Re-evaluation of stomach position as a simple prognostic factor in fetal left congenital diaphragmatic hernia: a multicenter survey in Japan.

OBJECTIVES: To document outcome and to explore prognostic factors in fetal left congenital diaphragmatic hernia (CDH). METHODS: This was a multicenter retrospective study of 109 patients with prenatally diagnosed isolated left CDH born between 2002 and 2007. The primary outcome was intact discharge, defined as discharge from hospital without major morbidities, such as a need for respiratory support including oxygen supplementation, tube feeding, parenteral nutrition or vasodilators. All patients were managed at perinatal centers with immediate resuscitation, gentle ventilation (mostly with high-frequency oscillatory ventilation) and surgery after stabilization. Prenatal data collected included liver and stomach position, lung-to-head ratio, gestational age at diagnosis and presence or absence of polyhydramnios. Stomach position was classified into four grades: Grade 0, abdominal; Grade 1, left thoracic; Grade 2, less than half of the stomach herniated into the right chest; and Grade 3, more than half of the stomach herniated into the right chest. RESULTS: Overall intact discharge and 90-day survival rates were 65.1% and 79.8%, respectively. Stomach herniation was classified as Grade 0 in 19.3% of cases, Grade 1 in 45.9%, Grade 2 in 13.8% and Grade 3 in 21.1%. Multivariate analysis revealed that liver position was the strongest prognostic variable for intact discharge, followed by stomach position. Based on our results, we divided patients into three groups according to liver (up vs. down) and stomach (Grade 0-2 vs. Grade 3) position. Intact discharge rates declined significantly from liver-down (Group I), to liver-up with stomach Grade 0-2 (Group II), to liver-up with stomach Grade 3 (Group III) (87.0%, 47.4% and 9.5% of cases, respectively). CONCLUSION: Current status and outcomes of prenatally diagnosed left CDH in Japan were surveyed. Stomach herniation into the right chest was not uncommon and its grade correlated with outcome. The combination of liver and stomach positions was useful to stratify patients into three groups (Group I-III) with different prognoses.

Effect of leupeptin, a protease inhibitor, on induction of bladder tumors in rats by n-butyl-n-(4-hydroxybutyl)nitrosamine.

Leupeptin, isolated from Actinomycetes, is a potent and specific inhibitor of proteases. We found that the administration of leupeptin enhanced that size of urinary bladder tumors induced in rats by the oral administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). BBN was given as a 0.05% solution in the drinking water for 6 weeks, and then animals were fed a diet with or without 0.1% leupeptin for 30 weeks. The average weight of the bladders with tumors in rats fed a leupeptin diet was about eight times that of rats on a diet without leupeptin, though the incidences and average numbers of tumors in the bladders were similar in the two groups.

High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma.

Survivin (SVV) is a family member of inhibitor of apoptosis proteins (IAPs) and its expression is cell cycle regulated. The gene is mapped to chromosome 17q25, the region of which is frequently gained in advanced stages of neuroblastoma (NBL). However, the role of SVV in NBL is poorly understood. Here we studied the clinical and biological role of SVV in NBL. A 1.9 kb SVV transcript was expressed in all of 9 NBL cell lines at higher levels than those in adult cancer cell lines. In 34 primary NBLs, high levels of SVV expression was significantly associated with age greater than 12 months (two sample t-test: P= 0.0003), advanced stages (P = 0.0136), sporadic tumors (P= 0.0027) and low levels of TrkA expression (P = 0.0030). In NBL cell lines, SVV mRNA expression was dramatically down-regulated in CHP134 and IMR32 cells undergoing apoptosis after treatment with all-trans retinoic acid (RA) or serum deprivation. It was only moderately decreased in cells (SH-SY5Y and CHP901) undergoing RA-induced differentiation. On the other hand, in proliferating NBL cells or RA-treated SK-N-AS line which is refractory to RA, the SVV mRNA remained at steady state levels or rather up-regulated. Furthermore, transfection of SVV into CHP134 cells induced remarkable inhibition of the RA-induced apoptosis. Collectively, our results suggest that high expression of SVV is a strong prognostic indicator for the advanced stage neuroblastomas, and that it could be one of the candidate genes for the 17q gain.

Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line.

Loss of heterozygosity of the distal region of chromosome 1p where tumor suppressor gene(s) might harbor is frequently observed in many human cancers including neuroblastoma (NBL) with MYCN amplification and poor prognosis. We have identified for the first time a homozygously deleted region at the marker D1S244 within the smallest region of overlap at 1p36.2-p36.3 in two NBL cell lines, NB-1 and NB-C201 (MASS-NB-SCH1), although our genotyping has suggested the possibility that both lines are derived from the same origin. The 800-kb PAC contig covering the entire region of homozygous deletion was made and partially sequenced (about 60%). The estimated length of the deleted region was 500 kb. We have, thus far, identified six genes within the region which include three known genes (DFF45, PGD, and CORT) as well as three other genes which have been reported during processing our present project for the last 3(1/2) years (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14). They include the genes related to apoptosis, glucose metabolism, ubiquitin-proteasome pathway, a neuronal microtubule-associated motor molecule and biogenesis of peroxisome. At least three genes (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14) were differentially expressed at high levels in favorable and at low levels in unfavorable subsets of primary neuroblastoma. Since the 1p distal region is reported to be imprinted, those differentially expressed genes could be the new members of the candidate NBL suppressor, although RT-PCR-SSCP analysis has demonstrated infrequent mutation of the genes so far identified. Full-sequencing and gene prediction for the region of homozygous deletion would elucidate more detailed structure of this region and might lead to discovery of additional candidate genes. Oncogene (2000) 19, 4302 - 4307

Frequent deletions and mutations of the beta-catenin gene are associated with overexpression of cyclin D1 and fibronectin and poorly differentiated histology in childhood hepatoblastoma.

Hepatoblastoma (HBL) is the most common malignant liver tumor in young children. Recent reports have shown that the beta-catenin gene was frequently mutated or deleted in HBLS: To elucidate the role of beta-catenin abnormalities in HBLs, we searched for mutations of beta-catenin and APC as well as expression of the target genes, cyclin D1, c-myc, and fibronectin, in 68 primary HBLS: The mutation analysis revealed that 44 (65%) tumors carried missense mutations or deletions of beta-catenin, all of which were somatic and targeted to the exon 3 encoding the amino acid residues involved in its degradation. However, no loss of function mutation of the APC gene was detected by the yeast functional assay. Of interest, beta-catenin mutation was significantly correlated with overexpression of the target genes, cyclin D1 and fibronectin, but not with that of c-myc in HBLs as measured by quantitative real-time reverse transcription-PCR. The immunohistochemical studies in 15 HBLs demonstrated that the nuclear/cytoplasmic accumulation of beta-catenin was positive in 13 tumors, 9 of which had the deletion or mutation of the gene. The significant correlation between the beta-catenin gene abnormality and the positive staining of cyclin D1 was also confirmed. Furthermore, the nuclear accumulation of beta-catenin was strongly associated with the poorly differentiated tumor cell components as well as with the positive staining of cyclin D1 within the tumor. Thus, our present results suggested that the gain of function mutation of beta-catenin played a crucial role in the malignant progression of HBL in vivo.

Relation of spontaneous passage of ureteral calculi to size.

A statistical analysis of 520 ureteral calculi was undertaken to elucidate the correlation between sizes of calculi and the probability of spontaneous passage. The mean length and width of 286 calculi passed spontaneously were 6.3 +/- 2.5 (S.D.) and 4.0 +/- 1.5 mm., respectively; those of 219 calculi removed surgically were 11.7 +/- 5.0 and 7.1 +/- 2.8 mm., respectively, the difference between the two groups being statistically significant. The rate of spontaneous passage of stones within one year after diagnosis was analyzed in relation to sizes of stones which were grouped at successive 1-mm. intervals both in length and width, the over-all rate of spontaneous passage being 53 per cent. It was concluded that stones larger than 8 mm. in width on x-ray films should be removed surgically, while in those smaller than 8 mm. in width higher chances of spontaneous passage by expectant treatment would be anticipated.

Flexible ureterorenoscopy.

The clinical applications of flexible ureterorenoscopes have fallen behind those of their rigid counterparts. Flexible endoscopes that possess a working channel and can also be employed for treatment have at last been developed. This instrument is particularly effective in the treatment of stones in the upper urinary tract, as it can easily follow mobile upper ureteral stones and calculi in the middle or lower renal calices, which are not as accessible with a rigid endoscope. It is important to remember not to exert too much force when inserting the instrument into the ureter, renal pelvis, or renal calices, and, if one remains calm, should the visual field become temporarily obscured, there should be little danger of damaging these structures. This method will probably be increasingly employed, not only for the treatment of stones in the upper urinary tract, but also for the removal of foreign bodies and the diagnosis and treatment of small pathologic conditions or lesions such as carcinoma in situ in which the roentgenologic presentation is unclear. For this expansion of instrument use to be ensured, it is necessary to improve the resolution of the fiberoptic endoscope image and increase the instrument's angulation capabilities, increase the range of accessories that can be employed with it, and also increase familiarity with the instruments on the part of urologists.

Strange hemodynamic attractor parameter with 1/R total artificial heart automatic control algorithm.

To evaluate the automatic control algorithm of the total artificial heart (TAH) as an entity, and not just as parts, a non-linear mathematical analyzing technique including chaos theory was utilized. Chronic experiments on the biventricular bypass type artificial heart implantation were performed in healthy adult goats after the natural ventricles were removed. Hemodynamic time series data were recorded under the awake standing condition with TAH 1/R and fixed driving. Time series data were recorded on a magnetic tape and analyzed on a personal computer system with an A-D converter. Using the nonlinear mathematical technique, the time series data were embedded into the phase space and the Lyapunov numerical method was carried out for the quantitative evaluation of the sensitive dependence on the initial condition of the reconstructed attractor. Calculation of the largest Lyapunov exponents suggested that the reconstructed attractor of the left pump output during TAH 1/R control was a larger dimensional strange attractor, a characteristic pattern of deterministic chaos. A total system indicating chaotic dynamics was thought to be a flexible and intelligent control system. Thus, our results suggest that 1/R TAH control may be suitable for the biventricular assist type total artificial heart.

[Two cases of duodenal tuberculosis].

The present study described 2 cases of patients with duodenal tuberculosis. Case 1 was a 55 year-old Japanese male patient with pulmonary tuberculosis and past medical history of subtotal gastrectomy (Billroth II reconstruction). Tubercle bacilli were positive both on smear and culture from his sputum and feces. Because of complaining right hypochondralgia, upper gastrointestinal endoscopy was performed and revealed multiple ringed ulcers in the afferent limb of duodenum. Histopathological study of biopsy specimen demonstrated granulomatous inflammation as well as acid-fast bacilli confirmed by Ziehl-Neelsen staining. Tissue culture was positive for M. tuberculosis. Colonic tuberculosis was demonstrated by barium enema. Case 2 was a 45 year-old male patient with pulmonary tuberculosis in association with severe uncontrolled diabetes mellitus. Sputum polymerase chain reaction test was positive for M. tuberculosis. Granulomatous inflammation and positive acid-fast bacilli in biopsy specimen obtained from ulcers in the descending portion of the duodenum made a diagnosis of duodenal tuberculosis. No other intestinal tuberculous lesion was recognized. Since 1988, 11 cases of duodenal tuberculosis including the presented two cases have been reported in Japan. Most of the recent cases had tuberculous lesions in the descending portion of the duodenum and were diagnosed as duodenal tuberculosis by endoscopic examinations, while the majority of the cases reported before 1987 had tuberculosis in the more distant portions of the duodenum and were diagnosed mainly by surgical procedures.

Effect of exogenous tetragastrin on gastric myoelectrical activity in humans.

It is known that cutaneous electrogastrography (EGG) undergoes a change after food ingestion, showing increases in frequency and amplitude compared with preprandial values, but the factors regulating such changes remain to be elucidated. Paying special attention to gastrin, one of gastrointestinal peptides released after food ingestion, we administered tetragastrin in an exogenous manner and evaluated its effects on EGG in the present study. In healthy subjects, the intramuscular injection of tetragastrin significantly increased EGG frequency dose-dependently, but caused no significant change in amplitude. These results suggest that the increase in endogenous gastrin release is one of the mechanisms which underlies the increase in EGG frequency after food ingestion.

A case of spontaneous esophageal rupture treated with conservative therapy.

A 51 year-old male was admitted because of abrupt hematemesis and loss of consciousness. Emergency endoscopy depicted a giant esophageal ulcer on the left side extending from the middle intrathoracic region to the lower intrathoracic region. Esophagography, performed on the second day of admission, revealed a huge cavity (10 cm x 7 cm) filled with contrast medium resulting from a rupture in the ulceration. His state of shock improved with conservative therapy and no severe mediastinitis was noted. The drainage from the cavity into the lumen of the esophagus was considered to be acceptable from esophagography and an endoscopic examination. Secondary to his stable condition and continuous drainage, this patient was treated conservatively throughout his clinical course. The patient was given intravenous hyperalimentation (IVH) until the 25th hospital day and was medicated with broad spectrum-antibiotics. On the 21st hospital day the size of the esophageal cavity was markedly decreased (7 cm x 2 cm). Only small irregular mucosa was noted on the esophagogram taken 6 weeks after admission. Six months after the onset, an X-ray examination revealed complete healing of the spontaneous esophageal rupture with no recurrence.

Wegener's granulomatosis with relapsed bleeding of gastric ulcers: a case report.

We treated a 55-year-old male patient with Wegener's granulomatosis (WG) associated with frequent gastric bleeding from multiple ulcerative lesions. Only a few cases of frequent hemorrhaging of peptic ulcers associated with WG have been reported. In our case, a gastric biopsy showed mononuclear cell infiltration in the submucosal area, without granulomas or vasculitis. An endoscopic maneuver, as well as administration of immunosuppressive agents, combined with an H2 receptor antagonist and proton pump inhibitor successfully eliminated the gastrointestinal bleeding. In this case, proof that the gastrointestinal involvement was pathologically related to WG could not be demonstrated because neither granulomas nor vasculitis were observed in the insufficient biopsy specimen of the stomach. It is also possible that the uremic state and cytotoxic agents worsened the gastrointestinal involvement. However, immunosuppressive therapy combined with routine antiulcer treatment was very effective in repairing the ulcerative lesions. The gastrointestinal involvement was considered a possible complication of the WG.

[Successful repair of TGA with ventricular septal defect, the outflow tract stenosis of the left ventricle and coarctation of the aortic arch].

A 9-month-old boy after the coarctectomy at 5 months old was successfully repaired by Senning procedure with closure of ventricular septal defect and resection of the membranous septal aneurysm causing the outflow tract stenosis of the left ventricle. Retrospectively, this case might have been possible to do Jatene procedure, however, attempts to resect the left ventricular outflow tract stenosis often failed to relieve stenosis completely. Therefore, the intraatrial switch operation seems to be better than the arterial switch operation when there is a possibility to remain left ventricular outflow tract stenosis. True estimation for these cases must await more case studies.

[Successful repair of total anomalous pulmonary venous connection and incomplete endocardial cushion defect associated with left isomerism].

Successful repair of a 8-month-old girl with polysplenia was reported. The cardiovascular anomalies were TAPVC (II b), incomplete ECD, interruption of inferior vena cava with hemiazygos continuation, bilateral superior vena cava, and left superior vena cava draining into the coronary sinus. Cardiopulmonary bypass was established with ascending aortic perfusion and caval cannulation. A left superior vena cava was directly cannulated after establishing partial bypass. In this case the left pulmonary vein drained into the right atrium near the orifice of the coronary sinus, so the atrial septal flap was made and sutured between the orifice of the left pulmonary vein and the coronary sinus in order to avoid late pulmonary vein obstruction. Then, atrium was separated by an intraatrial baffle which was sutured to the atrial septal flap. Recently, it becomes possible to surgical repair of polysplenia syndrome according to the advancements of the diagnostic methods, cardiopulmonary bypass, and the technique of the open heart surgery.

[Surgical treatment of coarctation of the aorta].

Repair of coarctation of the aorta was performed in 37 cases (31 patients, 6 patients of reoperation) ranging from 4 days old to 15 years old. Subclavian flap repair were performed in 15, resection and end-to-end anastomosis in 14, patch aortoplasty in 6, and interposition graft in 2. Subclavian flap angioplasty or end-to-end anastomosis is considered the procedure of choice in infants. However, the incidence of reoperation significantly increased in patients younger than age one month at initial subclavian flap repair. Mechanism of recurrent coarctation may be possibly related to retention of abnormal tissue, which is possibly ductal and/or intimal shelf, with the potential for proliferation and luminal narrowing. We suggest that in applicable case end-to-end anastomosis rather than subclavian flap angioplasty may be the surgical technique of choice in infants less than one month of age, and the most common reoperation technique was patch aortoplasty in re-stenosed cases.

[Investigation of gastric function and prevalence of Helicobacter pylori in non-ulcer dyspepsia].

One hundred and fourty four patients with non-ulcer dyspepsia (NUD), as defined by the working party of AGA in 1987, (67 men and 77 women, 16-76 years, mean age 42.9 +/- 1.2 years) and 34 asymptomatic controls (25 men and 9 women, 17-75 years, mean age 50.6 +/- 2.4 years) parameters of gastrophysiological function (gastric acid secretion, postprandial gastric emptying-acetaminophen method, serum gastrin levels and cutaneous electrogastrography (EGG)) and the prevalence of Helicobacter pylori (Hp) (histological and urease test of biopsy specimens) were investigated. Based on symptom patterns, there were 68 patients with dysmotility-like dyspepsia, 27 with ulcer-like dyspepsia, 17 with reflux-like dyspepsia, 6 with aerophagia and the 26 with nonspecific or idiopathic dyspepsia. The age distribution of NUD was predominant in the fourth decade, and the sex distribution was not significantly different. In general, hypersecretion of gastric acid and hypergastrinemia were rare in NUD patients. There was no significant difference in gastric acid secretion, basal and food stimulated serum gastrin levels and prevalence of Hp between the two groups. But 51 of 144 NUD patients (41.1%) had delayed gastric emptying (p < 0.05) compared to controls. Indeed gastric emptying was markedly prolonged in patients with dysmotility-like (58.1%) and reflux-like (42.9%) dyspepsia. On EGG, about a half of NUD patients showed evidence of bradygastria or tachygastria, in particular in the postprandial state, which was related to delayed gastric emptying. By chronic administration of cisapride, score of symptoms was significantly decreased and postprandial gastric emptying was significantly accelerated in delayed gastric emptying cases. We conclude that in NUD patients, in particular those with dysmotility-like dyspepsia, tests of postprandial gastric emptying and/or EGG are useful for investigation of gastric motor disorder and therapeutic effects of several prokinetic drugs clinically.

[Epidemiology of gastro-esophageal reflux disease].

Gastroesophageal reflux disease(GERD) is believed to be common and chronic gastrointestinal disorder. Quantitative estimates of the actual prevalence of GERD are difficult to obtain, because those who seek health care probably represent only a tip of the iceberg of people with GERD. The prevalence of heartburn and/or regurgitation, considered to be reasonably specific symptoms for the diagnosis of GERD, ranged from 10% to 48% for heartburn, from 9% to 45% for regurgitation and 21% to 59% for both/either in systematic review of GERD and reflux esophagitis(RE). It is widely accepted that the prevalence is lower in Asian countries, including Japan, compared with that in Western countries. However, the prevalence of RE in Japan may be increasing. In the case of heartburn and regurgitation in GERD and endoscopic findings in RE, different understandings of these terms by different investigators and subjects may have contributed to the range of results. Symptom definitions and what is understood by them should be among the most important considerations when undertaking population prevalence studies on reflux like symptoms, to allow comparisons to be made between studies.