High vs low CPAP strategy with aerosolized calfactant in preterm infants with respiratory distress syndrome.

BACKGROUND: Optimal CPAP strategy to prevent CPAP failure defined as need for endotracheal intubation is unknown. OBJECTIVE: To evaluate the risk of CPAP failure in infants treated with high vs low CPAP strategy while receiving aerosolized calfactant in the AERO-02 clinical trial and AERO-03 expanded access program. METHODS: Infants born between 29 0/7 to 36 6/7 weeks were included. Comparisons were made between low and high CPAP groups (Low, 4-7 cm H2O; High, 8-10 cm H2O). RESULTS: CPAP failure and pneumothorax were not different between the groups. Odds of CPAP failure were not different after adjustment for baseline characteristics (OR = 0.61; 95% CI: 0.29, 1.24). CONCLUSION: We found no difference in CPAP failure among infants who received aerosolized calfactant that were treated with high vs low CPAP strategy. Efficacy of high CPAP strategy with aerosolized surfactant treatment needs to be evaluated in future studies.

Uncertain in the face of change: Lack of contingency shift awareness during extinction is associated with higher fear-potentiated startle and PTSD symptoms in children.

Intolerance of uncertainty is a transdiagnostic risk factor for fear-related disorders and is associated with higher levels of anxiety in children and adolescents. It is unclear how uncertainty relates to development of psychopathology in children who have experienced trauma in early life. The present study used a fear-potentiated startle paradigm in children to examine associations between uncertainty (assessed as unawareness of a change in reinforcement during fear extinction) and symptoms of anxiety and posttraumatic stress disorder (PTSD), as well as startle potentiation to threat and safety cues. Results showed that unaware children had strong positive associations between trauma exposure and PTSD symptoms, whereas aware children did not. Uncertainty interacted with anxiety in that children who were both unaware and had higher anxiety displayed higher fear-potentiated startle to safety cues and did not show discrimination between threat and safety during fear conditioning. These results suggest that anxious children who persist in associating a threat cue with an aversive event during extinction, after repeated presentations of the no longer reinforced conditioned stimulus, may express psychophysiological phenotypes related to PTSD.

Why do four NICUs using identical RBC transfusion guidelines have different gestational age-adjusted RBC transfusion rates?

OBJECTIVE: To compare neonatal red blood cell (RBC) transfusion rates in four large Intermountain Healthcare NICUs, all of which adhere to the same RBC transfusion guidelines. STUDY DESIGN: This retrospective analysis was part of a transfusion-management quality-improvement project. De-identified data included RBC transfusions, clinical and laboratory findings, the anemia-prevention strategies in place in each NICU, and specific costs and outcomes. RESULT: Of 2389 NICU RBC transfusions given during the 4-year period studied, 98.9 ± 2.1% (mean ± S.D.) were compliant with our transfusion guidelines, with no difference in compliance between any of the four NICUs. However, RBC transfusion rates varied widely between the four, with averages ranging from 4.6 transfusions/1000 NICU days to 21.7/1000 NICU days (P < 0.00001). Gestational age-adjusted transfusion rates were correspondingly discordant (P < 0.00001). The lower-transfusing NICUs had written anemia-preventing guidelines, such as umbilical cord milking at very low birth weight delivery, use of cord blood for admission laboratory studies, and darbepoetin dosing for selected neonates. Rates of Bell stage ⩾ 2 necrotizing enterocolitis and grade ⩾ 3 intraventricular hemorrhage were lowest in the two lower-transfusing NICUs (P < 0.0002 and P < 0.0016). Average pharmacy costs for darbepoetin were $84/dose, with an average pharmacy cost of $269 per transfusion averted. With a cost of $900/RBC transfusion, the anemia-preventing strategies resulted in an estimated cost savings to Intermountain Healthcare of about $6970 per 1000 NICU days, or about $282,300 annually. CONCLUSION: Using transfusion guidelines has been shown previously to reduce practice variability, lower transfusion rates and diminish transfusion costs. Based on our present findings, we maintain that even when transfusion guidelines are in place and adhered to rigorously, RBC transfusion rates are reduced further if anemia-preventing strategies are also in place.

Aurora-A is a determinant of tamoxifen sensitivity through phosphorylation of ERα in breast cancer.

Despite the clinical success of tamoxifen, its resistance remains a major challenge in breast cancer. Here we show that Aurora-A determines tamoxifen sensitivity by regulation of oestrogen receptor (ER)α. Ectopic expression of Aurora-A decreases and depletion of Aurora-A enhances tamoxifen sensitivity in ERα-positive breast cancer. Elevated Aurora-A was significantly associated with the recurrence of ERα-positive tumours. Notably, Aurora-A inhibitor MLN8237, which is currently in clinical trial, synergizes with tamoxifen and overcomes tamoxifen resistance. Furthermore, Aurora-A interacts with and phosphorylates ERα on serine-167 and -305, leading to increase in ERα DNA-binding and transcriptional activity. Elevated levels of Aurora-A are significantly associated with disease-free survival in ERα-positive but not ERα-negative breast cancers. These data suggest that Aurora-A has a pivotal role in tamoxifen resistance and ERα is a bona fide substrate of Aurora-A. Thus, Aurora-A represents a prognostic marker in ERα-positive tumour and a critical therapeutic target in tamoxifen-resistant breast cancer, and Aurora-A inhibitor could be used as either an independent or concurrent agent in tamoxifen-resistant tumour.

A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer.

BACKGROUND: Histone deacetylases (HDACs) are crucial components of the oestrogen receptor (ER) transcriptional complex. Preclinically, HDAC inhibitors can reverse tamoxifen/aromatase inhibitor resistance in hormone receptor-positive breast cancer. This concept was examined in a phase II combination trial with correlative end points. METHODS: Patients with ER-positive metastatic breast cancer progressing on endocrine therapy were treated with 400 mg of vorinostat daily for 3 of 4 weeks and 20 mg tamoxifen daily, continuously. Histone acetylation and HDAC2 expression in peripheral blood mononuclear cells were also evaluated. RESULTS: In all, 43 patients (median age 56 years (31-71)) were treated, 25 (58%) received prior adjuvant tamoxifen, 29 (67%) failed one prior chemotherapy regimen, 42 (98%) progressed after one, and 23 (54%) after two aromatase inhibitors. The objective response rate by Response Evaluation Criteria in Solid Tumours criteria was 19% and the clinical benefit rate (response or stable disease >24 weeks) was 40%. The median response duration was 10.3 months (confidence interval: 8.1-12.4). Histone hyperacetylation and higher baseline HDAC2 levels correlated with response. CONCLUSION: The combination of vorinostat and tamoxifen is well tolerated and exhibits encouraging activity in reversing hormone resistance. Correlative studies suggest that HDAC2 expression is a predictive marker and histone hyperacetylation is a useful pharmacodynamic marker for the efficacy of this combination.

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker.

BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.

Childhood outcome after early high-frequency oscillatory ventilation for neonatal respiratory distress syndrome.

OBJECTIVE: In a previous multicenter controlled clinical trial, we randomly assigned surfactant-treated premature newborns with moderate to severe respiratory distress syndrome to early treatment with high-frequency oscillatory ventilation (HFOV) or to conventional ventilation (CV). Compared with control infants who were treated with CV, neonates who were treated with HFOV using a strategy designed to recruit and maintain lung volume and minimize oxygen exposure had clinical evidence of improved pulmonary outcome and less lung injury. We report a follow-up study designed to determine whether clinical differences persisted between these study groups. METHODS: Patients were recruited from 81 survivors at 1 center (Provo, Utah) and evaluated for sociodemographic and health history, growth, mental development, motor proficiency, and pulmonary function. RESULTS: Eighty-seven percent of the cohort who originally were assigned to treatment with HFOV (n = 36) or CV (n = 33) were seen in follow-up at a mean age of 77 months (6.4 years). There were no differences in the frequency of hospitalization, pulmonary illness, asthma, or disabilities. Growth, verbal IQ, and motor development were appropriate for age and not different between groups. Patients who initially were randomized to treatment with CV showed pulmonary function evidence of decreased peak expiratory flow, increased residual lung volume, and maldistribution of ventilation. CONCLUSION: Neurodevelopmental childhood outcome after early intervention HFOV was normal and not different compared with patients who were treated with CV. Surfactant replacement combined with early HFOV using a lung recruitment strategy ameliorates the acute lung injury in respiratory distress syndrome that predisposes some preterm infants to develop chronic lung disease.

Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells.

Constitutive activation of signal transducer and activator of transcription (STAT) proteins has been detected in a wide variety of human primary tumor specimens and tumor cell lines including blood malignancies, head and neck cancer, and breast cancer. We have previously demonstrated a high frequency of Stat3 DNA-binding activity that is constitutively-induced by an unknown mechanism in human breast cancer cell lines possessing elevated EGF receptor (EGF-R) and c-Src kinase activities. Using tyrosine kinase selective inhibitors, we show here that Src and JAK family tyrosine kinases cooperate to mediate constitutive Stat3 activation in the absence of EGF stimulation in model human breast cancer cell lines. Inhibition of Src or JAKs results in dose-dependent suppression of Stat3 DNA-binding activity, which is accompanied by growth inhibition and induction of programmed cell death. In addition, transfection of a dominant-negative form of Stat3 leads to growth inhibition involving apoptosis of breast cancer cells. These results indicate that the biological effects of the Src and JAK tyrosine kinase inhibitors are at least partially mediated by blocking Stat3 signaling. While EGF-R kinase activity is not required for constitutive Stat3 activation in breast cancer cells, EGF stimulation further increases STAT DNA-binding activity, consistent with an important role for EGF-R in STAT signaling and malignant progression. Analysis of primary breast tumor specimens from patients with advanced disease revealed that the majority exhibit elevated STAT DNA-binding activity compared to adjacent non-tumor tissues. Our findings, taken together, suggest that tyrosine kinases transduce signals through Stat3 protein that contribute to the growth and survival of human breast cancer cells in culture and potentially in vivo.

Temporary reversal of anticoagulation using oral vitamin K.

Brief reversal of oral anticoagulant therapy is frequently necessary prior to minor surgery or invasive procedures. We sought to determine the effect of an oral dose of 2.0 mg of vitamin K(1) on the international normalized ratio (INR) among patients with a stable therapeutic INR who were maintained on their daily dose of warfarin. We prospectively studied a convenience cohort of patients attending an anticoagulation clinic who had either just completed treatment for venous thromboembolism or were receiving prophylaxis for atrial fibrillation, cardiomyopathy, or peripheral vascular disease. Each patient received an oral dose of 2.0 mg of aqueous vitamin K(1). Serial INR measurements were taken over 1 week. There was wide variation in the INR response between patients, from no change to complete reversal of anticoagulation. The effect also varied widely over time. There was a significant inverse correlation between the fall in logarithm of the INR and the daily warfarin dose required to achieve an INR value of 2.5 (r=-0.52, p=0.011). Use of a 2.0 mg oral dose of vitamin K(1) does not reliably reverse (correct) a therapeutic INR in patients maintained on their daily dose of warfarin.

Chemoprevention of breast cancer in the older patient.

Age is the most important risk factor for the development of breast cancer. The risk of breast cancer continues to increase in American women until the age of 80 years. A family history of breast cancer helps identify those who possibly have the highest risk of developing breast cancer; however, most women who develop breast cancer do not have a first-degree relative with a history of breast cancer. Currently, the Gail model is a commonly used model to identify risk, and this model has now been validated in several populations of women undergoing screening for breast cancer. The first large-scale breast cancer prevention trial investigating the preventive effects of tamoxifen has demonstrated a decrease in the development of breast cancer by almost 50% in the women in the tamoxifen treatment arm as compared with those receiving placebo. The NSABP P-1 trial was the largest of the three tamoxifen breast cancer prevention trials and had the greatest power to detect a difference between the two treatment groups in breast cancer events. This trial also included the largest percentage of postmenopausal women. It is unclear why the Italian and Royal Marsden Hospital trials had negative results regarding the preventive effects of tamoxifen. These two trials were strikingly different from the NSABP P-1 trial, however, and they included a different population of women. The issues surrounding the use of HRT for treatment of hot flashes in the Italian and Royal Marsden Hospital trials adds to the controversy concerning the negative results of these trials. The new SERM, raloxifene, has shown promise in preliminary studies as a preventive agent for breast cancer. The STAR trial will open soon and will evaluate the efficacy of raloxifene in preventing breast cancer in a prospective fashion, comparing its efficacy with tamoxifen treatment. Other endpoints will evaluate side effects such as menopausal symptoms, endometrial cancer, thromboembolic events, and benefits regarding serum lipids and incidence of osteoporotic bone fractures. The development of SERMs results from an understanding of novel mechanisms of ER modulation and allows targeting for favorable effects in specific tissues. The challenge is to develop an ideal SERM that is effective in preventing breast cancer and does not increase the risk of endometrial cancer, while providing beneficial estrogenic effects on serum lipids and bone mineral density changes. Estrogen receptor-mediated intracellular processes are complex. There are at least two different types of estrogen receptors. The alpha receptors predominate in the breast and uterus, and the beta receptors predominate in the bone and blood vessels. Many proteins also interact with these receptors as co-activators or co-repressors. Transcription-activating factors modulate the effects of estrogen on its target genes. Future prevention strategies may use a combined targeted approach to inhibit ER-mediated cancer progression pathways. The retinoids are under investigation in prevention studies for a multitude of cancers, because they have been shown to inhibit cellular proliferation and to induce cellular differentiation. The retinoid 4HPR was selected for use in breast cancer prevention studies because of its low toxicity profile and prevention efficacy in preclinical studies. It is now being used in combination with tamoxifin in a phase II breast cancer prevention trial. Multiple surrogate endpoint biomarkers are being measured before and after treatment, including measurement of serum IGF-I levels. Future directions in breast cancer prevention include the development of more potent hormonal therapies that completely inhibit ER-mediated cancer progression and, ultimately, multitargeted therapies involving agents that work synergistically.

Severe Lhermitte-Duclos disease with unique germline mutation of PTEN.

Germline mutations in the PTEN gene have recently been identified in some individuals with Cowden disease (CD), Lhermitte-Duclos disease (LDD), and Bannayan-Zonana syndrome. We report on a patient with CD and LDD in whom a unique de novo germline missense mutation is present in the PTEN gene. Direct sequence analysis detected a transitional change (T-->C) at nucleotide 335, resulting in substitution of the amino acid proline for leucine. The mutation is in exon 5, which has been proposed as a "hot-spot" for germline mutations. Comparison of this patient's clinical course with the previously reported cases of CD and LDD shows more extensive and more severe clinical findings than reported previously. Findings in this patient contribute to the current understanding of germline PTEN mutations and clinical outcome.

Menopausal Status and the Impact of Early Recurrence on Breast Cancer Survival.

BACKGROUND: Breast cancer represents the leading form of invasive cancer among American women, killing nearly 50,000 annually. Several prognostic factors that are associated with survival include age, race, menopausal status, and the stage of disease at presentation. METHODS: Patient characteristics were collected based on a systematic chart audit of demographic features and medical, family, and social histories. We studied the survival of 220 patients with recurrent disease out of 1,429 consecutive patients with breast cancer seen over a 15-year period. RESULTS: Patients with a disease-free interval following diagnosis of less than 24 months were more frequently premenopausal and hormone receptor-negative than those with a disease-free interval of 24 months or greater. Patients with early recurrence had a shorter survival than patients with late recurrence. Menopausal status, nodal involvement, receptor status, and the site of recurrent disease were independent predictors of survival following recurrence. CONCLUSIONS: Premenopausal women with early recurrence of breast cancer experience a significantly shorter survival than those with late recurrence, even after adjustment for hormone receptor status and site of recurrence. This effect was not seen in postmenopausal women.

Nurse/physician collaborative practice: improving health care quality while decreasing cost.

Significant variations and inconsistency in both the physician's and nurse's approach to the treatment of neonates with a "rule-out sepsis" (R/O sepsis) diagnosis is seen as both high cost and low quality. Because R/O sepsis is seen as a diagnostic dilemma for practicing clinicians, there has been a widespread tendency to readily initiate antibiotic treatment, without adequate consideration of the high financial and morbidity costs associated with the complications of treating the noninfected infant. This study demonstrates that the use of an agreed upon risk profile facilitated the collaborative standardization of diagnosis and treatment of the R/O sepsis patient, improved quality, and reduced costs (by minimizing over treatment) without increasing risk. This collaborative approach enhanced nurse-physician relationships, resulting in significant cost savings as well as diminished anxiety and confusion among the parents of neonates diagnosed with R/O sepsis.

The Provo multicenter early high-frequency oscillatory ventilation trial: improved pulmonary and clinical outcome in respiratory distress syndrome.

OBJECTIVE: To compare the hospital course and clinical outcome of preterm infants with respiratory distress syndrome treated with surfactant and managed with high-frequency oscillatory ventilation (HFOV) or conventional mechanical ventilation (CV) as their primary mode of ventilator support. DESIGN: A prospective randomized clinical trial. SETTING: Three community-based level III neonatal intensive care units. SUBJECTS: A total of 125 neonates who were 35 weeks or less estimated gestation requiring intubation and assisted ventilation for respiratory distress syndrome with arterial to alveolar oxygen ratio less than .50. INTERVENTIONS: Patients were randomized to continue CV (61 patients) or be changed to HFOV (64 patients) after exogenous surfactant administration (100 mg/kg). HFOV was used in a strategy to promote lung recruitment and maintain lung volume. Protocol respiratory care guidelines were followed; otherwise routine care was provided by each neonatal intensive care unit. MEASUREMENTS AND MAIN RESULTS: No differences were noted in demographic features between the two study groups. The study population birth weight was 1.51 +/- .47 kg (mean +/- SD), gestational age was 30.9 +/- 2.5 weeks, and study entry age was 2 to 3 hours. Patients randomized to HFOV demonstrated the following significant findings compared with CV-treated patients: vasopressor support was less intensive; surfactant redosing was not as frequent; oxygenation improved more rapidly and remained higher during the first 7 days; fewer infants required prolonged supplemental oxygen or ventilator support; treatment failure was reduced; more patients survived without chronic lung disease at 30 days; need for continuous supplemental oxygen at discharge was less; frequency of necrotizing enterocolitis illness was lower; there were fewer abnormal hearing tests; and hospital costs were decreased. No differences were seen between the two study groups in the frequency or severity of patent ductus arteriosus, air leak, retinopathy of prematurity, or intraventricular hemorrhage. Length of hospital stay and survival to discharge were similar for HFOV- and CV-treated infants. CONCLUSIONS: When used early with a lung recruitment strategy, HFOV after surfactant replacement resulted in clinical outcomes consistent with a reduction in both acute and chronic lung injury. Benefit was evident for preterm infants both less than or equal to 1 kg and more than 1 kg. In addition, early HFOV treatment may have had a more global effect on patient health throughout the hospitalization, resulting in reduced morbidity and decreased health care cost.

Bites by non-native venomous snakes in the United States.

Fifty-four consultations regarding bites by venomous snakes not native to the United States are summarized. These are from a database of 164 consultations during the period 1977- 1995. At least 29 non-native snake species were involved with cobras making up -40% of the group. There was one fatality. A high percentage of venomous snakebites in the United States involve deliberate interaction with snakes. The proportion of bites by non-native species seems to be increasing. Some of the snake species involved are discussed, and some principles for management of these bites are given.

Nonlinear dobutamine pharmacokinetics in a pediatric population.

OBJECTIVE: To evaluate a linear kinetic model for dobutamine clearance. DESIGN: A prospective evaluation of pediatric patients receiving continuous infusions of dobutamine at varying doses. SETTING: A pediatric critical care unit. PATIENTS: Twelve patients age 2 days to 9 yrs and weighing 2.7 to 33 kg who required vasopressor therapy. Infusion rates for dobutamine ranged from 2 to 15 micrograms/kg.min. MEASUREMENTS AND MAIN RESULTS: Serum concentrations varied from 6.4 to 347 ng/mL (21 to 1151 nmol/L). Concentration was found to increase with dose. However, the relationship of clearance to steady-state concentration had a negative slope. Values for clearance varied from 32 to 625 mL/kg.min. Multiple analysis of variance on age, weight, and co-infused dopamine showed that these factors did not influence the relationship of clearance to steady-state concentration. Analysis to show an underlying model failed to differentiate Michaelis-Menten from nonlinear binding or mixed models on the basis of these data. CONCLUSIONS: Dobutamine pharmacokinetics do not appear to follow a simple linear model. Based on the current data, neither age nor the added infusion of dopamine affects the clearance of dobutamine.

Ceftizoxime disposition in neonates and infants during the first six months of life.

The single-dose pharmacokinetics of ceftizoxime sodium were studied in 52 neonates and infants between 0.1 and 189 days of age. Subjects received ceftizoxime 25 or 50 mg/kg iv over 15-30 minutes. The drug was administered q8-12h for five days to permit tolerance evaluation on repetitive dosing. No differences were observed in ceftizoxime pharmacokinetic parameter estimates relative to dose. However, marked differences were observed in ceftizoxime pharmacokinetic characteristics relative to infant age; ceftizoxime half-life and mean residence time decreased, whereas body clearance increased with infant age. Ceftizoxime volume of distribution remained relatively constant over infant age. No adverse effects associated with ceftizoxime administration were observed. These data suggest that ceftizoxime 50 mg/kg q12h be used for infants less than or equal to 2 weeks of age (less than or equal to 40 weeks postconceptional age) and that 50 mg/kg q8h be administered for older infants.

BALB/cAn B cells and T cells have distinct susceptibilities to cytotoxic effects of snake venom.

Previous studies have analyzed abilities of snake venoms to preferentially kill certain animal cells. Some studies have examined selective cytotoxic effects of snake venoms on B and T lymphocytes, but few studies have determined abilities of snake venoms to interact with B and T cells at distinct stages of cellular development. Thus, this study has analyzed susceptibilities of immature and mature BALB/cAn splenic B cells and T cells to cytotoxic effects of crude venoms of snakes belonging to the families of Crotalidae, Elapidae, and Viperidae. Both mitogen-stimulated and unstimulated BALB/cAn Ig- splenic T cells are sensitive to cytotoxic effects of snake venoms whereas mitogen-stimulated but not unstimulated Ig+ splenic B lymphocytes are sensitive to snake venoms. We also find that BALB/cAn myelomas but not B cell lymphomas are sensitive to cytotoxic effects of snake venoms. In addition, plaque forming cells making IgG1 subclass in BALB/cAn mitogen-stimulated spleens and in myelomas are preferentially killed by venom of pit viper Bothrops asper. Thus, the cytotoxic effects of crude snake venoms can distinguish BALB/cAn PFC making IgG1 subclass from other B and T cells.