As-needed use of fluticasone propionate nasal spray reduces symptoms of seasonal allergic rhinitis

BACKGROUND: The daily use of intranasal corticosteroids is approved for the treatment of seasonal allergic rhinitis. OBJECTIVE: Our objective was to test the effectiveness of as-needed use of intranasal corticosteroids in the treatment of seasonal allergic rhinitis. METHODS: A double-blind, placebo-controlled, randomized, parallel-group study of the as-needed usage of fluticasone propionate nasal spray in the management of seasonal allergic rhinitis was performed. Outcome measures were symptom score, Rhinitis Quality of Life Questionnaire (RQLQ), and the number of eosinophils and the level of eosinophilic cationic protein (ECP) in nasal lavage. RESULTS: Twenty-six subjects in each group completed the 4-week study. The median symptom score over the duration of the study in the placebo group was 8.5 versus 4.5 in the active group. The active group had significant improvement on the interim visit in the sleep, non-nose/eye, activities, nasal, practical, and overall domains (P <.05) of the RQLQ and on the final visit in the nasal symptom domain. The number of eosinophils was significantly lower in the active than in the placebo group at the final visit. Changes in ECP were not significant. CONCLUSION: As-needed fluticasone propionate nasal spray is efficacious in the treatment of seasonal allergic rhinitis.     

Fluoxetine-maintained obese humans: effect on food intake and body weight

The effects of fluoxetine on food intake, body weight, and mood of obese individuals was examined in a 16-week inpatient/outpatient study. Six male and eight female obese volunteers began the study (four male and five females completed all phases of the study). They lived in a residential laboratory during three one-week inpatient periods separated by a 5-week and an 8-week outpatient period. Following an initial 4-day placebo baseline, participants were maintained on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters (total daily energy intake, macronutrient intake, mean number of eating bouts, interbout interval), body weight, subjective effects, and task performance were measured several times during the day during inpatient periods; food intake questionnaires were completed daily during the outpatient periods. Fluoxetine significantly reduced daily energy intake derived from fat, carbohydrate, and protein by decreasing the mean number of eating bouts per day throughout the study. No other food intake parameter was affected. Body weight was significantly reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration. These results indicate that fluoxetine reduced food intake for at least 16 weeks in nondepressed obese individuals without specifically affecting carbohydrate intake. Weight that was lost during the first few weeks of daily fluoxetine administration was subsequently regained even though food intake remained reduced. Therefore, fluoxetine maintenance does not appear promising as a sole long-term therapy for obesity.     

Host-mediated effectors of tumor invasion: role of mast cells in matrix degradation

The role of collagenolytic enzymes in tumor invasion and metastasis has been emphasized, but the source of enzyme activity has remained unclear. Degradation of stromal connective tissue is a common feature of invasive neoplasia, and host-tumor cell interactions are probably important for localized collagenolysis. We have examined the role of mast cells in malignant cell invasion using cells derived from the rat mammary adenocarcinoma 13762NF. Histologic studies have shown increased numbers of mast cells at the zone of tumor invasion. Mast cell products and conditioned medium from such cells stimulated the production of collagenolytic enzymes by stromal fibroblasts as well as certain subpopulations of tumor cells in vitro. The tumor cell response to mast cell-mediated stimulation of collagenolysis appears to be related to the metastatic potential of the tumor cell. A subpopulation of host fibroblasts derived from the invading tumor zone was also found to be more responsive to mast cell factors than normal fibroblasts, as judged by collagenase production. Thus the mast cell has the potential to induce collagenolytic activity from both host fibroblasts and tumor cells.     

The effect of leuprolide acetate on ovulation induction with human menopausal gonadotropins in polycystic ovary syndrome

The use of exogenous gonadotropins for treatment of clomiphene-resistant chronic anovulation in women with the polycystic ovary syndrome (PCO) is hazardous and often ineffective, possibly because of the abnormal endogenous gonadotropin secretion characteristic of PCO. We evaluated the effect of leuprolide acetate, a long-acting GnRH agonist, on serum gonadotropin and sex steroid concentrations before and during human menopausal gonadotropin (hMG) induction of ovulation in women with PCO. In this controlled prospective randomized study, leuprolide was administered daily for 4 weeks, followed by concomitant hMG administration. Gonadotropin and steroid hormone concentrations were compared with those during ovulation induction cycles in women with PCO receiving hMG only. Daily administration of leuprolide for 4 weeks resulted in significantly decreased serum LH, estradiol, and testosterone concentrations, but no change in serum progesterone, FSH, and dehydroepiandrosterone sulfate. Compared to ovulation induction using hMG alone, leuprolide administration before and during hMG treatment prevented preovulatory rises in serum LH and P concentrations, while having no effect on serum FSH, testosterone, estradiol, and dehydroepiandrosterone sulfate. We conclude that leuprolide administered to women with PCO decreases gonadal steroid production and is capable of preventing premature luteinization during hMG induction of ovulation.     

Medical, psychological and social correlates of work disability among men with coronary artery disease

This study identifies the medical, psychologic and social factors that independently affect employment in patients with coronary artery disease (CAD). At coronary angiography, extensive clinical, psychological and social profiles were collected on 814 men younger than 60 years with documented CAD. Clinical factors studied included measures of symptom severity, prior myocardial infarction, coronary anatomy and left ventricular function. Psychosocial factors studied included the Minnesota Multiphasic Personality Inventory (MMPI), Zung Depression and Anxiety Scales, a type A structured interview, Jenkins Activity Survey and measures of education and social support. Multiple logistic regression analyses were used to assess the relative strength of the relation between these different factors and the patients' employment status. Many single factors differed between the 204 men (25%) who were disabled and the 610 (75%) who were not. Disabled men were less educated but no different in age, marital status or number of dependents. Disabled men had lower ejection fractions and higher indexes of angina, previous myocardial infarction and coexisting vascular disease. Disabled men also were more depressed and anxious and had lower ego strength and higher hypochondriasis scores on the MMPI, but were no different in type A behavior. By multivariable analysis, the most significant (p less than 0.01) independent predictors of work disability were, in decreasing order of importance, low education level, history of myocardial infarction, high levels of depression and high levels of hypochondriasis. It is concluded that psychological and social factors are strongly related to work status in patients with CAD, and may be more important than medical factors.     

Conservative versus liberal oxygenation targets in critically ill children: the randomised multiple-centre pilot Oxy-PICU trial

Background

Oxygen saturation monitoring for children receiving respiratory support is standard worldwide. No randomised clinical trials have compared peripheral oxygen saturation (SpO₂) targets for critically ill children. The harm of interventions to raise SpO₂ to >?94% may exceed their benefits.

Methods

We undertook an open, parallel-group randomised trial of children >?38 weeks completed gestation and <?16 years of age receiving invasive or non-invasive respiratory support and supplemental oxygen who were admitted urgently to one of three paediatric intensive care units. A ‘research without prior consent’ approach was employed. Children were randomly assigned to a liberal oxygenation group (SpO₂ targets >?94%) or a conservative oxygenation group (SpO₂ = 88–92% inclusive). Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between-group separation of SpO₂ and safety. The Oxy-PICU trial was registered before recruitment: ClinicalTrials.gov identifier NCT03040570.

Results

A total of 159 children met the inclusion criteria, of whom 119 (75%) were randomised between April and July 2017, representing a rate of 10 patients per month per site. The mean time to randomisation from first contact with an intensive care team was 1.9 (SD 2.2) h. Consent to continue in the study was obtained in 107 cases (90%); the children’s parents/legal representatives were supportive of the consent process. The median (interquartile range, IQR) of time-weighted individual mean SpO₂ was 94.9% (92.6–97.1) in the conservative oxygenation group and 97.5% (96.2–98.4) in the liberal group [difference 2.7%, 95% confidence interval (95% CI) 1.3–4.0%, p?<?0.001]. Median (IQR) time-weighted individual mean FiO₂ was 0.28 (0.24–0.37) in the conservative group and 0.37 (0.30–0.42) in the liberal group (difference 0.08, 95% CI 0.03–0.13, p?<?0.001). There were no significant between-group differences in length of stay, duration of organ support or mortality. Two prespecified serious adverse events (cardiac arrests) occurred, both in the liberal oxygenation group.

Conclusion

A definitive clinical trial of peripheral oxygen saturation targets is feasible in critically ill children.

     

Femoral Volumetric Bone Density,Geometry, and Strength in Relation to 25‐Hydroxy Vitamin D in Older Men

Low serum 25‐hydroxy vitamin D (25(OH)D) concentrations are associated with increased hip fracture risk and decreased femoral areal bone mineral density (BMD) among elderly men. Structural dimensions of the proximal femur and volumetric BMD in cortical and trabecular compartments are also associated with hip fracture risk. However, associations of volumetric BMD or structural dimensions with serum 25(OH)D concentrations among older men remain unclear. In a random sample of 1608 men aged ≥65 years from the Osteoporotic Fractures in Men Study (MrOS), baseline serum 25(OH)D concentrations were measured by liquid chromatography/mass spectrometry assays. Femoral neck geometry and volumetric BMD derived from quantitative computed tomography included integral, cortical, and trabecular volumetric BMD; cross‐sectional area; integral and cortical volume; and cortical volume as a percent of integral volume. We studied 888 men with vitamin D, parathyroid hormone (PTH), femoral neck geometry, and BMD measures. Whole‐bone femoral strength and load‐strength ratio from finite element (FE) analysis were also available for 356 men from this sample. Multivariable linear regression was used to estimate least square means of each femoral measure within quartiles of 25(OH)D adjusted for age, race, body mass index, height, latitude, and season of blood draw. Tests of linear trend in the means were performed across increasing quartile of serum 25(OH)D levels. Mean cortical volume (p trend = 0.006) and cortical volume as a percent of integral volume (p trend < 0.001) increased across increasing quartile of 25(OH)D level. However, overall femoral neck size (area and integral volume) did not vary by 25(OH)D level. Femoral neck volumetric BMD measures increased in a graded manner with higher 25(OH)D levels (p trend < 0.001). Femoral strength, but not load‐strength ratio, increased with increasing 25(OH)D. Adjustment for PTH did not materially change these associations. We conclude that in older men, higher levels of endogenous 25(OH)D may increase whole‐bone strength by increasing femoral volumetric BMD and cortical volume. © 2014 American Society for Bone and Mineral Research.     

Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance,epidemiology, and end results registry from 1998 to 2008

We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1‐T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five‐year cancer‐specific survival (CSS) and overall survival (OS) were analyzed using propensity‐score adjusted Cox proportional‐hazard models. Overall 5‐year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3–20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8–42.5%, P = 0.01) and radiation alone (29.3–44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.     

Controversies in translational research: drug self-administration

RATIONALE: Laboratory animal and human models of drug self-administration are used to evaluate potential pharmacotherapies for drug abuse, yet the utility of these models in predicting clinically useful medications is variable. OBJECTIVE: The objective of this study was to track how antagonist, agonist, and partial agonist medication approaches influence heroin and cocaine self-administration by rodents, non-human primates, and humans and to compare these results to clinical outcomes. RESULTS: Across species, heroin self-administration was decreased by all three medication approaches, paralleling their demonstrated clinical utility. The heroin data emphasize the importance of assessing a medication's abuse liability preclinically to predict medication abuse and compliance and of considering subject characteristics (e.g., opioid dependence) when interpreting medication effects. For cocaine, the effects of ecopipam, modafinil, and aripiprazole were consistent in the laboratory and clinic, provided that the medications were administered repeatedly before self-administration sessions. Modafinil attenuated cocaine's reinforcing effects in the human laboratory and improved treatment outcome, while ecopipam and aripiprazole increased the reinforcing effects of cocaine and do not appear promising in the clinic. CONCLUSIONS: The self-administration model has reliably identified medications to treat opioid dependence, and the recent data with modafinil suggest that the human laboratory model also identifies medications to treat cocaine dependence. There have been numerous false positives when subjective effects are the primary outcome measure, but not when self-administration is the outcome. Factors relevant to the predictive validity of self-administration procedures include medication maintenance and the concurrent assessment of a range of behaviors to determine abuse liability and the specificity of effect.     

A thiazolidinedione improves in vivo insulin action on skeletal muscle glycogen synthase in insulin-resistant monkeys

Thiazolidinediones (TZD) have been shown to have anti-diabetic effects including the ability to decrease fasting hyperglycemia and hyperinsulinemia, increase insulin-mediated glucose disposal rate (M) and decrease hepatic glucose production, but the mechanisms of action are not well established. To determine whether a TZD (R-102380, Sankyo Company Ltd., Tokyo, Japan) could improve insulin action on skeletal muscle glycogen synthase (GS), the rate-limiting enzyme in glycogen synthesis, 4 insulin-resistant obese monkeys were given 1 mg/kg/day R-102380 p.o. for a 6-week period. Skeletal muscle GS activity and glucose 6-phosphate (G6P) content were compared between pre-dosing and dosing periods before and during the maximal insulin-stimulation of a euglycemic hyperinsulinemic clamp. Compared to pre-dosing, insulin-stimulated GS activity and G6P content were increased by this TZD: GS independent activity (p = 0.02), GS total activity (p = 0.005), GS fractional activity (p = 0.06) and G6P content (p = 0.02). The change in GS activity induced by in vivo insulin (insulin-stimulated minus basal) was also increased by this TZD: GS independent activity (p = 0.03) and GS fractional activity (p = 0.04). We conclude that the TZD R-102380 improves insulin action at the skeletal muscle in part by increasing the activity of glycogen synthase. This improvement in insulin sensitivity may be a key factor in the anti-diabetic effect of the thiazolidinedione class of agents.