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H V Vinters

Publications and source records attributed to H V Vinters.

At least 19 recordsLinked to original sources
PubMed2003

Association between interleukin-1A polymorphism and cerebral amyloid angiopathy-related hemorrhage.

BACKGROUND AND PURPOSE: It has been suggested that the interleukin-1A (IL-1A) allele 2 is a risk factor for Alzheimer's disease (AD). Because cerebral amyloid angiopathy-related hemorrhage (CAAH) often coexists with AD, we examined the IL-1A polymorphism in CAAH. METHODS: In a case-control study, patients with pathologically verified CAAH, AD patients without intracerebral hemorrhage, and neuropathologically normal control subjects were studied. DNA was extracted from brain tissue, and IL-1A was genotyped. Logistic regression was used to examine the IL-1A polymorphism in CAAH patients with and without AD compared with AD and non-AD control subjects. RESULTS: There were 42 patients with CAAH, 232 AD patients, and 167 non-AD control subjects. In age-adjusted analyses, there was no association between possession of IL-1A allele 2 and risk of CAAH compared with AD control subjects (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.45 to 1.97; P=0.87) or non-AD control subjects (OR, 0.94; 95% CI, 0.47 to 1.87; P=0.86). Stratifying for the presence of apolipoprotein E epsilon2 or epsilon4 demonstrated the known increased risk of CAAH from these lipoprotein E alleles. Subgroup analyses demonstrated a nonsignificant excess of the IL-1A 2,2 genotype in patients with CAAH and AD compared with those CAAH patients who did not have histological evidence indicating AD (OR, 2.17; 95% CI, 0.15 to 122.3; P=0.64). Comparisons between CAAH patients with AD and AD control subjects and between CAAH patients without AD and non-AD control subjects did not demonstrate an association between CAAH and possession of either the IL-1A allele 2 or the 2,2 genotype. CONCLUSIONS: The IL-1A allele 2 or 2,2 genotype does not appear to be a major risk factor for CAAH.

Aged↗
PubMed2002

Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier.

BACKGROUND: Monocyte/macrophages are known to infiltrate the brain of patients with HIV-1 encephalitis (HIVE). In Alzheimer's disease brain, the origin of activated microglia has not been determined. MATERIALS AND METHODS: We employed the antigen retrieval technique, immunocytochemistry, immunofluorescense, and confocal microscopy to identify macrophages and microglia in relation to amyloid-beta plaques and the blood-brain barrier in autopsy brain tissues from patients with Alzheimer's disease (AD) and HIVE. RESULTS: In both conditions, cyclooxygenase-2 positive macrophages and, to a lesser degree, T and B cells infiltrate brain perivascular spaces and neuropil. The macrophages are distinguishable from ramified microglia, and decorate the vessels at the sites of apparent of endothelial tight junction protein ZO-1 disruption. The macrophages also infiltrate amyloid-beta plaques, display intracellular amyloid-beta and are surrounded by amyloid-beta-free lacunae. Furthermore, the macrophages partially encircle the walls of amyloid-beta-containing vessels in amyloid angiopathy, and exhibit intracellular amyloid-beta but not paracellular lacunae. Significantly larger zones of fibrinogen leakage surround the microvessels in HIVE brain tissues compared with AD tissues (P = 0.034), and AD tissues have significantly greater leakage than control tissues (P = 0.0339). The AD group differs from a normal control age-matched group with respect to both the area occupied by CD68 (P = 0.03) and cyclooxygenase-2 immunoreactive cells (P = 0.004). CONCLUSION: In both HIVE and AD, blood-borne activated monocyte/macrophages and lymphocytes appear to migrate through a disrupted blood-brain barrier. The lacunae around macrophages in amyloid-beta plaques but not in vessel walls are consistent with the ability of macrophages to phagocytize and clear amyloid-beta deposits in vitro.

AIDS Dementia Complex↗
PubMed2001

Dose-dependent toxicity of a commercially available demineralized bone matrix material.

STUDY DESIGN: A relative risk assessment was performed to determine the safety of three commercially available Grafton demineralized bone matrix quantities used in athymic rats. OBJECTIVE: To evaluate the possible dose-dependent adverse effects of a commercially available demineralized bone matrix containing glycerol. SUMMARY OF BACKGROUND DATA: Commercially available Grafton demineralized bone matrix contains glycerol. The toxic effects of glycerol leading to acute renal failure have been documented. The toxicity of this glycerol-containing substance in higher doses has not been reported. METHODS: Three doses of Grafton putty were implanted in the upper hind limb muscles of athymic nude rats. The rats were observed for adverse effects and early death. Histologic studies were performed. RESULTS: All eight of the rats implanted with the highest dose of Grafton putty (0.008 mL/g) died, five of them within 12 hours of implantation and three in 48 to 72 hours. One rat with the intermediate dose (0.004 mL/g) died within 12 hours of implantation. By 72 hours after implantation, three of the six rats (50%) with the intermediate dose had died. All six of the rats receiving the lowest dose (0.002cc/g) survived. The median lethal dose of Grafton putty in athymic rats was estimated to be 0.00469 mL/g body weight. Histologic analysis of the animals that received the high dose showed acute tubular necrosis, probably secondary to rhabdomyolysis. CONCLUSIONS: In athymic rats, large amounts of Grafton putty lead to death in a dose-dependent manner. Because the median lethal doses of Grafton putty (0.00469 mL/g) and glycerol (0.00442 mL/g) are comparable, a potential source of toxicity is the glycerol contained in the material. The results of this study suggest that high doses have the potential to cause acute renal failure. The authors suggest that clinical usage of Grafton putty in humans should be limited to no more than 2 mL/kg body weight of this material.

Animals↗
PubMed2001

Mitochondrial abnormalities in Alzheimer's disease.

The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

Adolescent↗
PubMed2001

Hamartin expression and interaction with tuberin in tumor cell lines and primary cultures.

Tuberous sclerosis (TSC) is a neurocutaneous disorder characterized by multi-system hamartomatous lesions, and results from a mutation in TSC1, that encodes hamartin, or TSC2, that encodes tuberin. We have examined hamartin expression in a diverse range of human and rat cell lines and primary cultured cells derived from tissues that express hamartin in vivo. Strong hamartin signal was detected in every cell line of human origin examined, representing neuronal, epithelial, lymphoid, renal, vascular smooth muscle, liver, and prostatic cells. Primary cell cultures of oligodendroglioma, meningioma, and glioblastoma multiforme origin were also found to express hamartin. Hamartin was also detected in the rat PC12 cell line, as well as purified primary cultures of rat cortical neurons, astrocytes, and oligodendroglia, with a stronger signal found in astrocytes. Using co-immunoprecipitation, we have also confirmed the physical interaction of tuberin and hamartin in a diverse range of human and rat cell types. These findings demonstrate that hamartin is widely expressed in human and rat cell lines and cultures, and demonstrate that hamartin expression is not lost during the establishment of tumor cell lines or primary cultures. This suggests that the cell lines and cultures studied may serve as useful in vitro models for biochemical investigations involving hamartin and tuberin both individually and as a complex, as well as studies to elucidate the mechanisms underlying the organ-specific pathology of TSC.

Animals↗
PubMed2001

Hamartin and tuberin expression in human tissues.

Tuberous sclerosis (TSC) is a bigenic autosomal dominant disease caused by mutations in one of two tumor-suppressor genes, TSC1 and TSC2, resulting in benign hamartomas and low grade neoplasms in multiple organs including brain, heart, kidney, and skin. We report the results of an immunohistochemical study of the expression of the TSC gene products, tuberin and hamartin, in multiple tissues obtained at autopsy from 12 non-TSC affected patients ranging in age from 20 weeks gestation to 8 years, and surgical specimens from some organs. Tuberin and hamartin are expressed and are colocalized in most tissues. Contrary to a previous report, immunostaining with our antisera detected hamartin in liver, small and large intestine, prostate, and testes. We did not detect significant developmental differences in tuberin or hamartin expression in comparable tissues from patients of different ages. Although tuberin and hamartin colocalize in most tissues and cell types, we provide data that hamartin is more abundantly expressed than tuberin in cells within some tissues including the distal nephron and a population of cells of the endocrine pancreas. These data support the hypothesis that hamartin and tuberin interact and may function together in many tissues where they are co-expressed, but also suggest that hamartin has a discrete and specialized function in certain cell types.

Blotting, Western↗
PubMed2001

The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease.

The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.

AIDS Dementia Complex↗
PubMed2001

Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B.

Tuberous sclerosis (TSC) is a multi-system disorder characterized by hamartomatous tumors and abnormal brain development, with multiple foci of disrupted neuronal migration and giant dysmorphic neurons within cortical tubers. TSC is associated with mutations in 2 genes, TSC1 and TSC2, which encode hamartin and tuberin, respectively. The functions of these proteins have yet to be determined. Recently, the Drosophila homologue of TSC2, gigas, has been shown to be required for the G2/M transition of the cell cycle. However, the mechanism of this action remains unknown. Because the cyclin-dependent kinase CDK1 forms a complex with cyclin B1 to trigger the G2/M transition, we hypothesized that tuberin interacts with CDK1 to regulate its activity. In the study reported in this paper, we have used co-immunoprecipitation and confocal microscopy to demonstrate that tuberin interacts with and co-localizes with CDK1 and its binding partner cyclin B1 in multiple cell types. We also demonstrate that hamartin interacts with CDK1 and cyclin B1. We further present evidence that tuberin interacts with the other regulatory subunit of CDK1, cyclin A. These findings suggest a direct role for tuberin and hamartin in modulating the activity of CDK1 during G2 and the G2/M transition. This is the first description of a role for both tuberin and hamartin in a common cellular function, providing a potential mechanism for the identical clinicopathologic manifestations that result when either of these proteins are inactivated.

Antibody Specificity↗
PubMed2001

Embolization of arteriovenous malformations with Onyx: clinicopathological experience in 23 patients.

OBJECTIVE: To report our experience in treatment of arteriovenous malformations (AVMs) using a new liquid embolic agent, Onyx (Micro Therapeutics, Inc., Irvine, CA). METHODS: Between January 1998 and May 1999, 23 patients (8 men and 15 women) were treated. The patients' average age was 40 years, with seizure being the most common presenting symptom (39%). The average Spetzler-Martin grade on presentation was 3. The average AVM volume before embolization was 14.5 cm3. RESULTS: We observed an average 63% reduction in AVM volume after 129 arterial feeders were embolized. There were four adverse events. Two patients experienced ischemia because of inadvertent occlusion of an arterial feeder. One of these patients made a full recovery, but the other patient had a permanent deficit. Two other patients experienced transient neurological deficits that resolved within 1 week of embolization. Permanent morbidity was thus 4% (1 of 23 patients). There were no deaths. Twelve patients underwent subsequent radiosurgery, and 11 patients had surgery that resulted in complete resection of their AVMs. Histopathological examinations showed mild acute inflammation in specimens resected 1 day after embolization. Chronic inflammatory changes were observed in specimens resected more than 4 days after embolization. In two patients, angionecrosis of the embolized vessels was noted. No evidence of parenchymal hemorrhage was observed in these patients, and vessel wall integrity was maintained as well. CONCLUSION: Onyx is a new nonadhesive liquid embolic agent that has been used to treat 23 patients at our institution with good results. Its nonadhesive nature and ease of use make it a promising agent in the future treatment of AVMs.

Adult↗
PubMed2001

Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease.

Few studies evaluate neuropathological correlates of behavioral changes in Alzheimer disease (AD). We identified 31 autopsy patients with a diagnosis of definite AD. Behavioral changes were assessed with the Neuropsychiatric Inventory. Brain sections were collected from bilateral orbitofrontal and left anterior cingulate, superior temporal, inferior parietal, occipital, and hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hippocampal cortices were reviewed for the presence of Lewy bodies (LBs). Hypothesis-driven correlational analyses were performed by the bootstrap method. Subgroup analyses contrasted a group with high scores of one specific behavior to a group with low scores after equating groups for other behaviors. NFT burden in the left orbitofrontal cortex across all 31 patients significantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs correlated significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within our hypotheses, also showed a significant relationship to agitation within the subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, including three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a significant relationship for the entire group (r = 0.38, p < 0.03) and for subgroups (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs showed a significant relationship only for the entire group (r = 0.25, p < or = 0.01). These observations suggest that agitation and aberrant motor behavior are correlates of greater NFT pathology in the orbitofrontal cortex in AD, whereas increasing apathy may relate to greater NFT burden in the anterior cingulate.

Aged↗
PubMed2000

Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism.

Amyloid plaques composed of the peptide Abeta are an integral part of Alzheimer's disease (AD) pathogenesis. We have modeled the process of amyloid plaque growth by monitoring the deposition of soluble Abeta onto amyloid in AD brain tissue or synthetic amyloid fibrils and show that it is mediated by two distinct kinetic processes. In the first phase, "dock", Abeta addition to the amyloid template is fully reversible (dissociation t(1/2) approximately 10 min), while in the second phase, "lock", the deposited peptide becomes irreversibly associated (dissociation t(1/2) >> 1000 min) with the template in a time-dependent manner. The most recently deposited peptide dissociates first while Abeta previously deposited becomes irreversibly "locked" onto the template. Thus, the transition from monomer to neurotoxic amyloid is mediated by interaction with the template, a mechanism that has also been proposed for the prion diseases. Interestingly, two Abeta peptides bearing primary sequence alterations implicated in heritable Abeta amyloidoses displayed faster lock-phase kinetics than wild-type Abeta. Inhibiting the initial weak docking interaction between depositing Abeta and the template is a viable therapeutic target to prevent the critical conformational transition in the conversion of Abeta((solution)) to Abeta((amyloid)) and thus prevent stable amyloid accumulation. While thermodynamics suggest that inhibiting amyloid assembly would be difficult, the present study illustrates that the protein misfolding diseases are kinetically vulnerable to intervention.

Amino Acid Substitution↗
PubMed2000

Activation barriers to structural transition determine deposition rates of Alzheimer's disease a beta amyloid.

Brain amyloid composed of the approximately 40-amino-acid human beta-amyloid peptide A beta is integral to Alzheimer's disease pathology. To probe the importance of a conformational transition in Abeta during amyloid growth, we synthesized and examined the solution conformation and amyloid deposition activity of A beta congeners designed to have similar solution structures but to vary substantially in their barriers to conformational transition. Although all these peptides adopt similar solution conformations, a covalently restricted Abeta congener designed to have a very high barrier to conformational rearrangement was inactive, while a peptide designed to have a reduced barrier to conformational transition displayed an enhanced deposition rate relative to wild-type A beta. The hyperactive peptide, which is linked to a heritable A beta amyloidosis characterized by massive amyloid deposition at an early age, displayed a reduced activation barrier to deposition consistent with a larger difference in activation entropy than in activation enthalpy relative to wild-type A beta. These results suggest that in Alzheimer's disease, as in the prion diseases, a conformational transition in the depositing peptide is essential for the conversion of soluble monomer to insoluble amyloid, and alterations in the activation barrier to this transition affect amyloidogenicity and directly contribute to human disease.

Alzheimer Disease↗
PubMed2000

Bilateral blindness and lumbosacral myelopathy associated with high-dose carmustine and cisplatin therapy.

PURPOSE: To report the early ocular pathologic findings associated with high-dose carmustine and cisplatin therapy. METHODS: A patient with metastatic breast carcinoma developed an acute onset of branch retinal artery occlusion, bilateral blindness, and a myelopathy involving the lower extremities after high-dose chemotherapy and bone marrow transplant. RESULTS: Histopathologic examination of the eye and optic nerves at autopsy disclosed nerve fiber layer infarction secondary to right inferior temporal retinal artery thrombosis. Patchy necrosis of both optic nerves, medulla oblongata, and spinal cord was associated with focal small-vessel thrombosis. CONCLUSIONS: The syndrome of retinal vascular occlusion, optic neuropathy, and myelopathy is associated with the high-dose chemotherapeutic agents carmustine and cisplatin. The distribution of necrosis suggests an ischemic event rather than direct neurotoxic effects.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Relationships between choline magnetic resonance spectroscopy, apparent diffusion coefficient and quantitative histopathology in human glioma.

This study sought to correlate quantitative presurgical proton magnetic resonance spectroscopic imaging (1H-MRSI) and diffusion imaging (DI) results with quantitative histopathological features of resected glioma tissue. The primary hypotheses were (1) glioma choline signal correlates with cell density, (2) glioma apparent diffusion coefficient (ADC) correlates inversely with cell density, (3) glioma choline signal correlates with cell proliferative index. Eighteen adult glioma patients were preoperatively imaged with 1H-MRSI and DI as part of clinically-indicated MRI evaluations. Cell density and proliferative index readings were made on surgical specimens obtained at surgery performed within 12 days of the radiologic scans. The resected tissue location was identified by comparing preoperative and postoperative MRI. The tumor to contralateral normalized choline signal ratio (nCho) and the ADC from resected tumor regions were measured from the preoperative imaging data. Counts of nuclei per high power field in 5-10 fields provided a quantitative measure of cell density. MIB-1 immunohistochemistry provided an index of the proportion of proliferating cells. There was a statistically significant inverse linear correlation between glioma ADC and cell density. There was also a statistically significant linear correlation between the glioma nCho and the cell density. The nCho measure did not significantly correlate with proliferative index. The results indicate that both ADC and spectroscopic choline measures are related to glioma cell density. Therefore they may prove useful for differentiating dense cellular neoplastic lesions from those that contain large proportions of acellular necrotic space.

Adult↗
PubMed2000

The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.

Loss of the tumour-suppressor gene TSC1 is responsible for hamartoma development in tuberous sclerosis complex (TSC), which renders several organs susceptible to benign tumours. Hamartin, the protein encoded by TSC1, contains a coiled-coil domain and is expressed in most adult tissues, although its function is unknown. Here we show that hamartin interacts with the ezrin-radixin-moesin (ERM) family of actin-binding proteins. Inhibition of hamartin function in cells containing focal adhesions results in loss of adhesion to the cell substrate, whereas overexpression of hamartin in cells lacking focal adhesions results in activation of the small GTP-binding protein Rho, assembly of actin stress fibres and formation of focal adhesions. Interaction of endogenous hamartin with ERM-family proteins is required for activation of Rho by serum or by lysophosphatidic acid (LPA). Our data indicate that disruption of adhesion to the cell matrix through loss of hamartin may initiate the development of TSC hamartomas and that a Rho-mediated signalling pathway regulating cell adhesion may constitute a rate-limiting step in tumour formation.

3T3 Cells↗
PubMed2000

Neuropathologic substrates of ischemic vascular dementia.

Ischemic vascular dementia (IVD) is a relatively uncommon entity, in the course of which multiple ischemic brain lesions result in progressive cognitive and memory impairment. Ischemic brain lesions may also aggravate the neuropsychologic deficit of Alzheimer disease (AD). In this review we summarize our experience based upon autopsy examination of the central nervous system in 20 patients (age range 68-92 years) enrolled in a longitudinal investigation of structural, neurochemical, functional neuroimaging, and neuropsychologic components of IVD, especially dementia associated with cerebral microvascular disease. While cystic infarcts were present in the CNS of 5 patients, the most commonly observed neuropathologic abnormalities were lacunar infarcts and microinfarcts--both types of lesion were encountered in over half of patients' brains. Evidence of (remote) hippocampal injury was found in 11/20 patients. Severe atherosclerosis and arterio/ arteriolosclerosis were both associated with the occurrence of multiple lacunar infarcts. Pronounced cerebral amyloid angiopathy (CAA) was noted in a single patient, who also showed other microscopic changes of severe AD. While fairly unusual as a nosologic entity, IVD appears to correlate with widespread small ischemic lesions distributed throughout the CNS. We furthermore propose an approach to quantifying the burden of ischemic vascular and parenchymal disease that may be associated with a dementia syndrome. A brief review of neuropathologic features of vascular dementia (both familial and sporadic) is presented.

Aged↗