Humans ; Kidney Failure, Chronic ; epidemiology ; physiopathology ; therapy ; Singapore ; epidemiology

INTRODUCTIONIgA nephritis (IgAN) is the most common glomerulonephritis worldwide. We aim to genotype SNPs (single nucleotide polymorphisms) genomewide in patients with IgAN to search for genetic clues to its aetiology.

MATERIALS AND METHODSGenotyping for 10,204 SNPs genomewide was done with the Gene Chip Human Mapping 10K Microarray (Affymetrix). Twenty-eight patients with IgAN and 30 normal subjects were screened and analysed for differences in genotype frequency, allele frequency and heterozygosity reduction.

RESULTSAmong the most significantly associated SNPs, 48 SNPs were found mapping directly to the intron of 42 genes that localised in 13 somatic chromosomes and chromosome X. Genotype distribution of these SNPs did not deviate from the Hardy-Weinberg equilibrium in normal subjects. The most significantly associated gene, glial cells missing homolog 1 (GCM, 2 =13.05, P = 0.000) is a transcription factor mapped to 6p12.2. GCM1 reported decreased in placenta of patients with pre-eclampsia. The second gene, Tenascin-R (TNR, 2 = 9.85, P = 0.002) is a glycoprotein and extra-cellular matrix component mapped to 1q25.1. Tenascin-R was associated with motor coordination impairment and enhanced anxiety profile in deficient mice. Interestingly, Triadin (TRDN, 2 = 9.16, P = 0.01) is an integral membrane protein mapped to 6q22.31 within the IgAN1 locus. Triadin was shown to participate in cardiac myocyte arrhythemia. However, there is no published study of these genes in IgAN.

CONCLUSIONForty-two associated genes (particularly GCM1, TNR and TRDN) are identified as possible susceptibility or marker genes for IgAN. Knowledge of their mesangial expression and binding capacity for IgA-containing complexes may help elucidate the pathogenesis of IgAN.

Animals ; Carrier Proteins ; genetics ; Case-Control Studies ; Chromosome Mapping ; methods ; Disease Susceptibility ; Genetic Markers ; Genetic Testing ; Genotype ; Glomerulonephritis, IGA ; diagnosis ; epidemiology ; genetics ; Humans ; Mice ; Microarray Analysis ; Muscle Proteins ; genetics ; Nuclear Proteins ; genetics ; Odds Ratio ; Pilot Projects ; Polymorphism, Single Nucleotide ; genetics ; Singapore ; epidemiology ; Statistics as Topic ; Tenascin ; genetics ; Transcription Factors ; genetics

INTRODUCTIONIn this study of 109 patients with IgA nephritis (IgAN), we compared the longterm effects on patients treated with angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ATRA) alone with respect to renal outcome in terms of ESRF from 1995 to 2006. The renal outcome is also correlated with the ACE gene ID polymorphism to study its influence on response to ACEI/ATRA therapy.

MATERIALS AND METHODSSeventy-seven patients were on treatment with ACEI/ATRA (22 on ACEI alone, 47 on ATRA alone and 8 on both). The other 32 patients were on no treatment (control group).

RESULTSCompared to controls, treated patients had lower serum creatinine (P <0.001), lower proteinuria (P <0.001) and fewer number progressing to ESRF (P <0.001). For those with the II and ID genotype there were significantly fewer patients with ESRF in the treatment group. With the DD genotype, treatment did not change the poor renal outcome with regard to ESRF. Patients on ACEI therapy had a higher incidence of ESRF compared to those on ATRA (P <0.001). For the control group, the projected number of years-to-ESRF was 10 years. For those on ACEI therapy it was 11 years, and for those on ATRA therapy it was 24 years. Among patients with the II genotype, those treated with ATRA had significantly less incidence of ESRF compared to those treated with ACEI (P <0.001).

CONCLUSIONATRA therapy was found to be effective in retarding disease progression to ESRF in IgAN compared to ACEI therapy. Genotyping showed better response to ATRA therapy only for those with the II genotype.

Adult ; Angiotensin II Type 1 Receptor Blockers ; therapeutic use ; Angiotensin-Converting Enzyme Inhibitors ; therapeutic use ; Case-Control Studies ; Disease Progression ; Female ; Genetic Predisposition to Disease ; genetics ; Glomerulonephritis, IGA ; complications ; drug therapy ; genetics ; Humans ; Hypertension ; complications ; drug therapy ; Kidney Failure, Chronic ; etiology ; Male ; Peptidyl-Dipeptidase A ; genetics ; Polymorphism, Genetic ; genetics ; Retrospective Studies

This paper explains some of the difficulties doctors face when taking up a career in research. It describes the efforts by the government and the Ministry of Health (MOH) to nurture the Clinician Scientist Programme. The nature of research and the mindset of clinicians who are passionate about research are explored and the reasons which drive some of them to pursue a research career. It discusses the need to have structured training for research and how continuing research education is necessary for the researcher. The paper discusses the goals for research and how we can achieve better research outcomes and the importance of good mentorship. It suggests ways to engage more doctors in research in the restructured hospitals by overcoming some of the problems they encounter. Finally, it relates the Biomedical Science initiative of the government through the National Research Foundation and the various programmes in Translational Clinical Research available for clinicians who are keen on a research career.
Career Choice ; Goals ; Humans ; Physicians ; Research Personnel ; supply & distribution ; Singapore ; Translational Medical Research ; education ; manpower

INTRODUCTIONMycotic aneurysms are associated with high mortality rates and are managed in the local setting with extra-anatomical bypass followed by ligation, exclusion and debridement of the aneurysm. This is the first case of successful endovascular stenting in an immunocompromised patient with Salmonella mycotic aneurysm.

CLINICAL PICTUREA middle-aged man who was HIV positive had Salmonella septicaemia. He developed abdominal pain 5 days after admission and a computed tomography (CT) scan of the abdomen revealed infrarenal aortitis. He developed a mycotic aneurysm 3 weeks later.

TREATMENTHe opted for endovascular stenting and after prolonged antibiotic therapy and negative blood cultures, he underwent the procedure using a Talent stent, with an iliac extension.

OUTCOMEHe was discharged 1 week after stenting and maintained on oral bactrim based on sensitivity. At 1-year follow-up, he remains well symptomatically and CT scan showed no endoleak or collection.

CONCLUSIONEndovascular stenting, though a fairly new procedure, can be successfully deployed even in a mycotic aneurysm in the right setting.

Aneurysm, Infected ; drug therapy ; surgery ; therapy ; HIV Infections ; physiopathology ; Humans ; Male ; Middle Aged ; Salmonella Infections ; drug therapy ; microbiology ; surgery ; Salmonella enteritidis ; Stents ; Trimethoprim, Sulfamethoxazole Drug Combination ; therapeutic use

INTRODUCTION: The National Early Warning Score (NEWS) is well established in acute medical units to identify acutely deteriorating patients and is shown to have good prognostic value. NEWS, however, has only been used in the Emergency Department as a triage tool. We aimed to evaluate the validity of NEWS in Acute Medical Ward (AMW) that treats predominantly acute infection-related conditions to the Internal Medicine service. MATERIALS AND METHODS: We undertook a retrospective cohort study and analysed NEWS records of all patients admitted to AMW at Singapore General Hospital between 1 August 2015 and 30 July 2017. The outcome was defined as deterioration that required transfer to Intermediate Care Area (ICA), Intensive Care Unit (ICU) or death within 24 hours of a vital signs observation set. RESULTS: A total of 298,743 vital signs observation sets were obtained from 11,300 patients. Area under receiver operating characteristic curve for any of the 3 outcomes (transfer to ICA, ICU or death) over a 24-hour period was 0.896 (95% confidence interval, 0.890-0.901). Event rate was noted to be high above 0.250 when the score was >9. In the medium-risk group (score of 5 or 6), event rate was <0.125. CONCLUSION NEWS accurately triages patients according to the likelihood of adverse outcomes in infection-related acute medical settings.

INTRODUCTIONIgA nephropathy is a disease where the pathogenesis is still poorly understood. Deoxyribonucleic acid (DNA) microarray technique allows tens of thousands of gene expressions to be examined at the same time. Commercial availability of microarray genechips has made this powerful tool accessible for wider utilisation in the study of diseases.

MATERIALS AND METHODSSeven patients with IgA nephropathy, 6 with minimal change nephrotic syndrome (MCNS) as patient controls and 7 normal healthy subjects were screened for the differential expression of genes, genome-wide. The Human Genome U133 Plus 2.0 Arrays (Affymetrix, USA) were used to quantitate the differential expression of 38,500 well-characterised human genes.

RESULTSA total of 7761 gene expressions were identified that have an IgAN/Normal gene expression ratio of 0.06-fold to 5.58-fold. About 35% of the altered gene expressions have no gene title or just a hypothetical protein label such as FLJ30679. Most of the remaining 65% are identified proteins where their importance to IgAN is not immediately apparent at this time. Among the 30 most upregulated and 30 most downregulated genes are Urotensin 2 (upregulated 3.09-fold, P <0.05) and Fatty-acid binding protein 6 (downregulated to 0.12-fold, P <0.05). Retinoic acid receptor alpha (vitamin A receptor) was also found downregulated to 0.41-fold (P <0.005). Taqman realtime polymerase chain reaction (PCR) for urotensin 2 and retinoic acid receptor alpha (RARA) were performed on 20 patients with IgA nephropathy and 11 with Minimal Change Disease and the data correlated with various clinical indices.

CONCLUSIONSThe findings suggest that there may be a therapeutic role for retinoic acid receptor alpha (RARA) in IgA nephropathy and a clinical monitoring role for Urotensin 2 in Minimal Change Disease.

Adult ; Aged ; Case-Control Studies ; Female ; Gene Expression ; Gene Expression Regulation ; Genome-Wide Association Study ; Glomerulonephritis, IGA ; genetics ; metabolism ; pathology ; Humans ; Immunoglobulin A ; genetics ; metabolism ; Male ; Middle Aged ; Nephrosis, Lipoid ; genetics ; metabolism ; pathology ; Oligonucleotide Array Sequence Analysis ; Polymerase Chain Reaction ; Receptors, G-Protein-Coupled ; genetics ; metabolism ; Receptors, Retinoic Acid ; genetics ; metabolism ; Tretinoin ; metabolism

Translational research (TR) can be defined as research where a discovery made in the laboratory (bench) can be applied in the diagnosis, treatment or prevention of a disease. Examples of medical discoveries contributing to translational medicine (TM) include the isolation of insulin by Banting (Nobel Laureate, 1923), the discovery of penicillin by Alexander Fleming (Nobel Laureate, 1945) and recently the discovery of the role of bacterium Helicobacter pylori in the causation of gastritis and peptic ulcer by Marshall and Warren (Nobel Laureates, 2005). Clinical research (CR) would be a more appropriate term for the bulk of research work undertaken by doctors. CR embraces both clinical based and laboratory-based research. The terminology "bedside to bench" applies more to CR as opposed to "bench to bedside" in the case of TR. But regardless of who does it, as long as the discovery can be translated to the bedside and results in improvement in patient care it can be considered a contribution to TM. Our work spans a 30-year period, involving laboratory-based research, clinical trials and genomics of IgA nephritis (Nx). This is a series of work to elucidate the pathogensis and therapy of IgANx. Plasma beta-thromboglobulin (BTG) an in-vivo index of platelet aggregation and anti-thrombin III increase due to a constant thrombogenecity resulting from platelet degranulation formed the basis for anti-platelet and low-dose warfarin therapy. A study of the natural history of IgANx revealed 2 courses, a slowly progressive course with end-stage renal failure (ESRF) at 7.7 years and a more rapid course at 3.3 years. Triple therapy (cyclophosphamide, persantin and low-dose warfarin) delayed progression to ESRF by about 8 years and for some patients up to 20 years. Documentation of abnormal suppressor T cell function provided the basis for immune therapy. Four patterns of proteinuria were present in IgANx and it is the quality and not so much the quantity of proteinuria which determined the prognosis. Low molecular weight proteinuria was a bad prognostic marker. A controlled therapeutic trial using ACEI/ATRA showed that therapy decreases proteinuria, improves renal function and converts non-selective to selective proteinuria. Subsequent work confirmed that it was the ATRA, not the ACEI which contributed to improved renal function. Individual anti proteinuria response to ATRA varies depending on ACE gene polymorphism. We found that the II genotype of the ACE gene was renoprotective and patients with this genotype had significantly reduced incidence of ESRF compared to those with the DD genotype. Patients responsive to ATRA therapy can retard progression to ESRF by up to 32 years. Mild renal failure can be reversed with possible regression of glomerulosclerosis because of glomerular remodelling by ATRA.
Disease Progression ; Evidence-Based Medicine ; history ; Genetic Predisposition to Disease ; Genomics ; history ; Glomerulonephritis, IGA ; genetics ; history ; History, 20th Century ; History, 21st Century ; Humans ; Polymorphism, Genetic ; Singapore

Apart from clinical, histological and biochemical indices, genomics are now being employed to unravel the pathogenetic mechanisms in the disease progression of IgA nephritis (IgAN). The results of angiotensin converting enzyme (ACE) gene polymorphism have been controversial. Those patients with the DD genotype seem to have a poorer prognosis. However, with high dose angiotensin receptor blocker (ARB) therapy, the ACE gene polymorphism status of a patient may no longer be a matter for concern as those with the DD genotype would also respond favourably to high dose ARB therapy. Association studies with gene sequencing and haplotypes have suggested that multiple genes are involved in the pathogenesis of IgAN. Some workers have reported a synergistic effect in the combined analysis of AGT-M235T and ACE I/D polymorphism. With the use of deoxyribo nucleic acid (DNA) microarray, tens of thousands of gene expressions genome-wide can be examined together simultaneously. A locus of familial IgAN has been described with strong evidence of linkage to IgAN1 on chromosome 6q22-23. Two other loci were reported at 4q26-31 and 17q12-22. DNA microarray techniques could also help in the identification of specific pathogenic genes that are up- or down-regulated and this may allow genome wide analyses of these genes and their role in the pathogenesis and progression of IgAN. Recently, using genome-wide association studies (GWAS) more loci for disease susceptibility for IgAN have been identified at 17p13, 8p23, 22q12, 1q32 and 6p21.
Angiotensin Receptor Antagonists ; administration & dosage ; Disease Progression ; Dose-Response Relationship, Drug ; Genomics ; methods ; Glomerulonephritis, IGA ; drug therapy ; genetics ; pathology ; Haplotypes ; Humans ; Molecular Sequence Data ; Polymorphism, Single Nucleotide

INTRODUCTIONThis study aimed to assess the outcome of percutaneous transluminal angioplasty (PTA) as the primary treatment for transplant renal artery stenosis (TxRAS).

MATERIALS AND METHODSA retrospective review of PTA of TxRAS from April 1999 to December 2008 was performed. Twenty-seven patients (17 males (M):10 females (F)) with the mean age of 49.5 years underwent PTA of TxRAS in the review period. Indications for PTA were suboptimal control of hypertension (n=12), impaired renal function (n=6) and both suboptimal control of hypertension and impaired renal function (n=9). All patients had doppler ultrasound scans prior to their PTA. In addition, 5 of these patients had computed tomography angiography (CTA) and another 7 had magnetic resonance angiography (MRA) evaluation. Mean follow-up period was 57.0 months (range, 7 to 108 months).

RESULTSThe stenotic lesions were located proximal to the anastomosis (n=2), at the anastomosis (n=15), and distal to the anastomosis (n=14). Technical success rate was 96.3%. One case was complicated by extensive dissection during PTA, resulting in subsequent graft failure. The overall clinical success rate was 76.9%. Seven out of 26 patients had restenoses (26.9% of cases). These were detected at a mean of 14.3 months post angioplasty (range, 5 to 38 months). All 7 patients underwent a second PTA successfully. Three of these patients required more than 1 repeat PTA.

CONCLUSIONPTA is safe and effective in the management of symptomatic TxRAS and should be the primary treatment of choice. Close surveillance for restenosis is required and when diagnosed, re-angioplasty can be performed.

Adult ; Angioplasty ; Female ; Humans ; Kidney Transplantation ; Male ; Middle Aged ; Postoperative Complications ; surgery ; Renal Artery Obstruction ; surgery ; Retrospective Studies ; Time Factors