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Biomedical subjects

J W Miller

Publications and source records attributed to J W Miller.

At least 91 records · Page 5Linked to original sources
PubMed1996

Preserved function in brain invaded by tumor.

OBJECTIVE: Intrinsic brain tumors can arise within regions of the cortex that are essential to language, motor, and somatosensory functions. Although it is commonly thought that such tumors can be safely resected, as long as the resection is limited to grossly abnormal cortex, functional mapping of the cerebral cortex during tumor resection does not support this contention. METHODS: We report our experience with 14 patients (9 men, 5 women; median age, 43 yr) with intrinsic brain tumors of varying degrees of malignancy (four glioblastomas multiforme, four anaplastic astrocytomas, two anaplastic oligodendrogliomas, one anaplastic mixed glioma, three gangliogliomas). Cortical mapping was performed either intraoperatively (n = 11) or extraoperatively via intracranial electrodes (n = 3). RESULTS: Tumors were found to grossly invade functioning cortices (frontal lobe language cortex, four tumors; temporal lobe language cortex, five tumors; motor cortex, four tumors; somatosensory cortex, one tumor). The gross invasion of functional cortex by tumor limited safe resection in all patients. Three patients experienced transient postoperative deficits caused by the proximity of the resection to functional cortex. One patient suffered a delayed postoperative hemorrhage, with resultant persistent motor aphasia. CONCLUSION: Intrinsic brain tumors grow by infiltration of normal brain. Consequently, brain that appears to be abnormal may remain functional, thus precluding safe tumor resection.

Adult↗
PubMed1996

Severe penetrating eye trauma caused by fish pick accidents.

PURPOSE AND METHODS: The authors describe three cases in which commercial fishermen presented with penetrating ocular injuries from fish picks, which are hand-held, fish-sorting tools with relatively blunt tips designed to partially penetrate fish and expedite handling. Ocular injuries from this tool have not been reported previously. RESULTS: Presenting visual acuity was light perception in two cases and hand motions in one case. Corneal laceration and vitreous hemorrhage were seen in all cases. Initial ultrasound showed no retinal detachment, and all patients underwent primary repair of the corneal laceration. However, within the first 2 months, follow-up ultrasound was suggestive of retinal detachment in all cases, and pars plana vitrectomy was performed. One patient who was found to have a retinal hole but no retinal detachment did well, with a visual acuity of 20/80. Two patients with retinal detachment did poorly, one with a dense epiretinal membrane and the other with a chronic irreparable retinal detachment and extensive subretinal fibrosis. CONCLUSIONS: These injuries differ from fish hook injuries because the instrument is much larger and is blunt in nature, imparting significant energy into the eye. Consequently, patients with these injuries have a much less favorable outcome.

Adult↗
PubMed1996

Cloning and mRNA expression of vascular endothelial growth factor in ischemic retinas of Macaca fascicularis.

PURPOSE: To identify and isolate cDNAs for the alternatively spliced vascular endothelial growth factor (VEGF) mRNAs present in retina and to compare the relative levels of the splice variants and localization of VEGF mRNA in nonischemic and ischemic adult simian retinas. METHODS: Retinas of cynomolgous monkeys were made ischemic by laser occlusion of the main branch retinal veins. Reverse transcription-polymerase chain reaction was used to amplify the VEGF coding region of RNA from ischemic and control retinas, and amplification products were analyzed by agarose gel electrophoresis, Southern blot, and nucleotide sequencing. Analysis of VEGF mRNA expression was accomplished by in situ hybridization. RESULTS: Control and ischemic retinas produce mRNAs that correspond to the 121 and 165 amino acid diffusible isoforms of VEGF, and relatively low levels of VEGF189, the heparin-binding isoform. There was no significant difference in the levels of the alternatively spliced VEGF transcripts between control and ischemic retinas. Cloning and sequencing revealed that simVEGF cDNAs are 99% identical to human VEGFs and are predicted to encode proteins identical to their respective human homologues. In situ hybridization of nonischemic retinas revealed a low level of VEGF mRNA in retinal ganglion cells and in the inner nuclear layer. VEGF mRNA levels were elevated in ischemic retinas as early as 1 day after laser vein occlusion, when there was a small but reproducible increase in signal. The expression peaked at approximately 13 days, coincident with maximal iris neovascularization, and was significantly reduced by 28 days, when the iris vessels largely regressed. CONCLUSIONS: The elevation of simVEGF121 and VEGF165 in ischemic retinas is consistent with a role for diffusible, retina-derived angiogenic factors in the development of ocular neovascularization.

Alternative Splicing↗
PubMed1996

A novel nonopioid action of enkephalins: competitive inhibition of the mammalian brain high affinity L-proline transporter.

The high affinity L-proline transporter (PROT) is a member of the family of Na+ (and Cl-)-dependent plasma membrane transport proteins that comprises transporters for several neurotransmitters, osmolytes, and metabolites. The brain-specific expression of PROT in a subset of putative glutamatergic pathways implies a specialized function for this novel transporter and its presumed natural substrate L-proline in excitatory synaptic transmission. However, definitive studies of the physiological role(s) of high affinity L-proline uptake have been precluded by the lack of specific uptake inhibitors. Here, we report that Leu- and Met-enkephalin and their des-tyrosyl derivatives potently and selectively inhibited high affinity L-proline uptake in rat hippocampal synaptosomes and in PROT-transfected HeLa cells. High concentrations of the opiate receptor antagonist naltrexone did not block the inhibitory actions of these peptides, arguing against an involvement of opioid receptors. Des-tyrosyl-Leu-enkephalin elevated the apparent K(m) of L-proline transport in transfected HeLa cells without altering the V(max). PROT-transfected HeLa cells did not accumulate [3H]Leu-enkephalin above background levels, demonstrating that enkephalins are not substrates for PROT. These findings indicate that enkephalins competitively inhibit mammalian brain PROT through a direct interaction with the transporter protein at or near the L-proline binding site. The high potency and specificity of des-tyrosyl-Leu-enkephalin make this compound a useful tool for elucidating the structure-function properties and physiological role(s) of PROT.

Amino Acid Transport Systems, Neutral↗
PubMed1995

Hyperhomocysteinemia and traditional cardiovascular disease risk factors in end-stage renal disease patients on dialysis: a case-control study.

Hyperhomocysteinemia occurs frequently in end-stage renal disease (ESRD), but its prevalence in comparison with traditional cardiovascular disease (CVD) risk factors is unknown. Fasting total plasma homocysteine, potential determinants of plasma homocysteine (i.e., plasma B-vitamins and serine), total and HDL cholesterol, glucose, and creatinine, were determined in 24 ESRD patients on dialysis, and 24 age, gender, and race matched Framingham Offspring Study controls with normal renal function. Presence of clinical CVD and CVD risk factors was established by standardized methods. Mean plasma homocysteine was markedly higher in the ESRD patients versus controls (22.7 vs. 9.5 mumol/l). ESRD patients were 33 times more likely than controls to have hyperhomocysteinemia (> 15.8 mumol/l) (95% confidence interval, 5.7-189.6). Hyperhomocysteinemia persisted in the ESRD patients despite normal to supernormal B-vitamin status. Plasma serine levels below the tenth percentile of the control distribution were found in 75% of the ESRD patients. Oral serine supplementation caused a 37% increase in mean plasma serine, but had no effect on plasma homocysteine in four ESRD patients with supernormal plasma folate, low plasma serine, and hyperhomocysteinemia. Given its unusually high prevalence, improved management of hyperhomocysteinemia might reduce CVD sequelae in ESRD.

Adult↗
PubMed1995

Denervation induced abnormal phosphorylation in hippocampal neurons.

This study demonstrates that combined dopaminergic and cholinergic denervation of the hippocampus results in the appearance of morphologically altered, Tau reactive, apical dendrites of granule cells in the rat dentate gyrus. The denervated granule cells and their apical dendrites also display immunoreactivity to a mitogen-activated protein kinase, ERK-1, and also evidence of abnormal phosphorylation of these dendrites as revealed by SMI-31 immunoreactivity. Dopaminergic denervation alone also causes mitogen activated protein kinase reactivity without the Tau-reactive apical dendrities. These results suggest an analogy to synaptophysin loss and the appearance of dendritic threads described in Alzheimer's disease (AD), as an early stage in the formation of neurofibrillary tangles (NFT). This is the first animal model in which abnormal phosphorylation of Tau has been shown to be produced experimentally in vivo.

Alzheimer Disease↗
PubMed1995

Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin.

OBJECTIVE: To investigate photodynamic therapy of experimental choroidal neovascularization using benzoporphyrin derivative monoacid (Verteporfin). METHODS: Photodynamic therapy using benzoporphyrin derivative monoacid was investigated in cynomolgus monkeys. Following intravenous injection of benzoporphyrin derivative monoacid (1 to 2 mg/kg) complexed with low-density lipoprotein, the eyes were irradiated with 692-nm light at a fluence of 50 to 150 J/cm2 and irradiance of 150 to 600 mW/cm2. Choroidal neovascularization was documented before photodynamic therapy and closure was demonstrated by fundus photography, fluorescein angiography, and light and electron microscopic examination. RESULTS: Following photodynamic therapy, vessels within choroidal neovascularization were occluded, and there was damage to the choroidal neovascularization endothelium and the subjacent choriocapillaris. Damage to the retinal pigment epithelium and photoreceptors was also observed. CONCLUSION: Photodynamic therapy with lipoprotein-delivered benzoporphyrin derivative monoacid was effective in this animal model of choroidal neovascularization and may be a promising, potentially selective, therapy for choroidal neovascularization.

Animals↗
PubMed1995

Behavioral and neurochemical changes in folate-deficient mice.

Weanling mice were fed an amino acid-based diet supplemented with 0 or 11.3 mumol folic acid/kg diet for approximately 38 days to study behavior and neurochemistry in folate deficiency. After approximately 5 wk, mice fed the unsupplemented diet weighted approximately 70% as much those fed the supplemented diet. After 2 wk, mice fed the unsupplemented diet consistently discarded (spilled) more food, and after approximately 5 wk, they had spilled 3 times more than mice fed the supplemented diet. Serum folate, brain folate and brain S-adenosylmethionine of mice fed the unsupplemented diet were 4, 53, and 60% as high, respectively, as those of mice fed the supplemented diet. Pathologic changes were not evident in brain, spinal cord, or skeletal muscle of folate-deficient mice. The hypothalamic 5-hydroxyindole acetic acid/serotonin ratio and caudate dopamine, homovanillic acid, and 3,4-dihydroxyphenylacetic acid concentrations were lower in deficient than control mice. Folate-deficient mice develop a behavioral activity, food spilling, which may have a neurochemical basis in the serotonin and dopamine systems.

Animals↗
PubMed1995

Retinal artery occlusion in rabbit eyes using human atheroma.

Previous animal models of central retinal artery occlusion using glass or latex embolic material may not simulate human disease. We have developed a rabbit model using human atherosclerotic material, which may be useful in developing embolus specific treatments, including thrombolysis or laser photodisruption. Fresh human atherosclerotic plaque was harvested from atherosclerotic human aorta by mechanical removal and suspension in normal saline. The suspension was agitated vigorously to produce small particles, which were separated into various sizes by filtration through mesh filters with specific pore sizes. The common carotid artery of the anesthetized rabbit was isolated by neck dissection and cannulated using a modified Seldinger technique. Suspensions of human atherosclerotic plaque were injected into the common carotid artery via this cannula. All animals were examined by slit lamp and fluorescein angiography before and after retinal artery occlusion. This model reliably produced retinal artery occlusion using human atherosclerotic plaque. Plaque particles less than 105 microns reliably produced branch retinal artery occlusion, while larger plaque particles less than 149 microns reliably produced central retinal artery occlusion. Sublingual nitroglycerin, at 0.1 mg/kg, intravenous verapamil, from 0.2 mg/kg to 2 mg/kg, and intracarotid urokinase given acutely in standard doses failed to cause reperfusion. This model will be very useful in the study and treatment of retinal vascular disorders as it may more closely simulate human disease over previous models using artificial embolic materials. Embolic specific treatment stategies, such as thrombolysis and laser photodisruption, may be further developed with this model.

Animals↗
PubMed1995

SD filtering for enhancement of a nuclear medicine image sequence.

This paper explores the use of an image sequence processing algorithm, called the simultaneous diagonalization (SD) filter, which can be effectively applied to long noisy image sequences. This filter was developed to filter a spatially invariant image sequence to form one new image in which a desired feature is enhanced and one or more undesired features (and noise) are suppressed in the filtered image. This filtering technique, applied to a long noisy image sequence, can be used to achieve significant data compression for image storage and provide surprisingly good enhanced image reconstructions. For this investigation, SD filtering is applied to a temporal image sequence, a renogram, with compression of a very noisy 180-image sequence to a 4-image set. The renogram, a nuclear medicine technique, was chosen due to its low signal-to-noise ratio over a long image sequence. Before the application of the SD filter, classical image processing techniques, median and averaging filtering, are used as a preliminary method to reduce the image sequence noise content. Compared to any of the images in the original image sequence, the reconstructed images are remarkably good. The SD filter with prefiltering, thus, can collect information distributed over a 180-image temporal sequence with low signal-to-noise ratio.

Algorithms↗
PubMed1995

Trait shyness in the elderly: evidence for an association with Parkinson's disease in family members and biochemical correlates.

The emergence of potential treatments to slow the progression of idiopathic Parkinson's disease (PD) has increased the need for early identification of persons at risk. Although considered controversial, some prior studies indicate that PD patients may have premorbid histories of greater trait introversion or shyness as well as increased rates of disorders associated with shyness (e.g., anxiety, affective disorders, and irritable bowel syndrome). Essential features of trait shyness include (a) inhibited and avoidant behaviors and (b) physiological hyperreactivity to the novel or unfamiliar. In parallel, (a) depression in PD patients is associated with increased harm avoidance (a possible serotonergic function), and (b) PD patients have premorbid and comorbid decreases in novelty-seeking (a possible dopaminergic function). Taken together, previous research suggests the following hypotheses: (1) given evidence for marked heritability of shyness, shy elderly should report higher rates of PD in their family members than would nonshy elderly; and (2) shy elderly without PD should exhibit psychological and biologic characteristics similar to those reported in PD. Two groups, representing the top 27% (n = 37) and bottom 31% (n = 43) of scores on a standardized shyness scale, were drawn from a larger cohort of 138 older adults (ages 50-90) living in an active retirement community. Seventeen percent of the shy versus 2% of the nonshy reported PD in a family member or self (P < .05). Shy elderly were significantly more anxious (P < .01) and depressed (P < .05) than were the nonshy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy.

The vitreous levels of the angiogenic polypeptide vascular endothelial growth factor (also known as vascular permeability factor) were measured and compared in eyes with and without proliferative diabetic retinopathy. Undiluted vitreous samples from 20 eyes were collected at the time of vitrectomy, and vascular endothelial growth factor levels were determined by using a time-resolved immunofluorometric assay. Vitreous vascular endothelial growth factor levels were significantly higher in eyes with proliferative diabetic retinopathy than in eyes without proliferative diabetic retinopathy (P = .006; Wilcoxon Rank Sum Test). The median vitreous concentration in the eyes with proliferative diabetic retinopathy was 29.1 pM and exceeded the known concentration required for the maximal proliferation of vascular endothelial cells in vitro. These data are consistent with vascular endothelial growth factor serving as a physiologically relevant angiogenic factor in proliferative diabetic retinopathy.

Diabetic Retinopathy↗
PubMed1994

Immunoreactive changes resulting from dopaminergic denervation of the dentate gyrus of the rat hippocampal formation.

The hypothesis that dopaminergic denervation is a factor in the development of hippocampal neurofibrillary tangles was tested in the rat with bilateral stereotaxic 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental area (VTA). This led to the postsynaptic appearance of cytoplasmic immunoreactivity to ubiquitin in neurons of the dentate gyrus. An additional postsynaptic morphologic abnormality was seen when the animals were pretreated with the D1 dopaminergic antagonist SCH 23390 and the VTA lesions were combined with septal lesions affecting cholinergic and GABAergic neurons projecting to the dentate gyrus. These changes consisted of a loss of dendritic microtubule associated protein (MAP-2) and tau immunoreactivity and a prominence of remaining dendrites in the molecular layer of the dentate gyrus. Additional investigation will be needed to determine if these transynaptic changes in dentate neurons, resulting from denervation, represent a precursor stage to neurofibrillary tangle development.

Animals↗
PubMed1994

Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism.

In a recent hypothesis [Selhub and Miller (1992) Am. J. Clin. Nutr. 55, 131-138], we proposed that homocysteinaemia arises from an interruption in S-adenosylmethionine's (AdoMet) coordinate regulation of homocysteine metabolism. The present study was undertaken to test a prediction of this hypothesis, that homocysteinaemia due to folate deficiency results from impaired homocysteine remethylation due to the deficiency and impaired synthesis of AdoMet, with the consequent inability of this metabolite to function as an activator of homocysteine catabolism through cystathionine synthesis. Rats were made folate-deficient by feeding them with a folate-free amino-acid-defined diet supplemented with succinylsulphathiazole. After 4 weeks, the deficient rats exhibited a 9.8-fold higher mean plasma homocysteine concentration and a 3.2-fold lower mean hepatic AdoMet concentration compared with folate-replete controls. Subsequent supplementation for 3 weeks of the folate-deficient rats with increasing levels of folate in the diet resulted in graded decreases in plasma homocysteine levels, accompanied by graded increases in hepatic AdoMet levels. Thus plasma homocysteine and hepatic AdoMet concentrations were inversely correlated as folate status was modified. In a second experiment, the elevation of plasma homocysteine in the deficient rats was found to be reversible within 3 days by intraperitoneal injections of ethionine. This effect of ethionine is thought to be exerted through S-adenosylethionine, which is formed in the liver of these rats. Like AdoMet, S-adenosylethionine is an activator of cystathionine beta-synthase and will effectively promote the catabolism of homocysteine through cystathionine synthesis. In crude liver homogenates of the rats treated with ethionine, cystathionine beta-synthase activity was 3-fold higher than that measured in homogenates from vehicle-treated controls.

Animals↗
PubMed1994

Modulation of human fibroblast activity by selected angiogenesis inhibitors.

Tenon's fibroblast (TF) bleb encapsulation is a common cause of filtering surgery failure. Various pharmacologic agents have been used in an attempt to inhibit this response. The effects of three angiogenesis inhibitors were studied. AGM-1470, a fumagillin analog and hydrocortisone 21-phosphate (HC21P) complexed with heparin or with the heparin analog beta-cyclodextrin tetradecasulfate (BCD-TDS) in modulating human tenon's fibroblasts in cell culture. It has been clinically demonstrated that well vascularized blebs are associated with a poorer prognosis. In addition to reducing bleb neovascularization, angiogenesis inhibitors may have an additional therapeutic role in decreasing fibroblast activity. Drug effects were assessed by studying cell growth rates by cell Coulter counting and rate of wound closure. TF's were grown in DMEM with 10% FBS and 1% PCN-strep with fungizone. Angiogenesis inhibitors were added to growth medium in varying concentrations: AGM-1470 alone, HC21P complexed with heparin and HC21P complexed with BCD-TDS. Controls were grown in control medium alone, medium with added ethanol, or with added BCD-TDS, heparin or HC21P. We found a dose related inhibition of cell growth with all of the angiogenesis inhibitor combinations, which was not seen in the control groups. Tenon's fibroblast proliferation was significantly inhibited by AGM-1470 as seen in the four higher concentrations (P < 0.05) with insignificant inhibition at the lowest concentration of AGM-1470 (P = 0.38). The heparin:HC21P and heparin:BCD-TDS combinations demonstrated significant inhibition at all concentrations (P < 0.05). Wound closure was significantly inhibited by all the added agents, except AGM-1470 and the controls. The rate of wound closure was significantly reduced by the highest concentrations of the heparin:HC21P and heparin:BCD-TDS combinations (P < 0.05), although it was not significantly affected by lower concentrations (P > 0.05). Rank order of potencies of these agents for inhibition of TF proliferation was AGM-1470, BCD-TDS:HC21P, heparin:HC21P, HC21P, while the rank order of potencies for these agents for inhibition of wound closure was HC21P, heparin:HC21P, BCD-TDS:HC21P, AGM-1470. These selected angiogenesis inhibitors appear to have marked inhibitory effects on TF proliferation and migration, which may have a potential clinical role in modulating wound healing associated with glaucoma filtering surgery.

Cell Division↗