49 research outputs found
Alternative (backdoor) androgen production and masculinization in the human fetus
Funding: The study was supported by the following grants: Chief Scientist Office (Scottish Executive, CZG/4/742) (PAF and PJOS) (http://www.cso.scot.nhs.uk/funding-2/); NHS Grampian Endowments 08/02 (PAF and PJOS) and 15/1/010 (PAF, PF, US, and PJOS) (https://www.nhsgcharities.com/); the Glasgow Childrenâs Hospital Research Charity Research Fund, YRSS/PHD/2016/05 (NW, MB, PJOS, and PAF) (http://www.glasgowchildrenshospitalcharity.org/research/glasgow-childrens-hospital-charity-research-fund); the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement number 212885 (PAF) (https://ec.europa.eu/research/fp7/index_en.cfm); Medical Research Council Grants MR/L010011/1 (PAF and PJOS) and MR/K501335/1 (MB, PAF, and PJOS) (https://mrc.ukri.org/); and the Kronprinsessan Lovisas Foundation, âStiftelsen Gunvor och Josef AnĂ©rs,â the âStiftelsen Jane och Dan Olssons,â and the âStiftelsen Tornspiranâ (KS and OS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD
The effect of extensive human presence at an early age on stress responses and reactivity of juvenile ostriches towards humans
CITATION: Muvhali, P. T., et al. 2018. The effect of extensive human presence at an early age on stress responses and reactivity of juvenile ostriches towards humans. Animals, 8(10):175, doi:10.3390/ani8100175.The original publication is available at http://www.mdpi.comPublication of this article was funded by the Stellenbosch University Open Access Fund.The effect of extensive human presence and regular gentle handling performed at an early
age (0â3 months old) on stress responses and reactivity of juvenile ostriches towards humans was
investigated. A total of 416 ostrich chicks over two years were exposed to one of three treatments
for three months after hatching; namely, Human Presence 1 (HP1, N = 144): extensive/prolonged
human presence with physical contact (touch, stroking), gentle human voice, and visual stimuli;
Human Presence 2 (HP2, N = 136): extensive/prolonged human presence without physical contact,
but with gentle human voice and visual stimuli; and the Standard treatment (S, N = 136): human
presence limited to routine feed and water supply as a control. At 7.5 months of age, the plasma
heterophil/lymphocyte (H/L) ratio was measured before and 72 h after feather harvesting and feather
clipping to determine acute stress responses, while chronic stress was measured by quantification of
corticosterone (CORT) concentrations in the floss feathers of the birds. Birdsâ behavioural response
towards a familiar or an unfamiliar handler was evaluated at 12 months using docility and fear tests,
and through behavioural observations conducted on random days between the ages of 8â13 months.
Willingness to approach, and to allow touch interactions, aggressiveness, and exhibition of sexual
display towards the handler, was recorded. No difference in the H/L ratios before and after feather harvesting and clipping was observed in HP1 birds, whereas H/L ratios showed a significant increase
72 h post feather harvesting and clipping in HP2 and S birds (p < 0.05). Birds from the S treatment
exhibited a significantly (p < 0.05) higher feather CORT concentration compared with HP1 birds,
while HP2 birds had intermediate responses. Birdsâ reactivity towards humans and temperament
as evaluated using behavioural observations, docility, and fear tests was not affected by treatment
(p > 0.05). However, HP1 and HP2 birds were more inclined (p < 0.05) to approach a familiar rather
than an unfamiliar handler during the behavioural observations, indicating an ability to distinguish
between a familiar and an unfamiliar handler. Overall, the results indicate that early gentle human
interactions with ostrich chicks can be beneficial in reducing physiological stress sensitivity later in
life and facilitate the ability of ostriches to distinguish between familiar and unfamiliar handlers.https://www.mdpi.com/2076-2615/8/10/175Publisher's versio
Human and mouse essentiality screens as a resource for disease gene discovery.
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery
Human and mouse essentiality screens as a resource for disease gene discovery
The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery
Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.
BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (â„18 years) with S aureus bacteraemia who had received â€96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment
COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study
Background:
The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms.
Methods:
International, prospective observational study of 60â109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms.
Results:
âTypicalâ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (â€â18 years: 69, 48, 23; 85%), older adults (â„â70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each Pâ<â0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country.
Interpretation:
This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men
Comparison of two CYP17 isoforms : implications for cortisol production in the South African Merino
Thesis (PhD)--Stellenbosch University, 2012.ENGLISH ABSTRACT: This study describes:
âą the comparison of the enzymatic activities of the two ovine cytochrome P450 17 -
hydroxylase/17,20-lyase (CYP17) isoforms expressed in non-steroidogenic COS-1 cells.
The Km and Vmax values for the metabolism of pregnenolone and progesterone were
determined, while time-dependent metabolism of pregnenolone, 17-hydroxypregenolone,
progesterone and 17-hydroxyprogesterone was also reported. The cloning and sequencing of
ovine cytochrome b5 is reported and was co-expressed with CYP17. The results showed that
the wild type 1 (WT1) isoform of ovine CYP17 produce more cortisol precursors than the
wild type 2 (WT2) isoform;
âą the analysis of the frequency distribution of the CYP17 genotypes within a South African
Merino population, which were divergently selected for (H-line) or against (L-line) the
ability of a ewe to rear multiple offspring per birthing opportunity. It was observed that the
CYP17 frequency distribution was the same within the H- and L-line, with 78.3 %
heterozygous WT1/WT2 and 21.7 % homozygous WT1/WT1. No homozygous WT2/WT2
individuals were identified;
âą the development of a UPLC-MS/MS method for the separation and quantification of all
thirteen adrenal steroids that are produced in the adrenal gland;
âą the relative contribution of the CYP17 genotypes in the total steroidogenic output in adult
adrenocortical cells from the adrenal glands of H- and L-line sheep, with particular emphasis
on cortisol production. The adrenocortical cells from the H-line sheep showed a marked
higher cortisol production than the L-line, while adrenocortical cells from homozygous
WT1/WT1 sheep also produced more cortisol than heterozygous WT1/WT2 sheep;
âą the blood cortisol responses upon the stimulation of the HPA axis by insulin induced
hypoglycaemia of the H- and L-line sheep with known CYP17 genotypes. It was observed
that the CYP17 genotype and selection line are important factors affecting the cortisol
responses of sheep, where L-line heterozygous WT1/WT2 sheep showed the lowest cortisol
response and glucose recovery; âą the association of the CYP17 genotype with behavioural responses of H- and L-line sheep to
flock isolation stress, as well as the association of the CYP17 genotype with ewe
reproduction and lamb output. While reproduction seemed to be unaffected by the CYP17
genotype, the behavioural stress responses of sheep to flock isolation correlated with the
CYP17 genotype, where the heterozygous WT1/WT2 genotype was associated with a wilder
nature.AFRIKAANSE OPSOMMING: Hierdie studie ondersoek:
âą die vergelyking van die ensiemaktiwiteite vir twee isoforme van skaap sitochroom P450
17 -hidroksilase/17,20-liase (CYP17), wat uitgedruk was in nie-steroĂŻed genererende COS-
1 selle. Die Km and Vmax waardes was bepaal vir die metabolisme van pregnenoloon en
progesteroon, terwyl die tyd-afhanklike metabolisme van pregnenoloon, 17-
hidroksiepregnenoloon, progesteroon en 17-hidroksieprogesteroon ook gerapporteer word.
Die klonering en volgorde bepaling van skaap sitochroom b5 was gedoen en gevolglik was
sitochroom b5 saam met CYP17 uitgedruk in COS-1 selle. Die resultate het gewys dat wilde
tipe 1 (WT1) meer voorlopers van kortisol produseer as wilde tipe 2 (WT2);
âą die frekwensie distrubusie van die CYP17 genotipes in ân Suid-Afrikaanse Merino
populasie, waar skape in teenoorgestelde rigtings geselekteer was vir (H-lyn) of teen (L-lyn)
die vermoĂ« van ân ooi om geboorte te gee aan veelvoudige lammers per lamgeleentheid. Die
frekwensie distrubusie van CYP17 was dieselfde in beide die H- en L-lyn, waar 78.3 % van
die populasie heterosigoties WT1/WT2 en 21.7 % homosigoties WT1/WT1 was. Geen
homosigote WT2/WT2 individue was geĂŻdentifiseer nie;
âą die ontwikkeling van ân UPLC-MS/MS metode vir die skeiding en kwantifisering van al
dertien steroĂŻede wat natuurlik geproduseer word in die bynier van die skaap;
âą die relatiewe bydrae van die CYP17 isoforme tot die totale steroĂŻedale uitsette vanuit die
bynier kortex selle, vanaf die byniere van H- en L-lyn skape, waar klem geplaas word op die
produksie van kortisol. Die bynierselle van die H-lyn skape het aansienlik meer kortisol
produseer as die L-lyn, terwyl die bynierselle van die homosigotiese WT1/WT1 skape ook
meer kortisol produseer het as heterosigotiese WT1/WT2 skape;
âą die bloed kortisol in reaksie tot die stimulering van die hipotalamus-hipofise-adrenale aksis,
deur insulien geĂŻnduseerde hipoglisemiese stress, in skape van die H- en L-lyne met bekende
CYP17 genotipes. Dit was gevind dat die kortisol reaksie geaffekteer word deur beide die
CYP17 genotipe en seleksie lyn, waar L-lyn heterosigotiese WT1/WT2 skape die minste
kortisol geproduseer het en die stadigste herstel van glukose vlakke getoon het; âą die assosiasie tussen die CYP17 genotipe en die gedrags reaksies op trop-isolasie, sowel as
ooi-reproduksie en lamuitset, van die H- en L-lyn skape. Die reproduksie parameters was
onafhanklik van die CYP17 genotipe, terwyl ân sterk assosiasie gevind was tussen die
CYP17 genotipe en gedrags reaksies op trop-isolasie. Die heterosigotiese WT1/WT2 skape
het ân wilder natuur getoon gedurende trop-isolasie in vergelyking met homosigotiese
WT1/WT1 skape