ALDH2 polymorphisms and bone mineral density in an elderly Japanese population.

INTRODUCTION: Osteoporosis is a multifactorial genetic disease which greatly increases the risk of bone fracture in elderly persons. METHODS: Four hundred and three recipients of a community health screening program were examined for the presence/absence of osteoporosis and 11 kinds of gene polymorphisms as a means of determining the relation between these gene polymorphisms and osteoporosis. The gene polymorphisms screened were: alcohol sensitivity-associated polymorphisms of alcohol dehydrogenase (ADH2) Arg47His, aldehyde dehydrogenase (ALDH2) Glu487Lys, smoking sensitivity-associated polymorphisms of glutathione S transferase (GST) M1, (GST)T1, NAD(P)H quinone oxidoreductase 1 (NQO1) C609T, inflammation-associated polymorphisms of interleukin-1beta (IL-1B)T-31C, tumor necrosis factor alpha (TNF-alpha) T-1031C, endothelial constitutive nitric oxide synthase (ecNOS) Glu298Asp, longevity-associated polymorphism of mitochondrial DNA (mtDNA) 5178 A/C, allergy-associated polymorphism of interleukin-4 (IL-4), and immunity-associated polymorphism of CD14. RESULTS: A significant association was found between the ALDH2Glu478Lys gene polymorphisms and osteoporosis. In the osteoporosis group of patients, a significant difference was noted between the Lys/Lys group and the group comprising Glu/Lys and Glu/Glu groups (namely, the genotypes including Glu alleles). In the Lys/Lys group, after age, sex, BMI, smoking history and alcohol consumption history had been adjusted for, the morbidity rate was significantly elevated [odds ratio (OR): 3.33; 95% confidence interval (95% CI): 1.28-8.71; p=0.014], and the effect was even more evident in the sub-group of women with osteoporosis (OR: 4.31; 95% CI: 1.24-14.92; p=0.021). CONCLUSIONS: The present results suggest that active prophylactic interventions such as dietary, exercise, and pharmacological therapies should be offered to non-carriers of the Glu allele (Lys/Lys).

The usefulness of laparoscopy-assisted distal gastrectomy in comparison with that of open distal gastrectomy for early gastric cancer.

BACKGROUND: The technique of laparoscopy-assisted distal gastrectomy (LADG) was developed for early gastric cancer, but its feasibility and the associated clinical outcome remain unclear. METHODS: We reviewed 24 patients who underwent LADG (LADG group) and 35 patients who underwent traditional open distal gastrectomy (ODG group) for early gastric cancer in our hospital, and compared the clinical data of the two groups. RESULTS: The clinical and pathological backgrounds of the patients in the two groups were similar. The duration of surgery was not significantly different between the two groups, but the blood loss in the LADG group was significantly less than that in the ODG group. The number of removed lymph nodes was not significantly different between the two groups. The times to the first passing of flatus, first walking, and the restarting of oral intake; the length of hospital stay; and the duration of epidural analgesia were significantly shorter in the LADG group. The morbidity rate in the LADG group was lower than that in the ODG group. CONCLUSIONS: LADG is a safe and minimally invasive surgical technique, after which we can expect a faster recovery.

[Evaluation of chemosensitivity testing by CD-DST, and TS and DPD activity in cases of colorectal liver].

We evaluated the usefulness of the following three in vitro assays in cases of resected colorectal liver metastases. Chemosensitivity by collagen gel droplet drug sensitivity test (CD-DST) was very low in all cases, suggesting this method is not predictive for this disease. In contrast, thymidylate synthetase (TS) activity and dihydropyrimidine dehydrogenase (DPD) activity in tumor tissue were high in many patients with recurrent disease. Thus, these enzyme activities are promising for assessment of clinical outcome following hepatic resection of colorectal liver metastases. Further analyses with large numbers of cases are needed to determine the significance of these in vitro studies.

[Significant role of cisplatin and 5-FU combination chemotherapy for first-line intensive treatment for advanced esophageal cancer].

We evaluated the efficacy of first-line chemotherapy consisting of cisplatin and 5-fluorouracil combination therapy (in the following, FP) in intensive treatment for esophageal cancer. This first-line chemotherapy was administered to 18 patients with squamous cell carcinoma. Three patients had T2 tumor, 10 had T3 and 5 had T4. Lymph node metastasis was detected in 10 patients and not detected in 8 patients. Five patients had distant metastasis. Ten patients showed a partial response and the response rate was 55.6%. Of these 10 patients, 5 were followed with surgery, 3 of whom survived without recurrence of the disease. Five patients were treated by FP, radiation therapy or combination of FP and radiation. Of these 5 patients, 2 showed a complete response. On the other hand, 8 nonresponders died from progressive disease, despite following intensive treatment. These results suggest that first-line chemotherapy by FP, which requires following intensive treatment, improves the overall long-term survival of advanced esophageal cancer patient.

Severe hypertriglyceridemia with plasma inhibitory factor(s) on lipoprotein lipase activity in a patient with a common Ser(447)-Ter LPL mutation.

Severe hypertriglyceridemia is a major risk for acute pancreatitis. So far, several mutations on the lipoprotein lipase (LPL) gene causing type I hyperlipidemia have been identified. However, the common mutation Ser(447)-Ter has been recently proposed to have a lowering effect on serum triglyceride concentrations in the general population. In this study, we analyzed blood from a patient suffering from severe hypertriglyceridemia and pancreatitis with the mutation on the lipoprotein lipase gene, Ser(447)-Ter. The patient's plasma showed inhibitory effects on the LPL activities from normal subjects. The bottom fraction separated by ultracentrifugation revealed enhanced effects as an inhibitory factor. The inhibitory effect observed in the bottom fraction was dose-dependent, stable at treatment of 65 degrees C for 30 min, and decreased significantly after being dialyzed using membranes with a cut-off molecular weight of 3500 or 6000 Da. The inhibitory effect was significantly higher when the post-heparin plasma was used from the patient or a subject with the same LPL mutation as an LPL source, compared to that from normal subjects. These results suggest that the patient has inhibitory factors in his plasma. Such inhibitory factors might cause severe hypertriglyceridemia in a case with the common mutation, which has been proposed to show the lowing effect on serum triglyceride concentrations in the general population.

Recurrence of myocarditis presenting as pacing and sensing failure after implantation of a permanent pacemaker at first onset.

A 31-year-old woman was admitted to hospital with loss of consciousness and generalized convulsions. Electrocardiography (ECG) showed complete atrioventricular block (AV block) with a pulse rate of 30 beats/min. Endomyocardial biopsy from the right ventricle showed massive necrosis and degeneration of myocardial cells with extensive infiltration of lymphocytes into the interstitial space. These pathological findings suggested fulminant myocarditis. Following glucocorticoid therapy, the patient became asymptomatic, but the AV block did not resolve completely and a bifocal pacemaker was implanted. However, similar symptoms recurred 7 years later. An ECG showed pacing and sensing failure linked to an increase in the pacing threshold and a decrease in the sensing threshold. Endomyocardial biopsy from the right ventricle again showed interstitial infiltration with lymphocytes and eosinophils. After glucocorticoid therapy, she became asymptomatic once more, and the improvement in the pacing and sensing failure, and cardiomegaly, was satisfactory. This patient represents a very rare case of recurrence of acute myocarditis without progression, as much as 7 years after its first occurrence. Glucocorticoid therapy was still effective in treating the recurrent myocarditis presenting with pacing and sensing failure.

A case report of advanced male breast cancer with an objective response to tamoxifen treatment.

A 70-year-old man presented with a firm tumor in his right breast first noticed eight years ago. The tumor had enlarged gradually and had produced an ulcer with bleeding. On physical examination, a huge tumor entirely occupied the right breast and extensively had infiltrated the chest wall. Chest X-ray and CT showed massive pleural effusion and multiple small nodular lesions in the lung. Invasive ductal carcinoma of the breast was diagnosed by incisional biopsy,confirming advanced breast cancer with lung metastases and bilateral pleural effusion(T4cN2M1, Stage IV). Because ER and PgR levels were 110 fmol/mg and 190 fmol/mg, respectively, and because his general condition was poor, we selected medical treatment with tamoxifen(TAM). Thirty-two weeks later, the tumor had showed pronounced reduction with scarring. The patient underwent local excision of the scar tissue. The quality of life of the patient was favorably improved and no severe adverse events were observed. The tumor in the chest wall recurred two months after the end of TAM treatment, possibly because the patient did not accept continuous TAM therapy. The patient died from complications of brain metastasis 32 months after the start of TAM treatment. We report a rare case of advanced male breast cancer and on the effectiveness of continuous TAM treatment.

Effect of probucol on repeat revascularization rate after percutaneous transluminal coronary angioplasty (from the Probucol Angioplasty Restenosis Trial [PART]).

To address the issue of whether probucol reduces clinical events after percutaneous transluminal coronary angioplasty (PTCA), we surveyed clinical status at 1 year after PTCA of 101 patients who had entered the Probucol Restenosis Angioplasty Trial. Repeat angioplasty at index lesions were required in 5 patients in the probucol group and in 12 in the control group, suggesting that probucol administered beginning 4 weeks before PTCA reduces repeat revascularization rates for 1 year.

The usefulness, indications, and complications of laparoscopy-assisted colectomy in comparison with those of open colectomy for colorectal carcinoma.

The technique of laparoscopy-assisted colectomy (LAC) was developed for benign and malignant diseases of the colon and rectum; however, its feasibility and the associated clinical outcome remain unclear. We reviewed 45 patients who underwent LAC (LAC group) and 62 patients who underwent traditional open surgery (Open group) for colorectal carcinoma in our hospital, and compared the clinical data between the two groups in an effort to determine whether LAC is really minimally invasive and if it enhances the quality of life. So that the backgrounds of the patients in both groups were almost the same, we only compared data of patients with colorectal carcinoma of stages 0, I, and II. The duration of surgery in the Open group was significantly shorter for all procedures except sigmoid resection, but the blood loss was not significantly different between any of the procedures except for right colectomy. The time to the first passing of flatus and restarting oral intake, length of hospital stay, and duration of epidural analgesia were significantly shorter in the LAC group. The morbidity and mortality rates in the LAC group were almost the same as those in the Open group at 29.5% and 3.3% versus 22.6% and 1.6%, respectively. However, five major complications of LAC for advanced colorectal carcinomas might be prevented by performing an open procedure. In conclusion, LAC is a safe and minimally invasive surgical technique following which we can expect a faster recovery; however, patients with advanced colorectal carcinomas must be carefully selected for this operation.

[Calcification in culprit lesions of coronary artery disease].

Coronary calcification, a type of coronary atherosclerosis, has recently been closely examined in clinical cardiology because its presence may influence the selection of interventional therapy. In addition, plaque instability is one of the most important factors in the mechanism of acute coronary syndrome, and calcium deposit is frequently detected in advanced lesions. However, little is known about the clinical significance of coronary calcification. The incidence of calcium deposits was investigated in the culprit lesions (culprit coronary calcification) of patients with serious coronary artery disease to discover any cardioprotective effect. Initial coronary angiography was performed in 179 consecutive patients with acute myocardial infarction with Q wave on electrocardiography (AMI group; male 139, female 40, mean age 60.2 +/- 10 yr) and in 119 consecutive patients with stable effort angina pectoris (SAP group; male 78, female 41, mean age 63.8 +/- 8 yr) for which balloon plasty or bypass surgery was necessary from 1990 to 1997. Culprit coronary calcification was defined positive if the calcification deposit was present cinefluoroscopically within 5 mm from the culprit point. The culprit point was defined as the narrowest point after successful intracoronary thrombolytic therapy or the latest point to be dilated during a balloon inflation in direct or rescue percutaneous transluminal coronary angioplasty in the AMI group, and the narrowest point of the culprit lesion in the SAP group. There was no statistical difference in clinical background between the 2 groups other than male dominance in the AMI group and high incidence of family history of ischemic heart disease in the SAP group (p < 0.05). Culprit coronary calcification in patients over 50 years old was less frequently positive in the AMI group than the SAP group (26% vs 66%, p < 0.005, respectively). In younger patients under 50 years old, the incidence of culprit coronary calcification was low (14-15%) in both groups. Culprit coronary calcification was frequently positive in the right or the left anterior descending coronary artery in the SAP group (p < 0.005). There was no incidental sex difference of culprit coronary calcification. This comparison suggests that if a plaque contains cinefluoroscopically visible calcification, it may be regarded as less vulnerable or having a history of chronic process of atherosclerosis which results in protecting plaque rupture.

[Three cases of severe hyponatremia under taking selective serotonin reuptake inhibitor (SSRI)].

The association between selective serotonin reuptake inhibitors(SSRIs) and hyponatremia has been documented throughout the world. In Japan, since SSRIs have recently come into use for patients with depression, there are only a few reports of hyponatremia associated with SSRIs. We present here three cases of the syndrome of inappropriate secretion of antidiuretic hormone(SIADH) associated with the administration of fluvoxamine for depression. They were admitted to our hospital because of deep coma, and revealed severe hyponatremia. Their serum sodium levels were 103-112 mEq/l, serum osmolalities were 227-241 mmol/kg, urine sodium levels were 38-107 mEq/l, and urine osmolalities were 352-781 mmol/kg. These patients were started on fluvoxamine 3 days-3 months previously. The diagnosis of SIADH in these patients was made based on hyponatremia, and low serum and high urine osmolalities. The fluvoxamine treatment was discontinued, and hypertonic saline was infused. Their serum sodium levels and osmolalities were subsequently normalized. None of the other known causes of hyponatremia, including diuretic therapy, tumors, and respiratory and central nervous system diseases, were present. High plasma AVP levels observed in the two cases suggest that SSRIs stimulate AVP secretion, thereby causing SIADH. Many reports have shown that people older than 70 years were at a particularly high risk of developing hyponatremia when SSRIs were used. In the future, since the use of SSRIs will be increasing, the water and electrolyte balance of elderly patients should be monitored carefully during SSRIs therapy.

Isolated coronary ostial stenosis associated with coronary vasospasm.

A 50-year-old woman was brought to the emergency room in a preshock condition. An emergency coronary angiogram revealed 90% ostial stenosis of the left coronary artery with delayed distal filling. After intracoronary nitrate, the degree of stenosis was reduced to 75%; no other coronary lesions were evident. The patient was found to have hyperthyroidism and she became euthyroid after a 2-month regimen of methimazole. A follow-up coronary angiogram showed that the left coronary artery had 50% ostial stenosis without delayed distal filling. At the same time, an aortogram showed complete occlusion of the right subclavian artery in its proximal site, a slight dilatation of the truncus brachiocephalic artery, and a diffuse wall irregularity of the abdominal aorta, suggestive of Takayasu's arteritis.

[A case of non-Hodgkin's lymphoma presenting with acute renal failure diagnosed by renal biopsy].

We report a case of non-Hodgkin's lymphoma (NHL) presenting with acute renal failure. A-56-year-old male was admitted to our hospital on October, 1997 with fever and renal dysfunction. Physical examination showed no abnormality except for hepatomegaly. Body surface lymphadenopathy was not observed. Computed tomography (CT) of the abdomen showed markedly enlarged kidneys bilaterally and a mass of soft tissue density, which was considered as a swelling lymph node, around the aortic artery. The renal biopsy revealed parenchymal involvement of the NHL cells without normal tubulo-interstitial structure, but the glomeruli were almost intact. Our case rapidly fell into oliguria and acute renal failure, hence needed hemodialysis. After chemotherapy was performed, his renal function gradually improved and the kidney became smaller on subsequent CT. Unfortunately, the patient happened to suffer from methicillin-resistant staphylococcus aureus (MRSA) infection in a neutropenic state and died. Necropsy revealed recovery of the renal interstitium without residual NHL cells. Renal lymphoma without any other organ or nodal involvement is a rare type of NHL, which considered primary renal lymphoma (PRL). However, we believe this case to have been a result of lymphomatous infiltration of the kidneys in disseminated lymphoma.

[A case of recurrent Guillain-Barré syndrome with myocarditis].

We report a 35-year-old man who recovered from an initial episode of Guillain-Barré syndrome (GBS) and had acute relapse after two years of asymptomatic interval. He had an acute muscle weakness with areflexia in his extremities following an upper respiratory tract infection in 1993. He was treated with plasma exchange and recovered completely within two months. Two years later he had a relapse of muscle weakness in the same distribution as the initial episode following the symptoms and signs of congestive heart failure. Biopsy of the heart muscle disclosed mild infiltration of lymphocytes with edema and fibrosis: the diagnosis of healing myocarditis was made. He underwent plasma exchange after the heart failure resolved and fully recovered neurologically within three months. The association of GBS and myocarditis is extremely rare. Moreover, there have been no reports describing recurrent GBS with myocarditis. Since GBS with myocarditis sometimes takes a fatal outcome, careful observation and treatment are mandatory.

Clinical manifestation and survival of patients with idiopathic bilateral atrial dilatation.

We studied the histories of eight patients who lacked clear evidence of cardiac abnormalities other than marked bilateral atrial dilatation and atrial fibrillation, which have rarely been discussed in the literature. From the time of their first visit to our hospital, the patients' chest radiographs and electrocardiograms showed markedly enlarged cardiac silhouettes and atrial fibrillation, respectively. Each patient's echocardiogram showed a marked bilateral atrial dilatation with almost normal wall motion of both ventricles. In one patient, inflammatory change was demonstrated by cardiac catheterization and endomyocardial biopsy from the right ventricle. Seven of our eight cases were elderly women. Over a long period after the diagnosis of cardiomegaly or arrhythmia, diuretics or digitalis offered good results in the treatment of edema and congestion in these patients. In view of the clinical courses included in the present study, we conclude that this disorder has a good prognosis.

Eosinophilic myocarditis associated with dense deposits of eosinophil cationic protein (ECP) in endomyocardium with high serum ECP.

A case of eosinophilic myocarditis following high serum levels of eosinophil cationic protein (ECP) is described. A 27 year old woman was admitted with New York Heart Association (NYHA) class III congestive heart failure. A haematological study showed hypereosinophilia with degranulation and vacuoles; the total eosinophil count was 7980/ml and the ECP serum concentration was noticeably high at 150 ng/ml. Endomyocardial biopsy from the right ventricle showed infiltration of eosinophils and dense deposits of ECP in the endocardium as well as the myocardium. Steroid treatment returned the total eosinophil count and serum ECP to normal, with satisfactory improvement in clinical features. Eosinophilia may cause cardiac damage, and this report confirms that eosinophil degranulation is toxic. Thus, serum ECP seems to be a reliable indicator for diagnosis and for determining treatment parameters of eosinophilic myocarditis.

Pharmacological properties of J-104132 (L-753,037), a potent, orally active, mixed ETA/ETB endothelin receptor antagonist.

J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist.