The knee prosthesis constraint dilemma: Biomechanical comparison between varus-valgus constrained implants and rotating hinge prosthesis. A cadaver study.

The real degree of constriction of rotating hinge knee (RHK) and condylar constrained prostheses (CCK) is a matter of discussion in revision knee arthroplasty. The objectives of this study are to compare the tibial rotation of both implants and validate the use of inertial sensors with optical tracking system as movement measurement tools. A total of 16 cadaver knees were used. Eight knees were replaced using a RHK (Endomodel LINK), and the remaining eight received a CCK prosthesis (LCCK, Zimmer). Tibial rotation range of motion was measured in full extension and at 30°, 60°, and 90° of flexion, with four continuous waveforms for each measurement. Measurements were made using two inertial sensors with specific software and compared with measurements obtained using the gold standard technique - the motion capture camera. The comparison of the accuracy of both measurement methods showed no statistically significant differences between inertial sensors and motion capture cameras, with p > .1; the mean error for tibial rotation was 0.21°. Tibial rotation in the RHK was significantly greater than in the CCK (5.25° vs. 2.28°, respectively), p < .05. We have shown that RHK permit greater tibial rotation, being closer to physiological values than CCKs. Inertial sensors have been validated as an effective and accurate method of measuring knee movement. The clinical significance: RHK appears to represent a lower constriction degree than CCK systems.

Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-γ agonist trifarotene.

BACKGROUND: First- and third-generation retinoids are the main treatment for acne. Even though efficacious, they lack full selectivity for retinoic acid receptor (RAR) γ, expressed in the epidermis and infundibulum. OBJECTIVES: To characterize the in vitro metabolism and the pharmacology of the novel retinoid trifarotene. MATERIALS AND METHODS: In vitro assays determined efficacy, potency and selectivity on RARs, as well as the activity on the expression of retinoid target genes in human keratinocytes and ex vivo cultured skin. In vivo studies investigated topical comedolytic, anti-inflammatory and depigmenting properties. The trifarotene-induced gene expression profile was investigated in nonlesional skin of patients with acne and compared with ex vivo and in vivo models. Finally, the metabolic stability in human keratinocytes and hepatic microsomes was established. RESULTS: Trifarotene is a selective RARγ agonist with > 20-fold selectivity over RARα and RARß. Trifarotene is active and stable in keratinocytes but rapidly metabolized by human hepatic microsomes, predicting improved safety. In vivo, trifarotene 0·01% applied topically is highly comedolytic and has anti-inflammatory and antipigmenting properties. Gene expression studies indicated potent activation of known retinoid-modulated processes (epidermal differentiation, proliferation, stress response, retinoic acid metabolism) and novel pathways (proteolysis, transport/skin hydration, cell adhesion) in ex vivo and in vivo models, as well as in human skin after 4 weeks of topical application of trifarotene 0·005% cream. CONCLUSIONS: Based on its RARγ selectivity, rapid degradation in human hepatic microsomes and pharmacological properties including potent modulation of epidermal processes, topical treatment with trifarotene could result in good efficacy and may present a favourable safety profile in acne and ichthyotic disorders.

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.

Integration of free-hand 3D ultrasound and mobile C-arm cone-beam CT: Feasibility and characterization for real-time guidance of needle insertion.

This work presents development of an integrated ultrasound (US)-cone-beam CT (CBCT) system for image-guided needle interventions, combining a low-cost ultrasound system (Interson VC 7.5MHz, Pleasanton, CA) with a mobile C-arm for fluoroscopy and CBCT via use of a surgical tracker. Imaging performance of the ultrasound system was characterized in terms of depth-dependent contrast-to-noise ratio (CNR) and spatial resolution. US-CBCT system was evaluated in phantom studies simulating three needle-based procedures: drug delivery, tumor ablation, and lumbar puncture. Low-cost ultrasound provided flexibility but exhibited modest CNR and spatial resolution that is likely limited to fairly superficial applications within a ∼10cm depth of view. Needle tip localization demonstrated target registration error 2.1-3.0mm using fiducial-based registration.

Feasibility of integrating a multi-camera optical tracking system in intra-operative electron radiation therapy scenarios.

Intra-operative electron radiation therapy (IOERT) combines surgery and ionizing radiation applied directly to an exposed unresected tumour mass or to a post-resection tumour bed. The radiation is collimated and conducted by a specific applicator docked to the linear accelerator. The dose distribution in tissues to be irradiated and in organs at risk can be planned through a pre-operative computed tomography (CT) study. However, surgical retraction of structures and resection of a tumour affecting normal tissues significantly modify the patient's geometry. Therefore, the treatment parameters (applicator dimension, pose (position and orientation), bevel angle, and beam energy) may require the original IOERT treatment plan to be modified depending on the actual surgical scenario. We propose the use of a multi-camera optical tracking system to reliably record the actual pose of the IOERT applicator in relation to the patient's anatomy in an environment prone to occlusion problems. This information can be integrated in the radio-surgical treatment planning system in order to generate a real-time accurate description of the IOERT scenario. We assessed the accuracy of the applicator pose by performing a phantom-based study that resembled three real clinical IOERT scenarios. The error obtained (2 mm) was below the acceptance threshold for external radiotherapy practice, thus encouraging future implementation of this approach in real clinical IOERT scenarios.

Intraoperative radiotherapy with electrons: fundamentals, results, and innovation.

RATIONALE AND OBJECTIVES: To analyse the programme activity and clinical innovation and/or technology developed over a period of 17 years with regard to the introduction and the use of intraoperative radiotherapy (IORT) as a therapeutic component in a medical-surgical multidisciplinary cancer hospital. MATERIAL AND METHODS: To standardise and record this procedure, the Radiation Oncology service has an institutional programme and protocols that must be completed by the different specialists involved. For 17 years, IORT procedures were recorded on a specific database that includes 23 variables with information recorded on institutional protocols. As part of the development and innovation activity, two technological tools were implemented (RADIANCE and MEDTING) in line with the standardisation of this modality in clinical practice. RESULTS: During the 17 years studied, 1,004 patients were treated through 1,036 IORT procedures. The state of the disease at the time of IORT was 77% primary and 23% recurrent. The origin and distribution of cancers were 62% gastrointestinal, 18% sarcomas, 5% pancreatic, 2% paediatric, 3% breast, 7% less common locations, and 2% others. The research and development projects have generated a patent on virtual planning (RADIANCE) and proof of concept to explore as a professional social network (MEDTING). During 2012, there were 69 IORT procedures. There was defined treatment volume (target or target region) in all of them, and 43 were conducted by the virtual planning RADIANCE system. Eighteen have been registered on the platform MEDTING as clinical cases. CONCLUSION: The IORT programme, developed in a university hospital with an academic tradition, and interdisciplinary surgical oncology, is a feasible care initiative, able to generate the necessary intense clinical activity for tending to the cancer patient. Moreover, it is a competitive source for research, development, and scientific innovation.

Research opportunities in intraoperative radiation therapy: the next decade 2013-2023

The reality of intraoperative radiation therapy (IORT) practice is consistent with an efficient and highly precise radiation therapy technique to safely boost areas at risk for local recurrence. Long-term clinical experience has shown that IORT-containing multi-modality regimens appear to improve local disease control, if not survival in many diseases. Research with IORT is a multidisciplinary scenario that covers knowledge from radiation beam adapted development to advance molecular biology for bio-predictability of outcome. The technical parameters employed in IORT procedures are important information to be recorded for quality assurance and clinical results analysis. In addition, specific treatment planning systems for IORT procedures are available, to help in the treatment decision-making process. A systematic revision of opportunities for research and innovation in IORT is reported including radiation beam modulation, delivery, dosimetry and planning; infrastructure and treatment factors; experimental and clinical radiobiology; clinical trials, innovation and translational research development (AU)

Research opportunities in intraoperative radiation therapy: the next decade 2013-2023.

The reality of intraoperative radiation therapy (IORT) practice is consistent with an efficient and highly precise radiation therapy technique to safely boost areas at risk for local recurrence. Long-term clinical experience has shown that IORT-containing multi-modality regimens appear to improve local disease control, if not survival in many diseases. Research with IORT is a multidisciplinary scenario that covers knowledge from radiation beam adapted development to advance molecular biology for bio-predictability of outcome. The technical parameters employed in IORT procedures are important information to be recorded for quality assurance and clinical results analysis. In addition, specific treatment planning systems for IORT procedures are available, to help in the treatment decision-making process. A systematic revision of opportunities for research and innovation in IORT is reported including radiation beam modulation, delivery, dosimetry and planning; infrastructure and treatment factors; experimental and clinical radiobiology; clinical trials, innovation and translational research development.

Behavioral, neurochemical and morphological changes induced by the overexpression of munc18-1a in brain of mice: relevance to schizophrenia.

Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D(1) receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.

A method for small-animal PET/CT alignment calibration.

Small-animal positron-emission tomography/computed tomography (PET/CT) scanners provide anatomical and molecular imaging, which enables the joint visualization and analysis of both types of data. A proper alignment calibration procedure is essential for small-animal imaging since resolution is much higher than that in human devices. This work presents an alignment phantom and two different calibration methods that provide a reliable and repeatable measurement of the spatial geometrical alignment between the PET and the CT subsystems of a hybrid scanner. The phantom can be built using laboratory materials, and it is meant to estimate the rigid spatial transformation that aligns both modalities. It consists of three glass capillaries filled with a positron-emitter solution and positioned in a non-coplanar triangular geometry inside the system field of view. The calibration methods proposed are both based on automatic line detection, but with different approaches to calculate the transformation of the lines between both modalities. Our results show an average accuracy of the alignment estimation of 0.39 mm over the whole field of view.

Software architecture for multi-bed FDK-based reconstruction in X-ray CT scanners.

Most small-animal X-ray computed tomography (CT) scanners are based on cone-beam geometry with a flat-panel detector orbiting in a circular trajectory. Image reconstruction in these systems is usually performed by approximate methods based on the algorithm proposed by Feldkamp et al. (FDK). Besides the implementation of the reconstruction algorithm itself, in order to design a real system it is necessary to take into account numerous issues so as to obtain the best quality images from the acquired data. This work presents a comprehensive, novel software architecture for small-animal CT scanners based on cone-beam geometry with circular scanning trajectory. The proposed architecture covers all the steps from the system calibration to the volume reconstruction and conversion into Hounsfield units. It includes an efficient implementation of an FDK-based reconstruction algorithm that takes advantage of system symmetries and allows for parallel reconstruction using a multiprocessor computer. Strategies for calibration and artifact correction are discussed to justify the strategies adopted. New procedures for multi-bed misalignment, beam-hardening, and Housfield units calibration are proposed. Experiments with phantoms and real data showed the suitability of the proposed software architecture for an X-ray small animal CT based on cone-beam geometry.

Detection of visual activation in the rat brain using 2-deoxy-2-[(18)F]fluoro-D: -glucose and statistical parametric mapping (SPM).

PURPOSE: This study was designed to assess changes in brain glucose metabolism in rats after visual stimulation. MATERIALS AND METHODS: We sought to determine whether visual activation in the rat brain could be detected using a small-animal positron emission tomography (PET) scanner and 2-deoxy-2-[(18)F]fluoro-D: -glucose (FDG). Eleven rats were divided into two groups: (a) five animals exposed to ambient light and (b) six animals stimulated by stroboscopic light (10 Hz) with one eye covered. Rats were injected with FDG and, after 45 min of visual stimulation, were sacrificed and scanned for 90 min in a dedicated PET tomograph. Images were reconstructed by a three-dimensional ordered subset expectation maximization algorithm (1.8 mm full width at half maximum). A region-of-interest (ROI) analysis was performed on 14 brain structures drawn on coronal sections. Statistical parametric mapping (SPM) adapted for small animals was also carried out. Additionally, the brains of three rats were sliced into 20-microm sections for autoradiography. RESULTS: Analysis of ROI data revealed significant differences between groups in the right superior colliculus, right thalamus, and brainstem (p < or = 0.05). SPM detected the same areas as the ROI approach. Autoradiographs confirmed the existence of hyperactivation in the left superior colliculus and auditory cortex. CONCLUSIONS: To our knowledge, this is the first report that uses FDG-PET and SPM analysis to show changes in rat brain glucose metabolism after a visual stimulus.

Differences in response to food stimuli in a rat model of obesity: in-vivo assessment of brain glucose metabolism.

OBJECTIVE: Food intake is regulated by factors that modulate caloric requirements as well as food's reinforcing properties. In this study, we measured brain glucose utilization to an olfactory stimulus (bacon scent), and we examined the role of food restriction and genetic predisposition to obesity on such brain metabolic activity. METHODS: Zucker obese (Ob) and lean (Le) rats were divided into four groups: (1) Ob ad-libitum fed, (2) Ob food restricted (70% of ad libitum), (3) Le ad-libitum fed and (4) Le food restricted. Rats were scanned using micro-positron emission tomography and 2-[(18)F]-fluoro-2-deoxy-D-glucose under two conditions: (1) baseline scan (no stimulation) and (2) challenge scan (food stimulation, FS). RESULTS: FS resulted in deactivation of the right and left hippocampus. Ob rats showed greater changes with FS than Le rats (deactivation of hippocampus and activation of the medial thalamus) and Ob but not Le animals deactivated the frontal cortex and activated the superior colliculus. Access to food resulted in an opposite pattern of metabolic changes to the food stimuli in olfactory nucleus (deactivated in unrestricted and activated in restricted) and in right insular/parietal cortex (activated in unrestricted and deactivated in restricted). In addition, restricted but not unrestricted animals activated the medial thalamus. CONCLUSIONS: The greater changes in the Ob rats suggest that leptin modulates the regional brain responses to a familiar food stimulus. Similarly, the differences in the pattern of responses with food restriction suggest that FS is influenced by access to food conditions. The main changes with FS occurred in the hippocampus, a region involved in memory, the insular cortex, a region involved with interoception (perception of internal sensations), the medial thalamus (region involved in alertness) and in regions involved with sensory perception (olfactory bulb, olfactory nucleus, occipital cortex, superior colliculus and parietal cortex), which corroborates their relevance in the perception of food.

Differential clinical, structural and P300 parameters in schizophrenia patients resistant to conventional neuroleptics.

Schizophrenia is a heterogeneous clinical condition that may reflect a variety of biological processes. In particular, treatment-resistant (TR) schizophrenia may have a distinct neurobiological substrate. Within the context of clinical data, a simultaneous study with different imaging techniques could help to elucidate differences in cerebral substrates among schizophrenia patients with different responses to treatment. In the present work we used a set of biological data (basal and longitudinal volumetry, and P300 event-related potential measurements) to compare TR and treatment-responsive chronic schizophrenia patients with healthy controls. The TR patients showed higher baseline clinical scores, a more severe basal profile of brain alterations, as well as a different outcome as regards to volume deficits. These data support the notion that biological substrates vary among groups of different psychotic patients, even when they have the same diagnosis, and that those substrates may be related to the response to treatment.

Changes in cortical volume with olanzapine in chronic schizophrenia.

INTRODUCTION: Atypical antipsychotics can affect cortical volume differently from traditional drugs. The study of the outcome of grey matter deficits in schizophrenia with olanzapine may be of particular interest in this context. METHODS: In this study, we evaluated the changes in the volume of gray matter in the cortex of 11 schizophrenic patients treated with olanzapine and in 11 healthy controls after three years of follow-up. After MR imaging, acquisition data were processed with a volumetric quantification method based on the Talairach atlas. The longitudinal change of volumetric data was corrected for differences in overall brain size. RESULTS: Patients showed greater reduction than controls in cortical volume in the frontal and parietal regions during follow-up. No relationship was observed between clinical and volumetric changes. CONCLUSION: Our data suggest that the profile of action of olanzapine on the cortical volume of chronically ill patients may be similar to that of typical antipsychotics. Other explanations, however, cannot be completely discarded for that outcome with our data.

Impact of ventricular enlargement on the measurement of metabolic activity in spatially normalized PET.

In pathologic brains with morphological alterations, the process of spatial normalization, as performed by SPM methods, may introduce a confounding effect in the measurement of metabolic activity data. To investigate the effect of the spatial normalization of PET images, we analyzed MRI and PET studies of 20 schizophrenic patients and 18 controls. Using a Talairach-based segmentation procedure and manual segmentation, we measured regional metabolic activity in the untransformed brains and after their spatial normalization. The effect of spatial normalization seems minimal for large ROIs like the main brain lobes, even in brains showing pronounced morphological abnormalities. However, the caudate nucleus shows a considerable change in metabolic activity values after normalization. This normalization effect is much larger in patients than in controls, and leads to artifactual differences between them. We obtained incorrect results (SPM analysis) regarding functional differences between patients and controls in the caudate due to this bias introduced by the spatial normalization. There was a significant correlation between the size of the lateral ventricles and the underestimation of metabolic activity of the caudate. Normalization bias seems to arise from a misalignment of the caudate in the normalized space, pixel overlap between the normalized caudate, and the caudate of the template being on average lower than 50% in both groups. Spatial normalization of the PET images of pathologic brains may introduce a potential source of error that should be taken into account in the analysis of functional data, in particular, in the study of small brain nuclei like the caudate.

Postoperative infections after major heart surgery and prevention of ventilator-associated pneumonia: a one-day European prevalence study (ESGNI-008).

Few data have been published on the prevalence of postoperative infection in patients undergoing major heart surgery (MHS). The degree of compliance with standard measures used to prevent them is unknown. This study assessed the prevalence of infections, particularly ventilator-associated pneumonia (VAP), in patients undergoing MHS in 42 institutions from 13 European countries. On the study day, there were 321 postoperative MHS patients, of whom 164 (51%) were mechanically ventilated. The overall prevalence of infection was 26.8%. Lower respiratory tract infections represented 57% of all the infections present on the study day. Other infections included intravenous-catheter-related bloodstream infections (2.8%), surgical site infections (2.2%), urinary tract infections (0.9%) and postoperative mediastinitis (0.9%). Of the mechanically ventilated patients, 55 (33.5%) were not being nursed in a semi-recumbent position, 36 (22%) had heat-moisture exchangers with no antibacterial filters, and intracuff pressure was not monitored in 78 patients (47.6%). Only 13 patients (8%) were given continuous subglottic suctioning, 64 patients (39%) did not receive postural oscillation, and gastric overdistension was not actively prevented in 23 patients (14%). In conclusion, these data from intensive care units across Europe provide information on postoperative infections in an important subset of the patient population, and stress the need for active interventions to prevent VAP in patients undergoing MHS.

Hypofrontality in men with first-episode psychosis.

BACKGROUND: Decreased metabolic activity in the prefrontal cortex during cognitive activation is a recurrent finding and a likely functional marker of schizophrenia. AIMS: To investigate the occurrence of hypofrontality in patients with first-episode psychosis, with or without evolution to schizophrenia. METHOD: We used fluorodeoxyglucose positron emission tomography during the performance of an attention task and magnetic resonance imaging to study the dorsolateral prefrontal region in 13 men with a first episode of psychosis. Data from patients who progressed to schizophrenia were compared with those of patients who did not meet criteria for this diagnosis after 2 years. RESULTS: Patients who developed schizophrenia demonstrated a significant hypofrontality in the dorsolateral prefrontal cortex in comparison with the non-schizophrenia and control groups. CONCLUSIONS: Our results suggest that hypofrontality could be a marker of schizophrenia at the time of the first psychotic episode, in agreement with neurodevelopmental theories of schizophrenia.

A European perspective on intravascular catheter-related infections: report on the microbiology workload, aetiology and antimicrobial susceptibility (ESGNI-005 Study).

The laboratory workload, microbiological techniques and aetiology of catheter-related infections in European hospitals are mostly unknown. The present study (ESGNI-005) comprised a 1-day (22 October 2001), laboratory-based, point-prevalence survey based on a questionnaire completed by microbiology laboratories in European (European Union (EU) and non-EU) hospitals. Also included were questions requesting retrospective information for the year 2000. In total, 151 hospitals from 26 European countries participated, of which 78.1% were teaching institutions. Overall, the estimated population served by these institutions was 121,363,800, and the estimated number of admissions during 2000 was 6,712,050. The total number of catheter tips processed during 2000 was 142,727, or 21/1,000 admissions, of which 23.7% were considered to be positive in the institutions using semiquantitative or quantitative techniques. Overall, EU centres received significantly more catheter tip samples/1,000 admissions and had a significantly higher rate of 'positivity' (p < 0.0001) than non-EU centres. Of the institutions surveyed, 11.4% (7.2% in EU countries and 23.7% in non-EU countries; p 0.04) used only qualitative techniques for catheter tip sample processing. On the day of the study, 167 microorganisms were recovered from significant catheter tip cultures (122 patients), of which Gram-positive bacteria represented 70.7%, Gram-negative bacteria 22.2%, and yeasts 7.2%. The five most common microorganisms were coagulase-negative staphylococci, Staphylococcus aureus, Candida spp., Enterococcus spp. and Pseudomonas spp. Overall, 19% of catheter tip cultures were polymicrobial. In the case of S. aureus, 40% of isolates were resistant to oxacillin, as were 63.4% of coagulase-negative staphylococcus isolates. Of 37 Gram-negative isolates, 35% were resistant to cefotaxime, 31% to ceftazidime, and 27% to ciprofloxacin. Imipenem and cefepime had the lowest reported rates of resistance (11%).

Clinical-epidemiological characteristics and outcome of patients with catheter-related bloodstream infections in Europe (ESGNI-006 Study).

This study analysed 89 episodes of catheter-related bloodstream infection (CR-BSI) occurring during one week in 107 hospitals from 21 European countries (1.02 episodes/1,000 admissions). Patients from European Union (EU) countries had a higher incidence of CR-BSI than patients from non-EU countries (1.55 vs. 0.33/1,000 admissions). Most (67%) catheters were non-tunneled central venous catheters, were in the jugular vein (44%), had been implanted for > 7 days (70%), were made of polyurethane (61%) and were multi-lumen (67%). In 36% of cases, catheters were implanted by physicians other than anaesthetists or surgeons, and 50% were inserted by junior staff.