Anti-resorptive agents reduce the size of resorption cavities: a three-dimensional dynamic bone histomorphometry study.

Alterations in resorption cavities and bone remodeling events during anti-resorptive treatment are believed to contribute to reductions in fracture risk. Here, we examine changes in the size of individual remodeling events associated with treatment with a selective estrogen receptor modulator (raloxifene) or a bisphosphonate (risedronate). Adult female rats (6months of age) were submitted to ovariectomy (n=17) or sham surgery (SHAM, n=5). One month after surgery, the ovariectomized animals were separated into three groups: untreated (OVX, n=5), raloxifene treated (OVX+Ral, n=6) and risedronate treated (OVX+Ris, n=6). At 10months of age, the lumbar vertebrae were submitted to three-dimensional dynamic bone histomorphometry to examine the size (depth, breadth and volume) of individual resorption cavities and formation events. Maximum resorption cavity depth did not differ between the SHAM (23.66±1.87µm, mean±SD) and OVX (22.88±3.69µm) groups but was smaller in the OVX+Ral (14.96±2.30µm) and OVX+Ris (14.94±2.70µm) groups (p<0.01). Anti-resorptive treatment was associated with reductions in the surface area of resorption cavities and the volume occupied by each resorption cavity (p<0.01 each). The surface area and volume of individual formation events (double-labeled events) in the OVX+Ris group were reduced as compared to other groups (p<0.02). Raloxifene treated animals showed similar amounts of bone remodeling (ES/BS and dLS/BS) compared to sham-operated controls but smaller cavity size (depth, breadth and volume). The current study shows that anti-resorptive agents influence the size of resorption cavities and individual remodeling events and that the effect of anti-resorptives on individual remodeling events may not always be directly related to the degree of suppression of bone remodeling.

A 1-year follow-on study from a randomised, head-to-head, multicentre, open-label study of two pandemic influenza vaccines in children.

INTRODUCTION: Pandemic influenza A H1N1 infections occurred worldwide from 2009. Children were particularly vulnerable. Novel vaccines were used during the pandemic. OBJECTIVE: To assess the persistence of antibody to H1N1 influenza 1 year after children aged 6 months to 12 years had been immunised with two doses of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine; and also to assess the immunogenicity and reactogenicity in this population of a single dose of 2010-11 trivalent seasonal influenza vaccine. DESIGN: Multicentre, open-label, follow-on from randomised, head-to-head trial. SETTING: Five UK sites (Southampton, Oxford, Bristol, London and Exeter). PARTICIPANTS: Children who completed last year's head-to-head randomised study were invited to participate. Children who had subsequently received a further dose of H1N1 vaccine, or who had already received a dose of 2010-11 trivalent seasonal influenza vaccine, were excluded. INTERVENTIONS: In the previous study, children were randomised (in a 1 : 1 ratio) to receive two doses, 21 days apart, of either a non-adjuvanted whole-virion H1N1 influenza vaccine or an AS03B-adjuvanted split-virion H1N1 influenza vaccine. In this follow-on study, a blood sample was taken to assess the persistence of antibody 1 year later, followed by administration of one 0.5 ml-dose of trivalent seasonal influenza vaccine. A second blood sample was taken 3 weeks later. MAIN OUTCOME MEASURES: Comparison between vaccines of the percentage of participants with a microneutralisation (MN) titre ≥ 1 : 40 and a haemagglutination titre ≥ 1 : 32, 1 year after vaccination. Immunogenicity of the trivalent seasonal influenza vaccine was assessed 3 weeks after vaccination by both the MN and the haemagglutination inhibition (HI) titres. Reactogenicity data were recorded for 7 days after vaccination. RESULTS: A total of 323 children were enrolled and 318 were included in the analysis of the persistence of antibody. One year after receipt of whole-virion vaccine, the MN titre was ≥ 1 : 40 in 32.4% of those vaccinated when < 3 years old and in 65.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 63.2% and 79.1% of children in the respective age groups. One year after receipt of the adjuvanted vaccine, the MN titre was ≥ 1 : 40 in 100% of those vaccinated when < 3 years old and in 96.9% of those vaccinated when ≥ 3 years old; the HI titre was ≥ 1 : 32 in 98.4% and 96.9% of children in the respective age groups. Three hundred and two children were given trivalent seasonal influenza vaccination. Three weeks later, sera were obtained from 282 children; 100% had an MN titre ≥ 1 : 40 and HI titre ≥ 1 : 32. Trivalent seasonal influenza vaccine was well tolerated, although in children < 5 years old, fever ≥ 38 °C was reported in 13.6% of those who had previously received whole-virion vaccine, and in 18.3% of those who had received adjuvanted vaccine. CONCLUSIONS: Nearly all children who received two doses of AS03B-adjuvanted split-virion pandemic H1N1 influenza vaccine had titres of antibody deemed protective (HI titre ≥ 1 : 32, MN titre ≥ 1 : 40) 1 year later. Children who received two doses of whole-virion vaccine had lower titres, although many were above the putative protective thresholds. One year after either pandemic vaccine, the 2010-11 trivalent seasonal influenza vaccine produced a marked serological response to the H1N1 component of the vaccine and was well tolerated. We propose to investigate whether or not previous receipt of monovalent influenza vaccines affected serological response to the H3N2 and B components of the 2010-11 seasonal influenza vaccine, using stored sera. TRIAL REGISTRATION: ClinicalTrials.gov NCT01239537. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Gold coast seaway smartrelease decision support system: optimising recycled water release in a sub tropical estuarine environment.

Gold Coast Water is responsible for the management of the water, recycled water and wastewater assets of the City of the Gold Coast on Australia's east coast. Excess treated recycled water is released at the Gold Coast Seaway, a man-made channel connecting the Broadwater Estuary with the Pacific Ocean, on an outgoing tide in order for the recycled water to be dispersed before the tide changes and re-enters the Broadwater estuary. Rapid population growth has placed increasing demands on the city's recycled water release system and an investigation of the capacity of the Broadwater to assimilate a greater volume of recycled water over a longer release period was undertaken in 2007. As an outcome, Gold Coast Water was granted an extension of the existing release licence from 10.5 hours per day to 13.3 hours per day from the Coombabah wastewater treatment plant (WWTP). The Seaway SmartRelease Project has been designed to optimise the release of the recycled water from the Coombabah WWTP in order to minimise the impact to the receiving estuarine water quality and maximise the cost efficiency of pumping. In order achieve this; an optimisation study that involves intensive hydrodynamic and water quality monitoring, numerical modelling and a web-based decision support system is underway. An intensive monitoring campaign provided information on water levels, currents, winds, waves, nutrients and bacterial levels within the Broadwater. This data was then used to calibrate and verify numerical models using the MIKE by DHI suite of software. The Decision Support System will then collect continually measured data such as water levels, interact with the WWTP SCADA system, run the numerical models and provide the optimal time window to release the required amount of recycled water from the WWTP within the licence specifications.

Three-dimensional surface texture visualization of bone tissue through epifluorescence-based serial block face imaging.

Serial block face imaging is a microscopy technique in which the top of a specimen is cut or ground away and a mosaic of images is collected of the newly revealed cross-section. Images collected from each slice are then digitally stacked to achieve 3D images. The development of fully automated image acquisition devices has made serial block face imaging more attractive by greatly reducing labour requirements. The technique is particularly attractive for studies of biological activity within cancellous bone as it has the capability of achieving direct, automated measures of biological and morphological traits and their associations with one another. When used with fluorescence microscopy, serial block face imaging has the potential to achieve 3D images of tissue as well as fluorescent markers of biological activity. Epifluorescence-based serial block face imaging presents a number of unique challenges for visualizing bone specimens due to noise generated by sub-surface signal and local variations in tissue autofluorescence. Here we present techniques for processing serial block face images of trabecular bone using a combination of non-uniform illumination correction, precise tiling of the mosaic in each cross-section, cross-section alignment for vertical stacking, removal of sub-surface signal and segmentation. The resulting techniques allow examination of bone surface texture that will enable 3D quantitative measures of biological processes in cancellous bone biopsies.

Exercise performance and quality of life following surgical repair of anomalous aortic origin of a coronary artery in the pediatric population.

OBJECTIVE: We sought to evaluate exercise performance and quality of life in children after surgical repair of anomalous aortic origin of a coronary artery with an interarterial course. METHODS: Patients who had surgery from October 2001 to January 2007 were eligible for inclusion. Exercise performance and quality of life were prospectively assessed by maximal exercise tests and age-appropriate questionnaires, respectively. We used t tests to compare pre- and postoperative exercise data and quality-of-life scores to published normative data. We performed linear regression analyses to assess associations between demographic, anatomic, and exercise variables and quality-of-life score. RESULTS: Of 25/27 patients, 64% were boys, 68% had anomalous right coronary, 32% were asymptomatic. Average age at surgery was 10.8 (+/-4.1) years; median follow-up was 14.5 (2 to 48) months. Postoperative percent-predicted exercise values were: peak heart rate 97 (+/-6), working capacity 91 (+/-15), maximal oxygen consumption 82 (+/-16). In those who had preoperative exercise testing (n = 11), resting and maximal heart rates decreased significantly without significant change in exercise performance. Average child quality of life was 85/100 (+/-13) and parent-proxy 88 (+/-11) compared with normal scores of 83 (+/-15) and 88 (+/-12), respectively. CONCLUSION: There is mild chronotropic impairment in children and adolescents following anomalous coronary artery repair without a decline in exercise performance. This does not appear to impair their overall quality of life. Because long-term effects on heart rate, exercise performance, and quality of life are unknown, serial exercise tests should be included as routine care of these patients.

Cat scratch disease presenting as acute encephalopathy.

An unusual case of primary meningo-encephalitis followed by partial complex seizure in a 9-year-old boy was found to be a symptom of cerebral Bartonella henselae infection or cat scratch disease. Despite one clinical relapse at 4 weeks post-presentation, he remained seizure free on carbamazepine for one year. Six months after stopping carbamazepine, however, he developed deja vu phenomena and absence seizures with EEG abnormality. Restarting carbamazepine improved his symptoms.

Soil carbon stocks and changes in the Republic of Ireland.

The soil carbon (C) stock of the Republic of Ireland is estimated to have been 2048 Mt in 1990 and 2021 Mt in 2000. Peat holds around 53% of the soil C stock, but on 17% of the land area. The C density of soils (tCha(-1)) is mapped at 2 km x 2 km resolution. The greatest soil C densities occur where deep raised bogs are the dominant soil; in these grid squares C density can reach 3000 tCha(-1). Most of the loss of soil C between 1990 and 2000-up to 23 MtC (1% of 1990 soil C stock)-was through industrial peat extraction. The average annual change in soil C stocks from 1990 to 2000 due to land use change was estimated at around 0.02% of the 1990 stock. Considering uncertainties in the data used to calculate soil C stocks and changes, the small average annual 'loss' could be regarded as 'no change'.

Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment.

Recent studies indicate that brain-derived neurotrophic factor (BDNF) may be implicated in the clinical action of antidepressant drugs. Repeated (2-3 weeks) administration of antidepressant drugs increases BDNF gene expression. The onset of this response as well as concomitant effects on the corresponding BDNF protein is however, unclear. The present study investigated the effects of acute and chronic administration of the selective serotonin reuptake inhibitor, fluoxetine (10mg/kg p.o.), upon regional rat brain levels of BDNF mRNA and protein expression. To improve the clinical significance of the study, fluoxetine was administered orally and mRNA and protein levels were determined ex vivo using the techniques of in situ hybridisation histochemistry and immunocytochemistry respectively. Direct measurement of BDNF protein was also carried out using enzyme-linked immunosorbent assay (ELISA). Four days of once daily oral administration of fluoxetine induced decreases in BDNF mRNA (hippocampus, medial habenular and paraventricular thalamic nuclei). Whilst 7 days of treatment showed a non-significant increase in BDNF mRNA, there were marked and region-specific increases following 14 days of treatment. BDNF protein levels remained unaltered until 21 days of fluoxetine treatment, when the numbers of BDNF immunoreactive cells were increased, reaching significance in the pyramidal cell layer of CA1 and CA3 regions of Ammon's horn (CA1 and CA3) but not in the other sub-regions of the hippocampus. Indicative of the highly regional change within the hippocampus, the ELISA method failed to demonstrate significant up-regulation at 21 days, measuring levels of BDNF protein in the whole hippocampus. In contrast to the detected time dependent and biphasic response of the BDNF gene, activity-regulated, cytoskeletal-associated protein (Arc) mRNA showed a gradual increase during the 14-day course of treatment. The results presented here show that BDNF is expressed differentially depending on length of fluoxetine administration, which could contribute in explaining the slow onset of antidepressant activity observed with selective serotonin reuptake inhibitors.

Characterization of the vestibulo-ocular reflex evoked by high-velocity movements.

OBJECTIVES/HYPOTHESIS: The horizontal angular vestibulo-ocular reflex (VOR) plays an important role in stabilizing images on the retina throughout head rotations. Current evidence suggests that the VOR behaves linearly at low velocities and nonlinearly at high velocities. The aim of the research was to evaluate and characterize the normal behavior of the reflex evoked by high-velocity head rotations. STUDY DESIGN: Case control study. METHODS: Manually applied head-thrust movements with peak velocities in the range of 100degrees to 500degrees/s and peak accelerations up to 7,000degrees/s were performed on normal volunteers. These head thrusts were comparable with those described in detail by Halmagi and coworkers. Eye and head movements were recorded using the magnetic search coil method. RESULTS: The gain of the VOR is linear at low velocities and saturates at head velocities greater than 350degrees/s. The values for the normal gain of the reflex were approximated by means of the area between two nonlinear functions. The directional difference parameter, exploring the symmetry of the reflex, indicated that the VOR in normal subjects is symmetric. CONCLUSION: The gain of the VOR in individuals with intact vestibular function is nonlinear at high angular head velocities. We propose a quantitative means using two nonlinear functions to characterize the normal range of values for the gain of the VOR in individuals with normal vestibular function. A directional difference parameter used in conjunction with the normal range of gains can detect small differences in the symmetry of the VOR and, consequently, reveal unilateral vestibular loss.

Childhood injury prevention advice: a survey of health professionals responses to common scenarios.

AIM: To determine the responses of health professionals when asked at what age a child could safely engage in a number of common activities and scenarios. METHODS: Eleven scenarios reflecting everyday activities were adapted from the BBC book Play it Safe. Questionnaires were completed by a convenience sample of health professionals. Respondents were asked to give the minimum age they felt a child could safely engage in each of the activities. The literature was searched for an evidential basis for answers to the activities and scenarios posed. RESULTS: A total of 215 questionnaires were completed. For all questions there was a spread in responses of at least 9 years. Recommended answers were found in the literature for six of the scenarios, however, in only four of these was this confirmed to have an evidential basis. Fifty-four per cent of responses were at least 2 or more years from these recommended answers. DISCUSSION: Injury prevention advice needs to be consistent and, where possible, evidentially based. Health professionals often need to rely on their own opinions to provide advice. This survey shows opinions vary and highlights the need for evidence-based guidelines for parents and professionals.

Linearity of canal-otolith interaction during eccentric rotation in humans.

During natural behavior, the head may simultaneously undergo rotation, transduced by the semicircular canals, and translation, transduced by the otolith organs. It has been demonstrated in monkey that the vestibulo-ocular reflexes (VORs) elicited by both endorgans (i.e., the angular and linear VORs, or AVOR and LVOR) sum linearly during combined rotation and translation, but this finding has proven more elusive in humans. To investigate the combined AVOR/LVOR response, six human subjects underwent yaw eccentric rotation at 3 Hz in darkness while displaced from the axis of rotation. Responses to on-center yaw rotation (AVOR alone) and interaural translation (LVOR alone) were also recorded. During eccentric rotation with the subject facing away from the axis of rotation (i.e., nose out), in which a yaw to the right occurs simultaneously with a translation to the right (i.e., translation in phase with rotation), the AVOR and LVOR acted synergistically. Responses were always out of phase with rotation, and became larger in magnitude as vergence increased. For nose-in eccentric rotation, during which translation is out of phase with rotation, the LVOR acted antagonistically to the AVOR. During near viewing, the LVOR often dominated the overall response when eccentricity was sufficiently large, producing eye movements that were in phase with the rotational stimuli. As vergence decreased, the LVOR influence diminished, eventually resulting in responses that were out of phase with rotation at lowest vergence. When the response to pure yaw rotation was vectorially removed from the responses to eccentric rotation, the results proved statistically indistinguishable from the LVOR recorded during interaural translation, suggesting that the ocular response to combined angular and linear motion reflects the linear combination of the AVOR and LVOR.

Asymmetric integration recorded from vestibular-only cells in response to position transients.

Angular and translational accelerations excite the semicircular canals and otolith organs, respectively. While canal afferents approximately encode head angular velocity due to the biomechanical integration performed by the canals, otolith signals have been found to approximate head translational acceleration. Because central vestibular pathways require velocity and position signals for their operation, the question has been raised as to how the integration of the otolith signals is accomplished. We recorded responses from 62 vestibular-only neurons in the vestibular nucleus of two monkeys to position transients in the naso-occipital and interaural orientations and varying directions in between. Responses to the transients were directionally asymmetric; one direction elicited a response that approximated the integral of the acceleration of the stimulus. In the opposite direction, the cells simply encoded the acceleration of the motion. We present a model that suggests that a neural integrator is not needed. Instead a neuron with a long membrane time constant and an excitatory postsynaptic potential duration that increases with the firing rate of the presynaptic cell can emulate the observed behavior.

In vitro activity of LY393558, an inhibitor of the 5-hydroxytryptamine transporter with 5-HT(1B/1D/2) receptor antagonist properties.

1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulphonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558) is a potent inhibitor of [3H]5-hydroxytryptamine ([3H]5-HT) uptake into rat cortical synaptosomes (pIC(50)=8.48+/-0.12). It produces a dextral shift of the 5-HT dose-response curves for the binding of GTPgamma[35S] to human 5-HT(1B) (pK(b)=9.05+/-0.14) and 5-HT(1D) (pK(b)=8.98+/-0.07) receptors and inhibits the contractile response of the rabbit saphenous vein to the 5-HT(1B/D) receptor agonist, sumatriptan (pK(b)=8.4+/-0.2). In addition, it is an antagonist at the 5-HT(2A) (pK(i)=7.29+/-0.19) and 5-HT(2B) (pK(i)=7.35+/-0.11) receptors. Presynaptic autoreceptor antagonist activity was demonstrated by its ability to potentiate the K(+)-induced outflow of [3H]5-HT from guinea pig cortical slices (pEC(50)=7.74+/-0.05 nM) in which the 5-HT transporter had been inhibited by a maximally effective concentration of paroxetine. It is concluded that LY393558 should be an effective antidepressant with the potential to produce an earlier onset of efficacy than selective serotonin uptake inhibitors.

Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates.

Opsoclonus is a dyskinesia consisting of involuntary, arrhythmic, chaotic, multidirectional saccades, without intersaccadic intervals. We used a magnetic scleral search coil technique to study opsoclonus in two patients with paraneoplastic complications of lung carcinoma. Eye movement recordings provided evidence that opsoclonus is a three-dimensional oscillation, consisting of torsional, horizontal, and vertical components. Torsional nystagmus was also present in one patient. Antineuronal antibody study revealed the presence of anti-Ta (Ma2 onco-neuronal antigen) antibodies in one patient, which had previously been associated only with paraneoplastic limbic encephalitis and brainstem dysfunction, but not opsoclonus, and only in patients with testicular or breast cancer. Neuropathologic examination revealed mild paraneoplastic encephalitis. Normal neurons identified in the nucleus raphe interpositus (rip) do not support postulated dysfunction of omnipause cells in the pathogenesis of opsoclonus. Computer simulation of a model of the saccadic system indicated that disinhibition of the oculomotor region of the fastigial nucleus (FOR) in the cerebellum can generate opsoclonus. Histopathological examination revealed inflammation and gliosis in the fastigial nucleus. This morphological finding is consistent with, but not necessary to confirm, damage to afferent projections to the FOR, as determined by the model. Malfunction of Purkinje cells in the dorsal vermis, which inhibit the FOR, may cause opsoclonus by disinhibiting it.

Frequency-dependent effects of glutamate antagonists on the vestibulo-ocular reflex of the cat.

In the central nervous system, sensory and motor signals at different frequencies are transmitted most effectively by neural elements that have different dynamic characteristics. Dynamic differences may be due, in part, to the dynamics of neurotransmitter receptors. For example, N-methyl-D-aspartate (NMDA) receptors are thought to be a component of the "neural integrator" of the vestibulo-ocular reflex (VOR), which generates a signal proportional to eye position. We measured the effects of blockade of NMDA and AMPA/kainate receptors on the gain and phase of the VOR at frequencies between 0.1 and 8 Hz in alert cats. The competitive NMDA antagonist, APV, and the non-competitive antagonists, MK-801 and ketamine, all caused a pronounced reduction in VOR gain. Gain was more strongly attenuated at low frequencies (0.1-1 Hz) than at higher frequencies (2-8 Hz). The phase lead of the eye with respect to the head was increased up to 30 degrees. In contrast, the reduction in gain associated with drowsiness or surgical anesthesia was not frequency-dependent. Blockade of AMPA/kainate receptors by the competitive antagonists, CNQX and NBQX, reduced the gain of the VOR at all frequencies tested. We evaluated our results using a control systems model. Our data are consistent with participation of NMDA receptors in neural integration, but suggest that NMDA receptors also participate in transmission by other components of the VOR pathway, and that neural integration also employs other receptors. One possibility is that between 0.1 and 10 Hz, higher-frequency signals are transmitted primarily by AMPA/kainate receptors, and lower frequencies by NMDA receptors. This arrangement would provide a biological substrate for selective motor learning within a small frequency range.

Click evoked EMG responses in sternocleidomastoid muscles: characteristics in normal subjects.

Recordings were obtained from a total of 25 normal subjects of the electromyographic (EMG) responses in the sternocleidomastoid muscle (SCM) to intense sound stimuli. While previous authors have demonstrated these responses exist, it has remained unclear whether the EMG response is unilateral or bilateral in nature. Accordingly, we chose a remote site, linked-wrists, for our reference electrodes so that we could be certain that no significant volume conduction of potentials could occur from the source in the SCM to the reference site. When this was done we found that if the sternum was used as a reference site, as was the case in previous studies, some subjects exhibited bilateral responses while in others, the response was ipsilateral. However, with linked-wrists as the reference site, responses were always purely ipsilateral. Furthermore, recordings that used the sternum or the ipsilateral mastoid process as active sites and linked-wrists as a reference, exhibited responses which were inverted. Thus, both the sternum and the ipsilateral mastoid process are electrically active due to volume conduction from the nearby source in the SCM. The ambiguity in previous recordings can be attributed to the use of these active sites as a reference. When SCM responses are recorded versus a remote, electrically inactive site, the responses are purely ipsilateral.

Model for the translational vestibuloocular reflex (VOR).

The function of the translational vestibuloocular reflex (tVOR) and the angular vestibuloocular reflex (aVOR) is to stabilize images on the retina during translational and rotational motion, respectively. It has generally been assumed that these two reflexes differ in their central processing because they differ significantly in their primary afferent behavior and characteristics at the motor level. So far, models of the tVOR have focused on the type of processing that the primary afferent signal must undergo before reaching the neural integrator. Here, we propose a model that does not require any prefiltering. It is known that the eye plant requires signals in phase with velocity and position. We propose that the velocity signal is obtained directly from the neural integrator, whereas the position signal is obtained directly from the primary afferents synapsing onto the oculomotor nuclei. This design proved sufficient to simulate eye movements in response to translational motion.