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Biomedical subjects

Michael A Smith

Publications and source records attributed to Michael A Smith.

At least 19 recordsLinked to original sources

Functional organization within a neural network trained to update target representations across 3-D saccades.

The goal of this study was to understand how neural networks solve the 3-D aspects of updating in the double-saccade task, where subjects make sequential saccades to the remembered locations of two targets. We trained a 3-layer, feed-forward neural network, using back-propagation, to calculate the 3-D motor error the second saccade. Network inputs were a 2-D topographic map of the direction of the second target in retinal coordinates, and 3-D vector representations of initial eye orientation and motor error of the first saccade in head-fixed coordinates. The network learned to account for all 3-D aspects of updating. Hidden-layer units (HLUs) showed retinal-coordinate visual receptive fields that were remapped across the first saccade. Two classes of HLUs emerged from the training, one class primarily implementing the linear aspects of updating using vector subtraction, the second class implementing the eye-orientation-dependent, non-linear aspects of updating. These mechanisms interacted at the unit level through gain-field-like input summations, and through the parallel "tweaking" of optimally-tuned HLU contributions to the output that shifted the overall population output vector to the correct second-saccade motor error. These observations may provide clues for the biological implementation of updating.

Animals↗

A method for pharmacokinetic modelling of dynamic contrast enhanced MRI studies of rapidly enhancing lesions acquired in a clinical setting.

Abnormal microcirculation is a feature of many neoplastic and non-neoplastic diseases. Physiological variables that characterize tissue microcirculation (capillary permeability and the volume of the extravascular extracellular fluid) are altered in pathological states. Pharmacokinetic analysis of dynamic contrast enhanced MRI (DCE-MRI) has found a widespread use in the assessment of abnormal microcirculation due to the direct link between the contrast agent kinetics and underlying microcirculatory properties. A representation of temporal variation of contrast agent concentration in blood plasma (C(p)(t)) is central to this analysis. In clinical applications of DCE-MRI, signal intensity curves derived from rapidly enhancing lesions often display a sigmoid shape during the initial phase of contrast uptake and rapid arrival at the equilibrium phase. In this work, the features of two principal methods for pharmacokinetic analysis of DCE-MRI which allow for theoretical representation of C(p)(t) are examined and combined to improve analysis of this particular class of DCE-MRI curves. The proposed method allows the representation of the initial sigmoid part of the enhancement profiles whilst retaining a realistic representation of C(p)(t) based on previously published measurements obtained in healthy volunteers. The results of the computer simulations indicate that in rapidly enhancing lesions, with the transfer constant K(trans) greater than 0.1 min(-1), the DCE-MRI acquisition can be restricted to 5 min post-injection and a mono-exponential representation of C(p)(t) decay is sufficient. Furthermore, non-ideal bolus delivery can be represented as a short constant rate infusion when the tissue under investigation exhibits a sigmoid pattern of contrast uptake.

Animals↗

Behavioral depression and positron emission tomography-determined serotonin 1A receptor binding potential in cynomolgus monkeys.

CONTEXT: Current animal models of depression are inadequate to further our understanding of depression. New models that allow for analysis of cognitive function and sex differences are needed. OBJECTIVE: To characterize serotonin 1A (5-HT(1A)) receptor binding potential (BP) and its relationship with specific characteristics of behavioral depression in cynomolgus monkeys. DESIGN: A 23-month case-control study. SETTING: Small social groups in the laboratory. Subjects Seventeen adult female cynomolgus monkeys. MAIN OUTCOME MEASURES: Serotonin 1A receptor BP was examined by positron emission tomography using the radioligand 4,2"-(methoxyphenyl)-1-[2"-(N-2"-pyridinyl)-p-fluorobenzamido]ethylpiperazine in the raphe, amygdala, hippocampus, and anterior cingulate cortex in monkeys characterized by behavioral observation as depressed or not depressed. Aggression, submission, affiliation, pathologic behaviors, and activity levels were determined by behavioral observation. Heart rate and hypothalamic-pituitary-adrenal function were also determined. RESULTS: Throughout the brain areas examined, there was a reduction in 5-HT(1A) BP in depressed monkeys. The 5-HT(1A) BP in the amygdala and hippocampus was associated with aggression and submission. Friendly interaction, grooming, and locomotion were associated with 5-HT(1A) BP in the left cingulate cortex, whereas attention directed toward the environment was associated with 5-HT(1A) BP in the right cingulate cortex. The 5-HT(1A) receptor BP was inversely associated with heart rate in the raphe, left cingulate, and right amygdala. CONCLUSIONS: This is the fourth in a series of studies that suggest that depressive behavior in adult female cynomolgus monkeys is similar to that observed in humans. It has been observed in 2 large groups of monkeys randomly selected from feral populations, suggesting that the capacity for depression is inherent in the species. This animal model holds promise to further our understanding of the basic mechanisms of affective behavior, the neuropathophysiologic characteristics of depression and the cognitive dysfunction that accompanies them, genetic and environmental factors that may affect depression risk, and the role of reproductive function in the excess depression risk in women.

Aggression↗

Dysphagia in the young male: the ringed esophagus.

The endoscopic view of the multi-ringed esophagus readily explains why the term "tracheal esophagus" is applicable. This entity may be undiagnosed until dysphagia and impactions secondary to strictures occur in the young male. Several factors point to a congenital rather than an acquired disorder. Treatment consists of slow, progressive dilatations that are repeated for recurrent dysphagia.

Adult↗

Prevalence of benign disease in patients undergoing resection for suspected lung cancer.

BACKGROUND: In this era of expanded lung cancer screening, accurate differentiation of benign from malignant lesions remains an important problem. We sought to characterize our experience with focal pulmonary lesions suggestive of lung cancer and subsequently proven benign on surgical resection. METHODS: A retrospective analysis was performed on 1,560 patients who underwent resection for focal pulmonary lesions at our institution from January 1995 to December 2002. Computed tomography and pathology reports were reviewed for all patients. Fluorine-18-fluorodeoxyglucose positron emission tomography studies were performed on 43 patients. RESULTS: Benign processes were found on pathologic examination in 140 patients (9%). Resection was accomplished by thoracotomy in 103 patients (74%), video-assisted thoracoscopy in 36 patients (26%), and sternotomy in 1 patient (0.7%). Seventy patients (50%) underwent mediastinoscopy before resection. There was 1 (0.7%) perioperative death. Pathologic diagnoses from the pulmonary resections revealed granulomatous inflammation in 91 patients (65%), hamartoma in 17 patients (12%), pneumonia or pneumonitis in 14 patients (10%), fibrosis in 5 patients (4%), and other in 13 patients (9%). Fluorine-18-fluorodeoxyglucose positron emission tomography imaging suggested malignancy in 22 of 43 patients and benign lesion in 20 of 43 patients (1 study was not interpretable). Thirty-eight patients underwent needle biopsy before surgery. Of these, 29 samples were nondiagnostic, 5 samples were negative, and 4 samples were considered positive for malignancy. CONCLUSIONS: Despite thorough clinical assessment, advanced imaging technology, and needle biopsy, many patients continue to undergo surgery for benign disease. Aggressive attempts to diagnose and treat early stage lung cancer must be tempered with this understanding.

Aged↗

Modest copper supplementation blocks molybdenosis in cattle.

It is widely accepted that ratios of dietary copper (Cu) to molybdenum (Mo) lower than 10:1 may produce molybdenosis in cattle, especially if sulfur concentrations are more than 3,000 ppm. Some authorities suggest that dietary Mo concentrations greater than 10 ppm are hazardous to cattle regardless of Cu concentration, but anecdotal reports suggest that this may not be the case. The original purpose of the experiment described in this report was to investigate whether supranutritional supplemental Cu could protect cattle against relatively high dietary Mo. Pregnant cows were grazed on 1 of 3 pastures: 1 with only background Mo, 1 with an average of 13 ppm Mo, and 1 that averaged 230 ppm Mo. Half the cows on the Mo pastures were supplemented with 17 ppm dietary Cu, the other half with the dietary supplement plus Cu boluses. Molybdenum effects were anticipated in the groups supplemented with 17 ppm Cu; however, despite increased tissue concentrations of Mo, only the 230 ppm Mo/17 ppm Cu group exhibited any effects. Moderate Cu supplementation permitted cows to graze a site heavily contaminated with Mo with no adverse effects on general health or reproduction.

Analysis of Variance↗

Pleural space problems after living lobar transplantation.

BACKGROUND: We reviewed our experience with adult living lobar lung transplant (LL) recipients to assess whether size and shape mismatch of the donor organ to the recipient pre-disposes to the development of pleural space problems (PSP). METHODS: Eighty-seven LL were performed on 84 adult recipients from 1993 through 2003. Seventy-six patients had cystic fibrosis. Patient records were examined for PSP, defined as air leak or bronchopleural fistula for more than 7 days; pneumothorax, loculated pleural effusions, or empyema in 68 patients for which complete data were available. RESULTS: There were 24 PSP identified for an overall incidence of 35%. The most common PSP was air leak/bronchopleural fistula, accounting for 38% of PSP. The second most common PSP was loculated pleural effusion (21% of PSP). Empyema was uncommon (2 patients, 3% of total patients) in our series of patients despite the large population of cystic fibrosis patients. In 4 of these patients, computed tomography-guided drainage was used for loculated effusions after chest tube removal. Three LL patients underwent surgery for persistent air leak and required muscle flap repair. One of these required subsequent omental transfer. Two LL patients required decortication for empyema. Many patients with PSP could be managed without further surgical intervention (14/24 patients). Donor-recipient height mismatch was not significantly different between PSP and non-PSP patients (p = 0.53). CONCLUSIONS: The incidence of PSP in LL recipients is similar to that reported in the literature on cadaveric transplant recipients. The relatively small lobe in the potentially contaminated chest cavity of cystic fibrosis recipients does not significantly pre-dispose to development of empyema despite immunosuppression. Many PSP can be managed non-operatively, although early aggressive intervention for large air leaks and judicious chest tube management are essential for a good outcome.

Adult↗

T1 measurement using a short acquisition period for quantitative cardiac applications.

Myocardial signal intensity curves for myocardial perfusion studies may be made quantitative by the use of T1 measurements made after the first-pass of contrast agent. A short data acquisition method for T1 mapping is presented in which all data for each T1 map are acquired in a short breath hold, and the slice geometry and timing in the cardiac cycle exactly match that of the dynamic first-pass perfusion sequence. This allows accurate image registration of the T1 map with the first-pass series of images. The T1 method is based on varying the preparation-pulse delay time of a saturation recovery sequence, and in this implementation employs an ECG-triggered, single-shot, spoiled gradient echo technique with SENSE reconstruction. The method allows T1 estimates of three slices to be made in fifteen heartbeats. For a range of samples with T1 values equivalent to those found in the myocardium during the first-pass of contrast agent, T1 estimates were accurate to within 6%, and the variation between slices was 2% or less.

Animals↗

Distributed population mechanism for the 3-D oculomotor reference frame transformation.

Human saccades require a nonlinear, eye orientation-dependent reference frame transformation to transform visual codes to the motor commands for eye muscles. Primate neurophysiology suggests that this transformation is performed between the superior colliculus and brain stem burst neurons, but provides little clues as to how this is done. To understand how the brain might accomplish this, we trained a 3-layer neural net to generate accurate commands for kinematically correct 3-D saccades. The inputs to the network were a 2-D, eye-centered, topographic map of Gaussian visual receptive fields and an efference copy of eye position in 6-dimensional, push-pull "neural integrator" coordinates. The output was an eye orientation displacement command in similar coordinates appropriate to drive brain stem burst neurons. The network learned to generate accurate, kinematically correct saccades, including the eye orientation-dependent tilts in saccade motor error commands required to match saccade trajectories to their visual input. Our analysis showed that the hidden units developed complex, eye-centered visual receptive fields, widely distributed fixed-vector motor commands, and "gain field"-like eye position sensitivities. The latter evoked subtle adjustments in the relative motor contributions of each hidden unit, thereby rotating the population motor vector into the correct correspondence with the visual target input for each eye orientation: a distributed population mechanism for the visuomotor reference frame transformation. These findings were robust; there was little variation across networks with between 9 and 49 hidden units. Because essentially the same observations have been reported in the visuomotor transformations of the real oculomotor system, as well as other visuomotor systems (although interpreted elsewhere in terms of other models) we suggest that the mechanism for visuomotor reference frame transformations identified here is the same solution used in the real brain.

Feedback↗

Modulation of grasping forces during object transport.

Subjects held an instrumented object in a tripod grasp and moved it in the horizontal plane in various directions. The contact forces at the digits were measured and the grip force was decomposed into 2 components: a manipulating force responsible for accelerating the object and a grasping force responsible for holding the object steady. The grasping forces increased during the movement, reaching a peak near the time of peak velocity. The grasping forces also exhibited directional tuning, but this tuning was idiosyncratic for each subject. Although the overall grip forces should be modulated with acceleration, the load force did not vary during the task. Therefore the increase in the grasping force is not required to prevent slip. Rather, it is suggested that grasping force increases during translational motion to stabilize the orientation of grasped objects.

Acceleration↗

Modelling the propagation of terahertz radiation through a tissue simulating phantom.

Terahertz (THz) frequency radiation, 0.1 THz to 20 THz, is being investigated for biomedical imaging applications following the introduction of pulsed THz sources that produce picosecond pulses and function at room temperature. Owing to the broadband nature of the radiation, spectral and temporal information is available from radiation that has interacted with a sample; this information is exploited in the development of biomedical imaging tools and sensors. In this work, models to aid interpretation of broadband THz spectra were developed and evaluated. THz radiation lies on the boundary between regions best considered using a deterministic electromagnetic approach and those better analysed using a stochastic approach incorporating quantum mechanical effects, so two computational models to simulate the propagation of THz radiation in an absorbing medium were compared. The first was a thin film analysis and the second a stochastic Monte Carlo model. The Cole-Cole model was used to predict the variation with frequency of the physical properties of the sample and scattering was neglected. The two models were compared with measurements from a highly absorbing water-based phantom. The Monte Carlo model gave a prediction closer to experiment over 0.1 to 3 THz. Knowledge of the frequency-dependent physical properties, including the scattering characteristics, of the absorbing media is necessary. The thin film model is computationally simple to implement but is restricted by the geometry of the sample it can describe. The Monte Carlo framework, despite being initially more complex, provides greater flexibility to investigate more complicated sample geometries.

Diagnostic Imaging↗

Multispectral classification techniques for terahertz pulsed imaging: an example in histopathology.

Terahertz pulsed imaging is a spectroscopic imaging modality using pulses of electromagnetic radiation (100 GHz-10 THz), and there has been recent interest in studying biomedical specimens. It is usual to display parametric images derived from the measured pulses. In this work, classification was achieved by applying multispectral clustering techniques to sets of parametric images. It was hypothesised that adequate information for clustering was carried in a small number of parametric images, providing these were weighted by complementary physical properties. Materials prepared for histopathological examination were chosen because their condition remained stable during long imaging periods and because their dehydrated state led to greater penetration of the radiation. Two specimens were examined in this pilot study, one of basal cell carcinoma and one of melanoma. Unsupervised ISODATA classification using three selected parametric terahertz pulsed images was compared qualitatively with k-means classification using the shape of the whole time series, and with conventional stained microscope slides. There was good qualitative agreement between the classifications. Classifications were consistent with the morphological appearances expected, but further work is required to determine if tumour discrimination is possible. The results have implications for the future development of the technique as the need for only a small number of features could lead to considerably reduced acquisition times.

Algorithms↗

Neural control of 3-D gaze shifts in the primate.

The neural mechanisms that specify target locations for gaze shifts and then convert these into desired patterns of coordinated eye and head movements are complex. Much of this complexity is only revealed when one takes a realistic three-dimensional (3-D) view of these processes, where fundamental computational problems such as kinematic redundancy, reference-frame transformations, and non-commutativity emerge. Here we review the underlying mechanisms and solutions for these problems, starting with a consideration of the kinematics of 3-D gaze shifts in human and non-human primates. We then consider the neural mechanisms, including cortical representation of gaze targets, the nature of the gaze motor command used by the superior colliculus, and how these gaze commands are decomposed into brainstem motor commands for the eyes and head. A general conclusion is that fairly simple coding mechanisms may be used to represent gaze at the cortical and collicular level, but this then necessitates complexity for the spatial updating of these representations and in the brainstem sensorimotor transformations that convert these signals into eye and head movements.

Animals↗

Recombinant human growth hormone treatment in elderly patients undergoing elective total hip replacement.

OBJECTIVE: Measures to prevent postoperative catabolism may be of greatest benefit in the elderly because of their reduced lean tissue reserve. We examined the effects of recombinant human growth hormone (GH) treatment on body composition and physical performance in elderly patients undergoing elective total hip replacement. METHODS: We recruited 33 patients (aged 60-82 years) scheduled for hip replacement. The study was double-blind and placebo-controlled with parallel groups. GH or placebo was administered for 14 weeks preoperatively (target GH dose 0.04 U/kg/day) and 4 weeks postoperatively (with dose doubled for first 2 weeks postoperatively). Serum IGF-I, body composition, mid-thigh muscle cross-sectional area, muscle strength and 4-min walking distance were measured at baseline, 2-3 days preoperatively and 4 weeks postoperatively. RESULTS: Mean serum IGF-I doubled during GH treatment. Lean body mass increased preoperatively by an average of 5.2% (representing 1.8 kg) with GH treatment (P < 0.05 vs. placebo), but fell postoperatively by 3% in both groups. Similar changes pre- and postoperatively were seen for mid-thigh muscle cross-sectional area, such that there was no net loss in the GH group but a fall of more than 10% in the placebo group (P < 0.005 vs. GH). There was a trend towards a favourable effect of GH on strength in the majority of muscles tested, but this was significant only for the abductors of the nonoperated hip (P < 0.02), where there was a 7% increase in strength over the whole study compared with a 25% decrease in the placebo group. Four-minute walking distance improved postoperatively by a mean of 26.9 m in the GH group compared with a 19.5 m reduction in the placebo group (P < 0.05). Dose-related side-effects were seen in the majority of patients receiving GH. CONCLUSIONS: In elderly patients undergoing total hip replacement, preoperative GH treatment results in improvements in lean body mass and skeletal muscle mass that are sufficient to offset postoperative losses. The treatment may also preserve or improve muscle strength and postoperative walking ability.

Aged↗

Comparison of anthropometric equations for estimation of total body water in peritoneal dialysis patients.

BACKGROUND: Several formulae exist for estimating total body water (TBW). We aimed to assess their validity in peritoneal dialysis patients by comparison with TBW estimated by deuterium oxide dilution (TBW(D)). METHODS: We compared the equations of Chertow (TBW(Cher)), Chumlea (TBW(Chum)), Hume and Weyers (TBW(HW)), Johansson (TBW(J)), Lee (TBW(L)), Watson (TBW(W)) and TBW as 58% of body weight (TBW(0.58Wt)) with TBW(D) in 31 peritoneal dialysis (PD) patients and 32 controls. Estimates were compared with TBW(D) using Bland and Altman comparison. Extracellular water (ECW) was also estimated by sodium bromide dilution. RESULTS: In PD patients, mean TBW(D) was 35.04 (SD 7.84) l. Estimates were greater for TBW(Cher), TBW(Chum), TBW(HW), TBW(J) and TBW(0.58Wt). Mean TBW(L) and TBW(W) did not differ from TBW(D). Ninety-five percent limits of agreement (LOA) compared with TBW(D) (as a percentage of the mean) were similar for all of the different equations in PD patients (between +/-15.4 and +/-17.3%) except TBW(0.58Wt), which was far greater (+/-26.4%). In controls, mean TBW(D) was 37.03 (SD 6.63) l. Estimates were greater for TBW(Cher), TBW(Chum), TBW(HW), TBW(J) and TBW(0.58Wt). Mean TBW(L) and TBW(W) did not differ from TBW(D). Ninety-five percent LOA compared with TBW(D) (as a percentage of the mean) were similar for all equations in the controls, and closer than in PD patients (between +/-9.1 and +/-11.5%) except TBW(0.58Wt), which was again far greater than the other equations (+/-28.1%). TBW(HW) - TBW(D) correlated with mean TBW (r=-0.412, P<0.05 in PD and r=-0.383, P<0.05 in controls). TBW(W) - TBW(D) (r=-0.539, P<0.005) correlated with mean TBW in PD. TBW(0.58Wt) - TBW(D) correlated with body mass index (BMI) (r=0.624, P<0.0001 in PD and r=0.829, P<0.0001 in controls) and ECW/TBW (r=0.406, P<0.05 in PD and r=0.411, P<0.02 in controls). CONCLUSIONS: Predictive equations were less accurate in PD than controls. TBW(0.58Wt) was most inaccurate, with systematic overestimation of TBW with increasing BMI and ECW/TBW. There were no differences in LOA with TBW(D) for the other equations within each group.

Adult↗

Genes for chlorogenate and hydroxycinnamate catabolism (hca) are linked to functionally related genes in the dca-pca-qui-pob-hca chromosomal cluster of Acinetobacter sp. strain ADP1.

Hydroxycinnamates are ubiquitous in the environment because of their contributions to the structure and defense mechanisms of plants. Additional plant products, many of which are formed in response to stress, support the growth of Acinetobacter sp. strain ADP1 through pathways encoded by genes in the dca-pca-qui-pob chromosomal cluster. In an appropriate genetic background, it was possible to select for an Acinetobacter strain that had lost the ability to grow with caffeate, a commonly occurring hydroxycinnamate. The newly identified mutation was shown to be a deletion in a gene designated hcaC and encoding a ligase required for conversion of commonly occurring hydroxycinnamates (caffeate, ferulate, coumarate, and 3,4-dihydroxyphenylpropionate) to thioesters. Linkage analysis showed that hcaC is linked to pobA. Downstream from hcaC and transcribed in the direction opposite the direction of pobA transcription are open reading frames designated hcaDEFG. Functions of these genes were inferred from sequence comparisons and from the properties of knockout mutants. HcaD corresponded to an acyl coenzyme A (acyl-CoA) dehydrogenase required for conversion of 3,4-dihydroxyphenylpropionyl-CoA to caffeoyl-CoA. HcaE appears to encode a member of a family of outer membrane proteins known as porins. Knockout mutations in hcaF confer no discernible phenotype. Knockout mutations in hcaG indicate that this gene encodes a membrane-associated esterase that hydrolyzes chlorogenate to quinate, which is metabolized in the periplasm, and caffeate, which is metabolized by intracellular enzymes. The chromosomal location of hcaG, between hcaC (required for growth with caffeate) and quiA (required for growth with quinate), provided the essential clue that led to the genetic test of HcaG as the esterase that produces caffeate and quinate from chlorogenate. Thus, in this study, organization within what is now established as the dca-pca-qui-pob-hca chromosomal cluster provided essential information about the function of genes in the environment.

Acinetobacter↗

PET-MR image fusion in soft tissue sarcoma: accuracy, reliability and practicality of interactive point-based and automated mutual information techniques.

The fusion of functional positron emission tomography (PET) data with anatomical magnetic resonance (MR) or computed tomography images, using a variety of interactive and automated techniques, is becoming commonplace, with the technique of choice dependent on the specific application. The case of PET-MR image fusion in soft tissue is complicated by a lack of conspicuous anatomical features and deviation from the rigid-body model. Here we compare a point-based external marker technique with an automated mutual information algorithm and discuss the practicality, reliability and accuracy of each when applied to the study of soft tissue sarcoma. Ten subjects with suspected sarcoma in the knee, thigh, groin, flank or back underwent MR and PET scanning after the attachment of nine external fiducial markers. In the assessment of the point-based technique, three error measures were considered: fiducial localisation error (FLE), fiducial registration error (FRE) and target registration error (TRE). FLE, which represents the accuracy with which the fiducial points can be located, is related to the FRE minimised by the registration algorithm. The registration accuracy is best characterised by the TRE, which is the distance between corresponding points in each image space after registration. In the absence of salient features within the target volume, the TRE can be measured at fiducials excluded from the registration process. To assess the mutual information technique, PET data, acquired after physically removing the markers, were reconstructed in a variety of ways and registered with MR. Having applied the transform suggested by the algorithm to the PET scan acquired before the markers were removed, the residual distance between PET and MR marker-pairs could be measured. The manual point-based technique yielded the best results (RMS TRE =8.3 mm, max =22.4 mm, min =1.7 mm), performing better than the automated algorithm (RMS TRE =20.0 mm, max =30.5 mm, min =7.7 mm) when registering filtered back-projection PET images to MR. Image reconstruction with an iterative algorithm or registration of a composite emission-transmission image did not improve the overall accuracy of the registration process. We have demonstrated that, in this application, point-based PET-MR registration using external markers is practical, reliable and accurate to within approximately 5 mm towards the fiducial centroid. The automated algorithm did not perform as reliably or as accurately.

Fluorodeoxyglucose F18↗