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I C Smith

Publications and source records attributed to I C Smith.

At least 37 records · Page 2Linked to original sources
PubMed1998

Caffeine- and noradrenaline-induced contractions of human vas deferens: contrasting effects of procaine, ryanodine and W-7.

1. The effects of ryanodine, procaine, and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) on noradrenaline (NA)- and caffeine-induced contractions of human vas deferens were investigated. 2. In the presence of nifedipine (1 microM), NA ( 100 microM) evoked biphasic contractions. Caffeine (20 mM) evoked repeatable tonic contractions. 3. Ryanodine (30 microM) inhibited the initial but not the secondary component of NA contractions. Procaine (1 and 10 mM) inhibited both components. Contractions induced by caffeine were unaffected by ryanodine or procaine. 4. The calmodulin antagonist W-7 (100 microM) reduced, in a reversible manner, both components of NA-induced response. Caffeine-induced contractions were also reduced in most preparations (8 of 11). In all preparations, contractions induced by caffeine were markedly inhibited after the washout of W-7. Higher doses of W-7 (300 microM) induced an increase in basal tension. 5. These results indicate that NA contracts the longitudinal muscle of human vas deferens by a ryanodine-sensitive calcium-induced calcium release (CICR) mechanism and, in addition, a ryanodine-insensitive pathway: both are sensitive to procaine. In contrast, contraction induced by caffeine is mediated by a pathway that is atypically insensitive to either ryanodine or procaine. The sensitivity of NA- and caffeine-induced contraction to W-7 suggests a role for calcium and its interaction with calmodulin in the response to both agents. The paradoxical action of W-7 is discussed.

Anesthetics, Local↗
PubMed1998

Gamma emission imaging in the management of breast disorders.

Breast cancer is the commonest malignancy to affect women. The malignant process may present clinicians with problems in establishing the diagnosis expeditiously, accurately staging the disease and assessing tumour response to primary systemic chemotherapy. Considerable recent interest has focused on the application of imaging techniques that utilize tumour-specific gamma-ray-emitting radiopharmaceuticals to resolve these problems. The wide availability of gamma camera systems makes single photon-imaging techniques, using radiopharmaceuticals incorporating conventional isotopes, attractive options. However, results concerning the detection of the primary breast cancer and the staging of axillary lymph nodes suggest that these techniques would appear to offer no significant advantages, when compared with those obtained using standard diagnostic methods. Dual gamma-ray-emission imaging by positron emission tomography (PET) may offer an alternative solution. Studies performed show that PET can accurately detect primary breast cancers, stage locoregional lymph nodes and visualize distant tumour metastases. Furthermore, PET may be able to monitor early tumour response to chemotherapy agents. It would appear, therefore, that dual gamma emission might have an important role to play in the management of patients with breast cancer.

Bone Neoplasms↗
PubMed1998

Hypercalcaemia in patients with cancer: aetiology and treatment.

Hypercalcaemia is one of the most common disorders occurring in patients with cancer and may have disabling symptoms. The mechanisms underlying hypercalcaemia associated with malignant disease, the symptoms attributable to and the treatment of this disorder are discussed in this paper.

Humans↗
PubMed1998

Electromechanical coupling in human vas deferens: effects of agents that modulate intracellular release of calcium.

1. The effects of ryanodine, cyclopiazonic acid (CPA) and caffeine on electromechanical coupling in human vas deferens were investigated. 2. High [K+]o (120 mM) evoked nifedipine-sensitive contractions of longitudinal and circular muscle which consisted of initial and secondary components. 3. Exposures to ryanodine (< or =10 microM) or CPA (< or = 3 microM) induced a change of basal tension, and higher doses (30 microM) induced intermittent rhythmic contractions of both muscle types in the quiescent tissue. In the presence of the drugs, contraction to high [K+]o was preceded by marked rhythmic activity. 4. In circular muscle, ryanodine (1-30 microM) or CPA (1-30 microM) reduced both components of contractions to high [K+]o. In longitudinal muscle, the drugs enhanced the initial component and prolonged the secondary component. High doses (> or = 10 microM) produced variable effects on the initial component. 5. Caffeine (20 mM) reliably contracted longitudinal, but not circular muscle. Pre-exposures to caffeine enhanced both components in the post-caffeine contractions of circular muscle to high [K+]o. In longitudinal muscle, only the initial component (post-caffeine) was enhanced. 6. Contractions evoked in longitudinal muscle by caffeine were not blocked by ryanodine (30 microM) or CPA (30 microM). However, the enhancement of post-caffeine contractions to high [K+]o was inhibited. 7. These results show that ryanodine and CPA produced comparable effects on the excitability of longitudinal and circular muscle in the quiescent tissue, but electromechanical coupling was affected differently. The findings suggest that the muscle types utilize different mechanisms to regulate elevations in cytosolic Ca2+ during stimulation. 8. Electromechanical coupling in both muscle types involves Ca2+ influx via nifedipine-sensitive voltage-operated calcium channels and activation of ryanodine-sensitive calcium-induced calcium release from the sarcoplasmic reticulum (SR). In longitudinal muscle, the SR also buffers increases in cytosolic Ca2+ via a pharmacologically distinct Ca2+ compartment (caffeine releasable but ryanodine/CPA-insensitive). In circular muscle, the SR (ryanodine/CPA-sensitive) serves mainly in the regulation of excitability of the quiescent tissue.

Caffeine↗
PubMed1998

Ryanodine- and cyclopiazonic acid-sensitive components in human vas deferens contractions to noradrenaline.

1. The role of calcium stores in noradrenaline- (NA) and caffeine-induced contractions of human vas deferens were investigated using ryanodine and cyclopiazonic acid (CPA) in the presence of the calcium antagonist, nifedipine (1 microM) or in calcium-free/EGTA (1 mM) medium. 2. In either media, NA (100 microM) evoked biphasic contractions of longitudinal muscle and tonic circular muscle contractions. Caffeine (20 mM) evoked longitudinal but not circular muscle contractions. 3. Ryanodine (1-30 microM) or CPA (1-30 microM) inhibited contractions of circular muscle, and the initial but not secondary component of longitudinal muscle contraction to NA. 4. In the presence of nifedipine, pre-exposure to caffeine caused a potentiation of circular muscle, and the initial but not secondary longitudinal muscle contractions to NA. The presence of ryanodine or CPA during the caffeine pre-exposures effectively blocked the potentiation of the initial component and reduced the secondary component of the subsequent responses to NA in longitudinal muscle. 5. In calcium-free media, caffeine pre-exposures had little effect on subsequent NA-induced contractions in circular muscle, but reduced both components in longitudinal muscle. The presence of ryanodine or CPA during caffeine pre-exposures produced no further effects on either component of the subsequent NA-induced contraction in longitudinal muscle. 6 In the presence of nifedipine or in calcium-free media, repeated applications of caffeine evoked contractions in longitudinal muscle which were not blocked by either ryanodine or CPA. 7. These results suggest that circular muscle contraction by NA and the initial component of longitudinal muscle to NA both utilize an intracellular pool of calcium that is triggered via a ryanodine-sensitive mechanism and replenished via a CPA-sensitive Ca2+-ATPase. 8. In longitudinal muscle, both the secondary component of its response to NA and contraction to caffeine appear to involve an unusual but pharmacologically distinct (ryanodine- and CPA-insensitive) pathway. 9. The quiescence to caffeine of circular muscle may be caused by a relative absence of the ryanodine- and CPA-insensitive pathway.

Adrenergic alpha-Agonists↗
PubMed1998

Staging of the axilla in breast cancer: accurate in vivo assessment using positron emission tomography with 2-(fluorine-18)-fluoro-2-deoxy-D-glucose.

OBJECTIVE: To evaluate the ability of positron emission tomography (PET) with 18F-fluoro-2-deoxy-D-glucose (18F-FDG) to determine noninvasively axillary lymph node status in patients with breast cancer. BACKGROUND: The presence of axillary lymph node metastasis is the most important prognostic factor in women with breast cancer. It signifies the presence of occult metastatic disease and indicates the need for adjuvant therapy. The only reliable way in which this important prognostic information may be obtained is by performing axillary dissection, which may be associated with significant complications and delay in discharge from the hospital. PET with 18F-FDG can visualize primary cancers in the breast and metastatic tumor deposits. METHODS: Fifty patients with untreated breast cancer had clinical examination of their axilla performed (graded as positive or negative), followed by PET of the axilla and midthorax. PET data were analyzed blindly and graded as positive or negative, depending on the presence or absence of axillary nodal metastases. Cytopathologic assessment of the axillary nodes was carried out within 1 week of PET, by fine-needle aspiration cytology in 5 patients and axillary dissection in 45; the excised specimens were examined by a single pathologist. RESULTS: The overall sensitivity of PET in 50 patients was 90% and the specificity was 97%. Clinical examination of the same patients had an overall sensitivity of 57% and a specificity of 90%. In the 24 patients with locally advanced breast cancer (T3, T4, TxN2), PET had a sensitivity of 93% and a specificity of 100%. In T1 tumors (seven patients), the sensitivity and specificity were 100%. PET had a high predictive value (>90%) and accuracy (94%) in staging the axilla. CONCLUSIONS: PET is a sensitive and specific method of staging the axilla in patients with breast cancer. It may obviate the need for axillary surgery in women with small primary tumors, define the women likely to benefit from axillary dissection, or allow radiotherapy to be substituted for surgery, particularly in post-menopausal women.

Adult↗
PubMed1998

Diagnosis of cancer in humans by 1H NMR of tissue biopsies.

We describe methodology for the diagnosis of human cancer, at high levels of accuracy, sensitivity, and specificity, by 1H NMR of tissue biopsies. This method is made robust and accurate by careful specimen preparation, and by multivariate analysis of spectral data. Examples are presented for the diagnosis of cancer of the prostate gland and the ovary. The potential for use of these methods noninvasively, in vivo, is shown to be very positive.

Adult↗
PubMed1998

Magnetic resonance spectroscopy in clinical chemistry: the present and the future.

Magnetic resonance spectroscopy is a powerful technique for the analysis of complex mixtures. Up to now, little of its potential in everyday clinical chemistry has been realized. An overview of the fundamentals, a discussion of the technology, and some outstanding examples of the clinical chemical research are presented. Clinical chemists are encouraged to seek out and apply this methodology to problems for which it is well suited.

Chemistry, Clinical↗
PubMed1997

An electrophysiological method for measuring the potassium permeability of the nerve perineurium.

An electrophysiological method is described for measuring the potassium permeability (PK) of the perineurium of the sciatic nerve of the frog. The method is based on the principle of grease-gap recording, in which an insulating compartment separates two surface recording electrodes. The sciatic nerves of frogs Rana temporaria and R. pipiens were isolated and mounted across a five compartment chamber, with Vaseline grease seals on the partitions between compartments. Compartments #1, #2 and #5 contained frog Ringer solution, #4 was filled with Vaseline and formed the grease gap, and #3 was the test compartment in which solutions could be changed. The nerve was stimulated via platinum electrodes in compartments #1 and #2, and DC potentials and compound action potentials (CAP) were recorded between Ag/AgCl electrodes connected through Ringer-agar bridges to compartments #3 and #5. In nerves with undamaged perineurium, changing from normal Ringer to high [K+] Ringer (100 mM, KCl replacing NaCl) for 2 min caused negligible change in DC potential or CAP, indicating that raised [K+] was not reaching the axon surface, and hence that the perineurium was exerting a diffusional restriction on K+ entry. In nerves damaged by stretching or drying, K+ pulses caused a depolarising change in DC potential (delta DC), and corresponding decline in CAP amplitude, consistent with a leaky perineurium allowing K+ entry and axonal depolarisation. Ringer made hypertonic by the addition of 2.5 M sucrose or 5 M NaCl caused increased perineurial permeability to K+. The method was calibrated by measuring the delta DC in response to raised [K+] in the range 5-100 mM [K+] in desheathed nerves; from this calibration curve relating delta DC to endoneurial [K+] it was possible to calculate the change in endoneurial [K+] occurring in intact preparations. The calculations showed that the undamaged perineurium had a PK of < 6.3 x 10(-7) cm.s-1, similar to the value calculated for in situ nerves using radioisotopic techniques, but less than the value reported for isolated perineurial cylinders. The method gives real-time information on the K+ permeability of the nerve perineurium and its modulation by experimental treatments.

Animals↗
PubMed1997

The classification of benign and malignant human prostate tissue by multivariate analysis of 1H magnetic resonance spectra.

1H magnetic resonance spectroscopy studies (360 MHz) were performed on specimens of benign (n = 66) and malignant (n = 21) human prostate tissue from 50 patients, and the spectral data were subjected to multivariate analysis, specifically linear-discriminant analysis. On the basis of histopathological assessments, an overall classification accuracy of 96.6% was achieved, with a sensitivity of 100% and a specificity of 95.5% in classifying benign prostatic hyperplasia from prostatic cancer. Resonances due to citrate, glutamate, and taurine were among the six spectral subregions identified by our algorithm as having diagnostic potential. Significantly higher levels of citrate were observed in glandular than in stromal benign prostatic hyperplasia (P < 0.05). This method shows excellent promise for the possibility of in vivo assessment of prostate tissue by magnetic resonance.

Discriminant Analysis↗
PubMed1997

Classification of 1H MR spectra of biopsies from untreated and recurrent ovarian cancer using linear discriminant analysis.

Proton (1H) magnetic resonance (MR) spectra of ex vivo biopsy samples of ovarian cancers provided biochemical information that was used to discriminate cancer from normal ovarian tissue. Possible differences present in intrinsically resistant tumors or changes in biochemistry after the induction of resistance were identified. Using multivariate techniques, in particular linear discriminant analysis (LDA), ovarian cancer was distinguished from normal ovarian tissue with a sensitivity of 100%, a specificity of 95% and an accuracy of 98%. Moreover, LDA was able to distinguish untreated ovarian cancer from recurrent ovarian cancer with a sensitivity of 92%, a specificity of 100%, and an accuracy of 97%; removal of the single "fuzzy" specimen increased the accuracy to 100%. Applications of this knowledge to in vivo measurements could lead to noninvasive diagnosis of ovarian cancer.

Biopsy↗
PubMed1995

Nuclear magnetic resonance spectroscopy.

The range of problems in clinical chemistry that can be addressed by MRS is wide. The number of applications reported in the literature is growing steadily, particularly since the study of the composition of physiological fluids and tissues, and the changes thereof in disease, are well suited to study by MRS. Moreover, the major technical limitations that have impeded its progress into the clinical laboratory in the past have been addressed. Recent hardware and software developments have further improved and simplified MRS analysis. Thus, it would be surprising if MRS of physiological fluids and tissues does not become an essential technique for clinical chemists and pathologists. In practice, three main obstacles remain to be overcome: a greater availability of instruments, a larger data base of spectral changes correlated with pathological conditions, and an enhanced supply of MR-trained individuals in the clinical environment.

Animals↗
PubMed1995

The human vas deferens: correlation of response pattern to noradrenaline and histological structure.

Specimens of human vas deferens were studied histologically and by measuring changes in response to adrenoceptor agonists. In intact tissues noradrenaline induced both lengthening and shortening responses which were identified with contractions of circular and longitudinal muscle respectively. The agonists phenylephrine or methoxamine evoked mainly shortening but little lengthening. The tissues were unresponsive to clonidine or isoprenaline. Longitudinal strips but not rings responded reliably to phenylephrine and to caffeine. The lengthening responses of intact specimens to noradrenaline were relatively insensitive to the antagonist phenoxybenzamine. In contrast both shortening and lengthening responses were inhibited by prazosin or phentolamine but not by idazoxan. A physiological function for the predominance of muscle types in different specimens is proposed. A pharmacological selectivity for the muscle types by alpha 1-selective adrenoceptor agonists and by phenoxybenzamine is discussed and the clinical implication considered.

Adrenergic alpha-Agonists↗
PubMed1995

Resolving anatomical details in lung parenchyma: theory and experiment for a structurally and magnetically inhomogeneous lung imaging model.

Lung parenchyma is, structurally and magnetically, a very inhomogeneous system. The strong local field gradients due to magnetic susceptibility variation across the air-tissue interfaces impose a spatially dependent phase on spins that are inhomogeneously distributed. As a result, the slice selection process can cause destructive interference and corresponding partial cancellation of the NMR signals from different parts of the slice. The mechanism of this effect was studied by expanding the internal magnetic field gradient as a Fourier series and determining the Fourier components with a foam model, which consists of air bubbles preferentially at the alveolar diameter. The effect of signal cancellation as a function of slice thickness is characterized by a sinc-like function with destructive interference of higher orders shown as lobes and the zeroth order as the main peak. Computer simulation of the slice selection process was conducted to illustrate the combined effects of signal cancellation and spatial average, and their dependence on slice thickness. Finally, images of rat lungs are presented to demonstrate the significant improvement in image quality by avoiding the high order destructive interference of NMR signals in the slice selection process.

Animals↗
PubMed1995

1H MR visible lipids in colon tissue from normal and carcinogen-treated rats.

Metabolic characteristics of colon mucosa, submucosa, muscularis and tumour specimens from four control (n = 105) and nine carcinogen (azoxymethane)-treated (n = 91) Sprague-Dawley rats were investigated by ex vivo 1H MRS. Ninety-seven per cent of pure mucosa samples (n = 59) yielded spectra with narrow lipid resonances (chemical shift delta of -(CH2)n-, 1.3 ppm; linewidth at half-height v1/2, 30-50 Hz). Eighty-two per cent of control mucosa samples with histologically proven submucosa contamination (n = 11) and 46% of control cross-sections (containing mucosa, submucosa and muscularis; n = 57) yielded spectra with broad lipid resonances (delta-(CH2)n-, 1.5 ppm; v1/2, 80-100 Hz) identical to those of adipose tissue surrounding rat colon. Thirty per cent of tumour samples (n = 10) yielded spectra with narrow lipid resonances while 70% contained no significant amount of MR visible lipids. We conclude that (i) lipids giving rise to broad resonances are in the heterogeneously distributed adipocytes of submucosa, (ii) lipids giving rise to narrow resonances are within the mucosa in an unknown structural environment, and (iii) the type and distribution of lipids in human and rat colon are similar. Tumours contained significantly more taurine than pure control mucosa (n = 15; p < 0.004) and pure mucosa containing aberrant crypt foci (putative preneoplasm, n = 36; p < 0.002). Our results suggest that the rat colon is a good model for 1H MR investigations of human colon carcinogenesis.

Animals↗
PubMed1995

Correlation between Gd-enhanced MR imaging and histopathology in treated and untreated 9L rat brain tumors.

Gadolinium-based MR imaging contrast agents cause signal enhancement of intracerebral tumors on T1-weighted MR images because they cross the compromised blood-brain barrier, increasing the T1 relaxation rate of extracellular water. Tumor extent measured by Gd-enhanced MR imaging often does not agree with T2-weighted MRI or biopsy measurements, due to possible peritumoral barrier defects or infiltration of tumor cells beyond the region of enhancement. In this study, the 9L rat brain tumor model was used to measure the correlation between tumor size measured by Gd-enhanced and unenhanced MRI and histological measurements. There was excellent agreement between Gd-enhanced MRI measurements and histology. Morphological features of untreated 9L intracranial tumors and those treated with radiation and/or cisplatin were compared with histological features. No significant change in intracranial tumor size was detected in the treated animals up to 7 days following treatment, despite substantial tumor necrosis evident on histological analysis.

Animals↗
PubMed1995

Classification of brain tumors by ex vivo 1H NMR spectroscopy.

Ex vivo biopsy samples (n = 42) from human brain tumors and normal brain have been examined by high-resolution proton magnetic resonance spectroscopy. Parameters from one-dimensional 1H spectra, two-dimensional COSY spectra, and transverse relaxation time (T2) data were used to classify the tumors according to the histopathological diagnoses. The ratio of the area between 3.4 and 3.1 ppm to that between 1.5 and 1.1 ppm distinguished glioblastomas from astrocytomas and normal brain, and appeared to be indicative of malignant potential. In support of the one-dimensional data, cross-peaks in the COSY spectra of brain specimens classified glioblastomas and metastases into one group and the more benign tumors, meningiomas, astrocytomas, and normal brain into a second group. The transverse relaxation of the resonance at 1.3 ppm was fitted by a model with two T2 values. The longer T2 value could be used to distinguish glioblastomas from normal brain, the latter having a much longer long T2 value. Astrocytomas showed a continuum of T2 values between glioblastomas and normal brain, with the grade of the astrocytoma correlating roughly with the value of the long T2 component.

Astrocytoma↗