Japanese individuals do not harbor the T594M mutation but do have the P592S mutation in the C-terminus of the beta-subunit of the epithelial sodium channel: the Ohasama study

OBJECTIVE: To assess the implications of polymorphisms of the amiloride-sensitive epithelial sodium channel in essential hypertension in the Japanese population by determining the incidence of the T594M mutation in the , subunit of the epithelial sodium channel, and by screening the C-terminus of the epithelial sodium channel. METHODS: Single-strand confirmational polymorphism (SSCP) analysis using two sets of primers which cover the last two-thirds of the last exon coding the B epithelial sodium channel and modification of a specific enzyme restriction site (NlaIII) for the T594M mutation were performed on 803 Japanese subjects. They were randomly selected from the study participants representative of a general population of Ohasama, Japan, who measured their home blood pressure. Polymerase chain reaction (PCR) products presenting a shift in SSCP gel, as well as controls, were directly sequenced by autoanalyser to identify the mutation. RESULTS: SSCP analysis identified altered migration in five subjects. Four SSCP variants found by sequencing were heterogeneous for the P592S (CCT to TCT) mutation conserving the PY motif, although it was not significantly associated with either home or casual blood pressure values. The resting polymorphism was at codon Thr 594, leading to no change in the amino acid sequence (ACG to ACA). None of the PCR products were modified by NlaIII, indicating the absence of the T594M mutation. CONCLUSIONS: The epithelial sodium channel variants at the C-terminus are not involved in the common form of essential hypertension in Japanese.     

Association between basal serum and leptin levels and changes in abdominal fat distribution during weight loss

The aim of this study was to evaluate the relationship between changes in abdominal fat areas and the baseline serum leptin levels of Japanese obese women during weight reduction. The study was performed on 100 obese female Japanese volunteers. We measured the BMI and abdominal fat areas (visceral, subcutaneous and total) by magnetic resonance imaging and determined the fasting serum leptin levels before and after a 3 month weight reduction program. We examined whether or not a relationship exists between the baseline leptin levels and the subsequent changes in the abdominal fat areas after a weight reduction program. Multiple linear regression analysis was performed to examine the relationship between the baseline leptin levels and changes in abdominal visceral, subcutaneous, and total fat areas, and demonstrated that the baseline leptin level was a significant predictive factor for changes in the abdominal visceral fat area in both pre and postmenopausal Japanese obese women. We thus concluded the relatively higher baseline leptin levels in Japanese obese women to be associated with a relatively smaller reduction in the amount of abdominal visceral fat after undergoing a weight reduction program.     

The effect of iodized oil on the TSH response to TRH in endemic goiter patients.

The TSH and T3 response to synthetic TRH was evaluated in 4 groups of patients: normal controls and goitrous subjects from the urban area of Sao Paulo (urinary iodine excretion: 172.2 +/- 48.3 mug I/g creatinine) and nongoitrous and goitrous subjects from the endemic areas of Sao Bento (urinary iodine excretion: 53.8 +/- 17.1 mug I/g). Plasma T4 and T3 were within our normal range in all groups of patients. The mean plasma TSH was significantly higher (5.2 +/- 3.3 muU/ml) in goitrous subjects living in Sao Bento as compared to normal control groups both in urban or endemic areas, and after TRH these patients had an exaggerated and sustained TSH response with a significantly higher peak level (21.1 +/- 7.9 muU/ml). T3 concentration rose in all subjects following TRH and all patients from the Sao Bento endemic areas had a significantly higher proportionate increase in plasma T3 at 120 min. After an injection of iodized oil basal plasma TSH returned to the normal range in the goitrous subjects from Sao Bento. The mean peak TSH response to TRH was 9.1 +/- 3.8 muU/ml at 3 months after the iodized oil injection, and only at 6 months after the iodized oil TSH response was significantly reduced (peak level: 6.1 +/- 2.4 muU/ml). It is confirmed that plasma TSH levels are increased in endemic goitrous patients but not in normal controls living in the same endemic area and it is suggested that the pituitary threshold for inhibition of secretion of TSH by T4 and T3 has been reset in these goitrous subjects to achieve a persistently higher secretion rate of TSH.     

CCL8 is a potential molecular candidate for the diagnosis of graft-versus-host disease

Although graft-versus-host disease (GVHD) is a life-threatening complication of hematopoietic stem-cell transplantation (HSCT), its current diagnosis depends mainly on clinical manifestations and invasive biopsies. Specific biomarkers for GVHD would facilitate early and accurate recognition of this grave condition. Using proteomics, we screened for plasma proteins specific for GVHD in a mouse model. One peak with 8972-Da molecular mass (m/z) retained a discriminatory value in 2 diagnostic groups (GVHD and normal controls) with increased expression in the disease and decreased expression during cyclosporin A treatment, and was barely detectable in syngeneic transplantation. Purification and mass analysis identified this molecule as CCL8, a member of a large chemokine family. In human samples, the serum concentration of CCL8 correlated closely with GVHD severity. All non-GVHD samples contained less than 48 pg/mL (mean +/- SE: 22.5 +/- 5.5 pg/mL, range: 12.6-48.0 pg/mL, n = 7). In sharp contrast, CCL8 was highly up-regulated in GVHD sera ranging from 52.0 to 333.6 pg/mL (mean +/- SE: 165.0 +/- 39.8 pg/mL, n = 7). Strikingly, 2 patients with severe fatal GVHD had extremely high levels of CCL8 (333.6 and 290.4 pg/mL. CCL8 is a promising specific serum marker for the early and accurate diagnosis of GVHD.     

Recombinant interferon-α-2a for treatment of chronic hepatitis C: results of a multicenter randomized controlled dose study

Abstract: To compare the efficacy of low and relatively high dosages of recombinant interferon (IFN)-α-2a in Japanese patients with chronic hepatitis C, as well as to characterize the type of patients who will respond well to a low-dosage treatment, 88 patients with histologically proven chronic hepatitis C were randomly assigned to two treatment groups; one treated with IFN-α-2a 6 MU daily for 2 weeks followed by 6 MU three times weekly for 22 weeks (6-MU group), and another given the same initial treatment followed by 3 MU three times weekly for 22 weeks (3-MU group). The rate of sustained normalization of ALT 6 months after the cessation of treatment was 33% in the 3-MU group and 40% in the 6-MU group (p=0.64). In addition, there was no difference in elimination of serum HCV-RNA 6 months after the cessation of treatment between the 3-MU group (26%) and 6-MU group (29%). Multivariate stepwise regression analysis revealed that serum HCV-RNA level (p=0.0035) and platelet count (p=0.0009) were independent variables useful in predicting a sustained response of ALT. The sustained response rate of ALT in patients with a serum HCV-RNA level less than 10⁵ copies/ml and serum platelet level above 15×10⁴/μl was 71%, whereas that in patients with a serum HCV-RNA level above 10⁵ copies/ml and serum platelet level less than 15×10⁴/μl was 12%. These results indicate that a high rate of sustained response to IFN therapy can be expected in chronic hepatitis C patients with a low serum level of HCV-RNA and a high level of platelets, even if treated with a low dose of IFN.     

A case of alveolar cell carcinoma accompanied by fluid and electrolyte depletion through production of voluminous amounts of lung liquids.

A patient is described who showed typical features of alveolar cell carcinoma, including production of a huge amount of clear frothy lung liquid (as much as 4 liter per day), diffuse dissemination of nodular lesions throughout the lung, and tall columnar cell proliferation outlining the alveolar walls uniformly without architectural destruction in the terminal lung unit. From the results of comparative serial analyses of biochemical components in the liquid and the serum, it is suggested that the excessive liquid production in this case should be due to abnormal secretory functioning of diffusely proliferated carcinoma cells.     

Effect of recombinant human erythropoietin on anticancer drug-induced anaemia

Anaemia was induced in rats with fluorouracil (5-FU) or cisplatin (CDDP) and the mechanisms of anaemia induction were analysed. Furthermore, the therapeutic effects of recombinant human erythropoietin (rHu Epo) on these anticancer drug-induced anaemias were investigated. In 5-FU-induced anaemia, marked serum erythropoietin (Epo) elevation was observed in inverse correlation to blood Hb concentration and Hb concentration rapidly recovered to normal levels. On the other hand, in CDDP-induced anaemia, serum Epo elevation was modest and the lowered Hb concentration persisted longer. Treatment with rHu Epo significantly improved both anticancer drug-induced anaemias but rHu Epo was more effective on CDDP-induced anaemia. These results suggest that rHu Epo might be useful for the therapy of anaemia associated with anticancer chemotherapy.