Abstract
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-DOPA is deficient in the developing albino eye, resulting in abnormalities of retinal development and visual impairment. Ongoing retinal development after birth has also been demonstrated ...in the developing albino eye offering a potential therapeutic window in humans. To study whether human equivalent doses of
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-DOPA/Carbidopa administered during the crucial postnatal period of neuroplasticity can rescue visual function, OCA C57BL/6 J-c2J OCA1 mice were treated with a 28-day course of oral
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-DOPA/Carbidopa at 3 different doses from 15 to 43 days postnatal age (PNA) and for 3 different lengths of treatment, to identify optimum dosage and treatment length. Visual electrophysiology, acuity, and retinal morphology were measured at 4, 5, 6, 12 and 16 weeks PNA and compared to untreated C57BL/6 J (WT) and OCA1 mice. Quantification of PEDF, βIII-tubulin and syntaxin-3 expression was also performed. Our data showed impaired retinal morphology, decreased retinal function and lower visual acuity in untreated OCA1 mice compared to WT mice. These changes were diminished or eliminated when treated with higher doses of
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-DOPA/Carbidopa. Our results demonstrate that oral
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-DOPA/Carbidopa supplementation at human equivalent doses during the postnatal critical period of retinal neuroplasticity can rescue visual retinal morphology and retinal function, via PEDF upregulation and modulation of retinal synaptogenesis, providing a further step towards developing an effective treatment for albinism patients.
Oculocutaneous albinism (OCA) and ocular albinism (OA) are inherited disorders of melanin biosynthesis, resulting in loss of pigment and severe visual deficits. OCA encompasses a range of subtypes ...with overlapping, often hypomorphic phenotypes. OCA1 is the most common cause of albinism in European populations and is inherited through autosomal recessive mutations in the Tyrosinase (TYR) gene. However, there is a high level of reported missing heritability, where only a single heterozygous mutation is found in TYR. This is also the case for other OCA subtypes including OCA2 caused by mutations in the OCA2 gene. Here we have interrogated the genetic cause of albinism in a well phenotyped, hypomorphic albinism population by sequencing a broad gene panel and performing segregation studies on phenotyped family members. Of eighteen probands we can confidently diagnose three with OA and OCA2, and one with a PAX6 mutation. Of six probands with only a single heterozygous mutation in TYR, all were found to have the two common variants S192Y and R402Q. Our results suggest that a combination of R402Q and S192Y with a deleterious mutation in a 'tri-allelic genotype' can account for missing heritability in some hypomorphic OCA1 albinism phenotypes.
A radiocarbon and tephra-dated sediment core from Lifebuoy Lake, located on the north-east coast of Kamchatka Peninsula, was analysed for pollen, spores, diatoms, chironomids and tephra in order to ...uncover regional environmental history.
The 6500-year environmental history of Lifebuoy Lake correlates with the broad regional patterns of vegetation development and climate dynamics with both diatoms and chironomids showing near-synchronous changes.
Between ca. 6300 and 3900calyrBP, the lake ecosystem was naturally enriched, with several Stephanodiscus species dominating the diatom plankton. This natural eutrophication state is likely to be due to a combination of the base-rich catchment geology, the fertilisation effect of several fires in the catchment, silica input from tephra layers and, possibly, nitrogen input from seabirds. The substantial tephra deposit at about 3850calyrBP might have stopped sedimentary phosphorus from entering the lake water thus decreasing the trophic state of the lake and facilitating the shift in diatom composition to a benthic Fragiliariaceae complex.
Both diatoms and chironomids showed simultaneous compositional changes, which are also reflected by statistically significant changes in their rates of change 300–400years after the arrival of Pinus pumila in the lake catchment. The rapid increase in both total diatom concentration and the percentage abundance of the large heavy species, Aulacoseira subarctica might be a response to the change in timing and intensity of lake spring turn-over due to the changes in the patterns of North Pacific atmospheric circulation, most notably westward shift of the Aleutian Low.
The two highest peaks in A. subarctica abundance at Lifebouy Lake occurred during opposite summer temperature inferences: the earlier peak (3500–2900calyrBP) coincided with warm summers and the latter peak (300calyrBP–present) occurred during the cold summer period. These imply that A. subarctica shows no direct response to the changes of summer air temperature. Instead, it appears to thrive during the periods of increased winter precipitation, thicker ice and late spring turn-over periods, i.e., shows indirect response to climate.
The clearest effect of tephra deposition on the lake ecosystem is above 908cm (ca. 3800calyrBP) where the tephra deposit might have caused the shift from Stephanodiscus-dominated planktonic assemblages to the Fragilariaceae complex of benthic species. Tephra deposits might have also contributed towards the development of eutrophic plankton from about 6300calyrBP. It is not certain if several tephra deposits influenced diatom and chironomid changes during the last 300years.
•6500years of environmental history from north-east Kamchatka examined.•Diatoms and chironomids show near synchronous compositional changes.•Natural eutrophication occurred between 6300 and 3900calyrBP.•A tephra deposit might have caused a shift from Stephanodiscus plankton to benthic Fragilariaceae.•Aulacoseira subarctica shows no direct response to summer air temperature.
The COVID-19 pandemic has impacted negatively on many areas of biomedical research and there is concern that academic recovery will take several years. This survey aimed to define the impact of the ...COVID-19 pandemic on UK ophthalmologists' research activities and understand the implications for recovery.
An online survey comprising multiple choice and free-text questions was designed, piloted and then distributed to Royal College of Ophthalmologists (RCOphth) members in January 2021. Respondent characteristics, research expectations and experiences through the pandemic were captured. Descriptive and comparative statistics were applied to quantitative data alongside content analysis of qualitative data.
In total, 148 respondents (3.7% of RCOphth membership) comprised 46 trainees (31.1%), 97 consultants (65.5%) and 5 SAS doctors (3.4%); 54 had clinical-academic roles (36.5%) and 65/94 (69.1%) ophthalmologists with fully clinical posts identified as research-active. Of 114 research-active respondents, 104 (91.2%) reported an impact on their research from COVID-19; negative impacts included loss of research time (n = 69), research delays (n = 96) and funding shortfalls (n = 63). Content analysis identified five common themes; type of research activity, clinical demands, institutional challenges, COVID-19 alignment and work-life balance.
UK ophthalmology research has been adversely impacted by the pandemic. A substantial proportion of UK ophthalmologists are research active, but 20.4% of those surveyed felt that the pandemic had made research less attractive. Strategic steps must be taken to nurture UK ophthalmologists' engagement with research, especially for those who currently do no research, if the profession is to align itself with the Government vision of 'Research for All'.
Context.
We present results from the first recorded stellar occultation by the large trans-Neptunian object (174567) Varda that was observed on September 10, 2018. Varda belongs to the ...high-inclination dynamically excited population, and has a satellite, Ilmarë, which is half the size of Varda.
Aims.
We determine the size and albedo of Varda and constrain its 3D shape and density.
Methods.
Thirteen different sites in the USA monitored the event, five of which detected an occultation by the main body. A best-fitting ellipse to the occultation chords provides the instantaneous limb of the body, from which the geometric albedo is computed. The size and shape of Varda are evaluated, and its bulk density is constrained using Varda’s mass as is known from previous works.
Results.
The best-fitting elliptical limb has semi-major (equatorial) axis of (383 ± 3) km and an apparent oblateness of 0.066 ± 0.047, corresponding to an apparent area-equivalent radius
R
′
equiv
= (370±7) km and geometric albedo
p
v
= 0.099 ± 0.002 assuming a visual absolute magnitude
H
V
= 3.81 ± 0.01. Using three possible rotational periods for the body (4.76, 5.91, and 7.87 h), we derive corresponding MacLaurin solutions. Furthermore, given the low-amplitude (0.06 ± 0.01) mag of the single-peaked rotational light-curve for the aforementioned periods, we consider the double periods. For the 5.91 h period (the most probable) and its double (11.82 h), we find bulk densities and true oblateness of
ρ
= (1.78 ± 0.06) g cm
−3
,
ɛ
= 0.235 ± 0.050, and
ρ
= (1.23 ± 0.04) g cm
−3
,
ɛ
= 0.080 ± 0.049. However, it must be noted that the other solutions cannot be excluded just yet.
Acute antibody‐mediated rejection (AMR) in heart transplantation is often associated with hemodynamic compromise, and is associated with increased mortality and development of accelerated transplant ...coronary artery disease (TCAD). The diagnosis of AMR has historically been controversial and outcomes with aggressive immunosuppressive therapy including plasmapheresis and cyclophosphamide are poor. Advances in diagnostic techniques like the demonstration of immunopathologic evidence for antibody‐mediated rejection by deposition of the complement split product C4d in tissue and detection of anti‐HLA antibodies by flow cytometry will assist in further characterizing AMR. Immunosuppression targeting B‐lymphocytes and use of m‐TOR inhibitors to alter the predilection to develop TCAD and improve survival in AMR remains to be proven.
AMR is increasingly recognized as an important cause of morbidity and mortality in heart transplantation but treatment strategies must now be developed.
ObjectiveLupus nephritis (LN) is an immune complex-mediated glomerular and tubulointerstitial disease in patients with SLE. Prediction of outcomes at the onset of LN diagnosis can guide decisions ...regarding intensity of monitoring and therapy for treatment success. Currently, no machine learning model of outcomes exists. Several outcomes modelling works have used univariate or linear modelling but were limited by the disease heterogeneity. We hypothesised that a combination of renal pathology results and routine clinical laboratory data could be used to develop and to cross-validate a clinically meaningful machine learning early decision support tool that predicts LN outcomes at approximately 1 year.MethodsTo address this hypothesis, patients with LN from a prospective longitudinal registry at the Medical University of South Carolina enrolled between 2003 and 2017 were identified if they had renal biopsies with International Society of Nephrology/Renal Pathology Society pathological classification. Clinical laboratory values at the time of diagnosis and outcome variables at approximately 1 year were recorded. Machine learning models were developed and cross-validated to predict suboptimal response.ResultsFive machine learning models predicted suboptimal response status in 10 times cross-validation with receiver operating characteristics area under the curve values >0.78. The most predictive variables were interstitial inflammation, interstitial fibrosis, activity score and chronicity score from renal pathology and urine protein-to-creatinine ratio, white blood cell count and haemoglobin from the clinical laboratories. A web-based tool was created for clinicians to enter these baseline clinical laboratory and histopathology variables to produce a probability score of suboptimal response.ConclusionGiven the heterogeneity of disease presentation in LN, it is important that risk prediction models incorporate several data elements. This report provides for the first time a clinical proof-of-concept tool that uses the five most predictive models and simplifies understanding of them through a web-based application.
Nystagmus is a disorder of uncontrolled eye movement and can occur as an isolated trait (idiopathic INS, IINS) or as part of multisystem disorders such as albinism, significant visual disorders or ...neurological disease. Eighty-one unrelated patients with nystagmus underwent routine ocular phenotyping using commonly available phenotyping methods and were grouped into four sub-cohorts according to the level of phenotyping information gained and their findings. DNA was extracted and sequenced using a broad utility next generation sequencing (NGS) gene panel. A clinical subpanel of genes for nystagmus/albinism was utilised and likely causal variants were prioritised according to methods currently employed by clinical diagnostic laboratories. We determine the likely underlying genetic cause for 43.2% of participants with similar yields regardless of prior phenotyping. This study demonstrates that a diagnostic workflow combining basic ocular phenotyping and a clinically available targeted NGS panel, can provide a high diagnostic yield for patients with infantile nystagmus, enabling access to disease specific management at a young age and reducing the need for multiple costly, often invasive tests. By describing diagnostic yield for groups of patients with incomplete phenotyping data, it also permits the subsequent design of 'real-world' diagnostic workflows and illustrates the changing role of genetic testing in modern diagnostic workflows for heterogeneous ophthalmic disorders.
Kamchatka is a remote, isolated and understudied area and is presumed to be pristine. Here we present the first high-resolution palaeolimnological investigation of the recent past. A short core ...representing the last 250years was taken from Olive-backed Lake situated in central Kamchatka. Lead-210 dating revealed that sediment accumulation has increased at the site since the 1960s and may be related to greater rates of catchment erosion associated with wetter winters in the region. Mercury and spheroidal carbonaceous particle (an unambiguous indicator of fossil fuel combustion) concentrations are low but clearly detectable indicating that both regional and global pollution sources are observed at this site. The recent increase in the flux of mercury is more related to catchment sources and catchment erosion than increases from regional or global sources. The diatom and chironomid populations are stable and do not show any statistically significant changes related to either the low levels of pollution, or to temperature and precipitation changes. The lake is not pristine since anthropogenic contamination has occurred but since there have been no significant effects on the flora and fauna the lake can be considered to be unimpacted. Olive-backed Lake may be a suitable reference site to benchmark the natural variability of a lake ecosystem.
•We present the first high-resolution palaeolimnological study for Kamchatka and use 210Pb to date recent lake sediments.•We show that mercury analysis indicates low level, but global sources of pollution.•We show that spheroidal carbonaceous particle (SCP) analysis indicates low level pollution from regional sources.•We found no impacts of changes in pollution or climate on either diatom or chironomid communities.•We address the difficulties in defining pristine as opposed to unimpacted lake ecosystems.
A sediment sequence was taken from a closed, high altitude lake (informal name Olive-backed Lake) in the central mountain range of Kamchatka, in the Russian Far East. The sequence was dated by ...radiocarbon and tephrochronology and used for multi-proxy analyses (chironomids, pollen, diatoms). Although the evolution of Beringian climate through the Holocene is primarily driven by global forcing mechanisms, regional controls, such as volcanic activity or vegetation dynamics, lead to a spatial heterogeneous response. This study aims to reconstruct past changes in the aquatic and terrestrial ecosystems and to separate the climate-driven response from a response to regional or localised environmental change. Radiocarbon dates from plant macrophytes gave a basal date of 7800calyr BP. Coring terminated in a tephra layer, so sedimentation at the lake started prior to this date, possibly in the early Holocene following local glacier retreat. Initially the catchment vegetation was dominated by Betula and Alnus woodland with a mosaic of open, wet, aquatic and semi-aquatic habitats. Between 7800 and 6000calyr BP the diatom-inferred lake water was pH4.4–5.3 and chironomid and diatom assemblages in the lake were initially dominated by a small number of acidophilic/acid tolerant taxa. The frequency of Pinus pumila (Siberian dwarf pine) pollen increased from 5000calyr BP and threshold analysis indicates that P. pumila arrived in the catchment between 4200 and 3000calyr BP. Its range expansion was probably mediated by strengthening of the Aleutian Low pressure system and increased winter snowfall. The diatom-inferred pH reconstructions show that after an initial period of low pH, pH gradually increased from 5500calyr BP to pH5.8 at 1500calyr BP. This trend of increasing pH through the Holocene is unusual in lake records, but the initially low pH may have resulted directly or indirectly from intense regional volcanic activity during the mid-Holocene. The chironomid-inferred July temperature reconstruction suggests cool periods between 3200–2800calyr BP and 1100–700calyr BP and a warmer period between 2800 and 1100calyr BP. Chironomid and diatom DCA scores decline from ca. 6000calyr BP, indicating compositional changes in these aquatic assemblages. In comparison declines in pollen PCA scores are delayed, starting ca. 5100calyr BP. The results suggest that while catchment vegetation was responding primarily to climate change, the biota within the lake and lake water chemistry were responding to localised environmental conditions.
•Sedimentation at Olive-backed Lake started prior to 7.8ka.•Initially the lake was acidic with low aquatic diversity, surrounded by Betula–Alnus woodland.•Pinus pumila advanced from 5ka, possibly in response to increasing depth and duration of snow cover.•Reconstructed lake pH shows an unusual increasing trend between 5 and 0.7ka.•Catchment vegetation responds primarily to climate and lake biota to tephras and climate.
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