A theoretical model of linearly filtered reverberation for pulsed active sonar in shallow water.

This paper presents a statistical model useful for characterizing pulsed active sonar reverberation in shallow water. The model is based on the fundamental assumption that reverberation consists of echoes from point scatterers having random positions, strengths, and Doppler dilations. Receive array beam patterns, simple propagation losses, and planar bistatic geometry are included. The probability distribution of uniformly dense scatterers as a function of echo delay and bearing is explicitly related to the change in the area from which scatterer echoes contribute to the reverberation, and is presented in closed form. The cross Q-function of the transmitted waveform and the linear filter applied to the received signal arises naturally from the development. This function, along with environmental spreading, determines the shape of the reverberation along the Doppler axis. The assumptions and simplifications under which the reverberation decouples into independent spatial (delay and bearing) and Doppler terms are presented.

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc.

Venous thromboembolism after surgery for inflammatory bowel disease: are there modifiable risk factors? Data from ACS NSQIP.

BACKGROUND: Although it is commonly reported that IBD patients are at increased risk for venous thromboembolic events, little real-world data exist regarding their postoperative incidence and related outcomes in everyday practice. OBJECTIVE: We aimed to identify the rate of venous thromboembolism and modifiable risk factors within a large cohort of surgical IBD patients. DESIGN: We performed a retrospective review of IBD patients who underwent colorectal procedures. PATIENTS: Patient data were obtained from the American College of Surgeons National Surgical Quality Improvement Program 2004 to 2010 Participant Use Data Files. MAIN OUTCOME MEASURES: The primary outcomes measured were short-term (30-day) postoperative venous thromboembolism (deep vein thrombosis and pulmonary embolism). Clinical variables were analyzed by univariate and multivariate analyses to identify modifiable risk factors for these events. RESULTS: A total of 10,431 operations were for Crohn's disease (52.1%) or ulcerative colitis (47.9%), and 242 (2.3%) venous thromboembolic events occurred (178 deep vein thromboses, 46 pulmonary embolisms, 18 both) for a combined rate of 1.4% in Crohn's disease and 3.3% in ulcerative colitis. Deep vein thrombosis and pulmonary embolism each occurred at a mean of 10.8 days postoperatively (range for each, 0-30 days). A multivariate model found that bleeding disorder, steroid use, anesthesia time, emergency surgery, hematocrit <37%,malnutrition, and functional status were potentially modifiable risk factors that remained associated (p < 0.05) with venous thromboembolism on regression analysis. Patients with thromboembolism had longer length of stay (18.8 vs 8.9 days), more complications (41% vs 18%), and a higher risk of death (4% vs 0.9%). LIMITATIONS: This study was limited by its retrospective design and its limited generalizability to nonparticipating hospitals. CONCLUSIONS: Inflammatory bowel disease patients are at increased risk for postoperative venous thromboembolism. Reducing preoperative anemia, steroid use, malnutrition, and anesthesia time may also reduce venous thromboembolism in this at-risk population. Risk-reducing, preventative strategies are needed in this at-risk population.

Biosynthesis of a linoleic acid allylic epoxide: mechanistic comparison with its chemical synthesis and leukotriene A biosynthesis.

Biosynthesis of the leukotriene A (LTA) class of epoxide is a lipoxygenase-catalyzed transformation requiring a fatty acid hydroperoxide substrate containing at least three double bonds. Here, we report on biosynthesis of a dienoic analog of LTA epoxides via a different enzymatic mechanism. Beginning with homolytic cleavage of the hydroperoxide moiety, a catalase/peroxidase-related hemoprotein from Anabaena PCC 7120, which occurs in a fusion protein with a linoleic acid 9R-lipoxygenase, dehydrates 9R-hydroperoxylinoleate to a highly unstable epoxide. Using methods we developed for isolating extremely labile compounds, we prepared and purified the epoxide and characterized its structure as 9R,10R-epoxy-octadeca-11E,13E-dienoate. This epoxide hydrolyzes to stable 9,14-diols that were reported before in linoleate autoxidation (Hamberg, M. 1983. Autoxidation of linoleic acid: Isolation and structure of four dihydroxy octadecadienoic acids. Biochim. Biophys. Acta 752: 353-356) and in incubations with the Anabaena enzyme (Lang, I., C. Göbel, A. Porzel, I. Heilmann, and I. Feussner. 2008. A lipoxygenase with linoleate diol synthase activity from Nostoc sp. PCC 7120. Biochem. J. 410: 347-357). We also prepared an equivalent epoxide from 13S-hydroperoxylinoleate using a "biomimetic" chemical method originally described for LTA(4) synthesis and showed that like LTA(4), the C18.2 epoxide conjugates readily with glutathione, a potential metabolic fate in vivo. We compare and contrast the mechanisms of LTA-type allylic epoxide synthesis by lipoxygenase, catalase/peroxidase, and chemical transformations. These findings provide new insights into the reactions of linoleic acid hydroperoxides and extend the known range of catalytic activities of catalase-related hemoproteins.

Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma?

RATIONALE: Little is known about the use of biomarkers in guiding treatment decisions in routine asthma management. The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness (BHR) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR. METHODS: After a 2-week run-in period, subjects (> or = 12 years) were randomized to one of three treatment groups. Two groups followed a BHR treatment strategy (based on clinical parameters [lung function, asthma symptoms, and bronchodilator use] and BHR) and were treated with either fluticasone propionate/salmeterol (FSC(BHR) group) or fluticasone propionate (FP(BHR) group) (n=156 each). The third group followed a clinical treatment algorithm (based on clinical parameters alone) and were treated with fluticasone propionate (FP(REF) group; n=154). All treatments were administered via Diskus. Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subject's derived severity class, which was based on clinical measures of asthma control with or without BHR. RESULTS: The mean total daily inhaled corticosteroids (ICS) dose during the double-blind treatment period was lower, although not statistically significant, in the FSC(BHR) group compared with the FP(BHR) group (a difference of -42.9 mcg; p=0.07). Compared with the FP(REF) group, the mean total daily ICS dose was higher in the FSC(BHR) group (a difference of 85.2 mcg) and was significantly higher in the FP(BHR) group (a difference of 131.2 mcg, p=0.037). CONCLUSION: This study demonstrated that for most subjects, control of BHR was maintained when treatment was directed toward control of clinical parameters. In addition, there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol.

Alternative medical treatment strategies for chronic hyperplastic eosinophilic sinusitis.

PURPOSE OF REVIEW: Chronic rhinosinusitis (CRS) is one of the most common chronic illnesses in the United States. Although CRS has been viewed traditionally as an infectious disease, treatment focused on antibiotics and surgery has not infrequently provided disappointing results. RECENT FINDINGS: Recently much of CRS has been shown to be an eosinophilic inflammatory disease and new anti-inflammatory treatments are being studied. SUMMARY: This review discusses medical management for chronic hyperplastic eosinophilic sinusitis, including antifungal treatment, low-dose macrolide treatment, antilipid mediator therapy, and new immune-modifying treatments.

Efficacy and safety of a novel, single-dose azithromycin microsphere formulation versus 10 days of levofloxacin for the treatment of acute bacterial sinusitis in adults.

OBJECTIVE: To compare the efficacy and safety of a single 2.0-g dose of a novel azithromycin microsphere formulation with that of 10 days of levofloxacin, 500 mg/d, when used to treat adults with uncomplicated acute bacterial maxillary sinusitis (ABS). STUDY DESIGN AND SETTING: An international, multicenter, randomized, double-blind, double-dummy trial. Eligible outpatients > or =18 years of age with clinical and radiographic evidence of ABS underwent maxillary sinus aspiration before randomization. Primary endpoint was clinical efficacy at the test-of-cure visit (day 17-24). RESULTS: Clinical success rates were 94.5% (242/256) in azithromycin-microspheres-treated patients and 92.8% (233/251) in the levofloxacin group. In patients with documented Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis, clinical cure rates were 97.3% (36/37), 96.3% (26/27), and 100% (8/8), respectively, for the azithromycin group and 92.3% (36/39), 100% (30/30), and 90.9% (10/11), respectively, for the levofloxacin group. CONCLUSIONS: Single-dose azithromycin microspheres provided clinical and bacteriologic efficacy and safety comparable to 10 days of levofloxacin. SIGNIFICANCE: A novel microsphere formulation of azithromycin given as a single dose was safe and effective for the treatment of ABS.

Asthma and rhinosinusitis.

Allergic rhinoconjunctivitis and asthma are becoming more common in industrialized societies, particularly in the second and third decades of life, when those affected are at a vital stage of their education and career. It is therefore of paramount importance that the treatment options available be effective, improve quality of life, and above all, they must be without any significant unwanted effects. National and international guidelines for the treatment of both allergic rhinitis and asthma have been released recently that put forward recommendations based on an extensive evidence-based review of the literature for the care of these diseases that would meet these goals of disease management.

Risk factors for dental erosion in 5-6 year old and 12-14 year old boys in Saudi Arabia.

MATERIAL AND METHODS: Dental examinations were carried out on 354 boys aged 5-6 years, and 862 boys aged 12-14 years, attending 40 schools in Riyadh. The prevalence of dental erosion was assessed using diagnostic criteria similar to those employed in the 1993 UK National Survey of Child Dental Health. RESULTS: Pronounced dental erosion (into dentine or dentine and pulp) was observed in 34% of 5-6 year olds and 26% of 12-14 year olds. Information on food and drink consumed and dietary habits was obtained by means of a questionnaire. Parents reported that 65% of 5-6 year old boys took a drink to bed. Water was the commonest drink consumed (37%) followed by carbonated soft drinks (21%). One third of parents reported that their son had something to eat in bed or during the night and 60% of this was sweet food or confectionery. Seventy per cent of 12-14 year old boys reported consuming drinks at night; these were mainly water (30%), carbonated soft drinks (27%) and tea or coffee, with sugar (18%). Forty-six per cent of the 12-14 year olds reported that they ate in bed at least once a week and 54% of this was sweet food or confectionery. When the dental examination and questionnaire results were correlated, a statistically significant relationship was found between the number of primary maxillary incisors with pronounced erosion of their palatal surfaces and the consumption of carbonated soft drinks at night (P=0.015). A significant relationship was also found between the number of permanent maxillary incisors with pronounced erosion on their palatal surfaces and the frequency of drinks at night (P=0.020), as well as the duration of drinks retained in the mouth (P=0.038). CONCLUSION: It is concluded that dental erosion is more common in the primary and permanent dentitions of Saudi Arabian boys compared with results for similar age groups from the United Kingdom.

30 years of preventive dentistry--and 30 years into the future.

Preventive dentistry has had a major impact on the prevalence of dental caries and, to a lesser extent, periodontal disease since the 1970s. It should continue to have a positive effect on the oral health of the community in the future. The factors behind improvements seen in oral health are many and varied but include changes in public health policy, technology and commercial decisions made in the industrial sector. As oral health has improved, and tooth retention increased, the focus of preventive dentistry has widened to include all population groups, increasingly including older adults, and to include a wider range of disorders. The major issues relevant to preventive dentistry which have occurred over the last 30 years are discussed. The authors will speculate on the impact that the prevention of oral disease might have over the next 30 years.

Milk alkali and hydrochlorothiazide: a case report.

Hypercalcemia is a relatively common clinical problem in both outpatient and inpatient settings. Primary pathophysiology is the entry of calcium that exceeds its excretion into urine or deposition in bone into circulation. Among a wide array of causes of hypercalcemia, hyperparathyroidism and malignancy are the most common, accounting for greater than 90 percent of cases. Concordantly, there has been a resurgence of milk-alkali syndrome associated with the ingestion of large amounts of calcium and absorbable alkali, making it the third leading cause of hypercalcemia (Beall and Scofield, 1995 and Picolos et al., 2005). This paper centers on a case of over-the-counter calcium and alkali ingestion for acid reflux leading to milk alkali with concordant use of thiazide diuretic for hypertension.

Evaluation of fluticasone propionate and fluticasone propionate/salmeterol combination on exercise in pediatric and adolescent patients with asthma.

OBJECTIVE: This study was designed to demonstrate that four weeks of fluticasone propionate (FP) 100 micrograms (mcg) combined with salmeterol 50 mcg twice daily (BID) via DISKUS(®) resulted in protection against bronchospasm induced by activity, as measured by standardized exercise challenge testing in pediatric and adolescent subjects who required regular use of inhaled corticosteroids for the treatment of persistent asthma. METHODS: Prior to study entry, all patients reported regular use of inhaled corticosteroids (ICS). During screening all patients demonstrated ≥20% fall in FEV(1) following exercise. RESULTS: A total of 231 subjects aged 4 to 17 were randomized to the two study treatments: 113 to the FP/salmeterol combination group (FSC) and 118 to receive FP 100 mcg BID. Of the subjects randomized, 106 (94%) subjects in the FSC 100/50 group and 108 (92%) subjects in the FP 100 group completed the study. At the end of treatment (Week 4), both FSC and FP protected against a fall in FEV(1) following exercise in patients who at baseline experienced ≥20% fall in FEV(1) following exercise. A mean decrease in FEV(1) of 9.9% was observed in the FSC 100/50 group as compared with a mean decrease of 11.1% in the FP 100 group; there was no statistical difference between treatments. CONCLUSION: Both FSC 100/50 and FP 100 provided protection against an exercised-induced fall in FEV(1); but statistically significant differences we not noted. Both treatments were well-tolerated over four weeks and FSC 100/50 had an adverse event profile comparable to that observed with FP 100.

Pneumococcal tricuspid valve endocarditis in a young african american: a case for inclusion of african americans in pneumococcal vaccine criteria.

Following the development of penicillin, complications from streptococcus pneumonia such as endocarditis have become rare. However, certain independent risk factors such as cigarette smoking and being of African-American (AA) decent have been associated with a higher incidence of invasive pneumococcal disease, but only cigarette smoking has been targeted by current recommendations from the Advisory Committee on Immunological Practices (ACIPs). We report a case of a young AA smoker, who developed an isolated tricuspid valve pneumococcal endocarditis. This case will illustrate the high susceptibility for invasive pneumococcus sequelae in AA, thereby raising the argument for the consideration of AA in the Pneumococcal Conjugate Vaccine (PCV) criteria, regardless of smoking history.

Eosinophilic pleural effusion: a rare manifestation of hypereosinophilic syndrome.

Several causes of eosinophilic pleural effusions have been described with malignancy being the commonest cause. Hypereosinophilic syndrome (HES) is a rare disease and very few cases have been reported of HES presenting as eosinophilic pleural effusion (EPE). We report a case of a 26-year-old male who presented with shortness of breath. He had bilateral pleural effusions, generalized lymphadenopathy, splenomegaly, and leukocytosis with marked peripheral blood eosinophilia. The pleural fluid was exudative, with 25%-30% eosinophilis, and absence of neoplastic cells. Hypereosinophilic syndrome was diagnosed after other causes of eosinophilia were excluded. He continued to be dyspneic with persistent accumulation of eosinophilic pleural fluid, even after his peripheral eosinophil count had normalized in response to treatment. This patient represents a very unusual presentation of HES with dyspnea and pleural effusions and demonstrates that treatment based on response of peripheral eosinophil counts, as is currently recommended, may not always be clinically adequate.

Safety of binodenoson, a selective adenosine A2A receptor agonist vasodilator pharmacological stress agent, in healthy subjects with mild intermittent asthma.

BACKGROUND: The pharmacological stress agents adenosine and dipyridamole are contraindicated in asthma patients because of the risk of adenosine receptor-mediated bronchospasm. Binodenoson, a selective adenosine A(2A) receptor agonist, produces maximal coronary hyperemia during pharmacological stress testing yet has a low affinity for the adenosine A(1), A(2B), and A(3) receptors that are probably responsible for bronchospasm. This study was conducted to assess the safety of binodenoson in 87 healthy young adult volunteers with documented mild, intermittent asthma. METHODS AND RESULTS: This study consisted of a dose-escalating, single-blinded phase and a placebo-controlled, double-blinded phase conducted in healthy, young adults with documented mild, intermittent, asthma. In the single-blinded phase, 3 sequential cohorts of 8 subjects received intravenous binodenoson (0.5, 1.0, and 1.5 microg/kg). In the double-blinded phase, commenced after medical review of results from the single-blinded phase, subjects were randomly assigned 2:1 to either binodenoson 1.5 microg/kg (n=41) or placebo (n=22). The primary end point was clinically significant bronchoconstriction, defined as a decrease in forced expiratory volume in 1 second of >/=20% from the preinjection measure. Secondary safety end points were changes from preinjection measure in forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow during the middle 50% of the forced vital capacity; vital signs; pulse oximetry; and adverse events. Binodenoson caused no clinically significant bronchoconstriction or alterations in pulmonary function parameters and transiently increased heart rate and systolic blood pressure. The most common treatment-emergent adverse events were tachycardia, dizziness, and flushing. CONCLUSIONS: Binodenoson was safe, well tolerated, and caused no clinically significant bronchoconstriction or pulmonary responses in a small population of healthy subjects with mild, intermittent asthma.

Asthma Control Test: reliability, validity, and responsiveness in patients not previously followed by asthma specialists.

BACKGROUND: The development of the Asthma Control Test (ACT), a short, simple, patient-based tool for identifying patients with poorly controlled asthma, was recently described in patients under the routine care of an asthma specialist. OBJECTIVES: We sought to evaluate the reliability and validity of the ACT in a longitudinal study of asthmatic patients new to the care of an asthma specialist. METHODS: Patients (n=313) completed the ACT and the Asthma Control Questionnaire (ACQ) at 2 physician visits (4-12 weeks apart). Pulmonary function was measured, and asthma specialists rated asthma control. RESULTS: Internal consistency reliability of the ACT was 0.85 (baseline) and 0.79 (follow-up). Test-retest reliability was 0.77. Criterion validity was demonstrated by significant correlations between baseline ACT scores and baseline specialists' ratings of asthma control (r=0.52, P<.001) and ACQ scores (r=-0.89, P<.001). Discriminant validity was demonstrated, with significant (P<.001) differences in mean ACT scores across patients differing in asthma control, pulmonary function, and treatment recommendation. Responsiveness of the ACT to changes in asthma control and lung function was demonstrated with significant correlations between changes in ACT scores and changes in specialists' ratings (r=0.44, P<.001), ACQ scores (r=-0.69, P<.001), and percent predicted FEV1 values (r=0.29, P<.001). An ACT score of 19 or less provided optimum balance of sensitivity (71%) and specificity (71%) for detecting uncontrolled asthma. CONCLUSIONS: The ACT is reliable, valid, and responsive to changes in asthma control over time in patients new to the care of asthma specialists. A cutoff score of 19 or less identifies patients with poorly controlled asthma. CLINICAL IMPLICATIONS: In a clinical setting the ACT should be a useful tool to help physicians identify patients with uncontrolled asthma and facilitate their ability to follow patients' progress with treatment.

Soluble CD23 and interleukin-1 receptor antagonist in human asthmatics following antigen challenge.

Two postulated intrinsic anti-inflammatory mechanisms in asthma include the low affinity IgE receptor, or CD23, and interleukin 1 receptor antagonist (IL-1ra). We investigated the role these mediators play in the asthmatic response by measuring local levels in human asthmatics before and after segmental allergen challenge and examined the effect of inhaled corticosteroids on soluble CD23 and IL-1ra levels. Ten subjects underwent bronchoscopy at baseline and 24 hours after antigen challenge. Prior to challenge and every 12 hours afterward subjects received beclomethasone 252 microg or placebo. Fluid was analyzed for sCD23 and IL-1ra using ELISA immunoassays. Eosinophil percentages significantly increased at 24 hours following antigen challenge. sCD23 levels were generally undetectable at baseline and increased significantly following antigen challenge. IL-1ra levels increased 28-fold in the late-phase response. Beclomethasone significantly reduced the late-phase eosinophil percentage at 24 hours compared with placebo but did not attenuate late-phase sCD23 or IL-1ra levels. Our data showed a significant rise in the levels of two mediators thought to play an important role in the attenuation of the asthmatic response. The finding that steroid treatment did not enhance these levels suggests that this may be an independent approach to asthma therapy that should be investigated.