Photobiomodulation for non-exudative age-related macular degeneration

BACKGROUND: Age‐related macular degeneration (AMD) is one of the leading causes of blindness in high‐income countries. The majority of cases of AMD are of the non‐exudative type. Experts have proposed photobiomodulation (PBM) therapy as a non‐invasive procedure to restore mitochondrial function, upregulate cytoprotective factors and prevent apoptotic cell death in retinal tissue affected by AMD. OBJECTIVES: To assess the effectiveness and safety of PBM compared to standard care, no treatment or sham treatment for people with non‐exudative AMD. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 5, 2020), Ovid MEDLINE, Embase, ISRCTN, ClinicalTrials.gov and the WHO ICTRP to 11 May 2020 with no language restrictions. SELECTION CRITERIA: The review included randomised controlled trials (RCTs) on participants receiving any type of PBM therapy for non‐exudative AMD compared to standard care, sham treatment or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We considered the following outcome measures at 12 months: best‐corrected visual acuity (BCVA) ; contrast sensitivity; near vision; low luminance density score; reading speed; vision‐related quality of life score; and adverse events such as progression of AMD and conversion to exudative AMD. We graded the certainty of the evidence using GRADE. MAIN RESULTS: We included two published RCTs from single centres in the UK and Canada, which recruited 60 participants (60 eyes) and 30 participants (46 eyes) respectively. Participants in these trials were people with non‐exudative AMD with Age‐Related Eye Disease Study (AREDS) categories 2 to 4. One study compared single wavelength PBM with no treatment. This study was at risk of performance bias because the study was not masked, and there was attrition bias. One study compared multi‐wavelength PBM with sham treatment and conflicts of interest were reported by study investigators. We also identified three eligible ongoing RCTs from searching the clinical trials database. When comparing PBM with sham treatment or no treatment for non‐exudative AMD, there was no evidence of any meaningful clinical difference in BCVA at 12 months (mean difference (MD) 0.02 logMAR, 95% confidence interval (CI) ‐0.02 to 0.05; 2 RCTs, 90 eyes; low‐certainty evidence). One study comparing multi‐wavelength PBM with sham treatment showed an improvement in contrast sensitivity at Level E (18 cycles/degree) at 12 months (MD 0.29 LogCS, 95% CI 0.23 to 0.35; 1 RCT, 46 eyes; low‐certainty evidence). Visual function and health‐related quality of life scores were comparable between single wavelength PBM and no treatment groups at 12 months (VFQ‐48 score MD 0.43, 95% CI ‐0.17 to 1.03; P = 0.16; 1 RCT, 47 eyes; low‐certainty evidence). When comparing PBM with sham treatment or no treatment for non‐exudative AMD, there was no evidence of any meaningful clinical difference in conversion to exudative AMD (risk ratio (RR) 0.97, 95% CI 0.17 to 5.44; 2 RCTs, 96 eyes; very low‐certainty evidence) at 12 months. There was inconclusive evidence that single wavelength PBM prevents the progression of AMD (RR 0.79, 95% CI 0.41 to 1.53; P = 0.48; 1 RCT, 50 eyes; low‐certainty evidence). Disease progression was defined as the development of advanced AMD or significant increase in drusen volume. No included study reported near vision, low luminance vision or reading speed outcomes

Creative Engagements and Cross-Disciplinary Approaches to the Study of Business

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How learning new words changes lexical networks during developmental language acquisition

The thesis uses connectionist ideas as a basis for understanding lexical processing, in particular how usage factors have an effect on lexical production in early development. The usage factors of word frequency, neighbourhood density and age-of-acquisition are considered and manipulated in word and non-word repetition tasks with children aged 2 to 12 years. First-order neighbourhood density refers to adjacent neighbours of a target word and second-order neighbourhood density refers to neighbours of first-order neighbours. First- and second-order neighbourhood changes over age were calculated. Experiments were conducted to see how these and the other usage factors interact. A particular focus was whether a phone string is processed differently depending on whether it is a word a child knows or is effectively a non-word (i.e. a word not acquired until a later age). A Generative Acquisition Hypothesis Processing Shift Model is proposed explaining how a string of phones that is a non-word (not known by a child of this age) is processed differently to when it is acquired and how this leads to different interactions between usage factors on lexical processing. The thesis then extends this model by investigating usage factors in Cantonese-English bilinguals as well as Cantonese monolinguals. The results provide a better understanding about how the lexicon develops over ages and how the links between words changes (using the neighbourhood density statistics) within children of different ages and between two languages in bilingual children

Investigating the role of peripheral serotonergic, purinergic and nitric oxide/cGMP pathways in the normal and pathological erectile process and the effect of Vardenafil on diabetic nephropathy

Serotonin (5-HT, 5-hydroxytrptamine), purinergic and nitric oxide (NO)/ cyclic guanosine monophosphate (cGMP) pathways have been implicated in human penile erection and erectile dysfunction (ED) and the later also involved in the pathogenesis of diabetic nephropathy (DN). The role and characterisation of the peripheral serotonergic and purinergic pathway in corpus cavernosal smooth muscle (CCSM) function was investigated. Electrical field stimulation of human and rabbit CCSM strips demonstrated the presence of neuronally-derived 5-HT acting on 5-HT(2A) receptors. Organ bath studies also showed that 5-HT caused CCSM contraction via 5-HT(1A), (1B), (2A) and (4) receptor subtypes, which was inhibited by doxazosin (an α-1 receptor antagonist known to have 5-HT inhibitory action). Immunohistochemistry and Western Blot analysis confirmed the presence of these 5-HT receptor subtypes in human CCSM. The effect of 5-HT and sodium nitroprusside (SNP; NO donor) on CCSM function from normal, diabetic and partial bladder outlet obstructed (PBOO) rabbit models were also assessed as these pathological models are associated with ED. There was no difference in 5-HT-induced CCSM contractions between the control and pathological models. In contrast, SNP-mediated relaxations were impaired in diabetic and PBOO rabbits. Vardenafil (phosphodiesterase type-5 inhibitor) improved the impaired CCSM relaxation in both models. Immunohistochemistry also identified the presence of purinergic P2Y6 receptors in human CCSM, which when activated induced tissue relaxation. Finally, the effect oral vardenafil treatment has on established renal impairment in diabetic rabbits was investigated. Vardenafil increased cGMP accumulation and improved renal function in DN. These findings suggests that targeting the peripheral serotonergic and purinergic pathways may be useful therapeutic options in treating ED. In addition, the use of vardenafil may be beneficial in the management of DN

On the localization of the cleavage site in human alpha‐2‐antiplasmin, involved in the generation of the non‐plasminogen binding form

Background: Alpha‐2‐antiplasmin (α2AP) is the main natural inhibitor of plasmin. The C‐terminus of α2AP is crucial for the initial interaction with plasmin(ogen) and the rapid inhibitory mechanism. Approximately 35% of circulating α2AP has lost its C‐terminus (non‐plasminogen binding α2AP/NPB‐α2AP) and thereby its rapid inhibitory capacity. The C‐terminal cleavage site of α2AP is still unknown. A commercially available monoclonal antibody against α2AP (TC 3AP) detects intact but not NPB‐α2AP, suggesting that the cleavage site is located N‐terminally from the epitope of TC 3AP. Objectives: To determine the epitope of TC 3AP and then to localize the C‐terminal cleavage site of α2AP. Methods: For epitope mapping of TC 3AP, commercially available plasma purified α2AP was enzymatically digested with Asp‐N, Glu‐C, or Lys‐N. The resulting peptides were immunoprecipitated using TC 3AP‐loaded Dynabeads® Protein G. Bound peptides were eluted and analyzed by liquid chromatography‐tandem mass spectometry (LC‐MS/MS). To localize the C‐terminal cleavage site precisely, α2AP (intact and NPB) was purified from plasma and analyzed by LC‐MS/MS after enzymatic digestion with Arg‐C. Results: We localized the epitope of TC 3AP between amino acid residues Asp428 and Gly439. LC‐MS/MS data from plasma purified α2AP showed that NPB‐α2AP results from cleavage at Gln421‐Asp422 as preferred site, but also after Leu417, Glu419, Gln420, or Asp422. Conclusions: The C‐terminal cleavage site of human α2AP is located N‐terminally from the TC 3AP epitope. Because C‐terminal cleavage of α2AP can occur after multiple residues, different proteases may be responsible for the generation of NPB‐α2AP

Referrals for proliferative diabetic retinopathy from two UK diabetic retinopathy screening services: a 10-year analysis of visual outcomes, requirement for vitrectomy, and mortality

\ua9 The Author(s) 2024. Background/objectives: To determine long-term outcomes of patients referred with proliferative diabetic retinopathy (PDR) from diabetic eye screening programmes (DESP) to tertiary care centres in the United Kingdom (UK). Methods: Retrospective multicentre study of patients referred from two DESPs in the UK over a 36-month period (2007–9) and followed-up for 10 years. Critical outcomes included severe vision loss (SVL) and the need for vitrectomy. Other outcomes assessed included moderate vision loss (MVL), and patient survival time. Univariate and multiple variable Cox proportional hazards regressions were used to analyse survival outcomes. Results: 212 eyes of 150 patients were referred with a diagnosis of PDR. 109 eyes of 72 patients were confirmed to have active PDR and included in the study. 61% of patients had low-risk PDR, while 39% exhibited high-risk features in at least one eye. Eight (7.3%) eyes developed SVL and 16 (14.7%) MVL during follow up. Vitrectomy was required in 24% (95% CI: 15 to 31%) of all PDR eyes and was most commonly performed for vitreous haemorrhage (65%). The 10-year survival in all PDR patients was 76% (95% CI: 63 to 85%) with the mean time to death for all deceased patients being 5.4 \ub1 3.6 years. On multivariable analysis, only age was found to have a significant association with the survival of patients with PDR. Conclusions: During the 10 year follow up SVL was uncommon, but MVL occurred in almost one-fifth of the eyes. Approximately 1 in 4 eyes required vitrectomy, highlighting its significance in patient management

A primary rodent triculture model to investigate the role of glia-neuron crosstalk in regulation of neuronal activity

Neuroinflammation and hyperexcitability have been implicated in the pathogenesis of neurodegenerative disease, and new models are required to investigate the cellular crosstalk involved in these processes. We developed an approach to generate a quantitative and reproducible triculture system that is suitable for pharmacological studies. While primary rat cells were previously grown in a coculture medium formulated to support only neurons and astrocytes, we now optimised a protocol to generate tricultures containing neurons, astrocytes and microglia by culturing in a medium designed to support all three cell types and adding exogenous microglia to cocultures. Immunocytochemistry was used to confirm the intended cell types were present. The percentage of ramified microglia in the tricultures decreases as the number of microglia present increases. Multi-electrode array recordings indicate that microglia in the triculture model suppress neuronal activity in a dose-dependent manner. Neurons in both cocultures and tricultures are responsive to the potassium channel blocker 4-aminopyridine, suggesting that neurons remained viable and functional in the triculture model. Furthermore, suppressed neuronal activity in tricultures correlates with decreased densities of dendritic spines and of the postsynaptic protein Homer1 along dendrites, indicative of a direct or indirect effect of microglia on synapse function. We thus present a functional triculture model, which, due to its more complete cellular composition, is a more relevant model than standard cocultures. The model can be used to probe glia-neuron interactions and subsequently aid the development of assays for drug discovery, using neuronal excitability as a functional endpoint

Disruption of endoplasmic reticulum-mitochondria tethering proteins in post-mortem Alzheimer's disease brain

Signaling between the endoplasmic reticulum (ER) and mitochondria regulates a number of key neuronal functions, many of which are perturbed in Alzheimer's disease. Moreover, damage to ER-mitochondria signaling is seen in cell and transgenic models of Alzheimer's disease. However, as yet there is little evidence that ER-mitochondria signaling is altered in human Alzheimer's disease brains. ER-mitochondria signaling is mediated by interactions between the integral ER protein VAPB and the outer mitochondrial membrane protein PTPIP51 which act to recruit and “tether” regions of ER to the mitochondrial surface. The VAPB-PTPIP51 tethers are now known to regulate a number of ER-mitochondria signaling functions including delivery of Ca2+from ER stores to mitochondria, mitochondrial ATP production, autophagy and synaptic activity. Here we investigate the VAPB-PTPIP51 tethers in post-mortem control and Alzheimer's disease brains. Quantification of ER-mitochondria signaling proteins by immunoblotting revealed loss of VAPB and PTPIP51 in cortex but not cerebellum at end-stage Alzheimer's disease. Proximity ligation assays were used to quantify the VAPB-PTPIP51 interaction in temporal cortex pyramidal neurons and cerebellar Purkinje cell neurons in control, Braak stage III-IV (early/mid-dementia) and Braak stage VI (severe dementia) cases. Pyramidal neurons degenerate in Alzheimer's disease whereas Purkinje cells are less affected. These studies revealed that the VAPB-PTPIP51 tethers are disrupted in Braak stage III-IV pyramidal but not Purkinje cell neurons. Thus, we identify a new pathogenic event in post-mortem Alzheimer's disease brains. The implications of our findings for Alzheimer's disease mechanisms are discussed

Neoadjuvant chemotherapy improves survival in patients with oesophageal mucinous adenocarcinoma: Post-hoc analysis of the UK MRC OE02 and OE05 trials

Background: Adenocarcinoma with more than 50% extracellular mucin is a relatively rare histological subtype of gastrointestinal adenocarcinomas. The clinical impact of extracellular mucin in oesophageal adenocarcinoma (OeAC) has not been investigated in detail. We hypothesised that patients with mucinous OeAC (OeACmucin) do not benefit from neoadjuvant chemotherapy. Methods: OeAC patients either treated by surgery alone in the OE02 trial (S-patients) or by neoadjuvant chemotherapy followed by surgery (CS-patients) in OE02 or OE05 trials were included. Cancers from 1055 resection specimens (OE02 [test cohort]: 187 CS, 185 S; OE05 [validation cohort]: 683 CS) were classified as either mucinous (more than 50% of the tumour area consists of extracellular mucin, OeACmucin) or non-mucinous adenocarcinoma (OeACnon-mucin). The relationship between histological phenotype, clinicopathological characteristics, survival and treatment was analysed. Results: Overall, 7.3% and 9.6% OeAC were classified as OeACmucin in OE02 and OE05, respectively. In OE02, the frequency of OeACmucin was similar in S and CS-patients. Patients with OeACmucin treated with surgery alone had a poorer overall survival compared with OeACnon-mucin patients (hazard ratio: 2.222, 95% confidence interval: 1.08–4.56, P = 0.025). Patients with OeACmucin treated with neoadjuvant chemotherapy and surgery had similar survival as OeACnon-mucin patients in test and validation cohort. Conclusions: This is the first study to suggest in a post-hoc analysis of material from two independent phase III clinical trials that the poor survival of patients with mucinous OeAC can be improved by neoadjuvant chemotherapy. Future studies are warranted to identify potential underlying biological, biochemical or pharmacokinetic interactions between extracellular mucin and chemotherapy