The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene.

BACKGROUND: Aldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring. CASE PRESENTATION: We describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG. CONCLUSION: Although a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase deficiency has been identified.

Diabetes and fasting during Ramadan.

Abstinence from food and liquid during daylight hours is observed by Muslim individuals during the month of Ramadan. Even though the Koran exempts the sick from fasting, many people with diabetes still fast during this religious period. It is essential for patients, family and healthcare professionals to be aware of the religious attitude to and health implications of fasting. Major changes in dietary habits, daily physical activities and sleeping patterns during Ramadan have significant impact on the glycaemic control, lipid profile, weight and dietary intake. Hence, the patient is encouraged to have appropriate pre-Ramadan assessment and education in order to stratify and modify his or her risk with fasting. Dose and timing adjustments to insulin and to some oral hypoglycaemic agents, especially sulphonylureas, may well be necessary during Ramadan.

Historical weather data for climate risk assessment.

Weather- and climate-related hazards are responsible for monetary losses, material damages, and societal consequences. Quantifying related risks is, therefore, an important societal task, particularly in view of future climate change. For this task, climate risk assessment increasingly uses model chains, which mainly build on data from the last few decades. The past record of events could play a role in this context. New numerical techniques can make use of historical weather data to simulate impacts quantitatively. However, using historical data for model applications differs from using recent products. Here, we provide an overview of climate risk assessment methodologies and of the properties of historical instrumental and documentary data. Using three examples, we then outline how historical environmental data can be used today in climate risk assessment by (1) developing and validating numerical model chains, (2) providing a large statistical sample which can be directly exploited to estimate hazards and to model present risks, and (3) establishing "worst-case" events which are relevant references in the present or future. The examples show that, in order to be successful, different sources (reanalyses, digitized instrumental data, and documentary data) and methods (dynamical downscaling and analog methods) need to be combined on a case-by-case basis.

Construction of the REACHES climate database based on historical documents of China.

This paper describes the methodology of an ongoing project of constructing an East Asian climate database REACHES based on Chinese historical documents. The record source is Compendium of Meteorological Records of China in the Last 3000 Years which collects meteorology and climate related records from mainly official and local chronicles along with a small number of other documents. We report the digitization of the records covering the period 1644-1795. An example of the original records is translated to illustrate the typical contents which contain time, location and type of events. Chinese historical times and location names are converted into Gregorian calendar and latitudes and longitudes. A hierarchical database system is developed that consists of the hierarchies of domains, main categories, subcategories, and further details. Historical events are then digitized and categorized into such a system. Code systems are developed at all levels such that the original descriptive entries are converted into digitized records suitable for treatment by computers. Statistics and characteristics of the digitized records in the database are described.

Impact of Genetic Loci Identified in Genome-Wide Association Studies on Diabetic Retinopathy in Chinese Patients With Type 2 Diabetes.

PURPOSE: Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2DM). Genome-wide association studies (GWAS) had identified novel DR-susceptibility genetic variants in various populations. We examined the associations of these DR-associated single nucleotide polymorphisms (SNPs) with severe DR in a Chinese T2DM cohort. METHODS: Cross-sectional case-control studies on sight-threatening DR (STDR) and proliferative DR (PDR) were performed. We genotyped 38 SNPs showing top association signals with DR in previous GWAS in 567 STDR cases, including 309 with PDR and 1490 non-DR controls. Multiple logistic regression models with adjustment for conventional risk factors, including age, sex, duration of diabetes, and presence of hypertension, were employed. RESULTS: The strongest association was found at INSR rs2115386, an intronic SNP of INSR: Padjusted = 9.13 × 10-4 (odds ratio [OR],1.28; 95% confidence interval [95%CI], 1.11-1.48) for STDR, and Padjusted= 1.12 × 10-4 (OR [95%CI],1.44 [1.20-1.74]) for PDR. rs599019 located downstream of COLEC12 (Padjusted = 0.019; OR [95%CI],1.19 [1.03-1.38]) and rs4462262 located at an intergenic region between ZWINT and MRPS35P3 (Padjusted = 0.041; OR [95%CI],1.38[1.01-1.89]) also were significantly associated with STDR, but not with PDR alone. On the other hand, MYT1L-LOC729897 rs10199521 (Padjusted = 0.022; OR [95%CI],1.25 [1.03-1.51]) and API5 rs899036 (Padjusted = 0.049; OR [95%CI],1.36 [1.00-1.85]) showed significant independent associations only with PDR. Similar results were obtained when hemoglobin A1c also was included in the adjustment models. CONCLUSIONS: We demonstrated the significant and independent associations of several GWAS-identified SNPs with DR in Chinese T2DM patients with severe DR. The findings on INSR rs2115386 are supportive of the role of insulin resistance, or the compensatory hyperinsulinemia, in the pathogenesis of DR.

Utility of stress testing and coronary calcification measurement for detection of coronary artery disease in women.

Accurate and safe diagnostic testing provides the crucial link between detection and optimal management of coronary artery disease (CAD). Noninvasive diagnostic testing for CAD may be less accurate in women than in men. Many noninvasive diagnostic modalities are available for this purpose. An exercise tolerance test provides an assessment of functional capacity and has the advantages of wide availability and low initial cost. However, exercise echocardiography may be the most cost-effective method for the initial assessment of coronary artery disease in intermediate-risk women owing to its higher sensitivity and specificity. Recent studies with electron-beam computed tomography reveal that women with no coronary calcification are very unlikely to have obstructive CAD. In symptomatic women with an intermediate likelihood of CAD, either an exercise treadmill test or exercise echocardiography is appropriate for initial screening and can provide useful prognostic information. Alternatively, an electron-beam computed tomographic scan with a 0 calcium score may spare many women with atypical chest pain or equivocal findings on an exercise tolerance test from undergoing more expensive stress imaging studies or coronary angiography. For high-risk symptomatic women, a more aggressive approach involving coronary angiography appears to be the preferred initial diagnostic strategy.

Elevated circulating pigment epithelium-derived factor predicts the progression of diabetic nephropathy in patients with type 2 diabetes.

CONTEXT: Pigment epithelium-derived factor (PEDF), a circulating glycoprotein with antiangiogenic, antioxidative, and anti-inflammatory properties, protects against diabetic nephropathy (DN) in animal models. OBJECTIVE: We investigated whether circulating PEDF predicted the progression of DN in a 4-year prospective study. DESIGN, SETTING, AND PARTICIPANTS: Baseline plasma PEDF levels were measured in type 2 diabetic subjects recruited from the Hong Kong West Diabetes Registry. The role of PEDF in predicting chronic kidney disease (CKD) and albuminuria progression was analyzed using Cox regression analysis. MAIN OUTCOME MEASURE: We evaluated CKD progression, defined as deterioration in CKD staging and a 25% or greater drop in estimated glomerular filtration rate (eGFR) according to International Society of Nephrology statements. RESULTS: At baseline, plasma PEDF levels increased progressively with CKD staging (P for trend <.001; n = 1136). Among 1071 subjects with baseline CKD stage ≤ 3, plasma PEDF levels were significantly higher in those with CKD progression (n = 171) during follow-up than those without (P < .001). Baseline PEDF was independently associated with CKD progression (hazard ratio = 2.76; 95% confidence interval = 1.39-5.47; P = .004), adjusted for age, sex, waist circumference, diabetes duration, hemoglobin A1c, systolic blood pressure, use of antihypertensive drugs, C-reactive protein, and eGFR. Elevated baseline PEDF was also associated with the development of microalbuminuria/albuminuria in a subgroup with normoalbuminuria and eGFR >60 mL/min/1.73 m(2) (n = 462) at baseline (hazard ratio = 2.75; 95% confidence interval = 1.01-7.49; P < .05), even after adjustment for potential confounders. CONCLUSIONS: Elevated PEDF levels may represent a compensatory change in type 2 diabetic patients with renal disease and appear to be a useful marker for evaluating the progression of DN.

Hypoadiponectinemia as an independent predictor for the progression of carotid atherosclerosis: a 5-year prospective study.

BACKGROUND: Hypoadiponectinemia predicts the development of diabetes and hypertension, both being potent atherosclerotic risk factors. Whether adiponectin predicts the progression of early atherosclerosis remains unclear. In this 5-year prospective study, we examined the relationship between serum adiponectin and carotid intima media thickness (CIMT), a marker of subclinical atherosclerosis. METHODS: A total of 265 subjects from the population-based Hong Kong Cardiovascular Risk Factor Prevalence Study, with no known cardiovascular disease, underwent CIMT measurement at baseline and at 5 years. RESULTS: In all, 129 men and 136 women, aged 54.6±12.3 years, were studied. Median CIMT at baseline was 0.63 mm (interquartile range 0.52-0.73 mm) and increased to 0.67 mm (0.56-0.78 mm) after 5 years (P<0.001). CIMT increment correlated with baseline adiponectin, age, and smoking (all P<0.05) and baseline CIMT (P<0.001), but not with sex, fasting glucose, lipid profiles, hypertension, or diabetes. In multiple linear regression analysis, baseline serum adiponectin level was an independent predictor of CIMT increment ß (standardized beta)=-0.17, P=0.015], after adjusting for age, smoking, baseline CIMT, hypertension, body mass index, fasting glucose, low-density lipoprotein cholesterol, and triglycerides. CONCLUSION: Hypoadiponectinemia predicted CIMT progression, independent of known predictive factors such as age, smoking, hyperlipidemia, and hypertension.

Adiponectin gene variants and the risk of coronary heart disease: a 16-year longitudinal study.

OBJECTIVE: Circulating adiponectin levels have been shown to be associated with a risk of coronary heart disease (CHD). However, its primary role in protecting against the development of CHD remains controversial due to conflicting observations in prospective studies. To gain further insight into the primary role of adiponectin, our major objective was to investigate the relationship between single nucleotide polymorphisms (SNPs) of the adiponectin gene (ADIPOQ) and incident CHD in a population-based cohort with no CHD at baseline. DESIGN AND METHODS: We conducted a 16-year longitudinal study in 2196 subjects from the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS). During 33 862 person-years of follow-up, 184 subjects developed CHD (cumulative incidence rate=5.4 per 1000 person-years). Nine ADIPOQ SNPs with potential functional relevance or shown to be associated with adiponectin levels and/or CHD were genotyped. RESULTS: Among the nine ADIPOQ SNPs, +276G>T (rs1501299) was independently associated with incident CHD in men but not in women, even after adjustments for traditional cardiovascular risk factors (Padjusted=5.5×10(-3) to 0.023; hazard ratio=1.39-1.54). Furthermore, there was a significant association of the T allele of +276G>T with a lower adiponectin level (P=0.027; ß (95% CI)=-0.05 (-0.10, -0.01). CONCLUSIONS: This study demonstrated that +276G>T may be an independent predictor of CHD development. Our findings suggest that low adiponectin levels, as may be influenced by +276G>T, confer a higher risk of CHD, in keeping with a role of hypoadiponectinaemia in the development of CHD in the general population.

Obesity as the common soil of non-alcoholic fatty liver disease and diabetes: Role of adipokines.

Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of liver conditions from simple steatosis, steatohepatitis to end-stage liver disease. The prevalence of NAFLD has been on the rise in many parts of the world, including Asia, and NAFLD is now the liver disease associated with the highest mortality, consequent to the increased risk of cardiovascular diseases and hepatocellular carcinoma. Whereas NAFLD is an independent risk factor for type 2 diabetes, increased hepatic and peripheral insulin resistance contribute to the pathogenesis of both NAFLD and diabetes, which are associated with enhanced cardiovascular risk. Studies in humans and animal models have suggested obesity as the common link of these two diseases, likely mediated by adipose tissue inflammation and dysregulated adipokine production in obesity. In the present review, we discuss recent advances in our understanding of the role of several novel adipokines (adiponectin, adipocyte fatty acid binding protein and fibroblast growth factor-21) in the pathophysiology of NAFLD and diabetes, as well as their use as potential biomarkers and therapeutic targets for dysglycemia in NAFLD patients.

Three case reports of maternal primary hyperparathyroidism in each trimester and a review of optimal management in pregnancy.

Primary hyperparathyroidism (PHPT) during pregnancy is associated with significant maternal and fetal risks. Prompt diagnosis and effective management during pregnancy can improve both maternal and fetal outcomes. However, there is no consensus with regard to conservative versus surgical management especially in the first and third trimester. We report three cases of PHPT associated with pregnancy that underwent parathyroidectomy each in a different trimester. Cases 1 and 2 were found to have hypercalcaemia and elevated parathyroid hormone levels in the second and first trimesters, respectively. Case 3 was known to have PHPT prenatally but previously declined parathyroidectomy. All three cases underwent parathyroidectomies during pregnancy without significant postoperative complications and all achieved favourable maternal and neonatal outcomes. Maternal hyperparathyroidism represents a preventable cause of maternal morbidity, with fetal morbidity and mortality. The benefits of parathyroidectomy with normalization of serum calcium in the mothers outweigh the risks of hypercalcaemia and suppression of the fetal parathyroid, especially where maternal vitamin D concentration is low.

Midfoot and hindfoot bone marrow edema identified by magnetic resonance imaging in feet of subjects with diabetes and neuropathic ulceration is common but of unknown clinical significance.

OBJECTIVE: We conducted a retrospective cohort study assessing the prevalence and clinical and radiological outcome of remote areas of bone marrow edema on magnetic resonance imaging (MRI) in the feet of subjects with diabetes and neuropathic foot ulceration. RESEARCH DESIGN AND METHODS: MRIs performed over 6 years looking for osteomyelitis associated with neuropathic lesions were assessed for remote areas of signal change. RESULTS: Seventy MRI studies were assessed. Remote areas of signal change were present in 21 (30%) subjects, involved midfoot or hindfoot in 20 subjects, were associated with younger age and renal replacement therapy, and did not predict future Charcot neuroarthropathy or infection at that site. Repeat MRIs in 11 subjects with such areas found that none had progressed, six had improved, and two had resolved; in 29 subjects without such areas, five had developed new areas. CONCLUSIONS: Bone marrow edema in the midfoot and hindfoot of subjects with diabetes and neuropathic lesions is common, often transient, and of unknown significance.

Carcinoma of the uncinate process of the pancreas presenting with deep vein thrombosis: a case report.

The uncinate process is a hook-like projection of the inferior aspect of the head of the pancreas. Carcinoma of the uncinate process of the pancreas is considered to be rare, difficult to diagnose and particularly devastating. The current method of detection is computed tomography. We report a case of carcinoma of the uncinate process of the pancreas in a patient who initially presented with deep vein thrombosis. The diagnosis of carcinoma of the uncinate process of the pancreas should be considered in patients who present with primary thromboembolic disease and other nonspecific signs.