Replication study for the association of new meta-analysis-derived risk loci with susceptibility to type 2 diabetes in 6,244 Japanese individuals.

AIMS/HYPOTHESIS: Additional susceptibility loci for type 2 diabetes have been identified by a meta-analysis of genome-wide association studies (GWASs) in European populations. To examine further the roles of these new loci, we performed a replication study for the association of these single-nucleotide polymorphism (SNP) loci with the disease in three independent Japanese populations. METHODS: We genotyped seven of the 11 SNPs that emerged in stage 2 of the meta-analysis for European GWASs (rs864745 in JAZF1, rs12779790 near CDC123/CAMK1D, rs7961581 near TSPAN8/LGR5, rs4607103 near ADAMTS9, rs10923931 in NOTCH2, rs1153188 near DCD and rs9472138 near VEGFA) for three independent Japanese populations (first set, 1,630 type 2 diabetes patients vs 1,064 controls; second set, 1,272 type 2 diabetes patients vs 856 controls; third set, 486 type 2 diabetes patients vs 936 controls) using a TaqMan assay. The association of the SNP loci in each population was analysed using a logistic regression analysis, adjusting for age, sex and BMI, and the data were evaluated by a meta-analysis. RESULTS: A meta-analysis for the three case-control studies identified a nominal association of rs864745 in JAZF1 with type 2 diabetes (OR 1.148, 95% CI 1.034-1.275, p = 0.0098, corrected p = 0.069). The association of other loci did not reach statistically significant levels (nominal p > 0.05). CONCLUSIONS/INTERPRETATION: From these results the contribution of these seven loci in conferring susceptibility to type 2 diabetes is considered minor in the Japanese population, if they are present.

Activated extracellular signal-regulated kinase correlates with cyst formation and transforming growth factor-beta expression in fetal obstructive uropathy.

Human renal dysplasia is frequently associated with urinary tract obstruction and the abnormal expression of mitogen-activated protein kinase (MAPK). Here, we determined the renal responses and MAPK expression in developing kidneys that were obstructed in fetal lambs. Kidneys were harvested at various times after obstruction (gestation day 60) through normal term (day 145). Dilation of Bowman's capsule and proximal tubules was seen 2 days after obstruction and involved the whole cortex 18 days later, with numerous cysts present throughout the kidney at term. The proliferation marker Ki-67 and transforming growth factor-beta (TGF-beta) were detected 2 days after obstruction and progressively increased in tubules, cysts, and the interstitium. In control kidneys, p38 was expressed in tubules only during the fetal stage, whereas phosphorylated extracellular signal-regulated kinase (P-ERK) was limited to ureteric buds and collecting ducts at all stages examined. However, Jun-N-terminal kinase (JNK) was absent in the fetal kidney but present in tubules at term. In obstructed kidneys, cyst epithelia were positive for p38 and P-ERK but negative for JNK throughout all stages. These studies show that P-ERK correlated spatially and temporally with Ki-67 and TGF-beta expression, which suggests that ERK may contribute to cyst formation and fibrosis in the obstructed fetal kidney.

Occupational allergic contact dermatitis from mioga (Zingiber mioga rosc.) in greenhouse cultivators.

UNLABELLED: Mioga (Zingiber mioga Rosc.) is a member of the ginger family (Zingiberaceae), which is native to tropical Asia. In Japan, the young flower buds are used as a spice, and hand dermatitis suspected as being an allergy to mioga has been recognized in mioga greenhouse cultivators. To investigate the extent of the problems and the causes of dermatitis, 20 householders cultivating mioga in their greenhouses were asked to participate in a questionnaire study. Consecutive patch tests were performed on some subjects with dermatitis. Self-reported questionnaires were distributed to the main cultivator in each household who attended a lecture of mioga cultivation methods held at an agriculture cooperative association in the area. Some subjects who answered as presenting or having had hand dermatitis were patch tested for mioga (as is), four kinds of mioga extracts, and three kinds of natural rubber gloves. RESULTS: 35 cultivators from 16 households answered the questionnaire. Eight of the 35 subjects (22.9 percent) answered that they had experienced hand dermatitis since they started mioga cultivation. Four of the 8 subjects were patch tested. Two of the 4 subjects showed allergic reactions to mioga (as is) and the extracts. The other two cases showed irritation to mioga (as is). The first two cases also showed allergic reactions to natural rubber gloves. To our knowledge, there is no previous report of allergic contact dermatitis from mioga.

Structural Characterization of Modified Lignin in Transgenic Tobacco Plants in Which the Activity of 4-Coumarate:Coenzyme A Ligase Is Depressed.

Transgenic tobacco (Nicotiana tabacum L.) plants in which the activity of 4-coumarate:coenzyme A ligase is very low contain a novel lignin in their xylem. Details of changes in hydroxycinnamic acids bound to cell walls and in the structure of the novel lignin were identified by base hydrolysis, alkaline nitrobenzene oxidation, pyrolysis-gas chromatography, and 13C-nuclear magnetic resonance analysis. In the brownish tissue of the transgenic plants, the levels of three hydroxycinnamic acids, p-coumaric, ferulic, and sinapic, which were bound to cell walls, were apparently increased as a result of down-regulation of the expression of the gene for 4-coumarate:coenzyme A ligase. Some of these hydroxycinnamic acids were linked to cell walls via ester and ether linkages. The accumulation of hydroxycinnamic acids also induced an increase in the level of condensed units in the novel lignin of the brownish tissue. Our data indicate that the behavior of some of the incorporated hydroxycinnamic acids resembles lignin monomers in the brownish tissue, and their accumulation results in dramatic changes in the biosynthesis of lignin in transgenic plants.

Leukocyte-specific expression of the pp52 (LSP1) promoter is controlled by the cis-acting pp52 silencer and anti-silencer elements.

pp52 (LSP1) is a leukocyte-specific phosphoprotein that binds the cytoskeleton and has been implicated in affecting cytoskeletal remodeling in a variety of leukocyte functions, including cell motility and chemotaxis. The expression of pp52 is restricted to leukocytes by a 549 bp tissue-specific promoter. Here, we show that promoter fragments smaller than the 549 bp pp52 promoter have activity in fibroblasts where pp52 is not normally expressed. Specifically, a truncated construct (+1 to -99) functioned as a basal promoter active in leukocytes and fibroblasts. We identified two upstream regions within the 549 bp pp52 promoter responsible for restricting pp52 promoter activity in fibroblasts. These two regions contained a silencer (pp52 NRE) and an anti-silencer (pp52 anti-NRE) with opposing activities controlling pp52 gene expression. The pp52 NRE was active in both leukocytes and fibroblasts while the pp52 anti-NRE was only active in leukocytes, thereby allowing pp52 gene transcription in leukocytes but not in fibroblasts. The pp52 NRE was localized to an 89 bp DNA segment between -324 and -235 in the 549 bp pp52 promoter and functioned as an active silencer element in a position and orientation independent manner. The pp52 anti-NRE was localized to a 33 bp segment between -383 and -350 of the 549 bp pp52 promoter and acted as an anti-silencer element against the pp52 NRE, but lacked any intrinsic enhancing activity on its own. These findings indicate that the tissue specificity of the pp52 promoter is determined by the pp52 anti-NRE anti-silencer which over-rides the general inhibitory activity of the pp52 NRE silencer.

The circadian blood pressure rhythm in non-diabetic hemodialysis patients.

This study investigates the circadian blood pressure variation of non-diabetic chronic hemodialysis (HD) patients on both HD and non-HD days as well as the factors affecting diurnal BP variation. Forty-nine HD patients aged 61.8 +/- 12.9 years who were on daytime HD for 97 +/- 68 months were studied. No significant difference was found in every daytime and nighttime BP between the first (HD) and the second (non-HD) day. However, the ratio nighttime/daytime BP was significantly higher on the second day. Each BP diurnal variability pattern was classified as either Dipper (D: the ratio nighttime/daytime mean BP 0.8-0.9), non-dipper (0.9 < ND < 1.0), or inverted dipper (ID > 1.0). More than 75% of the cases were classified as ND (26 cases) or ID (11 cases). The ultrafiltration rate in D was significantly less than that in ND and ID. The difference of plasma renin activity between pre- and post-HD (dRen) was significantly higher in ID than in D and ND. The amount of dialysis (Kt/V) was found to be significantly correlated with nighttime BP fall. Ultrafiltration, dRen and Kt/V were independent factors for the abnormal BP diurnal variability. In conclusion, the decreased nocturnal BP fall seen in non-diabetic HD patients is associated with increased extracellular fluid even in the patients without overt overhydration, whereas relatively insufficient amount of dialysis (low Kt/V) may be another possible cause. The increased dRen observed only in ID patients may reflect occult cardiovascular damage or functional disturbances in aortic and carotid baroreflexes caused by arterial structural changes.

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.

[A Japanese language version of the health-promoting lifestyle profile].

The development and initial psychometric evaluation of a Japanese version of the Health-Promoting Lifestyle Profile II (HPLP II) is described. The 52-item instrument was translated into Japanese and was found to be culturally relevant and reliable in a pilot study. The Japanese version was then administered to adiverse but predominantly Japanese group of 337 subjects residing in northern Japan. The Japanese version of the HPLP II was evaluated using factor analysis and reliability measurement. Six factors similar to those isolated previously during psychometric assessment of the English language version were extracted. Those six dimensions comprise the HPLP II subscales of: 1. Health responsibility, 2. Spiritual growth, 3. Physical activity, 4. Interpersonal relations, 5. Nutrition, and 6. Stress management. The alpha reliability coefficient for the total scale was 0.94 and the 2-week retest reliability was 0.91; the alpha coefficients for the subscales ranged from 0.70 to 0.87. The Japanese language version of the HPLP II appears to have sufficient validity and reliability for use by researchers who wish to describe the health-promoting components of lifestyle among the Japanese population and to explore differences and similarities in the health-promoting lifestyle of Japanese and American subjects or those of other ethnic groups. Further evaluations of measurement with different populations appears warranted. This instrument will enable researchers to investigate patterns and determinants of health-promoting lifestyle, as well as the effects of interventions to alter the lifestyle.

[Effect of a combination treatment using imipenem/cilastatin sodium with G-CSF on infections in neutropenic patients with hematological malignancies].

The clinical effectiveness of a combination treatment using imipenem/cilastatin sodium (IPM/CS) with G-CSF was studied in neutropenic patients (< 500/mm3) with hematological malignancies and secondary infections. Thirty seven patients were entered in the trial, and 30 patients were eligible. This combination was effective in 20 patients, thus the overall efficacy rate was 66.7 percent. The combination was effective in all 6 cases with septicemia, in 10 case out of 15 cases with fever after chemotherapy (efficacy rate; 66.7%), in 3 out of 8 cases with respiratory infections including 7 cases with pneumonia (efficacy rate; 37.5%), and a case with laryngopharyngitis. According to the order of the administration, the efficacy rates were 60.0% in 5 cases in whom G-CSF treatment was started before IPM/CS, 66.7% in 21 cases given both G-CSF and IPM/CS simultaneously, and 75.0% in 4 cases in whom IPM/CS was started before G-CSF. The difference was statistically not significant on the efficacy rates in the three groups. The efficacy in 18 cases treated with monotherapy on antibiotic was 72.2% and that in 12 cases treated with IPM/CS in combination with other antibiotics was 58.3%, and the difference in the efficacy rates in these two groups was not statistically significant. According to the neutrophil counts before and after the treatment, high response rate (60.0%) was obtained in cases of severe neutropenia (less than 100/mm3). Bacteriological examinations showed that all of bacteria detected as pathogens (10 strains of Gram-positive bacteria and 6 strains of Gram-negative bacteria) were eradicated, though 3 strains were replaced by other pathogens.(ABSTRACT TRUNCATED AT 250 WORDS)

[Trial digitalization of analog-data obtained from the AutoAnalyzer].

The AutoAnalzer(Basic Model) manufactured on Technicon corporation was a very useful instrument for clinical laboratory automation, but it was necessary to convert the data obtained from the instrument to digital values used the chart reader. This was very troublesome and there was apprehension that there would be errors in A-D conversion. We tried converting data obtained from the AutoAnalzer to a digital value by on-line connection of the instruments with minicomputers(LINC-8 and FACOM-R). The output of the recorder was converted to voltage(0 to 100 V) using a potentiometer, quantitated(0 to 1.000) by the A-D converter attached to LINC-8, and processed by the minicomputer. The control-box was an experimental device mainly designed for the convenience of users. The functions of the control-box were designated analytical items, No. of A-D converters, start and stop of the AutoAnalzer operation to the minicomputer. Employing the control-box, a technician operated this system freely, without direct computer operation. We established a generally satisfactory system for clinical laboratory automation using the minicomputer.

[A case of emphysematous cystitis].

Emphysematous cystitis is a rare lower urinary tract infection. Patients with diabetes mellitus, neurogenic bladder, and recurrent urinary tract infection are generally at higher risk of this disease. A 71-year-old woman with neurogenic bladder was referred from the internal medicine department because of urinary retention. Abdominal radiography and computed tomographic (CT) scanning revealed a characteristic accumulation of air in the wall and lumen of the urinary bladder. Emphysematous cystitis was improved by antibiotic therapy and urinary drainage. CT scan was a sensitive method for detecting early signs and confirming the diagnosis.

[The efficacy and safety of terazosin and tamsulosin in patients with urinary disturbance accompanying prostatic hypertrophy].

Terazosin (TE) and tamsulosin (TA) were allocated randomly to 38 patients who had urinary disturbance accompanying prostatic hypertrophy, and the efficacy and safety of the drugs were examined. Subjective symptoms due to I-PSS were improved significantly in both TE and TA groups. On the other hand, objective symptoms such as the maximum urinary flow and mean urinary flow were improved more in the TE group. TE showed hypotensive and cholesterol-decreasing effects in patients who also had hypertension and hyperlipemia. No unknown adverse reactions were observed in either groups, and the drugs were shown to be highly safe. TE was considered to be useful as the first choice drug for the patients with hypertension and or hyperlipemia and those with severe objective symptoms. TA was considered to be useful for the patients with impaired drug compliance or those with severe subjective symptoms though objective symptoms were not so severe.

[Lymphedema after radical prostatectomy: a case report].

We report a case of intractable lymphedema of the left leg following radical prostatectomy. The 69-year-old male patient complained of difficulty walking, caused by severe lymphedema. Intraarterial autologous lymphocyte transfusion therapy was performed because of failure of conventional conservative therapy, and the leg edema resolved almost completely. However, the treatment did not improve the penoscrotal edema necessitating excision of the edema and skin graft in a separate procedure. The post-operative course was excellent and the patient's performance status improved to 1 from 3.

[Fundamental evaluation of ELSA.F-beta HCG kit as an immunoradiometric assay specific for serum beta HCG].

We evaluated ELSA.F-beta HCG kit as an immunoradiometric assay (IRMA) specific for serum beta human chorionic gonadotropin (beta hCG). This IRMA was found to be highly sensitive to serum beta hCG; the minimum detectable concentration of beta hCG was 0.05 ng/ml. No significant effects on the standard curves were observed when first and second incubation time and temperature were varied from 30 min to 240 min and from 4 degrees C to 37 degrees C, respectively. Commercial LH, FSH, and TSH had little effect on the assay system; the cross-reactivity of commercial hCG was 2.5%, and 0.14% after unconjugated beta hCG with alpha-subunit was absorbed with ELSA-tube. Multiple dilutions of sera of pregnancy resulted in curves paralleling that obtained using standard beta hCG; the recovery of beta hCG added to the serum was 98.1 +/- 2.5% (mean +/- SD), and mean coefficient of variation of the interassay reproducibility of serum beta hCG (n = 10) was 6.7 +/- 2.8 (SD)%. Serum beta hCG concentration measured using ELSA.F-beta HCG kit was well correlated with that measured using conventional beta hCG RIA kit (r = +0.961, p less than 0.01), although values were lower than those measured with the latter (y = 0.35x + 0.26). Our results suggest that ELSA.F-beta HCG kit is a useful assay system for serum beta hCG.

[Spontaneous speech disturbances in so called transcortical motor aphasia--comparison of 3 cases with the different lesion sites].

So called transcortical motor aphasia (TCMA) is frequently subdivided, because the clinical features and the localization of the lesions are variable. The authors have been attempting to classify TCMA into three types according to the distribution of the lesions, such as Type F 1, Type F 2 and Type F 3. Case 1 N.S. belongs to Type F 1 showing the clinical features of TCMA with bleeding in the territory of the left anterior cerebral artery. Case 2 M.E. belongs to Type F 2 (published case). This case is similar to Luria's dynamic aphasia in its clinical features and results from the lesions including the posterior parts of left middle frontal gyrus. Case 3 N.T. belongs to Type F 3 who recovered from typical Broca aphasia after language training for four years. The case is similar to Goldstein's Type 1 of TCMA in its clinical features. These three cases are compared with regard to the fundamental bases of spontaneous speech disturbance. The items of comparison are as follows; the volume of speech production and the the time taken to start speech, word fluency test, cue effects necessary for the success of sentence constructions grammatical ability. The results are summerized in Table 2. Type F1 shows the most conspicuous defect of spontaneous speech, but no disturbance in grammatical ability. And when the top word of a sentence (a subject word) is given by the examiner, the patient can construct a structurally correct sentence. These findings imply that the spontaneous speech disturbance of Type F 1 is due to a defect of the starting mechanism of speech.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of enalapril and sairei-to on survival-time for the rat with subtotal nephrectomy.

The effect of an angiotensin-converting enzyme inhibitor, enalapril, and a Japanese medicinal plant named sairei-to, after administration either alone or in combination, on survival-time due to the protection of proteinuria and the preserving of renal function, was studied in the rat with subtotal nephrectomy. Resection of 2/3 of the left kidney and removal of the right kidney was performed in 28 male Wister rats (220-250 g). The rats were divided into four groups: (1) control (without sairei-to or enalapril); (2) with sairei-to (2.5% in rat chow); (3) with enalapril (50 mg/l in drinking water); and (4) the combination of enalapril and sairei-to. The actual survival-times until natural death after renal ablation in these four groups were 92 +/- 3, 128 +/- 8, 199 +/- 19, and 194 +/- 13 days, respectively. Urinary protein excretion and renal function were markedly protected in the enalapril-treated rats. Urinary endothelin excretion was also attenuated in enalapril-treated rats. Statistical analysis revealed the absence of benefits with sairei-to alone or in combination treatment. In conclusion, enalapril provides protection of proteinuria and preserves renal function, which results in a longer survival-time in the rats having subtotal nephrectomy. However, sairei-to does not show such beneficial effects.

Angiotensin-converting enzyme inhibitor-induced anemia and treatment for erythrocytosis in renal transplant recipients.

Erythrocytosis is not rare in renal transplant recipients, and phlebotomy is still the main treatment. Recently, the occurrence of angiotensin-converting enzyme (ACE) inhibitor induced anemia in patients on chronic hemodialysis and in renal transplant recipients has been reported. We herein report 5 transplant recipients whose hematocrit levels decreased while taking ACE inhibitors, including 2 patients treated with ACE inhibitors for erythrocytosis. The individual mean hematocrit values ranged from 35.0% to 54.7% before treatment and from 27.6% to 42.0% after treatment. The hematocrit level in the 2 patients with erythrocytosis decreased from 54.7% to 39.8% and 47.5% to 27.6%, respectively. Anemia improved after discontinuation or dosage reduction of the drugs. The patients were given the same immunosuppressive drugs, and had good renal function. ACE inhibitor-induced conspicuous anemia was not observed in the transplant recipient who received a kidney from a twin sibling and had not been taking any immunosuppressive drugs, nor in the 8 other patients with diabetes mellitus or chronic glomerulonephritis who served as controls. We conclude that ACE inhibitor-induced anemia may frequently arise in an immunosuppressed state. Based on these events, the ACE inhibitor can be used as a potent drug for erythrocytosis in post-transplant recipients.

A comparison of 3-D computed tomography versus 2-D radiography measurements of ulnar variance and ulnolunate distance during forearm rotation.

Positive ulnar variance is associated with ulnar impaction syndrome and ulnar variance is reported to increase with pronation. However, radiographic measurement can be affected markedly by the incident angle of the X-ray beam. We performed three-dimensional (3-D) computed tomography measurements of ulnar variance and ulnolunate distance during forearm rotation and compared these with plain radiographic measurements in 15 healthy wrists. From supination to pronation, ulnar variance increased in all cases on the radiographs; mean ulnar variance increased significantly and mean ulnolunate distance decreased significantly. However on 3-D imaging, ulna variance decreased in 12 cases on moving into pronation and increased in three cases; neither the mean ulnar variance nor mean ulnolunate distance changed significantly. Our results suggest that the forearm position in which ulnar variance increased varies among individuals. This may explain why some patients with ulnar impaction syndrome complain of wrist pain exacerbated by forearm supination. It also suggests that standard radiographic assessments of ulnar variance are unreliable.

Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation.

Phosphoinositide 3-kinase (PI3K) defines a family of lipid kinases that direct a wide range of cellular processes and cell fate decisions. Since its discovery, and that of its enzymatic antagonist PTEN, much of the focus on PI3K has been on its oncogenic potential. In recent years, studies on PI3K signaling in B lymphocytes have established the importance of this pathway in effecting B cell differentiation and associated molecular events such as V(D)J recombination and class switch recombination. Intriguing new findings also indicate that there is specificity in the PI3K pathway in B cells, including preferential expression or usage of particular PI3K isoforms and counter-regulation by the PTEN and SHIP phosphatases. The role of PI3K adaptor proteins (CD19, BCAP, and TC21) has also undergone revision to reflect both shared and unique properties. The emergence of Foxo1 as a critical PI3K regulatory target for B cell differentiation has united membrane proximal regulatory events orchestrated by PI3K/PTEN/SHIP with key transcriptional targets. Insights into the regulation and impact of PI3K signaling have been brought to bear in new treatments for B cell malignancies, and will also be an important topic of consideration for B cell-dependent autoimmune diseases.

The characteristics of in vitro biological activity of titanium surfaces anodically oxidized in chloride solutions.

Photo-functionalized radical reactions on TiO(2) have been correlated with adsorption of organic impurities and decreasing hydrophilicity of titanium-based biomaterials. Such reactive oxygen species (ROS) spontaneously generated on oxidized titanium surfaces may also have important roles against time-dependent degradation of biological ability and adherent micro-organisms. This study examined in vitro biological ability as a function of time and antimicrobial activity on oxidized titanium surfaces without photo-functionalization. Mechanically polished titanium and thermally oxidized titanium surfaces that had been stored for 4 wks showed adsorbed organic impurities with decreased surface hydrophilicity. Even after the storage period, anodically oxidized titanium surfaces enabled super-hydrophilicity without adsorption of organic impurities, because of the ROS and the hydrophilic functional groups generated on the surfaces. The osteogenic gene expressions of osteoblasts cultured on anodically oxidized titanium surfaces with or without storage were significantly higher than those on thermally oxidized titanium and polished titanium surfaces. Titanium surfaces anodically oxidized in a solution with chloride achieved antimicrobial activity against an oral microorganism due to the amount of ROS generated on the surface. Thus, titanium anodically oxidized in solution with chloride may have potential use for titanium-based internal fixation devices.