Smoking is a risk factor for pulmonary metastasis in colorectal cancer.

AIM: The hepatic microenvironment, which may include chronic inflammation and fibrosis, is considered to contribute to the pathogenesis of liver metastases of colorectal cancer. A similar mechanism is anticipated for pulmonary metastases, although no reports are available. Smoking causes pulmonary inflammation and fibrosis. Thus, we hypothesized that smokers would be especially affected by pulmonary metastases of colorectal cancer. In this study, we attempted to clarify the impact of smoking on pulmonary metastasis of colorectal cancer. METHOD: Between September 2005 and December 2010 we reviewed 567 patients with pathological Stage I, II or III colorectal cancer, whose clinicopathological background included a preoperative smoking history, pack-year history from medical records. Univariate and multivariate analyses using the Cox proportional hazard model were performed to determine the independent prognostic factors for pulmonary metastasis-free survival. RESULTS: Pulmonary metastases occurred in 39 (6.9%) patients. The smoking histories revealed 355 never smokers, 119 former smokers and 93 current smokers among the subjects. Multivariate analysis revealed that being a current smoker (hazard ratio = 2.72, 95% CI 1.18-6.25; P = 0.02) was an independent risk factor for pulmonary metastases. CONCLUSION: Smoking may be a risk factor for pulmonary metastasis of colorectal cancer. Cessation of smoking should be recommended to prevent pulmonary metastasis, although further basic and clinical studies are required.

Paternal height has an impact on birth weight of their offspring in a Japanese population: the Japan Environment and Children's Study.

This study examines the relationship between paternal height or body mass index (BMI) and birth weight of their offspring in a Japanese general population. The sample included 33,448 pregnant Japanese women and used fixed data, including maternal, paternal and infant characteristics, from the Japan Environment and Children's Study (JECS), an ongoing nationwide birth cohort study. Relationships between paternal height or BMI and infant birth weight [i.e., small for gestational age (SGA) and large for gestational age (LGA)] were examined using a multinomial logistic regression model. Since fetal programming may be a sex-specific process, male and female infants were analyzed separately. Multivariate analysis showed that the higher the paternal height, the higher the odds of LGA and the lower the odds of SGA in both male and female infants. The effects of paternal BMI on the odds of both SGA and LGA in male infants were similar to those of paternal height; however, paternal height had a stronger impact than BMI on the odds of male LGA. In addition, paternal BMI showed no association with the odds of SGA and only a weak association with the odds of LGA in female infants. This cohort study showed that paternal height was associated with birth weight of their offspring and had stronger effects than paternal BMI, suggesting that the impact of paternal height on infant birth weight could be explained by genetic factors. The sex-dependent effect of paternal BMI on infant birth weight may be due to epigenetic effects.

Incidence and clinical features of cytomegalovirus infection diagnosed by cytomegalovirus pp65 antigenemia assay during high dose corticosteroid therapy for collagen vascular diseases.

OBJECTIVE: To investigate the incidence and clinical features in patients with cytomegalovirus (CMV)-positive antigenemia during high dose corticosteroid therapy for collagen vascular diseases, and risk factors associated with it. PATIENTS AND METHODS: We examined retrospectively 35 consecutive patients for the presence of CMV-positive pp65 antigenemia. The patients were admitted to Saka General Hospital from 2000 to 2003, and were administered more than 0.5 mg/kg of body weight/day of peroral prednisolone for collagen vascular diseases. Characteristics of patients with and without CMV-positive antigenemia were compared. RESULTS: CMV-positive antigenemia was detected in 14 patients (40.0%), including six with microscopic polyangitis, three with rheumatoid arthritis, and five with other conditions. Three patients (8.6%) were diagnosed as having a CMV disease: pneumonitis or encephalitis. Symptoms and laboratory findings, including slight fever and a low increase in levels of hepatic enzymes and cytopenia, were observed in 10 of the 14 patients. Two patients died of CMV diseases refractory to ganciclovir. Ages of more than 70 years old were associated with the presence of CMV-positive antigenemia (relative risk = 4.5, 95% confidence interval = 1.14-17.6). CONCLUSION: CMV infection diagnosed by CMV pp65 antigenemia assay is not rare during high dose corticosteroid therapy for collagen vascular diseases, and advanced age is considered a risk factor for it. It has a variety of symptoms and laboratory findings, which are mild and nonspecific to this type of infection, and they may not be clearly noted as clinical signs of CMV infection, even in patients with CMV diseases whose prognoses can be unsatisfactory. During high dose corticosteroid therapy for collagen vascular diseases, careful attention should be paid to CMV infection.

Rapid screening method of abnormal insulin-receptor gene expression: allele-specific oligonucleotide hybridization by using silent polymorphisms.

An asymmetrical reduction in the levels of the insulin receptor mRNA transcribed from one allele was reported in some patients with severe insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM). To detect this abnormality, we designed the less laborious method; Allele-specific oligonucleotide hybridization of the amplified mRNA (cDNA) by using silent polymorphisms in the insulin receptor gene (nucleotide positions at 1686 and 1698). The allelic frequencies of C-1686 and T-1686 were 0.63 and 0.37, respectively (0.60 and 0.40 in 10 normal subjects, and 0.67 and 0.33 in 20 NIDDMs; n.s.). Similarly, the allelic frequencies of A-1698 and G-1698 were 0.47 and 0.53, respectively (0.50 and 0.50 in the normal subjects, and 0.45, and 0.55 in the NIDDMs; n.s.). These results suggest that these two polymorphisms are very common in Japanese. Nineteen (64%) out of 30 cases are heterozygous at one or two position(s), suggesting that it is possible to distinguish the mRNA transcribed from each of two alleles of the insulin receptor gene with using allele-specific oligonucleotide hybridization. Although we successfully measured the ratio of mRNA expression from two alleles of the gene in 20 NIDDMs, there was no patient whose mRNA transcribed from one allele of the insulin receptor gene was extremely decreased. We showed that allele-specific oligonucleotide hybridization method is useful for the screening of abnormal insulin-receptor gene expression.

Two patients with insulin resistance due to decreased levels of insulin-receptor mRNA.

Mutations have been identified in the insulin-receptor gene in insulin-resistant patients. We studied two patients with acanthosis nigricans and insulin resistance caused by a decrease in the number of cell surface insulin receptors. Patient 1 was an 11-yr-old boy with a fasting insulin level of 2130 pM; patient 2 was a 14-yr-old girl with hyperandrogenism and a fasting insulin level of 580-740 pM. Based on Southern-blotting studies, the structure of both alleles of the insulin-receptor gene in both patients appeared to be grossly normal. There was no evidence of insertions, deletions, or major rearrangements. Moreover, the nucleotide sequences of all 22 exons of the gene were normal in both patients. Thus, the predicted amino acid sequences of both patients' insulin receptors were normal. In Epstein-Barr virus-transformed lymphoblasts from patient 1, insulin-receptor mRNA levels were so low they could not be detected with an RNase A protection assay, whereas mRNA levels from patient 2 were in the lower half of the normal range. By use of a more sensitive assay based on the polymerase chain reaction, insulin-receptor mRNA could be detected in Epstein-Barr virus-transformed lymphoblasts from both patients. Moreover, because of the existence of silent polymorphisms in the nucleotide sequences, it was possible to differentiate the two alleles of the insulin-receptor gene in both patients. In patient 2, the two alleles were expressed asymmetrically, with 90% of the mRNA molecules having been transcribed from one allele but only 10% transcribed from the second allele. This suggests that there is an unidentified mutation in the underexpressed allele that acts in a cis-dominant fashion to decrease insulin-receptor mRNA levels. However, in patient 1, both alleles were expressed symmetrically in similarly low levels. Although not proven, it seems likely that the mutations that decrease insulin-receptor mRNA levels in patient 1 also map to the insulin-receptor locus.

Fasting plus prandial insulin supplements improve insulin secretory ability in NIDDM subjects.

To examine how insulin secretory ability is modified by strict glycemic control in non-insulin-dependent diabetes mellitus (NIDDM) subjects, basal and/or prandial insulin was supplemented for 4 wk in 24 diabetic subjects who were secondary failures to sulfonylurea treatment. One intermediate-acting insulin injection a day (n = 7) failed to suppress the rise in plasma C-peptide after meals and did not improve plasma C-peptide responses during a posttreatment oral glucose challenge. Continuous subcutaneous insulin infusion with a premeal bolus (n = 8) suppressed both fasting and meal-related rises in C-peptide and improved C-peptide response during the posttreatment oral glucose challenge. Daily insulin requirements during the 4 wk of treatment were reduced significantly by 52%. A short-acting insulin injection before each meal (n = 9) without basal supplementation suppressed the prandial rise in C-peptide and was associated with a significant reduction in daily insulin requirements during 4 wk of treatment by 28%. Diabetic subjects whose fasting and prandial hyperglycemia were less than 140 and less than 200 mg/dl, respectively, showed a significantly higher C-peptide response during oral glucose challenge after treatment than those whose insulin treatment only normalized (less than 200 mg/dl) prandial but not basal hyperglycemia (greater than 140 mg/dl). These results suggest that a short-term period of meal-related insulin treatment (which normalized prandial glycemia) increases residual beta-cell function in NIDDM subjects who failed long-term sulfonylurea administration. A basal insulin supplement alone was not effective. The effectiveness of a prandial insulin supplement may have been further improved by a combined basal and meal-related treatment program.

Identification of amino-acid polymorphism within the leucine zipper motif of mouse transcription factor A1.

Mouse transcription factor A1 (A1) is a mouse homologue of human E47, a ubiquitously expressed DNA-binding protein which contains a basic region, helix-loop-helix (HLH) and leucine zipper (LZ) motifs [Walker et al., Nucleic Acids Res. 18 (1990) 1159-1166]. Analyses of the nucleotide (nt) sequences of A1 cDNAs isolated from various mouse strains revealed amino acid (aa) polymorphism in the highly conserved region within the LZ motif. Interestingly, the location and pattern of aa deletions are identical to those previously described for the aa polymorphism within the human counterpart, E47 (E12) [Kamps et al., Cell 60 (1990) 547-555].

Normoglycemia per se but not normoinsulinemia is responsible for suppressing endogenous insulin secretion after oral glucose load in NIDDM.

It is well known that intensive insulin treatment of non-insulin-dependent diabetics (NIDDM) suppresses endogenous insulin secretion and thereafter improves it. To determine whether 'peripheral normo-insulinemia' or 'normoglycemia' established by the treatment is responsible for this suppression, the following five experiments were conducted on 15 well-controlled non-obese NIDDM patients. Experiment 1: a 100 g oral glucose load (OGL) was performed and blood glucose was monitored by an artificial endocrine pancreas (AP). Experiment 2: a 100 g OGL was done and blood glucose was normalized by AP-controlled insulin infusion. Experiments 3 and 4: a 100 g OGL was conducted while 'hyperglycemia' seen in experiment 1 was mimicked by AP-controlled glucose infusion with pre-programmed insulin infusion at the same rates as those in experiment 2 ('normoinsulinemia') or at rates 1.5 times higher than those in experiment 2 ('relative hyperinsulinemia'), respectively. Experiment 5: a 40 g OGL was conducted while AP-controlled insulin and glucose infusions were administered to make the plasma insulin level lower than in experiment 2 ('hypoinsulinemia') and to mimic the normoglycemic profile observed in experiment 2, respectively. In experiments 3 and 4, neither 'normoinsulinemia' nor 'relative hyperinsulinemia' suppressed the increase in plasma C-peptide after a 100 g OGL. In experiment 5, where the plasma insulin level showed a significantly (P less than 0.05) lower level than in experiment 2 and glycemia was normalized, C-peptide did not show a significant rise after OGL. These results indicate that 'normoglycemia' rather than 'normoinsulinemia' attained during exogenous insulin therapy, is responsible for suppressing endogenous insulin secretion against orally administered glucose.

Inhibitory effect of methylguanidine on insulin binding to its receptor. Mechanism underlying insulin resistance in uremia.

To elucidate the mechanism responsible for the decreased insulin binding to erythrocytes in uremic patients, the effects of incubation with sera obtained from uremic patients or with methylguanidine, respectively, on insulin binding were examined. Insulin binding to erythrocytes from uremic patients was lower than that from normal subjects (3.1 +/- 0.19% vs 6.6 +/- 0.33%, Mean +/- SEM, P less than .005), being due mainly to decreased binding affinity (58% of control). Incubation of erythrocytes with 1:5 diluted sera of uremic patients resulted in decreased insulin binding (65 +/- 5% of control) and this decrease was restored to the level of 78 +/- 3% of the controls after incubation with buffer for 12 h. Methylguanidine inhibited insulin binding to erythrocytes in a dose-dependent manner. Post-dialyzed serum with 100 ng/ml of methylguanidine (as seen in pre-dialyzed uremic patients) inhibited insulin binding to erythrocytes as much as pre-dialyzed serum (54.3 +/- 3% vs 47 +/- 1% of control). Incubation of IM-9 lymphocytes with 100 ng/ml of methylguanidine did not alter the insulin receptor mRNA level. These results suggest that methylguanidine inhibits insulin binding to its receptor, resulting in decreased insulin binding to erythrocytes.

Improvement in blunted glucagon response to insulin-induced hypoglycemia by strict glycemic control in diabetics.

To elucidate the mechanism of impaired pancreatic A cell function in hypoglycemia in diabetics, the effect of long-term strict glycemic regulations on hypoglycemia-induced glucagon secretion was studied. Firstly, the effect of plasma insulin concentrations on suppressing A cell was studied in healthy volunteers by injecting insulin at doses of 0.1 U/kg and 0.3 U/kg. With 0.3 U/kg of insulin, the rate of fall in glycemia and the nadir of blood glucose were made similar to those with 0.1 U/kg of insulin by glucose infusion with artificial endocrine pancreas. Plasma glucagon response after 0.3 U/kg of insulin was significantly suppressed as compared to that after 0.1 U/kg of insulin, demonstrating that not only hypoglycemic stimulus but also plasma insulin concentration were important determinants responsible for glucagon secretion in insulin-induced hypoglycemia. Secondly, effect of strict glycemic control was studied. Short-acting insulin at a dose of 0.1 U/kg was injected in an intravenous bolus form into 12 insulin-dependent (IDDM) and 9 non-insulin-dependent (NIDDM) diabetics before and 1-3 months after strict glycemic control with multiple insulin injections therapy. Before strict glycemic regulations in IDDM, no significant rise in plasma glucagon concentrations was observed during the insulin-induced hypoglycemia. In NIDDM, a rise in plasma glucagon concentrations was observed, though the response was delayed. After strict glycemic regulations, in patients with residual endogenous insulin secretion, the glucagon response to hypoglycemia improved considerably in IDDM and normalized in NIDDM. In IDDM and NIDDM, improvement in glucagon response to hypoglycemia related positively to daily urinary secretion rate of C-peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Longevity and diet in Okinawa, Japan: the past, present and future.

Japan has the longest life expectancy at birth (LEB) in the world. Okinawa, Japan's poorest prefecture, previously had the highest longevity indices in the country. However, the latest LEB for men in Okinawa is no higher than the national average. The purpose of this study is to examine why the longevity indices in Okinawa were once the highest in Japan, and to examine the reasons for their recent decline. In 1990, in Okinawa, the age-adjusted death rates (ADR) of the three leading causes of death were lower than their national averages. By 2000, the standard mortality ratios (SMR, Japan=100) of heart disease and cerebrovascular disease for both sexes in Okinawa had increased, compared to their 1990 levels. Both of the ADR of ischemic heart disease and the ADR of cerebrovascular disease for men increased to 45.5 and 63.5 in 2000, up from 42.9 and 59.1 in 1990, respectively, and the SMR of ischemic heart disease for men in Okinawa reached 101 in 2000. Consequently, the national ranking of Okinawa prefecture for LEB of men has dropped. As of 1988, in Okinawa, daily intake of meat and daily intake of pulses were both approximately 90 grams, which is about 20% and 30% higher than the national average, respectively. Also, as of 1988, daily intake of green and yellow vegetables in Okinawa was about 50% higher than the national average. However, by 1998, daily meat intake and fat energy ratio had surpassed 100 grams and 30%, respectively, and daily intake of pulses and green and yellow vegetables had declined to the level of the national average. Recently, young Japanese, particularly young men in Okinawa, have shown a tendency to avoid the traditional dishes of stewed meat and champuru.

[Two cases of idiopathic ventricular fibrillation with interesting electrocardiographic findings].

We encountered two cases of ventricular fibrillation (VF) without overt heart disease. The first case we report is that of a 47-year-old man, and the second case is a 39-year-old man. VF occurred in the night unrelated to myocardial ischemia or myocarditis. Their basic ECGs showed normal sinus rhythm, but neither QT prolongation nor abnormal Q wave was seen. But we could see IRBBB and ST segment elevation in the V1-2 lead not only in the acute phase, but also in the chronic phase. Abnormal findings were not found in noninvasive cardiac examinations, nor in cardiac catheterization and histological examinations. In the second case, VF was induced by electrical stimulation, and Disopyramide was found to be effective for the prevention of VF. The patient in the first case died suddenly two years after his first attack. Both cases have interesting ECG findings, and it may be that they play on important role in discovering the etiology of sudden cardiac death.

PP083. Clinic and out-of-clinic blood pressure changes during pregnancy by parity: Boshi study.

INTRODUCTION: Nulliparity is believed to be one of the risk factors for hypertension during pregnancy. However, the relationship between parity and out-of-clinic blood pressure during pregnancy is still unknown. OBJECTIVES: The aim of this study was to evaluate clinic blood pressure and blood pressure measured at home during pregnancy among nulliparous and multiparous women. METHODS: This study was a prospective cohort study. We examined blood pressure measured in the clinic and at home among 530 normotensive pregnant women who received antenatal care at a maternity hospital in Japan. Clinic blood pressures were obtained by duplicate measurements at each antenatal care visit. The participants were also required to measure their own blood pressures every morning at home while they were pregnant. A linear mixed model was used for analysis of the blood pressure course throughout pregnancy [1]. The SAS package (version 9.2) was used for the statistical analyses. RESULTS: A total of 315 nulliparous and 215 multiparous women were entered into this study (mean ages 30.1±4.6years and 33.0±4.1years, respectively). Clinic blood pressure during pregnancy among nulliparous women was significantly higher than that among multiparous women (P=0.02/P<0.0001 for systolic/diastolic blood pressure), whereas there were no significant differences in blood pressure measured at home during pregnancy between them (P=0.42/P=0.22 for systolic/diastolic blood pressure). CONCLUSION: Out-of-clinic blood pressure levels during pregnancy have been shown not to differ between nulliparous and multiparous women, while clinic blood pressure during pregnancy among nulliparous women is higher than that among multiparous women.

Architectural pattern of gastric adenocarcinoma--a 3-dimensional reconstruction study.

The 3-D microstructure of various adenocarcinomas was studied by graphic reconstruction of tubules and lumina from serial sections in four gastrectomy specimens in order to contribute to better diagnosis of the lesion by establishing the morphology of atypical glands. The cell nests in the moderately differentiated type had multiple anastomoses with one another forming a network, a pattern different from arborescent normal glands, while the lumina were separated into many small vesicles, giving the nests a porous character. Well differentiated tumours had more connections between the lumina forming a luminal network, whereas in the poorly differentiated lesions the nests also began to split into fragments. These findings provided a new viewpoint from which to establish an architectural basis for the discrimination of dysplastic from overtly malignant lesions.

Atypical glands in gastric adenoma. Three-dimensional architecture compared with carcinomatous and metaplastic glands.

The pathogenetic relationship of gastric adenoma to carcinoma remains unsettled, partly due to the difficulty in discriminating between the atypical tubules of adenoma and those of adenocarcinoma. Although it has been said that this discrimination should depend not only on cellular changes but also on disorganization of glands, the latter has not been described in accurate morphological terms. In view of this, gastrectomy specimens from three patients with tubular adenoma were submitted to graphic reconstruction of atypical glands from serial sections, and were compared with well differentiated adenocarcinoma and metaplastic mucosa. Reconstruction disclosed that in adenoma, unlike in metaplastic mucosa, atypical tubules had multiple connections with adjacent ones, forming a network. At some sites of anastomosis the lumen was also connected. Though this pattern was similar to that of well differentiated adenocarcinoma, the meshes of the network were much more coarse than in the latter, showing that adenoma was a mere miniature of adenocarcinoma. The porous structure, the commonest architecture of adenocarcinoma, was never found in adenoma. There were in addition giant glands with complicated branching which, together with microcysts forming at mucosal bottom, caused convolution and twisting of tubules, producing those abnormal patterns in section on which too much stress is placed.

Three-dimensional morphology of gastric adenocarcinoma. Atypical glands as a basis for histopathologic diagnosis.

The basic architectural pattern of adenocarcinoma was established by 3-D reconstruction of carcinomatous glands and their lumina from serial histologic sections in four gastrectomy specimens to establish strict morphologic criteria of adenocarcinoma and related lesions on structural basis. The carcinomatous glands in the moderately differentiated type had multiple anastomoses with one another forming a 3-D network, a pattern quite different from the arborescent normal glands, whereas the lumina were separated into many small parts, giving the cell masses a porous character. Well differentiated tumor had more connections between lumina, giving rise to the formation of dense luminal network, while in the poorly differentiated variety the glands lost unity, broken up into fragmental nests. These analyses provided a new viewpoint from which to establish a basis for the discrimination of dysplastic from overtly malignant lesions.

Morphometrical analysis on topographical difference in size distribution, number and volume of islets in the human pancreas.

Seven pancreases from nondiabetic autopsy cases were submitted to morphometrical analysis of the islets of Langerhans as a preliminary investigation of the diabetic pancreas. The pancreatic islets were approximately simulated by spheres of different sizes randomly dispersed in the three-dimensional space; thereon the parameters of Weibull function assumed for the distribution of islet radii were estimated stereologically from chord length measurements on histologic sections taken from different portions of the pancreas. By means of the estimated parameters topographical comparison of the number, volume, mean radius and size distribution of islets in a unit volume were performed. This islet distribution appeared to change the pattern gradually according to the position from the pancreatic head to the tail: the head was characterized by abundance of small islets that corresponded to a slightly higher islet population threat, whereas the tail by moderate increase of larger islets that caused a steep increase of islet volume here. To estimate parameters for the whole pancreas a histologic section from a range between the midposition of the pancreas and the one-fourth position from the splenic end was regarded to be a fairly good representative.

Islet morphometry in the diabetic pancreas of man.

Quantitative changes of the pancreatic islets in diabetes mellitus were analyzed by a stereological method. 26 maturity-onset and 5 growth-onset diabetics, and 37 nondiabetics including 9 hypertensives were selected from autopsy materials and the pancreases were subjected to histometry. The total islet volume Vi was 0.974 cm3 in the control, whereas it was only 0.596 and 0.255 cm3 in the maturity-onset and growth-onset diabetic groups, respectively. The hypertensive group gave almost the same value as the control. There was an obvious negative correlation between Vi and the maximum blood sugar level during glucose tolerance test, whether the case was diabetic or not. Moreover, in the diabetic group Vi diminished with descending age of onset. These findings indicate the importance of VI in the pathophysiology of diabetes and support the classical concept of insulin deficiency as the primary pathogenetic role. On the other hand, the total islet number Ni decreased with increasing mean radius r, and the diabetic and control cases shared a common regression of Ni on r. The diabetic pancreas was not characterized by Ni, r or by the distribution pattern of r.

Development of the human colonic adenocarcinoma from adenoma as a histopathologically continuous process.

The adenocarcinoma sequence of the human colon is usually divided into three separate steps according to the grade of epithelial dysplasia, i.e., adenomas with mild, moderate and severe dysplasia. In an attempt to re-examine whether or not this sequence can be morphologically separable as usually assumed, a total of 192 epithelial lesions including adenomas with various grades of dysplasia were analyzed, relying on morphometrical and multivariate-statistical techniques. Histologic features of epithelial lesions were characterized by 10 quantitative parameters and subjected to 10-variate cluster analysis. In the result of computations, separation of neoplastic lesions into different groups proved to be rather ambiguous, not justifying the classification into three groups as generally expected. It was concluded that adenocarcinoma can develop from adenoma as a seemingly continuous process which may involve more steps than usually assumed.