PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors.

Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key role in the pathogenesis of numerous cancers by altering cell growth, metabolism, proliferation and apoptosis. Interest in targeting the PI3K signaling cascade continues, as new agents are being clinically evaluated. PIK3CA mutations result in a constitutively active PI3K and are present in a subset of pancreatic cancers. Here we examine mutant PIK3CA-mediated pancreatic tumorigenesis and the response of PIK3CA mutant pancreatic cancers to dual PI3K/mammalian target of rapamycin (mTOR) inhibition. Two murine models were generated expressing a constitutively active PI3K within the pancreas. An increase in acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs) was identified. In one model these lesions were detected as early as 10 days of age. Invasive pancreatic ductal adenocarcinoma developed in these mice as early as 20 days of age. These cancers were highly sensitive to treatment with dual PI3K/mTOR inhibition. In the second model, PanINs and invasive cancer develop with a greater latency owing to a lesser degree of PI3K pathway activation in this murine model. In addition to PI3K pathway activation, increased ERK1/2 signaling is common in human pancreatic cancers. Phosphorylation of ERK1/2 was also investigated in these models. Phosphorylation of ERK1/2 is demonstrated in the pre-neoplastic lesions and invasive cancers. This activation of ERK1/2 is diminished with dual PI3K/mTOR inhibition. In summary, PIK3CA mutations can initiate pancreatic tumorigenesis and these cancers are particularly sensitive to dual PI3K/mTOR inhibition. Future studies of PI3K pathway inhibitors for patients with PIK3CA mutant pancreatic cancers are warranted.

PIK3CA and APC mutations are synergistic in the development of intestinal cancers.

Human colorectal cancers are known to possess multiple mutations, though how these mutations interact in tumor development and progression has not been fully investigated. We have previously described the FCPIK3ca* murine colon cancer model, which expresses a constitutively activated phosphoinositide-3 kinase (PI3K) in the intestinal epithelium. The expression of this dominantly active form of PI3K results in hyperplasia and invasive mucinous adenocarcinomas. These cancers form via a non-canonical mechanism of tumor initiation that is mediated through activation of PI3K and not through aberrations in WNT signaling. Since the Adenomatous Polyposis Coli (APC) gene is mutated in the majority of human colon cancers and often occurs simultaneously with PIK3CA mutations, we sought to better understand the interaction between APC and PIK3CA mutations in the mammalian intestine. In this study, we have generated mice in which the expression of a constitutively active PI3K and the loss of APC occur simultaneously in the distal small intestine and colon. Here, we demonstrate that expression of a dominant active PI3K synergizes with loss of APC activity resulting in a dramatic change in tumor multiplicity, size, morphology and invasiveness. Activation of the PI3K pathway is not able to directly activate WNT signaling through the nuclear localization of CTNNB1 (ß-catenin) in the absence of aberrant WNT signaling. Alterations at the transcriptional level, including increased CCND1, may be the etiology of synergy between these activated pathways.

Prevention of postpartum smoking relapse in mothers of infants in the neonatal intensive care unit.

OBJECTIVE: Approximately 40% of women who smoke tobacco quit smoking during pregnancy, yet up to 85% relapse after delivery. Those who resume smoking often do so by 2 to 8 weeks postpartum. Smoking mothers are more than twice as likely to quit breastfeeding by 10 weeks postpartum. The hospitalization of a newborn, while stressful, is an opportunity to emphasize the importance of a smoke-free environment for babies. Supporting maternal-infant bonding may reduce maternal stress and motivate mothers to remain smoke free and continue breastfeeding. The objective of this study was to reduce postpartum smoking relapse and prolong breastfeeding duration during the first 8 weeks postpartum in mothers who quit smoking just before or during pregnancy and have newborns admitted to the Neonatal Intensive Care Unit (NICU). STUDY DESIGN: This study was an Institutional Review Board-approved prospective randomized clinical trial. After informed consent, mothers of newborns admitted to the NICU were randomized to a control or intervention group. Both groups received weekly encouragement to remain smoke free and routine breastfeeding support. Mothers in the intervention group were also given enhanced support for maternal-infant bonding including information about newborn behaviors, and were encouraged to frequently hold their babies skin-to-skin. RESULT: More mothers were smoke free (81 vs 46%, P<0.001) and breastfeeding (86 vs 21%, P<0.001) in the intervention than in the control group at 8 weeks postpartum. CONCLUSION: Interventions to support mother-infant bonding during a newborn's hospitalization in the NICU are associated with reduced rates of smoking relapse and prolonged duration of breastfeeding during the first 8 weeks postpartum.

Use of propranolol for treatment of hemangiomas in PHACE syndrome.

We report the case of a 29-week preterm infant with PHACE (posterior fossa malformations, hemangionas, arterial anomalies, cardiac anomalies, eye anomalies) syndrome. PHACE syndrome is a neurocutaneous disorder with large facial segmental hemangionas associated with anomalies of the brain, eye, heart and aorta. The hemangiomas in our patient were problematic, distorting the airway and interfering with respirations to the point of requiring mechanical ventilation. Consultation with several different centers with medical expertize in treatment of congenital hemangiomas revealed different views on the best management strategy. In this infant, the hemangiomas progressed with failure to involute despite currently recommended therapy including corticosteroids and vincristine. Therefore, the infant was treated with propranolol and had significant regression of the hemangiomas. The use of propranolol for the treatment of infantile hemangiomas is reviewed.

Elevated total peripheral leukocyte count may identify risk for neurological disability in asphyxiated term neonates.

OBJECTIVE: The present study investigated the relationship between neurologic outcome and total circulating white blood cell (WBC) and absolute neutrophil counts (ANCs) in the first week of life in term infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: Long-term neurologic outcome at 18 months was measured retrospectively in 30 term neonates with HIE using the Pediatric Cerebral Performance Category Scale (PCPCS) score with outcomes dichotomized as either good or poor. We then compared white blood cell and ANC levels during the first 4 days of life and magnetic resonance imaging (MRI) obtained within the first month life between the two PCPCS groups. MRI was quantified using a validated scoring system. RESULTS: Neonates with good long-term outcomes had significantly lower MRI scores (indicating lesser injury) than neonates with poor outcomes. More importantly, neonates with poor outcomes had significantly higher WBC and ANC levels as early as12 h after birth and up to 96 h after birth compared to those with good outcomes. These data suggest that elevated peripheral neutrophil counts in the first 96 h of life may signal or predict adverse long-term outcome. CONCLUSIONS: Our findings suggest that elevated peripheral neutrophil counts in the first 96 h of life in term infants with HIE may contribute to abnormal neurodevelopmental outcome.

Reference ranges for thyroid function tests in premature infants beyond the first week of life.

OBJECTIVES: To establish reference ranges for the more sensitive assays of thyrotropin and the best available assays of free thyroxine in premature infants after the first week of life. STUDY DESIGN: Free thyroxine measurements by direct equilibrium dialysis and thyrotropin measurements by third generation immunometric assay were measured in 120 healthy premature infants 25 to 36 weeks' gestation at birth and every 3 weeks until hospital discharge. Infants were stratified by postconceptional age. Differences in free thyroxine and thyrotropin levels among groups were determined by ANOVA. Correlations between hormone measurements and gestational and postnatal ages were sought by linear regression analysis. Reference ranges were determined as arithmetic (free thyroxine) and geometric (thyrotropin) mean+/-2 SD ranges. RESULTS: From 120 infants, 164 samples were obtained and grouped by postconceptional age at sampling. Free thyroxine was not different among postconceptional age groups and did not correlate with gestational or postnatal age. The free thyroxine reference range based on these data was 10 to 33 pmol/l (0.8 to 2.6 ng/dl). Thyrotropin did not correlate with gestational age. There was a clinically trivial but statistically significant (r(2)=0.03, p<0.05) correlation of thyrotropin with postnatal age. The thyrotropin reference based on these data was 0.8 to 12 mU/l. CONCLUSIONS: Free thyroxine was closely regulated in these premature infants and levels were similar to those in older children and adults, once the natal surge in thyrotropin has subsided. After the first week of life a single range for each hormone appeared appropriate for all premature infants until 40 weeks postconceptional age.

Amount of dietary fat and type of soluble fiber independently modulate postabsorptive conversion of beta-carotene to vitamin A in mongolian gerbils.

Current dietary guidelines recommend a decrease in fat intake and an increase in fiber consumption. Decreased bioavailability (BV) of carotenoids is thought to be associated with both of these recommendations. A 2 x 4 factorial design was used to test the effects of dietary fat level at 10 or 30% of total energy and fiber type using no fiber, silica, citrus pectin or oat gum (7 g/100 g) on beta-carotene (betaC) BV in 4- to 5-wk-old Mongolian gerbils. We assessed BV as both accumulation of betaC and bioconversion of betaC to vitamin A (VA) in tissues. A VA- and betaC-deficient diet was fed for 1 wk followed by one of eight isocaloric, semipurified diets supplemented with carrot powder [ approximately 1 microgram betaC, 0.5 microgram alpha-carotene (alphaC)/kJ diet] for 2 wk (n = 12/group). Increasing dietary fat resulted in higher VA (P: = 0.074) and lower betaC (P: = 0.0001) stores in the liver, suggesting that consumption of high fat diets enhances conversion of betaC to VA. The effect of soluble fiber on hepatic VA storage was dependent on fiber type. Consumption of citrus pectin resulted in lower hepatic VA stores and higher hepatic betaC stores compared with all other groups, suggesting less conversion of betaC to VA. In contrast, consumption of oat gum resulted in hepatic VA and betaC stores that were higher (P = 0.012) and lower (P = 0.022), respectively, than those of citrus pectin-fed gerbils. The level of dietary fat consumed with soluble fiber had no interactive effects on hepatic VA, betaC or alphaC stores. Results demonstrate that betaC BV is independently affected by dietary fat level and type of soluble fiber, and suggest that these dietary components modulate postabsorptive conversion of betaC to VA. This study confirms the negative effects of citrus pectin on betaC BV, and suggests that oat gum does not adversely affect betaC BV.

The medium-term findings in coronary arteries by intravascular ultrasound in infants and children after heart transplantation.

OBJECTIVES: The study purposes were to determine 1) whether intravascular ultrasound (IVUS) was more sensitive than angiography for the detection of post-transplant coronary artery disease (PTCAD) in pediatric patients; and 2) whether those transplanted as neonates reacted differently than older patients. BACKGROUND: Experience with IVUS for the diagnosis of PTCAD in children is limited. METHODS: Patients were divided into two groups: those transplanted as neonates (early group) and those transplanted in infancy or childhood (late group). Morphometric analysis was performed, including maximal intimal thickness (MIT) and intimal index (II). Stanford classification was used to grade lesion severity. Acute rejection and cytomegalovirus (CMV) status were correlated with MIT and II. RESULTS: Thirty children were studied (early group, n = 13; late group, n = 17). All segments studied were angiographically normal. Mean MIT and mean II were significantly greater in the late group (0.26 +/- 0.14 vs. 0.13 +/- 0.04 mm, p < 0.001 and 0.11 +/- 0.07 vs. 0.07 +/- 0.03 mm, p = 0.04, respectively). There was a significant correlation between MIT and II in those who had acute rejection in the late group. Patients in the late group who were CMV-positive had a significantly higher MIT compared with those in the late group with negative serology (p = 0.04). CONCLUSIONS: Intravascular ultrasound was more sensitive than angiography in detecting PTCAD after pediatric heart transplantation. There is a possible role for acute rejection and CMV in the development of PTCAD.

Extracorporeal membrane oxygenation for perioperative support in neonatal and pediatric cardiac transplantation.

Currently there is a lack of consensus on guidelines in the clinical application of extracorporeal membrane oxygenation (ECMO) in neonatal and pediatric cardiac transplantation patients. In this context, given the limited data presently available through the Extracorporeal Life Support Organization (ELSO) Registry, we conducted a preliminary survey to specifically evaluate the practice of using ECMO as a bridge to cardiac transplantation or as posttransplantation therapy for failure to wean from cardiopulmonary bypass or graft failure. We received responses to our questionnaire from 95 of 118 (81%) centers located in the U.S.A. and abroad. Of the 95 centers that responded, 36 were performing neonatal/pediatric cardiac transplants, with 29 centers reporting the concomitant use of ECMO to support cardiac transplant patients. There was wide variability in the responses from the 29 centers to a selected list of relative ECMO contraindications. However, only 7 centers had specific ECMO entry criteria for cardiac transplant patients. Fifteen of the 29 centers provided relevant data on cardiac transplant patients including the proportions of neonatal (11 of 37) and pediatric (63 of 217) patients requiring ECMO; neonatal (2 of 5) and pediatric (16 of 27) patients surviving to transplant; and neonatal (1 of 5) and pediatric (12 of 27) patients surviving to hospital discharge. These findings confirm the important role of ECMO in providing perioperative support in neonatal and pediatric cardiac transplantation patients. However, the lack of consensus among centers contributes to uncertainty in the decision making process to offer ECMO and to utilize ECMO effectively in this high risk population. We recommend that institution-specific information be collected, either using the ELSO Registry (or by a similar multicentric database) to develop specific guidelines for ECMO applications in cardiac transplant patients, and to carefully monitor and follow up EMCO treated patients to further evaluate the efficacy of this limited resource.

Serum free thyroxine concentration is not reduced in premature infants with respiratory distress syndrome.

OBJECTIVE: We used improved methods of assay to determine whether pituitary-thyroid function is altered in premature infants with respiratory distress syndrome (RDS) during the first week of postnatal life. METHODS: Serum free thyroxine (T4) was measured by direct equilibrium dialysis, total thyroxine (TT4) by radioimmunoassay, and thyrotropin by a sensitive immunometric assay in 90 premature infants (45 healthy control subjects and 45 with RDS) during their first week of life after 25 to 30 weeks of gestation. Infants in the RDS group received exogenous surfactant therapy. RESULTS: Free T4 and thyrotropin concentrations of infants were not significantly different between RDS and control groups. As expected, infants with RDS had significantly lower serum total T4 concentrations compared with control infants (p < 0.001). This difference was present even after stratification for gestational age (25- to 27-week group, p = 0.012; 28- to 30-week group, p = 0.002). Lower total T4 concentrations were attributable to lower T4 binding to serum proteins among infants with RDS compared with control subjects, especially in the 25- to 27-week gestation group (p = 0.0075). CONCLUSION: These data indicate that pituitary-thyroid function is not altered in premature infants with RDS. The low total T4 state in these premature infants is attributable solely to reduced serum T4 binding, as is often seen in acute nonthyroidal illnesses.

Earth-Based Observations of the Galileo Probe Entry Site

Earth-based observations of Jupiter indicate that the Galileo probe probably entered Jupiter's atmosphere just inside a region that has less cloud cover and drier conditions than more than 99 percent of the rest of the planet. The visual appearance of the clouds at the site was generally dark at longer wavelengths. The tropospheric and stratospheric temperature fields have a strong longitudinal wave structure that is expected to manifest itself in the vertical temperature profile.

Collision of comet Shoemaker-Levy 9 with Jupiter observed by the NASA infrared telescope facility.

The National Aeronautics and Space Administration (NASA) Infrared Telescope Facility was used to investigate the collision of comet Shoemaker-Levy 9 with Jupiter from 12 July to 7 August 1994. Strong thermal infrared emission lasting several minutes was observed after the impacts of fragments C, G, and R. All impacts warmed the stratosphere and some the troposphere up to several degrees. The abundance of stratospheric ammonia increased by more than 50 times. Impact-related particles extended up to a level where the atmospheric pressure measured several millibars. The north polar near-infrared aurora brightened by nearly a factor of 5 a week after the impacts.

Infrared end-tidal CO2 measurement does not accurately predict arterial CO2 values or end-tidal to arterial PCO2 gradients in rabbits with lung injury.

End-tidal PCO2 (PETCO2) measurements from two commercially available neonatal infrared capnometers with different sampling systems and a mass spectrometer were compared with arterial PCO2 (PaCO2) to determine whether the former could predict the latter in mechanically ventilated rabbits with and without lung injury. The effects of tidal volume, ventilator frequency and type of lung injury on the gradient between PETCO2 and PaCO2 (delta P(a-ET)CO2) were evaluated. Twenty rabbits were studied: 10 without lung injury, 5 with saline lavage and 5 with lung injury by meconium instillation. Paired measurements of PETCO2 by two infrared capnometers and a mass spectrometer were compared to PaCO2. In the rabbits without lung injury, the values from the infrared capnometers and mass spectrometer correlated strongly with PaCO2 (r > or = 0.91) despite differences in the slopes of the linear regression between PETCO2 and PaCO2 and in delta P(a-ET)CO2 (P < 0.05). Values from the mainstream IR-capnometer more closely approximated the line of identity than the regression between the sidestream IR-capnometer values or the mass spectrometer and PaCO2, but tended to overestimate PaCO2. The delta P(a-ET)CO2 was similar at all tidal volumes and ventilator frequencies, regardless of capnometer type. In the rabbits with induced lung injury, while there was a positive correlation between the slopes of the regression between PETCO2 and PaCO2 for both capnometers (r > or = 0.70), none of the regression slopes approximated the line of identity. The delta P(a-ET)CO2 was greater in rabbits with injured than noninjured lungs (P < 0.05). The delta P(a-ET)CO2 was similar among capnometers regardless of tidal volume, ventilator frequency, or type of lung injury. The 95% confidence interval of plots PaCO2 against PETCO2 was large for rabbits with injured and noninjured lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Sudden infant death syndrome in infants evaluated by apnea programs in California.

Home apnea/bradycardia monitoring is frequently used in the management of infants at increased risk for sudden infant death syndrome (SIDS). However, some infants have died despite evaluation by infant apnea programs, and the benefits of home monitoring remain unproven. To determine the SIDS rate and risk factors of infants evaluated by infant apnea programs, 31 apnea programs and ten home monitor vendors in California were surveyed. Eleven (35%) of the apnea programs and four (40%) of the vendors responded. Information was obtained on 26 infants who died. Thirteen (50%) deaths were due to SIDS. Abnormal sleep studies did not predict death. Fifteen infants died despite a recommendation for home monitoring. Seven deaths occurred in association with technical errors or noncompliance with monitoring. Four deaths were due to nonaccidental trauma. The apnea programs evaluated 3,406 infants during a 5-year period; 1,841 had monitoring recommended. Term infants with apnea, subsequent siblings of SIDS victims, and infants evaluated at referral centers were more likely to have monitoring recommended than premature infants with apnea or infants evaluated at nonreferral centers (P less than .0001). Infants who had monitoring recommended were at equal risk of dying of SIDS as those who did not.

Controlled trial of furosemide therapy in infants with chronic lung disease.

To study the effects of furosemide therapy in infants with chronic lung disease (CLD), a double-blind controlled trial was designed. Seventeen infants with evidence of CLD (oxygen requirements greater than 30% at greater than 3 weeks of age and chest radiographic findings consistent with CLD) were studied. Pulmonary function was measured immediately before, and after 48 hours and 7 days of treatment with furosemide (1 mg/kg/12 hr intravenously or 2 mg/kg/12 hr orally) or placebo. Clinical status improved in six of seven infants who received furosemide and in two of 10 infants who received placebo (P less than 0.002). In the furosemide group, ventilator and oxygen requirements decreased (P less than 0.003); minute ventilation, alveolar ventilation, and dynamic compliance increased; and venous admixture decreased (P less than 0.05). There were no significant changes in the placebo group. Our findings suggest that furosemide significantly improves lung function during therapy in infants with CLD and allows earlier weaning from ventilatory support and supplemental oxygen.

Neonatal endotracheal flowmeter for tidal volume, airway pressure, and end-tidal gas.

We have designed a new endotracheal flowmeter to measure tidal volume, phasic and mean airway pressures, inspiratory time, and end-tidal PCO2 and PO2 in intubated infants. The flowmeter is light (11 g) and adds minimal dead space (1.0 ml) and resistance (2 cmH2O X 100 ml- X s) to the infant's airway. The volume signal (less than or equal to 10 ml) is linear to 7 Hz, and end-tidal gases can be measured at respiratory rates of 90 breaths/min. This flowmeter is particularly valuable for evaluation of rapid mechanical ventilation of very low birth weight infants.

Is there any chlorine monoxide in the stratosphere?

A ground-based search for stratospheric chlorine monoxide was carried out during May and October 1981 with an infrared heterodyne spectrometer in the solar absorption mode. Lines due to stratospheric nitric acid and tropospheric carbonyl sulfide were detected at about 0.2 percent absorptance levels, but the expected 0.1 percent lines of chlorine monoxide in this same region were not seen. Stratospheric chlorine monoxide is less abundant by at least a factor of 7 than is indicated by in situ measurements, and the upper limit for the integrated vertical column density of chlorine monoxide is 2.3 x 10(13) molecules per square centimeter at the 95 percent confidence level. These results imply that the release of chlorofluorocarbons may be significantly less important for the destruction of stratospheric ozone than is currently thought.

Discovery of natural gain amplification in the 10-micrometer carbon dioxide laser bands on Mars: a natural laser.

Fully resolved intensity profiles of various lines in the carbon dioxide band at 10.4 micrometers have been measured on Mars with an infrared heterodyne spectrometer. Analysis of the line shapes shows that the Mars atmosphere exhibits positive gain in these lines. The detection of natural optical gain amplification enables identification of these lines as a definite natural laser.