Randomized study of individualized induction therapy with or without VCR, and of maintenance of 4 or 12 courses in adult AML: JALSG-AML87. Japan Adult Leukemia Study Group (JALSG).

We asked 2 questions in this study. First was the additional effect of VCR in induction therapy, and the second was the duration of maintenance therapy. Adult AML were treated by an individualized response-oriented induction therapy with behenoyl Ara-C 200 mg/m2 daily + 6MP 70 mg/m2 daily + prednisolone 40 mg/m2 on days 1-4 + DNA 40 mg/m2 on days 1-3 and additionally on days 7, 8, 11, 12 (for M3, DNR 50 mg/m2 daily) (BHAC-DMP) until bone marrow became severely hypoplastic with less than 5% of blasts. Patients were randomized to BHAC-DMP or BHAC-DMP + VCR 0.35 mg/m2 on days 1-4. After obtaining CR, 3 courses of intensive consolidation therapy were given together with I.T. MTX+Ara-C+PSL. Maintenance intensification therapy was randomized to either 4 or 12 courses given every 2 months. Patients of age greater than or equal to 60 received about 2/3 reduced doses. From June 1987 to Sept. 1989, 265 consecutive adult AML were registered from 19 institutions and 258 were evaluable. Age ranged from 15 to 79 (med., 48). Out of 258, 200 (77.5%) achieved CR (80% in 209 of age less than 60 and 65% in 49 of age greater than or equal to 60). Unexpectedly, addition of VCR reduced the high CR rate of BHAC-DMP significantly (84% to 70%, p = 0.007). At the median follow-up of 37 mo., overall survival is 37%, and event-free survival (EVS) 27%. Survival, continuing CR and disease-free survival (DFS) rates of 200 CR cases are 45%, 40% and 35%, respectively. Patients received 12 courses of maintenance therapy showed better DFS (P = 0.0555). The VCR group had significantly worse EFS. By multivariate analysis, significant prognostic factors for the achievement of CR were age less than 60, PS 0-2 and no addition of VCR. Significant factors for longer DFS were induction of CR by one course, FAB M3 or M5 and age less than 50. The present multi-institutional study confirmed the high CR rates of the response-oriented individualized therapy reported from several centers in Japan, but failed to support an additional effect of VCR reported from one center.

Effect of selenium deficiency on cellular and extracellular glutathione peroxidases: immunochemical detection and mRNA analysis in rat kidney and serum.

To determine the effect of selenium (Se) deficiency on expression of glutathione peroxidase (GSH-Px) 1 and 2, we measured GSH-Px activity in rat serum, liver and kidneys, serum immunoreactive GSH-Px 2, and the mRNAs of kidney GSH-Px 1 and 2. We purified rat GSH-Px 2 and raised polyclonal antibodies. Immunoreactive GSH-Px 2 was measured by rocket immunoelectrophoresis. GSH-Px 2 was purified 1470-fold with a specific activity of 250 units/mg. Immunoblotting detected only GSH-Px 2 in rat serum, and much less GSH-Px 2 than GSH-Px 1 in kidney. Immunoblot signal of kidney GSH-Px 1 and 2 decreased progressively in Se deficient rats. Serum GSH-Px activity in Se deficient rats at 1, 2, 3, and 4 weeks declined to 33, 20, 10, and 9% of the control, while the serum level of immunoreactive GSH-Px 2 was 58, 24, 15, and 10% of the control, suggesting the presence of an inactive protein at week 1. GSH-Px activity declined to 4 and 11% of the control in the liver and kidney at 4 weeks. The mRNAs of kidney GSH-Px 1 and 2 showed similar decreases, and were 24 and 23% of the control at 4 weeks. GSH-Px mRNA levels were better preserved than GSH-Px activity, suggesting that GSH-Px expression was regulated at both pre-translational and translational levels.

Indications for an expandable metallic stent for tracheobronchial stenosis.

An expandable metallic stent was used in 9 patients with tracheobronchial stenosis. Of the 8 patients with malignant stenosis, 6 had extrinsic compression and 2 had intraluminal tumor invasion. The 1 patient with nonmalignant stenosis had postreconstruction bronchomalacia and granulation tissue affecting different parts of the tracheobronchial tree. The expandable metallic stent successfully dilated tracheobronchial stenosis due to extrinsic tumor compression and malacia. However, it was not effective for stenosis due to intraluminal tumor invasion or granulation tissue because of the growth of tumor or granulation tissue between the wires of the stent. However, an expandable metallic stent covered with Dacron mesh was effective in 1 patient with intraluminal tumor invasion because tumor growth was blocked by the mesh. We conclude that an expandable metallic stent is effective for tracheobronchial stenosis due to extrinsic tumor compression, but not for stenosis due to intraluminal tumor invasion or granulation tissue.

Induction of glutathione peroxidase in response to inactivation by nitric oxide.

To determine effect of nitric oxide (NO) on cellular glutathione peroxidase (GPX) level in living cells, we measured the activity, protein and mRNA of GPX in rat kidney (KNRK) cells under a high NO condition. Combined treatment of lipopolysaccharide (LPS, 1 microgram/ml) and tumor necrosis factor-alpha (TNF-alpha, 50 ng/ml) synergistically enhanced (23-folds) nitrite production from KNRK cells. This was suppressed by an inducible NO synthase (iNOS) inhibitor (aminoguanidine, N-nitro-L-arginine methylester hydrochloride) and arginase. iNOS expression was detected by RT-PCR in the treated cells. GPX was inactivated irreversibly when the cells had been homogenized before exposure to a NO donor, S-nitroso-N-acetylpenicillamine (SNAP). In living KNRK cells, SNAP and LPS + TNF-alpha exerted a transient effect on the GPX activity. The treatment with SNAP (200 microM) or sodium nitroprusside (200 microM) enhanced GPX gene expression, which was blocked by a NO scavenger, 2-phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide. GPX mRNA was markedly increased by the treatment with LPS + TNF-alpha, and aminoguanidine blocked the effect. In cells metabolically labeled with 75Se, LPS + TNF-alpha accelerated the incorporation of radioactivity into GPX molecule by 2.1-fold. These results suggest that inactivation of GPX by NO triggers a signal for inducing GPX gene expression in KNRK cells, thereby restoring the intracellular level of this indispensable enzyme.

Effect of obesity and troglitazone on expression of two glutathione peroxidases: cellular and extracellular types in serum, kidney and adipose tissue.

To determine the effect of obesity on expression of cellular- (C-) and extracellular (EC-) glutathione peroxidase (GPX) in serum, kidney and adipose tissue, we measured GPX in serum, kidneys and adipose tissue of the obese Otsuka-Long-Evans-Tokushima Fatty (OLETF) rat and its lean counterpart (LETO). We also investigated the effect of troglitazone. Five each of OLETF and LETO rats were fed diet with or without 0.2% troglitazone for 10 days. Final body weight, kidney weight, blood glucose and serum tumor necrosis factor-alpha (TNF-alpha) level were higher in OLETF rats than in LETO rats. Serum and kidney GPX activities were higher, but adipose tissue GPX activity was lower, in OLETF rats than in LETO rats. Troglitazone treatment decreased adipose tissue GPX activity and abolished overproduction of TNF-alpha in OLETF rats. Immunoblot analysis, for the first time, revealed that both obesity and troglitazone suppressed the protein signals for C-GPX and EC-GPX in adipose tissue. Serum protein carbonyl groups were increased in OLETF rats and troglitazone completely blocked this increase. Increased serum GPX activity in obese rat was due to the increased secretion of EC-GPX from the kidney. Troglitazone protected against the enhanced oxidative stress induced by obesity independently of the serum GPX concentration.

Effect of peroxisome proliferator on extracellular glutathione peroxidase in rat.

Glutathione peroxidase (GPX) activity measured using tert-butyl hydroperoxide as a substrate detects solely cellular/classical GPX (cGPX) in rat liver and kidney, and extracellular/plasma glutathione peroxidase (EC-GPX) in rat serum. To investigate the effect of peroxisome proliferator on EC-GPX, we measured activities of GPX and catalase in rat liver, kidney and serum, and then we performed immunoblot and Northern blot analyses in the kidney. Rats were fed on a diet containing either 2% (w/w) di-2-ethylhexyl phthalate (DEHP) or 0.25% (w/w) clofibrate for two or three weeks, respectively. Catalase activity was increased 1.4-fold (p < 0.001) in the treated liver, but not in the kidney. GPX activity was decreased to 59.2% (DEHP) and 70.4% (clofibrate) of the control (p < 0.001) in the serum but was unaltered in the liver and kidney. The immunoreactivity for EC-GPX was also significantly decreased in the DEHP-treated kidney compared with the control. The mRNA levels of EC-GPX and cGPX were unaltered. The immunostaining for 4-hydroxy-2-nonenal, a maker of lipid peroxide, was more intense in the treated kidney compared with the control. These results suggest that EC-GPX is post-transcriptionally decreased by peroxisome proliferator through the oxidative stress in the renal tubules. This may be a new deleterious effect of an endocrine disruptor DEHP.

Troglitazone inhibits the expression of inducible nitric oxide synthase in adipocytes in vitro and in vivo study in 3T3-L1 cells and Otsuka Long-Evans Tokushima Fatty rats.

The aim of this study was to determine the mechanism of troglitazone action on nitric oxide (NO) production via inducible NO synthase (iNOS) in adipocytes in vitro and in vivo. The treatment of 3T3-L1 adipocytes with the combination of lipopolysaccharide (LPS), tumor necrosis factor-alpha and interferon-gamma synergistically induced de novo iNOS expression leading to enhanced NO production. The NO production was inhibited by co-treatment with aminoguanidine or N-nitro-L-arginine methylester hydrochloride. Troglitazone inhibited the NO production in a dose dependent manner by the suppression of iNOS expression. In the 24 week-old Otsuka Long-Evans Tokushima Fatty (OLETF) rats, the mean weight and the blood glucose were 21% and 30%, respectively, higher than in their lean counterparts. The serum nitrite concentration was increased after injection of LPS (4 mg/kg, i.p.), more markedly in OLETF rats than in the lean rats. The epididymal fats from LPS-injected groups, but not the ones from the non-injected groups, expressed mRNA and protein of iNOS. Troglitazone pre-treatment blocked the LPS-induced expression of iNOS in adipose tissue and the increase in serum nitrite concentration. These results suggest that troglitazone inhibits the cytokine-induced NO production in adipocytes by blocking iNOS expression both in vitro and in vivo.

P300 response to tones and speech sounds after cochlear implant: a case report.

P300 potentials evoked by tones and spoken words were recorded from a 20-year-old man with a House-3M single-channel cochlear implant. Three months after cochlear implantation, there was a slight appearance of P300 response to both pure-tone stimuli and spoken-word stimuli; 6 months later, clearly identifiable P300 response to both pure-tone stimuli and spoken-word stimuli were obtained. These results are consistent with an encoding improvement for re-establishment of information processing after auditory rehabilitation.

A new mutation in the POU3F4 gene in a Japanese family with X-linked mixed deafness (DFN3).

OBJECTIVE: The molecular defect in patients with X-linked mixed deafness showing a perilymphatic gusher at stapedectomy (DFN3) has been attributed to mutations in the POU3F4 gene. This study aimed to clarify an allelic variant of this gene. STUDY DESIGN: This was a genetic study of a single Japanese family with DFN3. METHODS: Products of a polymerase chain reaction (PCR) were subjected to single-strand conformation polymorphism (SSCP) analysis. Direct sequencing of PCR products from patients and carriers showing SSCP variants was performed using the fluorescent dideoxy termination method and a sequencer. RESULTS: Sequencing of the PCR product revealed a 6-base deletion (TTCAAA) at nucleotides 601 to 606, resulting in a two-amino-acid deletion in the POU3F4 protein, (phenylalanine and lysine at amino acid residues 201 and 202). The deletion was adjacent to the site of a nonsense mutation previously described. CONCLUSION: Microdeletions at a previously undescribed location account for some clinically important POU3F4 mutations.

The kidney disease of Crow-Fukase (POEMS) syndrome: a clinico-pathological study of four cases.

We studied four cases of Crow-Fukase syndrome with renal dysfunction. Kidney specimens obtained by needle biopsy showed glomerular lesions resembling those seen in conditions characterized by microangiopathy. Common glomerular findings by light microscopy were mesangial expansion and narrowing of the capillary lumina. An enlarged subendothelial space and mesangial area with deposition of amorphous material as well as swelling and vacuolization of endothelial cells were observed by electron microscopy. In an active phase, severe mesangial edema and segmental mesangiolysis, and in a late stage, mesangial cell interposition and sclerosis were seen. Tests by immunofluorescence microscopy for the presence of immunoglobulins A, M, G, lambda and kappa light chains, C3, and C4 were negative. Decay accelerating factor was found in glomeruli and in the vascular pole. Other findings included lymph node angiosclerosis, peripheral nerve microangiopathy and hemangioma formation with endothelial cell proliferation. These observations suggest that chronic endothelial injury constitutes the basic pathology of Crow-Fukase syndrome. Hemodialysis was required to manage anasarca in three of the patients although serum creatinine levels were below 5.0 mg/dl. Urinalysis revealed mild abnormalities and did not reflect the severity of the glomerular lesion. Corticosteroids given to three of the patients were effective in controlling fever and the lymphadenopathy; in two cases the corticosteroids induced a recovery of renal function. Thus Crow-Fukase syndrome may be due to chronic endothelial injury; the clinical symptoms and renal involvement respond to corticosteroid therapy.

Successful resection of cardiac fibroma with ventricular tachycardia.

A 22-year-old male was admitted to Niigata University Hospital complaining of palpitation. Echocardiogram, cineangiogram, and Holter electrocardiogram revealed a cardiac fibroma complicated by ventricular tachycardia (VT). The tumor extended from the interventricular septum to the anterior surface of the left ventricle, and an electrophysiological study demonstrated that the focus of the VT was situated at the tumor. The tumor was excised successfully. The patient is doing well two years after operation without any antiarrhythmic drugs, and VT has not recurred.

Current strategy of circulatory support for profound heart failure.

The purpose of this study is to assess the current strategy of mechanical circulatory support for profound heart failure. In the last 10 years, 37 patients with profound heart failure underwent mechanical circulatory support after open heart surgery and 9 patients with non-cardiotomy cardiogenic shock received emergency circulatory support. All patients showed severe cardiac failure and/or fatal ventricular arrhythmia and required circulatory support as a life-saving measure. After cardiovascular surgery, 12 of those patients underwent venoarterial bypass (VAB), 13 had biventricular bypass (BVB), 8 had left ventricular bypass (LVB) and the remaining 4 patients received left ventricular assist device (LVAD). And 9 patients with non-cardiotomy cardiogenic shock received percutaneous cardiopulmonary support (or PCPS) as an emergency assist system. Weaning and discharge rates of the patients by the type of circulatory supports were 41.7% and 25.0% with VAB, 69.3% and 46.2% with BVB, 87.5% and 37.5% with LVB, 75.0% and 50.0% with LVAD, and 44.4% and 11.1% with PCPS, respectively. Clinical results of post-cardiotomy circulatory support (64.9% of weaning and 37.8% of discharge) were acceptable, but the patients with non-cardiotomy cardiac failure needed early application of more advanced circulatory support.

Effect of additional intraaortic balloon support during weaning from a left ventricular assist system.

A safe and reliable method of weaning from a left ventricular assist system (LVAS) is necessary for successful circulatory support in patients with marginal heart failure. The purpose of this study is to assess the effect of additional intraaortic balloon (IAB) support during weaning from an LVAS by means of the LV pressure-volume relationship. A pneumatic LVAS with a sac-type blood pump was implanted in six adult mongrel dogs weighing 14 to 20 kg. All dogs had a drainage cannula placed in the left atrium and an outflow conduit in the ascending aorta. Hemodynamic parameters, pulmonary arterial flow, and pump output were monitored. An IAB was inserted through the groin. A conductance catheter and microtip manometer were inserted into the LV cavity. As a combination driving mode, LVAS ejection in the early diastolic phase and IAB inflation in the late diastolic phase were applied. After evaluation of baseline LV function, the pressure-volume relationship was repeatedly measured during change of driving modes as isolated LVAS, LVAS + IAB (1:1), LVAS + IAB (2:1), and isolated IAB supports. Finally, LV failure was introduced by stepwise ligation of left coronary arteries, and the LV pressure-volume relationship was measured in each driving mode. Under normal conditions, the pressure-volume loop showed no significant change among the four driving modes. In contrast, the LV pressure-volume relationship significantly improved according to the degree of additional IAB support on LVAS assistance under the condition of LV failure. These results suggest that additional IAB support might improve LV energy during weaning from an LVAS.

Partially implantable piezoelectric middle ear hearing device. Long-term results.

In accordance with the 1992-1993 Japanese government approval of production and implementation in the health insurance system of the partially implantable piezoelectric middle ear device (P-MEI), we are conducting follow-up studies on the implanted patients. This article reports the results of the 16 cases, which are regarded as successful implantations because these patients are using the device every day as long as they are awake. A successful case is presented to illustrate the efficacy of the device.

Hearing results of canal wall reconstruction tympanoplasty for middle ear cholesteatoma in children.

OBJECTIVE: To investigate post-operative hearing results in children with middle ear cholesteatoma, and to analyze the correlation between hearing results and clinical factors and findings before and during the operation. PATIENTS AND METHODS: One hundred and twenty-four ears of 123 children were operated on for middle ear cholesteatoma at the age of 10 years or younger by canal wall reconstruction tympanoplasty and were followed up more than 1 year after the final operation. We evaluated the average air and bone conduction hearing levels at the speech ranges before the first operation (pre-operative hearing) and after the final operation (post-operative hearing). RESULTS: The mean of the average air conduction hearing level of 124 ears was significantly improved from 34.7 to 27.1 dB after the final operation. Among them, 84 ears (67.8%) showed a hearing level of 30 dB or less post-operatively. Post-operative hearing was better in the one-stage group than in the staged group. However, more than one-half of the ears which underwent type IV tympanoplasty in the staged group showed post-operative air conduction hearing level of < or =30 dB. Significant improvement in post-operative hearing was noted in ears with normal middle ear mucosa or middle ear effusion at the final operation. No correlation between hearing improvement and clinical factors such as age, type of cholesteatoma or presence of otitis media with effusion at the first operation was found. CONCLUSIONS: Children with middle ear cholesteatoma at the age of 10 years or younger exhibited good hearing post-operatively. Satisfactory hearing improvement is expected even in ears without the superstructure of the stapes if staged tympanoplasty is conducted. Canal wall reconstruction tympanoplasty for pediatric cholesteatoma was successful in terms of hearing results and the success was unrelated to various clinical factors.

Middle ear implant for humans.

In humans, a partially implantable middle ear implant (MEI) will first be applied, followed by a wholly implantable MEI, since with the former only an induction coil and a vibrator (to the stapes' head) are used. One of the various advantages of the partially implantable MEI vis-à-vis air conduction hearing aids is that the tone quality is of much higher fidelity, with less noise.

Evaluation of middle-ear implant: a six-month observation in cats.

The efficacy of a middle-ear implant was evaluated by measuring auditory brain stem responses. Middle-ear implants, including an input-transducer, an amplifier, a battery and an output-transducer, were implanted in cats. Most of the implants were kept functioning for a six-month period. Observation on the characteristics of these implants during this time showed allowable changes in an implant, now being prepared, for use in human subjects.

Stimulated otoacoustic emissions in children with sensorineural hearing loss.

Our previous studies of stimulated oto-acoustic emissions (OAEs) have revealed that the OAE threshold indicates the grade of inner ear impairment. The present study is a survey of OAE in children of school age. The mean OAE threshold values of 113 ears with normal hearing and 45 ears with functional deafness were 5.9 dB nHL and 6.2 dB nHL, respectively. In sensorineural loss the value was noted to increase according to its grade, classified into four groups, measuring 37.2 dB nHL in the group with severe loss higher than 91 dB. The findings suggest that the OAE threshold is useful for an indicator of inner ear function in children. There still remains the problem to be solved by a contrivance of noise removal for application of OAE to hearing tests in children of pre-school age.

Hearing results after tympanoplasty in elderly patients with middle ear cholesteatoma.

Many reports about the effect of aging on hearing results after tympanoplasty have been published. However, they have not been evaluated comprehensively, i.e. by taking into consideration other aspects which also affect the outcome. In this study, the effect of aging on hearing results after canal wall reconstruction tympanoplasty was assessed in 236 consecutive ears of 213 patients > 20 years old with middle ear cholesteatoma. The elderly group (n = 34), defined as patients > or = 60 years old, was compared to the younger groups in terms of hearing results of postoperative hearing level, hearing gain, A-B gap and change in bone conduction hearing level at 4000 Hz after adjustment for age, gender, staged operation, preoperative hearing level and type of tympanoplasty, all of which affect hearing results, using the generalized linear regression method. Postoperative hearing level and hearing gain were found to be better amongst patients aged 20-29 and 30-39 years than in the elderly group, whilst A-B gap did not differ between all age categories. Within the elderly group, air conduction hearing level was shown to have improved after surgery. Changes in bone conduction hearing level at 4000 Hz were not significantly different between the age groups, suggesting that operative stress, i.e. mechanical stress or ossicular manipulation stress, does not aggravate sensorineural hearing loss in the elderly. We conclude that surgeons should be encouraged to perform tympanoplasty aimed not only at eradicating the lesion itself but also at improving hearing acuity in the elderly.

Long term follow-up of secretory otitis media in children: the effects of adenotonsillectomy with insertion of a ventilation tube.

The long term effects of adenotonsillectomy and ventilation tube were studied in 78 children with serous otitis media. Duration of postoperative follow-up range from 2 to 8 years, with an average of 4.5 years. Repeated preoperative and postoperative pure tone audiometry as well as otoscopic examinations under a microscope were undertaken routinely for the assessment of the progress or improvement of the disorder. Three months after the operation, an average improvement of the hearing thresholds was 16.3 dB. However, it was 20.3 dB in the final examination. Under the otoscopic examinations, 35% of the ears were noted to have various kinds of pathological changes. Tympanic atelectasis of Grade I and II (Sadé) was noted in 17% of all the ears. Retraction pocket of the pars flaccida was found in 2%, permanent perforation in 4% and cholesteatoma in 2% of these ears.