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Biomedical subjects

M A Green

Publications and source records attributed to M A Green.

At least 55 records · Page 3Linked to original sources
PubMed1996

Release of CuPTSM from human serum albumin after addition of fatty acids.

Copper-62 labeled pyruvaldehyde bis (N4-methyl-thiosemicarbazonato) copper(II), CuPTSM, has been used to probe tissue perfusion by means of positron emission tomography. Despite promising results from animals, problems have been encountered in the use of 62CuPTSM to quantitate regional myocardial blood flow in humans. Ultrafiltration and plasma/erythrocyte partitioning studies with radiotracer have previously shown that CuPTSM is bound much more strongly by human serum albumin (HSA) than by dog serum albumin (DSA), limiting its ability to freely diffuse from blood into tissue. In this study, it is confirmed by electron spin resonance (ESR) that CuPTSM strongly binds to HSA with an apparent gparallel value of 2.12 and an apparent Aparallel value of 186 G. It is also shown that both spin-labeled stearic acid (5-SASL) and nonspin-labeled stearate inhibit CuPTSM binding to HSA. CuPTSM is completely released from HSA when the ratio of 5-SASL to HSA is 5:1. When pure sodium stearate is used, the binding of CuPTSM significantly decreased, about 73% of CuPTSM is released with a ratio of 4:1 stearate to HSA. These results highlight a means of liberating CuPTSM from HSA.

Electron Spin Resonance Spectroscopy↗
PubMed1996

CD44 expression in melanocytic lesions: a marker of malignant progression?

CD44 is the major human cell surface receptor for hyaluronate and functions in a diverse range of physiological processes. Alternative splicing of a single gene generates a family of splice variants (CD44vl-10) in addition to the standard isoform, CD44H. Expression of CD44, particularly CD44v6, has been described to correlate with metastasis formation in various tumours, although evidence in malignant melanoma is inconclusive. In this study, we explored the immunohistochemical pattern of CD44 expression in a range of melanocytic lesions using a panel of monoclonal antibodies raised to CD44H and the variants v3, v4/5, v6 and v8/9. Skin biopsies of 106 lesions from 100 patients were assessed and included benign and dysplastic naevi, melanoma in situ, malignant melanomas in horizontal and vertical growth phase, and cutaneous and lymph node metastases. CD44H was highly expressed in benign and dysplastic naevi and in melanoma in situ. However, expression with melanomas diminished with increasing invasiveness, and the pattern of expression observed correlated significantly with the growth phase of the lesion rather than its Breslow thickness. CD44 splice variants were not detected in any lesions. These results suggest a possible role for downregulation of CD44H in modulating the biological behaviour of malignant melanoma.

Humans↗
PubMed1996

Cutaneous overexpression of NT-3 increases sensory and sympathetic neuron number and enhances touch dome and hair follicle innervation.

Target-derived influences of nerve growth factor on neuronal survival and differentiation are well documented, though effects of other neurotrophins are less clear. To examine the influence of NT-3 neurotrophin overexpression in a target tissue of sensory and sympathetic neurons, transgenic mice were isolated that overexpress NT-3 in the epidermis. Overexpression of NT-3 led to a 42% increase in the number of dorsal root ganglia sensory neurons, a 70% increase in the number of trigeminal sensory neurons, and a 32% increase in sympathetic neurons. Elevated NT-3 also caused enlargement of touch dome mechanoreceptor units, sensory end organs innervated by slowly adapting type 1 (SA1) neurons. The enlarged touch dome units of the transgenics had an increased number of associated Merkel cells, cells at which SA1s terminate. An additional alteration of skin innervation in NT-3 transgenics was an increased density of myelinated circular endings associated with the piloneural complex. The enhancement of innervation to the skin was accompanied by a doubling in the number of sensory neurons expressing trkC. In addition, measures of nerve fibers in cross-sectional profiles of cutaneous saphenous nerves of transgenics showed a 60% increase in myelinated fibers. These results indicate that in vivo overexpression of NT-3 by the epidermis enhances the number of sensory and sympathetic neurons and the development of selected sensory endings of the skin.

Animals↗
PubMed1996

Predicting functional capacity during treadmill testing independent of exercise protocol.

Clinically useful estimates of VO2max from treadmill tests (GXT) may be made using protocol-specific equations. In many cases, GXT may proceed more effectively if the clinician is free to adjust speed and grade independent of a specific protocol. We sought to determine whether VO2max could be predicted from the estimated steady-state VO2 of the terminal exercise stage. Seventy clinically stable individuals performed GXT with direct measurement of VO2. Exercise was incremented each minute to optimize clinical examination. Measured VO2max was compared to the estimated steady-state VO2 of the terminal stage based on ACSM equations. Equations for walking or running were used based on the patient's observed method of ambulation. The measured VO2max was always less than the ACSM estimate, with a regular relationship between measured and estimated VO2max. No handrail support: VO2max = 0.869.ACSM -0.07; R2 = 0.955, SEE = 4.8 ml.min-1.kg-1 (N = 30). With handrail support: VO2max = 0.694.ACSM + 3.33; R2 = 0.833, SEE = 4.4 ml.min-1.kg-1 (N = 40). The equations were cross-validated with 20 patients. The correlation between predicted and observed values was r = 0.98 and 0.97 without and with handrail support, respectively. The mean absolute prediction error (3.1 and 4.1 ml.min-1.kg-1) were similar to protocol-specific equations. We conclude that VO2max can be predicted independent of treadmill protocol with approximately the same error as protocol-specific equations.

Adult↗
PubMed1996

Ocular and cerebral trauma in non-accidental injury in infancy: underlying mechanisms and implications for paediatric practice.

AIMS: To determine the sites, mechanisms, and clinical significance of injuries to the eyes and brains of children with non-accidental injuries in relation to differing levels of trauma. METHODS: A forensic pathological study of injuries in the eyes and brains of 23 consecutive children dying of non-accidental injuries over a 4 year period (1988-92) under the jurisdiction of Yorkshire and Humberside coroners. RESULTS: Sixteen children died from cerebral injuries and seven died from non-cerebral causes. There were high incidences of retinal detachment (63%) and subhyaloid (75%), intraretinal (75%), and perineural (68%) haemorrhages in CNS deaths. Local subhyaloid haemorrhages and retinal detachment were more common at the periphery and optic disc than at the equator. There was a strong correlation between CNS and eye trauma scores in all 23 children (r = 0.7551, p < 0.0001). Ranking of injuries by severity suggests progressively more trauma required for (a) subdural haemorrhage, (b) subhyaloid, intraretinal, perineural haemorrhages, and (c) retinal detachment. At highest trauma levels choroidal and vitreous haemorrhages were associated with additional cerebral lacerations, intracerebral and subarachnoid haemorrhages. CONCLUSIONS: In non-accidental (and probably accidental) infantile head injury the earliest eye injuries (coinciding with subdural haemorrhage) could be missed if indirect ophthalmoscopy is not performed. Retinal detachment and multiple (particularly choroidal/vitreous) haemorrhages may indicate additional cerebral lacerations and/or intracerebral haemorrhage. Vitreous traction is the likely cause of intraocular pathology.

Battered Child Syndrome↗
PubMed1996

Lymphocyte subset infiltration patterns and HLA antigen status in colorectal carcinomas and adenomas.

Fifty eight large bowel adenocarcinomas and 20 adenomas were studied immunohistochemically, using fresh frozen tissue sections, with regard to lymphocyte subpopulations (CD3, CD4, CD8, CD19, and CD20) in the inflammatory infiltrate and to expression of human leucocyte antigens (HLA-ABC, HLA-A2, and HLA-DR). The findings were related to differentiation and Duke's stage of carcinoma. The inflammatory infiltrate was found to have a phenotype that remained constant irrespective of the intensity of the inflammation. CD4 and CD3 positive cells predominated with fewer CD8 positive cells and a scanty diffuse CD19/20 positive cell population. CD19/20 follicular aggregates were common at the advancing margin of the carcinomas. There was no significant association with Duke's stage, differentiation or HLA status. HLA changes (ABC loss, A2 loss, and DR gain) were associated with differentiation, being more common and more extensive in poorly differentiated carcinomas. HLA-A2 loss was also associated with stage of progression of carcinoma. Inflammation associated with adenomas was found to have a similar phenotype to that associated with carcinomas. HLA changes in adenomas were uncommon, being seen in only one of our 20 cases.

Adenocarcinoma↗
PubMed1996

Tumor-selective radiopharmaceutical targeting via receptor-mediated endocytosis of gallium-67-deferoxamine-folate.

UNLABELLED: The receptor-mediated endocytosis uptake pathway for the vitamin folate was investigated as a target for tumor-selective radiopharmaceutical delivery. The molecular target for this delivery mechanism is a membrane-associated folate binding protein (FBP) that is overexpressed by a variety of malignant cell lines. METHODS: The ability of a 67Ga-labeled deferoxamine-folate conjugate (67Ga-DF-folate) to target tumor cells in vivo was examined using an athymic mouse tumor model. Subcutaneous inoculation of approximately 4 X 10(6) folate-receptor-positive KB (human nasopharyngeal carcinoma) cells into athymic mice yielded approximately 0.20 g tumors in 15 days, at which time either 67Ga-DF-folate, 67Ga-deferoxamine (67Ga-DF) or 67Ga-citrate was administered by intravenous injection. RESULTS: The 67Ga-DF-folate conjugate showed marked tumor-specific deposition in vivo, with 1.0 +/- 0.3% of the injected dose (%ID) in tumor at 4 hr postinjection (equating to 5.2 +/- 1.5 %ID/g tumor; n = 3 mice). Corresponding tumor-to-background ratios at 4 hr postinjection were: tumor/blood = 409 +/- 195; tumor/muscle = 124 +/- 47; tumor/liver = 11 +/- 3; and tumor/kidney = 2.6+/-0.9. Tumor uptake of 67Ga-DF-folate conjugate was effectively blocked by co-injection of 2.4+/-1.0 mg free folate. In control experiments, 67Ga-citrate exhibited tumor uptake of 2.2 +/- 0.4% of the injected dose (10.9 +/- 0.2 %ID/g tumor), but very poor target-to-background contrast (tumor/blood = 0.84 +/- 0.19; tumor/muscle = 5.4 +/- 0.7; tumor/liver = 2.3 +/- 0.2; and tumor/kidney = 2.4 +/- 0.3). Unconjugated 67Ga-deferoxamine showed no tumor affinity. CONCLUSION: Receptor-mediated endocytosis of radiolabeled folate-conjugates may offer a suitable mechanism for selectively delivering radiopharmaceuticals to tumors for diagnostic imaging and/or radiation therapy.

Animals↗
PubMed1996

Regional myocardial perfusion assessed with generator-produced copper-62-PTSM and PET.

UNLABELLED: We have previously demonstrated that myocardial perfusion can be estimated accurately in experimental animals with the generator-produced positron-emitting tracer, 62Cu-pyruvaldehyde bis (N4-methylthio- semicarbazone)(62Cu-PTSM) and PET. This study evaluated the feasibility of quantifying regional myocardial blood flow using 62Cu-PTSM and PET in human subjects. METHODS: Regional perfusion was estimated using a previously described and validated two-compartment model from dynamic PET scans obtained after an intravenous bolus of 62Cu-PTSM in 10 healthy volunteers and in 6 patients with coronary artery disease at rest: and in 9 of the volunteers and 4 of the patients after administration of dipyridamole intravenously. Flow estimates were compared with those obtained using H2(15)O. RESULTS: Contrast was high between myocardium and blood or lung with 62Cu-PTSM, resulting in high-quality myocardial images. Liver uptake was also high. At flows of up to 1.5 ml/g/min, flow estimated with 62Cu-PTSM correlated closely with estimates obtained with H2(15)O (y = 0.71x .21, n = 169 regional comparisons, r = 0.66, p < 0.55), but this relationship was not maintained at higher flows. CONCLUSION: The results demonstrate that quantification of myocardial perfusion with 62Cu-PTSM is feasible in human subjects but cannot be used to estimate hyperemic flows due most likely to the strong binding of the tracer to human serum albumin. Copper-62-PTSM congeners with less avidity for human albumin may prove more suitable for evaluation of hyperemic flows.

Adult↗
PubMed1995

Effects of specific versus cross-training on running performance.

The cross-training (XT) hypothesis suggests that despite the principle of specificity of training, athletes may improve performance in one mode of exercise by training using another mode. To test this hypothesis we studied 30 well-trained individuals (10 men, 20 women) in a randomized longitudinal trail. Subjects were evaluated before and after 8 weeks of enhanced training (+10%/week), accomplished by adding either running (R) or swimming (XT) to baseline running, versus continued baseline running (C). Both R (-26.4s) and XT (-13.2s) improved time trial (3.2 km) performance, whereas C did not (-5.4s). There were no significant changes during treadmill running in maximum oxygen uptake (VO2peak; -0.2, -6.0, and +2.7%), steady state submaximal VO2 at 2.68 m.s-1 (-1.2, -3.3 and +0.2 ml.kg-1.min-1), velocity at VO2peak (+0.05, +0.25 and +0.09 m.s-1) or accumulated O2 deficit (+11.2, -6.1 and +9.4%) in the R, XT or C groups, respectively. There was a significant increase in velocity associated with a blood lactate concentration of 4 mmol.l-1 in R but not in XT or C (+0.32, +0.07 and +0.08 m.s-1). There were significant changes in arm crank VO2peak (+5%) and arm crank VO2 at 4 mmol.l-1 (+6.4%) in XT. There was no significant changes in arm crank VO2peak (+1.3 and -7.7%) or arm crank VO2 at 4 mmol.l-1 (+0.8 and +0.4%) in R or C, respectively. The data suggest that muscularly non-similar XT may contribute to improved running performance but not to the same degree as increased specific training.

Adult↗
PubMed1995

Perinatal death as a consequence of fetal stabbing: was it murder?

At 22 weeks gestation, a fetus received a stab wound to the abdomen when the mother was subjected to a knife attack. Premature labour followed 2.5 weeks later. The baby received full intensive care, but died at 4.5 months of age from complications directly related to the premature birth. The person who committed the assault was indicted with murder of the infant according to the precept of transferred malice. In the absence of any clear legal precedent, the judge ruled that the indictment was not consistent with the principles of criminal law, since the malice directed towards the mother could not be regarded as being transferred to the fetus. This was because the wounding of a non-viable fetus with death following 4 months later did not amount to a deliberate killing, and in addition, it was not the intention of the Defendant at the time of the stabbing to kill the infant.

Journal Article↗
PubMed1995

Starch, gloves and extradural catheters.

We have investigated contamination of extradural catheters during normal handling with starch powdered gloves. In the laboratory, extradural catheters were handled in sterile fields with both powdered and non-powdered gloves, simulating preparation for patient insertion. The catheters together with glove samples were then examined using a Zeiss 940 scanning electron microscope. Microscopy of samples revealed starch contamination of the catheters handled with powdered gloves, especially in the side hole areas. We conclude that extradural catheters may be contaminated easily by starch powder from surgical gloves. This powder may then be deposited into the extradural space. The effect of starch in the extradural space is not known but starch is known to cause inflammatory and granulomatous reactions in other parts of the body as well as being directly allergenic. Powder contamination of catheters may be avoided easily by the use of powder-free gloves and we feel that these should be used whenever possible.

Analgesia, Epidural↗
PubMed1995

Relation between stage, grade, proliferation, and expression of p53 and CD44 in adenomas and carcinomas of the colorectum.

AIMS: To investigate the changes in and relations among p53, CD44 and MIB-1 expression in adenocarcinomas of the colorectum and to determine whether these changes are progressive across the adenoma-carcinoma sequence. METHODS: Expression of p53 protein, CD44 adhesion molecule and MIB-1 proliferation antigen was detected using immunohistochemistry in 68 colorectal carcinomas and 32 colorectal adenoma. The staining characteristics were compared with degree of dysplasia in adenomas, and differentiation and Dukes' stage in carcinomas. Results were analysed and assessed using Spearman's rank correlation and independent t tests. RESULTS: p53 staining was present in som adenomas and correlated with the degree of dysplasia. There was significantly more staining in carcinomas than adenomas and significant correlation between staining and Dukes' stage. CD44 staining was maximal in adenomas, diminished in carcinomas and was minimal in metastasising carcinomas. There was inverse correlation between p53 and CD44 expression across the adenoma-carcinoma-metastasising carcinoma sequence. MIB-1 expression was highest in carcinomas but did not correlate with either p53 or CD44 expression. CONCLUSIONS: There are progressive changes in p53, CD44 and MIB-1 expression in adenomas and carcinomas. A combination of these tests may prove useful in assessing which patients with adenomas are at greatest risk of progressing to carcinoma.

Adenocarcinoma↗
PubMed1995

Species-dependent binding of copper(II) bis(thiosemicarbazone) radiopharmaceuticals to serum albumin.

UNLABELLED: Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)-copper(II) (Cu-PTSM) is a generator-based PET radiopharmaceutical under investigation for use in evaluation of tissue perfusion. Despite promising results from animals, problems have been encountered in the use of 62Cu-PTSM to quantitate myocardial perfusion in humans at high flow rates, possibly due to species-dependent interactions of the tracer with serum albumin. METHODS: Ultrafiltration and plasma/erythrocyte partitioning studies were performed to assess the protein binding of 67Cu-labeled Cu-PTSM and six related copper(II) bis(thiosemicarbazone) complexes. RESULTS: These studies reveal significant interspecies variability in the strength of Cu-PTSM binding to serum albumin, with 67Cu-PTSM binding much more strongly to human albumin than to dog albumin. Most of the related Cu(II)-bis(thiosemicarbazone) complexes examined exhibit interspecies variability of albumin binding similar to that observed with Cu-PTSM. Two such complexes, Cu-ETS and Cu-n-PrTS, however, were identified that exhibit no preferential association with human serum albumin. CONCLUSION: Copper-62-PTSM exhibits substantial interspecies variability in the strength of its binding to serum albumin, which appears to explain the problems encountered in using animal data to predict 62Cu-PTSM behavior in humans. The 62Cu-ETS and 62Cu-n-PrTS complexes may be viable alternatives to 62Cu-PTSM for PET studies to evaluate quantitatively myocardial blood flow in humans.

Animals↗
PubMed1995

Role of target organ infection with cytomegalovirus in the pathogenesis of graft-versus-host disease.

Skin and rectal biopsy tissue from 34 allogeneic and 23 autologous BMT recipients was prospectively analysed for CMV using immunohistochemistry and PCR to investigate the hypothesis that target organ infection with CMV initiates and/or exacerbates GVHD. Biopsies were obtained prior to and at 3, 8 and 26 weeks after BMT and whenever GVHD was suspected. Surveillance specimens of peripheral blood leucocytes (PBL), urine and throat swabs were obtained every 2 weeks until 12 weeks after BMT, and whenever CMV was suspected. Cryostat sections were analysed immunohistochemically for CMV antigens and PBL and biopsies for CMV DNA by PCR. Of the 31 patients who engrafted, 28 (90%) developed GVHD clinically, confirmed histologically in 56 biopsies. GVHD proved clinically severe in 14 patients, 4 of whom had treatment-resistant GVHD. CMV was detected in PBL more frequently in patients with severe GVHD than in those with mild/moderate GVHD (29% vs. 7%). However, in all but one patient the onset of GVHD preceded detection of CMV. In biopsy specimens, CMV was detected in only 2 patients, 1 of whom had an exacerbation of GVHD temporally associated with CMV. Thus, despite a high incidence of GVHD in this series, with 56 episodes of GVHD in 28 patients, only 1 patient had CMV in biopsy tissue temporally associated with GVHD. This suggests that biopsy infection with CMV is not a major factor in initiating or exacerbating GVHD in this cohort. This study thus does not support a role for target organ infection with CMV in the pathogenesis of GVHD.

Adolescent↗
PubMed1995

Human herpes virus-6 infection in marrow graft recipients: role in pathogenesis of graft-versus-host disease. Newcastle upon Tyne Bone Marrow Transport Group.

To investigate the hypothesis that target organ infection with human herpes virus-6 (HHV-6) exacerbates the clinical severity of GVHD, skin and rectal biopsies from 34 allogeneic bone marrow transplant (BMT) recipients and 23 comparative autologous recipients were studied. Biopsies and heparinised blood samples were obtained from all patients prior to and at regular intervals after BMT, and whenever GVHD was suspected. HHV-6 antigen was detected in cryostat sections by immunohistochemistry, and HHV-6 DNA in peripheral blood leucocytes (PBL) and biopsies by nested PCR. Twenty-eight (90%) of the 31 patients who engrafted developed clinical GVHD, which was mild in five, moderately severe in nine and severe in 14. Overall, HHV-6 DNA was detected in PBl in 74% of autologous recipients and 76% of allogeneic recipients, and in biopsy tissue in 48% of autos and 71% of allos. However, HHV-6 DNA was detected in skin and/or rectal biopsies more frequently in allogeneic recipients with severe GVHD (92%) than in those with either moderate (55%) or mild GVHD (22%), suggesting an association (P = 0.004) between HHV-6 DNA in biopsy tissue and GVHD severity. A significant linear trend (P = 0.03) was identified between detection of HHV-6 DNA in biopsy tissue obtained prior to or concomitant with the onset of GVHD and increased GVHD severity, suggesting that HHV-6 was causally linked to GVHD rather than reactivated as a consequence of GVHD therapy. Thus this study supports a role for HHV-6 in the initiation and/or exacerbation of GVHD, and suggests that the presence of HHV-6 DNA in the skin or rectum may be a factor in determining GVHD severity. If confirmed, these findings may have implications for the management of allogeneic BMT recipients.

Adolescent↗
PubMed1994

Structure-distribution relationships for metal-labeled myocardial imaging agents: comparison of a series of cationic gallium (III) complexes with hexadentate bis(salicylaldimine) ligands.

A series of 10 cationic gallium(III) complexes with hexadentate bis(salicylaldimine) ligands were synthesized, characterized, radiolabeled with 67Ga, and screened in a rat model to assess their potential as 68Ga radiopharmaceuticals for imaging the heart with positron emission tomography. The tris(salicylaldimine) ligand precursors were synthesized by condensation of either bis(3-aminopropyl)ethylenediamine (BAPEN) or bis(2,2-dimethyl-3-aminopropyl)ethylenediamine (DM-BAPEN) with 3 equiv of a salicylaldehyde derivative containing alkyl, alkoxy, or alkylamino substituents in the 4, 5, or 6 position of the aromatic ring. The cationic six-coordinate gallium(III) bis(salicylaldimine) complexes were obtained by reaction of these tris(salicylaldimines) with tris(acetylacetonato)gallium(III). X-ray crystallographic confirmation of the molecular structure of Ga[(4,6-(MeO)2sal)2DM-BAPEN]+I- shows the Ga cation to adopt a pseudo-octahedral N4O2 coordination sphere with a trans configuration. All of the 67Ga complexes are lipophilic with measured octanol/water partition coefficients (P) varying from log P = 0.84 to 3.00. These 67Ga-labeled complexes are all found to exhibit significant myocardial uptake following intravenous administration to rats (ranging from 0.34 to 1.08% of the injected dose in myocardium at 1 min postinjection) combined with the desired myocardial retention of tracer.

Animals↗