Diverse immune responses to HBV surface epitope variants after vaccine booster in adolescents immunized in infancy.

OBJECTIVES: We aimed to investigate immunity against hepatitis B surface antigen (HBsAg) mutants before and after boosters in adolescents who had lost antibodies against HBsAg (anti-HBs) despite neonatal vaccination. METHODS: We recruited 142 participants from 15 to 21 years old who had received complete vaccination in infancy but became anti-HBs-negative. Cellular immunity to HBsAg and T-cell epitope variants was assessed before and after boosters. Antibody affinity to variants was assessed after boosters. RESULTS: After one dose of booster, 12 out of 140 (8.6%) participants remained anti-HBs-negative. Anti-HBs titres were higher in those participants <17 (geometric mean, 337.9 ± 10.9 vs. 157.4 ± 16.6 mIU/mL, p = 0.012). Before the booster, HBsAg-specific cell proliferation was present in 58 out of 64 (90.6%) participants. The proliferation response rates to T-cell epitopes were 37.8% and 72.6% (p < 0.001) before and after the booster, respectively. The stimulation index improved from 1.25 ± 1.70 to 2.53 ± 2.32 (p < 0.001) for various T-cell epitopes. HBsAg-specific interleukin (IL)-5- and interferon (IFN)-γ-secreting T-cells were enhanced (45 ± 10 and 50 ± 4 to 420 ± 328 and 355 ± 424 spot-forming cells/106 cells, respectively, p < 0.001). IFN-γ-secreting T cells to epitope 16-33 containing R24K and the antibody affinity to sG145R were still significantly lower than to the wild type. CONCLUSIONS: In immunized adolescents who lost anti-HBs, around 10% also lost immune memory. Cellular immunity to some T-cell epitope variants improved after the booster. Antibody affinity to sG145R and the IFN-γ-secreting cell response to some epitope 16-33 variants were still impaired even after booster administration.

Hepatocarcinogenesis in transgenic mice carrying hepatitis B virus pre-S/S gene with the sW172* mutation.

Hepatitis B virus (HBV) carrying the rtA181T/sW172* mutation conferred cross-resistance to adefovir and lamivudine. Cell-based and clinical studies indicated that HBV carrying this mutation had an increased oncogenic potential. Herein, we created transgenic mouse models to study the oncogenicity of the HBV pre-S/S gene containing this mutation. Transgenic mice were generated by transfer of the HBV pre-S/S gene together with its own promoter into C57B6 mice. Four lines of mice were created. Two of them carried wild-type gene and produced high and low levels of HBV surface antigen (HBsAg) (TgWT-H and L). The other two carried the sW172* mutation with high and low intrahepatic expression levels (TgSW172*-H and L). When sacrificed 18 months after birth, none of the TgWT mice developed hepatocellular carcinoma (HCC), whereas 6/26 (23.1%) TgSW172*-H and 2/24 (8.3%) TgSW172*-L mice developed HCC (TgWT vs TgSW172*; P=0.0021). Molecular analysis of liver tissues revealed significantly increased expression of glucose-regulated protein 78 and phosphorylated extracellular signal-regulated kinases 1 in TgSW172* mice, and decreased expression of B-cell lymphoma-extra large in TgSW172*-H mice. Higher proportion of apoptotic cells was found in TgSW172*-H mice, accompanied by increased cyclin E levels, suggesting increased hepatocyte turnover. Combined analysis of complimentary DNA microarray and microRNA array identified microRNA-873-mediated reduced expression of the CUB and Sushi multiple domains 3 (CSMD3) protein, a putative tumor suppressor, in TgSW172* mice. Our transgenic mice experiments confirmed that HBV pre-S/S gene carrying the sW172* mutation had an increased oncogenic potential. Increased endoplasmic reticulum stress response, more rapid hepatocyte turnover and decreased CSMD3 expression contributed to the hepatocarcinogenesis.

Recurring BALB/c mouse lung inflammatory responses to episodic allergen exposure.

This study detailed the sequence of recurring inflammatory events associated with episodic allergen exposures of mice resulting in airway hyperreactivity, sustained inflammation, goblet-cell hyperplasia, and fibrogenesis that characterize a lung with chronic asthma. Ovalbumin (OVA)-sensitized female BALB/c mice were exposed to saline-control or OVA aerosols for 1 h per day for episodes of 3 d/wk for up to 8 wk. Lung inflammation was assessed by inflammatory cell recoveries using bronchoalveolar lavages (BAL) and tissue collagenase dispersions. Cell accumulations were observed within airway submucosal and associated perivascular spaces using immunohistochemical and tinctorial staining methods. Airway responsiveness to methacholine aerosols were elevated after 2 wk and further enhanced to a sustained level after wk 4 and 8. Although by wk 8 diminished OVA-induced accumulations of eosinophils, neutrophils, and monocyte-macrophages were observed, suggesting diminished responsiveness, the BAL recovery of lymphocytes remained elevated. Airway but not perivascular lesions persisted with a proliferating cell population, epithelial goblet-cell hyperplasia, and evidence of enhanced collagen deposition. Examination of lung inflammatory cell content before the onset of the first, second, and fourth OVA exposure episodes demonstrated enhancements in residual BAL lymphocyte and BAL and tissue eosinophil recoveries with each exposure episode. Although tissue monocyte-macrophage numbers returned to baseline prior to each exposure episode, the greatest level of accumulation was observed after wk 4. These results provide the basis for establishing the inflammatory and exposure criteria by which episodic environmental exposures to allergen might result in the development of a remodeled lung in asthma.

Stimulation of phosphate uptake and polyphosphate accumulation by activated sludge microorganisms in response to sulfite addition.

Enhanced phosphate removal from wastewaters is dependent on the synthesis and intracellular accumulation of polyphosphate by sludge microorganisms. However the role played by polyphosphate in microbial metabolism and the factors that trigger its formation remain poorly-understood. Many examples of the accumulation of the biopolymer by environmental microorganisms are documented; these include a recent report of the presence of large polyphosphate inclusions in sulfur-oxidizing marine bacteria. To investigate whether any link might exist outside the marine environment between the presence of reduced sulfur compounds and enhanced levels of microbial phosphate uptake and polyphosphate accumulation, activated sludge cultures were grown under laboratory conditions in media that contained sulfite, thiosulfate, hydrosulfite or tetrathionate. Only in the presence of sulfite was there any evidence of a stimulatory effect; in medium that contained 0.5 mM sodium sulfite some 17% more phosphate was removed by the sludge, whilst there was an almost two-fold increase in intracellular polyphosphate levels. No indications of sulfite toxicity were observed.

Recording Bessel-like beam shapes generated by plasmonics lens.

In our study, we spun a negative photoresist layer on top of a plasmonic lens which was formed by adopting a metallic ring structure with a nano-scale width opening. We recorded the beam shape of the Bessel-like beam emitting from the plasmonic lens which formed a high aspect ratio structure. We found that the high aspect ratio structure was higher after exposure as the inner and outer diameter had increased. In addition, we used an oblique incidence on the negative resist metallic ring structure to produce an inclined micro-structure. Different exposure results were obtained with the two different metal thicknesses. Therefore, in our study, we not only proved that it is possible to record the shape of a Bessel-like beam, but we also demonstrated that it is possible to create a plasmonic lens which is capable of creating a high aspect ratio structure through exposure.

Acute gastroenteritis caused by multiple enteric pathogens in children.

Of 303 children hospitalized with acute non-bloody, non-mucoid diarrhoea, 69 (22.8%) had polymicrobial infection, including 52 (17.2%) multiple viral infection and 17 (5.6%) viral and bacterial co-infection. Rotavirus had the most important role in both categories; thus the control of rotavirus infection is crucial for maintaining children's health in Taiwan.

The effect of a user-guided request form for chest radiographs in a neonatal intensive care unit.

The objectives of this prospective, observational study were to determine the current indications of requesting chest radiograph in sick infants in a neonatal intensive care unit (NICU) and the effect of a user-guided request form for chest radiographs of sick infants. During the three-month study period, a total of 423 chest radiographs were requested on 159 sick newborn infants in the intensive area of this NICU. A majority (55.6%) of these chest radiographs were performed to verify positions tips of either central catheters (27.4%) or endotracheal tubes (28.1%). The number of chest radiographs done during the period when the user-guided request forms were utilised was significantly lower (1.24 per patient) than before (1.37 per patient) or after (1.58 per patients) the period when these forms were in use (p=0.01). The rate of radiological abnormalities detected in radiographs requested to verify position of tips of endotracheal tubes were significantly greater during the period when user-guided forms were used than when they were not (p=0.01). A significantly higher proportion of changes in management were instituted when the user-guided forms were in use than during the period when they were not used (p=0.03). We conclude that a user-guided radiographic request form helps doctors in NICU to carry out their management more effectively.

Left paraduodenal hernia presenting as intestinal obstruction: report of one case.

We report a case of internal hernia of the small intestine in a 13-year-old boy with presentation of partial intestinal obstruction. The patient suffered from recurrent abdominal pain and chronic constipation over the past few years. An abdominal mass was suspected from clinical manifestations and images derived from abdominal echography. Upper gastrointestinal contrast study revealed poor motility at the distal jejunum with barium stasis. Follow-up film on the next day delineated medially and downwardly displaced splenic flexure and proximal descending colon. At operation, total herniation of small intestine into a retroperitoneal space through a defect on left mesocolon was noted. A left paraduodenal (mesocolic) hernia was diagnosed. The patient made an uneventful recovery after the hernia was repaired. This report provides unusual image clues of internal hernias of the small intestine presenting as ileus. Though rare, paraduodenal hernia should be taken into account in a differential diagnosis of intestinal obstruction. Early surgical intervention allows uneventful recovery to occur and also prevents the possible complication of gangrenous bowels.

Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children.

OBJECTIVE: To compare the pharmacokinetics and metabolism of R(+)- and S(-)- ketorolac in children. METHODS: Children from 3 to 18 years old received 0.6 mg/kg racemic ketorolac intravenously. Serial blood samples were obtained for 12 hours, and urine was collected for 12 to 24 hours. Racemic ketorolac was measured in plasma, and racemic ketorolac, para-hydroxyketorolac, and ketorolac glucuronide were measured in urine by HPLC. S(-)- and R(+)-ketorolac were measured in plasma; S(-)- and R(+)-ketorolac and ketorolac glucuronide were measured in urine by chiral HPLC separation. Plasma pharmacokinetic parameters for racemic drug and both enantiomers were determined for each patient. RESULTS: Clearance of racemic ketorolac in children was approximately 2 times the clearance reported in adults. Clearance of the S(-) enantiomer was 4 times that of the R(+) enantiomer. Terminal half-life of S(-)-ketorolac was 40% that of the R(+) enantiomer, and the apparent volume of distribution of the S(-) enantiomer was greater than that of the R(+) form. Recovery of S(-)-ketorolac glucuronide was 2.3 times that of the R(+) enantiomer. CONCLUSION: The higher clearance in children suggests that the weight-adjusted dose of ketorolac may have to be greater for children to achieve plasma concentrations comparable to those of adults. Because of the greater clearance and shorter half-life of S(-)-ketorolac, pharmacokinetic predictions based on racemic assays may overestimate the duration of pharmacologic effect. Enantiomeric pharmacokinetic differences are best explained by stereoselective plasma protein binding. Selective glucuronidation of the S(-) enantiomer suggests that stereoselective metabolism may also be a contributing factor.

Syndrome of inappropriate antidiuretic hormone secretion in children following spinal fusion.

OBJECTIVES: a) To determine if antidiuretic hormone (ADH) is elevated in patients undergoing spinal fusion, especially in those who have clinical evidence of syndrome of inappropriate antidiuretic hormone (SIADH); b) to evaluate the relationship between ADH secretion and the secretion of atrial natriuretic peptide (ANP). SETTING: Tertiary care pediatric intensive care unit (ICU) in a university hospital. DESIGN: A prospective cross-sectional, observational study with factorial design. PATIENTS: Thirty patients > or = 10 yrs of age undergoing spinal fusion admitted to the ICU for postoperative care. INTERVENTIONS: Patients underwent anterior, posterior, or both anterior/posterior spinal fusion. Blood was collected for serial measurements of ADH, ANP and serum electrolyte levels. Heart rate, blood pressure and central venous pressure were measured. MEASUREMENTS AND MAIN RESULTS: Thirty children were studied. Nineteen had idiopathic scoliosis, nine had neuromuscular scoliosis, one had Marfan's disease, and one had congenital scoliosis. Ten (33%) children met clinical criteria of SIADH. There was no difference in duration of surgery, blood loss, volume of iv fluid administration pre- and intraoperatively, or type of scoliosis between those who developed SIADH and those who did not. Hemodynamic variables were similar in both groups. ADH levels increased in both groups immediately postoperatively and at 6 hrs after surgery, but were much more elevated in those patients with SIADH. Patients with SIADH also had significantly higher ADH levels preoperatively. In relation to serum osmolality, ADH was considerably higher in those with SIADH compared with those who did not. Although ANP values tended to be higher in the group with SIADH, this did not reach statistical significance. CONCLUSION: SIADH occurs in a subset of children who undergo spinal fusion. The diagnosis of SIADH can be made easily using clinical parameters which are well-defined. In the face of SIADH, continued volume expansion may be harmful, and should therefore be avoided.

A randomized comparison of ketorolac tromethamine and morphine for postoperative analgesia in critically ill children.

OBJECTIVES: To evaluate the efficacy of a single dose of ketorolac compared with morphine for the relief of pain in children, and to determine the safety of ketorolac. SETTING: Tertiary pediatric intensive care unit in a university-affiliated hospital. DESIGN: Prospective, randomized, double-blind, parallel, single-dose, positive control study. PATIENTS: Children admitted to the intensive care unit with postoperative pain. INTERVENTIONS: Patients received a single dose of either morphine or ketorolac as the first postoperative analgesic when the pain score indicated significant pain. Blood pressure, heart rate, and urine output were recorded, as well as blood urea nitrogen, creatinine, bleeding time, hematuria or proteinuria, and aspartate aminotransferase. Side effects such as nausea and vomiting were noted. Morphine was used for rescue treatment if the patient continued to have significant pain > or =30 mins after study drug administration. MEASUREMENTS AND MAIN RESULTS: Of the 102 children studied, 48 received morphine and 54 received ketorolac. The percentage of patients reporting pain relief in the first and second hours after drug administration was not different between groups. Likewise, the proportion of patients who met the criteria for pain relief during the entire evaluation period was not different between groups. There was a trend toward fewer patients who received ketorolac requiring remedication in the first 4 hrs compared with those who received morphine, but this trend did not reach statistical significance. More patients in the morphine group failed to achieve pain relief at any time after the dose compared with those who received ketorolac. There were no differences between the two groups in physiologic or laboratory variables. Vomiting was more common in patients who received ketorolac. CONCLUSION: Ketorolac is comparable to morphine in relief of postoperative pain in children. A single dose of ketorolac does not result in abnormal postoperative bleeding or alter renal function. However, ketorolac may cause nausea and vomiting in some patients.

Non-A, non-B, non-C hepatitis: its significance in pediatric patients and the role of GB virus-C.

OBJECTIVES: To delineate the importance of non-A, non-B, non-C (non-ABC) hepatitis, and the role of GB virus C (GBV-C) in children. METHODS: From 1980 to 1995, acute-onset viral hepatitis was diagnosed in 166 inpatients and categorized into type A, B, C, and non-ABC hepatitis according to the serologic markers or the results of polymerase chain reaction assay for HBV DNA or HCV ribonucleic acid (RNA) in the National Taiwan University Hospital. Non-ABC hepatitis was diagnosed in 57 patients (34%). GBV-C RNA was investigated by reverse transcription and nested polymerase chain reaction in 32 of the 57 patients with non-ABC hepatitis. The clinical and laboratory features of patients with acute non-ABC hepatitis were compared with the features of those with acute hepatitis A and B. RESULTS: The degree of abnormality in aminotransferase activities was milder in patients with non-ABC hepatitis than in those with hepatitis B; chronicity was noted in 12%. Fulminant hepatitis occurred in 16%, and the mortality rate was 56%. Young age carried a significantly higher risk of having a fulminant course (1.9 +/- 0.2 years of age vs 6.4 +/- 5.1 years of age in acute course; p < 0.05). Compared with fulminant hepatitis B, fulminant non-ABC hepatitis had a trend of a longer interval from onset to death (119.2 +/- 144.8 vs 15.2 +/- 8.4 days; p = 0.079). GBV-C RNA was detected in only two of the patients tested, both of whom had received transfusions; one had persistent viremia and fluctuating aminotransferase values. CONCLUSIONS: Non-ABC hepatitis plays an important role in the etiology of pediatric viral hepatitis; however, the role of GBV-C is minor. A search for other unknown viral agent(s) responsible for non-ABCG hepatitis is needed.

Idiopathic pulmonary hemorrhage in infancy. Clinical features and management with high frequency ventilation.

STUDY OBJECTIVES: To describe the clinical characteristics of infants with severe acute pulmonary hemorrhage and the effects of mechanical ventilation on gas exchange. SETTING: Tertiary care pediatric ICU in a university hospital. PATIENTS AND DESIGN: Case records of patients with severe acute pulmonary hemorrhage from January 1992 to July 1995 were reviewed. Acute pulmonary hemorrhage was defined as hemoptysis and/or epistaxis or blood obtained from endotracheal tube which could not be attributed to cardiac or vascular malformation, infectious process, or known trauma. INTERVENTIONS: Patients were initially managed with conventional ventilation. High frequency ventilation (HFV) was utilized when hypoxemia (PaO2/PAO2 < 0.2) and/or respiratory acidosis (PaCO2 > or = 60 mm Hg with pH < 7.25) persisted. MEASUREMENTS AND RESULTS: Six African-American male infants from Detroit, with a median age 2.3 months, presented with severe acute pulmonary hemorrhage. Chest radiographs showed diffuse bilateral infiltrates or opacification with a normal sized heart. All infants were managed with HFV, four by oscillation and two by jet. The indications for HFV were persistent hypoxemia (2), respiratory acidosis (1), and a combination of both (3). There was an improvement in pH and PaCO2, and a decreased need for oxygen 6 and 24 h after initiating HFV. PaO2/PAO2 and oxygenation index showed a tendency toward improvement. All infants survived, and there were no complications. No cause for pulmonary hemorrhage was found in any of the infants. CONCLUSIONS: Idiopathic acute pulmonary hemorrhage is a potentially life-threatening disorder encountered among inner-city infants. HFV is highly effective and safe in rapidly reversing the severe oxygenation and ventilation deficits in this setting.

Predicting outcome in children with severe acute respiratory failure treated with high-frequency ventilation.

OBJECTIVES: a) To demonstrate the effect of high-frequency ventilation on gas exchange in children with severe acute respiratory failure unresponsive to conventional ventilation; b) to identify patients at high risk of death early after institution of high-frequency ventilation. SETTING: Tertiary care pediatric intensive care unit in a university hospital. DESIGN: A cross-sectional, observational study with factorial design. PATIENTS: Thirty-one patients with severe acute respiratory failure defined as a Pao2/F1o2 of < 150 torr (< 20 kPa) with a positive end-expiratory pressure of > or = 8 cm H2O and/or Paco2 of > 60 torr (> 8 kPa) with an arterial pH < 7.25. INTERVENTIONS: Patients received either high-frequency oscillation or jet ventilation if respiratory failure was unresponsive to conventional ventilation and if the underlying disease process was deemed reversible. MEASUREMENTS AND MAIN RESULTS: Thirty-one children were managed with high-frequency ventilation, 11 children with jet and 20 children with oscillator. Arterial blood gases and level of ventilatory support were recorded before and at 6, 24, 48, 72, and 96 hrs after institution of high-frequency ventilation. There was an improvement in an arterial pH, Paco2, Pao2, and Pao2/FID2 6 hrs after institution of high-frequency ventilation (p < .01). This improvement, along with decreased need for oxygen, was sustained through the subsequent course. Twenty-three (74%) of 31 children treated with high-frequency ventilation survived. Survivors showed an increase in an arterial pH, Pao2, Pao2/FIO2, and a decrease in Paco2 within 6 hrs, whereas nonsurvivors did not. Oxygenation index was the best predictor of outcome. A combination of an initial oxygenation index of > 20 and failure to decrease the oxygenation index by > 20% by 6 hrs after initiation of high-frequency ventilation predicted death with 88% (7/8) sensitivity and 83% (19/23) specificity, with an odds ratio of 33 (p = .0036, 95% confidence interval 3-365). CONCLUSIONS: In patients with potentially reversible underlying diseases resulting in severe acute respiratory failure that is unresponsive to conventional ventilation, high-frequency ventilation improves gas exchange in a rapid and sustained fashion. The magnitude of impaired oxygenation and its improvement after high-frequency ventilation can predict outcome within 6 hrs.

Thenar hypoplasia in Klippel-Feil syndrome due to aberrant radial artery.

A 10-year-old boy with Klippel-Feil syndrome had progressive atrophy of the left thenar eminence and absence of left radial pulse. Neurophysiologic studies and angiography were normal. However, duplex sonography over the wrists revealed an aberrant left radial artery. We speculate that the thenar atrophy in this patient is congenital, which may be due to the anomaly of the left radial artery, and is further compromised by vascular compression in the thoracic outlet.

Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial.

OBJECTIVE: To study the effect of ribavirin aerosol therapy on the immediate clinical course of mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Pediatric intensive care unit (ICU) of a university teaching hospital. PATIENTS: Forty-one children requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract disease. INTERVENTIONS: Patients were stratified by the presence or absence of and underlying disease and then randomized to receive aerosolized ribavirin (20 mg/mL) or saline for 18 hrs/day for 5 days or until endotracheal extubation, whichever came first. MEASUREMENTS AND MAIN RESULTS: Dependent variables included the time course of the illness and the change in FIO2, ventilatory rate, PaO2/FIO2 ratio, and ventilatory-efficiency index of patients while they received aerosol therapy. Ribavirin- and placebo-treated patient groups were not significantly different in the number of ventilator days (6.4 +/- 6.9 vs. 8.2 +/- 10.1; p = .5), oxygen days (10.8 +/- 7.7 vs. 12.2 +/- 11.8; p = .9), ICU days (7.9 +/- 7.0 vs. 10.3 +/- 11.0; p = .7), or hospital days (12.9 +/- 9.7 vs. 16.2 +/- 14.0; p = .6) after the initiation of aerosol therapy. The change in FIO2, ventilatory rate, PaO2/FIO2 ratio, or ventilatory-efficiency index did not differ between the two groups. No ventilator malfunction was observed. There were six deaths caused by intractable hypoxemia in patients with underlying cardiopulmonary disease. Four of these deaths were in the placebo group and two in the ribavirin group (p = .5). CONCLUSIONS: Ribavirin aerosol therapy can be safely administered to mechanically ventilated children with severe respiratory syncytial virus lower respiratory tract disease. However, this therapy does not appear to affect immediate clinical outcome in such patients.

Differential diagnosis of extrahepatic biliary atresia from neonatal hepatitis: a prospective study.

The clinical presentations of cholestasis in infancy caused by neonatal hepatitis and biliary atresia are very similar. Diagnosis may be difficult on many occasions, but the surgical treatment of biliary atresia should be performed as early as possible. We established a 3-day workup protocol for the differential diagnosis of biliary atresia and neonatal hepatitis and compared the diagnostic accuracy, sensitivity, specificity, and predictive values of various methods. One hundred and twenty-six infants, including 84 with neonatal hepatitis (age, 65.1 +/- 24.1 days) and 42 with biliary atresia (age, 60.3 +/- 31.1 days), were studied prospectively from July 1982 to December 1990. The diagnostic accuracy of various methods was as follows: liver histology, 96.8%; color of duodenal juice, 91.6%; peak radioisotope count in duodenal juice, 84.2%; ultrasonographic examination of the hepatobiliary system, 80.2%; and persistence of clay-colored stool, 80.2%. After stepwise logistic regression, the diagnostic methods of significance were liver biopsy, color of duodenal juice, abdominal ultrasonography, and stool color. However, stool color and the onset of jaundice could not differentiate severe neonatal hepatitis from biliary atresia. The diagnostic methods of significance then were liver biopsy and duodenal juice color. With this 3-day protocol, no biliary atresia was missed although four cases of neonatal hepatitis were misdiagnosed, resulting in unnecessary laparotomy; we found an overall diagnostic accuracy of 96.8%. We conclude that this 3-day diagnostic protocol is very helpful in the differential diagnosis of neonatal hepatitis and biliary atresia. Liver histologic examination is the most reliable single test for the differential diagnosis.

Antiproliferative effect of esculetin on vascular smooth muscle cells: possible roles of signal transduction pathways.

The effect of esculetin, a coumarin derivative with lipoxygenase inhibitor activity, on the proliferation response of cultured rabbit vascular smooth muscle cells was studied. Proliferation response was determined by the uptake of tritiated thymidine. Esculetin (10(-5)-10(-4) M) dose dependently inhibited the enhanced proliferation stimulated by 5% fetal calf serum. The structure-activity relationship of esculetin and eight other coumarin derivatives indicates that two adjacent phenolic hydroxyl groups at the C-6 and C-7 positions in the coumarin skeleton are necessary for the potent antiproliferative effect. The antiproliferative effects of other lipoxygenase inhibitors, 5,8,11,14-eicosatetraynoic acid (ETYA) and ketoconazole, were comparable to the effect of esculetin. However, esculetin exhibited the greatest maximal suppression. The enhanced releases of 12-hydroxyeicosatetraenoic acid (12-HETE), prostaglandin E2 and 6-keto-prostaglandin F1 alpha in the culture medium of smooth muscle cells stimulated by 5% fetal calf serum were significantly reduced by esculetin. Furthermore, the fetal calf serum-stimulated protein tyrosine kinase activity was reduced by esculetin (10(-5)-10(-4) M) in a dose-dependent manner. In contrast, the protein kinase C activity stimulated by phorbol-12-myristate-13-acetate was not affected by esculetin (10(-6)-10(-4) M). These results suggest that the antiproliferative effect of esculetin on vascular smooth muscle cells may be partly mediated through inhibition of protein tyrosine kinase and modulated by inhibition of lipoxygenase.

Transporting the neurologically compromised child.

The initial evaluation, stabilization, and subsequent transport of the neurologically compromised child should take into account the pathophysiologic response of the CNS to a variety of injurious factors. Little can be done to avoid neuronal damage from the primary event. Secondary insults resulting from hypoxemia, ischemia, intracranial hypertension, and fluid shifts can and must be prevented to ensure maximum neuronal salvage, however. Maintenance of an adequate airway, breathing, and circulation assume an immediate and ongoing priority. Neuroresuscitation should be directed toward reversing alterations in cerebral metabolism, autoregulation, brain water, and ICP associated with individual pathologic states.