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Biomedical subjects

D I Rushton

Publications and source records attributed to D I Rushton.

At least 19 recordsLinked to original sources

The need for specialist review of pathology in paediatric cancer.

A retrospective histopathological review of 2104 cases of solid tumour was carried out to assess the variability in diagnosis of childhood cancer. Cases were subject to three independent, concurrent opinions from a national panel of specialist pathologists. The conformity between them was analysed using the percentage of agreement and the kappa statistic (kappa), a measure of the level of agreement beyond that which could occur by chance alone, and weighted kappa (w kappa), which demonstrates the degree of variation between opinions. The major groupings of the Birch-Marsden classification were used within which tumours were assigned for kappa analysis according to the clinical significance of the differential diagnoses. The mean agreement for all tumours together was 90%; kappa = 0.82, w kappa = 0.82. Retinoblastoma achieved the highest kappa value (1.0) and lymphoma the lowest (0.66). Of the cases, 16.5% had their original diagnoses amended and the panel confirmed the original diagnosis of paediatric pathologists in 89% of cases compared with 78% for general pathologists. The varying levels of agreement between experts confirm the difficulty of diagnosis in some tumour types, suggesting justification for specialist review in most diagnoses. Specialist training in paediatric pathology is also recommended.

Child

Colocalisation of vascular endothelial growth factor and its Flt-1 receptor in human placenta.

Vascular endothelial growth factor (VEGF) is an angiogenic protein which acts on both endothelial and trophoblast cells. In first trimester placenta, VEGF immunoreactive protein was detected in cytotrophoblast shell suggesting a role in the regulation of cytotrophoblast growth and differentiation as they also expressed VEGF receptor (flt-1) protein. VEGF and flt-1 immunoreactive proteins were expressed in Hofbauer cells within the villous mesenchyme, macrophages and in maternal decidual cells while weak VEGF immunoreactive protein was seen in syncytiotrophoblast surrounding the placental villi in first and second trimester placentae. At term, there was relatively weak VEGF and flt-1 immunostaining in the syncytiotrophoblast while intense VEGF immunostaining was seen in the Hofbauer and maternal decidual cells. Extravillous trophoblast showed immunostaining for flt-1 but no staining for VEGF. Both amnion and chorion expressed strong VEGF immunoreactivity throughout gestation. Smooth muscle cells surrounding the vein and arteries of the umbilical cord showed weak VEGF immunoreactivity while no immunoreactivity was localised in endothelial cells. VEGF stimulated parathyroid hormone-related protein (PTHrP) release (mean (+/- SD): basal, 0.96 +/- 0.03; 10 ng/ml VEGF165, 2.07 +/- 0.18 and 20 ng/ml VEGF165, 2.43 +/- 0.18 pmol/l/well of PTHrP1-86) in condition medium from immortalised first trimester trophoblast cell line. These results suggest that VEGF in addition to acting as an autocrine mitogen for trophoblast proliferation may also function as a paracrine mediator of vascular tone by releasing vasorelaxants from trophoblasts.

Cell Differentiation

Immunohistochemical localization of parathyroid hormone-related protein (PTHrP) in human term placenta and membranes.

Parathyroid hormone-related protein (PTHrP), the major factor responsible for hypercalcaemia of malignancy, is widely expressed in normal adult and fetal tissues. In this study, the distribution of PTHrP was examined in human term placenta and membranes by immunohistochemistry using antisera to PTHrP 1-34 and 37-67. PTHrP was detected in cuboidal epithelial cells of amnion and in cytotrophoblastic cells of chorionic laeve and adherent maternal decidua. In placenta, PTHrP 1-34 was detected in the syncytiotrophoblast, while PTHrP 37-67 activity was mainly present in the brush border of the syncytiotrophoblast. This study also identified PTHrP 37-67 associated with fetal vessels of placental villi. These findings may reflect the cellular distribution of intact PTHrP or sub-fragments derived by post-translational processing. Postulated actions of PTHrP in the uteroplacental unit include transport of calcium across the placenta, stretch of membranes, inhibition of uterine contractility, growth and differentiation, and vasoregulation.

Amnion

"Medullary ray glomerular counting" as a method of assessment of human nephrogenesis.

Renal weight (left-right combined), as a parameter of renal development, is required to be less than half the normal value for age for a statistically confident diagnosis of hypoplasia. "Medullary ray glomerular counting" (MRGC), counting cortical glomerular generations, has been proposed as a simple technique of possibly greater sensitivity. Recent development of the Disector method for the unbiased stereological estimation of total glomerular number has provided a, hitherto unavailable, "golden standard" with which to determine the diagnostic potential of MRCG. Both "true" (actual number of generations seen) and "assumed" (a subjective "guess" of the total number of generations) MRGC counts were determined in 11 pairs of kidneys from spontaneously aborted, normally developed, non-malformed fetuses (gestational age: 15-40 weeks). Each kidney was randomly analysed blind and on two separate occasions by two paediatric pathologists using a written protocol. Results were compared with unbiased stereological estimates of glomerular number. Intra- and inter-observer and intra- and inter-(left-right)renal reproducibility were analysed. In conclusion, MRGC, using "real" counts, is a highly reproducible parameter of renal development from 15-36 weeks' gestation. Sensitivity for detection of both hypoplasia and maturation delay increase with gestational age and generally exceeds that of renal weight.

Histological Techniques

Hazards of parenteral treatment: do particles count?

After prolonged parenteral nutrition a 12 month old infant died with pulmonary hypertension and granulomatous pulmonary arteritis. A review of necropsy findings in 41 infants who had been fed parenterally showed that two of these also had pulmonary artery granulomata, while none of 32 control patients who died from sudden infant death syndrome had similar findings. Particulate contaminants have been implicated in the pathogenesis of such lesions and these were quantified in amino acid/dextrose solutions and fat emulsions using automated particle counting and optical microscope counting respectively. Parenteral feed infusions compounded for a 3000 g infant according to standard nutritional regimens were found to include approximately 37,000 particles between 2 and 100 microns in size in one day's feed, of which 80% were derived from the fat emulsion. In-line end filtration of intravenous infusions may reduce the risk of particle associated complications. A suitable particle filter is required for use with lipid.

Arteritis

Postnatal encephaloclastic porencephaly--a new lesion?

A previously unrecognised and distinctive pattern of severe brain injury in extreme preterm neonates was observed recently. Fifteen neonates of birth weight 600-1270 g and gestation of 24-32 weeks showed relatively late development on cerebral ultrasound scan of extensive dense and cystic lesions involving the periphery of the brain. The extent of the changes was confirmed at postmortem examination in 11 babies. These changes have been called encephaloclastic porencephaly. The population of babies in whom this has occurred and their clinical outcome has been reviewed, with comparison between the evolution of the ultrasound changes and pathological findings at postmortem examination.

Brain

Clinical and pathological factors in spontaneous abortion following chorionic villus sampling.

Twenty-nine cases of spontaneous abortion following first-trimester chorionic villus sampling (CVS) were reviewed out of a series of 722 patients. Of the 29 cases, there were only four abnormal CVS results. Pathological examination was performed in 79 per cent of cases, and this did not identify any characteristic pathological feature associated with spontaneous abortion after CVS. There was no obvious difference in the pathological features following the transabdominal (TA) or the transcervical (TC) methods. The majority of miscarriages occurred within 4 weeks of the procedure, but 38 per cent of cases aborted between 7 and 14 weeks after CVS. The TC method was used in 22 patients; the TA in 6; and both methods in 1 patient. The TA method was associated with a significantly lower fetal loss rate than the TC method (TA 2 per cent, TC 9 per cent, p less than 0.001).

Abortion, Spontaneous

Exacerbation of bacterial toxicity to infant ferrets by influenza virus: possible role in sudden infant death syndrome.

Of several toxins examined, only staphylococcal alpha and gamma toxin, endotoxin, and diphtheria toxins were lethal for 5-day-old ferrets. Their toxicities were enhanced in animals infected at 1 day old with influenza virus, from 3-fold with staphylococcal gamma toxin through 14-fold for staphylococcal alpha toxin, 84-fold for endotoxin, and 219-fold for diphtheria toxin. No increased viral replication occurred in any tissue; thus the effects of the toxins were exacerbated by the infection, not vice versa. Neonates died suddenly without clinical symptoms as in human babies dying from the sudden infant death syndrome (SIDS). Pathologic examination showed inflammation in the upper respiratory tract, lung edema and collapse, and early bronchopneumonia in the toxin- and influenza virus-treated animals but not in those treated with toxin or virus alone. Thus, bacterial toxins could play a role in SIDS, this being more likely with a concomitant influenza virus infection.

Animals

West Midlands perinatal mortality survey, 1987. An audit of 300 perinatal autopsies.

As part of the West Midlands regional perinatal mortality survey an audit of perinatal autopsies was performed in 10 of 20 districts in the region. Autopsy reports were available from 300 of the 426 deaths (70%) reported in these districts. These were coded for 8 aspects including the clinical summary, body measurements, descriptive content, organ weights, post mortem radiology and microbiology, histology and other relevant investigations e.g., biochemistry, cytogenetics. Overall 44% of the autopsies failed to attain an arbitrary minimum score of 300, the mean score being 299. Excluding those autopsies performed at the regional centre these figures were 50% and 268 respectively. These data indicate that a high autopsy rate does not necessarily reflect a high quality of service and further emphasise the concerns that have been expressed by obstetricians, paediatricians, geneticists, parents and parliamentarians about the perinatal pathology services in the United Kingdom.

Autopsy

Pulmonary intravascular lipid in neonatal necropsy specimens.

The lungs of 482 liveborn infants were examined at necropsy for the presence of intravascular lipid. Forty one patients had received parenteral feeding (including lipid emulsion in 30), and 441 had died before starting feeds or had received enteral feeds alone. Tissue was processed into wax and then stained with Sudan black; intravascular lipid was found in 15 of 30 infants who had received intravenous fat (Intralipid), but in no others. Those patients with positive lipid staining had received significantly more fat during parenteral nutrition than those in whom intravascular lipid was not found but the two groups were otherwise clinically indistinguishable. Using this staining technique intravascular lipid can be shown relatively often, although only in patients who have received intravenous lipid emulsion. The location of fat, predominantly in small pulmonary capillaries, and the absence of lipid emboli in other organs, suggests that lipid coalescence takes place before death and is not a postmortem artefact. The clinical relevance remains uncertain.

Autopsy

Role of upper respiratory tract infection in the deaths occurring in neonatal ferrets infected with influenza virus.

Passive immunization of ferret neonates by colostrally-derived anti-influenza virus IgG did not entirely prevent infection when mothers were immunized with 1 or 2 doses of formalin inactivated vaccine with adjuvant (alhydrogel). Influenza virus replication was almost completely prevented in the lower respiratory tract but only slightly reduced in the upper respiratory tract leading to deaths in about 50% of the neonates. Such neonates showed at most only minor lesions in the lower respiratory tract but moderate to severe inflammatory changes in the upper respiratory tract of most animals. This supports previous results suggesting that deaths, reminiscent of the human sudden infant death syndrome (SIDS), may arise purely as a result of upper respiratory tract infection, possibly following obstruction of the airways.

Animals