Relationship between Pharmacokinetics and Pharmacodynamic Responses in Healthy Smokers Informs a Once-Daily Dosing Regimen for Nemiralisib.

Nemiralisib (GSK2269557), a potent inhaled inhibitor of phosphoinositide 3-kinase δ (PI3Kδ), is being developed for the treatment of respiratory disorders including chronic obstructive pulmonary disease. Determining the pharmacokinetic (PK) and pharmacodynamic (PD) responses of inhaled drugs early during drug development is key to informing the appropriate dose and preferred dose regimen in patients. We set out to measure PD changes in induced sputum in combination with drug concentrations in plasma and bronchoalveolar lavage (BAL) taken from healthy smokers (n = 56) treated for up to 14 days with increasing doses of inhaled nemiralisib (0.1-6.4 mg). Induced sputum analysis demonstrated a dose-dependent reduction in phosphatidylinositol-(4,5)-trisphosphate (PIP3, the product of PI3K activation), with a maximum placebo-corrected reduction of 23% (90% confidence interval [CI], 11%-34%) and 36% (90% CI, 11%-64%) after a single dose or after 14 days of treatment with nemiralisib, respectively (2 mg, once daily). Plasma analysis suggested a linear PK relationship with an observed accumulation of ∼3- to 4.5-fold (peak vs. trough) in plasma exposure after 14 days of nemiralisib treatment. The BAL analysis at trough confirmed higher levels of the drug in the lungs versus plasma (32-fold in the BAL fluid component, and 214-fold in the BAL cellular fraction). A comparison of the drug levels in plasma and the reductions in sputum PIP3 showed a direct relationship between exposure and PIP3 reduction. These results demonstrated target engagement upon treatment with inhaled nemiralisib and provide confidence for a once-daily dosing regimen.

Concomitant rectal cancer and abdominal aortic aneurysm: a management strategy.

The simultaneous occurrence of abdominal aortic aneurysm and rectal cancer is uncommon but represents a therapeutic dilemma. We report two patients in whom endovascular stenting of the aneurysm was not feasible. These patients were managed by an initial retroperitoneal aortic repair followed a few weeks later by an ultra low anterior resection.

Hoverfly (syrphidae) communities respond to varying structural retention after harvesting in canadian peatland black spruce forests.

Variable retention harvesting (VRH), in which trees are removed at variable intensity and spatial configuration across the landscape, retains greater forest structural heterogeneity than traditional clear-cut harvesting and is being recommended as an alternative for sustainable management of the boreal forest. Little is known about its effects on forest fauna; thus, we studied the influence of one type of VRH (harvesting with advanced regeneration [HARP]) on the Syrphidae (Diptera) community in northern Ontario forests of peatland black spruce (Picea mariana). We examined the effects of varying structural retention (from unharvested through partial retention to clear-cut) on syrphid species richness and abundance, and abundance of functional assemblages. Greater species richness and population abundances were found generally in harvested than in unharvested forests. Overall species richness and the abundance of four species (Platycheirus rosarum, Toxomerus marginatus, Xylota annulifera, and X. tuberculata) and larval predators were all higher in both clear-cut sites and those with structural retention than in unharvested sites. Similarly, overall species richness and the abundance of nine species were higher in clear-cut than in unharvested sites. Species responses are discussed in an ecological context. Differences among the levels of forest retention harvesting were relatively minor compared with those of the clear-cut and unharvested area, suggesting that local habitat characteristics may play a more important role in determining the syrphid community than the landscape configuration. However, a landscape level effect was evident, suggesting that syrphids may be useful in reflecting changes in stand structure at the landscape scale.

Digital optical imaging of green fluorescent proteins for tracking vascular gene expression: feasibility study in rabbit and human cell models.

PURPOSE: To investigate the feasibility of using a sensitive digital optical imaging technique to detect green fluorescent protein (GFP) expressed in rabbit vasculature and human arterial smooth muscle cells. MATERIALS AND METHODS: A GFP plasmid was transfected into human arterial smooth muscle cells to obtain a GFP-smooth muscle cell solution. This solution was imaged in cell phantoms by using a prototype digital optical imaging system. For in vivo validation, a GFP-lentivirus vector was transfected during surgery into the carotid arteries of two rabbits, and GFP-targeted vessels were harvested for digital optical imaging ex vivo. RESULTS: Optical imaging of cell phantoms resulted in a spatial resolution of 25 microm/pixel. Fluorescent signals were detected as diffusely distributed bright spots. At ex vivo optical imaging of arterial tissues, the average fluorescent signal was significantly higher (P <.05) in GFP-targeted tissues (mean +/- SD, 9,357.3 absolute units of density +/- 1,001.3) than in control tissues (5,633.7 absolute units of density +/- 985.2). Both fluorescence microscopic and immunohistochemical findings confirmed these differences between GFP-targeted and control vessels. CONCLUSION: The digital optical imaging system was sensitive to GFPs and may potentially provide an in vivo imaging tool to monitor and track vascular gene transfer and expression in experimental investigations.

Obstructing internal hernia complicating totally extraperitoneal inguinal hernia repair.

A case is presented of a totally extraperitoneal laparoscopic hernia repair complicated by internal herniation of small bowel through an inadvertent peritoneal defect.

Prenatal diagnosis and outcome of subamniotic hematomas.

Subamniotic hematomas are classical placental pathological lesions resulting from the rupture of chorionic vessels near the cord insertion. Most subamniotic hematomas are found after birth and result from excessive traction on the umbilical cord at delivery. The development of these lesions has been rarely reported in utero. We report here five cases of subamniotic hematomas diagnosed by ultrasound between 18 and 30 weeks of gestation. The sonographic features were those of a poorly reflective oval-shaped cystic mass overlying the fetal plate of the placenta and covered in a thin membrane. In all the cases, a cystic structure containing a thrombotic mass arising from the amniotic membrane, which was attached to the fetal placental surface, was found after delivery. A high maternal serum alpha-fetoprotein level was found retrospectively in the four cases for which this information was available. Two pregnancies were complicated by slow fetal growth, one by vaginal bleeding and one by polyhydramnios. These findings demonstrated that subamniotic hematoma can be accurately diagnosed in utero by ultrasound and differentiated from other lesions of the placental chorionic plate. The findings also show that, although the lesion is located between the chorion and the amnion, it can be associated with fetomaternal hemorrhage and with fetal growth restriction.

Separation of fetal and maternal ECG complexes from a mixed signal using an algorithm based on linear regression.

Fetal scalp ECG and Doppler ultrasound are the two methods universally used to derive the fetal heart rate (FHR) for cardiotocography. Other fetal signal sources have not been used successfully because of the complexity of the signal and the need for an additional maternal ECG input. In this paper, we present an algorithm for separating the fetal and maternal ECG signals obtained from intrauterine electrodes during labour. The algorithm detects all occurrences of ECG complexes and uses linear regression functions to compare each complex with a set templates. Sets of templates are identified as either maternal or fetal in origin and two signals are output for heart rate measurement. The outputs are also processed to eliminate artefacts that may occur when the maternal and fetal complexes are coincident. The algorithm processes 10 seconds of data at a time (in about 200 ms on a standard PC) while a further 10 s of data is being acquired. It has the advantage that no extra input is required, such as maternal ECG obtained from chest leads, and only assumes that two different populations of complexes of two different shapes are present in the input signal. The algorithm could also be used for the separation of fetal and maternal signals obtained from abdominal electrodes.

A Microsoft Windows based application for acquisition and replay of cardiotocograph data.

The electronic fetal monitor or cardiotocograph is an integral part of all modern labour wards. It records fetal heart and uterine contractions and charts this data as a cardiotocogram (CTG). The CTG is used to assess fetal well-being by the labour attendants and in some circumstances for research. A means to acquire and display the CTG by microcomputer as an aid to archiving and to obstetric research is presented. A Microsoft Windows-based application was written using Microsoft C version 7.0 to acquire and replay the CTG data. The application acquires the CTG data by using the RS232 serial link fitted on most modern fetal monitors. Additionally, comments and events can be entered by the user throughout recording. The data are saved to disk files which can be replayed on screen in the manner of a CTG. The data replay functions of the application calculates the uterine activity integral and active pressure for each contraction and for 15 min intervals. This calculated data is not available from many fetal monitors but is widely used for research into the mechanics of labour. This application provides an easy, reliable and accurate means of acquiring the CTG data, for archiving and research. It also provides a framework for further CTG analysis.

The use of the fetal electrocardiogram in labour.

It is clear that considerably more work needs to be done before fetal ECG waveform analysis can be adopted for the purposes of routine fetal monitoring. It must be decided exactly what we want fetal ECG waveform analysis to achieve. If it is to reduce the number of operative deliveries performed in the presence of normal or intermediate CTG patterns then the fetal ECG shows promise, but its physiological significance in this context remains uncertain. If fetal ECG analysis is to be related to outcome, as opposed to events in labour, then several very large well conducted randomised prospective controlled trials will be needed. At present a large multicentre study (European Community Concerted Action Project 1989) is taking place in which a large number of intrapartum ECG records are being collected, blinded to the clinician and stored onto optical disc via a personal computer. A multicentre study in the United Kingdom using the Nottingham system is also being planned. We need await the outcome of these to verify if any of a variety of fetal ECG variables can be related to outcome. It behoves us to validate fetal ECG analysis against outcome measures that truly indicate whether the labour process has compromised or damaged the fetus. We must not fall into the trap of yet again wholeheartedly embracing a test that has not been properly validated.

Fetal heart rate response to vibroacoustic stimulation during low and high heart rate variability episodes in late pregnancy.

In 52 women in late pregnancy, the mean durations of transient fetal tachycardia after vibroacoustic stimulation during low fetal heart rate variability (4.8 minutes) and high fetal heart rate variability (6.3 minutes) were similar. The fetal heart rate continued with high variability in all cases, suggesting that the fetus did not return to its prestimulation state after vibroacoustic stimulation during quiescence. In 10 women, the duration of high variability after vibroacoustic stimulation during low fetal heart rate variability was significantly shorter (mean, 22 minutes) than the preceding (mean, 36 minutes) or subsequent (mean, 43 minutes) high-variability components of complete rest activity cycles. In another 10 women, the duration of high variability after vibroacoustic stimulation during high fetal heart rate variability was similar to preceding and subsequent high-variability episodes. In these 20 women, the next complete rest-activity cycle after vibroacoustic stimulation was not different in duration to the complete cycle recorded on the previous day.

Parvovirus infection in hospital practice.

Eleven cases of human parvovirus (HPV) infection were diagnosed on the basis of positive IgM serology over a 9-month period in two London hospitals. These cases accounted for almost 30% of viral illness in which HPV serology had been requested. Ten of the cases presented with joint symptoms and/or rash and one case presented with evidence of a severe autoimmune haemolytic anaemia. Six patients had lymphadenopathy. Clinical and laboratory features of the cases are presented. HPV DNA was sought but not found in synovial fluid from one patient.

Pyogenic infection and rheumatoid arthritis.

Ten episodes of severe pyogenic infection occurring in nine patients with rheumatoid arthritis are reported. There was a wide range of presenting features including pyoarthrosis in 7 episodes. Three cases presented with meningitis, bacterial endocarditis and probable multiple abscesses respectively. Infection was caused by Staphylococcus aureus in 7 episodes and by Staphylococcus epidermidis, Streptococcus pneumoniae and beta-haemolytic Streptococcus in each of one episode. Three infective episodes were fatal. Pyogenic, especially staphylococcal, infection should be considered in patients with rheumatoid arthritis with unexplained illness with or without sudden deterioration in joint symptoms. It is important to recognize and treat infection rapidly.

Serum C-reactive protein measurement in pyoderma gangrenosum.

A case of pyoderma gangrenosum is reported in a patient with a past history of ulcerative colitis. Serial C-reactive protein (CRP) concentrations were measured and were found to be markedly elevated at presentation. Levels were also raised during two subsequent relapses. CRP levels proved to be a useful objective indicator of disease activity and response to therapy, and reflected changes in disease activity before the erythrocyte sedimentation rate.