Image-guided synovial biopsy with a focus on infection.

Image-guided biopsy of the synovium is a relatively uncommon but safe procedure with a high-diagnostic yield in the correct clinical scenario. Whilst surgical and arthroscopic techniques are still commonly performed and remain the gold standard, they are more invasive, expensive and not widely available. Ultrasound and X-ray-guided synovial biopsy are being increasingly performed by radiologists to diagnose both native and periprosthetic joint infection (PJI) to guide surgical and microbiological management. The purpose of this review article is to present the historical background to synovial biopsy particularly related to potential joint infection, including common and uncommon pathogens encountered, sampling techniques and pitfalls, focusing mainly on its role in PJI and its role in patient pathways and decision-making within a joint infection multi-disciplinary framework.

Morphology of the entering and exiting nerve as a differentiating feature of benign from malignant peripheral nerve sheath tumours of the brachial plexus.

OBJECTIVE: To identify if morphology of the entering and exiting nerve involved by a nerve sheath tumour in the brachial plexus can help differentiate between benign (B) and malignant (M) peripheral nerve sheath tumours (PNSTs). MATERIALS AND METHODS: Retrospective review of 85 patients with histologically confirmed primary PNSTs of the brachial plexus over a 12.5-year period. Clinical data and all available MRI studies were independently evaluated by 2 consultant musculoskeletal radiologists blinded to the final histopathological diagnosis assessing for maximal lesion dimension, visibility and morphology of the entering and exiting nerve, and other well-documented features of PNSTs. RESULTS: The study included 47 males and 38 females with mean age 46.7 years (range, 8-81 years). There were 73 BPNSTs and 12 MPNSTs. The entering nerve was not identified in 5 (7%), was normal in 17 (23%), was tapered in 38 (52%) and showed lobular enlargement in 13 (18%) BPNSTs compared with 0 (0%), 0 (0%), 2 (17%) and 10 (83%) MPNSTs respectively. The exiting nerve was not identified in 5 (7%), was normal in 20 (27%), was tapered in 42 (58%) and showed lobular enlargement in 6 (8%) BPNSTs compared with 4 (33%), 0 (0%), 2 (17%) and 6 (50%) MPNSTs respectively. Increasing tumour size, entering and exiting nerve morphology and suspected MRI diagnosis were statistically significant differentiators between BPNST and MPNST (p < 0.001). IOC for nerve status was poor to fair but improved to good if normal/tapered appearance were considered together with improved specificity of 81-91% for BPNST and sensitivity of 75-83%. CONCLUSIONS: Morphology of the adjacent nerve is a useful additional MRI feature for distinguishing BPNST from MPNST of the brachial plexus.

The role of MRI in image-guided needle biopsy of focal bone and soft tissue neoplasms.

Magnetic resonance imaging (MRI) plays a critical role in the management pathway of both soft tissue and bone neoplasms, from diagnosis through to post-treatment follow-up. There are a wide range of surgical, oncological, and combined treatment regimes but these rely on accurate histopathological diagnosis. This article reviews the role of MRI in the planning of image-guided needle biopsy for suspected soft tissue and bone tumors.

Gefitinib, cisplatin, and concurrent radiotherapy for locally advanced head and neck cancer: EGFR FISH, protein expression, and mutational status are not predictive biomarkers.

BACKGROUND: Gefitinib was demonstrated to be synergistic with cisplatin and radiotherapy (RT) in in vitro studies. Biomarkers predictive of response to gefitinib in squamous cell head and neck cancer is still lacking. METHODS: Thirty-one patients with locally advanced and easily accessible primary tumor sites for biopsies were recruited. Gefitinib was started 3 weeks before the start of cisplatin/concurrent radiotherapy (CTRT) and continued during the CTRT phase and thereafter for 4 months as consolidation phase. Two baselines and a repeat tumor sample were taken after 2 weeks of gefitinib alone to study its impact on tumor gene expression. Epidermal growth factor receptor (EGFR) protein expression, FISH and mutational status, and matrix metallopeptidase 11 (MMP11) protein expression were correlated with response and survival outcome. RESULTS: The overall response rate to gefitinib alone was 9.7%. The survival outcome is as follows: median disease free 1.3 years, median survival time 2.4 years, 3-year disease free 42.9%, and 3-year overall survival 48.4%. EGFR FISH, protein expression, and mutational status did not predict for response nor survival outcome of patients. Although MMP11 overexpression did not predict for response, it predicted significantly for a poorer survival outcome. CONCLUSIONS: Gefitinib can be combined safely with cisplatin/RT. More studies are needed to uncover predictive biomarkers of benefit to gefitinib.

The effects on cardiovascular autonomic control of repetitive arousal from sleep.

STUDY OBJECTIVES: To quantitatively assess autonomic cardiovascular control in normal young adults following exposure to repetitive acoustically-induced arousals from sleep. DESIGN: Respiration, R-R interval (RRI) and noninvasive measurements of continuous arterial blood pressure were monitored in subjects during the transition from relaxed wakefulness to stable Stage 2 sleep. These measurements were made under undisturbed conditions or conditions in which transient arousals were induced repetitively by acoustic stimulation. A mathematical model was used to partition the fluctuations in RRI into a component ("RSA") correlated with respiration and a component ("A representing baroreflex control of heart rate. The magnitudes and forms of each component before and after exposure to repetitive arousals were compared SETTING: Sleep disorders laboratory in a university setting. PATIENTS OR PARTICIPANTS: Ten healthy young adults (5 male, 5 female) with an average age of 20.4 +/- 2.0 y and mean body-mass index of 23.8 +/- 2.9 kg/m2. INTERVENTIONS: Each subject participated in multiple sleep studies consisting of 4 conditions with 2 nights in each condition. The first condition consisted of undisturbed sleep (control), while in the other 3 conditions, the subjects were aroused from sleep by repetitive auditory stimuli applied continuously over a duration of 50 minutes, with periodicities of 30 seconds, 1 minute, and 2 minutes of sleep. MEASUREMENTS AND RESULTS: Exposure to repetitive arousal (RA) did not alter mean heart rate or blood pressure. However, ABR and RSA gains estimated using the model, increased from the onset of Stage 1 sleep to the start of stable Stage 2 sleep under the control condition, but remained unchanged in all RA conditions. There were also significant increases in low-frequency oscillations of systolic blood pressure in the RA conditions versus no change in the control condition. CONCLUSIONS: Exposure to RA over durations approximating an hour produces cumulative effects on autonomic control that are subtle and can only be detected when advanced signal processing methods are employed. More specifically, the increases in ABR and RSA gains that accompany increasing sleep depth in normal sleep are prevented from occurring.

CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment.

The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.

Abnormal autonomic cardiac response to transient hypoxia in sickle cell anemia.

The objective of this study was to non-invasively assess cardiac autonomic control in subjects with sickle cell anemia (SCA) by tracking the changes in heart rate variability (HRV) that occur following brief exposure to a hypoxic stimulus. Five African-American SCA patients and seven healthy control subjects were recruited to participate in this study. Each subject was exposed to a controlled hypoxic stimulus consisting of five breaths of nitrogen. Time-varying spectral analysis of HRV was applied to estimate the cardiac autonomic response to the transient episode of hypoxia. The confounding effects of changes in respiration on the HRV spectral indices were reduced by using a computational model. A significant decrease in the parameters related to parasympathetic control was detected in the post-hypoxic responses of the SCA subjects relative to normal controls. The spectral index related to sympathetic activity, on the other hand, showed a tendency to increase the following hypoxic stimulation, but the change was not significant. This study suggests that there is some degree of cardiovascular autonomic dysfunction in SCA that is revealed by the response to transient hypoxia.

Retropharyngeal haemorrhage from a vertebral artery branch treated with distal flow arrest and particle embolisation.

Retropharyngeal haematoma is a rare cause of rapid neck swelling that may result in fatal upper respiratory airway obstruction. Reported causes include trauma, surgery, retropharyngeal inflammation, carotid aneurysm, aberrant artery at the thoracic inlet and bleeding diathesis. We report a 90-year-old man who developed rapid and progressive neck swelling following a minor traumatic episode. Computed tomography showed a large low-density retropharyngeal haematoma extending from the skull base to the mediastinum, with suspected extravasation. The right vertebral artery angiogram confirmed contrast agent extravasation arising from a small branch artery. This was treated with temporary distal flow arrest and particle embolisation.

Effects of ethidium and isometamidium on adenosine triphosphate catabolism and purine nucleotide synthesis in Ehrlich ascites tumor cells in vitro.

Ethidium and isometamidium induce the breakdown of intracellular adenosine triphosphate in Ehrlich ascites tumor cells incubated in vitro. Ethidium induces appreciable adenosine triphosphate breakdown only when cells are incubated without glucose, whereas isometamidium produces this effect both in the presence and absence of glucose. In cells treated with isometamidium, purine nucleoside monophosphates accumulate, whereas these are mostly dephosphorylated when ethidium is used. Both ethidium and isometamidium inhibit purine nucleotide synthesis and incorporation of precursors into nucleic acids, although the magnitudes of these effects varied with the precursor used. Isometamidium inhibited the conversion of inosinate to adenine and guanine nucleotides, and both compounds partially inhibited the accumulation of phosphoribosyl pyrophosphate.

Model-based stability assessment of ventilatory control in overweight adolescents with obstructive sleep apnea during NREM sleep.

Obstructive sleep apnea (OSA) involves the interplay of several different factors such as an unfavorable upper airway anatomy, deficiencies in pharyngeal muscle responsiveness, a low arousal threshold, and ventilatory control instability. Although the stability of ventilatory control has been extensively studied in adults, little is known about its characteristics in the pediatric population. In this study, we developed a novel experimental setup that allowed us to perturb the respiratory system during natural non-rapid eye movement (NREM) sleep conditions by manipulating the inspiratory pressure, provided by a bilevel pressure ventilator, to induce sighs after upper airway stabilization. Furthermore, we present a modeling framework that utilizes the noninvasively measured ventilatory responses to the induced sighs and spontaneous breathing data to obtain representations of the processes involved in the chemical regulation of respiration and extract their stability characteristics. After validation with simulated data, the modeling technique was applied to data collected experimentally from 11 OSA and 15 non-OSA overweight adolescents. Statistical analysis of the model-derived stability parameters revealed a significantly higher plant gain and lower controller gain in the OSA group (P = 0.046 and P = 0.007, respectively); however, no differences were found in loop gain (LG) and circulatory time delay between the groups. OSA severity and LG, within the 0.03-0.04-Hz frequency band, were significantly negatively associated (r = -0.434, P = 0.026). Contrary to what has been found in adults, our results suggest that in overweight adolescents, OSA is unlikely to be initiated through ventilatory instability resulting from elevated chemical loop gain.

Modeling the interaction between arousal and chemical drive in sleep-disordered breathing.

We have measured the ventilatory response to acoustically induced arousal in normal subjects and patients with obstructive sleep apnea syndrome (OSAS). The arousal responses are similar in magnitude and time-course over the first 3 breaths, but in OSAS the subsequent response declines much more rapidly. Incorporation of these empirical findings into an existing model of sleep-disordered breathing allows an improved characterization of state-chemoreflex interactions. The shorter time-course of the arousal response in OSAS promotes greater ventilatory and state instability at low-to-intermediate levels of CO2 gain.

Fuzzy assessment of sleep-disordered breathing during continuous positive airway pressure therapy.

We propose a new method of quantifying sleep-disordered breathing (SDB) for the purpose of automating continuous positive airway pressure (CPAP) titration. Our algorithm, based on fuzzy logic, emulates the less-than-crisp kind of decision-making generally employed at the human level. Three input variables were first derived on a breath-by-breath basis from respiratory airflow measurements. These were: (1) the relative duration of inspiratory flow limitation in each breath; (2) the degree of hypopnea relative to the past 15 breaths; and (3) the intensity of snoring. Using these descriptors as inputs, our fuzzy inference algorithm produced a "severity index" (SI) quantifying the degree of SDB. Severity index was determined in CPAP titration procedures conducted on one normal snorer and 12 patients with moderate-to-severe obstructive sleep apnea. SI computed over the last 6 minutes of each CPAP level was compared against other more-conventional indices of SDB, such as total pulmonary resistance (RL), the number of apneas and hypopneas (NAH), and the number of arousals (NAr). In all but one of the subjects, the correlation coefficients for SI vs each of RL, NAH, and NAr were significantly different from zero, but not different from each other. The group correlation coefficients for SI vs RL, NAH, and NAr were 0.89, 0.86, and 0.87, respectively, demonstrating that SI accurately quantifies SDB. SI collapses multiple features of the airflow pattern into a single index and, therefore, may be useful as a "feedback" variable for the automatic control of CPAP therapy.

Spectral indices of cardiac autonomic function in obstructive sleep apnea.

Spectral analysis of heart rate variability (HRV) is useful as a noninvasive means of assessing autonomic function in patients with obstructive sleep apnea (OSA). However, standard spectral measures, such as the ratio of low-frequency to high-frequency power (LHR) and normalized high-frequency power (NHFP), can be confounded by the abnormal breathing patterns that occur during sleep. To circumvent this limitation, we employed an autoregressive modeling approach to partition the RR time-series into a component that is correlated with respiration and a respiration-independent component. From these components, we derived two new spectral indices: the modified LHR (MLHR) and the average gain relating respiration to RR changes (GRSA). Six normals and seven OSA patients were studied in relaxed wakefulness and stage 2 sleep; during sleep, the OSA patients were studied without and with continuous positive airway pressure (CPAP) therapy. All four spectral indices showed significant differences between OSA patients and normals in both wakefulness and sleep, although the changes in MLHR and GRSA were substantially larger and less variable: MLHR (p < 0.0003) and GRSA (p < 0.0001) vs. LHR (p < 0.005) and NHFP (p < 0.004). However, in the OSA subjects, LHR and NHFP were unchanged by CPAP. By contrast, CPAP produced a highly significant increase in GRSA (p < 0.0004), as well as a decrease in MLHR (p < 0.03). Thus, by compensating for the effects of breathing pattern differences, MLHR and GRSA unmasked the effects of CPAP therapy, which has been shown in previous studies to reduce sympathetic activity and increase vagal cardiac modulation.

A model-based evaluation of the single-breath CO2 ventilatory response test.

The accuracy of the single-breath CO2 inhalation test as a method for determining peripheral chemoreflex gain (Gp) is evaluated through computer simulations using a mathematical model of the closed-loop respiratory control system. Estimates of Gp (G'p) are based on "corrected" changes in end-tidal PCO2, because the uncorrected end-tidal values do not accurately reflect changes in alveolar PCO2. The influence of the central chemoreflex on G'p is generally less than 10% but can become disproportionally more significant as the relative contribution of the peripheral chemoreflex diminishes. G'p tends to overestimate Gp with the inclusion of peripheral chemoreceptor rate sensitivity, but this effect is offset by the time constant for adaptation. The spontaneous variability of breathing can seriously impair the resolution of G'p. Averaging of G'p deduced from individual single-breath tests can lead to erroneous estimates of Gp even when a large number of repetitions are performed. This problem can be minimized by first ensemble averaging the data from individual single-breath tests and, then, computing G'p from the resulting mean changes.

Ventilatory response to randomly modulated hypercapnia and hypoxia in humans.

We have developed a new method for characterizing the ventilatory response to combined hypercapnia and hypoxia (HCVR-HVR) based on the results of a single test procedure. The method is designed to evoke both hypercapnic and hypoxic responses simultaneously and to enable quantification of their static and dynamic features using an estimation algorithm based on the prediction error method. In six healthy subjects, we measured HCVR-HVR by modulating the CO2 and O2 content of the inhaled mixture in the form of two statistically independent random sequences. A two-component dynamic model was found to provide an adequate description of the stimulation-response data sets. The model consisted of a CO2 subsystem and a CO2-O2 subsystem in which a multiplicative interaction between hypercapnia and hypoxia was assumed. The steady-state gains were 2.08 +/- 0.68 (SD) 1.min-1.Torr-1 for the CO2 subsystem and 0.10 +/- 0.05 l.min-1.Torr-1 for the CO2-O2 subsystem, and the corresponding time constants were 116.7 +/- 32.3 and 19.0 +/- 4.4 s, respectively. Our results suggest that the hypercapnic component of HCVR-HVR is mediated primarily by the central chemoreceptors, whereas the interaction component is mediated largely by the peripheral chemoreceptors.

Sleep-induced periodic breathing and apnea: a theoretical study.

To elucidate the mechanisms that lead to sleep-disordered breathing, we have developed a mathematical model that allows for dynamic interactions among the chemical control of respiration, changes in sleep-waking state, and changes in upper airway patency. The increase in steady-state arterial PCO2 accompanying sleep is shown to be inversely related to the ventilatory response to CO2. Chemical control of respiration becomes less stable during the light stage of sleep, despite a reduction in chemoresponsiveness, due to a concomitant increase in "plant gain" (i.e., responsiveness of blood gases to ventilatory changes). The withdrawal of the "wakefulness drive" during sleep onset represents a strong perturbation to respiratory control: higher magnitudes and rates of withdrawal of this drive favor instability. These results may account for the higher incidence of periodic breathing observed during light sleep and sleep onset. Periodic ventilation can also result from repetitive alternations between sleep onset and arousal. The potential for instability is further compounded if the possibility of upper airway occlusion is also included. In systems with high controller gains, instability is mediated primarily through chemoreflex overcompensation. However, in systems with depressed chemoresponsiveness, rapid sleep onset and large blood gas fluctuations trigger repetitive episodes of arousal and hyperpnea alternating with apneas that may or may not be obstructive. Between these extremes, more complex patterns can arise from the interaction between chemoreflex-mediated oscillations of shorter-cycle-duration (approximately 36 s) and longer-wavelength (approximately 60-80 s) state-driven oscillations.

Simulation of gas transport due to cardiogenic oscillations.

We simulated gas transport due to cardiogenic oscillations (CO) using a model developed to quantify the gas mixing due to high-frequency ventilation (16). The basic components of the model are 1) gas mixing by augmented transport, 2) symmetrical lung morphometry, and 3) a Lagrangian (moving) reference frame. The theoretical predictions of the model are in general agreement with published experimental studies that have examined the effect of CO on the nitrogen concentration obtained by intrapulmonary gas sampling and the effect of CO on regional and total anatomical dead space. Further, the model predicts that augmentation of gas transport due to CO is less, nearer to the alveolar regions of the lung, and that the effect of CO during normal tidal breathing is negligible, but that CO may contribute up to approximately 10% of the alveolar ventilation in patients with severe hypoventilation. The agreement between experimental and theoretical results suggests that it may not be necessary to invoke gas transport mechanisms specific to an asymmetrical bronchial tree to explain the major proportion of gas transport due to CO.

Minimization of lung pressure swings during high-frequency ventilation: a model.

The goal of this theoretical study was to develop a simple computational model for determining the lung pressure excursions that accompany the maintenance of adequate gas transport through high-frequency airway oscillations applied via the trachea (HFAO) and by transthoracic means (HFTO). Respiratory mechanics and gas transport parameters estimated from the preceding companion study (J. Appl. Physiol. 67: 985-992, 1989) were used in the model for computing tracheal, alveolar, pleural, and transpulmonary pressure swings. Comparison of model predictions with corresponding data obtained in dogs showed close agreement. The specification of eucapnia as a constraint led to results that were significantly different from previous findings which had assumed constant airflow. We used the model to identify "quasi-optimal" strategies for HFAO and HFTO application in which all pressure excursions were kept below the corresponding levels produced by conventional mechanical ventilation operating at 15 breaths/min. The model suggests the application of both HFAO and HFTO at frequencies substantially lower than the settings commonly employed in high-frequency ventilation. Application of HFAO at frequencies ranging from 1 to 4 Hz is recommended, whereas for HFTO the quasi-optimal range lies between 1 and 1.7 Hz. In patients with chronic obstructive pulmonary disease, pressure costs during HFAO or HFTO are minimized in the vicinity of 1 Hz.

Estimation of dynamic chemoresponsiveness in wakefulness and non-rapid-eye-movement sleep.

We developed a method for quantifying dynamic chemoresponsiveness on the basis of the ventilatory response to pseudorandom binary CO2 stimulation. The dynamic chemoreflex gain (GD) and effective time delay (TDeff) relating breath-to-breath fluctuations in alveolar PCO2 to ventilation were evaluated at frequencies between 0 and 0.05 Hz. Application of the method to simulated "data" showed that estimation errors in GD and TDeff were most likely to be minimized in the range of 0.01-0.03 Hz, corresponding to periodicities of 30-100 s. Estimation of TDeff was generally more susceptible to error than that of GD because of the limited time resolution of the breath-by-breath measurements. In eight awake normal adults, we compared estimates of GD derived from the pseudorandom binary CO2 stimulation test with peripheral and central hypercapnic sensitivities deduced from single-breath and Read rebreathing measurements in the same subject. GD at 0.02 Hz was highly correlated with peripheral hypercapnic sensitivity but poorly correlated with central hypercapnic sensitivity, underscoring the importance of the peripheral chemoreflexes in mediating ventilatory responses to phasic stimuli. Application of the procedure to a different group of 10 healthy volunteers during wakefulness and stage 2 sleep showed decreases in GD in 8 subjects but increases in 2 subjects. However, for the group as a whole, GD and TDeff did not change significantly between wakefulness and sleep. The proposed method may provide information more pertinent to periodic breathing than traditional CO2 response tests do, since the chemoreflex responses to phasic variations in blood gases are likely to be important in determining ventilatory control during sleep.

Lung pressures and gas transport during high-frequency airway and chest wall oscillation.

The major goal of this study was to compare gas exchange, tidal volume (VT), and dynamic lung pressures resulting from high-frequency airway oscillation (HFAO) with the corresponding effects in high-frequency chest wall oscillation (HFCWO). Eight anesthetized paralyzed dogs were maintained eucapnic with HFAO and HFCWO at frequencies ranging from 1 to 16 Hz in the former and 0.5 to 8 Hz in the latter. Tracheal (delta Ptr) and esophageal (delta Pes) pressure swings, VT, and arterial blood gases were measured in addition to respiratory impedance and static pressure-volume curves. Mean positive pressure (25-30 cmH2O) in the chest cuff associated with HFCWO generation decreased lung volume by approximately 200 ml and increased pulmonary impedance significantly. Aside from this decrease in functional residual capacity (FRC), no change in lung volume occurred as a result of dynamic factors during the course of HFCWO application. With HFAO, a small degree of hyperinflation occurred only at 16 Hz. Arterial PO2 decreased by 5 Torr on average during HFCWO. VT decreased with increasing frequency in both cases, but VT during HFCWO was smaller over the range of frequencies compared with HFAO. delta Pes and delta Ptr between 1 and 8 Hz were lower than the corresponding pressure swings obtained with conventional mechanical ventilation (CMV) applied at 0.25 Hz. delta Pes was minimized at 1 Hz during HFCWO; however, delta Ptr decreased continuously with decreasing frequency and, below 2 Hz, became progressively smaller than the corresponding values obtained with HFAO and CMV.