Facial segmental haemangioma with PHACE Syndrome successfully treated with oral propranolol.

PHACE syndrome describes the association of large segmental haemangioma with extracutaneous features (posterior fossa anomalies, arterial, cardiac, eye and endocrine anomalies). We report a case of segmental facial infantile haemangioma with PHACE syndrome treated successfully with oral propranolol without neurological sequelae.

Working while unwell: Workplace impairment in people with severe asthma.

BACKGROUND: Severe asthma affects quality of life; however, its impact on workplace productivity is poorly understood. OBJECTIVE: To compare workplace productivity-absenteeism and presenteeism-and impairment in daily activities in severe and non-severe asthma over time and identify characteristics associated with presenteeism in severe asthma. METHODS: The Severe Asthma Web-based Database is an ongoing observational registry from Australia, New Zealand and Singapore. At April 2017, 434 patients with severe asthma and 102 with non-severe asthma were enrolled (18-88 years; 59% female). Participants provided comprehensive clinical and questionnaire data at baseline and were followed-up every 6 months for 24 months. Absenteeism (percentage of time not at work), presenteeism (self-reported impairment at work) and impairment in daily activities outside work due to health problems in the last week were calculated. RESULTS: At baseline, 61.4% of participants with severe asthma and 66.2% with non-severe asthma under 65 years were employed. At younger ages (30-50 years), fewer severe asthma participants were employed (69% vs 100%). Presenteeism and impairment in daily activity were more frequently reported in severe asthma and in participants with poorer asthma control, poorer lung function and more past-year exacerbations (P < .01). Over time, deteriorating asthma control was associated with increasing presenteeism. Although absenteeism was not different between severe and non-severe asthma, worse asthma control was associated with absenteeism (P < .001). In participants with severe asthma, presenteeism was reported more frequently in those with poorer asthma control, poorer asthma-related quality of life and symptoms of depression or anxiety (P < .01). CONCLUSION AND CLINICAL RELEVANCE: Severe asthma was associated with impairment at work and outside the workplace. Improving asthma control and mental health may be important targets for optimizing workplace productivity in severe asthma. Presenteeism and absenteeism may represent key metrics for assessing intervention efficacy in people with severe asthma of working age.

Primary imatinib resistance in chronic myeloid leukemia patients in a developing country: BCR-ABL kinase domain mutations or BCR-ABL independent mechanisms?

Clinical resistance to imatinib (IM) in chronic myeloid leukemia (CML) carries adverse consequences. We investigated 22 CML patients who developed IM-resistance for BCR-ABL kinase domain (KD) mutations. The median follow-up for this study was 101.9 months (range: 22.2 to 176.5 months) and the estimated mean overall survival was 150.87 months (95% CI: 130.0 to 171.0). Five out of 22 patients tested positive for BCR-ABL KD mutations: 2 had T315I, 2 had E255K and 1 had V289F mutations. Of the remaining 17 patients who did not harbor BCR-ABL KD mutations, 11 patients received nilotinib while the rest continued on IM. All 17 achieved haematological remission but only 5 patients achieved complete cytogenetic remission, 4 of whom did so after switching to nilotinib. Our study shows that most of our IM-resistant patients do not test positive for BCR-ABL KD mutations by available testing methods and the role of second generation tyrosine kinase inhibitors remains undetermined. A critical analysis of the BCR-ABL KD mutations and the underlying mechanisms/ pathways of BCR-ABL independent IM-resistance along with potential treatments in the horizon will be discussed.

Pleural infection in a New Zealand centre: high incidence in Pacific people and RAPID score as a prognostic tool.

BACKGROUND: Whilst there is an increase in incidence of pleural infection worldwide, there is a paucity of New Zealand data. AIMS: This study looked at the epidemiology of pleural infection in a single New Zealand institution and evaluated the RAPID score as a prognostic tool. METHODS: A retrospective review was performed on patients with pleural infection over a 3-year period. Pleural infection was defined as having clinical evidence of infection and fulfilling one of the following: (i) positive pleural fluid Gram stain or culture, (ii) frank pus, (iii) pH <7.2 or (iv) radiological evidence of complex effusion. RESULTS: There were 108 patients; 76% were male, and mean age was 54 years. Two thirds of patients came from the most deprived areas. The dominant ethnic group was Pacific people (42%), which was twice as high as the Pacific population in the area (19%), P < 0.0001. After adjusting for deprivation, Pacific people were still over-represented, P = 0.0002. There were 14 deaths (13%), and these were associated with increasing age (P = 0.001) and urea (P = 0.007) but not ethnicity or socioeconomic deprivation. The RAPID score found that those in the high-risk (P = 0.026) and moderate-risk (P = 0.036) groups had significantly higher mortality compared with the low-risk group. CONCLUSION: The over-representation of Pacific people with pleural infection is not fully explained by socioeconomic deprivation, highlighting other factors at play, such as genetic susceptibility. The RAPID score was of clinical utility in predicting mortality in our population.

A case of chronic myeloid leukaemia in blast transformation with leukemic ascites.

Chronic Myeloid Leukaemia (CML) is a disease characterised by a distinctive marker that is the Philadelphia Chromosome and an ability to transform into blast phase, which confers a poor prognosis. The median survival was reported to be between three to six months in correlation to blast phase. Extramedullary involvement with CML to sites such as pleural, meningeal and bones have been reported. We report a case of 41-year-old man who was diagnosed with CML in blast phase and presented with ascites. Ultrasound of abdomen showed coarse echotexture of liver suggestive leukaemic infiltration to the liver. The liver profile was severely deranged and associated with coagulopathy. Flow cytometry analysis of the peritoneal fluid revealed presence of myeloblasts consistent with CML in blast crisis with leukaemic ascites. Bone marrow biopsy also confirmed disease transformation. He received standard induction chemotherapy for acute myeloid leukaemia with dose modifications based on liver enzymes performance. Our case highlights an unusual presentation of CML in blast crisis with leukaemic ascites and the challenges in managing cytotoxic treatments due to the liver infiltration.

Dismal outcome of therapy-related myeloid neoplasm associated with complex aberrant karyotypes and monosomal karyotype: a case report.

INTRODUCTION: Individuals who are exposed to cytotoxic agents are at risk of developing therapyrelated myeloid neoplasms (t-MN). Cytogenetic findings of a neoplasm play an important role in stratifying patients into different risk groups and thus predict the response to treatment and overall survival. CASE REPORT: A 59-year-old man was diagnosed with acute promyelocytic leukaemia. Following this, he underwent all-trans retinoic acid (ATRA) based chemotherapy and achieved remission. Four years later, the disease relapsed and he was given idarubicin, mitoxantrone and ATRA followed by maintenance chemotherapy (ATRA, mercaptopurine and methotrexate). He achieved a second remission for the next 11 years. During a follow-up later, his full blood picture showed leucocytosis, anaemia and leucoerythroblastic picture. Bone marrow examination showed hypercellular marrow with trilineage dysplasia, 3% blasts but no abnormal promyelocyte. Fluorescence in-situ hybridisation (FISH) study of the PML/RARA gene was negative. Karyotyping result revealed complex abnormalities and monosomal karyotype (MK). A diagnosis of therapy-related myelodysplastic syndrome/myeloproliferative neoplasm with unfavourable karyotypes and MK was made. The disease progressed rapidly and transformed into therapy-related acute myeloid leukaemia in less than four months, complicated with severe pneumonia. Despite aggressive treatment with antibiotics and chemotherapy, the patient succumbed to the illness two weeks after the diagnosis. DISCUSSION AND CONCLUSION: Diagnosis of t-MN should be suspected in patients with a history of receiving cytotoxic agents. Karyotyping analysis is crucial for risk stratification as MK in addition to complex aberrant karyotypes predicts unfavourable outcome. Further studies are required to address the optimal management for patients with t-MN.

Root canal treatment and special needs patients.

AIM: To identify current trends of root canal treatment for patients with special needs. METHODOLOGY: A postal questionnaire was sent to General Dentists in Victoria, Australia and Endodontists and Special Needs Dentists across Australia to determine the extent of root canal treatment performed on special needs patients. RESULTS: Over a four-month period, 1120 questionnaires were distributed with an overall response rate of 63.9% (n = 716). Response rates were 63.2% (n = 655), 68.5% (n = 50) and 100.0% (n = 11) amongst General Dentists, Endodontists and Special Needs Dentists, respectively. Endodontists (95.7%) and Special Needs Dentists (100.0%) performed significantly more root canal treatment on adult patients with special needs compared with 51.2% of General Dentists, (P < 0.001 and P = 0.001 respectively; Fisher's exact test). The most common reasons for not undertaking root canal treatment included limited cooperation, poor oral hygiene and uncontrolled movement. Amongst General Dentists, 75.7% opted for extraction in preference to root canal treatment. Significantly, more specialist practitioners performed root canal treatment utilizing conscious sedation (P < 0.001) and general anaesthesia (P = 0.003). Most specialist practitioners (69.1%) had undertaken single-visit root canal treatment on special needs patients compared with only 29.7% of General Dentists (P < 0.001). CONCLUSIONS: Root canal treatment in special needs patients was more likely to be carried out by specialist dental practitioners who were more likely to utilize a pharmacological approach for behaviour guidance and to perform single-visit root canal treatment compared with General Dentists. A multidisciplinary approach for special needs patients who require root canal treatment provides an opportunity for these patients to retain their dentition.

Fatal quinine-induced thrombocytopenia from pulmonary haemorrhage.

Severe drug-induced thrombocytopenia is a well known but rare complication of quinine. This paper presents a discussion on quinine-induced thrombocytopenia based on a patient who developed fatal thrombocytopenia and pulmonary haemorrhage.

NK/T cell lymphoma associated with peripheral eosinophilia.

NK/T cell lymphoma, nasal type is an aggressive and uncommon malignancy. Disease that occurs outside of the aerodigestive tract exhibits an even more aggressive clinical behaviour and does not respond as well to conventional therapy compared to its nasal counterpart. We report such a case of NK/T cell lymphoma, nasal type, that presented as an anterior chest wall mass, arising from the left pectoralis muscle. An interesting feature we wish to highlight is the associated eosinophilia that corresponded to disease activity, exhibiting fluctuations with surgical resection and chemotherapy. To the best of our knowledge this is the third reported case of NK/T cell lymphoma that is associated with peripheral eosinophilia. Our case highlights the role of certain NK cell subsets that play a major role in eosinophilic activation in NK/T lymphomas and calls for more research into further classification of this disease by virtue of its NK cell subsets.

Can we predict sputum eosinophilia from clinical assessment in patients referred to an adult asthma clinic?

BACKGROUND: There is overwhelming evidence that asthma guidelines aimed at reducing airway inflammation are superior to those based on clinical symptoms alone. This involves targeting eosinophilic inflammation with inhaled corticosteroids. AIM: Because induced sputum is not readily available, our study set out to investigate whether the collective or singular use of routine asthma investigations can predict sputum eosinophilia. METHODS: Eighty patients underwent skin prick testing, blood tests (IgE, full blood count), spirometry, exhaled fraction nitric oxide (FeNO), PD15 to hypertonic saline, and induced sputum testing at first assessment. A predictive model for sputum eosinophilia (defined as ≥3% eosinophils) was sought using routinely available tests. RESULTS: Fifty-four subjects underwent both induced sputum and FeNO testing. Seventeen (30%) revealed eosinophilic inflammation, nine (16%) neutrophilic, four (7%) mixed granulocytic and 26 (46%) paucigranulocytic. Positive predictors for sputum eosinophilia included low forced expiratory volume in 1 s (FEV(1))% predicted, raised serum eosinophil, positive smoking history, Polynesian ethnicity and negative asthma family history. There was a non-statistically significant trend for FeNO predicting sputum eosinophilia. The best combination of predictors was low FEV(1)% predicted, raised serum eosinophil, positive smoking history and negative family history of asthma. CONCLUSION: This study demonstrates that the serum eosinophil count and FEV(1) combined with aspects of a clinical history may provide a simple and practical alternative to assessment of airway (sputum) eosinophilia in the clinical setting. A full blood count can be performed at a substantially lesser cost and with greater accessibility than induced sputum. We feel the time has come for the clinical utility of the serum eosinophil count to be revisited.

Prevalence of Anemia and Its Association with Frailty, Physical Function and Cognition in Community-Dwelling Older Adults: Findings from the HOPE Study.

OBJECTIVES: The prevalence of anemia and its impact on frailty and physical function amongst the multiethnic older populations in the Southeast Asian (SEA) countries are often not well studied. Singapore, a nation comprised of multiethnic communities, is one of the most rapidly aging population globally. We aim to evaluate the prevalence of anemia and its impact on frailty, and physical function in Healthy Older People Everyday (HOPE)- an epidemiologic population-based study on community-dwelling older adults in Singapore. DESIGN: Cross-sectional study. SETTING: Community. PARTICIPANTS: 480 adults ≥ 65 years old. MEASUREMENTS: Data were collected from interviewers-administered questionnaires on socio-demographics, FRAIL scale, Mini-Mental State Examination, EQ-5D, Barthel Index, and Lawton index. Hemoglobin concentration and physical assessments, including anthropometry, grip strength, timed up-and-go (TUG) were measured. RESULTS: The overall prevalence of anemia was 15.2% (73 out of 480). The Indian ethnic group had the highest prevalence of anemia (32%, OR=3.02; 95%CI= 1.23-7.41) with the lowest hemoglobin concentration compared to the overall population (13.0±1.3g/L and 13.5±1.4g/L, p=0.02). Hemoglobin levels and anemia were significantly associated with frailty (OR=2.28; 95% CI=1.02-5.10), low grip strength (OR=1.79; 95% CI=1.01-3.03), ≥ one IADL impairment (OR=2.35; 95% CI=1.39-3.97). Each 1 g/dL increase in hemoglobin was associated with a 6% decrease in frailty odds after adjusting for potential covariates (OR = 0.94, 95% CI: 0.90-0.99). There was a significant difference in the mean TUG between the non-anemic (11.0±3.4 seconds) and anemic (12.3±6.0 seconds, p=0.01) counterparts, but no difference in the number of falls. CONCLUSION: In our multiethnic Asian population, anemia was adversely associated with frailty, decreased muscle strength, and IADL impairment. Health policies on anemia screening should be employed to avoid or potentially delay or reverse these adverse outcomes associated with anemia. Recognition, evaluation, and treatment of anemia amongst this vulnerable population is warranted.

Fever as a predictor of adverse outcomes in COVID-19.

BACKGROUND/INTRODUCTION: There are little data on outcomes of COVID-19 patients with the presence of fever compared to the presence of symptoms. AIM: We examined the associations between symptomology, presence of fever and outcomes of a COVID-19 cohort. DESIGN AND METHODS: Between 23 January and 30 April 2020, 554 COVID-19 patients were admitted to a tertiary hospital in Singapore. They were allocated into four groups based on symptomology and fever-Group 1: asymptomatic and afebrile, Group 2: symptomatic but afebrile, Group 3: febrile but asymptomatic and Group 4: symptomatic and febrile. The primary outcomes were intensive care unit (ICU) admissions and mortality. The composite end-point included ICU admissions, mortality or any COVID-19 related end-organ involvement. RESULTS: There were differences in ferritin (P=0.003), C-reactive protein (CRP) levels (P<0.001) and lymphopenia (P=0.033) across all groups, with the most favourable biochemical profile in Group 1, and the least in Group 4. Symptomatic groups (Groups 2 and 4) had higher ICU admissions (1.9% and 6.0%, respectively, P=0.003) than asymptomatic groups (Groups 1 and 3). Composite end-point was highest in Group 4 (24.0%), followed by Group 3 (8.6%), Group 2 (4.8%) and Group 1 (2.4%) (P<0.001). The presence of fever (OR 4.096, 95% CI 1.737-9.656, P=0.001) was associated with the composite end-point after adjusting for age, pulse rate, comorbidities, lymphocyte, ferritin and CRP. Presence of symptoms was not associated with the composite end-point. DISCUSSION/CONCLUSION: In this COVID-19 cohort, presence of fever was a predictor of adverse outcomes. This has implications on the management of febrile but asymptomatic COVID-19 patients.

Allele frequencies of six miniSTR loci of three ethnic populations in Singapore.

MiniSTR loci has demonstrated to be an effective approach to recover genetic information from degraded sample, due to the improved PCR efficiency of their reduced PCR product sizes. This study investigated the allele frequency of six miniSTR loci, D1S1677, D2S441, D4S2364, D10S1248, D14S1434 and D22S1045, in three Singapore populations. All loci showed a moderate degree of polymorphism with observed heterozygosity >0.6 for all three populations. The allele frequencies, forensic parameters and heterozygosity comparison with other CODIS STR in similar populations are presented.

MicroRNAs that affect the Fanconi Anemia/BRCA pathway are downregulated in imatinib-resistant chronic myeloid leukemia patients without detectable BCR-ABL kinase domain mutations.

Chronic myeloid leukemia (CML) patients who do not achieve landmark responses following treatment with imatinib mesylate (IM) are considered IM-resistant. Although IM-resistance can be due to BCR-ABL kinase domain (KD) mutations, many IM-resistant patients do not have detectable BCR-ABL KD mutations. MicroRNAs (miRNAs) are short non-coding RNAs that control gene expression. To investigate the role of miRNAs in IM-resistance, we recruited 8 chronic phase CML patients with IM-resistance who tested negative for BCR-ABL KD mutations and 2 healthy normal controls. Using miRNA sequencing, we identified 54 differentially expressed miRNAs; 43 of them downregulated. The 3 most differentially downregulated miRNAs were miR-146a-5p, miR-99b-5p and miR-151a-5p. Using real-time quantitative reverse transcriptase-polymerase chain reaction, the expression patterns of the 3 miRNAs were validated on the same cohort of 8 patients in addition to 3 other IM-resistant CML patients. In-silico analysis showed that the predicted gene targets are ATRIP, ATR, WDR48, RAD51C and FANCA genes which are involved in the Fanconi Anemia/BRCA pathway. This pathway regulates DNA damage response (DDR) and influences disease response to chemotherapy. Thus it is conceivable that DDR constitutes a key component in IM-resistance. Further research is needed to elucidate miRNA modulation of the predicted gene targets.

In vitro antimicrobial activity of natural toxins and animal venoms tested against Burkholderia pseudomallei.

BACKGROUND: Burkholderia pseudomallei are the causative agent of melioidosis. Increasing resistance of the disease to antibiotics is a severe problem in treatment regime and has led to intensification of the search for new drugs. Antimicrobial peptides are the most ubiquitous in nature as part of the innate immune system and host defense mechanism. METHODS: Here, we investigated a group of venoms (snakes, scorpions and honey bee venoms) for antimicrobial properties against two strains of Gram-negative bacteria Burkholderia pseudomallei by using disc-diffusion assay for in vitro susceptibility testing. The antibacterial activities of the venoms were compared with that of the isolated L-amino acid oxidase (LAAO) and phospholipase A2 (PLA2s) enzymes. MICs were determined using broth dilution method. Bacterial growth was assessed by measurement of optical density at the lowest dilutions (MIC 0.25 mg/ml). The cell viability was measured using tetrazolium salts (XTT) based cytotoxic assay. RESULTS: The studied venoms showed high antimicrobial activity. The venoms of C. adamanteus, Daboia russelli russelli, A. halys, P. australis, B. candidus and P. guttata were equally as effective as Chloramphenicol and Ceftazidime (30 microg/disc). Among those tested, phospholipase A2 enzymes (crotoxin B and daboiatoxin) showed the most potent antibacterial activity against Gram-negative (TES) bacteria. Naturally occurring venom peptides and phospholipase A2 proved to possess highly potent antimicrobial activity against Burkholderia pseudomallei. The XTT-assay results showed that the cell survival decreased with increasing concentrations (0.05-10 mg/mL) of Crotalus adamanteus venom, with no effect on the cell viability evident at 0.5 mg/mL. CONCLUSION: This antibacterial profile of snake venoms reported herein will be useful in the search for potential antibacterial agents against drug resistant microorganisms like B. pseudomallei.

Association of renal function and delta-aminolevulinic acid dehydratase polymorphism among Vietnamese and Singapore workers exposed to inorganic lead.

OBJECTIVES: To investigate the effect of delta-aminolevulinic acid dehydratase (ALAD) polymorphisms on the association between blood lead and renal function among Vietnamese and Singaporean workers who were exposed to low to medium levels of inorganic lead, and to study the distribution of ALAD polymorphism among Vietnamese, Chinese, Malays and Indians. METHODS: A total of 459 male and female workers were studied. Blood and urine were collected for each worker in order to determine ALAD genotype, blood lead, and urinary delta-aminolevulinic acid (ALAU). Renal function tests included urine albumin (Ualb), urine beta2 microglobulin (Ubeta2m), urinary alpha1 microglobulin (Ualpha1m), N-acetyl-glucosaminidas (NAG), and urine retinol blinding protein (RBP). A multiple regression model with interaction term was applied to fit the entire data and to explore the modifying effect of ALAD polymorphism on the relation of blood lead to each renal function parameter. RESULTS: ALAD1-1 was the predominant genotype for all the ethnic groups while ALAD2-2 was the rarest. The frequency of ALAD2 allele was higher among Malays (8.8%) and Indians (10.6%) compared to the Chinese (5.0%) and Vietnamese (4.3%). The geometric mean of blood lead for all workers was 19.0 microg/dl. The models for Ubeta2m, Ualpha1m, and NAG showed that the ALAD1-2/2-2 group had higher beta coefficients than the ALAD1-1 group. Corresponding to 10 microg/dl blood lead, ALAD1-1 homozygotes had an increment of 1.288 microg/g Cr, 1.175 mg/g Cr, and 1.995 U/g Cr for Ubeta2m, Ualpha1m, and NAG, respectively. ALAD1-2/2-2 subjects had higher increments of 3.802 microg/g Cr, 2.138 mg/g Cr, and 3.89 U/g Cr for Ubeta2m, Ualpha1m, and NAG, respectively. CONCLUSION: The frequency of the ALAD2 allele is as low in Vietnamese workers as in Chinese. Workers with the ALAD2 allele appeared more susceptible to the effects of lead (especially at higher levels) on renal function.

Y-chromosome STR haplotype diversity in three ethnic populations in Singapore.

In this study, 12 Y-STR loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS437, DYS438 and DYS439) were genotyped in the three major ethnic populations in Singapore, namely the Chinese, Malay and Indian. Allele frequency distribution, locus diversity, haplotype diversity and discrimination capacity were estimated. Analysis of molecular variance between the three ethnic populations indicated that 87.71% of the haplotypic variation is found within population and 12.29% is between populations (Fixation Index FST=0.123, p=0.000). Population pairwise comparisons showed significant Phist values between all population pairs, with the lowest (RST=0.05) for Chinese-Malay and the highest (RST=0.19) for Chinese-Indian.

Changes in cerebral hemodynamics and cerebral oxygenation during surgical evacuation for hypertensive intracerebral putaminal hemorrhage.

OBJECTIVES: The aim of this study was to evaluate the changes in cerebral hemodynamics, tissue oxygenation and blood flow before and after surgery for spontaneous intracerebral hematomas. METHODS: Eleven patients who underwent surgical decompression of spontaneous putaminal hematoma were studied. Intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygen (PtiO2), and carbon dioxide tensions (PtiCO2), brain pH and regional cerebral blood flow (rCBF) were recorded prior to removing the bone flap and then on skin closure on completion of the operation. RESULTS: Following surgical decompression, mean ICP decreased significantly (P < 0.05); mean CPP, PtiO2, brain pH and rCBF improved although the changes were not significant. CONCLUSION: Surgical decompression for spontaneous intracerebral hematomas leads to significant reductions in ICP. This is accompanied by improvements in CPP, PtiO2 and rCBF in the penumbra.

A two-stage approach identifies a Q344X mutation in the rhodopsin gene of a Chinese Singaporean family with autosomal dominant retinitis pigmentosa.

INTRODUCTION: Retinitis pigmentosa (RP) is a group of hereditary retinal diseases in which photoreceptor cells degenerate. It is both clinically and genetically heterogenous. Using a two-stage approach by combining linkage analysis with mutation detection, we have rapidly identified the gene locus and the mutation site of a Chinese Singaporean family with autosomal dominant RP. MATERIALS AND METHODS: Three Chinese Singaporean families were tested. One family showed autosomal dominant inheritance pattern, while the other two could be recessive or sporadic. Twelve di-nucleotide markers tightly linked to 6 genes known to be responsible for either autosomal dominant or recessive RP were selected for linkage analysis. Cosegregation of marker and disease inheritance pattern permits identification of the target candidate gene. RFLP (restriction fragment length polymorphism) markers were added to confirm the linkage result prior to the detailed mutation detection study. RESULTS: With this two-stage strategy, the autosomal dominant RP family showed the rhodopsin locus segregating concordantly with the disease. Mutation screening later identified a nonsense mutation 5261C>T in the last exon of rhodopsin gene. It predicted a Q344X changes at the C-terminus of the gene product, truncating it by 5 amino acids. CONCLUSION: This systematic approach facilitates molecular diagnosis of a genetically heterogenous disease like RP. This is the first report of an RP mutation in Singapore. This 5261C>T mutation has been reported in the Caucasian, but not the Chinese population. The relatively milder phenotype in this family showed similarity to the reported US family, indicating the correlation of mutation site to severity of disease regardless of ethnicity.

Elevated levels of factor VIII and subsequent risk of all-cause mortality: results from the MEGA follow-up study.

BACKGROUND: Factor VIII (FVIII) levels are increased in individuals with a non-O blood group and play a role in the etiology of thrombosis. High FVIII levels have also been associated with increased all-cause mortality. OBJECTIVE: We explored whether elevated FVIII levels are associated with an increased risk of death in patients who had venous thrombosis and in individuals from the general population, and to what extent this association is causal. METHODS: We followed 2178 patients with previous venous thrombosis and 2827 age and sex-matched community controls for on average 5.5 years and measured their FVIII levels and ABO blood group. RESULTS: All-cause mortality increased in a dose-response fashion with increasing percentiles of FVIII levels. In the thrombosis patients the risk was highest above the 97.5th percentile (FVIII > 199 IU dL(-1) ) with an adjusted hazard ratio (HR) of 3.1 (95% confidence interval [CI], 0.9-10.8) as compared with patients in the 25th percentile category (FVIII ≤ 85 IU dL(-1) ). The adjusted HR was 4.5 (95% CI, 1.4-14.3) in controls. Using non-O blood group as a measure of genetically elevated FVIII levels to determine a causal relationship between FVIII and death showed observed HRs of 0.99 (95% CI, 0.72-1.36) in patients and 1.25 (95% CI, 0.82-1.90) in controls. CONCLUSIONS: We showed a dose-response relationship between high FVIII levels and risk of death in venous thrombosis patients and in individuals from the general population. However, environmental factors, such as chronic comorbidities and chronic inflammation, are at least in part responsible for the association between factor VIII and mortality.