Fetal echocardiographic prediction score for perinatal mortality in tricuspid valve dysplasia and Ebstein's anomaly.

OBJECTIVES: Tricuspid valve dysplasia (TVD) and Ebstein's anomaly (EA) diagnosed by fetal echocardiography vary greatly in terms of clinical severity and prognosis. The Celermajer index and Simpson-Andrews-Sharland (SAS) score have been reported previously for the prediction of prognosis in cases of TVD/EA; however, they do not take into account the hemodynamic impact of left ventricular (LV) function, which has recently been implicated as being important in the pathophysiology of TVD/EA. The aim of this study was to develop a novel scoring system that includes LV function for the prediction of perinatal death in fetuses diagnosed with TVD/EA. METHODS: The clinical records of 36 fetuses diagnosed prenatally with TVD/EA between 2000 and 2015 in our hospital were reviewed. Univariate analysis was used to assess the association between perinatal death (defined as death between 22 weeks' gestation and 4 weeks after delivery) and gestational age at diagnosis, cardiothoracic area ratio (CTAR), degree of pulmonary artery flow, direction of ductal flow, right-to-left ventricular diameter ratio, tricuspid regurgitation (TR) maximum velocity, Celermajer index, SAS score and LV-Tei index. A new prognostic score, the TRIPP score (TRIcuspid malformation Prognosis Prediction score), was developed using the parameters found to be associated significantly with perinatal death. The predictive value of this score was assessed in an additional nine fetuses diagnosed with TVD/EA. RESULTS: Thirty-six fetuses were diagnosed prenatally with TVD/EA, two of which were terminated, one was lost to follow-up and two died before 22 weeks' gestation. Of the 31 included fetuses, 10 (32%) died in the perinatal period. Univariate analysis demonstrated that TR maximum velocity was significantly lower (2.22 ± 0.17 m/s vs 3.26 ± 0.12 m/s; P < 0.001) and SAS score was significantly higher (5.7 ± 0.6 points vs 2.8 ± 0.4 points; P = 0.0014) in cases of perinatal death than in surviving fetuses. The degree of pulmonary artery flow and the direction of ductal flow were also associated significantly with perinatal death (P < 0.01 for both). Notably, LV-Tei index was significantly higher in cases of perinatal death than in surviving fetuses (0.81 ± 0.08 vs 0.50 ± 0.05; P < 0.001). In contrast, there was no significant difference in Celermajer index, CTAR or right-to-left ventricular diameter ratio. Finally, we established a novel combinatorial scoring system, the TRIPP score, including the four significant factors: TR maximum velocity, pulmonary artery flow, direction of ductal flow and LV-Tei index. The TRIPP score was found to predict efficiently perinatal mortality in fetuses with TVD/EA. CONCLUSIONS: Our novel combinatorial score of echocardiographic parameters, the TRIPP score, including LV-Tei index, is easy to measure and provides a good tool for the prediction of perinatal mortality in fetuses diagnosed prenatally with TVD/EA. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Superselective intra-arterial cisplatin infusion and concomitant radiotherapy for maxillary sinus cancer.

BACKGROUND: The purpose of this study was to evaluate the efficacy of superselective cisplatin infusion with concomitant radiotherapy (RADPLAT) for previously untreated patients with the squamous cell carcinoma of maxillary sinus (SCC-MS). METHODS: Between 1999 and 2010, 54 patients were given superselective intra-arterial infusions of cisplatin (100-120 mg m(-2) per week) with simultaneous intra-venous infusions of thiosulfate to neutralise cisplatin toxicity and conventional radiotherapy (65-70 Gy). RESULTS: One patient (1.9%) was diagnosed with T2, 14 (25.9%) with T3, 27 (50%) with T4a, and 12 (22.2%) with T4b disease. Lymph-node involvement was present in 12 patients (22.2%). During the median follow-up period of 6.4 years, the 5-year local progression-free and overall survival rates were 65.8 and 67.9% for all patients, respectively. No patient died as a result of treatment toxicity or experienced a cerebrovascular accident. Osteonecrosis (n=5), brain necrosis (n=1), and ocular/visual problems (n=14) were observed as late adverse reactions. CONCLUSION: We have shown excellent overall survival and local progression-free rate in SCC-MS patients treated by RADPLAT with acceptable rates of acute and late toxicity. A multi-institutional trial is needed to prove that this strategy is a feasible and effective approach for the treatment of SCC-MS.

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.

[Long term outcome of arterial switch surgery for transposition of the great arteries: evaluation of the reconstruction of the pulmonary artery].

We assessed the effect of reconstructing the pulmonary artery during arterial switch surgery for transposition of the great arteries on late pulmonary stenosis. Sixty-five patients who underwent Lecompte procedure between September 1991 and December 2006 were divided, by the procedure used chronologically to reconstruct the pulmonary artery, into group XP (single pantaloon patch with equine pericardium, n = 11), group P (direct reconstruction, n = 47), and group AP (single pantaloon patch with fresh autopericardium, n = 7). Outcome and pulmonary stenosis on the most recent ultrasound cardiography (UCG) were compared in the 3 groups. The median follow-up was 13, 7.5, and 1.3 years, respectively. Both early and late mortalities were 1.5% (1/65). Although percutaneous trans-pulmonary angioplasty was necessary in 1, 13, and 3 patients, there was 1, 1, and 0 reoperation for pulmonary stenosis in the 3 groups, respectively. Pulmonary stenosis (pulmonary arterial maximum flow velocity > 3 m/sec on UCG) was present in 4 (40%). 14 (30%). and 3 patients (43%). Although there was no significant difference among the 3 procedures in preventing pulmonary stenosis 10 years after arterial switch surgery, direct reconstruction of the pulmonary artery may show a superior outcome, in particular, over 10 years after arterial switch surgery.

Early postnatal ataxia and abnormal cerebellar development in mice lacking Xeroderma pigmentosum Group A and Cockayne syndrome Group B DNA repair genes.

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are rare autosomal recessive disorders associated with a defect in the nucleotide excision repair (NER) pathway required for the removal of DNA damage induced by UV light and distorting chemical adducts. Although progressive neurological dysfunction is one of the hallmarks of CS and of some groups of XP patients, the causative mechanisms are largely unknown. Here we show that mice lacking both the XPA (XP-group A) and CSB (CS-group B) genes in contrast to the single mutants display severe growth retardation, ataxia, and motor dysfunction during early postnatal development. Their cerebella are hypoplastic and showed impaired foliation and stunted Purkinje cell dendrites. Reduced neurogenesis and increased apoptotic cell death occur in the cerebellar external granular layer. These findings suggest that XPA and CSB have additive roles in the mouse nervous system and support a crucial role for these genes in normal brain development.

Involvement of c-Jun N-terminal kinase and caspase 3-like protease in DNA damage-induced, p53-mediated apoptosis of cultured mouse cerebellar granule neurons.

In the previous studies, we have demonstrated that the tumor suppressor gene p53 is required for DNA strand break-induced neuronal apoptosis in organotypic slice cultures of cerebellum as well as in dissociated cerebellar neuron cultures. In this study, we further investigated the role of p53 in neuronal apoptosis, by examining whether caspases and c-Jun N-terminal kinase (JNK) are involved in the DNA strand break-induced apoptosis. The protein level of phospho-JNK increased in p53 wild-type mouse cerebellar granule neurons after exposure to bleomycin. On the other hand, the response was not observed in cerebellar granule neurons of p53-deficient mice. Caspase-3-like protease was activated and poly(ADP-ribose) polymerase (PARP) was cleaved in the bleomycin-induced apoptosis. Caspase-3-like protease inhibitor decreased the number of TUNEL-positive but not p53- or c-Jun-positive neurons in bleomycin-induced death. These results suggest that JNK and caspase-3-like protease are involved in the signaling cascade of DNA strand break-induced, p53-dependent apoptosis.

The effects of temperature on the mechanical performance in fatigued single muscle fibers of the frog induced by twitch and tetanus.

Muscle fatigue induced by consecutive twitches or tetani was studied in single skeletal muscle fibers of the frog, Rana japonica. The fatigue by twitch appeared sooner after the start of stimulation at lower temperatures (2-5 degrees C) than at higher ones (15-20 degrees C), while the fatigue by tetanus appeared sooner at higher temperatures. When a twitch-fatigued fiber was bathed in a solution with caffeine (15 mM), the contracture force was much higher than the fatigued force, while in tetanus fatigue, the force by caffeine was not different from the fatigued force. The length-force relation in fatigued fibers was compared with that in pre-fatigue at low and high temperatures. It was noticed that the ascending limb of the length-force curve in fatigued fibers by twitch was lower than that in pre-fatigue at the low temperatures; namely, the fatigue by twitch was more marked in shorter muscle length, while no marked change in the length-force relation was detected in the tetanus fatigue at the low and high temperatures. The maximum shortening velocity, measured by the slack test, decreased in both types of fatigue. These results suggest that the fatigue by twitch may be mainly due to the failure of activation of the contractile system, while in the fatigue by tetanus, the rate of the interaction between actin and myosin may be impaired due to the change in intracellular chemical environment.

Role of p53 in DNA strand break-induced apoptosis in organotypic slice culture from the mouse cerebellum.

Apoptosis occurs not only in mitotic cells but also in postmitotic neuronal cells. We previously suggested that the tumor suppressor gene p53 is required for DNA strand break-induced apoptosis in dissociated culture of cerebellar granule neurons. In this study, we examined the role of p53 in apoptosis using organotypic slice culture of cerebellum from p53 null and wild-type mice. Exposure to bleomycin significantly increased the numbers of TUNEL-, p53-, and c-Jun-positive neurons in the wild-type mouse cerebellar internal granular layer (IGL) and Purkinje cell layer (PL). However, in p53-deficient mice, these responses were not observed. These results are consistent with our previous observations in dissociated neuronal culture showing that the amount of c-Jun protein increases significantly after addition of bleomycin in p53 wild-type cerebellar granule cells. The results presented here also indicate that p53 is involved in DNA strand break-induced apoptosis of fully postmitotic central nervous system neurons and suggest that c-Jun expression occurs downstream of p53 expression.

Early increases in renal kallikrein secretion on administration of potassium or ATP-sensitive potassium channel blockers in rats.

1 This study aimed to examine whether administration of potassium or ATP-sensitive potassium channel (KATP channel) blockers caused early increases in renal kallikrein (KK) secretion. To clarify this mechanism, the effect on renal KK secretion of a KATP channel blocker was compared with the effect resulting from use of an osmotic diuretic or volume load. Furthermore, the effect on potassium-induced increases in renal KK secretion by an additional treatment using a KATP channel blocker was examined. Lastly, the effect of a KATP channel blocker on renal KK secretion was also examined in superfused slices of kidney cortex. 2 Intravenous infusion of potassium augmented renal KK secretion within 30 min while urine volume increased gradually in both the potassium loading and control groups. 3 Administration of the KATP channel blocker, 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (PNU-37883A) or glibenclamide, caused a dose-dependent increase in renal KK secretion. 4 The concentration of KK in urine was higher in the PNU-37883A group as compared to the osmotic-diuretic or volume-load group. 5 PNU-37883A had no additive effect on the potassium-induced increase in renal KK secretion. 6 Renal KK secretion increased in slices of kidney cortex incubated with PNU-37883A within 10 min of superfusion. 7 In conclusion, administration of both potassium and KATP channel blockers induced early increases in renal KK secretion in the absence of the washout phenomenon. Potassium loading may have increased renal KK secretion through the same mechanism as the KATP channel blocker.

Nonpeptide mimic of bradykinin with long-acting properties.

Kinins, members of a family of peptides released from kininogens by the action of kallikreins, have been implicated in a variety of biological activities including vasodilation, increased vascular permeability, contraction of smooth muscle cells and activation of sensory neurons. However, investigation of the physiological actions of kinins have been greatly hampered because its effects are curtailed by rapid proteolytic degradation. We examined the pharmacological characteristics of the first nonpeptide bradykinin receptor agonist 8-[2,6-dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl+ ++]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinolin e (FR190997). FR190997, whose structure is quite different from the natural peptide ligand, but is similar to the nonpeptide antagonists FR165649, FR167344 and FR173657, potently and selectively interacts with the human B2 receptor and markedly stimulates inositol phosphate formation in transfected Chinese hamster ovary (CHO) cells. FR190997 induces concentration-dependent contraction of isolated guinea pig ileum. In vivo, FR190997 mimics the biological action of bradykinin and induces hypotensive responses in rats with prolonged duration, presumably as a consequence of its resistance to proteolytic degradation. Therefore, FR190997 is a highly potent and subtype-selective nonpeptide agonist which displays high intrinsic activity at the bradykinin B2 receptor. This compound represents a powerful tool for further investigation of the physiology and pathophysiology of bradykinin receptors.

[Vein of Galen aneurysmal malformation: multi-staged feeder clipping in two neonatal cases with intractable heart failure].

The authors reported the surgical experience of two cases of vein of Galen aneurysmal malformation in the newborn, whose congestive high-output cardiac failure was intractable. Along with the intensive care to clinical manifestations of the heart failure, multi-staged feeder clipping was carried out to decrease the high-flow shunt of the malformation. As stages going on, heart failure was relieved gradually and cathecolamines were weaned. Although certain retardation became apparent in both cases, they are showing satisfactory development in the long-term follow up. By the recent advancement of the embolization technique, the embolization appears to have already taken place the treatment of choice for this malformation. According to the neonatal evaluation score of Lasjaunias, the embolization would no longer be recommendation in neonates, whose general condition scored less than eight points. The authors believe, based on our two cases, that multi-staged feeder clipping is one of the effective modality of treatment in neonates of the vein of Galen aneurysmal malformation with severe multiorgan failure.

New indicator for the Fontan operation: diameters of the pulmonary veins in patients with univentricular heart.

BACKGROUND: Operative survival after the Fontan procedure is good; however, there are some patients with disappointing results, especially those with atrial isomerism. OBJECTIVES: We tested whether the diameter of the pulmonary veins, which is reported as a useful indicator of pulmonary blood flow, predicts operative results after the Fontan operation. PATIENTS AND METHODS: We evaluated 30 consecutive patients undergoing either the bidirectional Glenn anastomosis (BDG) or the Fontan operation. Age at operation ranged from 3 to 81 months (mean 30). Diagnosis was right or left isomeric heart in 15 patients, double-outlet right ventricle in 4 and various other malformations in 11. BDG was performed in 16 patients and the Fontan operation in 14 patients. The diameters of the pulmonary veins were measured proximal to the entrance into the atrium in the late phase of a pulmonary arteriogram. The pulmonary vein (PV) index (in mm2/m2) was calculated from the sum of the cross-sectional areas of these veins divided by the body surface area. RESULTS: Of the patients undergoing BDG (+/- ancillary procedures), 12 had successful results and 4 had unsuccessful results. The PV index for hemodynamically successful patients was 361 +/- 153 and 275 +/- 60 mm2/m2 (mean +/- SD) for unsuccessful patients (p = 0.30). Of the patients who underwent the Fontan operation, 13 had successful and 1 had unsuccessful results. The PV index for successful patients was > 285 mm2/m2 and 137 mm2/m2 for the nonsuccessful patients. The new pulmonary vascular resistance (PVR) calculated by using the PV index (mean pressure difference between the pulmonary artery and the atrium/PV index) for BDG patients with successful or unsuccessful results was 2.0 +/- 0.5 or 3.5 +/- 0.2 mmHg/mm2 per m2, respectively (p < 0.01). The new PVR for Fontan patients with successful results was < 2.0 mmHg/mm2 per m2, while that for the patient with an unsuccessful result was 4.4. The new PVR completely separated patients into successful and unsuccessful groups, while conventionally calculated PVR did not (p = 0.63). CONCLUSIONS: PV index appears to be a useful morphological indicator of pulmonary blood flow and "new" PVR may improve the decision-making strategy for patients presenting with univentricular heart, especially those associated with isomeric heart.

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 2. Overcoming the species difference between guinea pig and man.

Recently we reported the identification of a series of 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridines as the first orally active non-peptide bradykinin (BK) B2 receptor antagonists (1-3). These compounds inhibited the specific binding of [3H]BK to guinea pig ileum membrane preparations expressing B2 receptors with nanomolar IC50's and also displayed in vivo functional antagonistic activities against BK-induced bronchoconstriction in guinea pigs at 1 mg/kg by oral administration. However, it was found that their affinities for the B2 receptors in human A-431 cells (human epidermoid carcinoma) were much lower. Intensive modifications of the terminal substituents at the glycine moiety elucidated the structure-activity relationships (SAR) for human B2 receptors, leading to an extended basic framework which incorporated a novel key pharmacophore. Thus, we overcame the species difference and identified the first clinical candidate 18c (FR167344) with IC50's of 0.66 and 1.4 nM for guinea pig ileum and human A-431 cells, respectively. This compound displayed in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.17 mg/kg by oral administration. This novel non-peptide B2 antagonist is extremely potent both in vitro and in vivo by oral administration and is expected to be the first member of a new class of drug for the treatment of various inflammatory diseases.

A novel class of orally active non-peptide bradykinin B2 receptor antagonists. 3. Discovering bioisosteres of the imidazo[1,2-a] pyridine moiety.

Recently we reported on overcoming the species difference of our first orally active non-peptide bradykinin (BK) B2 receptor antagonists, incorporating an 8-[[3-(N-acylglycyl-N-methylamino)-2, 6-dichlorobenzyl]oxy]-3-halo-2-methylimidazo[1,2-a]pyridine skeleton, leading to identification of the first clinical candidate 4a (FR167344). With this potent new lead compound in hand, we then investigated further refinement of the basic framework by replacement of the imidazo[1,2-a]pyridine moiety and discovered several bioisosteric heterocycles. Extensive optimization of these new heteroaromatic derivatives revealed the detailed structure-activity relationships (SAR) around the imidazo[1, 2-a]pyridine ring and the 2,6-dichlorobenzyl moiety, leading to the discovery of our second clinical candidate 87b (FR173657) which inhibited the specific binding of [3H]BK to recombinant human B2 receptors expressed in Chinese hamster ovary (CHO) cells and guinea pig ileum membrane preparations expressing B2 receptors with IC50's of 1.4 and 0.46 nM, respectively. This compound also displayed excellent in vivo functional antagonistic activity against BK-induced bronchoconstriction in guinea pigs with an ED50 value of 0.075 mg/kg by oral administration. Further modifications of the terminal substituents on the pyridine moiety led to a novel pharmacophore and resulted in the identification of 99 (FR184280), whose IC50 value for human B2 receptors (0.51 nM) was comparable to that of the second-generation peptide B2 antagonist Icatibant.

Pulmonary and systemic arteriovenous fistulas in patients with left isomerism.

Hepatic venous blood has been thought to play some role as a vasoactive agent in the development of pulmonary arteriovenous fistulas in patients with congenital heart disease. During the last 15 years, we have observed pulmonary arteriovenous fistulas in 3, and systemic arteriovenous fistulas in 2, patients from our 16 cases of left isomerism. During the same period, neither pulmonary nor systemic arteriovenous fistulas were detected among 50 patients with right isomerism. Pulmonary arteriovenous fistulas had developed in the absence of surgery in 1 of the patients. Both pulmonary and systemic fistulas were detected in an another patient, in whom the hepatic venous blood bypassed the pulmonary circulation. The level of somatostatin, which is known to reduce splanchnic blood flow, was high in the systemic venous blood of this patient. Although the mechanism of development of the fistulas has yet to be clarified, we should be aware that not only pulmonary, but also systemic arteriovenous fistulas can be found in patients with left isomerism, even prior to any surgical intervention.

Changes in c-Jun but not Bcl-2 family proteins in p53-dependent apoptosis of mouse cerebellar granule neurons induced by DNA damaging agent bleomycin.

Tumor suppressor gene p53 is a critical regulator of the cellular response to DNA damage. To examine the function of p53 in postmitotic CNS neurons, we cultured cerebellar granule cells from 15-day-old wild type and p53-deficient mice, and analyzed changes of protein expression in apoptosis elicited by DNA damage. When cerebellar granule cells from wild type mice were treated with bleomycin, a DNA strand-break inducing agent, neuronal death occurred. In contrast, cells from p53-deficient mice were resistant to bleomycin-induced neuronal death. Furthermore, cells from p53 heterozygous mice showed an intermediate resistance between wild type and p53-deficient mice. These results show that p53 is required for the bleomycin-induced cerebellar granule cell death. To examine which proteins are involved in this apoptosis, we examined changes in protein levels of the Bcl-2 family, including Bcl-2, Bcl-X and Bax. The relative amounts of these proteins did not change after bleomycin treatment, suggesting that the changes in the levels of these Bcl-2 family proteins are not necessary for apoptosis in this system. In contrast, the levels of c-Jun protein significantly increased 6 h after treatment with bleomycin in wild type but not in p53-deficient cerebellar granule cells. These results raise the possibility that c-Jun is required for p53-dependent neuronal apoptosis induced by bleomycin.

Biochemical and pharmacological characterization of FK706, a novel elastase inhibitor.

FK706, sodium 2-[4-[[(S)-1-[[(S)-2-[[(RS)-3, 3, 3-trifluoro-1-isopropyl-2-oxopropyl]aminocarbonyl]pyrrolidin -1-yl]carbonyl]-2-methylpropyl] aminocarbonyl] benzoylamino] acetate, C26H32F3N4NaO7, is a synthetic water-soluble inhibitor of human neutrophil elastase. This compound demonstrated a competitive and slow-binding inhibition of human neutrophil elastase with a Ki of 4.2 nM. In studies using synthetic substrates, FK706 inhibited human neutrophil elastase activity and porcine pancreatic elastase activity with respective IC50 values of 83 and 100 nM. FK706, however, inhibited more weakly, (IC50 values > 340 microM) other serine proteinases such as human pancreatic alpha-chymotrypsin, human pancreatic trypsin and human leukocyte cathepsin G. FK706 also effectively inhibited the hydrolysis of bovine neck ligament elastin (2 mg/ml final concentration) by human neutrophil elastase (4 microg/ml final concentration) with an IC50 value of 230 nM. FK706 protected animals against human neutrophil elastase (50 microg/animal)-induced lung hemorrhage with ED50 values of 2.4 microg/animal by intratracheal administration and 36.5 mg/kg by intravenous administration, respectively. Subcutaneous administration of FK706 significantly suppressed human neutrophil elastase (20 microg/paw)-induced paw edema in mice in a dose-dependent manner (47% inhibition at a dose of 100 mg/kg). These results suggest that FK706 would be a useful tool for investigating the role of human neutrophil elastase in inflammatory disorders associated with an excess of elastase, such as pulmonary emphysema, adult respiratory distress syndrome, septic shock, cystic fibrosis, chronic bronchitis and rheumatoid arthritis.

Loss of the xeroderma pigmentosum group A gene (XPA) enhances apoptosis of cultured cerebellar neurons induced by UV but not by low-K+ medium.

To study the involvement of the xeroderma pigmentosum group A gene (XPA) in neuronal apoptosis, we cultured cerebellar neurons from mice lacking XPA gene (XPA-/-) and induced apoptosis by exposure to UV irradiation or medium containing a low concentration of potassium (low-K+ medium). When cerebellar neurons from postnatal days 15-16 wild-type mice were treated with UV irradiation, apoptotic neuronal death was observed after 24-48 h. About 60% of neurons survived 48 h after UV irradiation at a dose of 5 J/m2. On the other hand, neurons from XPA-/- mice showed a significantly increased vulnerability to UV irradiation, and >90% of neurons died 48 h after UV irradiation at a dose of 5 J/m2. In contrast, low-K+ medium induced apoptosis of neurons from mice of each genotype with the same kinetics. These results suggest that the XPA gene is involved in neuronal DNA repair and that it thereby influences apoptosis induced by DNA damage in cultured cerebellar neurons.

Diameters of the pulmonary arteries and veins as an indicator of bilateral and unilateral pulmonary blood flow in patients with congenital heart disease.

OBJECTIVES: This study was done to clarify which diameter, that of the pulmonary arteries (PAs) or that of the pulmonary veins (PVs), more precisely reflects pulmonary blood flow (PBF) bilaterally and unilaterally. METHODS: To evaluate bilateral PBF, we studied 15 consecutive patients with Kawasaki disease as normal patients and 30 patients with tetralogy of Fallot who received cardiac catheterization. To evaluate unilateral PBF, 20 patients with various congenital heart diseases undergoing cineangiography and lung perfusion scintigraphy were studied. The diameter of PA was measured immediately proximal to the origin of the first lobar branches bilaterally, and right PA area, left PA area, PA area (mm2), and PA index (mm2/m2) were calculated. The diameter of PV was also measured distal to the junction with the left atrium. Right PV area, left PV area, PV area (mm2), and PV index (mm2/m2) were calculated from these diameters. Pulmonary blood flow (PBF) was obtained by the Fick method during catheterization. To evaluate unilateral PBF, PBF was divided into right and left PBF according to the right/left perfusion ratio measured by lung perfusion scintigraphy. RESULTS: Evaluation of bilateral PBF was as follows: in normal patients, PA and PV areas were correlated with body surface area (r = 0.88, p = 0.0001 and r = 0.93, p = 0.0001); PA index and PV index ranged from 248 to 436 (mean = 343) mm2/m2 and from 346 to 595 (mean = 466) mm2/m2, respectively, and were constant irrespective of body surface area; PA and PV areas were correlated with PBF in normal patients, as well as in patients with tetralogy of Fallot. There was a better correlation between PV area and PBF than between PA area and PBF in normal patients, as well as a significantly better correlation in patients with tetralogy of Fallot. Evaluation of unilateral PBF was as follows: right PV area was correlated with right PBF (p = 0.0002), while right PA area was not; left PV area and left PA area were correlated with left PBF; right/left PV area ratio was correlated with the right/left perfusion ratio with better agreement than right/left PA area ratio. CONCLUSION: Our data suggest that the size of PVs in patients with congenital heart disease may be more useful than the size of PAs to indicate bilateral and unilateral PBF than the size of PAs. Differences in PV area of each lung may be a suitable indicator of discrepancy in blood flow to each lung.