Influenza virus load in hospitalised patients.

1. Hospitalised patients with severe influenza have persistently high viral loads, for whom a different therapeutic approach may be needed. 2. Active screening of influenza infection should be performed in all high-risk patients hospitalised with febrile respiratory illness. Early diagnosis and treatment to suppress the high viral load may maximise clinical benefit. 3. For late presenting high risk patients with severe symptoms, their viral load may remain high, and initiation of antiviral treatment may still be worthwhile. 4. More stringent infection control measures, including strict droplet precautions and preferably isolation for an extended period of time may be necessary owing to prolonged viral shedding. 5. Randomised, controlled trials are indicated to address timing and dosage of treatment for severe influenza infection.

Outcomes of adults hospitalised with severe influenza.

BACKGROUND: The aim of this study was to investigate factors affecting clinical outcomes of adults hospitalised with severe seasonal influenza. METHODS: A prospective, observational cohort study was conducted over 24 months (2007-2008) in two acute, general hospitals. Consecutive, hospitalised adult patients were recruited and followed once their laboratory diagnosis of influenza A/B was established (based on viral antigen detection and virus isolation from nasopharyngeal aspirates collected per protocol). Outcomes studied included in-hospital death, length of stay and duration of oxygen therapy. Factors affecting outcomes were analysed using multivariate Cox proportional hazards models. Sequencing analysis on the neuraminidase gene was performed for available H1N1 isolates. RESULTS: 754 patients were studied (influenza A, n=539; >75% H3N2). Their mean age was 70+/-18 years; co-morbidities and serious complications were common (61-77%). Supplemental oxygen and ventilatory support was required in 401 (53.2%) and 41 (5.4%) patients, respectively. 39 (5.2%) patients died; pneumonia, respiratory failure and sepsis were the causes. 395 (52%) patients received antiviral (oseltamivir) treatment. Omission of antiviral treatment was associated with delayed presentation or negative antigen detection results. The mortality rate was 4.56 and 7.42 per 1000 patient-days in the treated and untreated patients, respectively; among those with co-morbidities, it was 5.62 and 11.64 per 1000 patient-days, respectively. In multivariate analysis, antiviral use was associated with reduced risk of death (adjusted HR (aHR) 0.27 (95% CI 0.13 to 0.55); p<0.001). Improved survival was observed with treatment started within 4 days from onset. Earlier hospital discharge (aHR 1.28 (95% CI 1.04 to 1.57); p=0.019) and faster discontinuation of oxygen therapy (aHR 1.30 (95% CI 1.01 to 1.69); p=0.043) was associated with early treatment within 2 days. Few (n=15) H1N1 isolates in this cohort had the H275Y mutation. CONCLUSIONS: Antiviral treatment for severe influenza is associated with reduced mortality and improved clinical outcomes.

Cardiovascular risks and metabolic syndrome in Hong Kong Chinese women with polycystic ovary syndrome.

BACKGROUND: Women with polycystic ovary syndrome (PCOS) frequently exhibit central obesity, glucose intolerance, atherogenic dyslipidaemia and hypertension which are characteristic features of the metabolic syndrome (MetS). METHODS: A total of 295 premenopausal Chinese women with PCOS diagnosed by the Rotterdam criteria (mean age: 30.2 +/- 6.4 years) and 98 control subjects without PCOS were evaluated for prevalence of MetS and cardiovascular risk factors, including dyslipidaemia and dysglycaemia. RESULTS: Using the 2005 modified Adult Treatment Panel III criteria, MetS (presence of three or more risk factors) was found in 24.9% of PCOS women compared to 3.1% of controls. The prevalence of MetS in PCOS women increased from 16.7% at under 30 years of age to 53.3% at over 40 years. MetS was also more prevalent in overweight and obese (41.3%) than normal-weight PCOS women (0.9%). However, multivariate regression analysis showed that women with PCOS had a 5-fold increase in risk of MetS (odds ratio 4.90; 95% confidence interval: 1.35-17.84) compared with women without PCOS even after controlling for age and BMI, suggesting PCOS alone is an independent risk factor for MetS. CONCLUSIONS: There is high prevalence of MetS in Hong Kong Chinese women with PCOS despite their relatively young age. Recognition of these cardiometabolic risk factors requires a high level of awareness in conjunction with early and regular screening.

The NCEP-ATPIII but not the IDF criteria for the metabolic syndrome identify Type 2 diabetic patients at increased risk of chronic kidney disease.

AIM: To examine the association between chronic kidney disease (CKD) and the metabolic syndrome (MetS) using both International Diabetes Federation (IDF) and National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATPIII) definitions in Chinese subjects with Type 2 diabetes. METHODS: Subjects with Type 2 diabetes were categorized according to the presence or absence of MetS by IDF or NCEP-ATPIII criteria. CKD was considered present if glomerular filtration rate, calculated using the abbreviated equation developed by the Modification of Diet in Renal Disease study with Chinese modification, was < 60 ml/min per 1.73 m2. Multivariate logistic regression analysis of the association between CKD and MetS by either definition was performed. RESULTS: Of 6350 subjects (mean age 55.1 +/- 13.3 years), 3439 (54.2%) and 3204 (50.5%) had MetS by IDF and NCEP-ATPIII definitions, respectively. Using the IDF definition, the presence of MetS was not associated with CKD [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.71, 1.29, P = 0.784]. In contrast, the association with CKD was significant when MetS was defined by the NCEP-ATPIII definition (OR 1.75, 95% CI 1.37, 2.24, P < 0.001). In subjects who did not have MetS (n = 2911) as defined by IDF criteria, 997 fulfilled the MetS criteria of NCEP-ATP III. The association with CKD was stronger, after adjustment for covariates, in these subjects (OR 1.42, 95% CI 1.03, 1.97, P = 0.032) compared with subjects who met IDF criteria of MetS. CONCLUSION: In Type 2 diabetes, NCEP-ATPIII, but not the IDF definition of MetS, identifies a subgroup of patients who have a higher risk of CKD.

Hypercytokinemia and hyperactivation of phospho-p38 mitogen-activated protein kinase in severe human influenza A virus infection.

BACKGROUND: We postulate that hypercytokinemia plays a role in immunopathogenesis of severe human influenza. METHODS: We prospectively studied 39 consecutive patients who were hospitalized with severe influenza A virus infection. On laboratory confirmation of the diagnosis, paired acute-phase (obtained at hospital admission) and convalescent-phase (obtained >10 days after hospital admission) plasma samples were collected for assay of 11 cytokines and chemokines (interleukin [IL] 1 beta; IL-6; IL-10; IL-12p70; tumor necrosis factor alpha; IL-8; monokine induced by interferon [IFN]-gamma; IFN-inducible protein 10; monocyte chemoattractant protein 1; regulated upon activation, normal T cell-expressed and secreted; and IFN-gamma) using cytometric bead-array analysis and enzyme-linked immunosorbent assay. Simultaneously, virus concentration in the acute-phase nasopharyngeal aspirate was determined using real-time quantitative reverse-transcriptase polymerase chain reaction. Intracellular signaling molecules regulating lymphocyte activation, phospho-p38 mitogen-activated protein kinase and phospho-extracellular signal-regulated protein kinase in CD4+ and CD8+ T lymphocytes were studied in the acute-phase samples using flow cytometric analysis and were compared with results for samples from healthy control subjects. RESULTS: Statistically significant increases in plasma IL-6 (3.7-fold increase), IL-8 (2.6-fold increase), IFN-induced protein 10 (4.9-fold increase), and monokine induced by IFN-gamma (2.3-fold increase) concentrations were detected during acute illness (P < .01 for all, by Wilcoxon signed-rank test); the highest concentrations were observed on symptom days 3 and 4. Corresponding plasma cytokine and chemokine concentrations and nasopharyngeal viral loads showed statistically significant correlations (rho = 0.41, 0.49, 0.54, and 0.46, respectively; P < or = .01). Phospho-p38 mitogen-activated protein kinase expression in CD4+ lymphocytes was increased, correlating with cytokine concentrations (e.g., for IFN-induced protein 10, rho = 0.78; P < .01); phospho-extracellular signal-regulated protein kinase was suppressed. Advanced age and comorbidity were associated with aberrant IL-6, IL-8, and monokine induced by IFN-gamma responses (P < .05, by Mann-Whitney U test). An elevated IL-6 concentration was independently associated with prolonged hospitalization (hospitalization for >5 days; P = .02), adjusted for age, comorbidity, and virus load. CONCLUSIONS: Hypercytokinemia (of proinflammatory and T helper 1 cytokines) is detected in severe influenza, correlating with clinical illness and virus concentration. Hyperactivation of phospho-p38 mitogen-activated protein kinase (in T helper cells) is possibly involved. Early viral suppression may attenuate these potentially deleterious cytokine responses.

Co-circulation of human metapneumovirus and SARS-associated coronavirus during a major nosocomial SARS outbreak in Hong Kong.

BACKGROUND: The clinico-epidemiological significance of human metapneumovirus (hMPV) detected during the SARS outbreak is unknown. OBJECTIVES: To characterize a nosocomial hMPV outbreak during the 2003 SARS epidemic. STUDY DESIGN AND METHODS: All available nasopharyngeal aspirate (NPA) collected from confirmed patients during the first 8 weeks of the SARS outbreak in 2003 were tested for hMPV by a nested RT-PCR assay targeting the F-gene. Clinico-epidemiological information was used to analyze the relationship of hMPV co-infection to specific risk factors (demographics/symptoms/outcomes; status as health-care workers (HCWs)/patients; history of exposure/contact; ward location). Multivariate logistic regression analysis was performed to determine independent risk factors. RESULTS: An hMPV outbreak occurred during 6-16 March 2003 (first week of the Hong Kong SARS epidemic). hMPV RNA was detected in 31 of 155 (20%) NPAs from SARS patients. HCW status (OR 2.72, 95% CI 1.11-6.68; p=0.029) or epidemiological linkage to the SARS outbreak ward (OR 3.59, 95% CI 1.42-9.05; p=0.007) were independent factors associated with hMPV infection. Symptoms of cough and coryza were more common in co-infected individuals (22.6% vs. 15.9%) but this was not statistically significant. Other clinical manifestations and outcomes were not different in co-infected patients. CONCLUSIONS: A major nosocomial hMPV outbreak involving HCWs occurred during the early SARS epidemic. Patients with dual hMPV and SARS infection were not sicker than those with SARS infection only.

A Chinese family with familial paraganglioma syndrome due to succinate dehydrogenase deficiency.

We report the genetic characteristics of a family with familial paraganglioma syndrome. The index patient was diagnosed with carcinoid tumour of the bronchus at the age of 30 years then later diagnosed with bilateral phaeochromocytoma. His sister had bilateral carotid body tumours. Mutational analyses of succinate dehydrogenase B and SDHD on the index patient showed him to be heterozygous for the M1I mutation of the SDHD gene. A genetic analysis revealed that his sister also had succinate dehydrogenase deficiency with the same mutation. Pre-symptomatic testing confirmed the genetic diagnosis, and led to a clinical diagnosis in an otherwise asymptomatic sibling. Comparison with other known cases of M1I mutation suggests that this is a founder mutation in the Chinese population. Genetic analysis of the succinate dehydrogenase genes can provide a specific diagnosis and allow for genetic screening of at-risk individuals.

Anti-SARS-CoV IgG response in relation to disease severity of severe acute respiratory syndrome.

BACKGROUND: The association between a robust or depressed antibody response and clinical severity of SARS remains unknown. OBJECTIVES: To study seroconversion and the magnitude of IgG responses in a SARS cohort with different disease severities. STUDY DESIGN AND METHOD: A retrospective analysis of all acute and convalescent-phase sera collected from a cohort of laboratory-confirmed SARS cases. Anti-SARS-CoV IgG antibody was detected using indirect immunofluorescence technique and quantified by two-fold serial dilutions. Characteristics of patients who seroconverted "early" (

Cryptococcosis in apparently immunocompetent patients.

BACKGROUND: Few reports have described the clinical and microbiological features of cryptococcosis in immunocompetent patients. AIM: To compare clinical presentations and outcomes of cryptococcosis in immunocompetent vs. immunocompromised patients. DESIGN: Retrospective case series. METHODS: All culture- or histology-confirmed cases (n = 46) of cryptococcosis in two acute hospitals in Hong Kong (1995-2005) were included. Clinical presentations, rates of fungaemia, cerebrospinal fluid (CSF) parameters and clinical outcomes were recorded. RESULTS: Twenty patients (43.5%) were apparently immunocompetent, 17 (37.0%) had predisposing factors other than HIV infection, and 9 (19.6%) were HIV-positive. Thirty-one (67.4%) presented with meningitis, four (8.7%) with pulmonary cryptococcosis, and 11 (23.9%) with extraneural, extrapulmonary cryptococcosis. Of the immunocompetent patients with retrievable isolates (n = 8), three (37.5%) were Cryptococcus gattii; all isolates (n = 6) from immunocompromised patients were Cryptococcus neoformans var. grubii. Immunocompetent patients more commonly presented with meningitis (80.0% vs. 47.1%, p = 0.03), and tended toward lower rates of fungaemia (10.0% vs. 35.3%, p = 0.06) and mortality (25.0% vs. 52.9%, p = 0.06). Death was associated with fungaemia (p = 0.01) and underlying malignancy (p < 0.01). In cryptococcal meningitis, immunocompetent patients had longer mean time from illness onset to presentation (34.4 vs. 12.6 days, p = 0.02), more intense inflammatory responses (CSF: white blood cells 108 vs. 35 x 10(9)/l, p = 0.03; protein 1.61 g/l vs. 0.79 g/l, p = 0.07), less fungaemia (0% vs. 26.7%, p = 0.04) and more satisfactory clinical outcomes (81.3% vs. 46.7%, p = 0.04). DISCUSSION: A substantial proportion of patients with cryptococcosis are apparently immunocompetent. C. neoformans var. grubii and C. gattii are the common causes. Immunocompetent patients tend to present with localized, indolent neurological disease, with more intense inflammatory responses but better clinical outcomes.

Metabolic syndrome by the international diabetes federation definition in Hong Kong Chinese.

In this report, we aimed to examine the impact of the new International Diabetes Federation (IDF) definition on the prevalence and clinical characteristics of subjects with metabolic syndrome (MES). Data were obtained from a prevalence survey for cardiovascular risk factors in a Hong Kong Chinese working population. There were 1513 subjects well representing all occupational groups from managers to general laborers [910 (60.1%) men and 603 (39.9%) women (mean age 37.5+/-9.2, median 37.0, range 18-66 years)]. The crude prevalence of MES defined by the IDF criterion was 7.4% (compared to other criteria: NCEP, 9.6%; WHO, 13.4% and EGIR, 8.9%). The age-standardized prevalence of MES by the IDF criterion was 8.8% in women and 7.3% in men. Subjects with MES defined by IDF criterion had higher body mass index and waist compared to those with MES defined by NCEP or WHO criteria, and lower triglyceride compared to those with MES defined by NCEP criterion after adjustment for age, gender and smoking. Non-MES subjects defined by IDF criterion had higher 2h glucose and insulin resistance compared to non-MES subjects defined by WHO. In conclusion, the new IDF criterion for MES is easy to implement in clinical practice. It may be potentially more 'specific' in identifying subjects with MES although compared to the NCEP criterion, it may have missed a proportion of subjects, especially men, who have metabolic derangement. Prospective and interventional studies are needed to validate the prognostic values of this new definition in comparison with other existing definitions.

Evidence for separate handling in vivo of different regions of the insulin molecule using A14- and B1-labeled insulin tracers.

To compare the metabolic characteristics and degradation of insulin tracers labeled unselectively, selectively at the A14 position (A14-monoiodoinsulin), and selectively at the B1 position (B1-monoiodoinsulin), we have followed the time course of disappearance of intact (immunoprecipitable [IP] and trichloroacetic acid [TCA] precipitable) iodoinsulin after bolus injection into greyhounds. We have used noncompartmental analysis to determine metabolic clearance rate (MCR) and apparent distribution space (DS). We have also measured the appearance of non-IP- and non-TCA-precipitable fragments, and have developed a mathematical model using compartmental analysis to explain the observed differences. B1-Monoiodoinsulin has a significantly higher MCR (16.3 ml/min/kg) than both A14-monoiodoinsulin (10.6 ml/min/kg) and unfractionated tracers (7.6 ml/min/kg) as determined by immunoprecipitation, and reaches the values observed for native insulin in greyhounds. MCR values obtained by TCA precipitation are approximately one-half of those obtained by IP for all 3 tracers. The concentration of non-IP fragments is significantly lower with B1-monoiodoinsulin than with the other tracers. Compartmental analysis suggests this to be due to greater intracellular retention of the B1 moiety during the experimental period. We conclude that: (1) by the criterion of MCR, B1-monoiodoinsulin seems to behave more like native insulin than other preparations tested; (2) the reduced MCR of A14-monoiodoinsulin raises doubts about its validity as a tracer for insulin; (3) a high-molecular-weight product of insulin degradation, which includes both the B1 and the A14-A19 regions of the molecule, is released into the circulation; and (4) smaller fragments containing A14-A19 reappear in the circulation more rapidly than fragments containing B1.(ABSTRACT TRUNCATED AT 250 WORDS)

Susceptibility to IDDM in a Chinese population. Role of HLA class II alleles.

MHC associations with IDDM in a Chinese population were studied to investigate genetic susceptibility to the disorder. The frequency of HLA-DR3 was significantly higher in the diabetic patients (19/49 [38.7%] vs. control subjects, 11/105 [10.5%], Pc less than 1.3 x 10(-3), RR = 5.3 [CI 2.3-12.1]), whereas DR4 was not (11/49 [22.4%] vs. 28/105 [26.7%], NS). The frequency of DR3/4 heterozygosity was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 0/105 [0%], P = 1.7 x 10(-3), RR = 31.5 [CI 3.8-263.6]). The frequency of DR3/9 heterozygosity also was higher in the diabetic patients (6/49 [12.2%] vs. control subjects, 2/105 [1.9%], P = 0.03, RR = 6.2 [CI 3.0-12.7]). No significant associations were noted between DQB1 alleles and IDDM. Among DR4-positive subjects, the frequency of DQB1 allele DQB1*0302 was higher in the diabetic patients (10/11 [90.0%] vs. control subjects, 12/24 [50%], Pc less than 0.05, RR = 7.0 [CI 1.3-38.0]), and the frequency of DQB1*0401 was significantly lower in the diabetic patients (2/11 [18.2%] vs. control subjects, 16/24 [66.7%], Pc = 0.04, RR = 0.1 [CI 0.02-0.46]). No DR4 subtype was associated significantly with IDDM. The frequency of DQA1*0501, a DQA1 allele, was higher in diabetic patients (22/41 [53.7%] vs. control subjects, 20/95 [21.1%], Pc less than 3 x 10(-3), RR = 4.3 [CI 2.0-9.3]). The frequency of DQA1*0301, which has been associated consistently with IDDM in other ethnic groups, was not significantly higher in the diabetic patients in this study (27/41 [65.9%] vs. control subjects, 53/95 [55.8%], NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Use of the 1997 American Diabetes Association diagnostic criteria for diabetes in a Hong Kong Chinese population.

OBJECTIVE: Recently, the American Diabetes Association (ADA) has proposed revised diagnostic criteria for diabetes. Lowering of the fasting plasma glucose (FPG) cutoff value is intended to reduce the discrepancy with the 2-h plasma glucose (PG) cutoff value and to encourage the use of FPG. We have applied these new criteria to data collected from a population-based prevalence survey in Hong Kong Chinese subjects of working age. RESEARCH DESIGN AND METHODS: The results of 1,513 oral glucose tolerance tests (OGTTs) from a previously published prevalence survey of glucose intolerance and cardiovascular risk factors in a Hong Kong Chinese working population were reexamined using the new criteria. Of the 1,513 subjects, 27 had a known history of diabetes. Of the remaining 1,486 subjects, 228 were also selected randomly for a second OGTT without prior knowledge of the result of the first test. RESULTS: After exclusion of the 27 subjects with a known history of diabetes, the crude prevalence of diabetes was 2.83% (n = 42) when the World Health Organization's (WHO) criteria were applied. When the criterion of FPG > or = 7.0 mmol/l was used, as recommended by the ADA, the prevalence of diabetes was 1.41% (n = 21). Twenty-nine subjects (1.95%) with FPG < 7.0 mmol/l had a 2-h PG > or = 11.1 mmol/l. Eight subjects (0.53%), previously without a diagnosis of diabetes according to the WHO criteria (FPG < 7.8 mmol/l and 2-h PG < 11.1 mmol/l), had FPG between 7.0 and 7.8 mmol/l and were classified as having diabetes by the ADA criteria. This classification gave a net change of -1.42% in the prevalence of diabetes between the use of FPG > or = 7.0 mmol/l alone and the use of WHO criteria. Among the 1,486 subjects with no known history of diabetes, those classified as having diabetes according to the ADA FPG criterion alone had higher HbA1c and fructosamine levels than diabetic subjects defined by the WHO criteria. Of the 228 subjects for whom two FPG measurements were available, those who had consistent definitions (diabetes, impaired fasting glucose, normal fasting glucose) on both occasions were considered to have reproducible tests, giving an overall reproducibility of 90.8% (207 of 228). CONCLUSIONS: Compared with the WHO criteria, the use of FPG to diagnose diabetes, as recommended by the ADA, was a more reproducible test and identified those subjects who had a greater degree of hyperglycemia. Although lowering of the cutoff value from 7.8 to 7.0 mmol/l increased the number of diagnoses among subjects with low FPG, the omission of the 2-h PG would lead to fewer subjects having their diabetes diagnosed.

Assessment of glucose tolerance test criteria for diagnosis of diabetes in Chinese subjects.

OBJECTIVE: To examine and compare WHO diagnostic criteria for diabetes mellitus. RESEARCH DESIGN AND METHOD: The relationship between FPG and 2-h glucose are examined in 680 OGTTs with a quadratic regression model and ROC analysis. Simultaneous measurements of HbA1 and fructosamine are also compared with multiple linear regression. RESULTS: Two hundred eighteen subjects (32%) had 2-h glucose greater than or equal to 11.1 mM, of which only 86 had FPG greater than or equal to 7.8 mM. Only 2 subjects had FPG greater than 7.8 mM and 2-h glucose less than 7.8 mM. Of subjects with 2-h glucose less than 7.8 mM (n = 332), only 9 had FPG greater than 6.0 mM. From the quadratic model, the predicted FPG corresponding to 2-h glucose = 11.1 mM was 5.7 mM, whereas the predicted 2-h glucose corresponding to FPG = 7.8 mM was 15.2 mM. ROC analysis showed that, with 2-h glucose greater than or equal to 11.1 mM as indicating diabetes, an FPG of 5.6 mM gave an intersect for sensitivity and specificity of 87%. HbA1 and fructosamine correlated more closely with 2-h glucose and area under the OGTT curve than with FPG. CONCLUSIONS: Given that a 2-h glucose cutoff of 11.1 mM can be justified from other studies, our results suggest that the FPG cutoff of 7.8 mM when used for screening purposes should be reduced. At a suggested value of 7.0 mM, specificity remains 98.5%, whereas sensitivity increases to 57%.

Combined use of fasting plasma glucose and HbA1c predicts the progression to diabetes in Chinese subjects.

OBJECTIVE: We have previously suggested using the paired values of fasting plasma glucose (FPG) and HbA1c to identify potential diabetic subjects. In this article, we followed up on 208 nondiabetic subjects and examined their rates of progression to diabetes. We analyzed their likelihood of becoming diabetic according to their baseline FPG and HbA1c concentrations. RESEARCH DESIGN AND METHODS: Between 1988 and 1995, 2,877 Chinese subjects with risk factors for diabetes underwent screening. Of these, 2,250 had FPG <7.8 mmol/l and 2-h plasma glucose (PG) <11.1 mmol/l. Of these 2,250 subjects, 265 were randomly recruited for an annual oral glucose tolerance test (OGTT) until they progressed to develop diabetes. Of those 265 subjects, 57 had baseline FPG > or =7.0 mmol/l and were excluded from the present analysis. Hence, the progression of glucose tolerance in 208 subjects who were nondiabetic according to the new American Diabetes Association diagnostic criteria (FPG < 7.0 mmol/l and 2-h PG < 11.1 mmol/l) was examined RESULTS: Of the 208 nondiabetic subjects, 26 (12.5%) were men and 182 (87.5%) were women. After a mean follow-up of 1.60 +/- 1.16 years (range 1-7, median 1), 44 (21.2%) progressed to develop diabetes and 164 (78.8%) remained nondiabetic. Those who were diabetic at the end of the study had a high likelihood ratio (LR) of 9.3 to have baseline FPG > or =6.1 mmol/l and baseline HbA1c > or =6.1%. This was compared with a low LR of 0.6-1.1 in diabetic subjects who had either FPG <6.1 mmol/l or HbA1c <6.1% or both at baseline. The crude rate of progression to diabetes was more than five times higher (44.1 vs. 8.1%) in those whose baseline FPG was > or =6.1 mmol/l and baseline HbA1c was > or =6.1% compared with those whose baseline FPG was <6.1 mmol/l and baseline HbA1c was <6.1%. CONCLUSIONS: For Chinese subjects with risk factors for glucose intolerance, the use of paired FPG and HbA1c values helped to identify potential diabetic subjects. Those with an FPG > or =6.1 mmol/l and HbA1c > or =6.1% had a rate of progression to diabetes more than five times higher than those with an FPG <6.1 mmol/l and an HbA1c <6.1% after a mean follow-up of 1.6 years. Those with an FPG > or =6.1 but <7.0 mmol/l, especially if their HbA1c was > or =6.1%, should undergo an OGTT to confirm diabetes. Subjects with an FPG <6.1 mmol/l and/or an HbA1c <6.1% should have regular screening using the paired values of FPG and HbA1c.

Comparison of insulin with or without continuation of oral hypoglycemic agents in the treatment of secondary failure in NIDDM patients.

OBJECTIVES: Optimal insulin regimens for non-insulin-dependent diabetes mellitus (NIDDM) patients with secondary failure are controversial. We evaluated the efficacy, side effects, and quality of life of patients receiving insulin either alone or in combination with their previous oral hypoglycemic agents (OHAs). RESEARCH DESIGN AND METHODS: Fifty-three Chinese patients with NIDDM (mean age 53.9 +/- 12.6 years, duration of diabetes 9.0 +/- 4.9 years, body wt 60.4 +/- 13.3 kg with corresponding body mass index 24.2 +/- 4.3 kg/m2, receiving the maximum dose of sulfonylurea and/or metformin) were confirmed to have OHA failure. Twenty-seven patients were randomized to continue OHAs and were given additional bedtime insulin (combination group); 26 patients were randomized to insulin therapy alone with twice-daily insulin (insulin group). Insulin doses were increased incrementally, aiming at fasting plasma glucose (FPG) < 7.8 mmol/l during a stabilization period of up to 8 weeks. Insulin dosage, body weight, glycemic control, and quality of life were assessed before and at 3 and 6 months after stabilization. RESULTS: Both groups showed similar improvement of glycemic control. For the combination group, FPG decreased from 13.5 +/- 2.7 to 8.9 +/- 3.0 mmol/l at 3 months (P < 0.0001) and to 8.6 +/- 2.5 mmol/l at 6 months (P < 0.0001). For the insulin group, FPG decreased from 13.5 +/- 3.6 to 7.5 +/-3.0 mmol/l at 3 months (P < 0.0001) and to 9.8 +/- 3.5 mmol/l at 6 months (P < 0.0001). No significant differences were observed between the groups. Similarly, both groups had significant improvement of fructosamine and glycosylated hemoglobin (HbA1c). Fructosamine fell from a mean of 458 to 365 mumol/l at 3 months (P < 0.0001) and to 371 mumol/l at 6 months (P < 0.0001) and from 484 to 325 mumol/l at 3 months (P < 0.0001) and to 350 mumol/l at 6 months (P < 0.0001) for the combination and insulin groups, respectively. HbA1c decreased from 10.2 to 8.4% at 3 months (P < 0.0001) and to 8.7% at 6 months (P < 0.0001) in the combination group and from 10.7 to 7.8% at 3 months (P < 0.0001) and to 8.4% at 6 months (P < 0.0001) in the insulin group. Despite similar improvement of glycemia, insulin requirements were very different. At 3 months, the combination group was receiving a mean of 14.4 U/day compared with 57.5 U/day in the insulin group (P < 0.0001). Similar findings were observed at 6 months (15.0 vs 57.2 U/day, P < 0>0001). Both groups gained weight. However, for the combination group, weight gain was 1.6 +/- 1.8 kg at 3 months and 2.1 +/- 2.5% kg at 6 months (both P < 0.0001 vs baseline), whereas for the insulin group, weight gain was 3.5 +/- 4.3 and 5.2 +/- 4.1 kg, respectively (both P < 0.0001 vs baseline). Weight gain was significantly greater in the insulin group (P < 0.05 at 3 months, and P < 0.005 at 6 months). Fasting plasma triglyceride decreased in the insulin group (1.8 +/- 1.0 to 1.4 +/- 0.8 mmol/l at 3 months [P < 0.005] and to 1.4 +/ 0.7 mmol/l at 6 months [P < 0.02] but not in the combination group. No changes were observed in total and high-density lipoprotein cholesterol. No severe hypoglycemic reactions were recorded in either group. Mild reactions occurred with similar frequency in both groups. Well-being and quality of life improved significantly in both groups. The majority of patients (82.7%) wanted to continue insulin beyond 6 months, irrespective of the treatment group. CONCLUSIONS: In NIDDM patients with secondary OHA failure, therapy with a combination of OHAs and insulin and with insulin alone was equally effective and well tolerated. However, combination therapy was associated with a lower insulin dose and less weight gain. Combination treatment may be considered when OHA failure occurs as a potential intermediate stage before full insulin replacement.

Fasting plasma glucose as a screening test for diabetes and its relationship with cardiovascular risk factors in Hong Kong Chinese.

OBJECTIVE: To evaluate the use of fasting plasma glucose (FPG) in the diagnosis of diabetes and the relationship between FPG and various cardiovascular risk factors in a community-based Hong Kong Chinese population. RESEARCH DESIGN AND METHODS: The results of 1,470 oral glucose tolerance tests from a prevalence survey for glucose intolerance and lipid abnormality in a Hong Kong Chinese working population were examined. Our previous report showed that an FPG of 5.7 mmol/l corresponded to a 2-h plasma glucose (PG) of 11.1 mmol/l, and we used this value as a cutoff value and examined the relationship between FPG and various cardiovascular risk factors in nondiabetic subjects. RESULTS: An FPG cutoff value of 7.8 mmol/l gave a sensitivity of 20.0% and a specificity of 100% in the diagnosis of diabetes (defined as 2-h PG > or = 11.1 mmol/l). We divided the non-diabetic subjects (FPG < 7.8 mmol/l and 2-h PG < 11.1 mmol/l) into two groups: subjects with FPG < 5.7 mmol/l and those with FPG > or = 5.7 mmol/l and < 7.8 mmol/l. Subjects in the latter group were older, had higher blood pressure, BMI, waist-to-hip ratio, 2-h PG, fasting and 2-h insulin, fasting serum triglyceride, VLDL cholesterol, apolipoprotein B, and urinary albumin concentrations, as well as lower plasma HDL cholesterol and HDL2 cholesterol concentrations. CONCLUSIONS: These findings suggest that an FPG cutoff value of 7.8 mmol/l, as recommended by the World Health Organization, was too high when applied to Chinese populations. As in the case of hyperlipidemia, plasma glucose concentration should be viewed as a continuum in terms of its relationship with cardiovascular risk.

Metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients.

OBJECTIVE: To compare the metabolic and hemodynamic effects of metformin and glibenclamide in normotensive NIDDM patients. RESEARCH DESIGN AND METHODS: After a 2-wk run-in period on dietary treatment alone, 12 Chinese normotensive patients with uncomplicated NIDDM were randomized to receive either metformin, or glibenclamide for 4 wk before being crossed-over to the alternative treatment for an additional 4 wk. Metabolic and hemodynamic index, including cardiac output estimation by impedance cardiography, were measured at baseline and at the end of each treatment period. RESULTS: Body mass index was reduced more with metformin than with glibenclamide, although glycemic control was similar with both drugs. Plasma total cholesterol concentration fell more with metformin (mean difference -0.65 mM, 95% confidence interval -0.96 to -0.32) than glibenclamide (mean difference -0.20 mM, 95% confidence interval -0.54-0.12) (P < 0.05). Compared with baseline values, erect diastolic blood pressure was reduced more by metformin (12.9% [95% confidence interval -21.5 to -4.4%]) than glibenclamide (-6.8% [95% confidence interval -14.9 to 1.2%]) (P < 0.001). The relative changes in the systemic vascular resistance index also differed between the two treatments (glibenclamide, 6.2 [-4.3 to 16.6%]; metformin, -1.2 [95% confidence interval -8.8-6.4%]) (P < 0.05)]. CONCLUSIONS: In normotensive NIDDM patients, treatment with metformin was associated with greater reductions in body weight, plasma total cholesterol concentration, and erect diastolic blood pressure, whereas the systemic vascular resistance index increased after treatment with glibenclamide. These findings merit long-term investigation.

Angiotensinogen T235 and ACE insertion/deletion polymorphisms associated with albuminuria in Chinese type 2 diabetic patients.

OBJECTIVE: Genetic polymorphisms of the renin-angiotensin system (RAS) have been implicated in the pathogenesis of diabetic proteinuria. Ethnic differences in the frequencies of these genotypes have also been reported. To date, most of these studies have been performed in white and Japanese populations. In this study, we examined the associations between albuminuria and RAS genetic polymorphisms in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In a case-control study, the ACE insertion/deletion (I/D) gene, the angiotensinogen (AGT) gene (M235T), and the angiotensin II (AII) type 1 receptor gene (AT1 A1166C) were examined in 110 Chinese type 2 diabetic patients. Increased urinary albumin excretion (UAE) was defined as > or = 30 mg/day on at least two occasions during a 6-week study period. RESULTS: Compared with whites, there were high frequencies of the AGT TT genotype in Chinese control subjects (120/183 = 70%) and type 2 diabetic patients (74/110 = 67%). The frequencies of the MM genotype were 5 and 3%, respectively, and those of the ACE DD genotype were 13 and 10%, respectively. Although 9% of subjects carried the C allele, the AT1 CC genotype was not found in either group. Chinese type 2 diabetic patients with increased albuminuria (n = 56) had higher systolic blood pressure (160 +/- 26 mmHg vs 145 +/- 27 mmHg, P < 0.001) than the normoalbuminuric patients (n = 54). Both the AGT TT genotype (78.6% [44/56] vs. 55.6% [30/54], odds ratio [OR]: 3.0 [1.3-6.8]) and the T allele (88% [99/112] vs. 77% [83/108], OR: 2.5 [1.3-5.4]) were associated with an increased risk of albuminuria. Patients with the AGT TT genotype (n = 74) had higher 24-h UAE than those with the MT or MM genotypes (n = 36) (median: 37.8 mg/day vs. 17.8 mg/day, P < 0.01). This association remained significant in patients with normotension (56 mg/day [n = 19] for patients with the TT genotype vs. 22 mg/day [n = 14] for those with the MT/MM genotype, P = 0.03). The D allele carriers (DD or DI, n = 61) had higher serum ACE activities (75.5 +/- 29 U/l vs. 60.5 +/- 36.3 U/l, P < 0.01) than the noncarriers (II genotype). The median 24-h UAE also tended to be higher in the D allele carriers (38.9 mg/day vs. 21.4 mg/day, P = 0.07). The lowest UAE was observed in patients with the MM/MT/II genotype (16.3 mg/day [n = 18]) and the highest, in patients with the TT/DD/DI genotype (52.3 mg/day [n = 43]). No association was found between the TT genotype or D allele and hypertension. CONCLUSIONS: The high frequencies of the TT genotype and T allele in Chinese populations may contribute to the high prevalence of albuminuria in patients with type 2 diabetes. The possibility of synergism between the AGT TT genotype and the ACE D allele should also be explored.

Factors determining the blood pressure response to enalapril and nifedipine in hypertension associated with NIDDM.

OBJECTIVE: To examine the factors that determine the blood pressure response to enalapril and nifedipine monotherapy in the treatment of hypertension associated with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS: After a 6-week placebo baseline period, 102 hypertensive NIDDM patients were randomly assigned, double-blindly, to treatment with nifedipine retard (slow release) (n = 52) or enalapril (n = 50). The daily dosage of enalapril was increased, if required, from 10 to 20 to 40 mg and that of nifedipine from 40 to 60 to 80 mg at 4-week intervals during the 12-week titration period. Blood pressure, 24-h urinary albumin excretion (UAE), biochemical data, and serum angiotensin-converting enzyme (ACE) activity were measured at weeks -6, -4, 0, 4, 8, and 12. At week 0, venous blood was also sampled for baseline plasma atrial natriuretic peptide, renin, aldosterone, and serum insulin concentrations. RESULTS: At week 12, the mean daily dose of enalapril was 35 +/- 11.4 mg, and 27 (57%) patients were receiving the maximum daily dose of 40 mg. In the nifedipine group, the mean daily drug dose was 50 +/- 12.9 mg, and 4 (8%) were receiving the maximum daily dose of 80 mg. Despite a dose-dependent fall in the serum ACE activity in the enalapril group, the mean arterial pressure (MAP) was reduced by only 8 mmHg throughout the 12-week titration period compared to a decline of 15, 18, and 19 mmHg at weeks 0, 4, and 12, respectively, in the nifedipine group (P = 0.01 between groups). In the enalapril group, changes in MAP between weeks 0 and 12 correlated significantly with baseline plasma glucose (r = 0.45, P = 0.001) and aldosterone concentrations (r = -0.32, P = 0.02) and UAE (r = 0.3, P = 0.04). There was no statistically significant correlation between the changes in MAP and baseline plasma renin concentration. On multivariate analysis, the baseline renal function, glycemic control, and plasma aldosterone and serum insulin concentrations were all independently related to the changes in blood pressure in the enalapril-treated patients. No such statistical associations were observed in the nifedipine group. CONCLUSIONS: In hypertensive NIDDM patients, the activity of the renin-angiotensin-aldosterone system, the level of serum insulin, glycemic control, renal function, and proteinuria may be important determinants of the blood pressure response to ACE inhibition. Good glycemic control may optimize the antihypertensive efficacy of concomitant ACE inhibitor therapy.