Role of glycerophosphodiester phosphodiesterase in rice leaf blades in elevated CO2 environments.

Glycerophosphodiester phosphodiesterase (GDPD; EC 3.1.4.46) is involved in plant phosphate (Pi) utilization and its expression is upregulated under phosphorus (P)-deficient conditions. Although rice was grown under P-sufficient conditions, the transcript levels of specific OsGDPD were upregulated in mature rice leaf blades (LB) in elevated CO2 (eCO2 ) environments. Expression and subcellular localization of GDPD, and contents of Pi, sugar phosphates and carbohydrates were analysed to clarify the physiological function of GDPD in rice under eCO2 . Under eCO2 , expression of specific OsGDPD increased only in mature rice LB in which low Pi concentrations were observed. Moreover, eCO2 -induced OsGDPD2 and OsGDPD3 were localized in the plastid, indicating that GDPD2 and GDPD3 may be related to plastidic functions, such as carbon assimilation. Although rice LB contained more carbohydrates under eCO2 than under ambient CO2 , the phosphoglucose content decreased under eCO2 , suggesting that the need for excess phosphoglucose to synthesize carbohydrates under eCO2 causes a local Pi deficiency. Furthermore, we confirmed that glycerol-3-phosphate produced by the catalysis of GDPD from glycerophosphodiester contributes to carbohydrate accumulation in rice LB. Our findings suggest that local Pi deficiency due to excess carbohydrate accumulation under eCO2 influences GDPD to enhance glycerophosphodiester hydrolysis.

Impact of an ultrasound-guided radiofrequency ablation training program on the outcomes in patients with hepatocellular carcinoma.

PURPOSE: The aim of this study was to retrospectively evaluate the impact of a training program on the safety and efficacy of percutaneous ultrasound-guided radiofrequency ablation (RFA) for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 227 patients with 296 HCC nodules who underwent percutaneous RFA with or without transcatheter arterial chemoembolization at our institution were included. There were 163 men and 64 women with a mean age of 74.2±8.3 (SD) years (range: 41-89 years). Percutaneous ultrasound-guided RFA was performed by three trainees (205 HCC nodules in 157 patients) or a mentor (91 HCC nodules in 70 patients) after preprocedural preparation including planning ultrasonography. We compared background-related, tumor-related, and treatment-related factors, and local recurrence and complication rates between the trainee group and the mentor group. Similarly, we compared these variables among the years 2015, 2016, and 2017 for trainee group. RESULTS: The proportion of easy-to-treat tumors in the trainee group (109/205; 53.2%) was greater than that in the mentor group (33/91; 36.3%) (P=0.020). No significant differences were observed in procedure difficulty among the years 2015, 2016, and 2017 for trainee group (easy-to-treat HCC nodules: 25/47; 53.2% vs. 39/79; 49.4% vs. 45/79; 57.0%. P=0.775). The local recurrence rate in the trainee group was 8.8% (18/205 HCC nodules) which was equivalent to 7.7% in the mentor group (7/91 HCC nodules). No significant differences were observed in local recurrence rate (8.8% vs. 7.7%, respectively; P=0.621) and major complication rate (1.3% vs. 1.4%, respectively; P=0.999) between the trainee group and the mentor group. No significant differences were observed in local recurrence rates ([5/47; 10.6%] vs. [11/79; 13.9%] vs. [2/79; 2.5%]) (P=0.109) and major complication rates ([1/36; 2.8%] vs. [1/62; 1.6%] vs. [0/59; 0%]) (P=0.701) between the years 2015, 2016, and 2017 for trainee group. CONCLUSION: A well supervised training program that includes planning ultrasonography fosters the efficacy and treatment quality of RFA for HCC.

Variation of major neutral oligosaccharides levels in human colostrum.

OBJECTIVES: Human colostrum is known to be important for the protection of infants against infection by pathogenic microorganisms. This protection is thought to be due, partially, to various neutral and acidic oligosaccharides that are present in colostrum and milk. However, the concentrations of each of the oligosaccharide of human colostrum have not yet been determined. The aim of this present study was to determine the concentration of each of the major neutral oligosaccharide for three consecutive days from the start of lactation. METHOD: We analyzed the level of each neutral oligosaccharide in human colostrum, for three consecutive days from the start of lactation, obtained from 12 healthy Japanese women (ranging in age from 21 to 35 years; primipara 6 and multipara 6). The ABO blood groups of the donors were determined: A, three; B, three; O, five; AB, one. The determined human milk oligosaccharides were 2'-fucosyllactose (2'-FL), 3-fucosyllactose (3-FL), lactodifucotetraose (LDFT), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), three lacto-N-fucopentaose (LNFP I, II and III) and two lacto-N-difucohexaose (LNFDH I and II) using high-performance liquid chromatography (HPLC) with two derivatization techniques. RESULTS: The concentrations of 2'-FL and LDFT in colostrum on day 1 were significantly higher than those on days 2 and 3 (P<0.05). An increase in LNT was observed on day 3 compared with day 1 (P<0.05). CONCLUSION: These changes in concentrations of 2'-FL, LDFT and LNT may reflect the requirements for prebiotics and anti-infection agents by human infants during early lactation.

Killer cell immunoglobulin-like receptor genotypes in Japanese patients with type 1 diabetes.

We investigated killer cell immunoglobulin-like receptor (KIR) genotypes in 92 patients with young-onset type 1 diabetes mellitus (YT1DM: < or =35 years old), 112 patients with adult-onset type 1 diabetes mellitus (AT1DM: >35 years old) and 240 control subjects. There were no differences in the frequency of KIR genotypes between controls and all the patients with T1DM or patients grouped according to age at onset of the disorder. However, when the subjects were classified into three groups according to combinations of the presence or absence of KIR3DS1/KIR3DL1 and its ligand human leukocyte antigen (HLA)-Bw4, or KIR2DL1 and its ligand HLA-C group 2, the genotype distribution was significantly different between the patients with AT1DM and controls [chi(2)= 5.993, 2 degrees of freedom (d.f.), P= 0.0500]. These data suggest that KIR polymorphisms may be associated with the age at onset of T1DM.

Metabolic syndrome is not associated with markers of subclinical atherosclerosis, serum adiponectin and endogenous androgen concentrations in Japanese men with Type 2 diabetes.

AIMS: Metabolic syndrome is characterized by its association with certain cardiovascular disease risk factors. The aim of this study was to investigate the relationships between metabolic syndrome and markers of subclinical atherosclerosis, serum adiponectin and endogenous androgen concentrations in Japanese men with Type 2 diabetes. METHODS: Using the 2005 International Diabetes Federation (IDF) definition, we assessed the prevalence of the metabolic syndrome in 424 consecutive men with Type 2 diabetes aged 40-75 years in a cross-sectional study. We compared characteristics including ultrasonographic carotid atherosclerosis markers, pulse-wave velocity (PWV), and serum adiponectin, free testosterone, and dehydroepiandrosterone sulphate (DHEA-S) concentrations in diabetic patients with and without the metabolic syndrome. RESULTS: The prevalence of the metabolic syndrome in Japanese men with Type 2 diabetes was 46.9%. Men with the metabolic syndrome had higher urinary albumin excretion rate than those without. Carotid intima-media thickness (0.97 +/- 0.26 vs. 0.91 +/- 0.18 mm), plaque score [3.3 (1.5-8.1) vs. 3.8 (1.3-6.2)], PWV (1818 +/- 331 vs. 1749 +/- 331 cm/s) and ankle-brachial index (1.10 +/- 0.14 vs. 1.08 +/- 0.16) did not differ significantly between patients with and without the metabolic syndrome. Similarly, serum adiponectin [3.70 (2.06-6.09) vs. 4.65 (3.09-7.02) microg/ml], free testosterone (36.4 +/- 10.7 vs. 34.7 +/- 11.1 pmol/l), and DHEA-S concentrations (3.29 +/- 1.83 vs. 3.17 +/- 1.63 micromol/l) did not differ significantly between groups, CONCLUSIONS: The metabolic syndrome, as defined by the IDF, is not significantly associated with subclinical atherosclerosis markers, serum adiponectin, or endogenous androgen concentrations in Japanese men with Type 2 diabetes.

Increased serum resistin levels in patients with type 2 diabetes are not linked with markers of insulin resistance and adiposity.

The role of resistin in human biology remains uncertain. We measured serum resistin levels in Japanese patients with (n=111) and without (n=98) type 2 diabetes mellitus and investigated the significance of this hormone in the pathophysiology of diabetes. The levels of serum adiponectin and leptin were also measured. Resistin levels were increased significantly in patients with type 2 diabetes compared with non-diabetic subjects (24.7+/-2.6 vs. 15.0+/-1.2 ng/ml, p=0.0013). However, there was no correlation in either patient group between serum resistin levels and markers of insulin resistance, obesity or hyperlipidaemia. These results were in direct contrast to the data of leptin or adiponectin, both of which were closely related to these clinical markers of diabetes. Multivariate regression analysis on the combined data of the two groups demonstrated that the presence of diabetes and HDL cholesterol levels were significant predictors of serum resistin levels (diabetes: beta=0.159, p=0.035; HDL: beta=-0.172, p=0.039). No correlation was observed between C-reactive protein and resistin adjusted for BMI. Taken together, these findings demonstrate that serum resistin levels are increased in patients with type 2 diabetes, but this increase is not linked to markers of insulin resistance or adiposity. Further studies are necessary to elucidate the significance of serum resistin concentration in human pathophysiology.

Preparation of a liquid nitrogen target for measurement of gamma-rays in the 14N(n, gamma)15N reaction as an intensity standard in energy regions up to 11 MeV.

We have developed a liquid nitrogen (N(2)) target that allows us to clearly measure gamma-rays below 2 MeV and to improve neutron beam availability. The intensity of the prompt 2223 keV gamma-ray from the (1)H(n, gamma) reaction in the present target could be reduced to about 160 in comparison with the one in the commercially available melamine (C(3)H(6)N(6)) target. The statistics of the full-energy-peak counts were improved by factors of 15-30 and about 4 in the energy regions below and above 2 MeV, respectively.

The association between end-stage diabetic nephropathy and methylenetetrahydrofolate reductase genotype with macroangiopathy in type 2 diabetes mellitus.

The T/T genotype of the methylenetetrahydrofolate reductase C677 T gene polymorphism is associated with elevated homocysteine levels and presumably with increased atherosclerotic risk. We evaluated the interaction between this gene polymorphism and end-stage diabetic nephropathy on the observed prevalence of macroangiopathy in type 2 diabetes mellitus. The methylenetetrahydrofolate reductase 677 C/T genotypes were determined in 174 type 2 diabetic patients: 80 with and 94 without renal failure due to diabetic nephropathy. In the patients with renal failure, the T/T genotype and T allele were significantly associated with macroangiopathy (T/T; 31 % vs. 2 %, P = 0.0001 T allele; 59 % vs. 29 %, P = 0.00014), whereas the associations were not significant in the patients without renal failure. In the multiple logistic regression analysis, age (10 years OR 4.05 [1.79 - 9.31], P < 0.0005) and 677 T allele (6.84 [2.12 - 22.05], P = 0.0013) were significantly associated with macroangiopathy in the patients with renal failure. In conclusion, this study demonstrated that the 677 T/T genotype and T allele of MTHFR were significantly associated with macroangiopathy in type 2 diabetic patients with renal failure. The MTHFR 677 T allele, together with renal dysfunction due to diabetic nephropathy, could be a strong risk factor for atherosclerotic disease.

Successful perioperative blood purification therapy in patients with maintenance hemodialysis therapy who underwent living donor liver transplantation.

Living donor liver transplantation (LDLT) is a treatment for end-stage liver failure, and was developed to overcome the distinct insufficiency of cadaveric donors. Case 1 is a 56-year-old man who had undergone maintenance hemodialysis therapy for 4 years. An LDLT was performed for the treatment of advanced liver cirrhosis and hepatocellular carcinoma. Continuous hemodiafiltration (CHDF) was performed from the 2nd to 5th days after the operation. Case 2 is a 55-year-old man with primary amyloidosis and chronic renal failure. An LDLT was performed for the treatment of severe abdominal distention caused by a large liver volume. Although CHDF was started at the 3rd day after the operation, it was discontinued within 24 hours because of an increased urinary volume. CHDF was required again from the 6th-8th days, after which the blood purification mode was switched to regular intermittent hemodialysis. Meanwhile, no major problems occurred in either case. In conclusion, CHDF was required for about 5 days from the 2nd day after the operation. The application of careful and aggressive blood purification therapy during the perioperative period is a key to successful LDLT in dialysis patients.

Intercellular adhesion molecule-1 (ICAM-1) polymorphism is associated with diabetic retinopathy in Type 2 diabetes mellitus.

AIMS: Leucocyte adhesion to the diabetic retinal vasculature has been implicated in the pathogenesis of diabetic retinopathy. We evaluated the relationship between genetic polymorphisms in leucocyte and endothelial cell adhesion molecules and diabetic retinopathy in Type 2 diabetes mellitus. METHODS: We determined ICAM-1, platelet endothelial cell adhesion molecule-1 (PECAM-1), and leucocyte endothelial adhesion molecule-1 (LECAM-1) genotypes in 81 patients with and 50 without diabetic retinopathy. RESULTS: The frequency of ICAM-1 469KK genotype and K allele were significantly higher in the patients with diabetic retinopathy than in those without retinopathy (genotype 42% vs. 20%, chi2 = 6.70, P = 0.035; allele 66% vs. 50%, chi2 = 6.49, P = 0.011). With regard to the PECAM-1 V125L and LECAM-1 P213S polymorphisms, there were no significant associations between the distribution of genotypes or allele frequencies and the presence of diabetic retinopathy. Independent of other risk factors, the ICAM-1 469KK genotype was associated with a 3.51-fold increased risk for retinopathy. CONCLUSIONS: These data suggest that the ICAM-1 469KK genotype could be a genetic risk factor for retinopathy in Type 2 diabetes mellitus.

Interleukin-6 polymorphism (-634C/G) in the promotor region and the progression of diabetic nephropathy in type 2 diabetes.

AIMS: Interleukin-6 (IL-6) is a multifunctional cytokine produced by many different cell types, including glomerular mesangial cells. Recently, a novel C/G polymorphism at position -634 in the promotor region of the IL-6 gene has been reported. The aim of this study was to investigate whether the -634C/G polymorphism is associated with an increased risk for progression to diabetic nephropathy as well as elevated levels of IL-6 secretion by peripheral blood mononuclear cells. METHODS: The frequency of the -634C/G polymorphism was determined in Japanese patients with Type 2 diabetes and either normoalbuminuria (n = 162), microalbuminuria (n = 138), or macroalbuminuria (n = 154) by polymerase chain reaction-restriction fragment length polymorphism analysis. The level of IL-6 secretion in relation to genotype was assessed in lipopolysaccharide or advanced glycation end products-stimulated IL-6 secretion by peripheral mononuclear cells. RESULTS: The frequency of the -634G/G genotype and -634*G allele was significantly increased in the patients with macroalbuminuria compared with patients with normoalbuminuria (genotype: chi2 = 6.787, Pc = 0.0368; allele: chi2 = 9.080, Pc = 0.0104). Stepwise multiple regression analysis in these patients showed that hypertension (F = 40.48) and IL-6-634 gene polymorphism (F = 5.48) were the relevant variables for the progression of Type 2 diabetic nephropathy. Analysis of the IL-6 secretion data revealed that individuals carrying the -634*G allele had a higher IL-6 secretion capacity than those without the *G allele (P < 0.05). CONCLUSIONS: These results suggest that the IL-6-634C/G polymorphism may be a possible genetic susceptibility factor for the progression of diabetic nephropathy.

Paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level as possible risk factors for exudative age-related macular degeneration.

PURPOSE: Paraoxonase (E.C.3.1.1.2) is a polymorphic protein shown to prevent low-density lipoprotein oxidation. Our purpose is to evaluate the hypothesis that paraoxonase gene polymorphisms and plasma oxidized low-density lipoprotein level play a role in the occurrence of exudative age-related macular degeneration. METHODS: We analyzed paraoxonase genotypes (A/B, Gln-Arg192 and L/M, Leu-Met54) and plasma oxidized low-density lipoprotein levels in 72 unrelated Japanese patients with exudative age-related macular degeneration and compared the results with those of 140 age-matched and sex-matched control subjects. RESULTS: The distribution of paraoxonase 192 and paraoxonase 54 polymorphisms was significantly different between the patients with age-related macular degeneration and control subjects (chi-square = 6.226, P =.0445, and chi-square = 6.863, P =.0323, respectively). The high frequency of the BB genotype at position 192 was observed in the exudative age-related macular degeneration group compared with control subjects (52.8% vs 35.0%, respectively; P =.0127). The high frequency of the LL genotype at position 54 was observed in the patients more than the controls (91.7% vs 77.1%, respectively; P =.0090). The mean (+/- SE) oxidized low-density lipoprotein levels in the patients was significantly higher than in the controls (19.1 +/- 1.0 vs 16.2 +/- 0.6 U/ml, P <.01). CONCLUSION: These results indicate that the paraoxonase gene polymorphisms may represent a possible genetic risk factor for age-related macular degeneration and that increased plasma oxidized low-density lipoprotein may be involved in the pathogenesis of age-related macular degeneration.

First confirmed canine case of Ehrlichia canis infection in Japan.

An 11-year-old castrated Pekinese dog that had been moved from Indonesia to Japan eight years previously was diagnosed with an Ehrlichia canis infection by haematological characteristics (normocytic anaemia, mild thrombocytopenia and hypergammaglobulinaemia) and serological findings (antibody titre to E canis 1:3,200 or more). The dog did not respond to treatment with tetracycline and died from renal failure. The diagnosis was confirmed postmortem by pathological evaluation and polymerase chain reaction (PCR) followed by sequencing of the 16S rRNA gene. Typical morulae of Ehrlichia were detected in the cytoplasm of macrophages in spleen tissue by immunohistological staining. Ehrlichia-like organisms were also detected in the spleen by electron microscopy. E canis-specific PCR analysis of DNA extracted from the spleen gave a positive signal, and sequence analysis of the fragment revealed that it was identical to part of the 16s rRNA gene of E canis. The dog was the first confirmed clinical case of E canis infection in Japan.

Protective effects of fluvastatin against reactive oxygen species induced DNA damage and mutagenesis.

Oxidative stress may be an important factor in the development of diabetic complications. Advanced glycation end-products have drown attention as potential sources of oxidative stress in diabetes. We investigated the protective effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on oxidative DNA damage from reactive oxygen species or advanced glycation end-products in vitro, as well as effects of main fluvastatin metabolites and other inhibitors of the same enzyme, pravastatin and simvastatin. Protective effects were assessed in terms of the DNA breakage rate in a single-stranded phage DNA system in vitro. DNA was exposed to either reactive oxygen species or advanced glycation end-products. Fluvastatin and its metabolites showed a strong protective effect comparable to those seen with thiourea and mannitol, though pravastatin and simvastatin did not exert clear protective effects. Furthermore, fluvastatin reduced the mutagenesis by reactive oxygen species or advanced glycation end-products in Salmonella typhimurium test strains. Both pravastatin and simvastatin still lacked protective activity. Fluvastatin and its metabolites protect against oxidative DNA damage and may reduce risk of consequent diabetic complications.

Oestrogen receptor-alpha gene polymorphism is associated with endometriosis, adenomyosis and leiomyomata.

Endometriosis, adenomyosis and leiomyomata develop in women of reproductive age and regress after menopause or ovariectomy, suggesting that they grow in an oestrogen-dependent fashion. We investigated whether polymorphism in the oestrogen receptor-alpha (ERalpha) gene is related to oestrogen-dependent benign uterine disease. A total of 203 women with regular menstrual cycles underwent laparotomy or laparoscopy and were diagnosed histologically with endometriosis, adenomyosis and/or leiomyomata. Patients with cervical carcinoma in situ, tubal occlusion or adhesion but no other gynaecological disease were considered to be disease-free. A total of 179 women undergoing annual health examination were grouped as reference population. The distribution of PVUII genotypes (PP, Pp, and pp) of the ERalpha gene was different between each pair of the four groups of endometriosis, adenomyosis/leiomyomata, disease-free, and reference population (P = 0.022-0.0005), except between the former two groups. The PP genotype was less frequent in the groups of endometriosis (P = 0.0002) and adenomyosis/leiomyomata (P = 0.002) as compared to that in the disease-free group. In the endometriosis group, there was no difference in the distribution of PVUII genotypes due to complicating diseases (adenomyosis and/or leiomyomata) or severity of the clinical stages. These results suggest that the PVUII polymorphism of the ERalpha gene is associated with the risk for endometriosis, adenomyosis, and leiomyomata.

Clinical evaluation of a radioimmunoprecipitation assay for IA-2 antibody and comparison of GAD antibody in type 1 diabetes mellitus.

We evaluated a insulinoma-associated protein (IA-2) antibody assay kit using 125I-labelled recombinant IA-2. IA-2 antibodies were present in patients with early-onset type 1 diabetes mellitus (DM) at frequencies of 74%, 67%, 57%, and 50% for respective periods <1 year, 1 < or =years<2, 2< or =years<3, and 3< or =years<4 after onset. IA-2 antibody frequency was low throughout the DM course as compared with glutamic acid decarboxylase (GAD) antibody frequency. No one had IA-2 antibody, but 29% still had positive GAD antibody titers after 11 years. Of the patients with 0

Prediction of diabetes in Biobreeding/Aburahi rats by the measurement of soluble L-selectin.

L-selectin was initially identified as a homing receptor, recently soluble L-selectin has been used as a marker of the inflammation. Therefore, we investigated the relation between the development of diabetes and serum L-selectin levels in the Biobreeding (BB) rats. Serum L-selectin were measured from 30 days old to the onset of diabetes or to 90 days old in Biobreeding (BB) rats and Wistar Furth (WF) rats. Significant elevation of L-selectin was found in diabetes prone (DP) rats from 45 days old to the onset of diabetes or through 90 days old. No elevation was found in other strain of rats. In histological study, all of DP rats had insulitis and no other strain of rats had it. Therefore, we conclude that the measurement of serum L-selectin could be useful tool to predict the onset of diabetes or presence of insulitis in BB rats.

Tumor necrosis factor microsatellite polymorphism influences the development of insulin dependency in adult-onset diabetes patients with the DRB1*1502-DQB1*0601 allele and anti-glutamic acid decarboxylase antibodies.

Recently, several studies have demonstrated that tumor necrosis factor microsatellite polymorphism (TNFalpha) contributes to the susceptibility of type 1 diabetes. This study investigates the influence of TNFalpha on the predisposition to insulin dependency in adult-onset diabetic patients with type 1 diabetes-protective human leukocyte antigen haplotypes. The TNFalpha of three groups of DRB1*1502DQB1*0601-positive diabetic patients who had initially been nonketotic and noninsulin dependent for more than 1 yr was analyzed. Group A included 11 antibodies to glutamic acid decarboxylase (GADab)-positive patients who developed insulin dependency within 4 yr of diabetes onset. Group B included 11 GADab-positive patients who remained noninsulin dependent for more than 12 yr. Group C included 12 GADab-negative type 2 diabetes, and a control group included 18 nondiabetic subjects. In the group C and control subjects, DRB1*1502-DQB1*0601 was strongly associated with the TNFalpha13 allele. DRB1*1502-DQB1*0601 was strongly associated with the TNFalpha12 allele among the group A patients, but not among the group B patients. Interestingly, sera from all patients with non-TNFalpha12 and non-TNFalpha13 in group B reacted with GAD65 protein by Western blot. These results suggest that TNFalpha is associated with a predisposition to progression to insulin dependency in GADab/DRB1*1502DQB1*0601-positive diabetic patients initially diagnosed with type 2 diabetes and that determination of these patients' TNFalpha genotype may allow for better prediction of their clinical course.

Thoracic aortic dissection in a patient with autosomal dominant polycystic kidney disease treated with maintenance hemodialysis.

A patient with autosomal dominant polycystic kidney disease (ADPKD) on maintenance hemodialysis (HD) experienced spreading back pain with a sudden onset, and was diagnosed with thoracic aortic dissection. Reports of ADPKD with aortic dissection are rare. Hypertension, which is essentially universal both among ADPKD and hemodialysis patients, is a known risk factor for aortic dissection. Additionally, some reports have indicated that patients with ADPKD have aortic fragility. We suspect that aortic dissection may be less rare than presently apparent among HD patients with ADPKD.

Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology.

Systemic mastocytosis is a disease of mast cell proliferation that may be associated with hematologic disorders. There are no features on examination that allow the diagnosis of systemic disease, and mast cell-derived mediators, which may be elevated in urine or blood, may also be elevated in individuals with severe allergic disorders. Thus, the diagnosis usually depends on results of bone marrow biopsy. To facilitate evaluation, surrogate markers of the extent and severity of the disease are needed. Because of the association of mastocytosis with hematologic disease, plasma levels were measured for soluble KIT (sKIT) and soluble interleukin-2 receptor alpha chain (sCD25), which are known to be cleaved in part from the mast cell surface and are elevated in some hematologic malignancies. Results revealed that levels of both soluble receptors are increased in systemic mastocytosis. Median plasma sKIT concentrations as expressed by AU/mL (1 AU = 1.4 ng/mL) were as follows: controls, 176 (n = 60); urticaria pigmentosa without systemic involvement, 194 (n = 8); systemic indolent mastocytosis, 511 (n = 30); systemic mastocytosis with an associated hematologic disorder, 1320 (n = 7); aggressive mastocytosis, 3390 (n = 3). Plasma sCD25 levels were elevated in systemic mastocytosis; the highest levels were associated with extensive bone marrow involvement. Levels of sKIT correlated with total tryptase levels, sCD25 levels, and bone marrow pathology. These results demonstrate that sKIT and sCD25 are useful surrogate markers of disease severity in patients with mastocytosis and should aid in diagnosis, in the selection of those needing a bone marrow biopsy, and in the documentation of disease progression. (Blood. 2000;96:1267-1273)