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The principle of the technique presented in this chapter is illustrated in Fig. 1. As with S1 mapping or riboprobe mapping, this technique can be used to determine precisely the start site of transcription of a mRNA sequence (1-3). Since this technique is relatively easier than other techniques, it is readily used for the primary determination of the transcription start site of a target gene. A radiolabeled probe derived entirely from within the gene is hybridized to mRNA complementary to the probe and extended using reverse transcriptase (RT). The cloned probe is normally derived from a region near the 5' end (cap site) of the gene and the extension reaction terminates at the extreme 5' end of the mRNA. Since only a small fragment of DNA probe is required as a primer, synthetic oligonucleotides are now almost exclusively used (although it is possible to use double-stranded DNA fragments or single-stranded primers generated by restriction enzyme digestion and gel electro-phoresis) (4). Fig. 1. The principle of primer extension analysis using a 5' end-labeled probe. The diagram illustrates how the 5' terminus of a poly(A)(+) mRNA might be determined using a 5' end-labeled single-stranded DNA probe (or synthetic oligonucleotide). Usually the probe would be a fragment derived from a cloned copy of the gene by cleavage with appropriate restriction enzymes or an oligonucleotide synthesized from the known cDNA sequence. The schematic representation of the autoradiogram demonstrates the results expected from a typical experimentLane 1, untreated probe; lanes 2 and 3, probe incubated under annealing conditions in the absence or presence of mRNA complementary to the probe, respectively, and then incubated with RT in the presence of unlabeled four deoxynucleoside trisphosfates (dNTPs). Only when complementary mRNA is present to form a hybrid with the primer, a primer extension product is synthesized as shown in lane 3.

1. An in vitro experiment was carried out to compare the inhibitory effect of SQ29,852 on human renal angiotensin converting enzyme (ACE) with those of captopril, enalapril and enalaprilat. 2. SQ29,852 strongly inhibited human renal ACE; its IC50 value was 1.5 x 10(-8) M. In terms of the IC50, SQ29,852's efficacy was about 1/10 of that of captopril and 1/28 of that of enalaprilat, but it was about 14 times more potent than enalapril. 3. SQ29,852 showed no inhibitory effects on cathepsin D, urinary kallikrein, renal renin, pepsin, trypsin and chymotrypsin. Its ACE-specificity was higher than that of captopril. 4. ACE inhibition by SQ29,852 was shown to be competitive, as revealed by Lineweaver-Burk plots. The affinity of SQ29,852 to ACE was shown to be high by a Ki value of 1.2 x 10(-8) M.

Linearly-polarized, 12-W Yb-doped double-clad fiber laser has been constructed by use of polarization-maintaining fibers and an in-line polarizer. 2.2-W green light was also obtained by second harmonic generation in a periodically-poled MgO:LiNbO 3 .

Mixed signals IC test generally requires the accurate analog measurement and/or the controlled interaction of digital function and analog measurement. The advanced mixed signals tester must provide the capability to control various test resources with synchronized/asynchronized timing in a real-time manner. This architectural concept contributes the accurate and repeatable testing of mixed signals IC with fast test throughput. For example, the integral linearity test of high resolution ADC is demonstrated by the sophisticated code measurement technique 10 times faster than the traditional analog measurement method by u-processor based control. Furthermore, the real-time DSP capability by the localized processors on the test resources under the sequence and timing control enables tester to emulate the complex mixed signals action such as communication devices. This makes the complex mixed signals testing much easier, more accurate and much faster for the following test using the DSP programming test condition, bit error rate test of modem, the 2B1Q Signal Generation with the specified jitter, and the vector error test, and so on. >

In this paper, an architecture of LUT-array-based PLD and a synthesis approach based on sum of generalized complex terms (SGCTs) expression are proposed. We formulate logic synthesis and layout for the LUT array into SGCT minimization so that the SGCT approach successfully merges these two synthesis stages. An SGCT generation procedure from an incompletely specified function is also presented. Experimental results demonstrate that the numbers of terms needed by our approach to map benchmark circuits into 2-LUT arrays and 3-LUT arrays are reduced to 70.7% and 85.1% on average of those by the existing approach, respectively.

Congestive heart failure is a common and serious complication in patients undergoing chronic dialysis. However, there have been no studies on preferential medical therapies to improve left ventricular function in haemodialysis patients. Beta-blocker treatment is known to improve left ventricular function in patients with dilated cardiomyopathy; moreover, plasma levels of noradrenaline and natriuretic peptides are sensitive markers of left ventricular dysfunction. The present study investigated whether beta-blocker treatment could improve left ventricular function in haemodialysis patients with a dilated left ventricle. Our study group comprised 14 haemodialysis patients with a dilated left ventricle, who had undergone maintenance haemodialysis for a mean of 11 years. The following haemodynamic parameters were evaluated before and after 4 months of treatment with the beta-blocker metoprolol: left ventricular dimension at end-systole and end-diastole, and fractional shortening. Plasma levels of noradrenaline, atrial natriuretic peptide and brain natriuretic peptide were also determined. Dry body weight and haemoglobin concentration showed no significant change after compared with before treatment with metoprolol. Heart rate decreased significantly, from 79+/-9 beats/min to 69+/-9 beats/min, but systolic blood pressure remained unchanged. The left ventricular dimension both at end-systole and at end-diastole was decreased, and fractional shortening increased significantly. Plasma levels of noradrenaline did not change significantly, but those of atrial natriuretic peptide and brain natriuretic peptide decreased markedly [from 100+/-89 pg/ml to 46+/-29 pg/ml (P=0.0051) and from 549+/-516 pg/ml to 140+/-128 pg/ml (P=0.0035) respectively]. In conclusion, beta-blocker therapy with metoprolol can markedly attenuate left ventricular remodelling and decrease the plasma levels of natriuretic peptides in haemodialysis patients with a dilated left ventricle.

In this review first I described the procedures of diagnosis in patients with essential hypertension. Blood pressure level, risk factor for cardiovascular disease and organ damage due to hypertension are essential in evaluating a patient with hypertension at outpatient clinic. Those criteria are based on Hypertension Treatment Guidelines 2000 published by Japanese Society of Hypertension last year. Next I described the outline of treatment of hypertensive patients according to the above guidelines. The guidelines is our interpretation of the world literature and of current opinions together with our largely documented experience based on the management of many hypertensive patients in Japan. The first-line antihypertensive drugs are long-acting Ca antagonists, ACE inhibitors, angiotensin II receptor antagonists, diuretics, beta-blockers and alpha-blockers.

We showed that the YMB-1-derived breast cancer cell line YMB-S, which proliferates in suspension without aggregation, exhibits complete loss of cell-cell adhesion despite the presence of E-cadherin-catenin complex and expression of free beta-catenin in the cytoplasm. Here, we describe beta-catenin gene regulation, interaction with E-cadherin, immunocytochemical localization, and their relation to growth rate in the YMB-1-derived cell line YMB-A, which forms tight junctions and displays anchorage-dependent growth. YMB-A cells proliferated more slowly than YMB-S cells. E-cadherin and APC gene product expression in YMB-A cells was significantly higher than that in YMB-S cells, whereas expression of beta-catenin, MUC1, and c-myc was lower in YMB-A cells than in YMB-S cells. According to immunocytochemical analysis, beta-catenin in YMB-A cells displayed membranous or submembranous localization, indicating that beta-catenin is mostly tethered to E-cadherin. Inhibition of E-cadherin expression in YMB-A cells by an antisense oligonucleotide did not change expression of whole cell beta-catenin protein, but increased nuclear beta-catenin protein level, c-myc expression, and cell growth rate. These results suggest that decreased expression of E-cadherin and APC and increased amount of beta-catenin in YMB-S cells lead to accumulation of beta-catenin in the nucleus, activate beta-catenin-LEF/TCF signaling pathway, and trigger c-myc proto-oncogene expression. c-Myc overexpression in breast cancer may be related to activated Wnt independent beta-catenin-LEF/TCF signaling.

A 54-year-old woman had been treated for hypertrophic cardiomyopathy and paroxysmal atrial fibrillation since 1992. She was admitted with paroxysmal atrial fibrillation which was resolved by medical treatment. However, on the next day, left lateral chest pain appeared. Computed tomography disclosed a low density area in the spleen. She received anticoagulant therapy under a diagnosis of splenic infarction, and the pain disappeared. Echocardiography showed hypertrophic cardiomyopathy with mid-ventricular obstruction. She was treated with cibenzoline to prevent paroxysmal atrial fibrillation attack and attenuate the hemodynamic load. After treatment, the pressure gradient decreased from 41 to 7 mmHg. This patient with hypertrophic cardiomyopathy suffered a rare isolated splenic infarction associated with paroxysmal atrial fibrillation.

To assess the effect of antihypertensive drugs on aortic distensibility, we evaluated the aortic distensibility of 33 hypertensive patients before and after antihypertensive treatment by using cine magnetic resonance imaging. Thirty three hypertensive patients were divided into three groups and treated for 12 weeks with 2-4 mg trichlormethiazide per day (n = 10), 80 mg nicardipine per day (n = 13) and 50 mg alacepril per day (n = 10). There were no significant differences in mean age and mean blood pressure among the three groups. Cine magnetic resonance was performed at ascending and descending aortic levels. Aortic area was measured at the maximum and minimum frames. The effect of antihypertensive therapy on aortic distensibility was evaluated as the percent change from before treatment to after treatment. There were no significant differences in pulse pressure before and after treatment with trichlormethiazide, nicardipine and alacepril. After treatment with these drugs, mean blood pressure in all groups decreased (trichlormethiazide and nicardipine, P.01; alacepril, P.05), (the maximum area--the minimum area) and aortic distensibility in all groups increased significantly (each P.01). Percent changes in aortic distensibility after treatment were significantly higher with nicardipine (ascending, 346.6 +/- 255.9%; descending, 338.8 +/- 246.5%, each P.05) and alacepril (ascending, 369.7 +/- 238.8%, P.05; descending, 306.9 +/- 123.3%, P.01) than with trichlormethiazide (ascending, 146.0 +/- 139.6%; descending, 129.3 +/- 97.5%). In conclusion, nicardipine and alacepril have a beneficial effect on aortic distensibility.

In this review angiotensin II receptor antagonists (Angiotensin antagonists are discussed on the efficacy and safety in the treatment of essential hypertension. Angiotensin antagonists are more complete renin angiotensin system blockade, and are potent as ACE inhibitors, but they have rarely troublesome dry cough specific to ACE inhibitors. Angiotensin antagonists have demonstrated an excellent tolerability profile. Angiotensin antagonists will have potentially greater protection from end-organ damage, since they have provided end-organ protection in animal experiments. These agents will be considered for first-line therapies in very near future.

The effects of a new dihydropyridine calcium antagonist, benidipine hydrochloride, on 24-hour blood pressure and blood pressure response to mental arithmetic test were investigated.Ten elderly patients with essential hypertension (mean age: 65+/-4 years; 7 male and 3 female).After a control period of 4 weeks, 4 mg benidipine was administered once daily in the morning for 12 weeks. Ambulatory blood pressure was monitored using a non-invasive automatic portable device with the cuff-oscillometric method at the end of both the control and treatment periods.Benidipine administration significantly decreased 24-hour blood pressure, while little change was noted in heart rate. Daytime blood pressure decreased significantly, from 148.2+/-11.5/90.8+/-8.8 to 133.8+/-9.2/82.5+/-10.8 mmHg. However, no significant decrease in nighttime diastolic blood pressure was noted, and the decrease in nighttime systolic blood pressure was small (from 129.8+/-9.9/77.1+/-7.6 to 121.8+/-10.1/74.7+/-9.1 mmHg). No significant changes were observed in diurnal variability of blood pressure and heart rate. The decrease in systolic blood pressure by benidipine administration showed a significant positive correlation with systolic blood pressure before treatment in the 24-hour and daytime periods. Single cosinor analysis showed that benidipine administration significantly decreased MESOR of both systolic and diastolic blood pressure, without an increase in amplitude. Both systolic and diastolic blood pressure during mental arithmetic test were significantly decreased after treatment with benidipine, and the increase in systolic blood pressure induced by mental arithmetic test was also significantly attenuated.These findings indicate that administration of benidipine once daily in the morning effectively decreases blood pressure and attenuates blood pressure response to mental stress. Neither reflex tachycardia, deterioration of diurnal blood pressure change, nor excessive lowering of nighttime blood pressure was observed after benidipine administration. It is suggested that benidipine is a potent and long-lasting calcium antagonist which may be useful for the treatment of elderly hypertensive patients with cardiovascular disease.

A 69-year-old woman was admitted because of increase of chest pain and dyspnea. Systolic murmur of Levine III/VI was heard. Electrocardiography showed ST depression caused by ischemia. Echocardiography revealed severe mitral regurgitation (MR) and inferoposterior hypokinetic wall motion. Left ventriculography revealed the presence of MR (II/IV). Coronary angiography showed severe organic stenosis of the right coronary artery. Based on these findings, the diagnosis was severe papillary muscle dysfunction caused by unstable angina. The lesion of the right coronary artery was successfully stented with a Palmaz-Schatz stent. During balloon inflation, the v wave of the pulmonary capillary pressure curve was greatly elevated. After the stent implantation, ST depression was normalized and MR improved dramatically. Therefore, we suppose that acute MR was induced by temporary papillary muscle dysfunction, and could be relieved with coronary angioplasty.

Thromboxane (Tx)A2 synthase inhibitors and thromboxane prostanoid (TP) receptor antagonists have been developed as anti-asthma drugs. TxA2 may contribute to airflow limitation and bronchial hyperresponsiveness, and these compounds have been demonstrated to improve them. However, it is not known whether TxA2 is involved in bronchial inflammation. To address this question, we explored the influences of OKY-046 (a TxA2 synthase inhibitor) and S-1452 (a TP receptor antagonist) on eosinophilic inflammation of the airways using a murine model. BALB/c mice sensitized with ovalbumin and challenged by repeated exposure to ovalbumin yielded marked eosinophilia in bronchoalveolar lavage fluid (BALF). Treatment with either compound significantly reduced the number of total cells and eosinophils in BALF in a dose-dependent manner. The production of interleukin (IL)-5, IL-2 and interferon (IFN)-gamma by antigen-stimulated splenic mononuclear cells (SMNC) was significantly decreased in mice treated with either compound compared to that in untreated mice. Furthermore, both compounds inhibited proliferation and cytokine production of SMNC in vitro. These results suggest that both OKY-046 and S-1452 are capable of inhibiting production of cytokines, which in turn inhibits eosinophil infiltration into the murine airway. Thus, both thromboxane A2 synthesis inhibitors and thromboxane prostanoid antagonists may be effective as anti-inflammatory drugs in the treatment of asthma.

Two breast cancer cell lines, YMB-S and ZR-75-1S, were established in our laboratory. They proliferated in suspension culture without aggregation in a complete liquid medium. We found that sodium butyrate (NaB) arrested the cells in the G0-G1 phase of the cell cycle, inhibited their proliferation, and induced cell-cell and cell-surface adhesion. In this study, we explored the mechanism of this adhesion. Adhesion was inhibited by an anti-E-cadherin antibody, suggesting a role for E-cadherin. However, there were no changes in the expression of E-cadherin, alpha-catenin, and beta-catenin. Northern blot analysis and cytofluorometry revealed that NaB-treated cells showed a lower expression of MUC1 than did untreated cells. To examine the possibility that the adhesion of these cells might be induced by decreased MUC1 expression, the level of MUCI expression was directly reduced using an antisense oligonucleotide. The MUC1 antisense oligonucleotide induced cell-cell and cell-surface adhesion of these breast cancer cells, just as NaB did. Our observations indicate that E-cadherin can be functionally suppressed by overexpression of MUC1 but resumes its activity after suppression of MUC1 expression. Thus, regulation of MUC1 might be a new strategy for cancer therapy.

1. The aim of this study was to elucidate the pathophysiological role of adrenomedullin and the relation between adrenomedullin and other hormones in patients with hypertrophic cardiomyopathy. 2. Fourteen patients with hypertrophic obstructive cardiomyopathy (HOCM), 26 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) and 14 normal control subjects participated in this study. Radioimmunoassay for plasma adrenomedullin concentration was performed with adrenomedullin-M antibody. Plasma levels of endothelin-1, atrial and brain natriuretic peptides and noradrenaline were also measured. 3. Plasma levels of adrenomedullin were higher in patients with hypertrophic cardiomyopathy (8.43 +/- 3.73 pmol/l) than in normal controls (5.24 +/- 0.44 pmol/l, P0.005). There was no significant difference between HOCM and HNCM patients. There was a weak correlation between plasma levels of adrenomedullin and total 12-lead QRS voltage in patients with hypertrophic cardiomyopathy (r = 0.323, P0.05). 4. Plasma levels of endothelin-1, atrial and brain natriuretic peptides were higher in hypertrophic cardiomyopathy than in normal controls. Endothelin-1 showed no significant difference between HOCM and HNCM patients, but atrial and brain natriuretic peptides were higher in HOCM than in HNCM patients. There was a positive correlation between plasma levels of adrenomedullin and endothelin-1 (r = 0.575, P0.0001), but no correlation between plasma levels of adrenomedullin and atrial natriuretic peptide, brain natriuretic peptide and noradrenaline. 5. Our results indicate that adrenomedullin may play an important role to maintain haemodynamics in patients with hypertrophic cardiomyopathy, and its action may be related to endothelin-1 but independent of atrial natriuretic peptide, brain natriuretic peptide and noradrenaline.

In order to examine the current status of antihypertensive drug therapy for elderly hypertensive patients, and the effect of clinical characteristics and drugs on their prognosis, 1669 hypertensive patients in the Chugoku and Shikoku districts, aged between 65 and 84 years, were enrolled and followed for 3 years. Of the 1669 patients enrolled, 1459 were selected for evaluation and 1127 patients were followed. Group A comprised 955 patients who had not suffered from any accident, group B comprised 139 patients who had suffered from a cerebral, cardiac, renal or other non-fatal accident, and group C comprised 33 patients who died. The mortality rate was 10.7/1000 patient.years and the morbidity rate was 55.6/1000 patient.years. The number of patients who received monotherapy was 736 (calcium channel blockers: #436, beta blockers: #100, angiotensin converting enzyme inhibitors: #80, diuretics: #64, alpha blockers: #16; others: #13). In group C, there were more male, and the patients were older and showed a higher level of serum creatinine concentration at enrollment compared with other groups. The use of diuretics and beta blockers tended to be low in this group. Among the three groups, however, there was no difference in blood pressure, heart rate or the use of each drug at enrollment. In summary, it is suggested that the different antihypertensive drug therapies die not influence the prognosis of elderly hypertensive patients.

The aim of this study was to compare the effects of a calcium antagonist, nicardipine SR, with an angiotensin-converting enzyme (ACE) inhibitor, alacepril, on the regression of left ventricular hypertrophy (LVH) and function. Twenty patients with LVH, aged 42-78 years, were treated with nicardipine SR or alacepril. Ten patients were treated with nicardipine SR (40-80 mg) for 21 months, and the other 10 patients were treated with alacepril (25-100 mg) for 18 months. All patients underwent echocardiography to assess left ventricular structure and function before and after the treatment. After nicardipine SR or alacepril treatment, blood pressure was decreased significantly from 176.0 +/- 13.9/97.0 +/- 5.3 mmHg to 140.0 +/- 14.0/77.4 +/- 7.2 mmHg and from 168.2 +/- 22.3/99.0 +/- 5.5 mmHg to 138.4 +/- 12.5/85.2 +/- 9.7 mmHg, respectively (both p0.01), whereas heart rate did not change (73.8 +/- 14.6 beats/min vs. 69.9 +/- 13.5 beats/min and 71.6 +/- 9.7 vs. 65.8 +/- 8.1 beats/min, respectively). The left ventricular mass index decreased significantly from 133.2 +/- 11.7 g/m2 to 114.4 +/- 15.7 g/m2 with nicardipine SR and from 137.1 +/- 14.8 g/m2 to 99.3 +/- 23.0 g/m2 with alacepril (both p0.01). The fractional shortening, peak shortening rate, and peak lengthening rate all improved significantly after each treatment. The end-systolic wall stress/left ventricular end-systolic volume index, as an index of left ventricular contractility, was decreased significantly after treatment with nicardipine SR but was not changed after treatment with alacepril. In conclusion, both nicardipine SR and alacepril similarly reduced LVH and improved left ventricular systolic and diastolic function. However, alacepril did not alter left ventricular contractility, whereas nicardipine SR decreased left ventricular contractility.

Carcinoembryonic antigen (CEA) has been clinically used as a serum marker for lung cancer, especially for pulmonary adenocarcinoma. Since we had developed a tumor marker against pulmonary adenocarcinoma, CAM 123-6 belonging to KL-6 MUC 1 mucin, we compared its clinical value with that of CEA, in combination with squamous cell carcinoma-related antigen (SCC) and neuron-specific enolase (NSE). The subjects were 30 patients with adenocarcinoma, 23 with squamous cell carcinoma, 16 with small cell carcinoma, and 20 with benign lung disease. For discriminating lung cancer from benign lung disease, the combination of CAM 123-6, SCC, and NSE showed 64% diagnostic accuracy, and the combination of CEA, SCC, and NSE 65%. In differentiating pulmonary adenocarcinoma from other lung cancer, the diagnostic accuracy of CAM 123-6 was 81% and that of CEA was 74%, although there was no significant difference between them. These observations indicate that the diagnostic accuracy of CAM 123-6 is similar to that of CEA. Neither marker is sufficiently specific to differentiate pulmonary adenocarcinoma from other forms of lung cancer.

A 38-year-old man was admitted to our hospital for detailed examination of fever, cough and yellow sputum. At the age of 32, be had mitral prosthesis for the first time, because of mitral regurgitation due to mitral valve prolapse. Four years previously, he had again undergone mitral prosthetic valve replacement due to prosthetic valve endocarditis due to staphylococcus epidemidis. This occasion, staphylococcus aureus was isolated by arterial blood culture. Transesophageal echocardiography detected vegetation attached to the mitral prosthetic valve and paravalvular leakage. The diagnosis was prosthetic valve endocarditis. He underwent a third mitral prosthetic valve replacement. Detection of the source of infection was difficult only by transthoracic echocardiography, and immediate transesophageal echocardiography seemed mandatory to diagnose bacterial endocarditis.

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP160 mmHg, diastolic BP90 approximately 10 mmHg. Systolic BPage + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

The effect of administration of an angiotensin-converting enzyme inhibitor, alacepril, on 24-hour blood pressure in the elderly hypertensive patients was investigated. Thirteen elderly hypertensive patients (mean age 71 +/- 5; 6 male and 7 female) participated in the present study. After 2 weeks of control period alacepril was administered 25-50 mg/day for 8 weeks. Ambulatory blood pressure monitoring with cuff-oscillometric method was performed at the end of both control and treatment periods. Alacepril administration for 8 weeks significantly decreased 24-hour blood pressure while it had little effect on heart rate. Daytime blood pressure was significantly decreased from 154 +/- 10/91 +/- 5 mmHg to 145 +/- 8/85 +/- 5 mmHg, while the change in nocturnal blood pressure was not significant: from 137 +/- 17/79 +/- 7 mmHg to 130 +/- 15/75 +/- 9 mmHg. Hyperbaric area of systolic blood pressure was also significantly decreased (from 295 +/- 185 mmHg x hour/day to 172 +/- 111 mmHg x hour/day), indicating that pressure load to the heart was effectively reduced. Administration of alacepril did not cause tachycardia in response to the decrease in blood pressure. Acrophase of both blood pressure and heart rate was changed to 11:00 a.m. These findings indicate that blockade of the renin-angiotensin system in the elderly hypertensive patients decreased blood pressure effectively without causing tachycardia or deterioration of diurnal variations of blood pressure. These hemodynamic changes produced by alacepril administration are favorable for the treatment of the elderly patients with cardiovascular disease.

A 35-year-old woman was admitted to our hospital because of a fever and a productive cough. She had undergone renal transplantation and had taken immunosuppressive drugs, a steroid, inhaled amphotericin-B, and pentamidine. She was treated with ganciclovir, because infection with cytomegalovirus was suspected but her symptoms did not resolve. A chest X-ray film and a computed tomogram showed an infiltrative shadow in the right lower lung field. Specimens obtained by transbronchial lung biopsy showed lipid-laden macrophages and oil droplets in alveolar spaces. Organisms of the genus nocardia were isolated from bronchial lavage fluid. The final diagnosis was lipoid pneumonia combined with pulmonary nocardiosis. After treatment with Imipenem.cilastatin sodiom, Exacin and Sulfamethoxazole.trimethoprim, her symptoms and the infiltrative shadows on the chest X-ray film resolved. We believe that this patient had an exogenous lipoid pneumonia caused by inhalation of deoxycholic acid in amphotericin-B solubilized liquid, in addition to pulmonary nocardiosis.

KL-6 is a mucinous glycoprotein expressed on Type 2 pneumonocytes, and serum levels of KL-6 are reported to be abnormally high in patients with interstitial pneumonia. A new assay kit for serum KL-6 (ED046) was used in the evaluation of patients with pneumonitis. To clarify whether KL-6 is a useful marker of pneumonitis activity, 649 subjects were studied, including 185 healthy controls, 187 patients with 3 types of interstitial lung diseases, and 277 patients with 4 types of non-interstitial lung diseases. The serum KL-6 level was significantly higher in the patients with pneumonitis (1285 +/- 1196 U/ml) than in the patients without pneumonitis (307 +/- 232 U/ml). The KL-6 level was also significantly higher in patients with clinically active pneumonitis (1708 +/- 1338 U/ml) than in those with inactive pneumonitis (820 +/- 796 U/ml) (p0.0001). Serum KL-6 levels correlated significantly with serum c-reactive protein, lactic dehydrogenase, and PaO2 values. These results suggest that the ED046 assay is useful for measuring KL-6 as a marker of pneumonitis activity.

A 37-year-old man with multiple nodules on a chest X-ray film, hypertension, and proteinuria was admitted to our hospital in September, 1993. Thirteen years earlier, he had been admitted to another hospital because of bloody sputum, fever, and dyspnea. He also had slight oral aphthae and slight iridocyclitis. A chest X-ray film at that time showed bilateral diffuse reticular shadows, and his illness was diagnosed as acute interstitial pneumonitis. Since that time, he had been continuously receiving tapering doses of prednisolone. His chest symptoms were relieved, and the findings on the chest X-ray film resolved with that treatment. In 1993, he also had positive tests for HBs antigen and for HLA-B51, and he was found to have renal vascular hypertension. Chest CT films and a pulmonary angiogram showed multiple aneurysms and occlusions of pulmonary arteries. A renal angiogram showed multiple intraparenchymal aneurysms of renal arteries. A specimen taken by open-lung biopsy showed healed endoarteritis obliterans of muscular arteries and no alveolitis. His illness was diagnosed as polyangiitis overlap syndrome, because of the unclassified systemic necrotizing vasculitis.

This study was undertaken to clarify whether the myocardial dysfunction observed in the hypertensive heart is an intrinsic property of the myocyte or not.We investigated left ventricular function and contractile function of myocytes from 30-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We also evaluated the effect of angiotensin II on contractile function of myocytes from both rats.The time constant of isovolumic pressure fall was significantly greater in SHR (13.2 +/- 0.6 ms) than in WKY (10.3 +/- 0.5 ms). The extent of shortening in isolated myocytes was significantly higher in SHR (11.3 +/- 0.4%) than in WKY (9.8 +/- 0.4%, P0.01). Both the normalized maximal velocity of shortening and the normalized maximal velocity of relengthening were significantly greater in SHR (2.12 +/- 0.08 and 2.10 +/- 0.08 s-1; both P0.01) than in WKY (1.76 +/- 0.06 and 1.75 +/- 0.07 s-1). Angiotensin II caused significant decreases in the extent of shortening, the normalized maximal velocity of shortening and the normalized maximal velocity of relengthening in isolated myocytes from SHR, but these parameters were unchanged in WKY.These results suggest that left ventricular diastolic dysfunction in SHR is not due to an intrinsic abnormality of the cardiac myocytes, and that angiotensin II suppresses the function of myocytes from hypertrophied hearts.

A 36-year-old woman who raised plants in a large greenhouse came to our hospital because of a cough and purulent sputum. A chest X-ray film showed infiltrative shadows in the left middle lung field. Aspergillus fumigatus was isolated from samples of sputum and bronchoalveolar lavage fluid obtained from the left B5. Biopsy specimens revealed hyphae elements of aspergillus species and eosinophils in a plug of viscous material. Also, eosinophils and lymphocytes had infiltrated through bronchial epithelium without aspergillus species. She was given a diagnosis of allergic aspergillosis caused by Aspergillus fumigatus. Fluconazole was given and her symptoms and infiltrative shadows improved. Seventy days after treatment with fluconazole began, her symptoms recurred along with an abnormal shadow in the left upper lung field on a chest x-ray film. Aspergillus flavus, but not Aspergillus fumigatus, was isolated from samples of sputum and bronchoalveolar lavage fluid obtained from the left lung (S1+2). Biopsy specimens of the lung showed eosinophilic pneumonia. She was treated with itraconazole and her symptoms and abnormal radiographic shadows disappeared. She had no asthmatic attack or central bronchiectasis du ring the illness. This was a case of allergic pulmonary aspergillosis without asthmatic symptoms. It is interesting that one species of aspergillus was replaced by another during treatment.

To elucidate the characteristics of end-organ damage in essential hypertension in the elderly, the progression of end-organ damage, with respect to deterioration of renal function and changes in the optic fundi, were compared between young and elderly essential hypertensive patients with the same left ventricular mass index (LVMI). Forty five elderly hypertensive patients (ageor = 65 years) were matched with 40 young patients (ageor = 55 years) for sex and LVMI. All studies were performed under hospitalisation to uniform the background of diet and daily activity. Compared with young hypertensive patients, elderly patients were characterised to have advanced end-organ damage. In young patients, the levels of progression of end-organ damage were significantly correlated with each other, while in elderly patients no relation was observed. In young patients, LVMI was significantly correlated with urinary and plasma noradrenaline, PRA and 24 h blood pressure. In elderly patients, LVMI correlated only with 24 h systolic blood pressure.

A 70-year-old man was admitted for diagnosis of an abnormal shadow on chest X-ray film. Chest X-ray films and chest tomograms showed a club-like shadow close to the pulmonary artery. The tumor was diagnosed as a small cell lung cancer, after transbronchial biopsy. The patient underwent chemotherapy and radiation therapy. This patient had small cell lung cancer that appeared on chest X-ray films to have a strange shape.

The goals of these preliminary studies were to evaluate the effects of a new angiotensin II receptor antagonist, TCV 116, on the daytime blood pressure profile in hospital inpatients with essential hypertension, and to evaluate the clinical efficacy and safety of this agent in outpatients with essential hypertension.In study 1, daytime blood pressure changes were studied in 28 inpatients with mild to moderate essential hypertension (systolic blood pressureor = 150 mmHg, diastolic blood pressureor = 90 mmHg). In study 2, 55 outpatients with essential hypertension (systolic blood pressureor = 160 mmHg, diastolic blood pressureor = 95 mmHg) were enrolled in a dose-finding study.In study 1, after a 1-week placebo run-in period, blood pressure and the pulse rate were measured every 2 h except at night. TCV 116 monotherapy was started at 1 mg/day and increased stepwise at 3- to 5-day intervals to 2, 4 and 8 mg/day until a predetermined reduction in blood pressure was achieved. The daytime profiles of blood pressure and the pulse rate were again monitored at the end of the treatment period. In study 2, after a 4-week placebo run-in period, TCV 116 alone was administered for 2 weeks at 1 mg/day. The dose was then increased to 2 mg/day and stepwise at 2-week intervals to 4 and 8 mg/day until a predetermined reduction in blood pressure was achieved. The total treatment period was 8-12 weeks.In study 1, a sufficient reduction in blood pressure was achieved in 19 of 28 patients (68%), with blood pressure significantly reduced at all measurement points, compared with the placebo run-in period. No differences were seen in the pulse rate. The only adverse reaction reported was a rash in one patient. In study 2, a sufficient reduction in blood pressure was achieved in 42 out of 55 patients (76%). The cumulative efficacy rate increased dose-dependently (15% at 1 mg/day, 38% at 2 mg/day, 60% at 4 mg/day and 76% at 8 mg/day). No differences were seen in the pulse rate. Adverse reactions were reported in three out of 55 patients (5.5%). No dry cough was reported by any of the patients.TCV 116, an angiotensin II receptor antagonist, has potential as an antihypertensive agent. A dose of 4-8 mg once per day appears to be appropriate for the treatment of patients with mild to moderate essential hypertension.

We encountered a 63-year-old man whose dry cough due to interstitial pneumonia had been successfully with an anti-thrombin drug, argatroban, which was given to treat exacerbated Buerger's disease. We therefore prospectively evaluated fibrinogen, fibrin-degradating product D-dimer, thrombin anti-thrombin III complex, and plasmin anti-plasmin complex in patients with interstitisal lung diseases. In a preliminary study, we found that some patients actually had elevated levels of these markers. These findings suggested that increased coagulability was involved in the pathophysiology of interstitial pneumonia. In this study, we measured the levels of serum-soluble thrombomodulin as a marker of endothelial cell damages that lead to hemostasis. We found that serum levels of thrombomodulin were high in about 35% of patients with sarcoidosis, interstitial pneumonia associated with collagen diseases, or idiopathic interstitial pneumonia. Furthermore, these levels decreased as the patients' conditions improved. Although further evaluation is needed, these results suggest that endothelial cell damage and hemostasis are involved in the pathophysiology of interstitial pneumonia.

A 60-year-old obese woman was admitted for evaluation of excessive daytime sleepiness, loud snoring, cyanosis, systemic edema, hypertension and diabetes mellitus. Laboratory examination showed severe hypoxemia, hypercapnea, metabolic alkalosis, hypokalemia and hyperaldosteronism. CT scan showed a left adrenal tumor. A diagnosis of obstructive sleep apnea syndrome associated with primary aldosteronism was established. Metabolic alkalosis, hypokalemia and sodium retention due to hyperaldosteronism were thought to be factors exacerbating her sleep apnea.