Cases, controls and confounders.
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Biomedical subjects
Publications and source records attributed to S Love.
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Conventional histological evaluation and subclassification of childhood ependymomas poorly predict their biological behaviour. The Ki-67 labelling index (Ki-67 LI), a measure of growth fraction, correlates with the biological behaviour of several neoplasms, and this retrospective study tested the hypothesis that Ki-67 LI is a prognostic indicator in childhood posterior fossa ependymomas. Immunocytochemistry using an antibody to Ki-67 was undertaken on 5 microns sections of formalin-fixed, paraffin-embedded tissue from 74 cases of childhood (age < 16 years.) posterior fossa ependymoma. A Ki-67 LI was established by counting the proportion of labelled nuclei in more than 1000 cells from several histological fields. Several clinical and histological variables (including Ki-67 LI) potentially associated with survival were entered into univariate and multivariate analyses using a Cox proportional hazards model. Variables that showed a significant and independent association with survival were Ki-67 LI (P < 0.002), whether total surgical resection had been achieved according to operation records (P < 0.03), and whether no adjuvant therapy had been given (P < 0.01). Age, sex, and the presence of necrosis or microvascular proliferation did not correlate with survival. In our defined population of patients with ependymomas, Ki-67 LI is a strong prognostic indicator. We recommend that Ki-67 LI is used in the histological evaluation of childhood posterior fossa ependymomas during trials of novel adjunctive therapies.
OBJECTIVE: Although radiotherapy is often used in the treatment of patients with low-grade astrocytomas, its value is still uncertain. Radiotherapy carries a risk of morbidity for patients and has time and cost implications for health services. We have assessed the value of two histological variables, p53 accumulation and Ki-67 expression, in predicting the response of astrocytomas to radiotherapy. The former antigen was assessed because many astrocytic tumors show mutations in the p53 gene, the function of which is crucial for mediating cell death after radiotherapy, and the latter was assessed because it is expressed only in proliferating tumor cells, which may show greater radiosensitivity than nonproliferating cells. METHODS: Immunohistochemistry was used to detect the accumulation of p53 and expression of Ki-67 in a retrospective series of 96 patients with supratentorial fibrillary astrocytomas, 58 of whom had received postoperative radiotherapy. The immunohistochemical data were correlated with survival after radiotherapy. RESULTS: There was no significant difference in survival between the patients who did and those who did not receive radiotherapy. The p53 and Ki-67 labeling indices did not correlate with survival in either the irradiated or the nonirradiated cohort, nor with overall survival in the series as a whole. CONCLUSION: Immunohistochemical assessment of p53 accumulation and Ki-67 expression does not help in predicting the survival of patients with supratentorial fibrillary astrocytomas or in predicting whether particular patients are likely to benefit from radiotherapy.
We have examined the ultrastructure of the trigeminal sensory nerve root in three patients with medically intractable trigeminal neuralgia. In one patient, the nerve root was sandwiched between a large vein and a small pontine artery, in the others compression was due to marked dolichoectasia of a verterbal artery. Because these were not amenable to microvascular decompression, a caudal rhizotomy was performed, by excising a short inferior segment of nerve root in the region of indentation. In all cases, examination revealed a zone of chronic demyelination in the proximal (centrally myelinated) part of the root, near its junction with peripheral nerve. The zone of demyelination contained closely packed axons without intervening glial cytoplasm. Also present were small numbers of thinly myelinated axons. In some cases a single thin myelin sheath encircled several adjacent axons that were still in close apposition. These findings indicate that the trigeminal neuralgia associated with vascular compression is due to demyelination. The demyelination is associated with some evidence of remyelination. The latter phenomenon may account in part for the long periods of remission, especially during the initial period after the onset of trigeminal neuralgia. The partly aberrant nature of the myelination within the region of vascular compression may contribute to the persistence of symptoms in some patients after decompressive surgery.
OBJECTIVES: Dementia in Alzheimer's disease correlates closely with loss of neocortical synapses. Similar synaptic loss has been shown in patients whose Alzheimer's disease is also associated with neocortical and brain stem Lewy bodies. The aim was to determine if dementia in Lewy body disease was associated with diminished concentrations of midfrontal cortex synaptophysin. METHODS: An immunobinding assay was used to measure synaptophysin in postmortem samples of midfrontal cortex from 89 patients with Alzheimer's disease (ages 59-100, mean 79), 22 with combined Lewy body disease and Alzheimer's disease (ages 69-103, mean 79), 15 demented patients with "pure" Lewy body disease (ages 57-80, mean 74), nine with neocortical and brain stem Lewy bodies who had Parkinson's disease but were not demented (ages 68-85, mean 79), and 20 neurologically normal controls (ages 58-89, mean 75). The diagnosis was confirmed in all cases by detailed neuropathological examination of the contralateral hemibrain. Seven of the patients in the pure Lewy body disease with dementia group had initially presented with parkinsonism and eight with dementia. RESULTS: Synaptophysin concentrations (arbitrary units (AU)/microg) in patients with Alzheimer's disease (mean 79 (SD 28)) or combined Lewy body disease and Alzheimer's disease (mean 83 (SD 33)) were significantly lower than in controls (mean 115 (SD 29)) (p=0.002). Synaptophysin concentrations in demented patients with pure Lewy body disease (mean 106 SD 39) and patients with Lewy body disease who were not demented (mean 101 (SD 18)) did not differ significantly from control values or from each other. CONCLUSION: Loss of midfrontal cortex synapses probably contributes to dementia in Lewy body disease when Alzheimer's disease is also present but not to the dementia of pure Lewy body disease.
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The current research was designed to assess the treatment needs of 42 substance-abusing women and the efficacy of a women-based, culturally influenced, multifaceted residential treatment program for women and their children. Women presented with multidimensional treatment needs, including limited educational/employment histories, significant child-care needs, and histories of victimization and psychological distress. Women remained in residence for an average of 259 days. In all, 88% of the women remained substance-free at discharge; 49% had jobs or were enrolled in school/job training. This integrated, gender/culture-based approach provides a model for more effective substance-abuse treatment for women and their families.
Ubiquitin is expressed in eukaryotic cells as precursors, fused via its carboxyl terminus either to other ubiquitin sequences in linear polyubiquitin arrays or to specific ribosomal proteins. In some of the polyubiquitin fusions a single amino acid (e.g., valine in humans) is attached to the carboxyl terminus. These gene products are rapidly (probably cotranslationally) cleaved by ubiquitin carboxyl-terminal hydrolase (UCH) enzymes; therefore, although ubiquitin precursors are suitable substrates for assays of UCH activity, they are difficult to isolate from nucleated cells. While the recombinant approach allows the production of ubiquitin precursors in prokaryotic cells (which do not contain the ubiquitin system), proteins produced in this manner require purification and may also be susceptible to modification by bacterial enzymes, e.g., adventitious proteolysis. As an alternative we have chemically synthesized human ubiquitin-valine. In the assay described here the cleavage of ubiquitin-valine to ubiquitin (77 and 76 residue proteins, respectively) by a purified recombinant Drosophila UCH was monitored by capillary electrophoresis. Mass spectrometry verified the precise cleavage of ubiquitin-valine, confirming that this synthetic protein is a UCH substrate. Synthetic ubiquitin-valine may serve as a generic substrate for UCHs allowing the purification and identification of new members of this enzyme family.
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From the somewhat conflicting published data on apolipoprotein E (apoE) genotype in hemorrhage due to cerebral amyloid angiopathy (CAA), it is unclear whether apoE genotype influences the risk of CAA-related hemorrhage independently of its association with concomitant Alzheimer's disease (AD). We determined the apoE genotypes of 36 patients presenting with cerebral hemorrhage associated with histologically confirmed CAA. The frequency of apoE epsilon 2 was 0.25 and the frequency of apoE epsilon 4 was 0.18. Patients with CAA-related hemorrhage and concomitant AD pathology (CERAD criteria, n = 17) had a high apoE epsilon 4 frequency, close to that in AD cases without hemorrhage. Patients in whom CAA-related hemorrhage occurred in the absence of significant AD pathology (n = 13) had an apoE epsilon 4 frequency somewhat lower than non-AD controls without hemorrhage. However, in CAA-related hemorrhage, the apoE epsilon 2 frequency was high regardless of whether significant AD pathology was present. We conclude that whereas possession of apoE epsilon 2 may be a risk factor for cerebral hemorrhage due to CAA, apoE epsilon 4 is a risk factor for concomitant AD but not an independent risk factor for CAA-related hemorrhage.
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Nine pony breed foals were reared indoors, then allocated to one of three groups infected with either 3.9 million (Group A) or 3.15 million (Group B) cold-conditioned third stage cyathostome larvae or kept as uninfected controls (Group C). The larvae were administered as a 'trickle' infection of 150000 larvae per dose, three times weekly. Blood biochemical and haematological analyses were performed weekly and faecal worm egg counts bi-weekly. Complete parasitological examinations were performed on all ponies at various times post-initial infection (PI): one infected animal at 9 weeks PI, four animals (three infected, one control) at 20 weeks PI and four animals (two infected, two controls) at 60-62 weeks PI. All ponies in the infected groups experienced a marked reduction in weight gain and two animals developed clinical disease: one pony developed intermittent diarrhoea and colic 8 weeks PI; another pony developed intermittent diarrhoea between 30 and 52 weeks PI. All infected ponies had decreased serum fructosamine concentrations and five had decreased serum albumin, which were first apparent 4-6 weeks PI. Alterations in the composition of serum globulins were detected in all ponies. Transient neutrophilia was observed in five animals from the infected groups 3-9 weeks PI. Serum alkaline phosphatase concentrations were increased in one pony between 30 and 60 weeks PI. During the course of the experiment, faecal samples from all infected animals were negative for worm eggs. At necropsy, cyathostome larvae were present within the mucosa of the large intestine of all infected ponies, however the mucosal larval counts varied considerably between individuals.
Tumors of central nervous system elements are uncommon in cystic teratomas and tend to be derived from glial or primitive neuroectodermal cells. We describe the case of a 23-year-old woman with a central neurocytoma arising in an otherwise mature cystic teratoma of the ovary. Histologically, the neurocytoma was composed of collections of oligodendroglioma like cells in a fibrillary matrix. Cytologically the tumor was identical in appearance to central neurocytomas occurring within the adult brain. It expressed synaptophysin and neuron-specific enolase, confirming its neuronal lineage, but not glial fibrillary acidic protein. The site of the tumor recapitulated the typical location of neurocytomas adjacent to the lateral ventricle in that in abutted onto an ependyma-lined cyst within the teratoma. The patient remains well and free of tumor 1 year after cystectomy, in keeping with favorable follow-up data for surgically excised central neurocytomas within the brain.
OBJECTIVE AND IMPORTANCE: The prognosis for patients with ependymomas is related to the adequacy of surgical clearance. It is, however, often not possible to obtain a macroscopically complete resection of tumors arising in the posterior fossa. This may be because of the involvement of structures, the sacrifice of which would result in unacceptable morbidity, or because of metastatic lesions at diagnosis. For those patients in whom initial surgery was incomplete, elective second-look surgery may allow more complete clearance of tumor. INTERVENTION: We have performed second-look surgery for fourth ventricle ependymomas in five patients: two women, aged 26 and 27 years, and three male patients, aged 4 months, 19 months, and 18 years. The 19-month-old male patient underwent early second-look surgery without receiving any interim chemotherapy. Second-look surgery on the other four patients was performed after they had received chemotherapy. No additional major morbidity was associated with the subsequent surgery, which achieved macroscopically complete clearances in four of the five patients. Three of four patients who underwent macroscopically complete resections were well, without clinical or radiological evidence of recurrent tumor, at 23, 25, and 34 months after their second operations. The 10-month-old patient who underwent early second-look complete resection relapsed locally at 33 months after surgery. Complete resection was not possible in one patient who had progressive tumor 8 months after second-look surgery. CONCLUSION: For patients in whom complete excision of fourth ventricle ependymomas is not possible at initial surgery, second-look procedures may enable macroscopic clearance to be achieved with little morbidity. A larger study is needed to evaluate this approach to treatment.
Transglutaminases are a family of calcium-dependent enzymes that catalyse the formation of covalent crosslinks between proteins. They have several diverse functions and are thought to be involved in cell differentiation, apoptosis and blood coagulation. We have investigated the expression of tissue transglutaminase in five fibrillary astrocytomas, five anaplastic astrocytomas and seven glioblastomas by immunohistochemistry. Strongly labelled tumour cells were seen in most of the fibrillary and anaplastic astrocytomas and all of the glioblastomas. Labelling was particularly prominent in the pseudopalisading tumour cells that surrounded foci of necrosis and apoptosis in glioblastomas. Most of the immunostained cells did not themselves show morphological features of apoptosis. In addition, apoptotic cells were demonstrated using in situ end-labelling and by in situ hybridization with digoxigenin-labelled poly(A) oligonucleotide probes. Apoptotic cells demonstrated by both of these methods were most numerous in anaplastic astrocytomas and glioblastomas. However, their distribution did not correlate with that of the tumour cells showing transglutaminase labelling. Strong transglutaminase labelling was also observed in the endothelial cells of vessels showing microvascular proliferation in all of the glioblastomas studied. In contrast, endothelial transglutaminase labelling was weak or absent in lower grade astrocytic tumours. Enhanced expression of transglutaminase by endothelial cells in glioblastomas may contribute to the high prevalence of vascular thrombosis and necrosis in these tumours.
We describe a patient who developed chronic bilateral trigeminal neuropathy that was found at autopsy to be due to lambda light chain amyloidosis involving the trigeminal nerves, ganglia and roots bilaterally, as well as part of the intrapontine course of the trigeminal nerve fibres. No amyloid was found elsewhere in the nervous system or systemically. Review of previous reports indicates that the clinical features of trigeminal amyloidosis are quite stereotyped, with initial trigeminal neuralgia or dysaesthesiae, and subsequent development of facial anaesthesia and weakness of muscles of mastication. The disorder is usually unilateral but may rarely, as in the present case, occur bilaterally.
To evaluate the effects of age and diet on the oral glucose tolerance test (OGTT) in healthy ponies, OGTTs were performed on 2 groups of British native breed ponies (Group A: 7 foals [6-9 months], Group B: 7 mature individuals [6-13 years]) when maintained on either a high fibre pelleted ration only (Groups A and B) or a hay only diet (Group B). Plasma glucose response, following oral glucose administration, for Group A (basal plasma glucose concentration [Glu0] 4.6 +/- 0.4 mmol/l (mean +/- s.d.) increasing to 11.5 +/- 1.3 mmol/l at 90 min) was significantly different (P < 0.05) from that observed for Group B (Glu0 of 4.3 +/- 0.2 mmol/l increasing to 6.8 +/- 1.3 mmol/l at 90 min), when fed the same diet. For Group B ponies, the plasma glucose response, following oral glucose administration, was significantly different (P < 0.05) when fed hay only (Glu0 4.6 +/- 0.4 mmol/l increasing to 9.6 +/- 2.1 mmol/l at 150 min) compared to when fed the high fibre pelleted ration. These results indicate that both age and diet have a significant effect on plasma glucose concentrations measured during an OGTT.