Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours.

BACKGROUND: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. METHODS: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). RESULTS: Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). CONCLUSIONS: At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. CLINICAL TRIAL REGISTRATION: NCT02579226.

Accelerating the development of implantable neurochemical biosensors by using existing clinically applied depth electrodes.

In this study, an implantable stereo-electroencephalography (sEEG) depth electrode was functionalised with an enzyme coating for enzyme-based biosensing of glucose and L-glutamate. This was done because personalised medicine could benefit from active real-time neurochemical monitoring on small spatial and temporal scales to further understand and treat neurological disorders. To achieve this, the sEEG depth electrode was characterised using cyclic voltammetry (CV), differential pulse voltammetry (DPV), square wave voltammetry (SWV), and electrochemical impedance spectroscopy (EIS) using several electrochemical redox mediators (potassium ferri/ferrocyanide, ruthenium hexamine chloride, and dopamine). To improve performance, the Pt sensors on the sEEG depth electrode were coated with platinum black and a crosslinked gelatin-enzyme film to enable enzymatic biosensing. This characterisation work showed that producing a useable electrode with a good electrochemical response showing the expected behaviour for a platinum electrode was possible. Coating with Pt black improved the sensitivity to H2O2 over unmodified electrodes and approached that of well-defined Pt macro disc electrodes. Measured current showed good dependence on concentration, and the calibration curves report good sensitivity of 29.65 nA/cm2/µM for glucose and 8.05 nA/cm2/µM for L-glutamate with a stable, repeatable, and linear response. These findings demonstrate that existing clinical electrode devices can be adapted for combined electrochemical and electrophysiological measurement in patients and obviate the need to develop new electrodes when existing clinically approved devices and the associated knowledge can be reused. This accelerates the time to use and application of in vivo and wearable biosensing for diagnosis, treatment, and personalised medicine.

Historical and Contemporary Management of Infantile Hepatic Hemangioma: A 30-year Single-center Experience.

OBJECTIVE: To describe outcome of infants with hemangioma(s) of the liver. SUMMARY OF BACKGROUND DATA: Infantile hepatic hemangiomas exhibit a diverse phenotype. We report our 30-year experience and describe optimal management based on precise radiological classification. METHODS: Retrospective review of 124 infants (66 female) 1986-2016. Categorical analysis with Chi2 and nonparametric comparison. Data expressed as median (range) and P < 0.05 considered significant. RESULTS: Lesions classified as focal (n = 70, 56%); multifocal (n = 47, 38%) or diffuse (n = 7, 6%) and of these 80(65%) were symptomatic (eg, cardiac failure n = 39, 31%; thrombocytopenia n = 12, 10%).Increased hepatic artery velocity was seen in 63 (56%). Median hepatic artery velocity was greatest in diffuse lesions [245 (175-376) cm/s vs focal 120 (34-242) cm/s vs multifocal 93 (36-313) cm/s; P = 0.0001]. Expectant management alone was followed in 55 (44%). Medical therapy was utilised in 57(46%) and sufficient for symptom control in 29/57 (51%). Propranolol therapy (from 2008) was sufficient for symptom control in 22/28 (79%). Surgery (hepatic artery ligation n = 26; resection n = 13; embolization n = 1) was required in 40 (32%). Median maximal lesion diameter was 3 (0.5-17.1) cm and greater in those requiring surgery (7 cm vs 4.9 cm; P = 0.04). The proportion requiring surgery decreased markedly in the propranolol era [pre-propranolol 25/48 (52%) vs post-propranolol 16/76 (21%) (P = 0.0003)]. Systematic follow-up with ultrasound to a median of 2.6 (0.02-16) years. CONCLUSIONS: A proportion of infantile hepatic hemangiomas remain asymptomatic permitting observation until resolution but the majority require complex multi-modal therapy. First-line pharmacotherapy with propranolol has reduced but not abolished the need for surgery.

SARS-CoV-2 Aptasensors Based on Electrochemical Impedance Spectroscopy and Low-Cost Gold Electrode Substrates.

SARS-CoV-2 diagnostic practices broadly involve either quantitative polymerase chain reaction (qPCR)-based nucleic amplification of viral sequences or antigen-based tests such as lateral flow assays (LFAs). Reverse transcriptase-qPCR can detect viral RNA and is the gold standard for sensitivity. However, the technique is time-consuming and requires expensive laboratory infrastructure and trained staff. LFAs are lower in cost and near real time, and because they are antigen-based, they have the potential to provide a more accurate indication of a disease state. However, LFAs are reported to have low real-world sensitivity and in most cases are only qualitative. Here, an antigen-based electrochemical aptamer sensor is presented, which has the potential to address some of these shortfalls. An aptamer, raised to the SARS-CoV-2 spike protein, was immobilized on a low-cost gold-coated polyester substrate adapted from the blood glucose testing industry. Clinically relevant detection levels for SARS-CoV-2 are achieved in a simple, label-free measurement format using sample incubation times as short as 15 min on nasopharyngeal swab samples. This assay can readily be optimized for mass manufacture and is compatible with a low-cost meter.

Integrated multi-material portable 3D-printed platform for electrochemical detection of dopamine and glucose.

3D-printing has become a fundamental part of research in many areas of investigation since it provides rapid and personalized production of parts that meet very specific user needs. Biosensing is not an exception, and production of electrochemical sensors that can detect a variety of redox mediators and biologically relevant molecules has been widely reported. However, most 3D-printed electrochemical sensors detailed in the literature rely on big, individual, single-material electrodes that require large sample volumes to perform effectively. Our work exploits multi-material fused filament fabrication 3D-printing to produce a compact electrochemical sensor able to operate with only 100 µL of sample. We report cyclic voltammetry, differential pulse voltammetry, and chronoamperometry results to assess sensor performance and sensitivity. We investigated the influence of layer print orientation and layer thickness on the electrochemical performance of the sensor, and used the optimal parameters to produce the final device. The integrated 3D-printed platform successfully detects electrochemical activity for hexaammineruthenium(III) chloride and potassium ferricyanide (0.1 mM to 2 mM in 100 mM KCl), dopamine (50 µM to 1 mM in 1×PBS), and glucose via mediated amperometric glucose oxidase enzyme-based sensing (1 mM to 12 mM in 1×PBS), indicating good acceptance of biological modification. These results reveal the exciting potential of multi-material 3D-printing and how it can be used for the rapid development of efficient, small, integrated, personalized electrochemical biosensors.

Particulate Oxalate-To-Sulfate Ratio as an Aqueous Processing Marker: Similarity Across Field Campaigns and Limitations.

Leveraging aerosol data from multiple airborne and surface-based field campaigns encompassing diverse environmental conditions, we calculate statistics of the oxalate-sulfate mass ratio (median: 0.0217; 95% confidence interval: 0.0154-0.0296; R = 0.76; N = 2,948). Ground-based measurements of the oxalate-sulfate ratio fall within our 95% confidence interval, suggesting the range is robust within the mixed layer for the submicrometer particle size range. We demonstrate that dust and biomass burning emissions can separately bias this ratio toward higher values by at least one order of magnitude. In the absence of these confounding factors, the 95% confidence interval of the ratio may be used to estimate the relative extent of aqueous processing by comparing inferred oxalate concentrations between air masses, with the assumption that sulfate primarily originates from aqueous processing.

Therapeutic strategies for stricturing Crohn's disease in childhood: a systematic review.

PURPOSE: Childhood stricturing Crohn's disease (CD) has significant morbidity. Interventions including resection, stricturoplasty and endoscopic balloon dilatation (EBD) are often required. Optimal intervention modality and timing, and use of adjuvant medical therapies, remains unclear. We aim to review the therapies used in paediatric stricturing CD. METHODS: A systematic review in accordance with PRISMA was performed (PROSPERO: CRD42020164464). Demographics, stricture features, interventions and outcomes were extracted. RESULTS: Fourteen studies were selected, including 177 patients (183 strictures). Strictures presented at 40.6 months (range 14-108) following CD diagnosis. Medical therapy was used in 142 patients for an average of 20.4 months (2-36), with a complete response in 11 (8%). Interventions were undertaken in 138 patients: 53 (38%) resections, 39 (28%) stricturoplasties, and 17 (12%) EBD. Complications occurred in 11% of resections, versus 15% stricturoplasties, versus 6% EBD (p = 0.223). At a median follow-up of 1.9 years (interquartile range 1.2-2.4) pooled stricture recurrence was 22%. Resection had 9% recurrence, versus 38% stricturoplasty, versus 47% EBD (p < 0.001). CONCLUSIONS: Resection is associated with a low incidence of recurrence and complications. There remains a paucity of evidence regarding adjuvant medical therapy and the role of EBD. We propose a minimum reported dataset for interventions in paediatric stricturing CD.

Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti-CD3ε mAb in new-onset type 1 diabetes mellitus patients.

AIMS: This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3ɛ mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose-response of an anti-CD3ɛ mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3ɛ target engagement and downmodulation. METHODS: Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose-ascending study consisted of three cohorts (n = 10 per cohort) at doses of 9, 18 or 27 mg respectively. The study allowed quantification of otelixizumab PK, CD3ɛ target engagement and its pharmacodynamic effect (CD3ε/TCR modulation on circulating T lymphocytes). RESULTS: Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng ml-1 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3ɛ target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of ~60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3ɛ/TCR downmodulation by Day 6. CONCLUSIONS: Data from this study revealed maximum target engagement and CD3ɛ/TCR modulation is achieved at doses of 18, 27 mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti-CD3ɛ mAbs.

Aircraft Measurements of Total Mercury and Monomethyl Mercury in Summertime Marine Stratus Cloudwater from Coastal California, USA.

Water samples from marine stratus clouds were collected during 16 aircraft flights above the Pacific Ocean near the Central California coast during the summer of 2016. These samples were analyzed for total mercury (THg), monomethyl mercury (MMHg), and 32 other chemical species in addition to aerosol physical parameters. The mean concentrations of THg and MMHg in the cloudwater samples were 9.2 ± 6.0 ng L-1 (2.3-33.8 ng L-1) ( N = 97) and 0.87 ± 0.66 ng L-1 (0.17-2.9 ng L-1) ( N = 22), respectively. This corresponds to 9.5% (3-21%) MMHg as a fraction of THg. Low and high nonsea salt calcium ion (nss-Ca2+) concentrations in cloudwater were used to classify flights as "marine" and "continental", respectively. Mean [MMHg]marine was significantly higher ( p < 0.05) than [MMHg]continental consistent with an ocean source of dimethyl Hg (DMHg) to the atmosphere. Mean THg in cloudwater was not significantly different between the two categories, indicating multiple emissions sources. Mean [THg]continental was correlated with pH, CO, NO3-, NH4+, and other trace metals, whereas [THg]marine was correlated with MMHg and Na+. THg concentrations were negatively correlated with altitude, consistent with ocean and land emissions, coupled with removal at the cloud-top due to drizzle formation.

Impact of Wildfire Emissions on Chloride and Bromide Depletion in Marine Aerosol Particles.

This work examines particulate chloride (Cl-) and bromide (Br-) depletion in marine aerosol particles influenced by wildfires at a coastal California site in the summers of 2013 and 2016. Chloride exhibited a dominant coarse mode due to sea salt influence, with substantially diminished concentrations during fire periods as compared to nonfire periods. Bromide exhibited a peak in the submicrometer range during fire and nonfire periods, with an additional supermicrometer peak in the latter periods. Chloride and Br- depletions were enhanced during fire periods as compared to nonfire periods. The highest observed %Cl- depletion occurred in the submicrometer range, with maximum values of 98.9% (0.32-0.56 µm) and 85.6% (0.56-1 µm) during fire and nonfire periods, respectively. The highest %Br- depletion occurred in the supermicrometer range during fire and nonfire periods with peak depletion between 1.8-3.2 µm (78.8% and 58.6%, respectively). When accounting for the neutralization of sulfate by ammonium, organic acid particles showed the greatest influence on Cl- depletion in the submicrometer range. These results have implications for aerosol hygroscopicity and radiative forcing in areas with wildfire influence owing to depletion effects on composition.

Temporal pharmacokinetic/pharmacodynamic interaction between human CD3ε antigen-targeted monoclonal antibody otelixizumab and CD3ε binding and expression in human peripheral blood mononuclear cell static culture.

Otelixizumab is a monoclonal antibody (mAb) directed to human CD3ε, a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of otelixizumab. At each time point, free, bound, and total CD3/TCR expression on both CD4+ and CD8+ T cells and the amount of free otelixizumab antibody in the supernatant were measured. The pharmacokinetics of free otelixizumab in the culture supernatants was saturable, with a shorter apparent half-life at low concentration. Correspondingly, a rapid, otelixizumab concentration-, and time-dependent reduction in CD3/TCR expression was observed. These combined observations were consistent with the phenomenon known as target-mediated drug disposition (TMDD). A mechanistic, mathematical pharmacokinetic/pharmacodynamic (PK/PD) model was then used to characterize the free otelixizumab-CD3 expression-time relationship. CD3/TCR modulation induced by otelixizumab was found to be relatively fast compared with the re-expression rate of CD3/TCR complexes following otelixizumab removal from supernatants. In summary, the CD3/TCR receptor has been shown to have a major role in determining otelixizumab disposition. A mechanistic PK/PD model successfully captured the PK and PD in vitro data, confirming TMDD by otelixizumab.

Population Pharmacokinetic Modeling and Exposure-Efficacy and Body Weight-Response Analyses for Tezepelumab in Patients With Severe, Uncontrolled Asthma.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. This analysis assessed the suitability of a fixed-dose regimen of tezepelumab 210 mg every 4 weeks (Q4W) in adults and adolescents with severe, uncontrolled asthma. A population pharmacokinetic model was developed using data from 1368 patients with asthma or healthy participants enrolled in 8 clinical studies (phases 1-3). Tezepelumab exposure-efficacy relationships were analyzed in the phase 3 NAVIGATOR study (NCT03347279), using asthma exacerbation rates over 52 weeks and changes in pre-bronchodilator forced expiratory volume in 1 s at week 52. Tezepelumab pharmacokinetics were well characterized by a 2-compartment linear disposition model with first-order absorption and elimination following subcutaneous and intravenous administration at 2.1-420 and 210-700 mg, respectively. There were no clinically relevant effects on tezepelumab pharmacokinetics from age (≥12 years), sex, race/ethnicity, renal or hepatic function, disease severity (inhaled corticosteroid dose level), concomitant asthma medication use, smoking history, or anti-drug antibodies. Body weight was the most influential covariate on tezepelumab exposure, but no meaningful differences in efficacy or safety were observed across body weight quartiles in patients with asthma who received tezepelumab 210 mg subcutaneously Q4W. There was no apparent relationship between tezepelumab exposure and efficacy at this dose regimen, suggesting that it is on the plateau of the exposure-response curve of tezepelumab. In conclusion, a fixed-dose regimen of tezepelumab 210 mg subcutaneously Q4W is appropriate for eligible adults and adolescents with severe, uncontrolled asthma.

Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

The political and social barriers for contraception in pest birds: a case study of Ovocontrol (nicarbazin).

In a joint program, Innolytics and the U.S. Department of Agriculture/Animal and Plant Health Inspection Service National Wildlife Research Center collaborated in the development of nicarbazin as an avian contraceptive, initially for resident Canada geese and subsequently for feral pigeons. Unfortunately, the introduction of the original goose product in 2005 was a commercial failure. Political and social barriers effectively thwarted attempts to establish the new technology with any meaningful market success. Although the market adoption of the pigeon contraceptive has been less difficult, the product still encounters significant social and political obstacles and opposition. Given the focus on instant results and gratification, the introduction of contraceptive technology for birds has been challenging and broad market acceptance remains elusive. Nevertheless, especially for short-lived and rapidly reproducing species, customers continue to replace outdated or ineffective techniques with the safer and more effective contraceptive tool.

Sex and hypertensive organ damage: stroke.

Stroke is a common cause of death and disability in both men and women. Differences in the incidence, presenting features and outcome after stroke have been reported between men and women. The global lifetime risk of stroke of approximately 25% is similar in men and women, although in women, the first cardiovascular event is more likely to be stroke than in men. Concerningly, there are reports of underuse of some treatments in women, although these differences may be diminishing over time. In addition, there are specific clinical challenges that can arise in women with stroke, such as stroke in people taking hormonal therapy, and stroke during pregnancy and stroke in the post-partum period. This review will cover these areas highlighting important differences and areas for future research. We found there are important differences in incidence of stroke, which differ by age. Further, there is concerning evidence that some treatments such as intravenous thrombolysis are underused in women. While there may be some differences in the relative effectiveness of treatments such as antiplatelet therapy and blood pressure reduction between men and women, for most aspects of stroke care, benefit is clear in both men and women and the emphasis must be on more equitable access. There is limited evidence to inform decision making during pregnancy and the post-partum period, but guidelines now exist and further research is needed in these areas.

Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Anifrolumab.

The type I interferon (IFN) signaling pathway is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Anifrolumab is a monoclonal antibody that targets the type I IFN receptor subunit 1. Anifrolumab is approved in several countries for patients with moderate to severe SLE receiving standard therapy. The approved dosing regimen of anifrolumab is a 300-mg dose administered intravenously every 4 weeks; this was initially based on the results of the Phase 2b MUSE and further confirmed in the Phase 3 TULIP-1 and TULIP-2 trials, in which anifrolumab 300-mg treatment was associated with clinically meaningful improvements in disease activity with an acceptable safety profile. There have been several published analyses of the pharmacokinetic and pharmacodynamic profile of anifrolumab, including a population-pharmacokinetic analysis of 5 clinical studies of healthy volunteers and patients with SLE, in which body weight and type I IFN gene expression were significant covariates identified for anifrolumab exposure and clearance. Additionally, the pooled Phase 3 SLE population has been used to evaluate how serum exposure may be related to clinical responses, safety risks, and pharmacodynamic effects of the 21-gene type I IFN gene signature (21-IFNGS). The relevance of 21-IFNGS with regard to clinical efficacy outcomes has also been analyzed. Herein, the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of anifrolumab as well as results of population-pharmacokinetics and exposure-response analyses are reviewed.

Development of a specialist ileoanal pouch surgery pathway: a multidisciplinary patient-centred approach.

Background: Restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the gold standard procedure for ulcerative colitis refractory to medical treatment, as an alternative to permanent end ileostomy. Gaining experience in pouch surgery is difficult as the procedure is performed infrequently. This study presents an institutional initiative to promote standardisation of multidisciplinary care in IPAA surgery. Methods: A dedicated pathway for patients who had an IPAA or are considering IPAA surgery was developed among colorectal surgeons, gastroenterologists, paediatric colorectal surgeons, inflammatory bowel disease (IBD) nurses, dietitians, stoma nurses, trainees in colorectal surgery. Pathway items were discussed and finalised via emails and videoconferences.The pathway included triaging of patients referred for IPAA surgery, preoperative IBD multidisciplinary team discussion and management plan for surgery, surgical review prior to surgery, peer to peer counselling, surgical technique, postoperative short-term and long-term follow-up, audit, research and training in IPAA surgery. Results: A multidisciplinary preoperative pathway was developed and a stepwise approach to minimally invasive ileoanal pouch surgery was formalised. A dedicated one-stop ileoanal pouch clinic was established integrating endoscopy and imaging on the same day of the consultation with the surgical and gastroenterology team. The clinic reviewed 72 patients over 24 months, and during the same time 36 patients underwent IPAA surgery at our institution. Conclusions: We have described our initial experience in establishing a specialist IPAA surgery pathway and have proposed outcome measures that we hope will support a subspecialty IPAA service.

Intestinal malrotation and Meckel's diverticulitis in a 19-month-old boy.

Acute intestinal obstruction is a common paediatric surgical emergency and should be considered in any child presenting with vomiting, abdominal pain and abdominal distension. Many causes of bowel obstruction arise from congenital anomalies and recognition of the underlying cause of obstruction can be challenging in these settings. These cases can be further complicated if two or more congenital anomalies are present. Malrotation of the gut is defined as a congenital developmental anomaly of the rotation of the intestine and encompasses a spectrum of abnormalities. Meckel's diverticulum is another congenital anomaly which occurs secondary to the failure of the vitellointestinal duct to close and can present in 2% of the population. We describe an interesting case of a 19-month-old-boy who presented acutely with symptoms of bowel obstruction and was found to have both intestinal malrotation and Meckel's diverticulum.

SB-656933, a novel CXCR2 selective antagonist, inhibits ex vivo neutrophil activation and ozone-induced airway inflammation in humans.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Receptor antagonists that block the binding of chemokines such as CXCL8 (IL-8) are effective in animals models of neutrophil-mediated inflammation. It has been hypothesized that selective inhibition of neutrophil trafficking and activation may be a useful adjunct for the treatment of inflammatory airway diseases such as chronic obstructive pulmonary disease or cystic fibrosis. A CXCR1/2 receptor antagonist has shown activity in an ozone challenge model in humans. WHAT THIS STUDY ADDS: SB-656933, a selective CXCR2 antagonist, is safe and well-tolerated at single doses and is shown to inhibit agonist (CXCL1)-mediated expression of the CD11b on peripheral blood neutrophils as well as ozone-induced airway neutrophilia in healthy subjects. AIMS: To determine the safety and tolerability of a novel selective CXCR2 antagonist and assess its pharmacodynamic effects using measures of neutrophil activation and function, including CD11b expression in whole blood and ozone-induced airway inflammation in healthy subjects. METHODS: Flow cytometric determination of ex vivo CXCL1-induced CD11b expression on peripheral blood neutrophils was performed following single dose oral administration of SB-656933 (dose range 2-1100 mg). A subsequent randomized study (placebo, 50 mg and 150 mg) was performed to explore the dose-response for ozone-induced airway inflammation, as measured by sputum biomarkers. RESULTS: Oral administration of SB-656933 resulted in significant inhibition of CXCL1-induced CD11b expression on peripheral blood neutrophils at single doses greater than or equal to 50 mg. Maximum inhibition (70%) relative to placebo was observed following administration of SB-656933 400 mg (95% CI 60%, 77%). This was sustained up to a dose of 1100 mg. Single doses of SB-656933 reduced ozone-induced airway inflammation in a dose-dependent manner. Relative to placebo, there were 55% (95% CI 20%, 75%) and 74% (95% CI 55%, 85%) fewer neutrophils in the sputum of subjects after a single dose of 50 mg or 150 mg, respectively. There was a corresponding reduction in myeloperoxidase concentrations in the sputum supernatant of 32.8% (95% CI 9.2, 50.3) and 50.5% (95% CI 33.3, 63.3). SB-656933 was safe and well-tolerated at all doses. CONCLUSIONS: SB-656933 is a CXCR2 antagonist that demonstrates dose-dependent effects on neutrophil activation and recruitment within a well-tolerated dose range. These data suggest that SB-656933 may be an effective agent in neutrophil-predominant diseases.