Biomedical subjects
Publications and source records attributed to S Kitamura.
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Heart transplantation is the most effective therapy for chronic severe heart failure, but there is an extreme shortage of hearts available. We examined the possibility that cardiomyocytes can be modified genetically prior to being grafted to the heart. We used a replication-defective retrovirus carrying the beta-galactosidase (beta-gal) reporter gene. The beta-gal gene was transduced into murine fetal cardiac myocytes by culturing a recombinant retrovirus-producing cell line in a Transwell plate hung into the primary cardiomyocyte culture. The cultured cells were stained with the di-beta-D-galactopyranoside (FDG) and were sorted by fluorescence-activated cell sorting (FACS). FACS analysis showed that 25.5 +/- 4.3% of the cardiomyocytes in a primary culture were positive for beta-gal activity. These cells were transplanted into the hearts of syngeneic adult mice. Expression of the beta-gal gene in the grafted cells was demonstrated by staining with 5-bromo-4-chloro-3-indoyl-beta-D-galactoside (X-gal). Gene expression was recognized as long as 6 mo after cell transplantation. Histologic analysis showed neither inflammation nor fibrous scar tissue on the host myocardium. This study demonstrated that genetically modified cardiac cells were transplantable to the heart.
We reported previously that cigarette smoking induces bronchoconstriction. In the present investigation we measured the level of peripheral venous blood leukotrienes, which are known to cause marked bronchoconstriction, and plasma complement C3a and C5a, which are known to have chemotactic and anaphylatoxic activities. All of these showed a significant increase after cigarette smoking. These data may suggest that the activation of complement induces the release of leukotrienes, and that these leukotrienes cause bronchoconstriction. It appears likely, therefore, that cigarette smoking induces an increase in peripheral venous blood leukotrienes and complement C3a and C5a, and that such an increase may elicit bronchoconstriction.
This study was intended to develop a simple method using a gas detector tube to detect the end of the service lives of chemical cartridges for organic solvent vapors. The practical usefulness of this method was confirmed by two series of experimental observations of cartridge service lives: (1) The breakthrough times for six organic solvents were determined by passing a test airflow through a cartridge, and the concentration at each breakthrough was measured with a gas chromatograph (GC). These GC-obtained concentrations were compared with the migrated vapor concentrations through each broken cartridge measured with a gas detector tube. (2) CS2 breakthrough of the cartridges used on 32 viscose rayon workers were measured with detector tubes, after which the residual service life of each cartridge was determined. In laboratory experiments the released concentrations detected by the gas detector tube were approximately equal to the final leak concentrations measured by GC. In a field survey the used cartridges exhibiting a stain of CS2 from detector tubes for concentrations greater than 4 ppm were found not to have enough residual adsorption capacity for CS2. Migrated concentrations of CS2 measured with detector tubes were found to be a reasonable predictor of remaining service life.
Effects of long-term left ventricular (LV) support on end-stage cardiomyopathy patients is unclear. We applied our LV assist system (LVAS) to six heart transplant candidates, aged 17 to 49, with dilated cardiomyopathy, including one dilated phase hypertrophied cardiomyopathy. LVAS was installed between the left atrium and the ascending aorta, and the pump was positioned parecorporeally. In all patients, their general condition improved, and their pump flows were kept at 4 to 5 L/min. Exercise was started after stabilization of their general condition under constant pump flow. Natural heart size and function were examined by echocardiography. In the beginning of assist, all patients showed impaired cardiac function and LV dilation. During LV assist, systolic function measured by ejection time improved in all patients. Left ventricular end-diastolic dimension (LVDd), showed a remarkable decrease in two patients, who were weaned from LVAS after 3 months of support. They are doing well more than 1 year and 3 years after removal; peak VO2 levels (ml/min/kg) were 30 at 1.2 years and 27 at 2.7 years after removal. In the other four patients, however, LVDd had no remarkable changes, and three could not be weaned from LVAS. The last was discontinued from LVAS after 5 months of support because of infection and died 2 months after removal. From this experience, long-term LVAS may provide the chance for recovery of the natural heart in patients with end-stage cardiomyopathy. The patients whose hearts showed remodeling were able to be weaned from LVAS, and their heart function maintained in good condition for several years.
The roles of prostaglandins and catecholamines in the hypotensive hemodynamic change during cardiopulmonary support with a venoarterial bypass (VAB) were investigated in a series of chronic animal experiments of gradually reduced pulmonary arterial blood flow (PAF). The VAB system consisted of a pulsatile ventricular assist device, an artificial lung, and the right atrium uptake and descending aorta return cannulae in four adult goats weighing 49-51 kg. The PAF was adjusted to 50, 10, and 0% of the total systemic blood flow. Indomethacin, an inhibitor of prostaglandin production; phentolamine, an alpha-antagonist of catecholamine; and noradrenaline, an agonist of catecholamine were administered at each PAF condition. The mean aortic pressure (mAoP) and the systemic vascular resistance decreased in proportion to the decrease in PAF. Indomethacin increased the mAoP at all PAF conditions, indicating a relationship between prostaglandins and hypotension. Phentolamine decreased the mAoP at all PAF conditions, indicating a normal response of catecholamine receptors. However, noradrenaline increased the mAoP at 50 and 10% PAF, but did not appreciably increase the value at 0% PAF, indicating complete response of catecholamine receptors to endogenous catecholamines at 0% PAF only. In conclusion, prostaglandins play a substantial role in hypotension during VAB, and catecholamines may subsequently increase in compensation for extreme hypotension.
Surgical treatment for aortic regurgitation (AR) caused by Behcet's disease is difficult due to the need to manipulate fragile, inflamed tissue. Valve detachment following aortic valve replacement (AVR) and suture detachment are serious postoperative complications. We investigated the surgical results in 11 patients. Between 1981 and July 1999, 11 patients, 9 males and 2 females, with AR caused by Behcet's disease underwent surgery. The age of these patients ranged from 33 to 60 years (mean, 45+/-8 years). The surgical procedures for AR were AVR in six patients and valved conduit operation in five patients. No patient died during the hospital stay. In a follow-up period ranging from 3 to 204 months (mean, 93+/-64 months) two patients died. Prosthetic valve detachment or suture detachment necessitating redo-operation occurred in four patients (36%) who then underwent a valved conduit procedure as a reoperation. Prosthetic valve detachment was higher in patients with AVR than in patients with a valved conduit operation. Valved conduit reconstruction is indicated in patients with AR caused by Behcet's disease in whom prevention of valve detachment is difficult even by current valve fixation methods.
BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a serious disease that induces hypoxemia and pulmonary hypertension, eventually leading to respiratory failure and right heart failure. We evaluated the results of surgical treatment in patients undergoing circulatory arrest under profound hypothermia. METHODS: Between February 1995 and June 1999, 24 cases of CTEPH were surgically treated. The age of patients (11 males and 13 females) ranged from 21 to 71 years (mean 49+/-15 years). Because of hypoxemia, severe pulmonary hypertension (mean pulmonary artery pressure 45+/-7 mmHg ), and low cardiac output, the functional class of these patients was New York Heart Association (NYHA) III or IV. Following a median sternotomy, profound hypothermia was induced using cardiopulmonary bypass, and pulmonary thromboendarterectomy in the bilateral pulmonary arteries was performed under intermittent circulatory arrest. Surgery was performed emergently in four patients. RESULTS: Of these 24 patients, 2 of 20 patients who underwent elective surgery and 3 of 4 patients who underwent emergent surgery died in the hospital. Symptoms of CTEPH markedly improved in 18 patients who survived the surgery. Pulmonary arterial pressure was decreased to 16+/-6 mmHg, and cardiac output was increased. CONCLUSIONS: When CTEPH is resistant to medical treatment, surgical treatment is useful. When surgical indications are carefully selected, pulmonary thromboendarterectomy using intermittent circulatory arrest under profound hypothermia is quite effective for treating CTEPH.
BACKGROUND: Partial left ventriculectomy (PLV) has been performed without standardized inclusion or exclusion criteria. METHODS: An international registry of PLV was expanded, updated, and refined to include 287 nonischemic cases voluntarily reported from 48 hospitals in 11 countries. RESULTS: Gender, age, ventricular dimension, etiology, ethnology, myocardial mass, operative variation, presence or absence of mitral regurgitation, and transplant indication had no effects on event-free survival, which was defined as absence of death or ventricular failure that required a ventricular assist device or listing for transplantation. Preoperative patient conditions, such as duration of symptoms (> 9 vs < 3 years; p = 0.001), New York Heart Association (NYHA) class (Class IV vs < Class IV; p = 0.002), depressed contractility (fractional shortening [FS] < 5% vs > 12%; p = 0.001), and refractory decompensation that required emergency procedure (p < 0.001) were associated with reduced event-free survival. Five or more cases in each hospital led to significantly better outcomes than the initial four cases. Rescue procedures for 14 patients nonsignificantly improved patient survival (2-year survival 52%) over event-free survival (2-year survival 48%; p = 0.49), with improved NYHA class among survivors (3.6 to 1.8; p < 0.001). Outcome was better in 1999 than in all series before 1999 (p = 0.02) most likely due to patient selection, which was refined to avoid known risk factors such as reduced proportion of patients in NYHA Class IV, FS < 5%, and hospitals with experience in 10 or less cases. A combination of these risk factors could have stratified 17 high-risk patients with 0% 1-year survival and 26 low-risk patients with 75% 2-year event-free survival. CONCLUSION: Avoidance of risk factors appears to improve survival and might help stratify high- or low-risk patients. Although less symptomatic patients with preserved contractility had better results after PLV, change of indication requires prospective randomized comparison with medical therapies or other approaches.
To test for the existence of genomic imprinting in human gynecologic tumors, we analyzed the allelic expression of human insulin-growth factor-II (IGF-II) genes. Genomic imprinting is the parental allele-specific expressions of genes, and recently imprinting of IGF-II gene has demonstrated that parental IGF-II was monoallelically expressed. To study whether IGF-II gene imprinting occurs in human gynecologic tumors, we examined allele-specific expression using an ApaI polymorphism in the 3' untranslated region of IGF-II gene exon 9. We used 19 gynecologic tumor cell lines, and 66 human gynecologic tumors. Four of 19 cell lines (21%) were informative, and three of these four cell lines (75%) revealed loss of imprinting (LOI). For gynecologic tumors, 24 of 66 were informative (36%), and 5 of the 24 (21%) had LOI. We have reported here that the IGF-II gene is expressed biallelically in some gynecologic tumors. We suggest that LOI of the IGF-II gene is involved in the development of some gynecologic tumors.
We examined the bacterial colonization of the upper respiratory tract of 110 patients with primary lung cancer (PLC), 75 patients with nonmalignant lung diseases (NMLD) and 45 healthy volunteers (HV), comparing the sensitivity of expectorated sputum, and throat and nasal swabs. The frequency of bacterial colonization of the upper respiratory tract was significantly higher in the PLC patients (59.1%) than in NMLD patients (37.3%, p < 0.01) and HV (37.8%, p < 0.01). The frequency of gram-negative colonization was significantly higher in PLC patients than in the other subjects (p < 0.01). Expectorated sputum and nasal swab were the most sensitive for detection of whole bacteria and methicillin-resistant Staphylococcus aureus in the patients with PLC. Our results showed that PLC patients are significantly more frequently colonized by bacteria in their upper respiratory tracts and that a combination culture of expectorated sputum and nasal swab is suitable to estimate the bacterial colonization of the upper respiratory tract in the patients.
We evaluated the effectiveness of the Helios gene gun system, a recently developed, commercially available gene gun device. Following skin transfection with beta-galactosidase or interleukin-12 cDNA using the gene gun, beta-galactosidase expression was detected exclusively in the epidermal cell layer, and transgene expression of IL-12 cDNA was maximal 2 days post-transfection and remained detectable for at least 5 additional days. Furthermore, particle-mediated delivery of IL-12 cDNA into epidermal cells overlying an intradermal tumor resulted in a significant suppression of tumor growth of Lewis lung carcinoma. Appreciable levels of IFN-gamma production were readily detected at the skin transfection site, and were induced from splenocytes and lymph node cells in the IL-12 treated mice. These results show that in vivo delivery of IL-12 cDNA into skin by the Helios gene gun device can have a useful routine application for cancer therapy research.
Sodium nifursyrenate [beta-(5-nitro-2-furyl)-p-carboxystyrene sodium salt, NSA-Na] is an antibacterial nitrofuran which has been widely used for prevention and treatment of bacterial infections in fish in Japan. When NSA-Na was anaerobically incubated with rabbit liver cytosol and 2-hydroxypyrimidine, 1-(p-carboxyphenyl)-5-cyano-3-oxo-1,4-pentadiene (cyano-pentadienone), 1-(p-carboxyphenyl)-5-cyano-3-oxo-1-pentanone (cyano-pentanone), and 1-(p-carboxyphenyl)-5-cyano-3-pentanone (cyano-pentanone) were isolated and identified as the metabolites of the nitrofuran. In addition, when cyano-pentenone and cyano-pentanone were aerobically incubated with the liver preparation and NADPH, 1-(p-carboxyphenyl)-5-cyano-3-hydroxy-1-pentene (cyano-pentenol) and 1-(p-carboxyphenyl)-5-cyano-3-pentanol (cyano-pentanol) were also isolated and identified as the metabolites of the nitrofuran in its further metabolism, respectively. The anaerobic incubation of NSA-Na with rat liver cytosol and 2-hydroxypyrimidine resulted in the formation of cyano-pentadienone and cyano-pentanone. In this case, however, cyano-pentenone was not detectable. On the other hand, when NSA-Na was anaerobically incubated with sea bream liver cytosol and NADPH, the formation of cyano-pentenone, cyano-pentanone, and cyanopentenol, but not cyano-pentadienone, was observed. Furthermore, cyano-pentanone was metabolized to cyano-pentanol by the fish liver preparation with NADPH under aerobic conditions. When NSA-Na was given orally to rabbits, cyano-pentanone, cyano-pentenol, cyano-pentanol, and beta-(acetamido-2-furyl)-p-carboxystyrene (acetamidofuran) were identified as the urinary metabolites of the nitrofuran.(ABSTRACT TRUNCATED AT 250 WORDS)