The treatment of uterine leiomyosarcoma: clinical outcomes of 18 cases and the effectiveness of chemotherapy.

PURPOSE: To investigate clinical outcomes with respect to the effectiveness of chemotherapy in the treatment of uterine leiomyosarcoma. METHODS: Study subjects were 18 patients with uterine leiomyosarcoma treated surgically at our hospital between February 1986 and December 2007. A chemotherapy regimen that combined ifosfamide, epirubicine, and cisplatin (IEP) was used as the main first-line chemotherapy. RESULTS: FIGO disease stages were as follows: Stage I (n = 11), Stage II (n = 1), Stage III (n = 3), Stage IV (n = 3). Five-year overall survival of patients with Stage I-III disease was 65.3% (95% CI: 46.1-92.4%). None of patients with Stage IV disease survived for more than two years. Of seven patients who suffered advanced or recurrent disease, six received IEP; the response rate was 50%, one complete response and two partial responses. CONCLUSIONS: The combination of surgery and chemotherapy seems to be an acceptable treatment for uterine leiomyosarcoma. IEP may be an active regimen for this aggressive disease.

Phospholipid acyl chain metabolism during the differentiation of murine leukemia cell lines. On the redistribution of polyunsaturated acyl chains among phospholipids.

Phospholipid acyl chain metabolism was investigated during the differentiation of murine myeloid leukemic cells (MI cells). Fatty acid composition of the phosphatidylethanolamine (PE) fraction showed no significant change, while a marked decrease in the polyunsaturated fatty acid content was observed in the phosphatidylcholine (PC) fraction during the course of differentiation. When these cells were incubated with [14C]arachidonate, it was actively incorporated initially into PC, and subsequently, gradually mobilized to PE from PC during the 72 h of culture. This characteristic redistribution was observed specifically with polyunsaturated acyl chains. Thus, the normal metabolic pathway of polyunsaturated fatty acids in these cells appears to consist of two steps: firstly fatty acids are incorporated from the external medium into the form of polyunsaturated PC, and, subsequently, are stored within cells as a metabolically stable pool after the conversion into the form of polyunsaturated PE. In differentiated cells, this redistribution pathway was significantly enhanced, suggesting a change in the activity of the deacylation-reacylation cycle during the course of differentiation,

Functional and histopathologic correlation in patients with dilated cardiomyopathy: an integrated evaluation by multivariate analysis.

To correlate left ventricular function and histologic features in patients with dilated cardiomyopathy, precise indexes of hemodynamics and semiquantitative histologic data were combined for multivariate analysis. Right endomyocardial biopsy was performed at the time of cardiac catheterization. Five hemodynamic indexes were used for functional assessment: ejection fraction, ratio of end-systolic stress to volume index, end-diastolic stress, time constant (T) of left ventricular pressure fall, and end-systolic stress. Six histologic findings (disarray of myofibers, hypertrophy of myofibers, scarcity of myofibrils, nuclear changes of myofibers, vacuolization of myofibers and proliferation of collagen fibers) were graded from (-) to (4+). Each finding was assigned to category (-) or (+) according to the absence or presence of significant abnormality. Ordinary statistical analysis revealed that, although ejection fraction was lower in category (+) for proliferation of collagen fibers, ratio of end-systolic to volume index was reduced for category (+) of hypertrophy of myofibers. A significant correlation was present between hypertrophy of myofibers and proliferation of collagen fibers by Spearman rank correlation. When principal component analysis was applied to the hemodynamic data, two principal components could be extracted. Fisher's discriminant analysis could clearly differentiate two categories (-) and (+) in the semiquantitative histologic finding of proliferation of collagen fibers. The analysis indicated that contractility was reduced with elevated afterload in that category (+). Thus, proliferation of collagen fibers may play a pivotal role in deteriorating contractility in patients with dilated cardiomyopathy.

Increased membrane permeability of skin fibroblasts from the spontaneously hypertensive rat.

Recently, we have demonstrated several abnormalities in Na+ and K+ homeostasis in cultured vascular smooth muscle cells derived from spontaneously hypertensive rats (SHR). To study whether similar defects can be identified in other cells of this rat strain, 86Rb and 22Na flux experiments as well as measurements of intracellular Na+ and K+ levels were performed in cultured skin fibroblasts of SHR and normotensive Wistar-Kyoto rats (WKY). The efflux rate constant (ke) for Rb+ (K+ analogue) was higher (p less than 0.001) in fibroblasts of SHR than in those of WKY (2.11 +/- 0.03 and 1.66 +/- 0.02 X 10-2/min; mean +/- SEM). The ouabain-insensitive influx rate constant (ki) for Rb+ was also higher (p less than 0.001) in fibroblasts of SHR than in those of WKY (13.26 +/- 0.41 and 10.71 +/- 0.27 X 10-2/min. On the other hand, the activity of the Na+-K+ pump of cells of SHR (44.81 +/- 0.81 X 10-2/min) was not different from that of cells of WKY (44.72 +/- 0.47 X 10-2/min). This parameter was obtained by calculating the ouabain-sensitive Rb+ influx rate constant. There was also no difference in the Na+ uptake (in the presence of ouabain) between cells of the two rat strains. Although there was no statistically significant difference in the measured intracellular total K+ levels between the two groups, on the basis of equilibrium distribution of 86Rb+, we calculated a significantly lower (p less than 0.001) level of exchangeable intracellular K+ in fibroblasts of SHR (98.2 +/- 1.2 mEq/L) as compared with cells of WKY (115.3 +/- 1.5 mEq/L). These findings indicate increased membrane permeability to K+ in fibroblasts of SHR and that this defect is likely to be innate to their membrane structure.

Bumetanide-sensitive sodium-22 transport in vascular smooth muscle cell of the spontaneously hypertensive rat.

The effect of bumetanide, a known probe of Na+, K+ cotransport, on 22Na+ uptake and washout was examined in serially passed cultured vascular smooth muscle cells of spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Wistar rats. In Ca2+-deficient medium, the drug exerted the greatest effect on 22Na+ washout in vascular smooth muscle cells from SHR and the least effect on cells from WKY. The respective mean values for the apparent bumetanide-sensitive 22Na+ washout rate constants (Ke; X 10(-2)/min) were 7.2, 4.3, and 1.7 for cells from SHR, WKY, and Wistar rats. In both 1 mM Ca2+ and Ca2+-deficient medium, in the presence of 1 mM ouabain, vascular smooth muscle cells from SHR had the highest plateau phase of 22Na+ uptake among the three cell preparations. All cells exhibited higher 22Na+ uptake in Ca2+-deficient medium than in 1 mM Ca2+ medium. Under this condition, bumetanide caused an additional rise in steady state 22Na+ uptake that was most pronounced in cells from SHR (21.3% versus 16.6% for Wistar rats and 4.8% for WKY). This finding indicates that a quantitatively greater inhibition of washout than of the uptake component of the bumetanide-sensitive 22Na+ transport occurs in Ca2+-deficient medium. It is concluded that, in Ca2+-deficient medium, the bumetanide-sensitive 22Na+ washout is higher in vascular smooth muscle cells of SHR than in those of normotensive controls and that this phenomenon reflects a higher Na+ turnover in vascular smooth muscle cell in the hypertensive rat strain.

Cadmium effect on the Na,K-ATPase system in cultured vascular smooth muscle cells.

The present study focuses on the interaction between cadmium (Cd) and the Na, K-ATPase system in in vitro grown vascular smooth muscle cells (VSMCs) derived from the rat carotid artery. In disrupted VSMCs rendered permeable by osmotic shock, Cd inhibited Na, K-ATPase; I50 was reached at 10(-5) M Cd. Mg-ATPase was also inhibited by Cd; I50 was attained at concentrations of 10(-4) M Cd. Cd inhibition of Na,K-ATPase in the VSMCs was noncompetitive with respect to Na, K, and ATP. Rubidium transport experiments performed with intact VSMCs demonstrated that within an incubation period of 150 minutes, a concentration of 10(-4) M Cd in the extracellular fluid exerted no acute effect on the Na-K pump. Within this time interval, intracellular Cd attained a concentration eightfold higher than the extracellular Cd concentration. Thus, it appears that under acute conditions Cd exerts its inhibitory effect on Na, K-ATPase only in disrupted VSMCs. The data further suggest that, in the VSMC, conditions under which Cd inhibits Na, K-ATPase are consistent with inhibition from the cytoplasmic side of the cell membrane.

Molecular cloning, sequencing and expression of cDNA encoding human trehalase.

A complete cDNA clone encoding human trehalase, a glycoprotein of brush-border membranes, has been isolated from a human kidney library. The cDNA encodes a protein of 583 amino acids with a calculated molecular weight of 66,595. Human enzyme contains a typical cleavable signal peptide at amino terminus, five potential glycosylation sites, and a hydrophobic region at carboxyl terminus where the protein is anchored to plasma membranes via glycosylphosphatidylinositol. The deduced amino acid sequence of the human enzyme showed similarity to sequences of the enzyme from rabbit, silk worm, Tenebrio molitor, Escherichia coli and yeast. Northern blots revealed that human trehalase mRNA of approx. 2.0 kb was found mainly in the kidney, liver and small intestine. Expression of the recombinant trehalase in E. coli provided a high level of the enzyme activity. The isolation and expression of cDNA for human trehalase should facilitate studies of the structure of the gene, as well as a basis for a better understanding of the catalytic mechanism.

Auscultatory perception of the fourth heart sound: effects of interval form fourth to first sound (S4-S1) and aging.

A clinically heterogeneous group of 48 subjects (aged 19 to 76 years) were searched for a fourth heart sound (S4) by three independent "blind" auscultators. Phonocardiograms recorded immediately after auscultation were measured by another "blind" observer. An S4 was identified in 32 subjects (67 per cent) in phonocardiograms with nominal filter peaks of both 70 and 35 hertz. Results in these subjects revealed two groups by auscultatory performance: those with an "easily heard" and those with an "easily missed" S4. Subjects with an "easily missed" S4 were significantly younger than those with an "easily heard" S4 (31.2 +/- 2.8 years versus 50.0 +/- 4.0 years, P less than 0.001). P-R and P-S4 intervals and relative amplitude of S4 (ratio of fourth to first heart sound [S1] amplitude) were not significantly different in the two groups. Splitting of the first heart sound (S1) was observed more frequently in the phonocardiogram of patients with an "easily missed" S4, but this trend did not reach statistical significance. The interval between S4 and the low frequency component of S1 was significantly short in those with an "easily heard" S4 (49.4 +/- 4.1 msec versus 70.0 +/- 5.0 msec, P less than 0.005). The mean S4-S1 (low frequency component) interval for the group with an "easily heard" S4 approximated 1 cycle length for S4 vibrations, a finding consistent with temporal acoustic summation. An alternate hypothesis is modification of S1.

Cardiovascular effects of a newly synthesized cardiotonic agent (TA-064) on normal and diseased hearts.

A new inotropic agent, TA-064, (-)-alpha-(3,4-dimethoxyphenethylaminomethyl)-4-hydroxybenzylalcohol, was shown to have strong effects in experimental animals. Its effectiveness and associated adverse effects were tested in humans invasively (n = 6) and noninvasively (n = 17). Increasing doses of intravenous infusion (1, 2, and 4 micrograms/kg/min) increased plasma levels to 15, 35, and 82 ng/ml, respectively, resulting in marked increases in the peak rate of left ventricular pressure rise (dP/dt) (1,450 +/- 63 to 3,042 +/- 349 mm Hg/s) (mean +/- standard error of the mean [SEM], p less than 0.01) and the ratio of dP/dt to left ventricular pressure at a developed pressure of 40 mm Hg (25 +/- 3 to 39 +/- 2 s-1) (p less than 0.01), with a reduction in left ventricular end-diastolic pressure (12 +/- 2 to 4 +/- 1 mm Hg) (p less than 0.01). Minimal or no changes were seen in heart rate and left ventricular systolic pressure. After a single oral dose (10 mg), the plasma level reached its peak at 90 minutes (16 +/- 9 ng/ml, n = 17). A positive inotropic effect was confirmed echocardiographically in both healthy volunteers (n = 8) and patients with congestive heart failure (CHF) (n = 9) who were maximally treated with conventional regimens: increase in mean velocity of circumferential fiber shortening (healthy volunteers: 1.29 +/- 0.05 to 1.60 +/- 0.11 circ/s [p less than 0.05]; patients with CHF: 0.69 +/- 0.08 to 0.93 +/- 0.09 circ/s [p less than 0.01]), ejection fraction (healthy volunteers: 68 +/- 2 to 75 +/- 2% [p less than 0.05], patients with CHF: 37 +/- 4 to 45 +/- 5% [p less than 0.01]) without change in heart rate. The cardiac index was increased only in the CHF group (2.71 +/- 0.22 to 3.21 +/- 0.24 liters/min/m2) (p less than 0.05). No significant untoward effects were observed. Thus TA-064 is a potent inotropic agent and can be used either parenterally or orally. Salutary effects can be expected in patients with congestive heart failure who are treated with digitalis and diuretic agents.

Hypertrophic nonobstructive cardiomyopathy: a precise assessment of hemodynamic characteristics and clinical implications.

A precise assessment of left ventricular function was performed in 20 patients with hypertrophic nonobstructive cardiomyopathy to elucidate the basic pathophysiology, and the data were compared with those in 22 normal subjects. Whereas end-diastolic pressure was high in those with cardiomyopathy, a more accurate index of preload, end-diastolic stress, did not differ from normal value. Afterload was about half the normal value. Both isovolumic indexes [peak positive dP/dt and (dP/dt)/DP40] and ejection phase indexes of contractility (ejection fraction) were in the normal range; however, the end-systolic stress volume ratio was significantly reduced (43% of the normal value). Although the left ventricular minute work index was in the normal range, the unit muscle performance (minute work/mass) was very low (49%). An abnormality of left ventricular relaxation was demonstrated by low peak negative dP/dt (56%) and prolonged time constant T (191%), and a stiff left ventricle was demonstrated by a high diastolic elastic stiffness constant (129%). These observations suggest that the contraction of a unit muscle is inappropriate to produce an adequate contraction of the whole ventricle, and that hypertrophy might be an adaptive process to maintain normal systolic function by increasing mass and reducing afterload.

Mechanisms of compensation and decompensation in dilated cardiomyopathy.

Left ventricular (LV) function was evaluated in 32 patients with dilated cardiomyopathy (DC) who underwent cardiac catheterization during the past 6 years (group 4), and the results were compared with the data of 30 normal subjects (group 1). The patients were divided into mildly (group 2, 12 patients) and severely symptomatic subgroups (group 3, 20 patients). DC was characterized by dilated and poorly contracting left ventricle with increased muscle mass, reduced cardiac output and elevated systemic vascular resistance. LV volume was larger, ejection fraction was lower, and end-diastolic and end-systolic stresses were higher in group 3 than in groups 1 and 2. No significant differences were seen in LV muscle mass and wall thickness between groups 2 and 3. A significant inverse correlation was seen between ejection fraction and end-systolic stress in patients with DC (Y = -0.05x + 48.7, r = 0.57, p less than 0.01). The slope of the correlation line between end-systolic stress and volume in DC (Y = 1.20x + 135, r = 0.52, p less than 0.02) was less steep than that of normal subjects (Y = 3.68x + 40, r = 0.64, p less than 0.001). These observations indicate that the primary problem of DC is depressed contractility.(ABSTRACT TRUNCATED AT 250 WORDS)

Clavicular Auscultation. Preferential clavicular transmission and amplification of aortic valve murmurs.

Clavicular transmission of aortic valve murmurs was investigated in 15 consecutive patients. In all patients, transmission to the clavicle of aortic systolic murmurs was detected both by auscultation and by phonocardiographic studies. Of seven patients with aortic diastolic murmurs, auscultation revealed clavicular transmission in six, but only four were recordable. There was increased murmur amplitude over the clavicle in 13 out of 15 cases. In contrast, murmurs were attenuated over the subclavian artery in eight out of nine and over the carotid artery in nine out of 11 patients. We conclude that clavicular auscultation regularly discloses aortic valve murmurs. The aortic systolic murmurs are consistently propagated to the clavicle, where they are usually conspicuously amplified. Aortic systolic murmurs are less frequently transmitted to the carotid and subclavian arteries, where they are usually considerably attenuated. Clavicular auscultation appears to be more rewarding than the traditional search for transmission of aortic murmurs to the carotid artery.

Noninvasive differentiation of cardiomyopathy from coronary disease; pulse transmission time and systolic time intervals.

Systolic time intervals and central pulse transmission time were compared in cardiomyopathy (CM) patients and age-and sex-matched patients with coronary artery disease (CAD). Significant differences were found in pulse transmission time (shorter in the CAD patients (p less than .001) and in the pre-ejection period (p less than .001), ejection time index (p less than .05), and in the ratio of the pre-ejection period to the left ventricular ejection time (p less than .001); all were markedly abnormal in the CM group. Pulse transmission time differences may have been the result of more generalized arteriosclerotic disease in the CAD patients. It appears that both systolic time intervals and pulse transmission time clearly distinguish CM from CAD.

The effect of near-maximal isometric stress on the presence and amplitude of fourth heart sounds.

Near-maximal isometric exercise (IHG) was employed to provoke new, or alter pre-existing fourth heart sounds (S4s) in ambulatory middle-aged normal subjects (N), hypertensive patients (HHD), and patients with coronary disease (CAD). S4 amplitudes and systolic time intervals (STIs) were measured blindly. No subjects without a resting S4 developed a new S4 during IHG. Increases and decreases of pre-existing S4 provoked by IHG were not statistically different among all groups. Among subjects matched for presence of S4, STIs during IHG showed significant shortening of the ejection time index and prolongation of Q-Im in the HHD group only. When the subjects who increased a resting S4 during IHG were compared with the subjects who decreased their resting S4 during IHG there were no significant differences in the responses of STIs. Thus, in these ambulatory, hypertensive patients, coronary patients, and normal subjects, near-maximal IHG did not induce new S4s and had variable effects on pre-existing S4s. Neither type of S4-response could be associated with corresponding changes in systolic time intervals.

Platelet-activating factor detected in bronchoalveolar lavage fluids from an asthmatic patient.

It recently has been recognized that platelet-activating factor (PAF) may be a mediator of asthma exacerbation. We had the opportunity to analyze bronchoalveolar lavage fluids from an asthmatic infant, which were characterized by neutrophil infiltration. The patient's lungs were washed on three occasions with saline during asthmatic attacks. PAF was found in each case on the basis of its ability to cause the immediate aggregation of washed rabbit platelets. The PAF detected was equivalent to 1-1.4 pmol of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine, three quarters of which were recovered in cell-associated form. By contrast, we did not detect PAF in bronchoalveolar exudates from patients with laryngeal stenosis or with respiratory distress syndrome. LysoPAF, the direct precursor as well as initial metabolite of PAF, was also analyzed after being converted to PAF by acetylation. There was a wide variation in the amount of lysoPAF present in individual patients, suggesting that lysoPAF levels cannot be taken as an indicator for the presence of PAF.

Postrest contraction in the ventricular papillary muscle of spontaneously diabetic WBN/Kob rat.

In the present study, we investigated the characteristics of the postrest contraction (PRC) in chronic diabetic ventricular muscle. We used WBN/Kob rats of 7-8 weeks as the spontaneously diabetic animal and Wistar rats of 7-8 weeks as the control. We found: (1) No significant differences were seen in the amplitude, the contracting speed, and the relaxing speed of electrically stimulated twitch tension between control and WBN/Kob rats. In addition, the relationship between amplitude of twitch tension and stimulus cycle lengths (0.2-5 sec) was very similar in both animals. (2) The ratios of the first twitch tension (T1) of PRC with various rest intervals (5-600 sec) to the steady-state tension (Tss) were significantly smaller in the diabetic rats than in the controls. (3) When the preparation was stimulated at shorter cycle lengths, the recovery process of PRC was separated into at least two components (fast and slow components). In the diabetic rats, the time constant (tau) of both components was significantly longer than in controls. (4) After caffeine (10(-3) M) treatment, tau of the fast component in the control rats became longer, whereas it remained unchanged in diabetic rats. These findings suggest a dysfunction of the intracellular calcium handling system in spontaneously diabetic heart that is likely to include impaired calcium sequestration and/or extrusion.

Recurrent bacterial meningitis. Secondary to malformation of the inner ear.

A 5-year-old girl with congenital sensorial deafness experienced four episodes of bacterial meningitis in a 13-month period. On the fourth episode, an extensive search for the cause of recurrent meningitis was conducted. Complete immunologic studies, humoral, cellular, and phagocytic, yielded negative results. Precise otological examination, i.e., skull roentgenograms, an inner ear target CT scan, and puncture of the eardrum, was attempted, which disclosed the inner ear malformation (Mondini's anomaly) and a cerebrospinal fluid (CSF) fistula. CSF discharge from the oval window was repaired surgically. Extensive otologic evaluation should be conducted in patients with recurrent bacterial meningitis.

[Clinical evaluation of a new cephem S-1108 in infants and children].

A clinical study in children has been performed on S-1108, a newly developed cephem antibiotic. S-1108 was given orally to 30 patients, at doses between 8 and 12 mg/kg/day in 3 divided doses for 2 to 10 days. Clinical evaluations were made on 26 patients consisting of 12 patients of pharyngitis, 5 of tonsillitis and of impetigo, one each of bronchitis, cystitis, lymphadenitis and cellulitis. Overall clinical effects were excellent in 10, good in 15, fair in 1 with an efficacy rate of 96%. As to adverse reactions, mild diarrhea (2 patients) and transients elevation of transaminases (one patient) were observed. These data suggest that S-1108 is a useful oral antibiotic for the treatment of bacterial infections in children.

[Clinical evaluation of a new oral penem, SY5555, in infants and children].

A clinical study was performed on SY5555, a newly developed penem antibiotic, in children. SY5555 was given orally to 14 patients at 19-29 mg/kg/day in 3 doses for 4 to 12 days. Clinical evaluations were made on the 14 patients including 4 with pharyngitis, 7 with tonsillitis, one with urinary tract infection, and 2 with impetigo. Overall clinical effects were excellent in 2, good in 12, with an efficacy rate of 100%. Causative organisms (Staphylococcus aureus and Streptococcus pyogenes) were all eradicated. As to adverse reactions, mild diarrhea was observed in 4 patients. These data suggest that SY5555 is a useful oral antibiotic for the treatment of bacterial infections in children.

[Clinical evaluation of a new parenteral cephem, cefozopran, in children].

Cefozopran (CZOP, SCE-2787), a new parenteral cephem, was evaluated for its antibacterial activity and clinical efficacy. CZOP, 24.0-78.0 mg/kg/day, was given to 11 pediatric patients in 3 dose a day via 30-minute drip infusion. Clinically evaluated were nine patients including 4 with acute pneumonia, 2 with urinary tract infections, 2 with lymphadenitis and 1 with sepsis. Two patients were excluded because of possible non-bacterial infections. Clinical efficacies were excellent in 5, good in 3 and fair in 1. Bacteriological responses were confirmed for 5 strains in 5 patients. Four strains were eradicated, but one strain was not. MICs of CZOP were equal to those of ceftazidime. Side effects or abnormal laboratory test results were observed in 3 patients; diarrhea in 1, elevated GPT in 1 and thrombocytosis in 1, but none of them was significant.