An incipient late-onset retinal degeneration with a C1QTNF5 mutation: a case report with an 11-year follow-up.

PURPOSE: The purpose of this study was to describe and diagnose the difficulty in a long-term follow-up (eleven years) patient with a very early presentation of late-onset retinal degeneration (L-ORD) and the significance of electrophysiological examinations and follow-up in assessing undiagnosed inherited retinal diseases. METHODS: This is an observational case report of a 56-year-old woman, with scattered multiple yellow-white retinal dots firstly diagnosed as fundus albipunctatus. Ten years after presentation, a deterioration in rod and cone responses in ff-ERG was detected, which allowed us to discard the first diagnostic hypothesis and proceed with a genetic testing. RESULTS: Ten years after presentation, she presented a clear progression of the abnormal photoreceptor response with a cone and rod involvement in ff-ERG, which was not compatible with the previous suspicion of fundus albipunctatus. Six months later, genetic testing results together with the typical progression of atrophic patchy lesions in multimodal imaging allowed a certain diagnosis of L-ORD, caused by an already reported pathogenic variant in the C1QTNF5 gene (c.563C > T; p. Pro188 Leu). CONCLUSIONS: We demonstrate the importance of the ff-ERG examination and the follow-up (or ERG and imaging repetition) in the differential diagnosis of an incipient L-ORD, which can be easily misdiagnosed in the early stages, before the appearance of the characteristic chorioretinal atrophy seen with the progression of this rare disease.

New Methods for the Quantification of Ingested Nano- and Ultrafine Plastics in Seabirds.

Plastic ingestion has been documented in a plethora of taxa. However, there is a significant gap in the detection of nano- and ultrafine particles due to size limitations of commonly used techniques. Using two Australian seabird species as case studies, the flesh-footed shearwater (FFSH) Ardenna carneipes and short-tailed shearwater (STSH) A. tenuirostris, we tested a novel approach of flow cytometry to quantify ingested particles <70 µm in the fecal precursor (guano; colon and cloacal contents) of both species. This method provided the first baseline data set for these species for plastics in the 200 nm-70 µm particle size ranges and detected a mean of 553.50 ± 91.21 and 350.70 ± 52.08 plastics (count/mg fecal precursor, wet mass) in STSH and FFSH, respectively, whereas Fourier transform infrared spectroscopy (FT-IR) provided accurate measurements of polymer compositions and quantities in the size range above 5.5 × 5.5 µm2. The abundance of nano- and ultrafine particles in the guano (count/mg) was not significantly different between species (p-value = 0.051), suggesting that foraging distribution or prey items, but not species, may contribute to the consumption of small plastics. In addition, there was no correlation between macroplastics in the stomach compared to the fecal precursor, indicating that small particles are likely bioaccumulating (e.g., through shedding and digestive fragmentation) and/or being directly ingested. Combining flow cytometry with FT-IR provides a powerful quantitative and qualitative analysis tool for detecting particles orders of magnitude smaller than that are currently explored with wider applications across taxa and marine environments.

Target parameters and bias in non-causal change-score analyses with measurement errors.

In studies where the outcome is a change-score, it is often debated whether or not the analysis should adjust for the baseline score. When the aim is to make causal inference, it has been argued that the two analyses (adjusted vs. unadjusted) target different causal parameters, which may both be relevant. However, these arguments are not applicable when the aim is to make predictions rather than to estimate causal effects. When the scores are measured with error, there have been attempts to quantify the bias resulting from adjustment for the (mis-)measured baseline score or lack thereof. However, these bias results have been derived under an unrealistically simple model, and assuming that the target parameter is the unadjusted (for the true baseline score) association, thus dismissing the adjusted association as a possibly relevant target parameter. In this paper we address these limitations. We argue that, even if the aim is to make predictions, there are two possibly relevant target parameters; one adjusted for the baseline score and one unadjusted. We consider both the simple case when there are no measurement errors, and the more complex case when the scores are measured with error. For the latter case, we consider a more realistic model than previous authors. Under this model we derive analytic expressions for the biases that arise when adjusting or not adjusting for the (mis-)measured baseline score, with respect to the two possible target parameters. Finally, we use these expressions to discuss when adjustment is warranted in change-score analyses.

A Novel Mouse Model for Late-Onset Retinal Degeneration (L-ORD) Develops RPE Abnormalities Due to the Loss of C1qtnf5/Ctrp5.

Late-onset retinal degeneration (L-ORD) is an autosomal dominant macular dystrophy resulting from mutations in the gene CTRP5/C1QTNF5. A mouse model (Ctrp5+/-) for the most common S163R developed many features of human clinical disease. We generated a novel homozygous Ctrp5 gene knock-out (Ctrp5-/-) mouse model to further study the mechanism of L-ORD. The retinal morphology of these mice was evaluated by retinal imaging, light microscopy, and transmission electron microscopy (TEM) at 6, 11, and 18.5 mo. Expression of Ctrp5 was analyzed using immunostaining and qRT-PCR. The Ctrp5-/- mice showed lack of both Ctrp5 transcript and protein. Presence of a significantly larger number of autofluorescent spots was observed in Ctrp5-/- mice compared to the WT (P < 0.0001) at 19 mo. Increased RPE stress with vacuolization and thinning was observed as early as 6 mo in Ctrp5-/- mice. Further, ultrastructural analyses revealed a progressive accumulation of basal laminar sub-RPE deposits in Ctrp5-/- mice from 11 mo. The Ctrp5-/- mice shared retinal and RPE pathology that matches with that previously described for Ctrp5+/- mice suggesting that pathology in these mice results from the loss of functional CTRP5 and that the presence of CTRP5 is critical for normal RPE and retinal function.

Wartime captivity and homecoming: culture, stigma, and coping strategies of formerly abducted women in post-conflict northern Uganda.

One of the three durable solutions to mass displacement preferred by leading agencies is that survivors return to their home communities. It is believed that families and communities provide the best hope for recovery and reintegration owing to familiarity, care, and shared culture. Yet, these 'places of hope and comfort' can also be, potentially, a hostile environment in which stigma can flourish. Women who were abducted by the Lord's Resistance Army in northern Uganda find that achieving meaningful reintegration into their communities is a distant prospect despite being the home culture they once shared. The stigmatisation of formerly abducted persons by home community members who have never been abducted renders them 'outsiders' upon return. Meaningful relationships with fellow community members and access to cultural, social, and economic systems are hampered by the women's traumatic past. This experience has significant implications for these women, negotiating their journey to recovery and reintegration into home communities.

Autosomal Dominant Gyrate Atrophy-Like Choroidal Dystrophy Revisited: 45 Years Follow-Up and Association with a Novel C1QTNF5 Missense Variant.

We present a long-term follow-up in autosomal dominant gyrate atrophy-like choroidal dystrophy (adGALCD) and propose a possible genotype/phenotype correlation. Ophthalmic examination of six patients from two families revealed confluent areas of choroidal atrophy resembling gyrate atrophy, starting in the second decade of life. Progression continued centrally, reaching the fovea at about 60 years of age. Subretinal deposits, retinal pigmentation or choroidal neovascularization as seen in late-onset retinal degeneration (LORD) were not observed. Whole genome sequencing revealed a novel missense variant in the C1QTNF5 gene (p.(Q180E)) which was found in heterozygous state in all affected subjects. Haplotype analysis showed that this variant found in both families is identical by descent. Three-dimensional modeling of the possible supramolecular assemblies of C1QTNF5 revealed that the p.(Q180E) variant led to the destabilization of protein tertiary and quaternary structures, affecting both the stability of the single protomer and the entire globular head, thus exerting detrimental effects on the formation of C1QTNF5 trimeric globular domains and their interaction. In conclusion, we propose that the p.(Q180E) variant causes a specific phenotype, adGALCD, that differs in multiple clinical aspects from LORD. Disruption of optimal cell-adhesion mechanisms is expected when analyzing the effects of the point mutation at the protein level.

A combination of combat experience, early abduction, and severe traumatization fuels appetitive aggression and violence among abductees of rebel war in Northern Uganda.

Individuals who perpetrate violence may likely perceive violence as appealing and infliction of violence to derive pleasure is termed as appetitive aggression. Individuals who were abducted as children into an armed group often experience a higher number of traumatic event types, that is traumatic load and are usually socialized in a violence-endorsing environment. This study aims to investigate the interaction between age at initial abduction with that of traumatic load, and their influence on appetitive aggression along with perpetration of violent acts by former members of an armed rebel group of both sexes. Semi-structured interviews were conducted among a target group of formerly abducted rebel-war survivors (including participants with and without combat experience) from Northern Uganda. Participants included 596 women and 570 men with N = 1,166 (Mage = 32.58, SDage = 9.76, range: 18-80 years). We conducted robust linear regression models to investigate the influence of age at initial abduction, traumatic load, combat experience, and biological sex on appetitive aggression as well as their perpetrated violent acts. Our study shows, appetitive aggression and the number of perpetrated violent acts were specifically increased in individuals who were abducted young, experienced several traumatic events in their lifetime, and with previous combat experience. For perpetrated violence men showed increased levels whereas for appetitive aggression the association was independent of biological sex. Therefore, early abducted individuals with a higher traumatic load, who have combat experience, need to be given special intervention to prevent any further violence.

Dual-centered ANCOVA: Resolving contradictory results from Lord's paradox with implications for reducing bias in longitudinal analyses.

INTRODUCTION: Valid causal inferences are necessary to use developmental research to improve adolescent outcomes. What type of change should be analyzed to approximate causal inferences from longitudinal data? Difference-score and ANCOVA-type analyses often produce contradictory results, a problem known as Lord's paradox. This study investigates 2-group, 2-wave difference-score analyses and ANCOVA, and introduces a method that produces consistent results, namely dual-centered ANCOVA, which is compared to pretest matching. METHODS: These methods are tested first on two datasets simulated to fit each of Lord's contrasting results. The methods are then applied to data investigating the longitudinal associations of parent-adolescent discussions about sexual risks on subsequent unprotected sexual behaviors in 4753 American adolescents (62.2% whites). RESULTS: The results replicate Lord's contradictory results for all datasets. Dual-centered ANCOVA and pretest matching both produce consistent results, but dual-centered ANCOVA replicates the original results for difference-score analyses, whereas pretest matching replicates the original ANCOVA results. Thus, the two sets of consistent results differ from each other as much as the original discrepancy rather than reducing bias. CONCLUSION: The least biased analysis is the one whose null hypothesis best approximates a plausible change pattern to represent a no-treatment effect. When difference-score analyses are thought to approximate valid causal inferences as closely as ANCOVA-type analyses, dual-centered ANCOVA estimates the difference-score effect while retaining the advantages of ANCOVA in statistical power and covariate inclusion. These findings are widely applicable to longitudinal analyses that incorporate one or both of these basic methods to analyze change.

The effects of thermal and mechanical material properties on tumorous tissue during hyperthermia treatment.

Although there have been numerous reports in several articles about the viscoelastic properties of biological tissues, no effort has been made to investigate the combined thermal and mechanical behavior of the viscoelastic tissue. At present, the model of thermo-viscoelasticity theory with variable thermal conductivity and rheological properties of the volume is considered to investigate bio-thermo-mechanics behavior in living tissue within the context of the Lord-Shulman theory. The model is applied to a limited thickness, cancerous layer problem. The problem was solved analytically in the transformed domain using Laplace transform as a tool. The exact solution is obtained in the context of transformation Laplace. Numerical results are given and illustrated graphically for the distributions of temperature, displacement, and stress. Some correlations are produced with the results obtained for the absence of the thermal relaxation parameter. The effects of variable thermal and volume materials properties, blood perfusion rate on the behavior of various fields are examined.

Simpson's Paradox is suppression, but Lord's Paradox is neither: clarification of and correction to Tu, Gunnell, and Gilthorpe (2008).

Tu et al. (Emerg Themes Epidemiol 5:2, 2008. https://doi.org/10.1186/1742-7622-5-2) asserted that suppression, Simpson's Paradox, and Lord's Paradox are all the same phenomenon-the reversal paradox. In the reversal paradox, the association between an outcome variable and an explanatory (predictor) variable is reversed when another explanatory variable is added to the analysis. More specifically, Tu et al. (2008) purported to demonstrate that these three paradoxes are different manifestations of the same phenomenon, differently named depending on the scaling of the outcome variable, the explanatory variable, and the third variable. According to Tu et al. (2008), when all three variables are continuous, the phenomenon is called suppression; when all three variables are categorical, the phenomenon is called Simpson's Paradox; and when the outcome variable and the third variable are continuous but the explanatory variable is categorical, the phenomenon is called Lord's Paradox. We show that (a) the strong form of Simpson's Paradox is equivalent to negative suppression for a 2 × 2 × 2 contingency table, (b) the weak form of Simpson's Paradox is equivalent to classical suppression for a 2 × 2 × 2 contingency table, and (c) Lord's Paradox is not the same phenomenon as suppression or Simpson's Paradox.

Berkeley Moynihan - early transfusionist and blood transfusion recipient.

Lord Sir Berkeley Moynihan (1865-1936) was a surgeon at the General Infirmary in Leeds (Yorkshire) from 1893, rising during his career to be one of the foremost surgeons in the UK whose reputation reached its pinnacle at the outbreak of the First World War (WW1). He was the only surgeon after Lister to be made a Baronet. In a letter to The Lancet in 1918, he claimed to have used blood transfusion on some of his patients during the 10-year period prior to that date. If true, this statement would make him the first surgeon in England to routinely use transfusion prior to WW1. This review investigates this claim using currently available evidence from Moynihan's personal records and publications, as well as published information from his colleagues.

Lord Adrian, MD, PRS, OM.

Edgar Douglas Adrian was an outstandingly brilliant, Nobel prize-winning neurophysiologist. He is remembered for developing the all-or-none principle of muscle contraction, and for explaining the minutiae of motor and sensory nerve transmission. He showed that the afferent effect in a neuron depends on the pattern in time of the impulses travelling in it, thereby providing a quantitative basis of nervous behaviour. With Sir Charles Sherrington, he was awarded the Nobel Prize in 1932 for discoveries on the functions of the neurons.

Late-Onset Retinal Degeneration.

Patients with late-onset retinal degeneration (LORD) usually present with nyctalopia in the fifth or sixth decade of life. The fundus shows yellowish-white, punctate deposits, usually progressive and giving rise to scalloped areas of retinal pigment epithelium (RPE) atrophy in the mid-periphery and posterior pole (Fig. 23.1). The anterior segment shows elongated zonules with central lens insertion and transillumination defect in the iris, due to iris atrophy.

Tunica Vaginalis Thickening, Hemorrhagic Infiltration and Inflammatory Changes in 8 Children with Primary Hydrocele; Reactive Mesothelial Hyperplasia? A Prospective Clinical Study.

The aim of this study is to describe an entity of primary hydrocele accompanied with fibrosis, thickening and hemorrhagic infiltration of parietal layer of tunica vaginalis (PLTV). During a 4-year period (2011-2014), 94 boys (2.5-14 years old) underwent primary hydrocele repair. Hydrocele was right sided in 55 (58.5 %), left sided in 26 (28.7%) and bilateral in 12 patients (13.8%). Eighty three out of 94 patients (88.30%) had communicating hydrocele and the rest eleven patients (11.7%) had non-communicating. Our case group consists of 8 patients (8.51%) based on operative findings consistent with PLTV induration, thickening and hemorrhagic infiltration. Preoperative ultrasonography did not reveal any pathology of the intrascrotal structures besides hydrocele. There weren't hyperechoic reflections or septa within the fluid. Evaluation of thickness of the PLTV was not feasible. Presence of lymph or exudate was excluded after fluid biochemical analysis. Tunica vaginalis histological examination confirmed thickening, hemorrhagic infiltration and inflammation, while there was absence of mesothelial cells. Immunochemistry for desmin was positive, excluding malignant mesothelioma. One patient underwent high ligation of the patent processus vaginalis and PLTV sheath fenestration, but one year later, he faced a recurrence. An elective second surgery was conducted via scrotal incision and Jaboulay operation was performed. The latter methodology was our treatment choice in other 7 out of 8 patients. During a 2-year postoperative follow-up, no other patient had any recurrence. We conclude that in primary hydrocele with macroscopic features indicative of tunica vaginalis inflammation, reversion of the tunica should be a part of operative strategy instead of sheath fenestration, in order to minimize the recurrence.

Photoacclimatory and photoprotective responses to cold versus heat stress in high latitude reef corals.

Corals at the world's southernmost coral reef of Lord Howe Island (LHI) experience large temperature and light fluctuations and need to deal with periods of cold temperature (<18°C), but few studies have investigated how corals are able to cope with these conditions. Our study characterized the response of key photophysiological parameters, as well as photoacclimatory and photoprotective pigments (chlorophylls, xanthophylls, and ß-carotene), to short-term (5-d) cold stress (~15°C; 7°C below control) in three LHI coral species hosting distinct Symbiodinium ITS2 types, and compared the coral-symbiont response to that under elevated temperature (~29°C; 7°C above control). Under cold stress, Stylophora sp. hosting Symbiodinium C118 showed the strongest effects with regard to losses of photochemical performance and symbionts. Pocillopora damicornis hosting Symbiodinium C100/C118 showed less severe bleaching responses to reduced temperature than to elevated temperature, while Porites heronensis hosting Symbiodinium C111* withstood both reduced and elevated temperature. Under cold stress, photoprotection in the form of xanthophyll de-epoxidation increased in unbleached P. heronensis (by 178%) and bleached Stylophora sp. (by 225%), while under heat stress this parameter increased in unbleached P. heronensis (by 182%) and in bleached P. damicornis (by 286%). The xanthophyll pool size was stable in all species at all temperatures. Our comparative study demonstrates high variability in the bleaching vulnerability of these coral species to low and high thermal extremes and shows that this variability is not solely determined by the ability to activate xanthophyll de-epoxidation.

Ecological speciation in sympatric palms: 1. Gene expression, selection and pleiotropy.

Ecological speciation requires divergent selection, reproductive isolation and a genetic mechanism to link the two. We examined the role of gene expression and coding sequence evolution in this process using two species of Howea palms that have diverged sympatrically on Lord Howe Island, Australia. These palms are associated with distinct soil types and have displaced flowering times, representing an ideal candidate for ecological speciation. We generated large amounts of RNA-Seq data from multiple individuals and tissue types collected on the island from each of the two species. We found that differentially expressed loci as well as those with divergent coding sequences between Howea species were associated with known ecological and phenotypic differences, including response to salinity, drought, pH and flowering time. From these loci, we identified potential 'ecological speciation genes' and further validate their effect on flowering time by knocking out orthologous loci in a model plant species. Finally, we put forward six plausible ecological speciation loci, providing support for the hypothesis that pleiotropy could help to overcome the antagonism between selection and recombination during speciation with gene flow.

The macular degeneration-linked C1QTNF5 (S163) mutation causes higher-order structural rearrangements.

The C1q-tumor necrosis factor 5 (C1QTNF5) protein plays a significant role in retinal pigmented epithelium (RPE) cellular adhesion. The C1QTNF5 gene is co-transcribed with the frizzled-related protein (MFRP) gene. A Ser-to-Arg mutation at site 163 (S163R) in C1QTNF5 is known to cause late-onset retinal macular degeneration (L-ORMD). Here we also found that C1QTNF5 monomers can multimerize into a bouquet-like octadecamer. We found that a novel intermolecular hydrogen-bond network of S163 that glues adjacent globular heads of C1QTNF5 together was weakened or abolished by the R163 pathogenic mutation. These findings could underlie the structural basis of this protein's adhesive function and relate to the pathogenesis of its S163R mutation. Additionally, the fact that C1QTNF5 immobilized to a resin selectively enriched detergent extracted membrane-bound MFRP, further confirmed their interaction, implying functions other than cellular adhesion for C1QTNF5.

Long-run real-time PCR analysis of repetitive nuclear elements as a novel tool for DNA damage quantification in single cells: an approach validated on mouse oocytes and fibroblasts.

Since DNA damage is of great importance in various biological processes, its rate is frequently assessed both in research studies and in medical diagnostics. The most precise methods of quantifying DNA damage are based on real-time PCR. However, in the conventional version, they require a large amount of genetic material and therefore their usefulness is limited to multicellular samples. Here, we present a novel approach to long-run real-time PCR-based DNA-damage quantification (L1-LORD-Q), which consists in amplification of long interspersed nuclear elements (L1) and allows for analysis of single-cell genomes. The L1-LORD-Q was compared with alternative methods of measuring DNA breaks (Bioanalyzer system, γ-H2AX foci staining), which confirmed its accuracy. Furthermore, it was demonstrated that the L1-LORD-Q is sensitive enough to distinguish between different levels of UV-induced DNA damage. The method was validated on mouse oocytes and fibroblasts, but the general idea is universal and can be applied to various types of cells and species.

Detection and Differentiation of Entomopathogenic Serratia spp. to Inform Reintroduction of the Critically Endangered Lord Howe Island Stick Insect Dryococelus australis.

Once rodents have been successfully eradicated from Lord Howe Island, Australia, the critically endangered Lord Howe Island stick insect (Dryococelus australis (Montrouzier)) may be reintroduced, a century after it was thought to have become extinct. In captive populations of D. australis, elevated mortalities have been associated with bacterial pathogens. To better define the infectious risk posed by entomopathogens to the reintroduction program, we investigated the bacteria isolated from captive D. australis kept at Melbourne Zoo and on Lord Howe Island and from environmental samples and free-living invertebrates collected on various parts of the island. At Melbourne Zoo, Serratia and Pseudomonas spp. were the bacteria most frequently isolated between 2013 and 2019. Serratia spp. were also the organisms most frequently isolated from insects sampled in April 2019 from the captive population on Lord Howe Island. In addition, Serratia spp. were isolated from a range of environmental samples collected on Lord Howe Island during March-April 2019. These environmental isolates had a broader range of biochemical and molecular characteristics than those obtained from the captive insect populations. A large proportion of these isolates were urease positive and had biochemical profiles previously not described for Serratia spp. This study highlights the need for better surveillance for potential pathogens in understudied regions and sites. We conclude that infections caused by Serratia spp. might pose a problem to the captive breeding program for D. australis but that the risk of introducing novel pathogens to Lord Howe Island through infected insects is low. Our study explores some of the potential risks involved in captive breeding and provides a valuable example of using pathogen surveillance to better inform an invertebrate conservation program.

Genetic Affinities and Adaptation of the South-West Coast Populations of India.

Evolutionary event has not only altered the genetic structure of human populations but also associated with social and cultural transformation. South Asian populations were the result of migration and admixture of genetically and culturally diverse groups. Most of the genetic studies pointed to large-scale admixture events between Ancestral North Indian (ANI) and Ancestral South Indian (ASI) groups, also additional layers of recent admixture. In the present study, we have analyzed 213 individuals inhabited in South-west coast India with traditional warriors and feudal lord status and historically associated with migratory events from North/North West India and possible admixture with West Eurasian populations, whose genetic links are still missing. Analysis of autosomal Single Nucleotide Polymorphism (SNP) markers suggests that these groups possibly derived their ancestry from some groups of North West India having additional Middle Eastern genetic components. Higher distribution of West Eurasian mitochondrial haplogroups also points to female-mediated admixture. Estimation of Effective Migration Surface (EEMS) analysis indicates Central India and Godavari basin as a crucial transition zone for population migration from North and North West India to South-west coastal India. Selection screen using 3 distinct outlier-based approaches revealed genetic signatures related to Immunity and protection from Viral infections. Thus, our study suggests that the South-west coastal groups with traditional warriors and feudal lords' status are of a distinct lineage compared to Dravidian and Gangetic plain Indo-Europeans and are remnants of very early migrations from North West India following the Godavari basin to Karnataka and Kerala.