the median birth weight in the population: lower than the median (LTM) and higher than the median (HTM). A logistic regression model was applied to analyse associations between the general characteristics of the dogs (sex, age, neuter status), early life parameters (birth weight, growth rates) and overweight at adulthood. Birth weight was the only early-life parameter found to be associated with overweight (p value = 0.032) with a prevalence of overweight of 70% among the dogs with LTM birth weight vs. 47% in dogs born with HTM birth weight. Overweight was also associated with age and neuter status (p value = 0.029 and 0.005 respectively). Our results suggest that, as in humans, dogs with the lowest birth weights are more likely to become overweight at adulthood. More studies are needed to further examine this relationship and to explore the underlying mechanisms. A subsequent objective could be to identify preventive strategies such as an adapted early nutrition programme for at-risk individuals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243820PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728192PMC
February 2021

COVID-19: ensuring safe clinical teaching at university optometry schools.

Ophthalmic Physiol Opt 2021 01 10;41(1):144-156. Epub 2020 Dec 10.

State University of New York (SUNY), College of Optometry, New York, USA.

The COVID-19 pandemic has been spreading across the globe for several months. The nature of the virus (SARS-CoV-2) with easy person-to-person transmissions and the severe clinical course observed in some people necessitated unprecedented modifications of everyday social interactions. These included the temporary suspension of considerable elements of clinical teaching at optometry schools worldwide. This article describes the challenges optometry schools were facing in early to mid 2020. The paper highlights the experiences of six universities in five countries on four continents. Strategies to minimise the risk of virus transmission, to ensure safe clinical optometric teaching and how to overcome the challenges presented by COVID-19 are described. An outlook on opportunities to further improve optometric education is provided.
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http://dx.doi.org/10.1111/opo.12764DOI Listing
January 2021

Molecular architecture and domain arrangement of the placental malaria protein VAR2CSA suggests a model for carbohydrate binding.

J Biol Chem 2020 12 29;295(52):18589-18603. Epub 2020 Oct 29.

Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA. Electronic address:

VAR2CSA is the placental-malaria-specific member of the antigenically variant erythrocyte membrane protein 1 (PfEMP1) family. It is expressed on the surface of infected host red blood cells and binds to specific chondroitin-4-sulfate chains of the placental proteoglycan receptor. The functional ∼310 kDa ectodomain of VAR2CSA is a multidomain protein that requires a minimum 12-mer chondroitin-4-sulfate molecule for specific, high affinity receptor binding. However, it is not known how the individual domains are organized and interact to create the receptor-binding surface, limiting efforts to exploit its potential as an effective vaccine or drug target. Using small angle X-ray scattering and single particle reconstruction from negative-stained electron micrographs of the ectodomain and multidomain constructs, we have determined the structural architecture of VAR2CSA. The relative locations of the domains creates two distinct pores that can each accommodate the 12-mer of chondroitin-4-sulfate, suggesting a model for receptor binding. This model has important implications for understanding cytoadherence of infected red blood cells and potentially provides a starting point for developing novel strategies to prevent and/or treat placental malaria.
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http://dx.doi.org/10.1074/jbc.RA120.014676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939466PMC
December 2020

Effects of High-Fat Diet at Two Energetic Levels on Fecal Microbiota, Colonic Barrier, and Metabolic Parameters in Dogs.

Front Vet Sci 2020 25;7:566282. Epub 2020 Sep 25.

Nutrition, PhysioPathology and Pharmacology Unit (NP3), Oniris, College of Veterinary Medicine, Food Sciences and Engineering, CRNH, Nantes, France.

Increased consumption of energy-rich foods is a key factor in overweight, obesity, and associated metabolic disorders. This would be, at least in part, related to microbiota disturbance. In rodent models of obesity, microbiota disruption has been associated with alteration of the intestinal barrier, endotoxemia, inflammation grade, and insulin sensitivity. The aim of the present study was to assess the effects of a high-fat diet (HFD), fed at two energetic levels, on microbiota, intestinal barrier, and inflammatory and metabolic parameters in dogs. A HFD (33% fat as fed, 4,830 kcal/kg) was given to 24 healthy Beagle dogs at 100% (HF-100; = 8) and at 150% (HF-150; = 16) of their maintenance energy requirements for 8 weeks. Analysis of similarity revealed a significant difference in gut microbiota β-diversity following the diet compared to week 0 in both groups while α-diversity was lower only in the HF-150 group. Firmicutes/Bacteroidetes ratio was higher in the HF-150 group compared to the HF-100 group at weeks 2 and 8. A reduction in insulin sensitivity was observed over time in the HF150 group. Neither endotoxemia nor inflammation was observed in either group, did not find supporting data for the hypothesis that the microbiota is involved in the decline of insulin sensitivity through metabolic endotoxemia and low-grade inflammation. Colonic permeability was increased at week 4 in both groups and returned to initial levels at week 8, and was associated with modifications to the expression of genes involved in colonic barrier function. The increase in intestinal permeability may have been caused by the altered intestinal microbiota and increased expression of genes encoding tight junction proteins might indicate a compensatory mechanism to restore normal permeability. Although simultaneous changes to the microbiota, barrier permeability, inflammatory, and metabolic status have not been observed, such a causal link cannot be excluded in dogs overfed on a HFD. Further studies are necessary to better understand the link between HFD, intestinal microbiota and the host.
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http://dx.doi.org/10.3389/fvets.2020.566282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545960PMC
September 2020

Letter from America.

Ophthalmic Physiol Opt 2020 Nov 5;40(6):708-709. Epub 2020 Oct 5.

University of California, Berkeley, USA.

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http://dx.doi.org/10.1111/opo.12740DOI Listing
November 2020

Esomeprazole reduces sperm motility index by targeting the spermic cholinergic machinery: A mechanistic study for the association between use of proton pump inhibitors and reduced sperm motility index.

Biochem Pharmacol 2020 12 28;182:114212. Epub 2020 Aug 28.

Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. Electronic address:

Recent studies have linked prolonged use of the most commonly prescribed proton pump inhibitors (PPIs) with declined human sperm function and infertility. Here, we report for the first time the most plausible underlying mechanism for this unwarranted secondary mode of action. We followed up on a recent serendipitous discovery in our laboratory regarding PPIs' off-target action and performed detailed pharmacodynamic analyses by combining in silico and in vitro studies to determine the off-target effect of one of the most commonly used PPI, esomeprazole, on the key human acetylcholine biosynthesizing enzyme, choline acetyltransferase (ChAT; EC 2.3.1.6). A pivotal enzyme in the spermic cholinergic system that governs the sperm motility, concentration and quality. Our results were conclusive and showed that both the racemic form, omeprazole and its pure S-enantiomer, esomeprazole, acted as potent mixed-competitive inhibitor of human ChAT with a global inhibition constant (K) of 88 nM (95%CI: 10-167 nM) for esomeprazole and 178 nM (95%CI: 140-230 nM) for the racemic drug omeprazole. Most importantly, esomeprazole substantially reduces both total number of motile sperm (by 36%, p < 0.001; and 21% p < 0.0001, at 10 and 100 nM, respectively) as well as the total number of sperm with progressive motility (by 42% p < 0.0016 and by 26% p < 0.0001, respectively) after 60 min relative to 20 min incubation in our ex vivo functional assay performed on ejaculated human sperm. In conclusion, this study presents a completely new perspective regarding PPIs secondary mode of action/unwarranted side effects and calls for further mechanistic and larger clinical studies to elucidate the role of PPIs in infertility.
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http://dx.doi.org/10.1016/j.bcp.2020.114212DOI Listing
December 2020

Use of reduced-energy content maintenance diets for modest weight reduction in overweight cats and dogs.

Res Vet Sci 2020 Aug 1;131:194-205. Epub 2020 May 1.

Institute of Lifecourse and Medical Sciences, University of Liverpool, Leahurst Campus, Chester High Road, Neston, Wirral CH64 7TE, United Kingdom; Institute of Veterinary Science, University of Liverpool, Leahurst Campus, Chester High Road, Neston, Wirral CH64 7TE, United Kingdom. Electronic address:

One option for controlled weight loss for dogs and cats in overweight condition could be to modestly restrict caloric intake using a reduced-energy ('light') maintenance diet, but there is no prior research on the safety and efficacy of such an approach. A prospective observational cohort study was performed in 67 overweight dogs and 17 overweight cats undergoing weight loss using reduced-energy maintenance diets from one manufacturer. Diets were fed at approximately 80% of maintenance energy requirements for ideal bodyweight for a period of 8 weeks. Essential nutrient intake was estimated for each dog and cat and compared with minimum requirement (MR) or adequate intake (AI, when no MR had been demonstrated) as set by the National Research Council in 2006. Weight loss was seen in 56/67 dogs (84%), losing a median of 4.7% (range 15.2% loss to 10.0% gain) of their starting body weight (SBW). Weight loss was also seen in all 17 cats, losing a median of 6.4% (range 2.0 loss to 15.2% loss) of SBW. Of the essential nutrients examined, only selenium, choline, potassium, and riboflavin were less than NRC recommendations in a minority of animals. However, no signs of any nutrient deficiency were observed in any of the dogs or cats during the study. In summary, modestly energy restricting overweight dogs and cats when feeding a low-energy maintenance diet can induce weight loss and might be a useful initial step for weight management. Although no adverse effects were seen, borderline intake of some micronutrients warrants further consideration.
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http://dx.doi.org/10.1016/j.rvsc.2020.04.019DOI Listing
August 2020

Normal Testosterone but Higher Luteinizing Hormone Plasma Levels in Men With Hypersexual Disorder.

Sex Med 2020 Jun 12;8(2):243-250. Epub 2020 Mar 12.

Department of Clinical Sciences/Psychiatry, Umeå University, Umeå, Sweden; Department of Clinical Neuroscience/Psychiatry, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

Introduction: Hypersexual disorder as suggested to be included in the Diagnostic and Statistical Manual of Mental Disorders-5 integrates aspects of sexual desire deregulation, impulsivity, and compulsivity. However, it is unknown how it affects gonadal activity and the function of the hypothalamus-pituitary-gonadal (HPG) axis.

Aim: The aim of this study was to investigate testosterone and luteinizing hormone (LH) levels in hypersexual men compared with healthy controls. Furthermore, we investigated associations between epigenetic markers and hormone levels.

Methods: Basal morning plasma levels of testosterone, LH, and sex hormone-binding globulin (SHBG) were assessed in 67 hypersexual men (mean age: 39.2 years) compared with 39 age-matched healthy controls (mean age: 37.5 years). The Sexual Compulsivity Scale and the Hypersexual Disorder: Current Assessment Scale were used for assessing hypersexual behavior, the Montgomery-Åsberg Depression Scale-self rating was used for depression severity, and the Childhood Trauma Questionnaire (CTQ) was used for assessing history of childhood adversity. The genome-wide methylation pattern of more than 850 K CpG sites was measured in whole blood using the Illumina Infinium Methylation EPIC BeadChip. CpG sites located within 2,000 bp of the transcriptional start site of hypothalamus pituitary adrenal (HPA) and HPG axis-coupled genes were included.

Main Outcome Measures: Testosterone and LH plasma levels in association with clinical rating and a secondary outcome was the epigenetic profile of HPA and HPG axis-coupled CpG sites with testosterone and LH levels.

Results: LH plasma levels were significantly higher in patients with hypersexual disorder than in healthy volunteers. No significant differences in plasma testosterone, follicle stimulating hormone, prolactin, and SHBG levels were found between the groups. There were no significant associations between DNA methylation of HPA and HPG axis-coupled genes and plasma testosterone or LH levels after multiple testing corrections.

Conclusions: Subtle dysregulation of the HPG axis, with increased LH plasma levels but no difference in testosterone levels may be present in hypersexual men. Chatzittofis A, Boström AE, Öberg KG, et al. Normal Testosterone but Higher Luteinizing Hormone Plasma Levels in Men With Hypersexual Disorder. Sex Med 2020;8:243-250.
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http://dx.doi.org/10.1016/j.esxm.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261685PMC
June 2020

The Harvard Medical School Pathways Curriculum: Reimagining Developmentally Appropriate Medical Education for Contemporary Learners.

Acad Med 2020 11;95(11):1687-1695

E.M. Hundert is dean for medical education and professor in residence of global health and social medicine at Harvard Medical School, Boston, Massachusetts.

As the U.S. health care system changes and technology alters how doctors work and learn, medical schools and their faculty are compelled to modify their curricula and teaching methods. In this article, educational leaders and key faculty describe how the Pathways curriculum was conceived, designed, and implemented at Harvard Medical School. Faculty were committed to the principle that educators should focus on how students learn and their ability to apply what they learn in the evaluation and care of patients. Using the best evidence from the cognitive sciences about adult learning, they made major changes in the pedagogical approach employed in the classroom and clinic. The curriculum was built upon 4 foundational principles: to enhance critical thinking and provide developmentally appropriate content; to ensure both horizontal integration between courses and vertical integration between phases of the curriculum; to engage learners, foster curiosity, and reinforce the importance of student ownership and responsibility for their learning; and to support students' transformation to a professional dedicated to the care of their patients and to their obligations for lifelong, self-directed learning.The practice of medicine is rapidly evolving and will undoubtedly change in multiple ways over the career of a physician. By emphasizing personal responsibility, professionalism, and thinking skills over content transfer, the authors believe this curriculum will prepare students not only for the first day of practice but also for an uncertain future in the biological sciences, health and disease, and the nation's health care system, which they will encounter in the decades to come.
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http://dx.doi.org/10.1097/ACM.0000000000003270DOI Listing
November 2020

Muscle Strength, Size, and Composition Following 12 Months of Gender-affirming Treatment in Transgender Individuals.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Laboratory Medicine, Division of Clinical Physiology, Karolinska Institutet, and Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.

Context: As many sports are divided in male/female categories, governing bodies have formed regulations on the eligibility for transgender individuals to compete in these categories. Yet, the magnitude of change in muscle mass and strength with gender-affirming treatment remains insufficiently explored.

Objective: This study explored the effects of gender-affirming treatment on muscle function, size, and composition during 12 months of therapy.

Design, Settings, Participants: In this single-center observational cohort study, untrained transgender women (TW, n = 11) and transgender men (TM, n = 12), approved to start gender-affirming medical interventions, underwent assessments at baseline, 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement, and 4 and 12 months after treatment initiation.

Main Outcome Measures: Knee extensor and flexor strength were assessed at all examination time points, and muscle size and radiological density (using magnetic resonance imaging and computed tomography) at baseline and 12 months after treatment initiation.

Results: Thigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps cross-sectional area (CSA) (15%) and radiological density (6%). In TW, the corresponding parameters decreased by -5% (muscle volume) and -4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained their strength levels.

Conclusions: One year of gender-affirming treatment resulted in robust increases in muscle mass and strength in TM, but modest changes in TW. These findings add new knowledge on the magnitude of changes in muscle function, size, and composition with cross-hormone therapy, which could be relevant when evaluating the transgender eligibility rules for athletic competitions.
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http://dx.doi.org/10.1210/clinem/dgz247DOI Listing
March 2020

Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons.

Elife 2019 11 20;8. Epub 2019 Nov 20.

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom.

Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.
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http://dx.doi.org/10.7554/eLife.48718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894925PMC
November 2019

Metabolisable energy content in canine and feline foods is best predicted by the NRC2006 equation.

PLoS One 2019 27;14(9):e0223099. Epub 2019 Sep 27.

Institute of Ageing and Chronic Disease, University of Liverpool, Neston, Cheshire, United Kingdom.

Although animal trials are the most accurate approach to determine the metabolisable energy (ME) content of pet food, these are expensive and labour-intensive. Instead, various equations have been proposed to predict ME content, but no single method is universally recommended. Data from canine and feline feeding studies, conducted according to Association of American Feed Control Officials recommendations, over a 6-year period at a single research site, were utilised to determine the performance of different predictive equations. Predictive equations tested included the modified Atwater (MA equation), NRC 2006 equations using both crude fibre (NRC 2006cf) and total dietary fibre (NRC 2006tdf), and new equations reported in the most recent study assessing ME predictive equations (Hall equations; PLoS ONE 8(1): e54405). Where appropriate, equations were tested using both predicted gross energy (GE) and GE measured by bomb calorimetry. Associations between measured and predicted ME were compared with Deming regression, whilst agreement was assessed with Bland-Altman plots. 335 feeding trials were included, comprising 207 canine (182 dry food; 25 wet food) and 128 feline trials (104 dry food, 24 wet food). Predicted ME was positively associated with measured ME whatever the equation used (P<0.001 for all). Agreement between predicted and actual ME was worst for the MA equation, for all food types, with evidence of both a systematic bias and proportional errors evident for all food types. The NRC 2006cf and Hall equations were intermediate in performance, whilst the NRC 2006tdf equations performed best especially when using measured rather than predicted GE, with the narrowest 95% limits of agreement, minimal bias and proportional error. In conclusion, when predicting ME content of pet food, veterinarians, nutritionists, pet food manufacturers and regulatory bodies are strongly advised to use the NRC 2006tdf equations and using measured rather than predicted GE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223099PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6764676PMC
April 2020

Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling: A DNA methylation analysis of miRNA genes.

Epigenetics 2020 Jan - Feb;15(1-2):145-160. Epub 2019 Sep 22.

Department of Clinical Sciences/Psychiatry, Umeå University, Umeå, Sweden.

Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification 'Compulsive Sexual Behavior Disorder' is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD - cg18222192 (MIR708)( < 10E-05, = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.
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http://dx.doi.org/10.1080/15592294.2019.1656157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961682PMC
April 2021

Targeting Nuclear Receptors with PROTAC degraders.

Mol Cell Endocrinol 2019 08 21;493:110452. Epub 2019 May 21.

Halda Therapeutics, 23 Business Park, Branford, CT, 06405, USA. Electronic address:

Nuclear receptors comprise a class of intracellular transcription factors whose major role is to act as sensors of various stimuli and to convert the external signal into a transcriptional output. Nuclear receptors (NRs) achieve this by possessing a ligand binding domain, which can bind cell permeable agonists, a DNA-binding domain, which binds the upstream sequences of target genes, and a regulatory domain that recruits the transcriptional machinery. The ligand binding alters the activation state of the NR, either by activating or inactivating its transcriptional output. Given the central role of NRs in signal transduction, many currently approved therapeutics modulate the activity of NRs. Here we discuss how PROTAC degraders afford a novel approach to abrogate the downstream signaling activity of NRs. We highlight six broad functional reasons why PROTAC degraders are preferable to the classical ligand binding pocket antagonists, with specific examples provided for each category. Lastly, as Androgen Receptor and Estrogen Receptor PROTAC degraders are being pursued as treatment for prostate cancer and breast cancer, respectively, a rationale is provided for the translational utility for the degradation of these two NRs.
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http://dx.doi.org/10.1016/j.mce.2019.110452DOI Listing
August 2019

Comparison of the effects of different kibble shape on voluntary food intake and palatability of weight loss diets in pet dogs.

Res Vet Sci 2019 Jun 1;124:375-382. Epub 2019 May 1.

Institute of Ageing and Chronic Disease, University of Liverpool, Leahurst Campus, Chester High Road, Neston, Wirral CH64 7TE, United Kingdom. Electronic address:

Altering characteristics of a dry proprietary diet can increase chewing, slow ingestion speed and reduce voluntary food intake. Panels of healthy research dogs consumed kibbled weight loss diets with either a l round (pastille) or a cross shape. Two panels ('small-size' panel, dogs<10 kg 'all-size' panel, dogs with a range of sizes) were used to determine palatability (study 1), whilst a third panel ('consumption kinetics panel') was used to determine voluntary food intake [VFI] and meal duration (study 2). Study 3 was a field trial where the cross kibble was fed to client-owned overweight dogs undergoing controlled weight loss, and attitudes of owners were sort. In study 1, dogs in the all-size panel consumed more of the cross-kibble diet than of the round-kibble diet (P < .001), but there was no significant difference in dogs of the small-size panel (P = 1.000). In study 2, VFI was broadly similar for both diets, with no difference in total consumption across all four meals (P = .370). However, meal duration was significantly longer for the cross kibble (meal 1: 292 s; meal 2: 650 s) compared with the round kibble (meal 1: 186 s; meal 2: 282, P < .001 for both). In study 3, owners observed more chewing behaviour (P = .031), slower ingestion speed (P = .031), and a significant decrease in food-seeking behaviour (P = .020) when eating the cross-kibble compared with the round-kibble. Altering the kibble shape of a canine therapeutic weight loss diet can decrease ingestion speed without affecting palatability, but studies are now required to determine the effect on outcomes of weight management.
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http://dx.doi.org/10.1016/j.rvsc.2019.04.023DOI Listing
June 2019

Insulin Receptor Associates with Promoters Genome-wide and Regulates Gene Expression.

Cell 2019 04 4;177(3):722-736.e22. Epub 2019 Apr 4.

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in prevalent chronic diseases. IR binds insulin at the cell surface and transduces rapid signaling via cytoplasmic kinases. However, mechanisms mediating long-term effects of insulin remain unclear. Here, we show that IR associates with RNA polymerase II in the nucleus, with striking enrichment at promoters genome-wide. The target genes were highly enriched for insulin-related functions including lipid metabolism and protein synthesis and diseases including diabetes, neurodegeneration, and cancer. IR chromatin binding was increased by insulin and impaired in an insulin-resistant disease model. Promoter binding by IR was mediated by coregulator host cell factor-1 (HCF-1) and transcription factors, revealing an HCF-1-dependent pathway for gene regulation by insulin. These results show that IR interacts with transcriptional machinery at promoters and identify a pathway regulating genes linked to insulin's effects in physiology and disease.
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http://dx.doi.org/10.1016/j.cell.2019.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478446PMC
April 2019

Retinal blood oxygen saturation and aqueous humour biomarkers in early diabetic retinopathy.

Acta Ophthalmol 2019 Aug 28;97(5):e673-e679. Epub 2019 Jan 28.

Retina Research Group, School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada.

Purpose: The aim of this study was to assess the relationship between retinal blood oxygen saturation (SO ) and specific aqueous humour (AH) concentrations of proangiogenic biomarkers in diabetic patients with nonproliferative diabetic retinopathy (NPDR) and to compare them with those of matched control subjects.

Methods: The sample comprised 14 participants with mild-to-moderate NPDR (69.1 ± 6.6 years) and 17 age-matched healthy controls (69.7 ± 6.3 years); all participants were previously scheduled for routine cataract extraction with intraocular lens implantation. Multiplex cytokine analyses of specific biomarkers, including vascular endothelial growth factor A (VEGF-A), angiopoietin2 (Ang2), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and interleukin-8 (IL-8) were performed by BioPlex 200 system. Six non-invasive hyperspectral retinal images were acquired.

Results: Mean SO was significantly higher in both arterioles (94.4 ± 1.9 versus 93.0 ± 1.6) and venules (64.4 ± 5.6 versus 55.9 ± 4.8) of NPDR than in the healthy controls (p < 0.001). AH levels of HGF (p = 0.018), Ang2 (p = 0.005) and IL-8 (p = 0.034) were significantly higher, and EGF (p = 0.030) was significantly lower in NPDR subjects. The study demonstrated a correlation between venular retinal blood oxygen saturation and proangiogenic factors HGF (r = 0.558, p = 0.038), Ang2 (r = 0.556, p = 0.039) and EGF (r = -0.554, p = 0.040), but did not find any correlation for IL-8 (r = 0.330, p = 0.249) even though this biomarker was significantly higher in the diabetic group.

Conclusion: To our knowledge, the present study is the first report considering the association between SO and AH concentrations of protein biomarkers in diabetic retinopathy. The biomarkers of interest have been shown to participate in cell death, which may explain higher oxygen saturation in NPDR.
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http://dx.doi.org/10.1111/aos.14016DOI Listing
August 2019

All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome.

Exp Eye Res 2019 06 14;183:88-97. Epub 2018 Nov 14.

Department of Vision Science, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Vision Science Research Program, Ophthalmology and Vision Science, University of Toronto, Toronto, ON, Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address:

Glaucoma describes a distinct optic neuropathy with complex etiology and a variety of associated risk factors, but with similar pathological endpoints. Risk factors such as age, increased intraocular pressure (IOP), low mean arterial pressure, and autoimmune disease, can all be associated with death of retinal ganglion cells (RGCs) and optic nerve head remodeling. Today, IOP management remains the standard of care, even though IOP elevation is not pathognomonic of glaucoma, and patients can continue to lose vision despite effective IOP control. A contemporary view of glaucoma as a complex, neurodegenerative disease has developed, along with the recognition of a need for new disease modifying retinal treatment strategies and improved outcomes. However, the distinction between risk factors triggering the disease process and retinal injury responses is not always clear. In this review, we attempt to distinguish between the various triggers, and their association with subsequent key RGC injury mechanisms. We propose that distinct glaucomatous risk factors result in similar retinal and optic nerve injury cascades, including oxidative and metabolic stress, glial reactivity, and altered inflammatory responses, which induce common molecular signals to induce RGC apoptosis. This organization forms a coherent disease framework and presents conserved targets for therapeutic intervention that are not limited to specific risk factors.
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http://dx.doi.org/10.1016/j.exer.2018.11.005DOI Listing
June 2019

Androgen Receptor Polymorphism and Female Sexual Function and Desire.

J Sex Med 2018 11;15(11):1537-1546

Department of Sexological Research, Psychiatric Center Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark.

Introduction: The effect of testosterone depends on the exposure of and the sensitivity of the androgen receptor (AR). It has been shown that a cytosine-adenine-guanine (CAG) trinucleotide repeat polymorphism in the AR gene has an impact on AR functional capacity in men. However, large studies are lacking on the impact of this polymorphism on female sexual function.

Aim: To determine whether the CAG repeat length was associated with different aspects of women's sexual function and dysfunction, including desire, arousal, lubrication, orgasm, satisfaction, sexual pain, and sexually related personal distress.

Methods: This cross-sectional study included 529 healthy women, aged 19-65 years. Participants completed a questionnaire to provide demographic and sexual data. The CAG repeat length was analyzed in a blood sample. The correlations between CAG repeat lengths and different aspects of sexual function were calculated. Independent Student t-tests were performed to evaluate differences in the mean number of CAG repeats in the short and long allele and of the biallelic mean length determined by simple calculation and X-inactivation analysis, respectively, between women with sexual problems and women without sexual problems. P values <.05 were considered statistically significant.

Main Outcome Measure: We used the Female Sexual Function Index, with 6 subdomains, to distinguish between women without and women with impaired sexual function; low sexual desire; impaired arousal, lubrication, or orgasm; diminished satisfaction; or pain during sex. The Female Sexual Distress Scale was used to measure sexually related personal distress.

Results: Overall, we found that increasing numbers of CAG repeats were correlated to increased sexual function. We found that women with problems achieving orgasm had a significantly lower number of CAG repeats than women that reported no problems reaching orgasm. We found no associations between CAG repeat lengths and other aspects of female sexual dysfunction, including hypoactive sexual desire disorder.

Clinical Implications: The results could indicate an impact of the AR on women's sexual function, including the ability to reach orgasm.

Strength & Limitations: This is a large study using validated sexual questionnaires. A limitation is the cross-sectional design. Owing to the study design, this study is explorative and hypothesis generating.

Conclusion: In this large cross-sectional study, we demonstrated that CAG repeat length is positively correlated to sexual function and that women with a reduced ability to reach orgasm had smaller numbers of CAG repeats in the AR gene than women with no orgasmic problems. These findings indicated that androgens and ARs might play a role in women's sexual function. Wåhlin-Jacobsen S, Flanagan JN, Pedersen AT, Kristensen E, Arver S, Giraldi A. Androgen Receptor Polymorphism and Female Sexual Function and Desire. J Sex Med 2018;15:1537-1546.
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http://dx.doi.org/10.1016/j.jsxm.2018.09.013DOI Listing
November 2018

Male reproductive health statement (XIIIth international symposium on Spermatology, may 9th-12th 2018, Stockholm, Sweden.

Basic Clin Androl 2018 29;28:13. Epub 2018 Oct 29.

22GReD Laboratory INSERM U1103 - CNRS UMR6293, Faculty de Medicine, CRBC, Université Clermont Auvergne (UCA), 63000 Clermont-Ferrand, France.

On the occasion of the held from 9 to 13 May 2018 in Stockholm (Sweden), participants (guest speakers and audience) collectively felt the need to make a public statement on the general issue of male reproductive health. Our intention is to raise awareness of what we believe is a neglected area of research despite alarming situations around the world. The disclosure strategy desired by the co-authors is to bring it to the attention of the greatest number partly by considering co-publication in the various periodicals dealing with Reproductive Biology and Andrology. BaCA's editorial office accepted this mission and found it natural that our periodical, the official journal of the French Andrology Society (SALF), should carry this message.
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http://dx.doi.org/10.1186/s12610-018-0077-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205799PMC
October 2018

Dynamics of testosterone levels in patients with newly detected glucose abnormalities and acute myocardial infarction.

Diab Vasc Dis Res 2018 11 3;15(6):511-518. Epub 2018 Oct 3.

1 Division of Cardiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Objective: Low testosterone has been associated with increased cardiovascular risk and glucose abnormalities. This study explored the prevalence of low testosterone, dynamics over time and prognostic implications in acute myocardial infarction patients with or without glucose abnormalities.

Methods: Male acute myocardial infarction patients (n = 123) and healthy controls (n = 124) were categorised as having normal or abnormal glucose tolerance (impaired glucose tolerance or diabetes) by oral glucose tolerance testing. Testosterone was measured at hospital admission, discharge, 3 and 12 months thereafter in patients. Patients and controls were followed for 11 years for major cardiovascular events (cardiovascular death/acute myocardial infarction/stroke/severe heart failure).

Results: At hospital admission, more patients had low testosterone (⩽300 ng/dl) and lower median levels than controls (64 vs 28%; p < 0.001 and 243 vs 380 ng/dl; p < 0.01). At the subsequent time points, testosterone had increased to 311, 345 and 357 ng/dl. Patients with abnormal glucose tolerance had the highest prevalence (75%) of low levels. In adjusted Cox regression models, neither total nor free testosterone predicted major cardiovascular events.

Conclusion: Low testosterone levels were common in male acute myocardial infarction patients in the acute phase, especially in the presence of abnormal glucose tolerance, but increased over time indicating that testosterone measured in close proximity to acute myocardial infarction should be interpreted with caution.
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http://dx.doi.org/10.1177/1479164118802543DOI Listing
November 2018

An international multi-centre cohort study of weight loss in overweight cats: Differences in outcome in different geographical locations.

PLoS One 2018 25;13(7):e0200414. Epub 2018 Jul 25.

Institute of Ageing and Chronic Disease, University of Liverpool, Neston, Cheshire, United Kingdom.

Introduction: Feline obesity is a worldwide concern which has recently been formally classified as a disease by the veterinary community. Management involves invoking controlled weight loss by feeding a purpose-formulated food in restricted quantities and altering physical activity. Most weight loss studies conducted in cats have been undertaken in research cat colonies from single geographic locations. The aim of this multi-centre cohort study was to determine the efficacy of a short-term dietary weight loss intervention in overweight pet cats across a range of geographical locations globally.

Materials And Methods: A 3-month (median 13 weeks, inter-quartile range [IQR] 12-15 weeks) weight loss programme was conducted at 188 veterinary practices in 22 countries, and involving 730 cats, 413 of which completed the programme and had complete data available. All were fed commercially available dry or wet weight loss diets, and median energy intake was 53 kcal/kg BW0.711/day. The Royal Canin Ethics Committee approved the study, and owners gave informed consent. Owners completed behavioural questionnaires assessing begging, physical activity and quality of life (QOL). Linear mixed models were used to assess the respective influence of time, age, and initial body condition score (BCS) on weight loss and behavioural observations.

Results: At baseline, median age was 72 months (range 12-200 months) and median BCS was 8 (range 7-9). In all, 402/413 cats (97%) lost weight (mean 10.6±6.3%) during the programme at a rate of 0.8 ±0.50%/week. Based upon owner questionnaires, activity and QOL improved (both P<0.001), while begging behaviour decreased (P<0.001) during weight loss. The main factor influencing percentage weight loss was geographical location (P<0.001), with cats in North America losing less weight (median 7.2%, IQR: 4.4-10.4%) than those in both Europe (10.7%, 6-8-15.4%) and South America (10.0%, 6.2-15.4%). Differences in weight loss were also observed amongst countries (P<0.001), with cats in Argentina, Germany, and Italy losing more weight than cats in the USA, and cats in Germany also losing more weight than cats in Portugal.

Discussion/conclusion: Most of the overweight cats enrolled in this international multi-centre study successfully lost weight. The reason for the differences in percentage weight loss amongst geographical locations requires further study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200414PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6059437PMC
January 2019

Metabolic and functional changes in transgender individuals following cross-sex hormone treatment: Design and methods of the GEnder Dysphoria Treatment in Sweden (GETS) study.

Contemp Clin Trials Commun 2018 Jun 12;10:148-153. Epub 2018 Apr 12.

Department of Laboratory Medicine, Karolinska Institutet, Unit of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.

Background: Although the divergent male and female differentiation depends on key genes, many biological differences seen in men and women are driven by relative differences in estrogen and testosterone levels. Gender dysphoria denotes the distress that gender incongruence with the assigned sex at birth may cause. Gender-affirming treatment includes medical intervention such as inhibition of endogenous sex hormones and subsequent replacement with cross-sex hormones. The aim of this study is to investigate consequences of an altered sex hormone profile on different tissues and metabolic risk factors. By studying subjects undergoing gender-affirming medical intervention with sex hormones, we have the unique opportunity to distinguish between genetic and hormonal effects.

Methods: The study is a single center observational cohort study conducted in Stockholm, Sweden. The subjects are examined at four time points; before initiation of treatment, after endogenous sex hormone inhibition, and three and eleven months following sex hormone treatment. Examinations include blood samples, skeletal muscle-, adipose- and skin tissue biopsies, arteriography, echocardiography, carotid Doppler examination, whole body MRI, CT of muscle and measurements of muscle strength.

Results: The primary outcome measure is transcriptomic and epigenomic changes in skeletal muscle. Secondary outcome measures include transcriptomic and epigenomic changes associated with metabolism in adipose and skin, muscle strength, fat cell size and ability to release fatty acids from adipose tissue, cardiovascular function, and body composition.

Conclusions: This study will provide novel information on the role of sex hormone treatment in skeletal muscle, adipose and skin, and its relation to cardiovascular and metabolic disease.
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http://dx.doi.org/10.1016/j.conctc.2018.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046513PMC
June 2018
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