Survey of recognition and utilization of guidelines for the diagnosis and management of bronchial asthma in Japan.

BACKGROUND: In Japan in 1993, the Japanese Society of Allergology (JSA) developed guidelines for diagnosis and management of asthma (JGL), which were based on the concept that asthma is a chronic inflammatory disorder of the airway. METHODS: This survey study was intended to investigate the recognition and utilization of JGL among physicians who had treated asthma. The survey comprised two methods: a quantitative mail survey and a qualitative door-to-door survey conducted by trained interviewers. RESULTS: In the mail survey, a total of 1028 physicians responded; 552 members of the JSA and 476 nonmembers. Ninety-four percent of JSA members were aware of adult asthma management guidelines, while 53% of nonmembers were aware of them. Although approximately half of the physicians, both members and nonmembers, found differences between the asthma management policies in JGL and their previous policies, most of them utilized JGL once they read it. In the qualitative door-to-door survey, 80-90% of physicians evaluated JGL as good after they read it. CONCLUSIONS: JGL was recognized and utilized by most JSA members, but only half of nonmember physicians were aware of JGL, although they utilized JGL after they read it. Further action to implement JGL among nonspecialist physicians is needed to improve management of asthma.

[Surgical repair of postinfarction ventricular septal defect: modified Komeda-David procedure].

Since Cooley first reported surgical repair of postinfarction ventricular septal defect in 1957, there have been technical improvements in this procedure. However, the outcome of surgery has not been gratifying thus far. In 1990, Komeda and associates reported a single patch of bovine pericardium sutured to the healthy myocardium around the infarcted area on the left side of the septum that excludes the infarcted myocardium from the left ventricular cavity; a procedure based on a completely different idea. Since the satisfactory outcome of the surgical treatment in this procedure was obtained in a series of 12 patients, this surgical procedure has been in widespread use in Japan. On the other hand, this procedure has a drawback that there is a difficulty in suturing the patch and may lead to a postoperative residual shunt. We investigated a modified surgical procedure that could overcome this difficulty and would like to report it in this paper. At first, the perforated area should be covered with a felt strip and closed with mattress sutures. Secondly, the infarcted myocardium from the left ventricular cavity should be obliterated using a two-patch method. The primary advantage of this procedure is that it achieves a broader range of vision than a single patch method and enables easy suturing. Additionally, the development of a residual shunt can be prevented owing to the closure of perforation even if sutures fail to hold and leakage occurs. The tow-patch method has the advantage of avoiding tension against sutures since the patch is not everted around the sutures. However, the question arises whether only the healthy myocardium can be picked out and sutured without fail. In order to make the two-patch method more reloable the perforation should be closed in advance.

[Estimation of left internal thoracic artery flow reserve after coronary artery bypass grafting using Doppler flow wire].

The usefulness of the left internal thoracic artery (LITA) for aortocoronary bypass grafting is now established. Reports of variation in LITA graft function are rare. Graft flow was measured using a Doppler flow wire to estimate graft function in 27 patients (24 males, 3 females) who underwent LITA grafting to the left anterior descending artery. Patients were classified into the following 3 groups: Group A consisted of 9 patients with normal left ventricular function and no native flow; Group B consisted of 11 patients with normal ventricular function and good native flow; Group C consisted of 7 patients with abnormal left ventricular function and no native flow. LITA graft function was also estimated 1 year after operation in 12 of these 27 patients (4 in each group). Diastolic/systolic velocity ratio (DSVR) and flow reserve were determined in the proximal, middle, and distal portions of the LITA graft and native left anterior descending artery before and after papaverine administration (8-10 mg). DSVR was significantly higher in the distal portion than in the proximal portion (p < 0.01), but this value did not change after papaverine administration. After 1 year, DSVR in the proximal portion was significantly higher in Group C than in Groups A or B (p < 0.05 for both). Four weeks after operation, the flow reserve of the distal portion was significantly higher in Group A than in Group C (p < 0.001). After 1 year, this value was significantly higher in Group A than in either Groups B or C (p < 0.01, p < 0.001, respectively). The rate of increase in flow reserve in the distal portion was significantly greater in Group A (23.4%) than in groups B (2.53%) or C (1.94%; p < 0.05 for both). The distal portion of the LITA was the best measurement site, since the flow pattern in the LITA graft varied throughout all portions. Diastolic flow velocity in the LITA graft was dominant in patients with myocardial damage. The results indicate that flow reserve of the LITA graft depends on antegrade native coronary flow and distal myocardial damage.

[An experience with St. Jude medical prosthetic 19A-HP which resulted in restricted opening at an early stage after operation].

St. Jude medical hemodynamic plus series is positively used for aortic valve replacement (AVR) of small orifice because it can increase the orifice area by 26% compared with conventional prosthetic valves of the same size. We performed AVR with SJM 19A-HP on a patient having aortic stenosis with regurgitation using horizontal mattress suturing technique. The aortic orifice size was 18.9 mm at the preoperative measurement. The course after the operation was uneventful until 9 days after the operation when cinefluoroscopy revealed symmetrical restriction of opening of valve leaflets. We are now monitoring the clinical course at the patient has not developed any symptoms though the LV-Ao pressures gradient is 60 mmHg by Doppler echocardiography. As the restriction of valve leaflet opening was symmetrical, it is not likely that an excess of the ligature or remnant caused the restriction; structural problems of St. Jude medical prosthesis appear to be a more reasonable explanation. Since the orifice ring of this prosthesis is not reinforced, longitudinal forces applied to the hinge may alter the shape of the ring, thus restricting the movement of valve leaflets. In the present case, forced insertion of 19A-HP instead of more desirable 17-HP is considered to have caused longitudinal forces acting on the hinge.

[A epidemiologic study on the prevalence of the allergic diseases in school children in Kyoto City].

UNLABELLED: The prevalence of allergic diseases in school children in Kyoto City (17,906 children) was examined with the questionnaire which was prepared by the Study Group of Epidemiology of Allergic Diseases funded by the Ministry of Public Welfare in 1993. RESULTS: 1) The number of valid reply was 16,176 (reply rate 90.3%). The reply rate of each question was from 89.5% to 98.9% (average 95.7%). 2) The prevalence of bronchial asthma was 4.9% in the elementary school children, 3.5% in the junior high school children and 4.5% in total, and the prevalence in boys was higher than girls (ratio 1.6). The prevalence of wheezing was 6.5%, 2.7% and 5.5%, respectively, and the sex ratio was 1.2. 3) The prevalence of atopic dermatitis was 5.3% in elementary school children, 4.0% in junior high school children and 5.0% in total, and the prevalence in boys was lower than girls (ratio 0.87). 4) The prevalence of allergic rhinitis was 19.8% in elementary school children, 21.2% in junior high school children and 20.3% in total, and the prevalence in boys was higher than girls (ratio 1.3). 5) The prevalence of allergic conjunctivitis was 11.9% in elementary school children, 15.4% in junior high school children and 13.0% in total and the prevalence in boys was almost same as girls (ratio 0.98). 6) The prevalence of any allergic diseases was 32.2% in elementary school children, 31.7% in junior high school children and 32.1% in total and the prevalence in boys was higher than girls (ratio 1.2).

[Replacement of the aortic root with woven and knitted Dacron composite graft].

Some of the patients with annuloaortic ectasia or Stanford type A require aortic root replacement. If conventional Bentall procedure is employed in such cases, aortic root will become a cylindrical shape totally lacking sinus of Valsalva because the procedure utilizes a straight tube. The sinuses of Valsalva support an important role in opening and closing the valvar leaflets, and opening of the coronary arteries, together with the interleaflet triangles and the sinutubular junction. In this study, we performed aortic root replacement with composite graft which consisted of two types of graft including 30 mm Knitted Dacron Graft (Gelsoft) with different dilation rates and 30 mm Woven Dacron Graft (Hemashield) as well as bioprosthesis (27 mm Carpentier-Edwards), in order to reconstruct sinus of Valsalva. Post-operative angiography revealed an excellent diastolic coronary flow, as evidenced by proximal Knitted graft of 37 mm in diameter, distal Woven graft of 30.3 mm in diameter and Doppler flow DSVR (Diastolic/Systolic Velocity Ration) of 2.2 measured at the left coronary orifice. Since it is difficult to obtain homograft at present, this procedure would be worth trying during aortic root replacement.

[Epidemiological research on incidence of atopic disease in infants and children in relation to their nutrition in infancy].

Incidence and relative risk of atopic disease (atopic dermatitis; AD, bronchial asthma; BA, allergic rhinitis; AR) in Japanese infants and children in relation to their nutrition in infancy was analyzed from the data of the epidemiological survey which was conducted for 10,000 mothers of infants and children in 1993. A total of 4,610 replies were received: 2,714 from mothers of infants (12 months old) and 1,896 from mothers of children (2 years old). The subjects were allocated to following 3 groups based on their nutrition during first 3 months after birth; the breast-fed group (BF), the formula-fed group (EF), the mixed-fed group (MF). Incidence of atopic disease in BF, FF and MF was 23.5%, 22.2% and 21.8%, respectively and no statistical difference could be found among these 3 groups. AD was developed 17.0%, 14.4% and 13.9%; BA was 4.4%, 8.5% and 5.2%; AR was 4.9%, 6.5% and 5.8% in BF, FF and MF, respectively. Incidence of AD was significantly different between BF and MF (p < 0.01). Incidence of BA was also significantly different between BF and FF (p < 0.01). Risk of onset of BA and AR in FF was higher (adjusted odds ratio 2.2, 95% confidence interval 1.5-3.2 and adjusted odds ratio 1.5, 95% confidence interval 1.0-2.2, respectively) than that of BF controlled by age and family history with Cochran-Mantel-Haenzel test. With multiple logistic regression analysis, relative risk of the onset of BA in FF at the age of one year was 2.1, 95% confidence interval 1.2-3.5 and at the age of two years old was 2.5, 95% confidence interval 1.4-4.4. These results suggest that the breast-fed have certain suppression effects on incidence of bronchial asthma in infants and children.

Survey of family history on allergy in 1-year-old and 6-year-old children.

A retrospective survey of a family history of allergy employing a special questionnaire for children was performed. The survey included 1-year-old (n = 267) and 6-year-old children (n = 410) with allergies as well as 1-year-old (n = 313) and 6-year-old children (n = 329) without allergies. An 'Allergy Risk Score' (ARS) for each subject was calculated according to the history of allergy in three family members: father, mother and a sibling. Each family member was scored as 2.0 (overt history of allergies), 1.0 (provable), 0.5 (possible) or 0 (absent), and the ARS of the subjects was calculated as the total of the family members' scores. The ARS of children in the allergy groups was statistically higher than that of the control groups in both age groups. The ARS increased with an increase in the odds ratio (an approximate value of the risk), especially in 6-year-old children. An ARS calculated on the basis of family history could be a useful and practical index for estimating the risk of allergy development in children, and may be helpful in predicting and preventing allergies in infants and children.

Serum levels of interleukin 4 and soluble CD23 in children with allergic disorders.

UNLABELLED: In order to clarify the clinical significance of serum interleukin 4 (IL-4) levels, we measured serum IL-4 concentrations in allergic and non-allergic children using a highly sensitive sandwich ELISA. The limit of detection of the assay was 0.15 pg/ml in serum samples. Serum IL-4 was detected in 96.3% (53/55) of non-allergic controls, in 92.9% (183/197) of allergic children, in 70% (7/10) of cord blood samples and in 86.7% (26/30) of neonates. The IL-4 levels in sera from non-allergic controls were relatively constant during the ages examined and all samples were under 1.5 pg/ml. In allergic children, the serum levels of IL-4 were significantly elevated, particularly at age 13-24 months. The serum levels of IL-4 did not differ in children with different clinical manifestations of allergy, such as bronchial asthma, and atopic dermatitis. The serum level of soluble CD23 (sCD23) showed an age-dependent change in allergic and non-allergic children and was significantly higher in allergic than in non-allergic infants aged 7 to 12 months, but not in other age groups. There was no significant correlation among serum levels of IL-4, sCD23 and IgE. CONCLUSION: It is suggested that the measurement of serum IL-4 and sCD23 is helpful in the examination of allergic patients in infancy and early childhood, but neither the serum level of IL-4 nor sCD23 directly reflects in vivo IgE production.

Comparative effect of 100 versus 250 micrograms/m2/day of G-CSF in pediatric patients with neutropenia induced by chemotherapy.

In pediatric patients with various malignancies, the effect of two different doses of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on chemotherapy-induced neutropenia was examined. Each patient was treated with two courses of the same chemotherapeutic regimen. Following each course, either 100 micrograms/m2 or 250 micrograms/m2 of rhG-CSF was infused daily starting 48 hours after the cessation of chemotherapy and continuing for 14 consecutive days. A total of 29 patients (34 cycles of therapy) were eligible for the study. Both the duration of neutropenia (< 0.5 x 10(9)/l) and median days from the nadir of neutrophils to recovery, > 0.5 x 10(9)/l, were significantly shorter when 250 micrograms/m2 was given. Moreover, the nadir counts of neutrophils and the duration of fever with neutropenia were, although not significant, in favor of 250 micrograms/m2 administration. No differences were observed in the frequency and severity of side effects.

[Serum ECP level of infants of atopic dermatitis].

Forty-seven infants with atopic dermatitis (AD) were examined for ECP (eosinophil cationic protein) levels in sera at 3 to 4, 6 to 7, 12 and 18 months after birth. ECP levels in AD were significantly higher than those of control infants at every examination. The levels of ECP in AD were significantly correlated with the severity of dermatitis judged by a slightly modified version of the method of Businco et al. We concluded that ECP levels in sera are a useful marker for the severity of dermatitis in infants with AD.

[Questionnaire survey on "The guidelines on diagnosis and treatment of asthma" edited by the Japanese Society of Allergology (1993)].

A questionnaire on the evaluation of "The Guidelines on Diagnosis and Management of Asthma" edited by the Japanese Society of Allergology in 1993 was sent to 586 physicians consisting of specialists authorized by the Japanese Society of Allergology and the board members of this Society, who treated patients with bronchial asthma. Of total 306 (52.2%) who responded, 177 (57.8%) answered the questions on adult asthma only, 65 (21.2%) on childhood asthma only and 52 (17.9%) on both adult and childhood asthma. In total, we had 229 respondents on adult asthma and 117 on childhood asthma. As a result, on drug therapy for chronic asthma, it was pointed out that the use of oral anti-allergics, oral steroids and inhaled beta-stimulants was excessive whereas the use of DSCG, inhaled steroids and long acting theophylline was slightly insufficient in both adults and children. On the management of acute episodes, the excessive use of beta-stimulants (inhaled, oral and injections) and the lack of the use of parenteral steroids and oxygen inhalation were pointed out in adults. The lack of oxygen inhalation also got a higher percent in children. Nevertheless, the guidelines were found to be highly regarded as a whole: "Very good" was 6.1% in adults (6.8% in children). "Appropriate" 38.0% (33.3%), "Almost appropriate" 52.0% (52.1%) and "Inappropriate" 3.9% (3.4%).

A case of common variable immunodeficiency associated with cyclic thrombocytopenia.

A 12 year old boy was found to be deficient in immunoglobulins (Ig) A, G2 and G4, and common variable immunodeficiency was diagnosed. He also had cyclic thrombocytopenia at intervals of approximately 28-30 days. His bone marrow revealed normocellular with slightly decreased megakaryocytes. In vitro colony assays showed markedly imparied megakaryocytopoiesis, erythropoiesis and granulopoiesis. Platelet-associated IgG was elevated at his thrombocytopenic phase. Direct Coombs' test was repeatedly positive. Although not defined at present, we suggest the autoimmune nature of the disease.

Developmental changes of GM-CSF gene inducibility in embryonal carcinoma cells.

Murine embryonal carcinoma (EC) P19 cells, a tissue culture model of early embryonic development, failed to produce cytokines, such as interleukin-3 (IL-3), IL-4, granulocytemacrophage colony stimulating factor (GM-CSF) and interferon-beta (IFN-beta) at the mRNA level. Differentiation induced by retinoic acid (RA) released this repression to produce some cytokines. GM-CSF and IFN-beta genes were expressed in response to PMA/A23187, poly(I):poly(C), IL-1 alpha, forskolin, or LPS stimulation in differentiated P19 cells, whereas IL-3 and IL-4 genes were not expressed. To elucidate the mechanism of the GM-CSF gene induction after differentiation, we transfected a series of 5' deletion mutants of the mouse GM-CSF promoter fused to the bacterial CAT gene. The 740-bp fragment of the 5'-flanking region mediated the positive response. Deletion analysis revealed that the 5' boundary region of the DNA element required for activation lies between positions -95 and -84 and the region upstream of position -95 appears inhibitory. These results indicate that the maturation of the transcriptional machinery after differentiation results in the activation of the GM-CSF gene.

Age-related acute adriamycin cardiotoxicity in mice.

Myocardial mitochondrial function after acute adriamycin exposure was compared in infant and adult mice. Heart mitochondrial were isolated 48 h after an intraperitoneal injection of adriamycin. Concentrations of adriamycin in serum and heart tissue were not significantly different between infant and adult mice. Oxygen consumption (state 3 respiration), and respiratory control ratio (RCR) were studied polarographically. Enzyme activities in the respiratory chain [succinate-cytochrome c reductase (SCCR), NADH-cytochrome c reductase (NCCR), cytochrome c oxidase (CCO)], and adenine nucleotide translocase (ANT) were assayed. After saline injection (control), no significant differences were detected in state 3 respiration, RCR, and enzyme activity of ANT between infant and adult mice. The respective enzyme activities of SCCR, NCCR, and CCO in adult mice were significantly lower than those in infant mice. After adriamycin injection in adult mice, there were significant decreases in state 3 respiration (using glutamate and malate as substrates from 239 +/- 25 to 160 +/- 50 nanoatom O2/min/mg protein), RCR (using glutamate and malate as substrates from 7.2 +/- 1.0 to 4.4 +/- 1.4), and enzyme activities of SCCR (from 279 +/- 30 to 178 +/- 28 nmol/min/mg protein) and NCCR (from 331 +/- 43 to 237 +/- 30 nmol/min/mg protein), but there were no significant changes in infant mice. No significant changes in enzyme activities of CCO and ANT were found in either infant or adult mice following the administration of adriamycin. In conclusion, adriamycin is less toxic on the myocardial mitochondrial function in infant mice than in adult mice.

Involvement of CD11b/CD18 in enhanced neutrophil adhesion by Fc gamma receptor stimulation.

Neutrophils showed a rapid and transient adhesion to immunoglobulin G (IgG)-coated plates compared with their adhesion to bovine serum albumin (BSA)-coated plates: the adhesion reached a peak after 15 min of incubation and then gradually returned to almost the basal state in 60 min. The addition of monomeric IgG or anti-Fc gamma RII monoclonal antibody (mAb) (IV.3) suppressed the increase in adhesion, whereas anti-Fc gamma RIII mAb (3G8) was hardly effective, indicating that the interaction of Fc gamma R, especially Fc gamma RII, with coated IgG is involved in the process. Adhesion was also blocked by cytochalasin B, suggesting that functional actin filament structures are crucial. Protein kinase inhibitors, erbstatin and genistein, inhibited the adhesion in a dose-dependent manner. The adhesion was inhibited by anti-CD11b (M1/70) and anti-CD18 (MHM23, TS1/18) mAbs. Moreover, neutrophils from a patient with complete leukocyte adhesion deficiency syndrome did not show increased adhesion to IgG-coated plates. The adhesion of neutrophils to fibrinogen- and BSA-coated plates was also increased when Fc gamma R was stimulated in the fluid phase with soluble aggregated IgG, which was also inhibited by anti-CD11b mAb. Stimulation of neutrophil Fc gamma R with soluble aggregated IgG enhanced the expression of CD11b in concert with the enhanced adhesion. These data collectively suggest that stimulation via Fc gamma R evokes a tyrosine kinase-dependent and actin filament-dependent intracellular signal that enhances the specific and nonspecific adhesive activity of neutrophils, presumably through the activation of CD11b/CD18.

[Pathophysiology of infantile hydrocephalus: studies with multivariate analysis].

We investigated factors relating to intellectual outcome in 21 patients with infantile hydrocephalus. Every patient had received V-P shunt operation before, and was followed up for at least one year. The intellectual development was evaluated with multivariate analysis, and was found to be contributed independently by etiology of hydrocephalus, age at onset, association of epilepsy, and shunt troubles. Thus, those with congenital hydrocephalus, onset after the neonatal period, epilepsy or shunt troubles were related to poor intelligence, while those with acquired hydrocephalus, onset during the neonatal period, and without epilepsy were related to favorable outcome. Among the patients, early onset was correlated with early surgical intervention, which also may have been a determining factor. We also conducted multivariate analysis with the results of somatosensory evoked potentials (SEPs) and visual evoked potentials (VEPs) as objective variables. For both SEPs and VEPs, etiology was considered to be the most important, but other factors also contributed considerably, including CT scan findings, current developmental status, and association of congenital anomalies and epilepsy. Clinical pictures of patients with infantile hydrocephalus apparently are very complicated, being determined by multiple factors, but these cerebral evoked potentials are thought to be useful in the evaluation and follow-up of the patients with infantile hydrocephalus.

Indication for anti-epileptic drug treatment of benign childhood epilepsy with centro-temporal spikes.

To approach the problem concerning whether or not anti-epileptic treatment of benign childhood epilepsy with centro-temporal spikes (BCECT) is necessary, we retrospectively studied 6 untreated and 39 treated patients with BCECT and compared their clinical findings after 2 years of observation. Then we selected 6 untreated and 28 treated patients from the same series who had been free from attacks for more than 2 years to determine whether the mode of onset (multiple seizures or isolated one for the first month of the illness) was related to the duration of active epilepsy in these two groups. This comparative study of untreated and treated patients followed for 2 years revealed no differences in the interval between first visit and start of attack-free period between the two groups. The mean duration of active epilepsy in those with only isolated seizures at onset was significantly shorter than that in those with multiple seizures at onset. Anti-epileptic medication may be unnecessary in patients with isolated seizure during sleep; it does not affect the natural course of BCECT. Treatment is necessary for a longer period in patients with multiple seizures at onset than in those with isolated seizures at onset.

Effect of dibutyryl cyclic AMP and interferon-gamma on Fc gamma receptor expression on eosinophils.

We studied the effect of dibutyryl cyclic adenosine-3',5'-monophosphate (dbcAMP) and several cytokines on the expression of IgG Fc receptor subclasses (Fc gamma RI, Fc gamma RII, and Fc gamma RIII) and low-affinity IgE Fc receptors (Fc epsilon RII/CD23) on peripheral eosinophils and on eosinophils differentiated in vitro from cord blood mononuclear cells by interleukin 5 (IL-5). These eosinophils expressed Fc gamma RII, and few, if any, Fc gamma RI and Fc gamma RIII as determined by flow cytometry with specific monoclonal antibodies. dbcAMP enhanced the Fc gamma RII expression, but did not induce the Fc gamma RI and Fc gamma RIII expression. Interferon-gamma (IFN-gamma) enhanced Fc gamma RII expression at the same degree as did dbcAMP. IFN-gamma also induced Fc gamma RIII expression on peripheral eosinophils but not on eosinophils grown in the presence of IL-5. Eosinophils grown in the presence of IL-5 showed a relatively immature phenotype, determined by electron microscopy and the low content of eosinophil cationic protein. Contrary to its enhancing effect on Fc gamma RII expression, dbcAMP suppressed the IFN-gamma-induced Fc gamma RIII expression on peripheral eosinophils. Other cytokines examined did not show any effects on Fc gamma R expression. Fc epsilon RII/CD23 expression was neither detected nor induced. These results indicate that expression of Fc gamma RII and Fc gamma RIII on eosinophils is regulated differently and that cAMP and IFN-gamma play important roles in the regulation of Fc gamma R expression.

Phenytoin reduces neonatal hypoxic-ischemic brain damage in rats.

We investigated the possible protective effect of phenytoin on hypoxic-ischemic brain damage in neonatal rats. Six-day-old rats underwent ligation of the left carotid artery followed by exposure to an 8% oxygen atmosphere for 2.5 hrs. We sacrificed the animals 72 hrs later and assessed the hypoxic-ischemic brain damage histologically. Phenytoin (50 mg/kg), administered intraperitoneally 1 hr before the hypoxia, reduced hypoxic-ischemic infarction in the cerebral cortex and striatum, and attenuated neuronal necrosis in the hippocampus. The plasma concentration of phenytoin after injection was 11.1 +/- 1.9 micrograms/ml (mean +/- S.E.M.) at 1 hr and 22.9 +/- 1.4 micrograms/ml at 4 hrs. Percent volumes of the infarction calculated by dividing the sum of damaged areas by the total area in serial coronal sections were 79 +/- 3% (mean +/- S.E.M.) in vehicle controls versus 13 +/- 6% in phenytoin-treated pups in the cerebral cortex, and 79 +/- 4% in vehicle controls versus 12 +/- 5% in phenytoin-treated pups in the striatum. We semiquantitatively investigated the hypoxic-ischemic change in 5 hippocampal areas: dentate gyrus, CA4, CA3, CA1, and subiculum, in the dorsal hippocampus. Pre-hypoxic treatment with phenytoin reduced hypoxic-ischemic damage in all areas examined. When phenytoin was administered immediately after the hypoxia, there was no difference between vehicle-injected controls and phenytoin-treated pups. These results demonstrate that phenytoin can reduce neonatal hypoxic-ischemic brain damage.