Sex-based differences in CD103+ dendritic cells promote female-predominant Th2 cytokine production during allergic asthma.

BACKGROUND: Gender disparities in adult patients with asthma regarding its prevalence and severity are mainly due to enhanced type 2 T-helper (Th2) cytokine production in female patients compared to that in male patients. However, the pathways mediating this effect remain unclear. OBJECTIVE: We aimed to determine the roles of two major subsets of dendritic cells (DCs) in females, specifically those displaying CD11b or CD103, during enhanced Th2 priming after allergen exposure, using an ovalbumin-induced asthma mouse model. METHODS: Sex-based differences in the number of DCs at inflamed sites, costimulatory molecule expression on DCs, and the ability of DCs to differentiate naïve CD4+ T cells into Th2 population were evaluated after allergen exposure in asthmatic mice. In addition, we assessed the role of 17ß-oestradiol in CD103+ DC function during Th2 priming in vitro. RESULTS: The number of CD11bhigh DCs and CD103+ DCs in the lung and bronchial lymph node (BLN) was increased to a greater extent in female mice than in male mice at 16 to 20 hours after ovalbumin (OVA) inhalation. In BLNs, CD86 and I-A/I-E expression levels and antigen uptake ability in CD103+ DCs, but not in CD11bhigh DCs, were greater in female mice than in male mice. Furthermore, CD4+ T cells cultured with CD103+ DCs from female mice produced higher levels of interleukin (IL)-4, IL-5, and IL-13, compared with CD4+ T cells cultured with CD103+ DCs from male mice. The 17ß-oestradiol-oriented enhancement of CD86 expression on CD103+ DCs after allergen exposure induced the enhanced IL-5 production from CD4+ T cells. CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that with regard to asthma, enhanced Th2 cytokine production in females might be attributed to 17ß-oestradiol-mediated Th2-oriented CD103+ DCs in the BLN.

Sitagliptin improves glycaemic excursion after a meal or after an oral glucose load in Japanese subjects with impaired glucose tolerance.

AIMS: To evaluate the efficacy and tolerability of sitagliptin in subjects with impaired glucose tolerance (IGT). METHODS: In a double-blind, parallel-group study, 242 Japanese subjects with IGT, determined by a 75-g oral glucose tolerance test (OGTT) at week -1, were randomized (1 : 1 : 1) to placebo (n = 83), sitagliptin 25 mg (n = 82) or 50 mg (n = 77) once daily for 8 weeks. Glycaemic variables were assessed using another OGTT at week 7 and meal tolerance tests (MTTs) at weeks 0 and 8. Primary and secondary endpoints were percent change from baseline in glucose total area under the curve 0-2 h (AUC(0 -2 h)) during the MTT and OGTT, respectively. RESULTS: Least squares mean percent change from baseline in glucose AUC(0 -2 h) during the MTT were -2.4, -9.5 and -11.5%, and during the OGTT were -3.7, -21.4 and -20.1% with placebo, sitagliptin 25 mg once daily, and 50 mg once daily, respectively (p < 0.001 for either sitagliptin dose vs placebo in both tests). Sitagliptin treatment enhanced early insulin response during the OGTT and decreased total insulin response, assessed as the total AUC(0 -2 h) during the MTT. Sitagliptin treatment also suppressed glucagon response during the MTT. The incidence of adverse events, including hypoglycaemia, was low and generally similar in all treatment groups. CONCLUSIONS: Treatment with sitagliptin significantly reduced glucose excursions during both an MTT and an OGTT; this effect was associated with an increase in early insulin secretion after oral glucose loading as well as a blunted glucagon response during an MTT. Sitagliptin was generally well tolerated in subjects with IGT.

Effects of once-daily sitagliptin on 24-h glucose control following 4 weeks of treatment in Japanese patients with type 2 diabetes mellitus.

The aim of the study was to assess the efficacy/safety of once- (100 mg q.d.) or twice-daily (50 mg b.i.d.) sitagliptin 100 mg/day in Japanese patients with type 2 diabetes (T2DM). In this randomized, double-blind study, 80 patients with inadequate glycemic control (HbA1c=6.5-10%; FPG

Sex-related splenocyte function in a murine model of allergic asthma.

BACKGROUND: The prevalence and severity of asthma are higher among boys than girls, but the ratios are reversed after puberty. These observations strongly suggest that sex hormones have a role in the pathogenesis of the disease. However, the mechanisms underlying the gender differences in asthma are not fully understood. OBJECTIVE: The aim of this study was to investigate sex differences in allergic inflammation in terms of immune function. METHODS: Male and female C57BL/6 mice were sensitized and challenged with ovalbumin (OVA). OVA-specific IgE in serum and airway inflammation were compared between sexes. Splenocytes from OVA-sensitized male or female donor mice were transferred to male or female naïve recipient mice. Subsequently, the recipient mice were challenged, followed by the evaluation of OVA-specific IgE and airway inflammation. Cytokines secreted from splenocytes of the sensitized mice were measured. RESULTS: The levels of OVA-specific IgE and the allergen-induced airway inflammation were higher in female than in the male mice. The contents of T-helper type 2 (Th2) cytokines, IL-4, IL-5 and IL-13, in the bronchoalveolar lavage fluid from female mice were higher than those from male mice. The airway inflammation in female recipients transferred with splenocytes from female donors was more severe than that in any other combination of recipients and donors. Splenocytes from the sensitized female mice produced more of the Th2 cytokine, IL-5, than those from the sensitized male mice upon stimulation with OVA. CONCLUSION: Our findings suggest that the sex difference in allergic airway inflammation may be attributable to the sex difference in not only the hormonal environment but also in the immune cells themselves.

Heat treatment strengthens human dentin.

The flexural strength of Type I collagen, the major organic component of human dentin, increases with heat. We hypothesized that human dentin can be strengthened by heating, which may help prevent fracture of non-vital teeth after restoration. Beam-shaped dentin specimens were obtained from the crowns of human third molars. The dentinal tubular orientations were arranged to run parallel or perpendicular to loading surfaces. The flexural and microtensile strengths of dentin in the parallel specimens were 2- to 2.4-fold greater after being heated between 110 degrees C and 140 degrees C for 1 hr. The stress intensity factors at fracture also increased after specimens were heated. The x-ray diffraction analyses suggested that shrinking of the lateral packing of the collagen triple-helices from 14 A to 11 A was the probable cause of the strengthening of heated dentin. We conclude that heat treatment strengthens human dentin.

Isovolaemic haemodilution decreases the shivering threshold in rabbits.

BACKGROUND AND OBJECTIVE: The inhibition of thermoregulatory control by anaesthesia is manifested by reduced vasoconstriction and shivering thresholds. As intraoperative bleeding can result in haemodynamic changes, including vasoconstriction, we investigated the effect of experimental bleeding on the shivering threshold in rabbits. METHODS: Twenty-four rabbits were randomly assigned to one of three treatment strategies: (1) no blood removal (control), (2) 5 mL kg(-1) isovolaemic blood removal and (3) 10 mL kg(-1) isovolaemic blood removal. After tracheal intubation under isoflurane anaesthesia, anaesthesia was maintained with 50% nitrous oxide in oxygen. The removed blood volume was replaced with the same volume of warm hydroxyethyl starch colloid solution. Oesophageal temperature was measured as a core temperature at 1-min intervals. After blood removal, the animal's body was cooled at a rate of 2-3 degrees C h(-1) by perfusing water at 10 degrees C through a U-shaped thermode positioned in the colon. Hypothermic shivering was evaluated by visual inspection, and the core temperature at which shivering was triggered was identified as the thermoregulatory threshold for this response. RESULTS: Just before the cooling, the body temperature of the animals was around 38.6 degrees C in all of the three groups. The shivering threshold in the control group was 37.2 +/- 0.2 degrees C (mean +/- SD). The shivering thresholds in the 5 mL kg(-1) (36.9 degrees +/- 0.3 degrees C) and 10 mL kg(-1) (36.5 degrees +/- 0.5 degrees C) blood removal groups were significantly lower and in proportion with the volume of blood removed than that in the control group. CONCLUSION: Isovolaemic haemodilution decreased the shivering threshold in rabbits in proportion with the volume of blood removed.

Urinary bladder and oesophageal temperatures correlate better in patients with high rather than low urinary flow rates during non-cardiac surgery.

BACKGROUND AND OBJECTIVE: To investigate the effect of urinary flow rate on the urinary bladder temperature, we compared the accuracy and precision of urinary bladder temperature with oesophageal temperature at both high and low urine flow rates. METHODS: Twenty-four patients ASA physical status I or II who were undergoing tympanoplasty were randomly assigned to two groups with different intravenous fluid volumes: high (10 mL kg(-1) h(-1), n = 12) and low (3 mL kg(-1) h(-1), n = 12). General anaesthesia was induced with propofol and maintained with sevoflurane (1.5-2.5%) in nitrous oxide and oxygen. Urinary bladder temperature was measured using a Foley urinary catheter; distal oesophageal temperature was measured using a stethoscope thermocouple. These temperatures were measured every 5 min during surgery and the accuracy and precision of urinary bladder temperature with oesophageal temperature were determined using regression and Bland and Altman analyses. RESULTS: The correlation coefficient for oesophageal and urinary bladder temperature was 0.90 in the high urinary volume group and 0.75 in the low urinary volume group. The offset (oesophageal-urinary bladder) was -0.13 +/- 0.32 degrees C and -0.46 +/- 0.45 degrees C, respectively. CONCLUSION: Urinary bladder temperature appears to be more accurate at high urinary flow rates than at low urinary flow rates for clinical use.

Use of a HpaII-polymerase chain reaction assay to study DNA methylation in the Pgk-1 CpG island of mouse embryos at the time of X-chromosome inactivation.

A HpaII-PCR assay was used to study DNA methylation in individual mouse embryos. It was found that HpaII site H-7 in the CpG island of the X-chromosome-linked Pgk-1 gene is less than or equal to 10% methylated in oocytes and male embryos but becomes 40% methylated in female embryos at 6.5 days; about the time of X-chromosome inactivation of the inner cell mass.

Biopersistence of inhaled nickel oxide nanoparticles in rat lung.

In order to investigate whether or not airborne nanoparticles with a minimum agglomeration could be used for exposure tests on animals, we developed a nanoparticle generation system and examined the biological effects of the particles in an inhalation study. The generation system was composed of an ultrasonic nebulizer and diffusion dryers, and 30 Wistar male rats were exposed to nickel oxide (NiO) nanoparticles for 4 wk (6 h/day). The geometric mean diameter of the particles and the daily average exposure concentration determined by a combination of a differential mobility analyzer and a condensation nucleus counter in the exposure chamber were 139 +/- 12 nm and 1.0 +/- 0.5 x 10(5) particles/cm3, respectively. At 4 days and 1 and 3 mo after the inhalation, each group of 10 rats were sacrificed and NiO nanoparticles deposited in the lung were determined by chemical analysis and the biopersistence (biological half time) was calculated. The deposited amount of NiO nanoparticles in the rat lungs at 4 days after the inhalation was 29 +/- 4 microg. The retained particle amount in the rat lungs after the inhalation exponentially decreased and the calculated biological half time was 62 days. The histopathological change was not severe just after the inhalation nor throughout the observation time. We concluded that nanoparticles with a minimum agglomeration were dispersed stably in the chamber and exposed to rats for 4 wk and that deposited amounts in the rat lungs and the biopersistence of the particles and the biological response in lung were detected.

Use of PIXE/PIGE for sequential Ca and F measurements in root carious model.

The progress of caries has conventionally been evaluated by checking changes in mineral density using transverse microradiography (TMR). Recent advances have seen development of a new measurement system, using in-air micro proton induced X-ray/gamma-ray emission (PIXE/PIGE). PIXE/PIGE enables analysis of distributions and concentrations of multiple mineral elements in a carious lesion. The aim of this study was to evaluate the effectiveness of PIXE/PIGE for investigating the development of root caries. In summary, we successfully established a multi-elemental sequential measuring method using in-air micro-PIXE/PIGE to identify the dynamic distributions and concentrations of Ca and F in human root dentin. The PIXE/PIGE potentially offers a useful advantageous technique for studying carious development by using as a combination with conventional techniques such as TMR and Micro-computed tomography (µCT).

Randomly controlled study of chemotherapy versus chemoimmunotherapy in postoperative gastric cancer patients.

From September 1979 through March 1981, a total of 302 patients with gastric cancer and undergoing gastrectomy at the Department of Surgery at Chiba University Hospital and its 14 affiliated hospitals was studied for clinical effectiveness of immunotherapy with Nocardia rubra cell wall skeleton. The patients were stratified by gross stage of cancer and degree of operative curability. They were then assigned randomly to either chemotherapy group or chemotherapy plus immunotherapy group. Immunotherapy used was intradermal injection of 400 micrograms of N. rubra cell wall skeleton which was given weekly for the first month and monthly thereafter. After the specimen was examined microscopically, the patients were classified by histological stage of cancer and radicality of surgical intervention into curative or noncurative groups. The patients were surveyed for survival period in December 1981. The postoperative survival rate was compared in patients of histologically curative or noncurative resection cases between the two treatment groups. No statistical difference was detected between the groups in age, sex, or operative procedures that might influence the patient's survival. As a result, statistical intergroup difference in survival rates was not seen in patients of the curative group, probably due to a short observation period. However, the intergroup difference in survival rates was statistically significant in patients of the noncurative group (p less than 0.01). These results indicate the adjunctive effect of N. rubra cell wall skeleton as an immunotherapeutic agent in patients undergoing gastrectomy for gastric cancer.

Malignant potential of homozygous and heterozygous complete moles.

There are two main mechanisms of origin for complete hydatidiform mole: (a) fertilization of an empty egg by a haploid sperm followed by duplication (monospermic mole); and (b) fertilization of such an egg by two haploid spermatozoa (dispermic mole). The former is inevitably homozygous (homozygous mole), whereas the latter may be heterozygous for a given genetic marker (heterozygous mole). A recent cytogenetic study showed that three cases of choriocarcinoma were undoubtedly heterozygous, which prompted us to compare the incidence of postmolar sequelae between patients with homozygous moles and those with heterozygous moles. Making use of chromosomal heteromorphisms and human lymphocyte antigen and phosphoglucuromutase 1 polymorphisms, we established the androgenetic origin of a complete mole in 49 of 56 cases. Homozygosity was confirmed in 21 moles, and heterozygosity was confirmed in five. Three of five patients with heterozygous moles developed postmolar trophoblastic disease, whereas none of the 21 patients with homozygous moles suffered postmolar trophoblastic disease except one who showed signs of degenerating residual trophoblasts. Consistent with this observation is the fact that all of the four destructive moles studied here were of dispermic origin. Thus, heterozygous moles seem to have a higher malignant potential than do homozygous moles.

Crystal structure of Thermoactinomyces vulgaris R-47 alpha-amylase II (TVAII) hydrolyzing cyclodextrins and pullulan at 2.6 A resolution.

The crystal structure of Thermoactinomyces vulgaris R-47 alpha-Amylase II (TVAII) has been determined by multiple isomorphous replacement at 2.6 A resolution. TVAII was crystallized in an orthorhombic system with the space group P212121 and the cell dimensions a=118.5 A, b=119.5 A, c=114.5 A. There are two molecules in an asymmetric unit, related by the non-crystallographic 2-fold symmetry. Diffraction data were collected at 113 K and the cell dimensions reduced to a=114.6 A, b=117.9 A, c=114.2 A, and the model was refined against 7.0-2.6 A resolution data giving an R-factor of 0.204 (Rfree=0.272). The final model consists of 1170 amino acid residues (two molecules) and 478 water molecules with good chemical geometry. TVAII has three domains, A, B, and C, like other alpha-amylases. Domain A with a (beta/alpha)8 barrel structure and domain C with a beta-sandwich structure are very similar to those found in other alpha-amylases. Additionally, TVAII has an extra domain N composed of 121 amino acid residues at the N-terminal site, which has a beta-barrel-like structure consisting of seven antiparallel beta-strands. Domain N is one of the driving forces in the formation of the dimer structure of TVAII, but its role in the enzyme activity is still not clear. TVAII does not have the Ca2+ binding site that connects domains A and B in other alpha-amylases, rather the NZ atom of Lys299 of TVAII serves as the connector between these domains. TVAII can hydrolyze cyclodextrins and pullulan as well as starch. Based on a structural comparison with the complex between a mutant cyclodextrin glucanotransferase and a beta-cyclodextrin derivative, Phe286 located at domain B is considered the residue most likely to recognize the hydrophobic cavity of cyclodextrins. The active-site cleft of TVAII is wider and shallower than that of other alpha-amylases, and seems to be suitable for the binding of pullulan which is expected not to adopt the helical structure of amylose.

Crystal structure of the E166A mutant of extended-spectrum beta-lactamase Toho-1 at 1.8 A resolution.

Bacterial resistance to beta-lactams is mainly due to the production of beta-lactamase. Especially through the production of extended-spectrum beta-lactamases (ESBLs), bacteria have acquired resistance not only to penicillins, but also to expanded-spectrum cephems. Here, we describe the crystal structure of the E166A mutant of class A beta-lactamase Toho-1 at 1.8 A resolution, the first reported tertiary structure of an ESBL. Instead of the wild-type enzyme, a mutant Toho-1, in which Glu166 was replaced with alanine, was used for this study, because of the strong tendency of the wild-type enzyme to form twinned crystals. The overall structure of Toho-1 is similar to the crystal structures of non-ESBLs, with no pronounced backbone rearrangement of the framework. However, there are some notable local changes. First, a difference in the disposition of an arginine residue, which is at position 244 in non-ESBLs but at position 276 in Toho-1 and other ESBLs, was revealed and the role of this arginine residue is discussed. Moreover, changes in the hydrogen-bonding pattern and in the formation of the hydrophobic core were also observed near the Omega loop. In particular, the lack of hydrogen bonds in the vicinity of the Omega loop could be a cause of the extended substrate specificity of Toho-1. Through the generation of a model for the enzyme-substrate complex, a conformational change of Toho-1 occurring on complex formation is discussed based on the active-site cleft structure and the substrate profile.

Evaluation of appropriate blood level in continuous intravenous infusion from trough concentrations after oral administration based on area under trough level in tacrolimus and cyclosporine therapy.

The target blood concentrations of tacrolimus (TAC) and cyclosporine (CYA) during continuous intravenous infusion (C(ss)) have been determined based on clinical experience. However, it is desirable that C(ss) should be set so that the AUC after intravenous infusion is equal to the AUC after oral administration (AUC(po)). Accordingly, we performed 12-hour monitoring of blood concentrations to calculate C(ss) from the blood trough levels (C(TL)) on 15 kidney recipients administered TAC and 12 recipients administered CYA (Neoral). We used an area under the trough level (AUTL) as a new pharmacokinetic parameter. The C(ss) was evaluated from C(TL), AUC(po), and AUTL was calculated to be C(ss) = C(TL) x (AUC(po)/AUTL). In addition, AUTL/AUC(po) ratio and blood peak/trough level ratio (C(max)/C(min)) were examined to compare pharmacokinetics of TAC and CYA. The formula for TAC was C(ss) = C(TL) x 1.40 and that for CYA, C(ss) = C(TL) x 2.55. The calculated target C(ss) of TAC was 1.40 times that of C(TL), which was similar to the present clinical C(TL). In contrast, the calculated target C(ss) of CYA was 2.55 times the C(TL), and therefore an extremely high C(ss) was necessary to obtain a sufficient AUC that will be available after oral administration. Consequently, intravenous administration of CYA twice a day was considered to be more appropriate to obtain sufficient CYA pharmacokinetics, rather than a continuous intravenous administration. We conclude that the formula, C(ss) = C(TL) x (AUC(po)/AUTL) was useful to calculate the target blood concentration of calcineurin inhibitors when changing from continuous intravenous infusion to oral administration of these drugs.

Pharmacokinetic differences between morning and evening administration of cyclosporine and tacrolimus therapy.

We performed 24-hour monitoring of cyclosporine (NEO) and tacrolimus (TAC) blood concentrations, evaluating pharmacokinetic parameters and characterizing circadian variations. The monitoring was performed in 10 instances on nine patients administered NEO and 12 out of 11 patients administered TAC. All cases were administered equally divided doses of drugs twice daily orally. Blood samples were taken before and 1, 2, 3, 4, 6, and 12 hours after NEO or TAC administration in the morning and evening. The pharmacokinetic parameters were compared between morning and evening administrations of both drugs. AUC0-12, AUC0-4, C(max), C2, and C(max)/C(min) of NEO and TAC were significantly lower during the evening compared with morning administrations. C(min) values were significantly higher in the evening. T(max) of NEO was longer in evening, although there was not a significant difference; T(max) of TAC was significantly longer in the evening. We found that NEO and TAC administrations in the evening resulted in reduced bioavailability and delayed absorption when compared with drug administrations in the morning. It was thought that the difference in bioavailability between morning and evening administrations was smaller with TAC, because TAC shows lower peak levels and a flatter blood concentration curve than NEO. C(min) was higher after evening administration than morning because of delayed absorption, though the bioavailability of both drugs decreased in the evening. These results suggest that we have to appreciate apparently high trough levels.

Optimal dose and target trough level in cyclosporine and tacrolimus conversion in renal transplantation as evaluated by lymphocyte drug sensitivity and pharmacokinetic parameters.

We evaluated the relative clinical potency of cyclosporine (CyA) and tacrolimus (Tac) using pharmacodynamic and pharmacokinetic parameters of the drug to obtain the most suitable converting dose and target trough level. The relative pharmacodynamic potency was examined by the mean ratio of drug concentrations giving 50% inhibition of blastogenesis of lymphocytes (IC50) in 66 chronic renal failure patients. The relative potency estimated from clinical pharmacokinetic parameters was examined by the mean ratio of each pharmacokinetic parameter value of CyA versus Tac. The pharmacokinetic parameters were estimated by 12-hour monitoring of drug blood concentrations in seven CyA patients and seven Tac patients. The mean IC50 ratio of CyA and Tac (CyA/Tac of IC50) was 25.1. The mean area under the concentration-time curve (AUC) ratio (CyA/Tac of AUC) was 25.5, the mean trough level (C(min)) ratio (CyA/Tac of C(min)) was 13.2, and the mean dose per body weight ratio was 25.2. The relative potency estimated from AUC that is the most reliable pharmacokinetic parameter for the estimation of clinical efficacy of calcineurin inhibitors appeared to agree with the relative pharmacodynamic potency estimated from IC50. The data suggest that TAC 25-fold more potent than CyA, which represents a suitable converting dose ratio, and that target trough level of CyA is about 13-fold greater than Tac based on CyA/Tac of C(min). We conclude that these relative values may be useful to estimate the suitable dose and target trough levels to convert between CyA and Tac.

Short-term follow-up after endoscopic mucosectomy of early esophageal cancer and aldehyde dehydrogenase-2 genotype in Japanese alcoholics.

The risk of the future development of primary esophageal cancer after endoscopic esophageal mucosal resection of esophageal cancer is not known; hence, there are no established guidelines for follow-up surveillance programs. Simultaneous occurrence of multiple cancers associated with esophageal cancer is common among heavy drinkers who have the inactive form of aldehyde dehydrogenase-2 (ALDH2) as a risk factor. Thirty-four Japanese male alcoholics with intraepithelial or mucosal squamous cell carcinoma in the esophagus were treated by endoscopic esophageal mucosal resection, followed by endoscopy and esophageal iodine staining, to find the additional development of primary esophageal cancer. Primary esophageal squamous cell carcinoma was detected in nine patients (26.5%) at 3-21 months after the first cancer diagnosis. Cancer occurred more frequently in patients with inactive ALDH2 than it did in those with active ALDH2 [42.1% (8 of 19) versus 6.7% (1 of 15), P = 0.047], and it occurred more frequently in those with multiple esophageal cancers than it did in those without them [60.0% (6 of 10) versus 12.5% (3 of 24), P = 0.009]. Kaplan-Meier estimates of the proportions of patients with additional primary esophageal cancers showed that patients with inactive ALDH2 (P = 0.024) or multiple esophageal cancers (P = 0.007) had a significantly increased likelihood of the development of additional cancer. Close follow-up examinations using endoscopy and iodine staining are needed for such high-risk patients.

Surfactant replacement therapy with a single postventilatory dose of a reconstituted bovine surfactant in preterm neonates with respiratory distress syndrome: final analysis of a multicenter, double-blind, randomized trial and comparison with similar trials. The Surfactant-TA Study Group.

The effects of a single dose of surfactant TA were assessed in premature neonates (birth weight 750 to 1749 g) with respiratory distress syndrome (RDS) in a multicenter, double-blind, randomized clinical trial. Only neonates with surfactant deficiency and without ultrasonographic evidence of intracranial hemorrhage greater than or equal to grade II were enrolled. Fifty-four patients received surfactant (100 mg of phospholipid per kilogram of body weight) and 46 patients received an air placebo within 8 hours of life. Treatment with this surfactant resulted in a significant reduction in the severity of RDS with a concomitant increase in the proportion of neonates with mild disease. The frequency of pulmonary interstitial emphysema and of pneumothorax was significantly lower in treated neonates compared with control neonates (2% vs 26%, P = .0008, and 7% vs 39%, P = .0004, respectively). The frequency of intracranial hemorrhage was significantly lower in the surfactant group compared with the control group (20% vs 54%, P = .0008) and was also reduced for the smallest neonates in the surfactant group (13% vs 73%, P = .00008). When categorized according to severity of intracranial hemorrhage and severity of bronchopulmonary dysplasia, the surfactant group was at a significant advantage (adjusted Cochran-Mantel-Haenszel X2 = 10.72, P less than .001 and X2 = 4.43, P = .036, respectively). The proportion of neonates surviving without intracranial hemorrhage and/or bronchopulmonary dysplasia was 63% in the surfactant group vs 26% in the control group (P = .0004); as for the smallest neonates, it was 58% in the surfactant group vs 4% in the control group (P = .0002). There were no differences between the groups with respect to the frequency of patent ductus arteriosus (46% vs 37%), pulmonary hemorrhage (6% vs 7%), necrotizing enterocolitis (0% vs 2%), sepsis (4% vs 2%), retinopathy of prematurity (13% vs 22%), or death (15% vs 22%). It is concluded that treatment with the single-dose surfactant regimen used in this study reduces the severity of respiratory distress during the 48 hours after treatment and decreases the major pulmonary morbidity and intracranial hemorrhage in premature neonates with RDS. Further studies are needed to determine whether (1) treatment at birth or as soon as after RDS is diagnosed and (2) the use of multiple dose of this surfactant would result in any additional benefits.

Recent trends in the prevalence of Down syndrome in Japan, 1980-1997.

The aims of the present study were to determine recent trends in the prevalence of Down syndrome (DS) in Japan, and to determine whether recent changes in demographic and social habits and access to prenatal diagnosis have influenced the livebirth rates of DS. Livebirth statistics indicate that the birth rate in Japan has decreased for women in their 20s and has increased for those in their 30s and 40s. During an 18-year period between 1980 and 1997, 1,299 consecutive DS infants were born among a total of 2,232,694 births, a rate corresponding to approximately 10% of all births in Japan over the same period. The increasing risk of DS with advancing maternal age was confirmed. The overall prevalence was 5.82 DS births per 10,000 livebirths (8.3-9.7 per 10,000 after correction according to the estimated ascertainment ratio: 60-70%). The prevalence rate by year of child birth represents a statistically significant increase (P = 0.001). In conclusion, recent trends in the prevalence of DS in Japan from 1980 to 1997 failed to show a consistent tendency to decrease, probably because of the concomitant increase in pregnancy in advanced maternal age.