Mwtlai wyd di? : o^l-drefedigaethedd, Cymru'r oesoedd canol a Dafydd ap Gwilym

Mae'r traethawd hwn yn trafod agweddau ar Gymru'r Oesoedd Canol a gwaith Dafydd ap Gwilym yng ngoleuni rhai o brif syniadau theori 61-drefedigaethol. Man cychwyn y drafodaeth yw 61-drefedigaethedd a'i berthynas a Chymru'r Oesoedd Canol. Dadansoddir perthnasedd syniadau'r theori i Gymru oes Dafydd ap Gwilym, cyn eu defhyddio'n ymarferol i gynnig darlleniadau o'r cerddi. Cais y ddwy bennod gyntaf baratoi'r ffordd ar gyfer cynnig atebion i'r problemau sy'n codi gydag 61-drefedigaethedd. Edrych y bennod gyntaf ar ddiffinio'r 61- drefedigaethol yn gyffredinol ac mewn cyd-destun Cymraeg a Chymreig. Trafodir perthynas benodol yr Oesoedd Canol ag 61-drefedigaethedd yn yr ail bennod. Canolbwyntia'r drydedd bennod ar feirniadaeth lenyddol a hanesyddiaeth Gymreig. Cyfeirir at y dadlau a fu ynghylch defhyddio'r theori i drafod llenyddiaeth Gymraeg a Chymreig. Yn y bedwaredd bennod, ceir trafodaeth ar ddulliau ymdriniaethau beirniadol o drafod Dafydd ap Gwilym. Arwain hyn at ail ran y drafodaeth sy'n edrych ar waith Dafydd yn fwy manwl o safbwynt rhai o brif syniadau'r theori. Y Trydydd Gofod a dynwared yw ffocws y burned bennod, a dadansoddir cywydd 'Y Cleddyf (71) yng ngoleuni'r syniadau hyn. Mae'r Trydydd Gofod hefyd yn sail ar gyfer dehongli 41 Ddymuno Lladd y Gwr Eiddig' (116) a 'Trech a gais nag a geidw' (112) yn y chweched bennod. Demyddir hybridedd yn y seithfed bennod i ddehongli Trafferth mewn Tafarn'(73). Edrychir yn benodol ar y deuoliaethau diwylliannol a welir yn y gerdd hon. Yn yr wythfed bennod, manylir ar berthynas y carwr a'r ceiliog bronfraith yng ngoleuni'r hollt. Yn y dehongliad o 'Y Ceiliog Bronfraith' (49), dadansoddir perthynas y ddau o safbwynt awdurdod y naill dros y Hall. Archwilir perthynas Eiddig a'r carwr yn y nawfed bennod a defnyddir model y canol/ymylon i edrych ar ddelweddau unigol o'r cerddi, gan ganolbwyntio yn arbennig ar gymeriad Eiddig. Cyflwynir casgliadau'r ymchwil fel pennod glo

Lithium overdose and delayed severe neurotoxicity:timing for renal replacement therapy and restarting of lithium

This is a case report of a man in his 60s who presented to an English hospital following a significant lithium overdose. He was monitored for 24 hours, and then renal replacement therapy was initiated after assessment by the renal team. As soon as the lithium level returned to normal therapeutic levels (from 4.7 mEq/L to 0.67 mEq/L), lithium was restarted by the medical team. At this point, the patient developed new slurred speech and later catatonia. In this case report, we discuss the factors that could determine which patients are at risk of neurotoxicity following lithium overdose and the appropriate decision regarding when and how to consider initiation of renal replacement therapy and restarting of lithium

Acute kidney injury risk factor recognition in three teaching hospitals in Ethiopia

Background. A key objective of the Nephrology Sister Centre Programme between the renal units in Cardiff and Addis Ababa, sponsored by the International Society of Nephrology, is to facilitate development of the local clinical service in Ethiopia specifically focused on the management of acute kidney injury (AKI). Objectives. To examine the relationship between AKI risk factor recognition and monitoring of renal function in three hospitals in Ethiopia. Methods. Cross-sectional data were gathered regarding renal function monitoring, recording the presence of AKI risk-associated comorbidities and prescription of nephrotoxic medications across the disciplines of medicine, surgery, obstetrics and gynaecology. Results. Patients were more likely to have their renal function checked at the hospital with specialist services. Across all centres, the highest proportion of patients who had renal function measurements were those admitted to a medical ward. There was a positive relationship between documented comorbidities and the measurement of renal function but not between the prescription of nephrotoxic drugs and measurement of renal function. Conclusion. There was great variability in the extent to which doctors recognised the presence of risk factors for the development of AKI. Failure to identify these risk factors represents a lost opportunity to identify patients at high risk of developing renal injury who would benefit from renal function monitoring

Acute kidney injury risk factor recognition in three teaching hospitals in Ethiopia

Background. A key objective of the Nephrology Sister Centre Programme between the renal units in Cardiff and Addis Ababa, sponsored by the International Society of Nephrology, is to facilitate development of the local clinical service in Ethiopia specifically focused on the management of acute kidney injury (AKI). Objectives. To examine the relationship between AKI risk factor recognition and monitoring of renal function in three hospitals in Ethiopia. Methods. Cross-sectional data were gathered regarding renal function monitoring, recording the presence of AKI risk-associated comorbidities and prescription of nephrotoxic medications across the disciplines of medicine, surgery, obstetrics and gynaecology. Results. Patients were more likely to have their renal function checked at the hospital with specialist services. Across all centres, the highest proportion of patients who had renal function measurements were those admitted to a medical ward. There was a positive relationship between documented comorbidities and the measurement of renal function but not between the prescription of nephrotoxic drugs and measurement of renal function. Conclusion. There was great variability in the extent to which doctors recognised the presence of risk factors for the development of AKI. Failure to identify these risk factors represents a lost opportunity to identify patients at high risk of developing renal injury who would benefit from renal function monitoring

Relative resistance of HIV-1 founder viruses to control by interferon-alpha

Background: Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed. Results: The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNβ (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNβ, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses. Conclusions: The establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection

A genome-wide association study for late-onset Alzheimer's disease using DNA pooling

Background: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case – control sample, reducing costs through the use of DNA pooling. Methods: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case – control sample used to construct the pools. Results: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach. For 109 SNPs outside the APOE locus, we obtained uncorrected p-values ≤ 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 × 10-6 for our strongest finding, rs727153. rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine – retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 × 10-7). Conclusion: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD

LRG1 destabilizes tumor vessels and restricts immunotherapeutic potency

Background: A poorly functioning tumor vasculature is pro-oncogenic and may impede the delivery of therapeutics. Normalizing the vasculature, therefore, may be beneficial. We previously reported that the secreted glycoprotein leucine-rich α-2-glycoprotein 1 (LRG1) contributes to pathogenic neovascularization. Here, we investigate whether LRG1 in tumors is vasculopathic and whether its inhibition has therapeutic utility. Methods: Tumor growth and vascular structure were analyzed in subcutaneous and genetically engineered mouse models in wild-type and Lrg1 knockout mice. The effects of LRG1 antibody blockade as monotherapy, or in combination with co-therapies, on vascular function, tumor growth, and infiltrated lymphocytes were investigated. Findings: In mouse models of cancer, Lrg1 expression was induced in tumor endothelial cells, consistent with an increase in protein expression in human cancers. The expression of LRG1 affected tumor progression as Lrg1 gene deletion, or treatment with a LRG1 function-blocking antibody, inhibited tumor growth and improved survival. Inhibition of LRG1 increased endothelial cell pericyte coverage and improved vascular function, resulting in enhanced efficacy of cisplatin chemotherapy, adoptive T cell therapy, and immune checkpoint inhibition (anti-PD1) therapy. With immunotherapy, LRG1 inhibition led to a significant shift in the tumor microenvironment from being predominantly immune silent to immune active. Conclusions: LRG1 drives vascular abnormalization, and its inhibition represents a novel and effective means of improving the efficacy of cancer therapeutics. Funding: Wellcome Trust (206413/B/17/Z), UKRI/MRC (G1000466, MR/N006410/1, MC/PC/14118, and MR/L008742/1), BHF (PG/16/50/32182), Health and Care Research Wales (CA05), CRUK (C42412/A24416 and A17196), ERC (ColonCan 311301 and AngioMature 787181), and DFG (CRC1366)