Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Letnik:
66
Journal Article
Recenzirano
Odprti dostop
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
In a randomized clinical trial of 86 hospitalized COVID-19 patients comparing standard care to treatment with 300mL convalescent plasma containing high titers of neutralizing SARS-CoV-2 antibodies, ...no overall clinical benefit was observed. Using a comprehensive translational approach, we unravel the virological and immunological responses following treatment to disentangle which COVID-19 patients may benefit and should be the focus of future studies. Convalescent plasma is safe, does not improve survival, has no effect on the disease course, nor does plasma enhance viral clearance in the respiratory tract, influence SARS-CoV-2 antibody development or serum proinflammatory cytokines levels. Here, we show that the vast majority of patients already had potent neutralizing SARS-CoV-2 antibodies at hospital admission and with comparable titers to carefully selected plasma donors. This resulted in the decision to terminate the trial prematurely. Treatment with convalescent plasma should be studied early in the disease course or at least preceding autologous humoral response development.
Various functional outcomes after upper blepharoplasty are reported in the literature. We systematically reviewed the literature to assess the objective and subjective functional effects of upper ...blepharoplasty.
After a systematic search of four search engines (Pubmed, Embase, Cinahl and Cochraine), any study on objective and subjective (patient reported) functional outcome after upper blepharoplasty was subjected to a quality assessment for possible inclusion in the review. The intervention was defined as a solitary surgical upper blepharoplasty containing the removal of skin, with or without the removal of a strip of orbicularis oculi muscle and/or upper orbital fat. Eligible studies were randomized controlled trials, controlled trials, cohort studies and case series (n ≥ 10).
A total of 3525 studies were assessed, of which 28 studies were included in this systematic review. Favorable outcomes after an upper blepharoplasty were reported and included enlarged visual field, enhanced quality of life related to fewer headaches and improved vision. Furthermore, sensitivity of the eyelids decreased, with differences in recovery. Outcomes for eyebrow height, astigmatism, contrast sensitivity and eyelid kinematics were not consistent between the studies. No meta-analysis could be performed due to the limited scope of included studies and the great variety in outcomes and blepharoplasty techniques.
Upper blepharoplasty is accompanied by a great variety of beneficial functional outcomes including an increased visual field and improvement in headache- and vision-related quality of life. Further research is needed, especially where results are conflicting (effects on eye dryness and eyebrow height) and/or the data are limited (contrast sensitivity, astigmatism).
To elucidate the functional epigenomic landscape of articular cartilage in osteoarthritis (OA) affected knee and hip joints in relation to gene expression.
Using Illumina Infinium HumanMethylation450 ...BeadChip arrays, genome-wide DNA methylation was measured in 31 preserved and lesioned cartilage sample pairs (14 knees and 17 hips) from patients who underwent a total joint replacement due to primary OA. Using previously published genome-wide expression data of 33 pairs of cartilage samples, of which 13 pairs were overlapping with the current methylation dataset, we assessed gene expression differences in differentially methylated regions (DMRs).
Principal component analysis of the methylation data revealed distinct clustering of knee and hip samples, irrespective of OA pathophysiology. A total of 6272 CpG dinucleotides were differentially methylated between the two joints, comprising a total of 357 DMRs containing 1817 CpGs and 245 unique genes. Enrichment analysis of genes proximal of the DMRs revealed significant enrichment for developmental pathways and homeobox (HOX) genes. Subsequent transcriptomic analysis of DMR genes exposed distinct knee and hip expression patterns.
Our findings reveal consistent DMRs between knee and hip articular cartilage that marked transcriptomic differences among HOX genes, which were not reflecting the temporal sequential HOX expression pattern during development. This implies distinct mechanisms for maintaining cartilage integrity in adulthood, thereby contributing to our understanding of cartilage homeostasis and future tissue regeneration approaches.
Under homeostatic conditions, dendritic cells (DCs) continuously patrol the intestinal lamina propria. Upon antigen encounter, DCs initiate C‐C motif chemokine receptor 7 (CCR7) expression and ...migrate into lymph nodes to direct T cell activation and differentiation. The mechanistic underpinnings of DC migration from the tissues to lymph nodes have been largely elucidated, contributing greatly to our understanding of DC functionality and intestinal immunity. In contrast, the molecular mechanisms allowing DCs to efficiently migrate through the complex extracellular matrix of the intestinal lamina propria prior to antigen encounter are still incompletely understood. Here we show that small intestinal murine CD11b+CD103+ DCs express Placenta‐expressed transcript 1 (Plet1), a glycophoshatidylinositol (GPI)‐anchored surface protein involved in migration of keratinocytes during wound healing. In the absence of Plet1, CD11b+CD103+ DCs display aberrant migratory behavior, and accumulate in the small intestine, independent of CCR7 responsiveness. RNA‐sequencing indicated involvement of Plet1 in extracellular matrix‐interactiveness, and subsequent in‐vitro migration assays revealed that Plet1 augments the ability of DCs to migrate through extracellular matrix containing environments. In conclusion, our findings reveal that expression of Plet1 facilitates homeostatic interstitial migration of small intestinal DCs.
Naïve D103+ dendritic cells need to efficiently patrol the intestine in order to scan for pathogens. Efficiency of this migration depends on expression of Plet1, a microbiota‐regulated molecule also used by keratinocytes. These findings reveal a mechanistic link between migratory events during wound healing and immunity.
Cone photoreceptor disorders form a clinical spectrum of diseases that include progressive cone dystrophy (CD) and complete and incomplete achromatopsia (ACHM). The underlying disease mechanisms of ...autosomal recessive (ar)CD are largely unknown. Our aim was to identify causative genes for these disorders by genome-wide homozygosity mapping. We investigated 75 ACHM, 97 arCD, and 20 early-onset arCD probands and excluded the involvement of known genes for ACHM and arCD. Subsequently, we performed high-resolution SNP analysis and identified large homozygous regions spanning the PDE6C gene in one sibling pair with early-onset arCD and one sibling pair with incomplete ACHM. The PDE6C gene encodes the cone α subunit of cyclic guanosine monophosphate (cGMP) phosphodiesterase, which converts cGMP to 5′-GMP, and thereby plays an essential role in cone phototransduction. Sequence analysis of the coding region of PDE6C revealed homozygous missense mutations (p.R29W, p.Y323N) in both sibling pairs. Sequence analysis of 104 probands with arCD and 10 probands with ACHM revealed compound heterozygous PDE6C mutations in three complete ACHM patients from two families. One patient had a frameshift mutation and a splice defect; the other two had a splice defect and a missense variant (p.M455V). Cross-sectional retinal imaging via optical coherence tomography revealed a more pronounced absence of cone photoreceptors in patients with ACHM compared to patients with early-onset arCD. Our findings identify PDE6C as a gene for cone photoreceptor disorders and show that arCD and ACHM constitute genetically and clinically overlapping phenotypes.
Primary cilia are sensory organelles present on most mammalian cells. The assembly and maintenance of primary cilia are facilitated by intraflagellar transport (IFT), a bidirectional protein ...trafficking along the cilium. Mutations in genes coding for IFT components have been associated with a group of diseases called ciliopathies. These genetic disorders can affect a variety of organs including the retina. Using whole exome sequencing in three families, we identified mutations in Intraflagellar Transport 172 Homolog IFT172 (Chlamydomonas) that underlie an isolated retinal degeneration and Bardet-Biedl syndrome. Extensive functional analyses of the identified mutations in cell culture, rat retina and in zebrafish demonstrated their hypomorphic or null nature. It has recently been reported that mutations in IFT172 cause a severe ciliopathy syndrome involving skeletal, renal, hepatic and retinal abnormalities (Jeune and Mainzer-Saldino syndromes). Here, we report for the first time that mutations in this gene can also lead to an isolated form of retinal degeneration. The functional data for the mutations can partially explain milder phenotypes; however, the involvement of modifying alleles in the IFT172-associated phenotypes cannot be excluded. These findings expand the spectrum of disease associated with mutations in IFT172 and suggest that mutations in genes originally reported to be associated with syndromic ciliopathies should also be considered in subjects with non-syndromic retinal dystrophy.
Summary
Background
Helicobacter pylori prevalence in Western countries has been declining simultaneously with increases in childhood asthma and allergic diseases; prior studies have linked these ...phenomena.
Aims
To examine the association between H. pylori colonisation in children and risk of asthma and related conditions at school age. We secondly examined additional effects of maternal H. pylori status by pairing with children's status.
Methods
This study was embedded in a multi‐ethnic population‐based cohort in Rotterdam, The Netherlands. We measured anti‐H. pylori and anti‐CagA antibodies in serum of children obtained at age 6 years, and of their mothers obtained during midpregnancy. Asthma or related conditions were reported for children at age 6 years. We used multivariate logistic regression analyses among 3797 subjects.
Results
In children, the H. pylori positivity rate was 8.7%, and 29.2% of these were CagA‐positive. A child's colonisation with a CagA‐negative‐H. pylori strain was associated with an increased risk of asthma (Odds ratio 2.11; 95% CI 1.23–3.60), but this differed for European (3.64; 1.97–6.73) and non‐European (0.52; 0.14–1.89) children. When taking into account maternal H. pylori status, only H. pylori‐positive children with an H. pylori‐negative mother had increased risk of asthma (2.42; 1.11–5.27), accounting for 3.4% of the asthma risk.
Conclusions
Colonisation of a European child with a CagA‐negative‐H. pylori strain at age 6 was associated with an increased prevalence of asthma, but there was no association for non‐European children. The underlying mechanisms for the observed risk differences require further research.
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people worldwide. Cuticular drusen (CD) is a clinical subtype of AMD, which typically displays an ...earlier age at onset, and has a strong genetic component. Genetic studies support a role for rare sequence variants in CD susceptibility, and rare sequence variants in the CFH gene have been identified in 8.8% of CD cases. To further explore the role of rare variants in CD, we performed whole exome sequencing (WES) in 14 affected members of six families and 12 sporadic cases with CD. We detected rare sequence variants in CFH and FBLN5, which previously were shown to harbor rare variants in patients with CD. In addition, we detected heterozygous rare sequence variants in several genes encoding components of the extracellular matrix (ECM), including FBLN1, FBLN3/EFEMP1, FBLN5, FBLN6/HMCN1, FBN2, and COL15A1. Two rare pathogenic variants were identified in the COL15A1 gene: one in a sporadic case and another was found to segregate in a family with six affected individuals with CD. In addition, two rare pathogenic variants were identified in the FGL1 gene in three unrelated CD cases. These findings suggest that alterations in the ECM and in the coagulation pathway may play a role in the pathogenesis of CD. The identified candidate genes require further analyses in larger cohorts to confirm their role in the CD subtype of AMD. No evidence was found of rare sequence variants in a single gene that segregate with CD in the six families, suggesting that the disease is genetically heterogeneous.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intercellular spread of plant viruses involves passage of the viral genome or virion through a plasmodesma (PD). Some viruses severely modify the PD structure, as they assemble a virion carrying ...tubule composed of the viral movement protein (MP) inside the PD channel. Successful modulation of the host plant to allow infection requires an intimate interaction between viral proteins and both structural and regulatory host proteins. To date, however, very few host proteins are known to promote virus spread. Plasmodesmata-located proteins (PDLPs) localised in the PD have been shown to contribute to tubule formation in cauliflower mosaic virus and grapevine fanleaf virus infections. In this study, we have investigated the role of PDLPs in intercellular transport of another tubule-forming virus, cowpea mosaic virus. The MP of this virus was found to interact with PDLPs in the PD, as was shown for other tubule-forming viruses. Expression of PDLPs and MPs in protoplasts in the absence of a PD revealed that these proteins do not co-localise at the site of tubule initiation. Furthermore, we show that tubule assembly in protoplasts does not require an interaction with PDLPs at the base of the tubule, as has been observed
in planta
. These results suggest that a physical interaction between MPs and PDLPs is not required for assembly of the movement tubule and that the beneficial role of PDLPs in virus movement is confined to the structural context of the PD.
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