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Biomedical subjects

R L Hamilton

Publications and source records attributed to R L Hamilton.

At least 55 records · Page 3Linked to original sources
PubMed1998

Genes for apolipoprotein B and microsomal triglyceride transfer protein are expressed in the heart: evidence that the heart has the capacity to synthesize and secrete lipoproteins.

BACKGROUND: Expression of both the apolipoprotein B (apoB) gene and the microsomal triglyceride transfer protein (MTP) gene is required for the assembly and secretion of triglyceride-rich lipoproteins in the liver and intestine. Both genes have been assumed to be silent in the heart. METHODS AND RESULTS: Northern blot and RNase protection analyses showed that the apoB and MTP genes were expressed in the hearts of mice and humans. In situ hybridization studies revealed that the apoB mRNA was produced in cardiac myocytes. Electron microscopy of human cardiac myocytes revealed lipid-staining particles of relatively small diameter (approximately 250 A) within the Golgi apparatus. CONCLUSIONS: These studies strongly suggest that the heart synthesizes and secretes apoB-containing lipoproteins.

Animals↗
PubMed1998

Neurodevelopmental anomalies in children with neuroblastoma.

BACKGROUND: Case reports have associated neuroblastoma, a cancer derived from the embryonal neural crest, with aganglionosis coli and neurofibromatosis type I. The aim of the current study was to test the hypothesis that neuroblastoma is part of a global defect in neurodevelopment. METHODS: Neuropathologic findings from autopsies of children who died of neuroblastoma during the period 1980-1995 at the Children's Hospital of Pittsburgh were reviewed for macroscopic and microscopic abnormalities. As controls, autopsies of children who had died of other primary extracranial cancers over the same time period also were studied. Medical records of neuroblastoma patients for whom autopsies were available were reviewed for clinical evidence of preexisting nonmalignant neurologic disease. RESULTS: Of 145 children diagnosed with neuroblastoma, 49 had died, and autopsies not restricting examination of the brain had been performed on 13. Macroscopic anatomic abnormalities (a small cerebellum and the absence of the corpus callosum) were noted in one patient who was known to have been mentally retarded without having a defined syndrome. Microscopic abnormalities of cytoarchitecture were noted in that patient as well as 3 of the 12 other patients (focal cortical dysplasia [fcd], n = 3; leptomeningeal heterotopia, n = 1; abortive sulcation or flattened gyri, n = 2). None of 3 patients with only microscopic abnormalities had clinical evidence of problems with neurodevelopment. Of the 26 children with nonneuroblastoma cancers for whom complete autopsies were available, 1 infant had major macroscopic structural abnormalities of the brain. None of these patients had microscopic abnormalities (P < 0.01). CONCLUSIONS: Children with neuroblastoma have an increased incidence of abnormalities of brain cytoarchitecture, particularly fcd. These abnormalities are generally asymptomatic and are diagnosed by histologic examination. Such abnormalities cannot be attributed to chemotherapy and are not observed in other children with non-central nervous system tumors. These findings are consistent with the concept that neuroblastoma may occur in the setting of a more global defect in neurodevelopment. A blinded review of larger numbers of cases will be needed to verify these data.

Adolescent↗
PubMed1998

Primary parafalcine chondrosarcoma in a child.

Intracranial cartilaginous tumors are rare lesions, usually arising from the skull base in older individuals. We report the case of a 12-year-old girl with a low-grade type chondrosarcoma arising from the falx cerebri. To our knowledge this is the first such case reported in a child. She was treated with gross total surgical resection followed by external beam radiation because there was evidence of dural infiltration by tumor in and around the superior sagittal sinus. The patient remains progression free 9 months after surgery.

Brain Neoplasms↗
PubMed1998

A reproducible model of circulatory arrest and remote resuscitation in rats for NMR investigation.

BACKGROUND AND PURPOSE: Because noninvasive physiological monitoring of cerebral blood flow, metabolic integrity, and brain ion and water homeostasis can now be accomplished with new, state-of-the-art MR spectroscopy and imaging techniques, it is appropriate to develop controllable and reproducible animal models that permit prolonged circulatory arrest and resuscitation in the magnet and also allow for studies of long-term survival and outcome. We have developed such a model in rats that involves minimal surgical preparations and can achieve resuscitation remotely within precisely controlled time. METHODS: Cardiac arrest was induced by asphyxiation, the duration of which ranged from 8 to 24 minutes. Resuscitation was achieved remotely by a slow, intra-aortic infusion of oxygenated blood (withdrawn either from the same rat before asphyxia or from a healthy donor rat) along with a resuscitation cocktail containing heparin (50 U/100 g), sodium bicarbonate (0.1 mEq/100 g), and epinephrine (4 micrograms/100 g). The body temperature was measured by a tympanic thermocouple probe and was controlled either by a heating pad (constant tympanic temperature = 37 degrees C) or by warm ambient air (constant air temperature = 37 degrees C). Interleaved 31P/1H nuclear magnetic resonance (NMR) spectroscopy was used in a selected group of rats to measure the cerebral metabolism before and during approximately 20 minutes of circulatory arrest and after resuscitation. RESULTS: The overall success rate of resuscitation, irrespective of the duration of cardiac arrest, was 82% (51 of 62). With a programmed infusion pump, the success rate was even higher (95%). The survival time for rats subjected to 15 and 19 minutes of asphyxia with core temperature tightly controlled was significantly lower than that with ambient temperature control (P < 0.001 and P < 0.04, respectively). High-quality NMR spectra can be obtained continuously without interference from the resuscitation effort. Final histological examinations taken 5 days after resuscitation showed typical neuronal damages, similar to those found in other global ischemia models. CONCLUSIONS: Because the no-flow time and resuscitation time can be precisely controlled, this outcome model is ideally suited for studies of ischemic and reperfusion injuries in the brain and possibly in other critical organs, permitting continuous assessment of long-term recovery and follow-up in the same animals.

Animals↗
PubMed1998

Case of the month: September 1997--a 26 year old woman with new onset seizures.

A twenty-six year old, previously healthy nurse presented with new onset of seizures and was given a clinical diagnosis of herpes simplex encephalitis. After treatment with acyclovir there was incomplete resolution of the lesions by MRI scans and within a few months the patient's neurologic symptoms worsened, prompting a stereotactic biopsy. A diagnosis of progressive multifocal leukoencephalopathy (PML) was made using electron microscopy, and in situ hybridization studies. Subsequent to this biopsy, she was shown to be infected with human immunodeficiency virus (HIV) and had a CD4 T-cell count of 63. She had no known risk factors for HIV infections and had been tested as recently as eighteen months previously during her pregnancy. Neither the husband nor the child were positive for HIV. PML as a presenting sign of HIV infection is rare.

Adult↗
PubMed1998

Case of the month: February 1998--82 year old man with progressive visual defects.

An 82 year old man with a recurrent prolactin-secreting pituitary adenoma had clinically asymptomaptic fungal growth in necrotic tissue adjacent to the tumor. This fungus was characterized by clumps of basophilic hyphae with pigment production. Ascus formation containing nucleated conidiopores was present. The asci had tapered and cylindrical beaks making Microascus sp. the most likely diagnosis, however, without cultures, Pseudoallesheria boydii could not eliminated. The patient was treated with Amphotericin B and there was no evidence of intracranial extension 4 months later.

Adenoma↗
PubMed1998

Chylomicron-sized lipid particles are formed in the setting of apolipoprotein B deficiency.

The mechanisms for packaging large quantities of neutral lipids into apolipoprotein (apo) B-containing lipoproteins (chylomicrons or VLDL) are incompletely understood. However, several lines of evidence have suggested that the addition of core lipids to apoB to form a lipoprotein particle within the endoplasmic reticulum (ER) may involve two steps: first, the addition of small amounts of core lipids to membrane-bound apoB, generating a lipid-poor, small apoB-containing particle, and second, the fusion of that particle with a larger, independently formed triglyceride-rich and apoB-free "lipid particle." We sought to test this two-step hypothesis of apoB core lipidation by using electron microscopy to compare chylomicron assembly in mice that are genetically deficient in the ability to synthesize apoB in the intestine to control mice. In 19-day gestational mice (fasting setting) that were deficient in intestinal apoB synthesis, chylomicron-sized lipid particles in the lumen of the enterocyte ER were even more abundant and were 2- to 3-fold larger than those in the enterocytes of normal control mice. However, there were fewer lipid-staining particles in the Golgi apparatus, and many fewer particles in the extracellular space, compared with normal control mice. In both types of newborn suckling mice, much larger lipid particles were assembled within the lumen of the ER. They were however, less abundant and rarely reached the Golgi apparatus in fatty enterocytes of intestines deficient in apoB synthesis. These observations provide in vivo evidence that chylomicron formation could involve the synthesis of apoB-free triglyceride-rich particles within the endoplasmic reticulum (ER) lumen, and that the transport of these lipid particles out of the ER to Golgi apparatus and interstitium is facilitated by the acquisition of apoB.

Animals↗
PubMed1997

Proliferation index as a predictor of prognosis in malignant gliomas of childhood.

BACKGROUND: The prognosis for children with high grade gliomas remains somewhat unpredictable because histologic features alone provide an imperfect assessment of the biologic behavior of a given lesion. Whereas some patients experience prolonged disease control after surgery and adjuvant therapy, others with lesions that appear comparable exhibit rapid disease progression and death. METHODS: Because proliferative activity may provide a potential correlate of biologic aggressiveness, the authors examined the relationship between MIB-1 labeling index and outcome in a series of 29 archival pediatric malignant nonbrainstem gliomas from patients treated consecutively at the study institution between 1975 and 1992, in which clinical, histologic, diagnostic, and therapeutic parameters were previously defined. Three patients who died perioperatively were excluded from outcome analyses. All tumors were rereviewed by two neuropathologists and classified as Grade 3 or 4 lesions based on contemporary guidelines. RESULTS: Among the specimens from the 26 patients who survived the perioperative period, a striking difference in outcome was apparent between tumors with MIB-1 indices < 12 (n = 10) and those with indices > 12 (n = 16). Median progression free survival was >48 months in the low MIB-1 group compared with only 6 months in the high MIB-1 group (P = 0.014, rank-sum test). Median overall survival was >48 months in the low MIB-1 group compared with only 16 months in the high MIB-1 group (P = 0.012). MIB-1 index remained associated with survival after taking into account the effect of resection extent, which also correlated strongly with outcome in this cohort. Although MIB-1 index was associated with histopathologic grade (Grade 3: 11.9 +/- 9.7 vs. Grade 4: 27.3 +/- 19.0; P = 0.015, Fisher's exact test), it proved to be a much stronger predictor of outcome than histology. CONCLUSIONS: MIB-1 index may supplement routine histologic classification as a means for improving the accuracy of predicting the biologic behavior of childhood malignant gliomas and may provide a basis for stratifying patients in future malignant glioma studies and refining therapeutic decision-making.

Antibodies, Monoclonal↗
PubMed1997

The relationship between TP53 mutations and overexpression of p53 and prognosis in malignant gliomas of childhood.

The prognosis for children with high-grade gliomas remains somewhat unpredictable. Although prolonged disease control is sometimes achieved after surgery, radiotherapy, and chemotherapy, most patients exhibit rapid disease progression. Because p53-dependent apoptosis mechanisms are involved in the cytotoxic effects of irradiation and chemotherapy, we questioned whether p53 status might be associated with outcome in childhood malignant gliomas. Therefore, we examined p53 status, both immunohistochemically and by direct sequencing of exons 5-8, in a series of 29 archival pediatric malignant non-brainstem gliomas treated consecutively at our institution between 1975 and 1992. Eighteen tumors had dense p53 staining in the majority of cells, although only 11 had mutations of the p53 gene (TP53). On univariate analysis, there was a significant association between p53 overexpression and a shorter progression-free survival (PFS) and overall survival (OS; P = 0.019 and 0.013, respectively; rank sum test). In addition, there was a significant association between TP53 mutations and a poorer PFS (P = 0.04), and a strong trend toward a shorter OS among patients with TP53 mutations (P = 0.06). Median PFS and OS for patients with TP53-mutated tumors were 6 months and 16 months, respectively, and for those with p53 overexpression 5.5 months and 14 months, respectively, versus 16 months and 25 months, respectively, for those without TP53 mutations and 25 months and >4 years, respectively, for those without p53 overexpression. The percentage of patients in this series with TP53 mutations (37.9%) was substantially higher than in previous studies of childhood gliomas and comparable to the frequency of mutations noted in adult gliomas. However, both TP53 mutation and p53 overexpression were significantly less frequent in tumors from children younger than 4 than from older children (P = 0.02 and 0.01, respectively). These results indicate that p53 mutation and expression status may be associated with prognosis in childhood malignant gliomas, and thus may provide a basis for stratifying patients biologically in future malignant glioma studies.

Adolescent↗
PubMed1997

Immunohistochemical study of GABA(A) receptor beta2/3 subunits in the hippocampal formation of aged brains with Alzheimer-related neuropathologic changes.

In AD, it is hypothesized that one factor contributing to the vulnerability of neurons is a delicate balance of excitatory and inhibitory inputs. To examine this hypothesis we have initiated a number of studies examining the role of the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the neurodegeneration of AD. As an initial investigation into the GABAergic system in AD, we employed immunocytochemical techniques and examined the distribution and density of the GABAA receptor subunits beta2/3 within the hippocampus of 13 subjects with a clinical diagnosis of AD and 6 nondemented elderly subjects. Collectively, these 19 subjects presented with a broad range of pathologic severity (i.e., Braak stages I-VI). Density measurements of nine hippocampal regions demonstrated highest levels of beta2/3 immunolabeling in the inner molecular layer of the dentate gyrus > CA1 > CA2, while the lowest levels were found in the granular layer of the dentate gyrus < or = CA4 < CA3 field. Despite these regional variations no significant difference in the mean density of beta2/3 immunolabeling was observed when comparing the pathologically mild (stages I and II), moderate (stages III and IV), and severe (stages V and VI) groups. These data suggest that in the hippocampus receptor subunits associated with GABAergic neurotransmission are relatively maintained even until the terminal stages of the disease.

Aged↗
PubMed1997

January 1997--7 year old girl with seizures.

A seven year old girl presented with six month history of seizures. An MRI scan showed a cortical lesion in the left temporal lobe which was resected. Neuropathologic examination demonstrated meningioangiomatosis, an unusual hamartomatous condition sometimes associated with neurofibromatosis 2. Approximately 50 cases of meningioangiomatosis have been reported in the literature. These are reviewed and compared to the current case.

Angiomatosis↗
PubMed1997

February 1997--9 year old girl with hydrocephalus.

A nine year old girl presented with nausea vomiting and hydrocephalus. Imaging studies demonstrated a large right thalamic mass with areas of cystic change or necrosis. Sections of resected material showed perivascular pseudorosettes, necrosis, endothelial proliferation, numerous mitoses, densely cellular areas and numerous foci with a clear-cell morphology. This case is used to illustrate the features of anaplastic ependymomas and to discuss the relationship of the histologic features to prognosis.

Brain Neoplasms↗
PubMed1997

The molecular biology of ependymomas.

Intracranial ependymomas are the third most common primary brain tumor in the pediatric population. Although an anaplastic variant is recognized, numerous studies examining the prognostic implications of histological features, such as necrosis, endothelial proliferation and mitoses, have yielded contradictory results. In order to improve outcome prediction in affected patients and to refine therapeutic decision-making, there is a strong need for identifying relevant biological correlates of tumor behavior. The molecular biology of tumors is a rapidly expanding field and includes investigations into cytogenetics, oncogenes, growth factors, growth factor receptors, hormonal receptors, proliferation markers, apoptosis, cell cycle genes and cell adhesion molecules, as well as factors potentially related to therapeutic resistance, such as the multidrug resistance gene. The molecular biology of astrocytic tumors in adults has been the subject of many studies; however, relatively few studies have been focused on ependymomas. Herein we review potential oncological markers in ependymomas that have been identified to date and highlight the limitations of our current knowledge as a basis for defining areas for future investigation.

Brain Neoplasms↗
PubMed1997

December 1996--cervicomedullary tumor.

A cervicomedullary tumor in a 22-month-old female with an eight-month history of symptoms showed the histological features of a pilocytic astrocytoma but had many areas of palisading cells identical to those described in polar spongioblastomas. The tumor recurred 18 months later and showed predominately pilocytic features. The case is used to discuss polar spongioblastomas and tumors which can histologically simulate them.

Astrocytoma↗
PubMed1997

Case of the month. July 1996--precocious puberty.

A 4 year old girl presented with precocious puberty. She had pubic hair, breast buds and showed a height and weight well above the 95th percentile. An MRI scan of the head revealed a discrete mass in the tuber cinereum which was surgically removed. Microscopic examination showed a hypothalamic hamartoma. The clinical, radiologic and microscopic findings in this case are "classic" for hypothalamic hamartoma Other clinical presentations are discussed. The patient's symptoms have regressed following surgery and there has been no regrowth in six months.

Child, Preschool↗
PubMed1997

Case of the month. September 1996--new onset hemiparesis.

A 44 year old woman developed left hemiparesis. CT scan showed a contrast enhancing lesion in the right periventricular area. A stereotactic biopsy was performed. The initial impression was that of an astrocytic neoplasm, however the presence of perivascular lymphocytes and numerous foamy macrophages led to consultation. Special studies demonstrated demyelination and lymphocytic infiltrate with relative axonal preservation consistent with multiple sclerosis. Additional history from the patient revealed a flu-like illness one week prior to the hemiparesis and a history of transitory visual problems, possibly early manifestations of her multiple sclerosis.

Adult↗