Post-transplant renal function and cardiovascular events are closely associated with the aortic calcification index in renal transplant recipients.

INTRODUCTION: The aortic calcification index (ACI) is reported to be closely associated with renal dysfunction and cardiovascular events; however, its implication in renal transplant recipients has not been well examined. In this study, we investigated the relationship between pretransplant ACI, ACI progression, post-transplant renal function, and post-transplant cardiovascular events in renal transplant recipients. PATIENTS AND METHODS: The study from June 1996 to Jan 2012 included 61 renal transplant recipients (living donors, 47; cadaveric donors, 14). The median follow-up period was 60 months. ACI was quantitatively measured on abdominal computed tomography. The relationship between age, dialysis period, estimated glomerular filtration rate (eGFR), and pre- and post-transplant ACI was longitudinally evaluated. Risk factors for post-transplant ACI progression were determined by logistic regression analysis. Patient background and the incidence of post-transplant cardiovascular events were also assessed. RESULTS: The pretransplant ACI (median 4.2%) significantly correlated with age at transplant, dialysis period, and diabetes mellitus. ACI gradually increased up to 2.8 times at 10 years after transplantation. Post-transplant eGFR significantly correlated with ACI progression in patients with chronic kidney disease of stage ≥ 3. Logistic regression analyses showed that age at transplantation, post-transplant period, cadaveric donors, and post-transplant chronic kidney disease stage 3 were risk factors for post-transplant ACI progression. The pretransplant ACI was higher (median 66%) in 3 patients who experienced post-transplant cardiovascular events. CONCLUSIONS: ACI progression closely correlates with age and post-transplant renal function. A high pretransplant ACI is a risk factor for post-transplant cardiovascular events in renal transplant recipients.

A primary retroperitoneal serous cystadenocarcinoma with clinically aggressive behavior.

CASE REPORT: We describe a 44-year-old woman with a primary retroperitoneal serous cystadenocarcinoma as the fourth report in the world literature. A contrast-enhanced computed tomographic scan of the abdomen demonstrated a mass with enhanced solid mural nodules and septa in the left retroperitoneum. Serum CA19-9 was elevated at 181 U/ml. The patient underwent a complete resection of the retroperitoneal tumor with a partial resection of the psoas major muscle and its fascia. Pathological examination showed a well-differentiated papillary serous cystadenocarcinoma of ovarian type and locoregional lymph node metastases. Seven months after surgery, the patient developed a pelvic recurrence, and underwent a total hysterectomy, a left salpingo-oophorectomy and a resection of the metastatic mesenteric mass. Two months after the second surgery, serum CA19-9 and CA125 increased to 1,114 U/ml and 218 U/ml, respectively. A solitary liver metastasis was confirmed on a computed tomographic scan. The patient is now being treated with weekly docetaxel and carboplatin. CONCLUSION: The present case illustrates the clinically aggressive nature of a primary retroperitoneal serous cystadenocarcinoma.

Coffee consumption and serum aminotransferases in middle-aged Japanese men.

We investigated the relation between coffee drinking and serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations among 7313 Japanese men receiving a health examination, excluding former alcohol drinkers and men with a history of chronic liver disease. Serum AST > 40 and/or ALT > 40 U/L was defined as liver inflammation. Adjustment was made for alcohol use, smoking, body mass index, serum marker for hepatitis virus infection, and other possible confounders. Adjusted odds ratios of liver inflammation were 1.00 (reference), 0.80, 0.69, and 0.61 for men drinking < 1, 1-2, 3-4, and > or = 5 cups of coffee daily, respectively. Among 6898 men without liver inflammation, serum AST and ALT were inversely associated with coffee consumption, and alcohol-related rise in AST was attenuated with coffee drinking. These findings suggest coffee may have an effect of suppressing the rise of serum aminotransferase, partly by inhibiting the alcohol-related elevation. Studies regarding biological mechanism are warranted.

Functional uncoupling of T-cell receptor engagement and Lck activation in anergic human thymic CD4+ T cells.

Human thymic CD1a-CD4+ T cells in the final stage of thymic maturation are susceptible to anergy induced by a superantigen, toxic shock syndrome toxin-1 (TSST-1). Thymic CD4+ T-cell blasts, established by stimulating human thymic CD1a-CD4+ T cells with TSST-1 in vitro, produce a low level of interleukin-2 after restimulation with TSST-1, whereas TSST-1-induced adult peripheral blood (APB) CD4+ T-cell blasts produce high levels of interleukin-2. The extent of tyrosine phosphorylation of the T-cell receptor zeta chain induced after restimulation with TSST-1 was 2-4-fold higher in APB CD4+ T-cell blasts than in thymic CD4+ T-cell blasts. The tyrosine kinase activity of Lck was low in both thymic and APB CD4+ T-cell blasts before restimulation with TSST-1. After restimulation, the Lck kinase activity increased in APB CD4+ T-cell blasts but not in thymic CD4+ T-cell blasts. Surprisingly, Lck was highly tyrosine-phosphorylated in both thymic and APB CD4+ T-cell blasts before restimulation with TSST-1. After restimulation, it was markedly dephosphorylated in APB CD4+ T-cell blasts but not in thymic CD4+ T-cell blasts. Lck from APB CD4+ T-cell blasts bound the peptide containing the phosphotyrosine at the negative regulatory site of Lck-505 indicating that the site of dephosphorylation in TSST-1-activated T-cell blasts is Tyr-505. Confocal microscopy demonstrated that colocalization of Lck and CD45 was induced after restimulation with TSST-1 in APB CD4+ T-cell blasts but not in thymic CD4+ T-cell blasts. Further, remarkable accumulation of Lck in the membrane raft was observed in restimulated APB CD4+ T-cell blasts but not in thymic CD4+ T-cell blasts. These data indicate that interaction between Lck and CD45 is suppressed physically in thymic CD4+ T-cell blasts and plays a critical role in sustaining an anergic state.

Immunopathophysiological aspects of an emerging neonatal infectious disease induced by a bacterial superantigen.

We recently discovered an emerging neonatal infectious disease, neonatal toxic shock syndrome-like (TSS-like) exanthematous disease (NTED), which is induced by a superantigen, TSS toxin-1 (TSST-1), produced by methicillin-resistant Staphylococcus aureus (MRSA). Here, we analyzed the activation and the response of TSST-1-reactive Vss2(+) T cells in NTED patients during the acute and recovery phases and in asymptomatic infants exposed to MRSA. In the acute phase, Vss2(+) T cells were anergic to stimulation with TSST-1 and underwent marked expansion, but by 2 months after disease onset, their numbers had declined to about 10% of the control level. Although the percentage of Vss2(+) T cells in the ten asymptomatic neonatal MRSA carriers was within the control range, these individuals could be divided into two groups on the basis of Vss2(+) T-cell activation. Vss2(+)CD4(+) T cells from three of these infants (Group 1) highly expressed CD45RO and were anergic to TSST-1, whereas in the other seven asymptomatic neonatal MRSA carriers (Group 2), these cells expressed CD45RO at the control level and were highly responsive to stimulation with TSST-1. The serum anti-TSST-1 IgG Ab titer was negligible in the four NTED patients in the acute phase and the three asymptomatic neonatal MRSA carriers in Group 1, but it was high in the seven asymptomatic carriers in Group 2. We suggest that maternally derived anti-TSST-1 IgGs helps to suppress T-cell activation by TSST-1 and protects infants from developing NTED.

Activation of the beta-catenin gene by interstitial deletions involving exon 3 as an early event in colorectal tumorigenesis.

beta-Catenin has been identified as an oncogene in several tumors including colorectal cancers. beta-Catenin gene is activated by interstitial deletions involving exon 3 in colorectal carcinomas of Japanese population, in contrast to amino acid substitutions detected among Caucasian population. The aim of this study was to examine the type and frequency of beta-catenin gene mutation during early stages of colorectal tumorigenesis. We screened 100 colorectal adenomas for somatic mutations in the beta-catenin gene by single-strand conformation polymorphism method, as well as polymerase chain reaction amplification. In cases with mutations, sequencing analyses and immunohistochemical staining were also performed. Somatic interstitial deletions of 272-413 bp, each of which included all parts of exon 3, were detected in three tumors. However, no adenoma carried missense mutations. We confirmed accumulation of aberrant beta-catenin protein in cytoplasm and nuclei of adenoma cells by immunohistochemical analysis. Our results suggested that activation of the beta-catenin gene by interstitial deletions involving exon 3 might be less frequent compared with frequent alterations of adenomatous polyposis coli (APC) gene, but could be an early event in colorectal tumorigenesis equivalent to APC gene alterations in the Japanese population.

Relationship between serologically diagnosed chronic atrophic gastritis, Helicobacter pylori, and environmental factors in Japanese men.

BACKGROUND: Whereas chronic atrophic gastritis is known to be an intermediate stage in gastric carcinogenesis, information is sparse about factors associated with this precancerous lesion except for Helicobacter pylori. METHODS: In a cross-sectional study of 566 men aged 50-55 years in the Japan Self-Defense Forces, we examined the relation of H. pylori infection, smoking, alcohol use, and dietary factors to the prevalence of chronic atrophic gastritis as determined by serum pepsinogen I and pepsinogen II (I/II ratio < 3.0. and pepsinogen I < 70 ng/ml). Chronic atrophic gastritis was classified as severe when the pepsinogen I/II ratio was < 2.0, and as moderate otherwise. RESULTS: The overall prevalence of chronic atrophic gastritis was 35.7% (202 of 566). The seropositivity of H. pylori was associated with a 10-fold increase in the risk of chronic atrophic gastritis, and the association was much stronger for moderate atrophic gastritis. Neither cigarette smoking nor alcohol consumption was related to the overall risk of chronic atrophic gastritis. Consumption of vegetables and fruits was each unrelated to chronic atrophic gastritis whether examined as a whole or separately for moderate and severe atrophic gastritis. Green tea was related to decreased risk of severe atrophic gastritis, although not statistically significant, whereas garlic consumption showed no protective association. CONCLUSIONS: The findings corroborate that H. pylori infection has an important role in the development of chronic atrophic gastritis in middle-aged Japanese men. Green tea consumption may be protective against the advance of atrophic gastritis. Vegetables, fruits, or garlic had no protective effect against the development of atrophic gastritis in the study.

Is communication to endocardium necessary for angiogenesis in transmyocardial laser revascularization?

There is evidence of angiogenesis being induced after transmyocardial laser revascularization (TMLR), although the precise mechanism has not been fully elucidated. This study was designed to examine whether or not blood flow from the left ventricle through the channels is essential for angiogenesis following TMLR. Ten dogs underwent the creation of two types of laser channels in the left ventricle: 1) a transmural channel (TMC), which penetrates the myocardium, and 2) a non-transmural channel (NTMC), which does not open to the epicardium. The animals were sacrificed on the 28th postoperative day and the vascular density was examined. Vessels with smooth muscle media were seen within or around the channel remnant. The vessel density was compared between TMC and NTMC. The outer and inner halves of the myocardium in the TMC region were compared in the same way. The density of vessels within and around the channel remnants was significantly higher in TMC than in NTMC (1.439 versus 0.685 vessels/microscopic visual field (mvf=40X); p=0.0025). The vascular density was significantly higher in the region adjacent to TMC than in a distant region (>3 mm from the channel center). The vascular density was significantly higher in the outer half than in the inner half of the myocardium (1.730 versus 1.180 vessels/mvf: p=0.0459). These findings demonstrate that communication to the left ventricular lumen enhances angiogenesis of TMLR, although blood flow in the channel did not exist 4 weeks after TMLR and angiogenesis tended to be more highly enhanced in the outer half than in the inner half of the myocardium.

[Kidney].

Kidney is one of the major target organ for angiotensin II (AT-II). The presence of three types of AT-II receptors, AT-II type 1, type 2, type 4 receptor (AT1, AT2, and AT4 receptor, respectively) were reported in kidney. AT1 receptor is the main type of receptor in kidney and mediates most of physiological effects of AT-II in kidney. The population of AT2 receptor is small in kidney. However, AT2 receptor also seems to play an important role for development and apoptosis in kidney. AT4 receptor is the receptor for angiotensin IV, but the physiological function is still unknown.

Coffee drinking and serum gamma-glutamyltransferase: an extended study of Self-Defense Officials of Japan.

PURPOSE: To examine the effect of coffee drinking on serum gamma-glutamyltransferase (GGT) level in relation to alcohol drinking, smoking, and degree of obesity in middle-aged Japanese men. METHODS: From 1986 to 1994, a total of 7,637 male officials of the Self-Defense Forces of Japan aged 48-59 years received a preretirement health examination. Coffee drinking was ascertained by a self-administered questionnaire, and serum GGT level was measured. After excluding 1,360 men with a possible pathologic condition influencing liver enzyme levels and 182 former alcohol drinkers, effect of coffee drinking on serum GGT was examined by a multiple linear regression model and analysis of variance adjusting for alcohol drinking, smoking, and body mass index (BMI). RESULTS: The adjusted percentage of difference in serum GGT was -4.3 (95% CI = -5.0; -3.5) per cup of coffee. The inverse coffee-GGT relation was most prominent among men drinking > or = 30 ml of ethanol and smoking > or = 15 cigarettes daily; and positive associations of alcohol and smoking with GGT were attenuated by coffee drinking, more clearly among men with BMI > or = 25.00 kg/m2. Adjusted percentages of difference in serum GGT were -2.6% (p = 0.0003) per cup of brewed coffee, and -5.1% (p = 0.0001) per cup of instant coffee, independently of each other. CONCLUSIONS: The present study suggests that coffee consumption may weaken GGT-induction by alcohol, and possibly by smoking. These effect modifications by coffee may differ according to the degree of obesity.

Habitual coffee consumption and blood pressure: A study of self-defense officials in Japan.

The study aims to examine the relationship between habitual coffee consumption and blood pressure. The subjects were 3336 male self-defense officials aged 48-56 years, who received a preretirement health examination at the Self-Defense Forces Fukuoka Hospital between October 1986 and December 1992. Average coffee intake in the past year was ascertained by a self-administered questionnaire. A significant inverse relation between habitual coffee consumption and blood pressure was found with and without adjustment for alcohol use, cigarette smoking, body mass index, glucose tolerance, and green tea intake. Green tea, another major source of caffeine intake in Japanese, was unrelated to blood pressure. The adjusted mean differences per cup of coffee consumed per day were -0.6 mmHg (95% confident interval [CI]: -0.9 to -0.3, p = 0.0001) in systolic blood pressure and -0.4 mmHg (95% CI: -0.5 to -0.2, p = 0.0002) in diastolic blood pressure. Habitual coffee drinkers had lower blood pressure than non-drinkers at any levels of alcohol use, cigarette smoking, obesity, and glucose intolerance. Our findings consolidate the previous observation that habitual coffee consumption was associated with lower blood pressure.

Relationship of cigarette smoking, alcohol use, recreational exercise and obesity with serum lipid atherogenicity: a study of self-defense officials in Japan.

We investigated the relationship of cigarette smoking, alcohol use, recreational exercise and obesity with serum lipid atherogenicity because of paucity of epidemiological studies. The subjects were 2,228 male officials of the Self-Defense Forces in Japan, who were aged 49-55 years and received a preretirement health examination in the period from 1991 to 1992. A self-administered questionnaire was used to ascertain cigarette smoking, alcohol use and recreational exercise. Serum total cholesterol (TC) and low-density-lipoprotein cholesterol (LDL-C) were increased with increasing levels of body mass index (BMI) and waist-to-hip ratio (WHR), and decreased with increasing levels of cigarette smoking and alcohol use. Serum high-density-lipoprotein cholesterol (HDL-C) was positively associated with alcohol use and recreational exercise, and negatively associated with cigarette smoking, BMI and WHR. BMI and alcohol use were most strongly associated with both LDL-C/HDL-C and TC/HDL-C ratios with BMI in an atherogenic direction and alcohol use in an antiatherogenic direction. Recreational exercise was weakly associated with less atherogenic lipid profile. BMI was the strongest determinant of serum lipid atherogenicity whereas alcohol use was most antiatherogenic. WHR was less important than BMI in the determination of serum lipid atherogenicity in Japanese men.

Exanthematous disease induced by toxic shock syndrome toxin 1 in the early neonatal period.

BACKGROUND: We have seen a number of patients who developed systemic exanthema and thrombocytopenia in the first week of life. Although nearly 100% of the patients were carriers of meticillin-resistant Staphylococcus aureus (MRSA), no clear link between MRSA and this exanthematous disease has yet been made. METHODS: 20 neonates with exanthema and thrombocytopenia were selected for study. To see whether superantigenic exotoxins from MRSA are involved in the pathogensis of the exanthematous disease, we studied the production of these exotoxins by MRSA isolates from the neonates. We studied the expression of T-cell-receptor Vbeta and CD45RO in T cells taken from four of the neonates. We also analysed the DNA sequences of 16 cloned Vbeta2-positive T-cell-receptor-chain genes taken from two of the neonates. FINDINGS: Although most of the patients recovered within 5 days of onset of the exanthematous disease without any active treatment, two preterm infants died in the recovery phase. All patients showed colonisation by MRSA. The MRSA produced toxic shock syndrome toxin-1 (TSST-1). The number of T cells positive for T-cell-receptor Vbeta2, reactive to TSST-1, was increased in the four patients studied (p<0.0001), and these T cells expressed CD45RO (p=0.0185). None of the Vbeta2 clones had the same junctional sequences. INTERPRETATION: The polyclonal expansion of Vbeta2-positive T cells in patients colonised by TSST-1-producing MRSA suggests that the pathogenic micro-organism of this neonatal exanthematous disease is S aureus, mainly MRSA, and that in its pathogenesis it activates T cells by TSST-1. Although the pathogenesis of both this exanthematous disease and toxic shock syndrome are fundamentally the same, a diagnosis of toxic shock syndrome cannot be made in this case, based on the clinical criteria for toxic shock syndrome. We propose neonatal toxic-shock-syndrome-like exanthematous disease (NTED) as the name for this disease.

cDNA cloning, expression, and mutagenesis of scytalone dehydratase needed for pathogenicity of the rice blast fungus, Pyricularia oryzae.

We purified scytalone dehydratase from the rice blast fungus, Pyricularia oryzae, and cloned its cDNA on the basis of its amino acid sequence. The deduced amino acid sequence was 62% identical to the scytalone dehydratase from Colletotrichum lagenarium. The expression of this gene was induced transcriptionally in the stationary phase when melanin synthesis occurs. We constructed a heterologous expression system for the enzyme in Escherichia coli, did deletion analysis with this system, and found that a C-terminal region is essential for the enzyme function.

Post-thymic maturation of migrating human thymic single-positive T cells: thymic CD1a- CD4+ T cells are more susceptible to anergy induction by toxic shock syndrome toxin-1 than cord blood CD4+ T cells.

To determine whether human CD4+ T cells undergo post-thymic maturation, we compared the susceptibility to anergy induction in human thymic CD1a- CD4+ single-positive (CD4+), cord blood (CB) CD4+, and adult peripheral blood (APB) CD4+ T cells by stimulation with toxic shock syndrome toxin-1 (TSST-1). Most TSST-1-induced T cell blasts derived from either T cell preparation expressed TCR Vbeta2, which determines the potential reactivity to TSST-1. Most thymic CD4+ T cell blast preparations exhibited little or no production of IL-2 and IL-4 after restimulation with TSST-1 and only marginal responses after stimulation with rIL-2 or a combination of PMA and calcium ionophore, while the APB CD4+ T cell blasts showed high responses to these stimuli. The responses of CB CD4+ T cell blasts to these stimuli varied, ranging from minimal to relatively high. Studies of DNA fragmentation showed that there was no significant cell death of thymic CD4+ T cell blasts. Most thymic CD1a- CD4+ and CB CD4+ T cells were CD38 positive. APB CD4+ T cell blasts derived from the CD38+ fraction and from the CD38- fraction exhibited equally high responses to restimulation with TSST-1. These results indicate that thymic CD1a- CD4+ and CB CD4+ T cells are inherently highly susceptible to anergy induction by bacterial superantigens and that thymic CD1a- CD4+ T cells are less mature than CB CD4+ T cells, suggesting that post-thymic maturation in thymic T cells migrating to the periphery is required for acquisition of full reactivity to antigenic stimulation.

Physiological control of a total artificial heart: conductance- and arterial pressure-based control.

To obtain a physiological response by a total artificial heart (TAH), while eliminating the hemodynamic abnormalities commonly observed with its use, we proposed the use of a conductance- and arterial pressure-based method (1/R control) to determine TAH cardiac output. In this study, we endeavored to make use of a variable more closely tied to central nervous system (CNS) efferents, systemic conductance, to provide the CNS with more direct control over the output of the TAH. The control equation that calculates the target cardiac output of the TAH was constructed on the basis of measurement of blood pressures and TAH flow. The 1/R control method was tested in TAH-recipient goats with an automatic method by using a microcomputer. In 1/R control animals, the typical TAH pathologies, such as mild arterial hypertension and substantial systemic venous hypertension, did not occur. Cardiac output varied according to daily activity level and exercise in a manner similar to that observed in natural heart goats. These results indicate that we have determined a control method for the TAH that avoids hemodynamic abnormalities exhibited by other TAH control systems and that exhibits physiological responses to exercise and daily activities under the conditions tested. The stability of the control and the complete lack of inappropriate excursions in cardiac output is suggestive of CNS involvement in stabilizing the system.

Anticipation of job loss or job change and cardiovascular risk factors: a study of retiring self-defense officials in Japan.

Self-defense officials in Japan are to retire at the age of early 50s. This unique situation prompted the authors to investigate whether preexisting morbid conditions cause any difficulty in finding a post-retirement job and whether anticipation of job loss or job change, as measured by the status of post-retirement job and months remaining until retirement, was related to biological cardiovascular risk factors. The subjects were 2,228 male self-defense officials who received a preretirement health examination at three Self-Defense Forces Hospitals from 1991 to 1992; the period in time remaining until retirement ranged from 1-40 months (median 12 months), and 62% had one year or less until the retirement. The defined preexisting illnesses included a wide range of chronic, non-communicable diseases. Overall, the preexisting illness was unrelated to the determination of a post-retirement job. In men having 6 months or less until retirement, however, the security of post-retirement job was less frequent when they had the preexisting illness, especially cardiovascular diseases. In 1,839 men excluding those with the preexisting illness, the period until retirement was not adversely related to obesity, blood pressure, serum lipids, serum uric acid, or glucose intolerance whether the post-retirement job had been secured or not. The findings suggest that the preexisting illness decreases the chance of obtaining a post-retirement job, but do not provide any evidence that anticipation of job loss or job change due to early retirement exerts an adverse effect on biological cardiovascular risk factors.