Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b.

CONTEXT: Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory α subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNAS region were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary. CASE DESCRIPTION: A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XLαs, and exon A/B-DMR but not STX16 or the Gsα coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XLαs-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions. CONCLUSIONS: Our results indicate that maternally derived copy-number gains in the GNAS region mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation.

Pleiotropic effects of sitagliptin versus voglibose in patients with type 2 diabetes inadequately controlled via diet and/or a single oral antihyperglycemic agent: a multicenter, randomized trial.

PURPOSE: A step-up strategy for diet therapy and/or single oral antihyperglycemic agent (OHA) regimens has not yet been established. The aim of this study was to evaluate hemoglobin A1c (HbA1c) as a primary end point, and the pleiotropic effects on metabolic and cardiovascular parameters as secondary end points, of sitagliptin versus voglibose in patients with type 2 diabetes with inadequate glycemic control while on diet therapy and/or treatment with a single OHA. METHODS: In this multicenter, randomized, open-label, parallel-group trial, a total of 260 patients with inadequately controlled type 2 diabetes (HbA1c levels >6.9%) were randomly assigned to receive either sitagliptin (50 mg, once daily) or voglibose (0.6 mg, thrice daily) for 12 weeks. The primary end point was HbA1c levels. RESULTS: Patients receiving sitagliptin showed a significantly greater decrease in HbA1c levels (-0.78±0.69%) compared with those receiving voglibose (-0.30±0.78%). Sitagliptin treatment also lowered serum alkaline phosphatase levels and increased serum creatinine, uric acid, cystatin-C and homeostasis model assessment-ß values. Voglibose increased low-density lipoprotein-cholesterol levels and altered serum levels of several fatty acids, and increased Δ-5 desaturase activity. Both drugs increased serum adiponectin. The incidence of adverse events (AEs) was significantly lower in the sitagliptin group, due to the decreased incidence of gastrointestinal AEs. CONCLUSIONS: Sitagliptin shows superior antihyperglycemic effects compared with voglibose as a first-line or second-line therapy. However, both agents possess unique pleiotropic effects that lead to reduced cardiovascular risk in Japanese people with type 2 diabetes. TRIAL REGISTRATION NUMBER: UMIN 000003503.

[A review of urinary examination--what medical practice expects now and what urinary examinations have to provide in the future].

Urinary examination can be performed frequently because of its non-invasive nature. To take advantage of this advantage, it is important to inform clinicians about the following: not only analytical results of chemical as well as morphological components but also easy-to-understand factors that are comprehensively analyzed, causing these components to emerge in urine. Here we review issues with the guidelines for hematuria diagnosis and management guidelines for chronic kidney disease. We report issues with the standard urinary erythrocyte count to define hematuria, the significance of urinary albumin test strips in the prevention of CKD or CVD development, and information on the morphologies of urinary erythrocytes.

[Pitfalls in measuring urinary proteins: age-related changes in urinary creatinine excretion that affect the urine protein/creatinine ratio].

Knowing the amount of protein excreted in the urine is important in determining the severity and activity of renal diseases. In general, screening tests have been carried out using the urine dipstick. However, there are limitations in determining the amount of urinary protein excretion using qualitative tests for protein in spot urine samples due to the concentration and dilution of urine. Therefore, when using spot urine samples, it is helpful to calculate the urine protein/creatinine ratio (P/C) by simultaneous measurement of urinary creatinine for determining daily protein excretion. We examined P/C measurements using the dipstick method in 22,718 subjects who visited our hospital for health examinations. The results showed positive rates for qualitative urinary protein (1 + and more) of 4.2% for males and 2.7% for females. Also positive rates for P/C (150 mg/g.cre and more) were found of 7.7% for males and 10.2% for females. The results showed a reversal of positive rates for males and females compared with the results of qualitative urinary protein. In addition, P/C showed a higher positive rate in 70 years old or older both for males and females. The distribution of urinary creatinine levels simultaneously measured by dipstick method showed that the percentage of diluted urine with urinary creatinine level less than 50 mg/dL was 6.8% for males and 18.3% for females overall. Females showed a higher rate and the percentage tended to increase with age both for males and females. From these results, it was suggested that changes in urinary creatinine excretion with age that affect the P/C ratio are large. We then measured the albumin excretion rate in the 24-hour urine as well as examined the correlation between the urinary creatinine concentration and albumin index with regard to age and sex in 1,280 diabetic patients. The results showed that daily urinary creatinine excretion overall in males, overall in females, in males over 80 years old and in females over 80 years old were 1.063 +/- 0.428 g/day (mean +/- S.D.), 0.714 +/- 0.270 g/day, 0.666 +/- 0.201 g/day, and 0.531 +/- 0.017 g/day, respectively, which showed large variations. From these results, creatinine correction, in which uniformity of daily urinary creatinine excretion is the principle, is useful for assessment of short-term fluctuations in the individuals. However, it is indicated that there is a problem when used for screening, from young people to the elderly.

Pancreatic exocrine and endocrine events occur concomitantly but independently during the course of fulminant type 1 diabetes.

Although pancreatic exocrine enzymes are often elevated in patients with fulminant type 1 diabetes, the onset of this elevation and its significance in disease development remain unclear. We therefore investigated the significance of elevated serum enzyme concentrations and pancreatic swelling in the development of fulminant type 1 diabetes. Serum pancreatic exocrine enzymes, including amylase, elastase-I, lipase and trypsin, were measured during the course of the disease in 11 patients with fulminant type 1 diabetes (3 men and 8 women; a range of age 24-73 years, median 33 years; a range of HbA1c at onset 4.5-6.7%, median 6.0%), all of whom developed ketotic diabetes requiring intensive insulin therapy within a month. At least one pancreatic exocrine enzyme was elevated in each patient during the course of the disease. The concentration of enzymes on admission could not be correlated with urinary excretion of C-peptide. The time course of increase in serum amylase varied in these patients. In conclusion, neither the level of serum amylase nor the swelling of pancreas was associated with the onset or severity of fulminant type 1 diabetes. The pancreatic exocrine and endocrine events may occur concomitantly but independently during the course of fulminant type 1 diabetes.

Subacute thyroiditis developed in identical twins two years apart.

A 34-year-old woman was referred to our hospital complaining of sore throat and arthralgia. She had low-grade fever, tachycardia, and goiter with tenderness. Laboratory data revealed thyrotoxicosis and tests for acute inflammatory markers were positive. Thyroidal radioactive iodine uptake was below normal. Ultrasonography of thyroid revealed mild thyroid enlargement and hypoechogenic areas consistent with tenderness. Subacute thyroiditis was diagnosed and prednisone was administered. Two years later, her identical twin sister, who lives separately, was referred to our hospital because of neck pain, low-grade fever, and palpitation. She exhibited the same clinical picture as her twin sister, and was also diagnosed as having subacute thyroiditis. Although the cause of subacute thyroiditis remains unclear, viral infection has been implicated in the onset of subacute thyroiditis in genetically predisposed individuals. We could not identify the viruses, but heterozygotes for HLA-B35, which has been reported to be linked with subacute thyroiditis, were found in the twins. This supports the suspicion that genetic factors, including this HLA haplotype, play a critical role in the onset of subacute thyroiditis.