Pseudohypoaldosteronism (PHA) is characterized by congenital resistance of the kidney and/or other mineralocorticoid target tissues to aldosterone, resulting in excessive salt wasting. Although the mineralocorticoid receptor (MR) was suggested as a potential locus of the defect in this disease, no such abnormality was found in 3 recently reported cases, one of whom belongs to this series of 5 patients. Molecular studies of the MR complementary DNA and gene in this series of sporadic cases of pseudohypoaldosteronism are reported. Four of these patients had multiple mineralocorticoid target tissue resistance, whereas 1 had transient isolated resistance in the kidney. A nonconservative homozygous mutation (C944-->T944, Ala241-->Val241) was identified in the complementary DNA of 4 of the patients but was also found in 62 of 100 normal alleles. One of these 4 patients had an additional conservative heterozygous mutation (A760-->G760, Ileu180-->Val180), which was also present in 11 of 100 normal alleles. None of the patients had any abnormalities in the first untranslated exon and 0.9 kilobases of the 5'-regulatory region of the MR gene, which were fully sequenced and compared with the normal sequence. It is concluded that the mutations identified in 4 of these 5 patients with PHA are polymorphisms, which on their own have no apparent pathophysiological significance. It is hypothesized that the defect causing PHA might be in a post-MR step of aldosterone action or in an unsuspected nonclassic receptor for this hormone.
It is well known that hyperglycemia is associated with increased mortality from cardiovascular disease (CVD) and all-cause mortality. It has recently been reported that subjects with low fasting plasma glucose (FPG) levels also had a high risk of CVD and all-cause mortality (1). However, there is a paucity of information about the etiologic basis underlying the association between low FPG and increased CVD and all-cause mortality. Thus, in the present study, we investigated the association of FPG levels with white blood cell (WBC) counts, which indicate a state of low-grade systemic inflammation.We investigated the cross-sectional association of WBC counts with FPG levels among 3,256 Japanese men aged 34 -69 years. The subjects were divided into six categories according to FPG level: Ͻ80 mg/dl, 80 to Ͻ90 mg/dl, 90 to Ͻ100 mg/dl, 100 to Ͻ110 mg/dl, 110 to Ͻ126 mg/dl, and diabetes.The crude mean WBC counts were 6, 409, 6,308, 6,111, 6,111, 6,109, and 6,610 cells/mm 3 in the subjects with FPG levels of Ͻ80 mg/dl, 80 to Ͻ90 mg/dl, 90 to Ͻ100 mg/dl, 100 to Ͻ110 mg/dl, 110 to Ͻ126 mg/dl, and diabetes, respectively. The crude mean WBC counts differed significantly by FPG category and showed a U-shaped association with FPG levels (P value for quadratic trend Ͻ0.001). Even after adjusting for age, BMI, smoking, alcohol, health status, and other factors associated with elevated WBC count or glycometabolism, the respective adjusted-mean WBC counts were 6,273, 6,255, 6,175, 6,165, 6,075, and 6,429 cells/mm 3 . The WBC count maintained a U-shaped association with FPG level (P value for quadratic trend ϭ 0.041).Although it is well known that hyperglycemia is the cause of microvascular complications in several organs, there are few studies on the adverse effect of hypoglycemia. Early studies of hypoglycemia focused on brain damage and heart dysfunction. An acute decrease in FPG is recognized as the cause of them, whereas the long-term effect of low FPG remains unclear.Infection and inflammation may contribute to vascular injury and atherogenesis. Inflammation may also promote atherosclerotic plaque ruptures and thrombosis (2,3). WBC serves as an important biomarker for these disease processes.This study shows that the U-shaped association between WBC counts and FPG levels (especially low FPG levels) involves higher WBC counts that could not be linked to inflammatory disease or other factors or to any disease known to increase WBC counts. These findings suggest that a state of low-grade systemic inflammation may be present not only in diabetic subjects but also in people with low FPG, possibly explaining in part the high risk of CVD and all-cause mortality of such people. • (1) to clinical practice continues to be a major challenge (2,3). Physicians in training present a unique opportunity for shaping practice behavior. We tested the effect of an intramural contest on the outcome of diabetes management by 155 medical residents at a major U.S. teaching hospital. The contest was approved by the house staff leadership and w...
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