Biomedical subjects
Publications and source records attributed to E T Hedley-Whyte.
A case of a recurrent posterior fossa subependymoma in a 60-year-old man is reported. In the recurrent tumor, the vasculature had undergone apparent sarcomatous proliferation of the endothelial cells. The bizarre cells expanded and replaced the vessel walls, and stained for Factor VIII-related antigen. The literature on gliosarcomas arising in brain tumors other than high-grade gliomas is reviewed.
Astrocytomas, including glioblastoma multiforme, represent the most frequent and deadly primary neoplasms of the human nervous system. Despite a number of previous cytogenetic and oncogene studies primarily focusing on malignant astrocytomas, the primary mechanism of tumor initiation has remained obscure. The loss or inactivation of "tumor suppressor" genes are thought to play a fundamental role in the development of many human cancers. Thus, we have analyzed astrocytomas of various histological malignancy grades with polymorphic DNA markers to search for specific chromosomal deletions potentially pointing to loci containing tumor suppressor genes. Loss of constitutional heterozygosity indicating chromosomal loss or deletions was most frequently seen for markers on the short arm of chromosome 17 in 50% of the informative tumors (5 of 10 informative cases) and, to a lesser extent, for markers on chromosomes 1 and 10. Deletions on chromosome 17p were seen in both low-grade and high-grade malignant astrocytomas, suggesting that this chromosome may contain a tumor suppressor gene associated with the early events in tumorigenesis. The common region of deletions on the short arm of chromosome 17 is, therefore, clearly distinct from the gene causing von Recklinghausen neurofibromatosis (NF1), a tumor syndrome associated with glial tumors that maps to the long arm of chromosome 17. The search for progressively smaller deletions on chromosome 17p in astrocytomas may be the way to clone and characterize this locus, thus leading to insights into normal and abnormal growth and differentiation of glial cells.
A patient with two intracerebral glioblastomas of differing histology with metastases to the liver in the absence of surgery is reported. The gliomatous nature of the lesions was confirmed by staining for glial fibrillary acidic protein. Histological and immunohistochemical evidence suggests that the metastases arose from the more poorly differentiated of the intracerebral tumors. One of the intracerebral tumors had enhanced expression of the ras p21 oncogene as compared to the other tumors and as compared to nonmalignant brain tissue from this patient.
Recent evidence indicates that vasoactive intestinal peptide (VIP) may be involved in normal pituitary function. Immunocytochemistry was used to localize VIP in human biopsied pituitary adenomas and postmortem anterior pituitary glands. Paraffin sections were immunostained for VIP with the avidin-biotin-peroxidase technique. Strong VIP-like immunoreactivity (VIP-LI) was observed in 16 of 17 prolactinomas, 12 of 14 growth hormone-secreting tumors associated with acromegaly, four of 12 ACTH-secreting tumors, and 14 of 18 nonfunctioning pituitary adenomas. In most cases, VIP was colocalized with the classical pituitary hormones. Six of the 18 nonfunctioning tumors had no demonstrable hormone immunoreactivity; five of these stained strongly for VIP, whereas one was negative. Of 18 normal anterior pituitaries, 12 showed strong diffuse staining for VIP throughout the gland. One pituitary with VIP-LI came from an individual who had undergone pituitary stalk transection. Double-immunoenzyme labeling and immunoelectron microscopy demonstrated VIP-LI in many lactotrophs, scattered thyrotrophs, corticotrophs, and in an occasional gonadotroph. These results suggest the following: 1) VIP is present in more than one cell type in normal and adenomatous human pituitaries; and 2) VIP may be involved in the function and development of pituitary tumors.
The histopathological and immunopathological features of peripheral neuropathy were investigated in 21 patients with the acquired immunopathological syndrome (AIDS) or AIDS-related complex (ARC). Clinical syndromes observed in the 11 (52%) symptomatic patients included distal symmetrical polyneuropathy (DSPN) and chronic inflammatory demyelinative polyneuropathy (CIDP). Specimens from 19 of 20 patients (95%), both symptomatic and asymptomatic, had histopathological evidence of moderate or severe demyelination (79%), axonal degeneration (36%), and mononuclear cell inflammation (37%). Nerves from patients with CIDP and DSPN showed similar degrees of demyelination and axonal degeneration, but inflammation was more intense in CIDP. Immunohistochemical staining identified the majority of inflammatory cells as T lymphocytes or macrophages, with a predominance of CD8+ cytotoxic/suppressor cells. Diffuse immunostaining for human leukocyte antigen (HLA)-DR was present on endothelial cells, mononuclear inflammatory cells, and Schwann cells, and variable patchy immunostaining for HLA-DR was present on nerve fibers. Control nerve specimens showed staining for HLA-DR limited to endothelial, and a few mononuclear cells. The patterns of immunostaining were similar for AIDS and ARC patients. Human immunodeficiency virus (HIV) was cultured from peripheral nerve in 3 patients, but HIV antigen was not detected by immunohistochemical staining of 8 specimens. The findings implicate HIV infection in nerve, with T cell- and macrophage-mediated tissue destruction as the pathogenetic mechanism of the AIDS/ARC neuropathy.
Axonal regeneration across 64 median nerve grafts in 34 rabbits was studied histologically to determine the optimal conditions for nerve allografting. Axonal regeneration across allografts in cyclosporin A-treated animals was satisfactory, but it occurred more slowly and with more inflammation and fibrosis than in autografts. Without immunosuppression, fresh allografts were rejected. However, in immunocompetent hosts, allografts rendered less immunogenic by predegeneration were not rejected, and axonal regeneration occurred. The combination of cyclosporin A and nerve graft predegeneration produced the most substantial axonal regeneration, comparable to autografts. The observations suggest that nerve allograft survival may be optimally effected by cyclosporin A treatment coupled with reduction in the immunogenicity of the grafts, such as by predegeneration.
An adolescent girl with idiopathic hypothalamic dysfunction and hypopituitarism was treated with human growth hormone between 1969 and 1979, dying of parainfluenza pneumonia 2 months after her last hormone treatment. Although she had no signs of progressive neurologic disease, reexamination of autopsy material revealed a focus of spongiform change and astrogliosis in the corpus striatum. Thus, this growth hormone recipient, who died of intercurrent infection, was unexpectedly found to be in an early, preclinical phase of Creutzfeldt-Jakob disease.
The monoclonal antibody Hy2D4 was found to label a previously undescribed subset of rat and human anterior pituitary cells. The antibody binding site appears to be a carbohydrate moiety previously named "X hapten." Double-label immunofluorescence studies in both normal rat and postmortem human pituitaries showed that this antigen is distributed on a subset of adrenocorticotropic hormone (ACTH)-positive cells, but is not detectable in cells immunoreactive for growth hormone, prolactin (PRL), thyroid-stimulating hormone, or luteinizing hormone. Since X hapten labeling revealed a biological subdivision of corticotroph cells, it was expected that some ACTH-positive tumors would be immunoreactive, but that tumors of other hormonal types would be negative. Instead, in 21 surgical specimens examined, tumors of all hormonal types were found to show immunoreactivity. To determine whether experimental proliferative changes in the pituitary could explain the shift in the cell type expressing the antigen, PRL-cell hyperplasia was induced in rats through chronic (8-week) exposure to diethylstilbestrol. The fraction of X-positive cells increased in these hyperplastic glands almost ninefold and, as in human adenomas, many non-corticotroph cells expressed the X marker in this model. However, the non-corticotroph cells expressing X were predominantly growth hormone cells, not the proliferative PRL cells. Thus, expression of the antigen does not necessarily imply that a cell is in a proliferative mode. While it is not known what role an altered expression of this antigen might play, the antibody offers a probe into cellular biology of human and experimental pituitary tumors.
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A 56-year-old woman with metastatic breast carcinoma presented on her terminal hospital admission with diplopia secondary to bilateral abducens nerve palsies. Postmortem examination revealed a sellar mass composed of an unsuspected pituitary adenoma infiltrated by metastatic carcinoma. Review of the literature revealed only seven patients with this rare neoplasm-to-neoplasm metastasis, none of whom were reported to have had abducens palsies.
Pituitary tumors in which no excess hormone secretion can be identified clinically have been considered as nonfunctioning or null-cell adenomas. Immunocytochemical data presented here suggest that many of these tumors contain subunits of the glycoprotein hormones. Of 160 patients referred for pituitary surgery, 37 (23%) had no evidence of excess hormone secretion on preoperative endocrine evaluation. Immunocytochemical staining of these tumors was carried out using antibodies specific for prolactin, growth hormone, adrenocorticotropic hormone, the beta subunits of luteinizing hormone (beta-LH), follicle-stimulating hormone (beta-FSH), and thyroid-stimulating hormone (beta-TSH), and the alpha subunit. One or more of these pituitary hormones were detected in 73% of cases. The alpha and beta subunits were detected most frequently, being found in 68% of cases; 27% had staining for one or more beta subunits and 37.9% had staining for both alpha and beta subunits. The incidence was: beta-FSH in 58%, beta-LH in 47%, beta-TSH in 33%, and the alpha subunit in 42%. Staining for multiple glycoprotein hormones was common (52%), and mixed glycoprotein hormones and prolactin cell types were found in 16% of cases. These data suggest that most apparently nonfunctioning pituitary tumors contain immunoreactive hormones and the majority of these are subunits of the glycoprotein hormones. Since the glycoprotein hormone beta subunits must combine with the alpha subunit to produce biologically active hormones, the production of the subunits alone may not have endocrine manifestations.
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Dexamethasone ameliorates cerebral edema, but its effect on normal blood-brain barrier is unknown, as is the site of action. Sixteen normal mice were given dexamethasone, 3 mg/kg intramuscularly or 2 mg/kg intravenously. One to two hours later 10 mg of horseradish peroxidase (HRP) in 0.1 ml of saline was administered intravenously and allowed to circulate for 15 minutes. Brain slices were examined by light and electron microscopy. The number of HRP-permeable arteriolar segments per brain was less in dexamethasone-treated than in control mice (p less than 0.001). In addition, the number of small HRP-filled endothelial vesicles of capillaries and of HRP-permeable and -impermeable arterial segments was less in dexamethasone-treated mice than that for similar vessels in control mice (p less than 0.005, p less than 0.05, and p less than 0.01, respectively). The total number of small vesicles and the number of larger HRP-filled vesicles in arterioles was the same in treated and control mice. Dexamethasone therefore decreased the normal permeability of cerebral blood vessels to HRP. This decrease was accompanied by a decrease in the number of HRP-containing small endothelial vesicles. These data suggest that dexamethasone influences cerebral edema by decreasing the permeability of the cerebral vasculature for macromolecules.
A patient with a discrete metastasis in the ventral hypothalamus and optic chiasm is reported, who developed an abnormal daily rhythm of oral temperature without alteration of the 24-h mean temperature. This region, its afferents, and its efferents appear to be important in the neural regulation of human circadian rhythmicity.
Twenty-four cats were divided into two groups and treated with an intravenous infusion of either fluosol DA or dextran. One-half of the animals in each group were ventilated with room air and one-half with 100% oxygen. The right middle cerebral artery was occluded for a period of 4 hours through a transorbital approach. Regional blood flow by the hydrogen clearance method was measured before and after the infusion of fluosol DA or dextran, after oxygenation in the animals on 100% oxygen, three times during the period of ischemia, and after reperfusion. Regional cerebral blood flow increased slightly with the infusion of fluosol or dextran, decreased slightly with hyperoxygenation in the animals so treated, and decreased markedly in the right hemisphere during temporary occlusion of the right middle cerebral artery in all groups. With reperfusion regional flows in the right hemisphere varied considerably, with some animals showing hyperperfusion and others essentially no flow. There was no significant difference in average regional cerebral blood flow between any of the groups. The severity of infarction in all groups was directly related to the decrease in regional cerebral blood flow in the right hemisphere during temporary occlusion. There was also a strong correlation between the regional cerebral blood flow in the right hemisphere after reperfusion and the severity of infarction. In general, the animals showing normal or increased flow after reperfusion had small infarcts and those showing no reflow had large infarcts. Mortality was high in all groups, was not significantly different between any of the groups, and was highly correlated to the size of infarction. In brief, in this study fluosol offered no advantage over dextran, and probably neither agent, in the dose used, offered any protection against cerebral ischemia.
Beginning at age 12, a boy with idiopathic hypopituitarism was treated with cadaver pituitary-derived human growth hormone during the period from 1963 to 1969. Fifteen years after the last treatment, the then 32-year-old man developed Creutzfeldt-Jakob disease (CJD). The illness was atypical in showing predominantly cerebellar signs, little mental deterioration, and no abnormal movements or periodic EEG activity. Examination of the embalmed brain, 7 months after interment, revealed the characteristic changes of CJD mainly in the cerebellum and basal ganglia. This case establishes the contamination of at least two American lots of human growth hormone and, together with other cases of iatrogenic disease, suggests that virus enters the brain from the blood, rather than along neural pathways.
Circumscribed pink areas 0.3-1.0 cm in diameter seen in deeper parts of otherwise well-fixed brains are usually ascribed to inadequate fixation. Twenty-three patients with pink areas in their fixed brains had evidence of inflammation in at least one organ. Blood vessels in the pink areas contained bacteria. Postmortem cultures identified the organisms in 16 cases. Gram-negative bacteria were the most common. Sharply delineated pink areas in well-fixed brains correlate with postmortem intravascular growth of bacteria.
Myocardial contrast echocardiography can define in vivo the area at risk for necrosis after coronary occlusion. However, if this technique is to be used, it cannot be intrinsically toxic to the heart or other critical organs. To determine the functional and pathologic effects of contrast echocardiography, six intracoronary, six intrarenal and six intracarotid artery injections of 2 to 6 cc of a commonly employed contrast agent (agitated Renografin-saline solution) were performed in five dogs. A sixth dog served as a sham to assess any deleterious effects of the model preparation. Two-dimensional echocardiographic images and electrocardiograms were recorded during intracoronary injections, and heart rate, blood pressure, left ventricular end-diastolic pressure and rate of rise of left ventricular pressure (dP/dt) were continuously monitored. At 24 hours, echocardiographic and hemodynamic measurements were repeated, the dogs were killed and the heart, brain and kidneys were removed and prepared for light microscopic examination. Quantitative analysis of left ventricular wall motion was performed on control, peak contrast, post-contrast and 24 hour studies. With each intracoronary injection, there were transient decreases in blood pressure (p = 0.05 versus control) and increases in left ventricular end-diastolic pressure (p = 0.04 versus control). These were associated with depression of wall motion in contrast-enhanced regions (p = 0.01 versus control) and ST-T segment changes on the electrocardiogram. No significant change in heart rate or left ventricular dP/dt was noted. All variables normalized with the clearance of the contrast effect and remained normal to 24 hours. Light microscopic examination revealed no myocardial or cerebral changes attributable to the contrast agent injections.(ABSTRACT TRUNCATED AT 250 WORDS)