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Biomedical subjects

J W Miller

Publications and source records attributed to J W Miller.

At least 37 records · Page 2Linked to original sources
PubMed2001

High prevalence of low serum vitamin B12 in a multi-ethnic Israeli population.

This study ascertained serum vitamin B12 levels among patients with Gaucher disease and among healthy Israelis. Serum B12 and metabolites' levels were studied in consecutive adult patients with Gaucher disease not treated with enzyme plus Ashkenazi Jewish neighbour-controls, together with healthy blood-donor volunteers of various ethnicities. Each group showed a high incidence of low serum B12 concentrations, with a 22.3% incidence among Ashkenazi Jews and 40% among patients with Gaucher disease. These findings raise questions on the individual and community levels of serum B12. We recommend evaluation of B12 levels among geographically contingent peoples.

Adult↗
PubMed2001

Deafferentation-induced abnormal neurofilament phosphorylation in red nucleus neurones.

Hippocampal deafferentation has been proposed as a pathogenetic mechanism for neurofibrillary tangle (NFT) formation in human mesolimbocortical dementia. We previously developed a rodent model of hippocampal deafferentation involving bilateral destructive lesions of the ventrotegmental area (VTA), septum of the medial forebrain and entorhinal cortex combined with pharmacological inhibition of serotonin 5-HT2 and dopamine D1 receptors. Unexpectedly, we observed an alteration in phosphorylated neurofilament protein immunoreactivity and argyrophilia in magnocellular neurones of the red nucleus. Here, we determined the neuroanatomical, pharmacological and temporal requirements for this effect on red nucleus neurones. We found that abnormal phosphorylation and argyrophilia were critically dependent on bilateral destruction of the VTA and antagonism of 5-HT2 receptors. Although extensive neurofilament hyperphosphorylation and argyrophilia were observed in red nucleus magnocellular neurones within nine days of treatment, no NFTs were formed and these effects were transitory. Resolution of these cytoskeletal abnormalities was accompanied by increased expression of the calcium binding protein, parvalbumin, suggesting that alterations in intraneuronal calcium levels may modify the deafferentation response.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

The absence of interictal spikes with documented seizures suggests extratemporal epilepsy.

PURPOSE: To determine the demographic and clinical characteristics of patients who have documented epileptic seizures on long-term video-EEG monitoring who do not have interictal spikes. METHODS: The records of 1,223 monitoring studies from 919 patients who underwent noninvasive long-term video-EEG monitoring were reviewed. In 28 patients (3.0% of monitored patients, 4.4% of patients with electrographic evidence of epilepsy), no interictal spikes were found despite the occurrence of at least one recorded electrographic seizure. The demographic, medical, neuropsychological, and EEG data of these patients were compared with those of 28 matched control patients with documented interictal spikes. RESULTS: Extratemporal seizures were significantly more frequent in the patients with at least one recorded epileptic seizure but without interictal spikes compared with patients with epileptic seizures and interictal spikes (p = 0.031). The only other significant difference between the groups (p = 0.016) was a later age at seizure onset (18.3 vs. 10.7 years) for the patients without interictal spikes. Age at evaluation, gender, handedness, clinical seizure type, family history of epilepsy, history of febrile seizures, neuropsychological testing, and neurologic and psychiatric history did not differ between the two groups. CONCLUSIONS: In patients with documented epilepsy without interictal spikes on EEG monitoring, the possibility of an extratemporal focus should be considered.

Adolescent↗
PubMed2001

Photodynamic therapy: the nurse's role.

Patients with neovascular (wet) age-related macular degeneration, the leading cause of blindness in persons older than 50 years in developed countries, experience severe visual loss due to choroidal neovascularization, the growth of abnormal vessels under the retina. Photodynamic therapy is a new treatment modality that combines an intravenous injection of a photosensitizing drug, such as verteporfin, and nonthermal laser light application, which destroys choroidal neovascularization without damaging normal surrounding tissue. It has led to new challenges for nurses working in the ambulatory laser setting, including medication preparation, drug administration, and education regarding precautions and potential systemic side effects of photodynamic therapy.

Choroidal Neovascularization↗
PubMed2001

Does lowering plasma homocysteine reduce vascular disease risk?

A recent study indicates that lowering homocysteine with folic acid and vitamin B6 significantly reduces the incidence of abnormal exercise electrocardiography tests and thus decreases the risk of atherosclerotic disease. Questions about study design and sample size, however, suggest that this conclusion may be premature.

Folic Acid↗
PubMed2001

Is the left cerebral hemisphere more prone to epileptogenesis than the right?

PURPOSE: To determine if there is evidence that the left cerebral hemisphere is more prone to epileptogenesis than the right hemisphere. METHODS: We examined 532 patients with localization-related epilepsy, as documented by long-term EEG-video monitor studies. We identified those with interictal epileptiform patterns on EEG confined to one hemisphere, those with clinical seizures that arose only from one side, and individuals with neuropsychological deficits lateralizing more to one cerebral hemisphere than the other. These data were then related to the handedness of the subjects. RESULTS: For left-handed patients, interictal discharges were significantly more likely to be confined to the left side, seizures more frequently arose from only the left hemisphere, and neuropsychological deficits lateralized more often to the left brain. In contrast, for right-handed subjects, there were no significant differences in unilateral localization of either interictal discharges or of seizure onsets, nor did neuropsychological deficits lateralize more often to one side or the other. Although, as a group, left-handers had an earlier age of onset of epilepsy than right-handers, the lateralizing EEG and neuropsychological patterns seen in left-handers were not related to age of onset of epilepsy, febrile seizures, family history of either epilepsy or left-handedness, or other risk factors. CONCLUSION: In localization-related epilepsy, there is a significant association of left-handedness with left hemispheric lateralization of epileptiform EEG patterns and neuropsychological deficits. These findings do not clearly reflect a greater left than right cerebral hemispheric vulnerability to epileptogenesis, except possibly in left-handers.

Adult↗
PubMed2000

Recruitment of human muscleblind proteins to (CUG)(n) expansions associated with myotonic dystrophy.

Myotonic dystrophy (DM1) is an autosomal dominant neuromuscular disorder associated with a (CTG)(n) expansion in the 3'-untranslated region of the DM1 protein kinase (DMPK) gene. To explain disease pathogenesis, the RNA dominance model proposes that the DM1 mutation produces a gain-of-function at the RNA level in which CUG repeats form RNA hairpins that sequester nuclear factors required for proper muscle development and maintenance. Here, we identify the triplet repeat expansion (EXP) RNA-binding proteins as candidate sequestered factors. As predicted by the RNA dominance model, binding of the EXP proteins is specific for dsCUG RNAs and proportional to the size of the triplet repeat expansion. Remarkably, the EXP proteins are homologous to the Drosophila muscleblind proteins required for terminal differentiation of muscle and photoreceptor cells. EXP expression is also activated during mammalian myoblast differentiation, but the EXP proteins accumulate in nuclear foci in DM1 cells. We propose that DM1 disease is caused by aberrant recruitment of the EXP proteins to the DMPK transcript (CUG)(n) expansion.

Amino Acid Sequence↗
PubMed2000

Determination of blood folate using acid extraction and internally standardized gas chromatography-mass spectrometry detection.

Whole blood folate level is a superior indicator of folate nutritional status than serum/plasma level. Problems with and lack of confidence in results of current whole blood folate assays have limited its popularity for assessing folate nutritional status. Here, an acid extraction GCMS detection method that measures total folate whole blood is presented. Folates are released from the matrix of whole blood and cleaved to para-aminobenzoic acid (pABA) by acid hydrolysis in the presence of [(13)C(6)]pABA as internal standard (IS). The hydrolysate is passed over a C18 resin to remove heme. The pABA isotopomers are ethyl esterified, isolated on C18 resin, and trifluoroacetylated. Following normal-phase HPLC separation, the isotopomers are silylated to their tBDMS derivatives. The abundance of these derivatives are measured at m/z 324 for [(13)C(6)]pABA as IS and m/z 318 for pABA from whole blood folate. Our method uses readily available chemicals and our results agree well with those using Lactobacillus casei, the current gold standard reference assay. The presence of folate analogs (methotrexate) or antibacterials (sulfonamines) does not affect our method. This feature makes it useful in monitoring folate status of patients undergoing chemotherapy. Before using our method, pABA supplements must be discontinued for a few days.

Acids↗
PubMed2000

Fos expression and 2-deoxyglucose uptake following seizures in developing genetically epilepsy-prone rats.

Juvenile genetically epilepsy-prone rats (GEPR)-3s display one of three types of seizures in response to sound: a typical class 3 seizure consisting of an explosive running/bouncing episode followed by a clonic seizure (audiogenic response score, ARS-3); an ARS-3 seizure followed by a forebrain seizure that includes facial and forelimb (F&F) clonus with rearing (ARS-3f); or, a running/bouncing episode followed by a severe tonic seizure with complete hindlimb extension (ARS-9) not accompanied with subsequent F&F clonus. The adult seizure phenotype, manifest in all GEPR-3s by age 45 days of age, consists of an ARS-3 not followed by F&F clonus or tonic extension. The present studies sought to determine the neuronal networks activated during these various developmental convulsive patterns by examining anatomical patterns of [(14)C]2-deoxyglucose (2-DG) uptake or immediate-early-gene (Fos) expression subsequent to seizures. Many, but not all, brain areas of control rats showed age-related increases in Fos expression in response to the acoustic stimulation. An age effect was not observed in 2-DG uptake. In GEPRs, the profiles of Fos expression and 2-DG uptake following seizures were often parallel; however, there were notable exceptions. For example, increased 2-DG uptake in the cochlear nuclei, central region of the inferior colliculi, and the substantia nigra were not accompanied by increased Fos expression in these areas regardless of the seizure phenotypes. Reciprocally, other regions, particularly in the amygdala, ventromedial hypothalamus and parabrachial areas, displayed intense seizure related Fos labeling without detectable increases in 2-DG uptake. Fos and 2-DG uptake patterns in response to acoustic stimulation varied according to brain region, seizure phenotype and severity. In general, the degree of 2-DG uptake correlated with seizure severity. For example, the ARS-9 seizures, being the most intense, resulted in significant increases in 2-DG uptake in almost all brain regions examined. 2-DG uptake following the ARS-3f and ARS-3 seizures, although increased, did not reach statistical significance in most brain areas. In contrast to the 2-DG findings, a seizure-severity dependent effect was not seen with Fos. Rather, the induction of Fos associated with acoustic stimulation and seizure was more associated with age and seizure-phenotype. Thus, the developmental profiles of Fos expression and 2-DG uptake in response to seizures are distinctly different and concurrent examination of both markers is useful in the identification of brain circuitry involved in seizure development.

Acoustic Stimulation↗
PubMed2000

Angiography of fluoresceinated anti-vascular endothelial growth factor antibody and dextrans in experimental choroidal neovascularization.

OBJECTIVE: To determine if anti-vascular endothelial growth factor antibody and a range of dextrans with varying diffusion radii and molecular weights are permeable through experimental choroidal neovascularization (CNV). METHODS: Choroidal neovascularization was induced in 10 cynomolgus monkey retinas by means of argon laser injury. Digital fundus fluorescein angiograms were performed with fluorescein sodium, fluoresceinated IgG antibodies (anti-vascular endothelial growth factor and a control antibody), and fluoresceinated dextrans with molecular weights of 4, 20, 40, 70 and 150 kd. The 40- and 70-kd dextrans straddle the effective diffusion radius of IgG. For each reagent, early and late angiograms were performed in a standardized fashion, with follow-up images obtained to monitor residual fluorescence. RESULTS: Perfusion of retinal vessels and choroidal vasculature was seen with all reagents. Fluorescein and 4- and 20-kd dextran leaked rapidly from the CNV within the first minute. Angiography with the use of 40-kd dextran and fluoresceinated antibody, either anti-vascular endothelial growth factor or control IgG, showed fluorescence within the CNV that increased during the first 1 to 5 hours, with mild leakage from the CNV. By 24 hours, fluorescence in the CNV was minimal, although in some cases persistent fluorescence in the surrounding tissue was evident up to 2 weeks. The 70-kd dextran showed fluorescence within the CNV and leakage in 1 of 3 eyes. The 150-kd dextran showed fluorescence within the CNV but did not demonstrate leakage. CONCLUSIONS: Fluoresceinated antibodies and dextran with smaller effective diffusion radii showed CNV perfusion and leakage. Dextrans with larger effective diffusion radii (70 kd and 150 kd) perfused into CNV but did not show leakage consistently. CLINICAL RELEVANCE: Determining the permeablity of antibodies and molecules of similar size through CNV can help ascertain the feasibility of using intravenously administered antibodies against angiogenic growth factors as a future treatment for choroidal neovascularization.

Animals↗
PubMed2000

A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes.

OBJECTIVE: To evaluate short-term safety and the effects on visual acuity and fluorescein angiography of single or multiple sessions of photodynamic therapy with verteporfin for choroidal neovascularization (CNV) not related to age-related macular degeneration (AMD), including pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. DESIGN: A nonrandomized, multicenter, open-label, dose-escalation phase 1 and 2 clinical trial. SETTING: Four ophthalmic centers in Europe and North America providing retinal care. PARTICIPANTS: Thirteen patients with subfoveal CNV due to pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, or idiopathic causes. METHODS: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of photodynamic therapy treatments with verteporfin. Follow-up ranged from 12 weeks for patients who were treated once to 43 weeks for patients who were treated up to 4 times. RESULTS: Verteporfin therapy was well tolerated in patients with CNV not related to AMD. No deterioration in visual acuity was observed; most patients gained at least 1 line of vision. Reduction in the size of leakage area from classic CNV was noted in all patients as early as 1 week after verteporfin therapy, with complete absence of leakage from classic CNV in almost half of the patients. Improvement in visual acuity after verteporfin therapy was greatest (+6, +8, and +9 lines) in 3 patients with relatively poor initial visual acuity (between 20/200 and 20/800). Up to 4 treatments were found to have short-term safety even with retreatment intervals as short as 4 weeks. CONCLUSIONS: Treatment of CNV not related to AMD with verteporfin therapy achieves short-term cessation of fluorescein leakage from CNV in a small number of patients without loss of vision. Further randomized clinical trials including a larger number of patients are under way to confirm whether verteporfin therapy is beneficial for subfoveal CNV not related to AMD.

Adult↗
PubMed2000

Endothelin-1-mediated retinal artery vasospasm and the rabbit electroretinogram.

Electroretinogram (ERG) changes invariably accompany the selective interruption of the retinal circulation that occurs in human central retinal artery occlusion. Since arteriolar ligation or ocular hypertension in the rabbit eye is occasionally used to model human central retinal artery occlusion, we conducted the present study to determine whether selective interruption of the retinal circulation of the rabbit eye alters retinal function as measured by the ERG. The vasoconstrictor, endothelin-1, was injected into the vitreous of rabbits' eyes to induce complete vasospasm and selective interruption of the retinal circulation. This procedure was compared to vascular ligation of the ophthalmic and ciliary arteries in which both the retinal and choroidal circulations were interrupted. A total of 8 rabbits was studied. Circulation was monitored angiographically in half of the eyes, and retinal function was monitored by the ERG in the remaining eyes. Endothelin-1 obliterated retinal arteriolar blood flow without affecting choroidal blood flow for at least 1 hr. Although ERG a-wave amplitude showed a small decline over 2 hr, b-wave and oscillatory potential amplitudes (measures of inner retinal function) showed no loss over this period. In contrast, ligation of the ophthalmic and ciliary arteries produced complete obliteration of both retinal arteriolar and choroidal blood flow and complete loss of the ERG after 2 min. Endothelin-1 induces acute, selective interruption of retinal arteriolar blood flow which has no significant physiologic effect on inner retinal function of the rabbit as monitored by the ERG. The avascular rabbit retina appears to be a poor choice for modeling human retinal artery occlusion.

Animals↗
PubMed2000

Vitamin E and memory: is it vascular protection?

Vitamin E per unit serum cholesterol has been found to correlate with memory performance in a recent analysis of data from the Third National Health and Nutrition Examination Survey. Because vitamin E is thought to be protective against vascular disease, this finding is consistent with the growing body of evidence that implicates vascular disease and vascular disease risk factors in age-related cognitive decline and Alzheimer's disease.

Cholesterol↗
PubMed2000

Diffusion of high molecular weight compounds through sclera.

PURPOSE: To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size. METHODS: Fresh rabbit sclera was mounted in a two-chamber diffusion apparatus, and its permeability to sodium fluorescein, fluorescein isothiocyanate (FITC)-conjugated bovine serum albumin, FITC-IgG, and FITC dextrans ranging in molecular weight from 4 to 150 kDa was determined by fluorescence spectrophotometry. Electron microscopy was used to assess the impact of the experimental design on scleral ultrastructural integrity. The effect of the diffusion apparatus on scleral hydration was examined. Rabbit scleral permeability was compared with previously reported data for human and bovine sclera. RESULTS: Scleral permeability decreased with increasing molecular weight and molecular radius, consistent with previous human and bovine data. Molecular radius was a better predictor of scleral permeability than molecular weight. The sclera was more permeable to globular proteins than to linear dextrans of similar molecular weight. The experimental apparatus did not alter scleral ultrastructure. Permeability of rabbit sclera was similar to human sclera but greater than bovine sclera. CONCLUSIONS: Large molecules, such as IgG, diffuse across sclera in a manner consistent with porous diffusion through a fiber matrix. Transscleral delivery of immunoglobulins and other large compounds to the choroid and retina may be feasible.

Animals↗
PubMed2000

Transscleral delivery of bioactive protein to the choroid and retina.

PURPOSE: To investigate the feasibility of transscleral drug delivery to the choroid and retina. METHODS: An osmotic pump was used to deliver IgG across the sclera of pigmented rabbits, and levels were measured in the choroid, retina, vitreous humor, aqueous humor, orbit, and plasma over 28 days. This method was then used to deliver an anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb), and its effect on inhibiting vascular endothelial growth factor (VEGF)-induced leukostasis in the choroid and retina was determined by measuring tissue myeloperoxidase (MPO) activity. RESULTS: Levels of retinal and choroidal IgG were significantly higher than baseline at all points up to 28 days (P < or = 0.01). IgG levels in the orbit, vitreous humor, aqueous humor, and plasma were negligible (P > 0.05). MPO activity in the choroid of eyes treated with anti-ICAM-1 mAb was 80% less (P = 0.01) than in eyes receiving an equal rate of delivery of an isotype control antibody. Inhibition of MPO activity in the retina was 70% (P = 0.01). The plasma concentration of anti-ICAM-1 mAb was 31,000-fold less than the concentration in the osmotic pump. CONCLUSIONS: Minimally invasive transscleral delivery can be used to deliver therapeutic levels of bioactive drugs to the choroid and retina with negligible systemic absorption. This method of ocular drug delivery may be used in the treatment of a variety of chorioretinal disorders.

Animals↗
PubMed2000

Photodynamic therapy using Lu-Tex induces apoptosis in vitro, and its effect is potentiated by angiostatin in retinal capillary endothelial cells.

PURPOSE: To examine the effect of combining angiostatin with photodynamic therapy (PDT) using Lutetium Texaphyrin (Lu-Tex; Alcon, Fort Worth, TX) as a photosensitizer in bovine retinal capillary endothelial (BRCE) and retinal pigment epithelial (RPE) cells and to determine the mode of PDT-induced cell death in these cell lines. METHODS: Cultured BRCE and RPE cells were incubated with angiostatin (500 ng/ml) for 18 hours and subjected to Lu-Tex/PDT, using treatment parameters previously optimized (3 microgram/ml Lu-Tex for 30 minutes followed by timed irradiation at 732 nm). Cellular survival was assessed after a 1-week cellular proliferation. Data were analyzed using Student's t-test. Caspase 3 activity was monitored in cells after PDT using a fluorogenic substrate, (Asp-Glu-Val-Asp)-AFC (7-amino-4-trifluoromethyl coumarin) [DEVD-AFC], of caspase 3. After PDT, expression of Bcl-2, Bcl-x(L), Bax, and Bak was also examined in cell lysates by Western blot analysis. RESULTS: A synergistic cytotoxic effect of angiostatin and Lu-Tex/PDT was observed in BRCE cells at all fluences used (5, 10, and 20 J/cm(2); P </= 0.05). These findings applied only if angiostatin was delivered before PDT. No such interactive killing effect was observed in RPE cells. Caspase 3 activity was elevated within 10 minutes of PDT in BRCE and RPE cells and was fluence dependent. Differential modulation of Bcl-2 family members was observed after PDT in BRCE and RPE cells. CONCLUSIONS: The combination of angiostatin and Lu-Tex/PDT potentiates the cytotoxic effect of Lu-Tex/PDT on BRCE but not on RPE cells. This may provide a strategy to increase the selectivity of PDT in damaging capillary endothelial cells with less damage to RPE cells. Lu-Tex/PDT induces rapid caspase-dependent apoptosis in BRCE and RPE cells. Furthermore, Lu-Tex/PDT induces apoptosis through selective modulation of members of the Bcl-2 family and differs between BRCE and RPE cells.

Angiostatins↗
PubMed1999

The pathogenesis of choroidal neovascularization in patients with age-related macular degeneration.

Laser photocoagulation and several experimental treatments for choroidal neovascularization (CNV) in patients with age-related macular degeneration attempt to ablate the neovascularization, but do not address underlying angiogenic stimuli. As a result, recurrences are a major problem. Drug treatment to counter the growth of CNV would be a major advance, but its development is impeded by lack of knowledge concerning the stimuli and other molecular signals involved in the pathogenesis of CNV. Herein we explore clues that can be gleaned from clinical, epidemiological, pathological, and experimental data. These suggest that abnormalities of the extracellular matrix of retinal pigmented epithelial (RPE) cells may promote a pro-angiogenic RPE phenotype that contributes to the development of CNV. This provides a general hypothesis that can be tested, but it is also necessary to test hypotheses regarding the specific alterations in gene expression that contribute to CNV. Identification of alterations in gene expression will provide targets for rational design of drug treatment.

Choroid Diseases↗