Progression and perceptual responses to blood flow restriction resistance training among people with multiple sclerosis.

PURPOSE: Resistance exercise can attenuate muscular impairments associated with multiple sclerosis (MS), and blood flow restriction (BFR) may provide a viable alternative to prescribing heavy training loads. The purpose of this investigation was to examine the progression of upper and lower body low-load (30% of one-repetition maximum [1RM]) resistance training (RT) with BFR applied intermittently during the exercise intervals (RT + BFR) versus volume-matched heavy-load (65% of 1RM) RT. METHODS: Men and women with MS (n = 16) were randomly assigned to low-load RT + BFR (applied intermittently) or heavy-load RT and completed 12 weeks (2 × /week) of RT that consisted of bilateral chest press, seated row, shoulder press, leg press, leg extension, and leg curl exercises. Exercise load, tonnage, and rating of perceived exertion were assessed at baseline and every 6 weeks. RESULTS: Training load increased to a greater extent and sometimes earlier for RT + BFR (57.7-106.3%) than heavy-load RT (42.3-54.3%) during chest press, seated row, and leg curl exercises, while there were similar increases (63.5-101.1%) for shoulder press, leg extension, and leg press exercises. Exercise tonnage was greater across all exercises for RT + BFR than heavy-load RT, although tonnage only increased during the chest press (70.7-80.0%) and leg extension (89.1%) exercises. Perceptions of exertion (4.8-7.2 au) and compliance (97.9-99.0%) were similar for both interventions. CONCLUSION: The training-induced increases in load, high compliance, and moderate levels of exertion suggested that RT + BFR and heavy-load RT are viable interventions among people with MS. RT + BFR may be a preferred modality if heavy loads are not well tolerated and/or to promote early-phase training responses.

Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease.

BACKGROUND: Whether androgen deficiency among men increases the risk of cardiovascular (CV) events or is merely a disease marker remains a subject of intense scientific interest. OBJECTIVES: Among male subjects in the AIM-HIGH Trial with metabolic syndrome and low baseline levels of high-density lipoprotein (HDL)-cholesterol who were randomized to niacin or placebo plus simvastatin, we examined the relationship between low baseline testosterone (T) concentrations and subsequent CV outcomes during a mean 3-year follow-up. METHODS: In this post hoc analysis of men with available baseline plasma T concentrations, we examined the relationship between clinical/demographic characteristics and T concentrations both as a continuous and dichotomous variable (<300 ng/dL ["low T"] vs. ≥300 ng/dL ["normal T"]) on rates of pre-specified CV outcomes, using Cox proportional hazards models. RESULTS: Among 2118 male participants in whom T concentrations were measured, 643 (30%) had low T and 1475 had normal T concentrations at baseline. The low T group had higher rates of diabetes mellitus, hypertension, elevated body mass index, metabolic syndrome, higher blood glucose, hemoglobin A1c, and triglyceride levels, but lower levels of both low-density lipoprotein and HDL-cholesterol, and a lower rate of prior myocardial infarction (MI). Men with low T had a higher risk of the primary composite outcome of coronary heart disease (CHD) death, MI, stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07, and a higher risk of the CHD death, MI, and stroke composite endpoint (11.8% vs. 8.2%; final adjusted HR 1.37, P = .04), respectively. CONCLUSIONS: In this post hoc analysis, there was an association between low baseline testosterone concentrations and increased risk of subsequent CV events in androgen-deficient men with established CV disease and metabolic syndrome, particularly for the composite secondary endpoint of CHD death, MI, and stroke. CONDENSED ABSTRACT: In this AIM-HIGH Trial post hoc analysis of 2118 men with metabolic syndrome and low HDL-cholesterol with available baseline plasma testosterone (T) samples, 643 males (30%) had low T (mean: 229 ng/dL) and 1475 (70%) had normal T (mean: 444 ng/dL) concentrations. The "low T" group had a 24% higher risk of the primary 5-component endpoint (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07). There was also a 31% higher risk of the secondary composite endpoint: coronary heart disease death, myocardial infarction, and stroke (11.8% vs. 8.2%, final adjusted HR 1.37, P = .04) in the low vs. normal T group, respectively.

Raltegravir pharmacokinetics before and during treatment with ombitasvir, paritaprevir/ritonavir plus dasabuvir in adults with human immunodeficiency virus-1 and hepatitis C virus coinfection: AIDS Clinical Trials Group sub-study A5334s.

AIMS: AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized. METHODS: Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV. RESULTS: Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV. CONCLUSIONS: The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide.

Novel transcripts from a distinct promoter that encode the full-length AKT1 in human breast cancer cells.

BACKGROUND: The serine-threonine kinase AKT1 plays essential roles during normal mammary gland development as well as the initiation and progression of breast cancer. AKT1 is generally considered a ubiquitously expressed gene, and its persistent activation is transcriptionally controlled by regulatory elements characteristic of housekeeping gene promoters. We recently identified a novel Akt1 transcript in mice (Akt1m), which is induced by growth factors and their signal transducers of transcription from a previously unknown promoter. The purpose of this study was to examine whether normal and neoplastic human breast epithelial cells express an orthologous AKT1m transcript and whether its expression is deregulated in cancer cells. METHODS: Initial sequence analyses were performed using the UCSC Genome Browser and GenBank to assess the potential occurrence of an AKT1m transcript variant in human cells and to identify conserved promoter sequences that are orthologous to the murine Akt1m. Quantitative RT-PCR was used to determine the transcriptional activation of AKT1m in mouse mammary tumors as well as 41 normal and neoplastic human breast epithelial cell lines and selected primary breast cancers. RESULTS: We identified four new AKT1 transcript variants in human breast cancer cells that are orthologous to the murine Akt1m and that encode the full-length kinase. These transcripts originate from an alternative promoter that is conserved between humans and mice. Akt1m is upregulated in the majority of luminal-type and basal-type mammary cancers in four different genetically engineered mouse models. Similarly, a subset of human breast cancer cell lines and primary breast cancers exhibited a higher expression of orthologous AKT1m transcripts. CONCLUSIONS: The existence of an alternative promoter that drives the expression of the unique AKT1m transcript may provide a mechanism by which the levels of AKT1 can be temporally and spatially regulated at particular physiological states, such as cancer, where a heightened activity of this kinase is required.

The two faces of Janus kinases and their respective STATs in mammary gland development and cancer.

Since its discovery as "just another kinase" more than twenty years ago, the family of JAK tyrosine kinases and their respective Signal Transducers and Activators of Transcription (STATs) has been a center of attention in the areas of signal transduction, development, and cancer. The subsequent designation of JAKs as Janus kinases after the mythical two-faced Roman God of the doorways accurately portrays the analogous and sometimes contrasting molecular and biological characteristics of these tyrosine kinases. The two "faces" of JAKs are their structurally similar kinase and pseudo-kinase domains. As essential parts of various transmembrane receptor complexes, these tyrosine kinases function at cellular gateways and relay signals from growth factors to their respective intracellular targets. The multifaceted nature of JAKs becomes evident from their ability to activate specific STATs during distinct phases of normal mammary gland development. Studies in breast cancer cells and genetically engineered mouse models also show that JAK/STAT signaling possesses a "two-faced" role during breast cancer initiation and progression. This review will highlight recent findings about important biological functions of JAKs and STATs during normal mammogenesis, with particular emphasis on the Jak2/Stat5 pathway as well as Jak1/2/Stat3 signaling complexes. In addition, we will discuss how the importance of these signaling networks changes during carcinogenesis. With JAK inhibitors currently under development to treat myeloproliferative disorders, determining the essential functions of JAKs at particular stages of disease initiation and progression is of critical importance to predict the efficacy of these agents for targeted therapies against breast cancer.

Compatibility and Safety Implications Associated with Interfacing Medical Devices in Neonatal Respiratory Care: A Case Example Using the Inhaled Nitric Oxide Delivery System.

Over the past decade, international organizations have instituted strict regulations for the safe use of connected medical devices. The International Organization for Standardization and the Medical Device Single Audit Program instituted certifications to ensure that connected devices are compatible and operate within their proper clinical parameters. These efforts came about, in part, as a consequence of clinicians' decisions to use nonstandard, modified, or improvised devices for purposes outside the original manufacturers' approved parameters. Unapproved device modifications can be associated with increased risk of dosing errors, monitoring errors, tubing misconnections and serious or potentially fatal adverse events; furthermore, health care providers who implement unapproved device modifications may assume legal and financial liability should harm come to patients as a consequence of the modification. Using the inhaled nitric oxide delivery system as an example, the objective of this paper is to raise awareness of the potential dangers associated with unapproved modification and interfacing of therapeutic gas delivery systems and ventilators in the neonatal intensive care unit setting. The paper also highlights the rationale and necessity for rigorous validation processes that ensure that interfaced medical devices perform as intended in the clinical setting.

Coproporphyrin I Can Serve as an Endogenous Biomarker for OATP1B1 Inhibition: Assessment Using a Glecaprevir/Pibrentasvir Clinical Study.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are involved in the disposition of a variety of commonly prescribed drugs. The evaluation of OATP1B1/1B3 inhibition potential by investigational drugs is of interest during clinical drug development due to various adverse events associated with increased exposures of their substrates. Regulatory guidance documents on the in vitro assessment of OATP1B1/1B3 inhibition potential are conservative with up to a third of predictions resulting in false positives. This work investigated the utility of OATP1B1/1B3 endogenous biomarkers, coproporphyrin (CP)-I and CP-III, to assess clinical inhibition of OATP1B1/1B3 and potentially eliminate the need for prospective clinical drug-drug interaction (DDI) studies. Correlations between CP-I exposures and various OATP1B1 static DDI predictions were also evaluated. Glecaprevir/pibrentasvir (GLE/PIB) 300/120 mg fixed-dose combination is known to cause clinical inhibition of OATP1B1/1B3. In a clinical study evaluating the relative bioavailability of various formulations of GLE/PIB regimen, CP-I peak plasma concentration (Cmax ) ratio and 0-16-hour area under the concentration-time curve (AUC0-16 ) ratio relative to baseline increased with increasing GLE exposures, whereas there was a modest correlation between GLE exposure and CP-III Cmax ratio but no correlation with CP-III AUC0-16 ratio. This suggests that CP-I is superior to CP-III as an endogenous biomarker for evaluation of OATP1B1 inhibition. There was a significant correlation between CP-I and GLE Cmax (R2  = 0.65; P < 0.001) across individual subjects. Correlation analysis between GLE OATP1B1 R values and CP-I exposures (Cmax ratio and AUC0-16 ratio) suggests that an R value of > 3 can predict a biologically meaningful inhibition of OATP1B1 when the inhibitor clinical pharmacokinetic parameters are available.

Optimizing Chronic Pain Treatment with Enhanced Neuroplastic Responsiveness: A Pilot Randomized Controlled Trial.

Chronic pain affects mental and physical health and alters brain structure and function. Interventions that reduce chronic pain are also associated with changes in the brain. A number of non-invasive strategies can promote improved learning and memory and increase neuroplasticity in older adults. Intermittent fasting and glucose administration represent two such strategies with the potential to optimize the neurobiological environment to increase responsiveness to recognized pain treatments. The purpose of the pilot study was to test the feasibility and acceptability of intermittent fasting and glucose administration paired with a recognized pain treatment activity, relaxation and guided imagery. A total of 32 adults (44% W, 56% M), 50 to 85 years of age, with chronic knee pain for three months or greater participated in the study. Four sessions were completed over an approximate two-week period. Findings indicate the ability to recruit, randomize, and retain participants in the protocol. The procedures and measures were reasonable and completed without incident. Participant adherence was high and exit interview feedback positive. In summary, the pilot study was feasible and acceptable, providing the evidence necessary to move forward with a larger clinical trial.

Effect of manual compressive therapy on latent myofascial trigger point pressure pain thresholds.

OBJECTIVE: This study compared the effects of 90 s of manual compressive therapy (MCT) on latent myofascial trigger points (LTPs) for 3 sessions per week for 4 weeks to determine changes in individual pressure pain threshold (PPT). A total of 30 (15 males, 15 females; age = 22 ±â€¯4 y/o, height = 175 ±â€¯18 cm, weight = 162.5 ±â€¯57.5 kg) symptomatic subjects with LTPs volunteered for the study. METHODS: PPT was measured at baseline and pre- and post-treatment for all 12 sessions with a pressure algometer across the 4-week treatment time frame. The MCT was applied to the control group on their LTP at pressure intended to provide a sham condition (1/10 on verbalized analog scale (VAS)). Two experimental groups had MCT applied either directly on the LTP (d-TP) or in close-proximity to their LTP (cp-TP) at moderate pressure (7/10 on VAS). RESULTS: There was a significant increase in PPT from the first through twelfth treatment sessions (p < 0.001, partial η2 = 0.914). A significant increase in PPTs between treatment groups was acutely observed from pre- to post-therapy tests (p = 0.001, partial η2 = 0.146). The differences between pre- versus post-treatment PPT measures indicated significant differences (d-TP vs. control, p < 0.001; cp-TP vs. control, p = 0.007). No differences were observed between experimental groups (p = 0.215). CONCLUSIONS: PPT continued to increase after several weeks of MCT when applied directly on or within 2.5 cm of an identified LTP compared to control.

Elagolix Pharmacokinetic Profiles in Women With Renal or Hepatic Impairment.

The aim of these studies was to assess the safety and pharmacokinetics of elagolix, an oral nonpeptide gonadotropin-releasing hormone antagonist following oral administration in women with renal or hepatic impairment. Two phase 1 studies were conducted in adult women with normal renal function versus renal impairment (reduced study), and normal hepatic function versus hepatic impairment (full study design). All women received a single dose of elagolix 200 mg (renal) or 150 mg (hepatic). Intensive pharmacokinetic blood samples were collected. Elagolix exposures were comparable in women with normal renal function and those with moderate/severe renal impairment or end-stage renal disease. Elagolix exposures also appeared to be similar in women with normal hepatic function and women with mild hepatic impairment. Elagolix area under the curve in women with moderate hepatic impairment and with severe hepatic impairment was approximately 3-fold and 7-fold higher than in women with normal hepatic function. The adverse event incidence was low, with the main events being mild nausea and headache. No dosage adjustment was needed in women with renal impairment or women with mild hepatic impairment. Although an elagolix dose of 150 mg once daily may be used in women with moderate hepatic impairment for up to 6 months, this elagolix dose should not be used in women with severe hepatic impairment.

Changes in outcomes (1996-2004) for pediatric oncology and hematopoietic stem cell transplant patients requiring invasive mechanical ventilation.

OBJECTIVE: To assess the following hypotheses regarding mechanically ventilated pediatric oncology patients, including those receiving hematopoietic stem cell transplant (HSCT) and those not receiving HSCT: 1) outcomes are more favorable for nontransplant oncology patients than for those requiring HSCT; 2) outcomes have improved for both populations over time; and 3) there are factors available during the time of mechanical ventilation that identify patients with a higher likelihood of dying. DESIGN: Retrospective review. SETTING: Free-standing, tertiary care, pediatric hematology oncology hospital. PATIENTS: All patients requiring invasive mechanical ventilation with a diagnosis of cancer or following HSCT from January 1996 to December 2004. INTERVENTIONS: Bivariate and multivariate analysis. Dates of admission were grouped into time periods for analysis: 1996-1998, 1999-2001, and 2002-2004. MEASUREMENTS AND MAIN RESULTS: There were 401 courses of mechanical ventilation (329 patients) analyzed. Forty-five percent of HSCT admissions (92 of 206) vs. 75% of non-HSCT oncology admissions (146 of 195) were extubated and discharged from the pediatric intensive care unit (p < .0001). Twenty-five percent of HSCT vs. 60% of non-HSCT admissions survived 6 months (p < .0001). Among admissions with an abnormal chest radiograph and a PaO2/FiO2 ratio <200, pediatric intensive care unit survival increased for each successive time period, with 45% of HSCT and 83% of non-HSCT admissions surviving during 2002-2004. In multivariate analysis of all study patients, Pediatric Risk of Mortality scores on the day of intubation, allogeneic HSCT, cardiovascular failure, hepatic failure, neurologic failure, a previous course of mechanical ventilation within 6 months, and the time period intubated were associated with mortality. With the exception of time period, these same variables were associated with mortality in multivariate analysis of only HSCT patients. CONCLUSIONS: HSCT patients who require mechanical ventilation have worse outcomes than non-HSCT oncology patients. Outcomes for both groups have improved over time. Allogeneic transplant, higher Pediatric Risk of Mortality scores, need for repeated mechanical ventilation, and concomitant organ system dysfunction are risk factors for death.

Induction of pro- and anti-inflammatory molecules in a mouse model of pneumococcal pneumonia after influenza.

Mortality after influenza is often due to secondary bacterial pneumonia with Streptococcus pneumoniae, particularly in the elderly. The reasons for the high fatality rate seen with this disease are unclear. To further characterize the pathogenesis of pneumonia after influenza in a mouse model, we examined the pathology and immunology that leads to fatal infection. Influenza-infected mice were either euthanized 24 h after secondary infection with S. pneumoniae for determination of pathology, bacterial cultures, and levels of immune effectors or were followed by use of a live imaging system for development of pneumonia. Influenza-infected mice challenged with each of 3 serotypes of pneumococcus developed a severe, necrotic pneumonia and met endpoints for euthanasia in 24 to 60 h. Strikingly elevated levels of both pro- and anti-inflammatory molecules including interleukins 6 and 10, macrophage inflammatory protein 1alpha, and chemokine KC were present in the blood. High levels of these cytokines and chemokines as well as tumor necrosis factor alpha, interleukin 1beta, and heme oxygenase 1 were present in the lungs, accompanied by a massive influx of neutrophils. Mortality correlated with the development of pneumonia and lung inflammation but not with bacteremia. This model has the potential to help us understand the pathogenesis of severe lung infections.

Outcome of severe sepsis in pediatric oncology patients.

OBJECTIVE: To describe survival to intensive care unit (ICU) discharge and 6-month survival in a large cohort of pediatric oncology patients with severe sepsis. DESIGN: Retrospective analysis. SETTING: The ICU of a single pediatric oncology center. PATIENTS: Patients with cancer admitted to the ICU of St. Jude Children's Research Hospital between January 1, 1990, and December 31, 2002, who met the following criteria: 1) severe sepsis by ACCP/SCCM (American College of Chest Physicians/Society of Critical Care Medicine) Consensus Conference criteria and 2) receipt of fluid boluses of > or =30 mL/kg to correct hypoperfusion or receipt of a dopamine infusion of >5 microg.kg.min for inotropic support. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data evaluated were demographic variables, oncologic diagnosis and time from diagnosis to ICU admission, Pediatric Risk of Mortality III score and absolute neutrophil count at admission, use of inotropes or pressors, use of mechanical ventilation, maximum organ system failure score, blood culture results, survival to ICU discharge, and 6-month survival. We identified 446 ICU admissions of 359 eligible patients. Overall ICU mortality was 76 of 446 (17%): 40 of 132 (30%) in post-bone marrow transplant (BMT) admissions and 36 of 314 (12%) in non-BMT admissions (p < .0001). In the 106 admissions requiring both mechanical ventilation and inotropic support, ICU mortality was 68 of 106 (64%). Regarding individual patients, 6-month survival was 170 of 248 (69%) among non-BMT patients vs. 43 of 111 (39%) for BMT patients (p < .001). When the 38 patients who survived to ICU discharge after requiring both mechanical ventilation and inotropic/vasopressor support are considered, 27 (71%) were alive 6 months after ICU discharge (22 of 27 [81%] non-BMT vs. 5 of 27 BMT [19%; p < .001]). ICU mortality varied by causative pathogen, from 63% for fungal sepsis (12 of 19) to 9% (5 of 53) for Gram-negative sepsis. Logistic regression analysis of factors significantly associated with ICU mortality in admissions requiring both mechanical ventilation and inotropic support identified four variables: BMT (odds ratio, 2.9; 95% confidence interval, 1.1-7.4; p = .03); fungal sepsis (odds ratio, 10.7; 95% confidence interval, 1.2-94.4; p = .03); use of multiple inotropes (odds ratio, 4.1; 95% confidence interval, 1.4-11.8; p = .01); and Pediatric Risk of Mortality III score (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; p = .04). CONCLUSIONS: In a large series of pediatric oncology patients with severe sepsis, ICU mortality was only 17% overall, although mortality remained quite high in the higher acuity patients. Mortality among the higher acuity patients was significantly associated with only a small number of variables. The number of patients alive at 6 months and the encouraging ICU survival rate further justifies the use of aggressive ICU interventions in this population.

Mouse models of breast cancer.

Breast cancer is the most common cause of cancer death in women worldwide. This malignancy is a complex disease, which is defined by an intrinsic heterogeneity on the histopathological and molecular level as well as response to therapy and outcome. In addition to classical histopathological features, breast cancer can be categorized into at least five major subtypes based on comprehensive gene expression profiling: luminal A, luminal B, basal-like, ERBB2-positive, and normal-like breast cancer. Genetically engineered mouse models can serve as tools to study the molecular underpinnings for this disease. Given the genetic complexity that drives the initiation and progression of individual breast cancer subtypes, it is evident that certain models can reflect only particular aspects of this malignancy. In this book chapter, we will primarily focus on advances in modeling breast cancer at defined stages of carcinogenesis using genetically engineered mice. We will discuss the ability as well as shortcomings of these models to faithfully recapitulate the spectrum of human breast cancer subtypes.

Late-onset delayed excretion of methotrexate.

Pleural effusions, ascites, and renal dysfunction decrease the plasma excretion of methotrexate (MTX). However, it is not known what effect these complications have on MTX clearance when they arise after the plasma MTX concentration has fallen to an undetectable level. We describe the clinical course and pharmacokinetics of MTX in a patient with acute lymphoblastic leukemia who experienced pleural effusions, ascites, and renal failure during the weeks after treatment with high-dose MTX (1.63 g/m2 i.v. over 24 h). The patient's normal initial MTX clearance rate (107 ml/min/m2) was consistent with his undetectable plasma level of MTX on day 9 after the infusion. His plasma MTX concentration then gradually increased as his renal function declined, reaching a peak of 0.72 microM on day 15. This unusual finding of an undetectable plasma MTX concentration that subsequently rose to persistent, potentially toxic levels was explained only by a pharmacokinetic model that accounted both for a third space at the time of treatment and for the subsequent decrease in the systemic elimination rate. Therefore, the finding of a physiologic third space during MTX administration combined with the detection of renal dysfunction in the following weeks should be an indication for prolonged therapeutic drug monitoring.

Heme oxygenase-1 messenger RNA expression is induced in peripheral blood mononuclear cells of pediatric cancer patients with systemic inflammatory response syndrome.

OBJECTIVE: To determine whether heme oxygenase-1 messenger RNA expression in peripheral blood mononuclear cells is induced in pediatric cancer patients with the systemic inflammatory response syndrome (SIRS) and whether this expression correlates with the heme oxygenase-1 products, bilirubin and carboxyhemoglobin. DESIGN: Prospective, controlled study. SETTING: A tertiary care pediatric oncology hospital. PATIENTS: Fourteen patients admitted to the intensive care unit with a diagnosis of SIRS by American College of Chest Physicians/Society for Critical Care Medicine consensus criteria and 17 control patients (off therapy, no acute illness). INTERVENTIONS: Blood for bilirubin, carboxyhemoglobin, and heme oxygenase-1 messenger RNA expression was collected at study entry. SIRS patients continued to have samples collected every 12 hrs for 1 wk or until intensive care unit discharge. Heme oxygenase-1, bilirubin, and carboxyhemoglobin levels of SIRS patients were compared with controls, and correlation between heme oxygenase-1 and products was assessed. MEASUREMENTS AND MAIN RESULTS: Within 48 hrs of study entry, maximum heme oxygenase-1 expression for all SIRS patients compared with controls was 5.5 +/- 1.0 vs. 1.1 +/- 0.1 (p < .0006). Maximum expression was > or =2.3-fold in 13 of 14 SIRS patients. Maximum heme oxygenase-1 expression also differed from minimum (5.5 +/- 1.0 vs. 1.6 +/- 0.3, p < .003). Maximum bilirubin and carboxyhemoglobin levels within 48 hrs of study entry differed between SIRS patients and controls (3.0 +/- 0.8 vs. 0.3 +/- 0.1, p = .006; and 1.2 +/- 0.2 vs. 0.6 +/- 0.1, p = .001, respectively). Bilirubin, but not carboxyhemoglobin, correlated with heme oxygenase-1 expression (p = .0013). CONCLUSIONS: Heme oxygenase-1 messenger RNA, bilirubin, and carboxyhemoglobin levels were increased within 48 hrs of admission in pediatric cancer patients with SIRS. Heme oxygenase-1 expression correlated with serum bilirubin levels. The increase in heme oxygenase-1 expression may add to the understanding of the increase in serum bilirubin observed in patients with SIRS/sepsis. These findings support a role for heme oxygenase-1 in the physiologic response to inflammatory stress.

Does point-of-purchase nutrition labeling influence meal selections? A test in an Army cafeteria.

OBJECTIVE: This study assessed the effectiveness of nutrition labeling on sales of targeted entrees and measured the perceived influence that factors such as taste, quality, appearance, fat content, calorie content, and price had on meal selection behavior within an Army cafeteria. METHODS: A quasi-experimental design was used to compare targeted entrée sales between a 1-year baseline period and two 30-day postintervention periods, after the placement of entrée nutrition labels. A brief questionnaire, distributed to 149 patrons, measured the perceived influence of the aforementioned factors on selections. RESULTS: Analysis of variance detected no significant differences in sales between baseline and the two intervention periods; the factors of taste and quality were rated most influential to meal selection (p < 0.000). CONCLUSIONS: A marketing campaign focusing on the health attributes of targeted entrée items was not successful in boosting sales. Sensory attributes (i.e., taste, quality, and appearance) appear to be more influential to meal selection.

Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis.

Stat5 (signal transducer and activator of transcription 5) is an essential mediator of cytokine receptor signaling and plays important roles in the proliferation of alveolar progenitors and the survival of functionally differentiated epithelial cells in the mammary gland. A deregulated expression and activation of Stat5 leads to precocious alveolar development in the absence of pregnancy hormones, impaired mammary gland remodeling following the cessation of lactation, and mammary tumor formation. We reported previously that Stat5 induces the transcription of the Akt1 gene from a novel promoter. In this report, we provide experimental evidence that Akt1 is an essential mediator for the biological function of Stat5 as a survival factor. Additionally, Stat5 controls the expression of the regulatory and catalytic subunits of the phosphatidylinositol 3-kinase (PI3K) (p85α and p110α), thereby greatly augmenting signaling through the prosurvival PI3K/Akt pathway. In agreement with this model, we observed that the constitutive activation of Stat5 cooperates with the loss of function of the tumor suppressor PTEN by accelerating the formation of preneoplastic lesions and mammary tumors. The mammary gland-specific ablation of Stat5 is sufficient to prevent mammary carcinogenesis in a genuine mouse model for Cowden syndrome. Therefore, targeting the Jak2/Stat5 pathway might be a suitable strategy to prevent breast cancer in patients that carry a mutant PTEN allele.

Comparative reliability of the make and break tests for hip abduction assessment.

OBJECTIVE: To investigate the reliability of "make test" (MT) and "break test" (BT) of hip abduction using hand-held dynamometry. DESIGN: A repeated measures reliability assessment design for the estimation of inter-rater reliability, in which pairs of testers rated each subject in a 2/3 fractional factorial was used. Both tests ("BT" and "MT") were performed on both legs twice by 2 testers, for a total of 16 ratings for each participant. PARTICIPANTS: 39 healthy subjects between the ages of 21 and 70 years old volunteered. MAIN OUTCOME MEASURE: Variance components were computed from the repeated measures to assess inter-rater reliability of measurement. Reliability was estimated as a ratio of variance components. RESULTS: Both tests proved to be highly reliable in nature with values above 0.87 overall. Further examination revealed that gender had a small effect on reliability, yet differences in results were noted between raters on the BT more than the MT. CONCLUSIONS: Hip abduction strength can be measured and reproduced between testers reliably using both a "MT" and "BT" and a long lever arm with pelvic stabilization. Statistically, the "MT" appears to be slightly more reliable than the "BT", but clinically, the "BT" is more practical and convenient.

Gain-of-function of Stat5 leads to excessive granulopoiesis and lethal extravasation of granulocytes to the lung.

The Signal Transducer and Activator of Transcription 5 (Stat5) plays a significant role in normal hematopoiesis and a variety of hematopoietic malignancies. Deficiency in Stat5 causes impaired cytokine-mediated proliferation and survival of progenitors and their differentiated descendants along major hematopoietic lineages such as erythroid, lymphoid, and myeloid cells. Overexpression and persistent activation of Stat5 are sufficient for neoplastic transformation and development of multi-lineage leukemia in a transplant model. Little is known, however, whether a continuous activation of this signal transducer is essential for the maintenance of hematopoietic malignancies. To address this issue, we developed transgenic mice that express a hyperactive mutant of Stat5 in hematopoietic progenitors and derived lineages in a ligand-controlled manner. In contrast to the transplant model, expression of mutant Stat5 did not adversely affect normal hematopoiesis in the presence of endogenous wildtype Stat5 alleles. However, the gain-of-function of this signal transducer in mice that carry Stat5a/b hypomorphic alleles resulted in abnormally high numbers of circulating granulocytes that caused severe airway obstruction. Downregulation of hyperactive Stat5 in diseased animals restored normal granulopoiesis, which also resulted in a swift clearance of granulocytes from the lung. Moreover, we demonstrate that Stat5 promotes the initiation and maintenance of severe granulophilia in a cell autonomous manner. The results of this study show that the gain-of-function of Stat5 causes excessive granulopoiesis and prolonged survival of granulocytes in circulation. Collectively, our findings underline the critical importance of Stat5 in maintaining a normal balance between myeloid and lymphoid cells during hematopoiesis, and we provide direct evidence for a function of Stat5 in granulophilia-associated pulmonary dysfunction.