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Biomedical subjects

S Topp

Publications and source records attributed to S Topp.

At least 19 recordsLinked to original sources
PubMed2001

Characterisation of gene expression changes following permanent MCAO in the rat using subtractive hybridisation.

Failure of several putative neuroprotectants in large multicentred clinical trials has re-focussed attention on the predictability of pre-clinical animal models of stroke. Model characterisation and relationship to heterogeneous patient sub-groups remains of paramount importance. Information gained from magnetic resonance imaging (MRI) signatures indicates that the Zea Longa model of rat middle cerebral artery occlusion may be more representative of slowly evolving infarcts. Understanding the molecular changes over several hours following cerebral ischaemia will allow detailed characterisation of the adaptive response to brain injury. Using a fully characterised model of Zea Longa middle cerebral artery occlusion we have used the representational difference analysis (RDA) subtractive hybridisation method to identify transcripts that accumulate in the ischaemic cortex. Along with a number of established ischaemia-induced gene products (including MCP-1, TIMP-1, hsp 70) we were also able to identify nine genes which have not previously been shown to accumulate following focal ischaemia (including SOCS-3, GADD45gamma, Xin).

Animals↗
PubMed2001

Evaluation of CA1 damage using single-voxel 1H-MRS and un-biased stereology: Can non-invasive measures of N-acetyl-asparate following global ischemia be used as a reliable measure of neuronal damage?

Global brain ischemia provoked by transient occlusion of the carotid arteries (2VO) in gerbils results in a severe loss of neurons in the hippocampal CA1 region. We measured the concentration of the neuron specific N-acetyl-aspartate, [NAA], in the gerbil dorsal hippocampus by proton MR spectroscopy (1H-MRS) in situ, and HPLC, 4 days after global ischemia. The [NAA] was correlated with graded hippocampus damage scoring and stereologically determined neuronal density. A basal hippocampal [NAA] of 8.37+/-0.10 and 9.81+/-0.44 mmol/l were found from HPLC and 1H-MRS, respectively. HPLC measurements of [NAA] obtained from hippocampus 4 days after 2VO showed a 20% reduction in the [NAA] following 4 min of ischemia (P<0.001). 1H-MRS measurements on gerbils subjected to 4 or 8 min of ischemia showed a similar 24% decline in the [NAA] (P<0.05). Thus, there was correlation between the HPLC and 1H-MRS determined NAA decline. There was also a significant correlation between 1H-MRS [NAA] and the corresponding reduction in CA1 neuronal density (P<0.004). In summary our findings show that single voxel 1H-MRS can be used as a supplement to histological evaluation of neuronal injury in studies after global brain ischemia. Accordingly, volume selective spectroscopy has a potential for assessment of neuroprotective therapeutic compounds/strategies with respect to neuronal rescue for delayed ischemic brain damage.

Animals↗
PubMed2001

Are grammatical representations useful for learning from biological sequence data?--a case study.

This paper investigates whether Chomsky-like grammar representations are useful for learning cost-effective, comprehensible predictors of members of biological sequence families. The Inductive Logic Programming (ILP) Bayesian approach to learning from positive examples is used to generate a grammar for recognising a class of proteins known as human neuropeptide precursors (NPPs). Collectively, five of the co-authors of this paper, have extensive expertise on NPPs and general bioinformatics methods. Their motivation for generating a NPP grammar was that none of the existing bioinformatics methods could provide sufficient cost-savings during the search for new NPPs. Prior to this project experienced specialists at SmithKline Beecham had tried for many months to hand-code such a grammar but without success. Our best predictor makes the search for novel NPPs more than 100 times more efficient than randomly selecting proteins for synthesis and testing them for biological activity. As far as these authors are aware, this is both the first biological grammar learnt using ILP and the first real-world scientific application of the ILP Bayesian approach to learning from positive examples. A group of features is derived from this grammar. Other groups of features of NPPs are derived using other learning strategies. Amalgams of these groups are formed. A recognition model is generated for each amalgam using C4.5 and C4.5rules and its performance is measured using both predictive accuracy and a new cost function, Relative Advantage (RA). The highest RA was achieved by a model which includes grammar-derived features. This RA is significantly higher than the best RA achieved without the use of the grammar-derived features. Predictive accuracy is not a good measure of performance for this domain because it does not discriminate well between NPP recognition models: despite covering varying numbers of (the rare) positives, all the models are awarded a similar (high) score by predictive accuracy because they all exclude most of the abundant negatives.

Bayes Theorem↗
PubMed2000

Split-cava technique: liver splitting for two adult recipients.

Split-liver transplantation for 2 adult recipients is a challenging procedure because of the need to split through the midplane of the donor liver. In applied techniques, usually the middle hepatic vein is retained with the left split and the vena cava retained with the right split graft, particularly to avoid serious venous congestion of the right graft after reperfusion. The indispensable division of the caudate lobe veins lead to uncertain viability of liver segment I, and resection might be necessary. To provide optimal venous drainage of both hemiliver grafts, we developed the split-cava technique. This article describes our new technique of liver splitting, which has been successfully used in 2 in situ harvesting procedures.

Adult↗
PubMed2000

Split liver transplantation (SLT).

OBJECTIVES: In the last three decades liver transplantation (LT) has become a standard procedure for terminal liver failure. Anyway the procedure is highly limited by the availability of donor organs. The use of segmental liver grafts from living or cadaver donors are an attractive way to increase the donor pool for LT in adults and children. METHODS: Between 1991 and April 1999 we performed 647 liver transplantations in 416 adults and 231 children. 431 OLT, 124 SLT and 92 LRLT. Commonly used segmental liver grafts are the full right graft, the full left graft, the left lateral lobe graft and the right extended graft from living or cadaver donors respectively. RESULTS: The 1-year survival of elective SLT in adults is 80.5% and in children 84.3% (SLT + LRLT). CONCLUSIONS: Splitting procedures in liver transplantation are a promising completion to whole organ transplantations. The results of split liver (SLT) and living related liver transplantations (LRLT) are comparable to whole organ transplantations. These methods are able to increase the organ pool and thus decrease the pretransplant mortality both in children and adults.

Adult↗
PubMed1999

Localized in vivo 1H NMR spectroscopy of murine tumours: effect of blood flow reduction.

Single voxel 1H localized spectroscopy (PRESS at 300 MHz) was used to monitor physiological and biochemical changes induced by hydralazine (5 mg/kg, i.p.) in murine C3H mammary tumours. In addition to a significant increase (by 52%, maximal at 30 min) in the intensity of the 1.32 ppm signal (predominantly from lactate, consistent with a selective reduction in tumour blood supply by hydralazine), downfield shifts in the resonance frequencies of 1H signals were observed. In particular, the signal initially at 3.24 ppm (total choline, tCho) shifted by 0.050 ppm (maximal at 13 min), whereas water shifted by 0.086 ppm. Lactate intensity and water and tCho resonance frequencies returned to control values at approximately 100 min after treatment. No significant changes in the resonance frequencies of water or tCho were observed over this time period in the tumours of mice given saline. In vitro studies showed that, while the resonance frequency of water was temperature dependent, the main components of the tCho signal (choline, phosphorylcholine and glycerophosphorylcholine) were more than 30-fold less sensitive to temperature. It was concluded that the shift in the water resonance frequency was due to the combined effects of tumour temperature reduction and a paramagnetic shift from increased deoxyhaemoglobin levels, whereas the tCho signal was only affected by the paramagnetic shifts.

Animals↗
PubMed1999

Systemic effects and side effects of interstitial techniques used in liver tissue.

BACKGROUND: Percutaneous ethanol injection (PEI) and cryosurgery are increasingly used for the treatment of liver malignancies. To create a safety margin and to destroy completely diffusely growing tumors, the precise destruction of healthy liver tissue is necessary. Little is known about the effects of operating on this type of tissue. This study evaluated the effects and side effects of PEI and cryosurgery when applied to normal parenchyma of the liver. STUDY DESIGN: Two groups of six minipigs each were treated with either PEI or cryosurgery to create necrosis in the liver. During and after the procedures, vital signs were monitored and necrotic areas were observed by ultrasonography. Standard and immunohistochemistry stains were made from samples of the necrosis, the liver, and the lung. RESULTS: In the PEI group, thromboembolic complications occurred in all animals (fatality rate 50%). Hematogenous spread of hepatocytes was demonstrated by immunohistochemistry and was a cause of pulmonary embolism. In the cryosurgery group, neither specific complications nor signs of cell spillage occurred. Because of an isolating effect of blood perfusion, hepatocytes close to the portal triads were less damaged, vital cells were present in the periphery, and the necroses were smaller than the induced lesions. CONCLUSIONS: The effect of PEI in healthy liver tissue is unpredictable. This makes the creation of a safety margin or the treatment of a diffusely infiltrating tumor impossible. PEI always introduces the risk of hematogenous cell spread. Effects of cryosurgery are less dependent on tissue qualities. In both techniques, the real extent of complete tissue destruction cannot be visualized by ultrasonography.

Animals↗
PubMed1999

N-Acetylaspartate distribution in rat brain striatum during acute brain ischemia.

Brain N-acetylaspartate (NAA) can be quantified by in vivo proton magnetic resonance spectroscopy (1H-MRS) and is used in clinical settings as a marker of neuronal density. It is, however, uncertain whether the change in brain NAA content in acute stroke is reliably measured by 1H-MRS and how NAA is distributed within the ischemic area. Rats were exposed to middle cerebral artery occlusion. Preischemic values of [NAA] in striatum were 11 mmol/L by 1H-MRS and 8 mmol/kg by HPLC. The methods showed a comparable reduction during the 8 hours of ischemia. The interstitial level of [NAA] ([NAA]e) was determined by microdialysis using [3H]NAA to assess in vivo recovery. After induction of ischemia, [NAA]e increased linearly from 70 micromol/L to a peak level of 2 mmol/L after 2 to 3 hours before declining to 0.7 mmol/L at 7 hours. For comparison, [NAA]e was measured in striatum during global ischemia, revealing that [NAA]e increased linearly to 4 mmol/L after 3 hours and this level was maintained for the next 4 h. From the change in in vivo recovery of the interstitial space volume marker [14C]mannitol, the relative amount of NAA distributed in the interstitial space was calculated to be 0.2% of the total brain NAA during normal conditions and only 2 to 6% during ischemia. It was concluded that the majority of brain NAA is intracellularly located during ischemia despite large increases of interstitial [NAA]. Thus, MR quantification of NAA during acute ischemia reflects primarily changes in intracellular levels of NAA.

Acute Disease↗
PubMed1998

Volumetric spectroscopic imaging with spiral-based k-space trajectories.

Spiral-based k-space trajectories were applied in a spectroscopic imaging sequence with time-varying readout gradients to collect volumetric chemical shift information. In addition to spectroscopic imaging of low signal-to-noise ratio (SNR) brain metabolites, the spiral trajectories were used to rapidly collect reference signals from the high SNR water signal to automatically phase the spectra and to aid the reconstruction of metabolite maps. Spectral-spatial pulses were used for excitation and water suppression. The pulses were designed to achieve stable phase profiles in the presence of up to 20% variation in the radiofrequency field. A gridding algorithm was used to resample the data onto a rectilinear grid before fast Fourier transforms. This method was demonstrated by in vivo imaging of brain metabolites at 1.5 T with 10 slices of 18 x 18 pixels each. Nominal voxel size was 1.1 cc, spectral bandwidth was 400 Hz, scan time was 18 min for the metabolite scan and 3 min for the reference scan.

Aspartic Acid↗
PubMed1998

Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain.

We have performed a multicentre trial to assess the performance of three techniques for absolute quantification of cerebral metabolites using in vivo proton nuclear magnetic resonance (NMR). The techniques included were 1) an internal water standard method, 2) an external standard method based on phantom replacement, and 3) a more sophisticated method incorporating elements of both the internal and external standard approaches, together with compartmental analysis of brain water. Only the internal water standard technique could be readily implemented at all participating sites and gave acceptable precision and interlaboratory reproducibility. This method was insensitive to many of the experimental factors affecting the performance of the alternative techniques, including effects related to loading, standing waves and B1 inhomogeneities; and practical issues of phantom positioning, user expertise and examination duration. However, the internal water standard method assumes a value for the concentration of NMR-visible water within the spectroscopic volume of interest. In general, it is necessary to modify this assumed concentration on the basis of the grey matter, white matter and cerebrospinal fluid (CSF) content of the volume, and the NMR-visible water content of the grey and white matter fractions. Combining data from 11 sites, the concentrations of the principal NMR-visible metabolites in the brains of healthy subjects (age range 20-35 years) determined using the internal water standard method were (mean+/-SD): [NAA]=10.0+/-3.4 mM (n=53), [tCho]=1.9+/-1.0 mM (n=51), [Cr + PCr]=6.5+/-3.7 mM (n=51). Evidence of system instability and other sources of error at some participating sites reinforces the need for rigorous quality assurance in quantitative spectroscopy.

Adult↗
PubMed1998

[Differences in properties of interstitial procedures and their effect on clinical applications].

The effects of percutaneous ethanol injection (PEI) and cryosurgery (CS) on normal liver tissue are investigated in a mini-pig model. It was not possible to create a circumscribed, reproducible necrosis by PEI; there was a high incidence of thromboembolic complications. Due to the discrepancy between the temperatures necessary to induce freezing and to induce total cell destruction, the necroses were smaller than the ice balls induced by CS and contained vital cells in their periphery. In conclusion, PEI should not be used when ethanol spreading into normal parenchyma has to be assumed, and the difference in size between ice ball and complete necrosis has to be considered in tumor treatment by CS.

Animals↗
PubMed1997

Quantification of brain metabolites in amyotrophic lateral sclerosis by localized proton magnetic resonance spectroscopy.

We performed proton magnetic resonance spectroscopy (1H-MRS) in patients with motor neuron disease (MND) to determine the absolute in vivo concentrations in the brain of the metabolites N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr/PCr). We examined the spectra acquired from a 20 x 20 x 20-mm3 voxel placed in the motor cortex and in the cerebellum from seven patients with clinically probable or definite amyotrophic lateral sclerosis (ALS) according to the El Escorial criteria, from three patients with suspected ALS (progressive muscular atrophy), and from eight normal control subjects. We estimated the concentrations of the metabolites using the water signal as an internal standard. The concentrations of Cho and Cr/PCr in both brain regions, as well as the concentration of NAA in the cerebellum, were unaltered in the MND patients compared with the controls. Only MND patients with both upper and lower motor neuron signs had a significantly decreased concentration of NAA (9.13 +/- 0.28 mM, mean +/- SEM) in the primary motor cortex when compared with healthy controls (10.03 +/- 0.22 mM). In conclusion, the slightly decreased concentration of NAA in the primary motor cortex from ALS patients may represent a loss of neurons in this region.

Adult↗
PubMed1996

Quantitative 1D saturation profiles on chalk by NMR.

Quantitative one-dimensional saturation profiles showing the distribution of water and oil in chalk core samples are calculated from NMR measurements utilizing a 1D CSI spectroscopy pulse sequence. Saturation profiles may be acquired under conditions of fluid flow through the sample. Results reveal that strong saturation gradients exist in chalk core samples after core floods, due to capillary effects. The method is useful in analysis of corefloods, e.g., for determination of capillary pressure functions.

Calcium Carbonate↗
PubMed1985

A method for assessing the height of the patella.

In 150 normal subjects the distance (P) between the upper and lower limits of the articular surface of the patella, and the shortest distance (T) between this same lower limit and the tibial plateau, were measured in standard lateral views of the knee in about 30 degrees of flexion. The limits of confidence of the T/P ratio are shown in the Table. The 5% upper limit of normality of this ratio is 1.11 (one-sided). This method of determining the position of the patella is accurate and more simple than those previously described.

Adult↗