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M D Brown

Publications and source records attributed to M D Brown.

At least 91 records · Page 5Linked to original sources
PubMed1998

MITOMAP: a human mitochondrial genome database--1998 update.

We have continued to develop MITOMAP (http://www.gen.emory. edu/MITOMAP ), a comprehensive database for the human mitochondrial DNA (mtDNA). MITOMAP uses the mtDNA sequence as the unifying element for bringing together information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population associated variation, and gene-gene interactions. Over the past year we have increased the degree of interlinking of MITOMAP information available on the web page, by using our generalized information management system, GENOME. As increasingly larger regions of the human genome are sequenced and characterized, the need for integrating such information is growing. Consequently, MITOMAP and GENOME provide a valuable reference for the mitochondrial biologist, in addition to being a model for the development of comprehensive, information storage and retrieval systems for other components of the human genome. This paper documents the changes to MITOMAP which have been implemented over the past year.

Computer Communication Networks↗
PubMed1998

Capillary growth in overloaded, hypertrophic adult rat skeletal muscle: an ultrastructural study.

We examined the early stages of angiogenesis in overloaded m. extensor digitorum longus following extirpation of the agonist m. tibialis anterior. Capillary-to-fibre ratio increased after 1 week (1.54+/-0.02) vs. control (1.38+/0.06; P < 0.01) and resulted in a greater tortuosity of the capillary bed at 2 weeks, indicating the presence of lateral sprouts or anastomoses. Capillary endothelial cells (ECs) showed ultrastructural signs of activation, were thickened, and had irregular luminal and abluminal surfaces. The proportion of ECs with abluminal processes increased after overload (13.5+/-0.6% vs. 2.0+/-1.5%, 1 week vs. contralateral, P < 0.01; 12.5+/-2.6% vs. 3.5+/-0.6%, 2 weeks vs. contralateral, P < 0.01), whereas there was no significant change in proportion of luminal processes. Abluminal processes occurred in approximately 13% of capillaries in overloaded muscles (P < 0.01 v. control and contralateral), and most were associated with focal breakage of the basement membrane (BM). Small sprouts (<3 microm in diameter) comprised of one or two ECs sometimes lacked a lumen, and others had a slitlike or vacuolelike lumen between adjacent ECs or vacuolelike lumen formed by fusion of vesicles within a single EC. Endothelial mitosis was occasionally seen in nonsprouting capillaries with intact BM, increasing the average number of ECs per capillary from approximately 1.7 in control muscles to 2.1 after 1 week of overload (P < 0.05) when bromodeoxyuridine incorporation was also higher (P < 0.001). We conclude that muscle overload induces capillary growth by sprouting of existing capillaries, probably due to mechanical stretch acting from the abluminal side of the vessels.

Animals↗
PubMed1998

Rac1-dependent actin filament organization in growth cones is necessary for beta1-integrin-mediated advance but not for growth on poly-D-lysine.

The activity of filopodia and lamellipodia determines the advance, motility, adhesion, and sensory capacity of neuronal growth cones. The shape and dynamics of these highly motile structures originate from the continuous reorganization of the actin cytoskeleton in response to extracellular signals. The small GTPases, Rac1, Rho, and CDC42, regulate the organization of actin filament structures in nonneuronal cells; yet, their role in growth cone motility and neurite outgrowth is poorly understood. We investigated in vitro the function of Rac1 in neurite outgrowth and differentiation by introducing purified recombinant mutants of Rac1 into primary chick embryo motor neurons via trituration. Endogenous Rac1 was expressed in growth cone bodies as well as in the tips and shafts of filopodia, where it often colocalized with actin filament structures. The introduction of constitutively active Rac1 resulted in an increase in rhodamine-phalloidin staining, presumably from an accumulation of actin filaments in growth cones, while dominant negative Rac1 caused a decrease in rhodamine-phalloidin staining. Nevertheless, both Rac1 mutants retarded growth cone advance, and hence attenuated neurite outgrowth and inhibited differentiation of neurites into axons and dendrites on laminin and fibronectin. In contrast, on poly-D-lysine, neither Rac1 mutant affected growth cone advance, neurite outgrowth, or neurite differentiation despite inducing similar changes in the amount of rhodamine-phalloidin staining in growth cones. Our data demonstrate that Rac1 regulates actin filament organization in neuronal growth cones and is pivotal for beta1 integrin-mediated growth cone advance, but not for growth on poly-D-lysine.

Actins↗
PubMed1998

Internal division of capillaries in rat skeletal muscle in response to chronic vasodilator treatment with alpha1-antagonist prazosin.

Chronic vasodilatation represents a stimulus for capillary growth associated with increased luminal shear stress. We have examined the ultrastructure of more than 2000 capillaries to establish whether the sequence of angiogenesis in response to this stimulus is similar to that described during development and under pathological circumstances. Administration of the alpha1-blocker prazosin to rats for 2 weeks led to a greater capillary length density in extensor hallucis proprius muscles without any change in capillary tortuosity: Jv(c,f)=262+/-54 compared with 350+/-17 mm-2, control compared with prazosin (P<0.002). There were obvious signs of endothelial cell (EC) activation after prazosin treatment, including an increased proportion of capillaries with rough endoplasmic reticulum, large cytoplasmic vacuoles, thickened endothelium and an irregular luminal surface. Capillaries from control muscles had a maximum of three ECs in cross section, whereas four ECs were noted in 0.8+0.5% of capillaries after 1 week (n.s.) and 2.5+/-0.9% after 2 weeks (P<0.01) of treatment. This could be due to elongation and/or migration of ECs, as cell proliferation has not been described at these time points. There was also an increase in the proportion of capillaries having a narrow, slit-like lumen (1.7+/-0. 8% of controls; 7.1+/-1.9% at 1 week; 8.8+/-2.5% at 2 weeks; P<0.02), some of which were smaller in size (less than 2 microm diameter) than in controls (3-5 microm) and/or "seamless", i.e. lacking EC junctions. These may represent newly formed vessels. Focal discontinuity of the basement membrane and abluminal EC processes were rarely seen, and capillary growth by abluminal sprouting appeared to be very infrequent (less than 0.001% of profiles). Of more importance was growth starting from the luminal side. Significantly more thin cytoplasmic processes were observed protruding into the lumen of capillaries after 1 week (47.5+/-6.2%, P<0.001) and 2 weeks of prazosin (34.2+/-5.5%, P<0.05) than in control vessels (16.7+/-3.9%). Some of these traversed the entire lumen and connected with endothelium of the opposite side, probably involving membrane fusion, resulting in the appearance of a double lumen. Individual capillaries with a complete double lumen were observed after 2 weeks' prazosin but comparatively rarely, in only four out of six muscles. These findings indicate a pattern of luminal growth which is completely different from intussusceptive growth previously described during development, and from the abluminal capillary sprouting seen under pathological circumstances.

Adrenergic alpha-Antagonists↗
PubMed1998

Malignant fibrous tumors.

Dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), and malignant fibrous histiocytoma (MFH) are rare soft tissue sarcomas of intermediate to high-grade malignancy that the dermatologist must evaluate and treat. DFSP is a fibrohistiocytic tumor of intermediate malignancy characterized by aggressive local growth and propensity to recur after surgical excision. AFX is a superficial malignant tumor that arises on sun-exposed surfaces and is characterized by local aggressive behavior. MFH is the most aggressive of the fibrohistiocytic tumors with a high local recurrence rate and significant metastatic rate usually associated with a poor prognosis. This article reviews the epidemiology, pathogenesis, clinical presentation, histology, management, prognosis, and follow-up of these malignant tumors.

Chemotherapy, Adjuvant↗
PubMed1998

Lack of involvement of basic fibroblast growth factor (FGF-2) in capillary growth in skeletal muscles exposed to long-term contractile activity.

Fibroblast growth factors (FGFs) are involved in stimulation of angiogenesis in tumors and other pathological circumstances. Increased activity of normal skeletal muscles resulting from chronic electrical stimulation is a very potent stimulus for capillary growth but a relationship between the initiation of this angiogenesis and the involvement of autocrine growth factors has yet to be established. Although FGF expression has been reported in muscles stimulated for 3 weeks, capillary growth is underway significantly earlier, beginning around 3 days. The present experiments have therefore studied the possible involvement of basic fibroblast growth factor (FGF-2) in stimulated rat fast skeletal muscles prior to, and coincident with, capillary growth. Muscle contractions were induced via electrodes implanted in the vicinity of the peroneal nerve and maintained for 8h/day for 2, 4 or 7 days. Capillary/fiber ratio (C/F), based on staining of capillary endothelium for alkaline phosphatase, was not changed in either extensor digitorum longus (EDL) or tibialis anterior (TA) after 2 days stimulation, but increased in TA stimulated for 4 days and in both muscles after 7 days. The expression of mRNA for FGF-2, detected by ribonuclease protection assay, was decreased in all stimulated muscles compared with control or contralateral muscles; immunohistochemistry showed FGF-2 gene product in nerves and larger blood vessels but not in capillaries. There was no evidence from immunohistochemistry for up-regulation of receptors flg and bek for FGF-2. The presence of FGF-2, flg and bek in arterioles may indicate a possible role for FGF-2 in the regulation of blood flow since we have previously shown it to be a dilator of small arterioles. However, based on the lack of correlation between changes in capillary density and the expression of mRNA and protein for FGF-2 and its receptors, it is unlikely that it is directly linked with the initiation of angiogenesis resulting from chronic activity in skeletal muscles.

Journal Article↗
PubMed1998

mtDNA haplogroup X: An ancient link between Europe/Western Asia and North America?

On the basis of comprehensive RFLP analysis, it has been inferred that approximately 97% of Native American mtDNAs belong to one of four major founding mtDNA lineages, designated haplogroups "A"-"D." It has been proposed that a fifth mtDNA haplogroup (haplogroup X) represents a minor founding lineage in Native Americans. Unlike haplogroups A-D, haplogroup X is also found at low frequencies in modern European populations. To investigate the origins, diversity, and continental relationships of this haplogroup, we performed mtDNA high-resolution RFLP and complete control region (CR) sequence analysis on 22 putative Native American haplogroup X and 14 putative European haplogroup X mtDNAs. The results identified a consensus haplogroup X motif that characterizes our European and Native American samples. Among Native Americans, haplogroup X appears to be essentially restricted to northern Amerindian groups, including the Ojibwa, the Nuu-Chah-Nulth, the Sioux, and the Yakima, although we also observed this haplogroup in the Na-Dene-speaking Navajo. Median network analysis indicated that European and Native American haplogroup X mtDNAs, although distinct, nevertheless are distantly related to each other. Time estimates for the arrival of X in North America are 12,000-36,000 years ago, depending on the number of assumed founders, thus supporting the conclusion that the peoples harboring haplogroup X were among the original founders of Native American populations. To date, haplogroup X has not been unambiguously identified in Asia, raising the possibility that some Native American founders were of Caucasian ancestry.

Asia, Western↗
PubMed1998

Nonsteroidal anti-inflammatory drugs and gastroduodenal injury.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a commonly prescribed and over-the-counter class of drugs in the United States, with widespread use for various indications. The increased risk of gastrointestinal toxicity with the use of nonsteroidal medications has been well recognized. Pathogenesis of nonsteroidal toxicity is direct as well as systemic, secondary to prostaglandin inhibition. There are several risk factors to identify patients at a high risk for nonsteroidal toxicity. NSAID-related ulcer complications can be reduced by prophylaxis with prostaglandin analog drugs such as misoprostol or high-dosage proton-pump inhibition.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1998

Insulin sensitivity is associated with blood pressure response to sodium in older hypertensives.

The purpose of this study was to determine whether sodium-resistant hypertensives are more insulin resistant and whether dietary sodium restriction improves insulin sensitivity in older hypertensives. Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test to determine the insulin sensitivity index (SI) after 1 wk each of low- (20 mmol.l-1.day-1) and high- (200 mmol.l-1.day-1) sodium diets in 21 older (63 +/- 2 yr) hypertensives. Subjects were grouped on the difference in mean arterial blood pressure (MABP) between diets [sodium sensitive (SS): > or = 5-mmHg increase in MABP on the high-sodium diet (n = 14); sodium resistant (SR): < 5-mmHg increase in MABP on the high-sodium diet (n = 7)]. There was no dietary sodium effect on fasting plasma insulin or SI. An analysis of variance indicated a significant (P = 0.0002) group effect, with SS individuals having lower fasting plasma insulins on the low- (13 +/- 2 vs. 27 +/- 3 microU/ml) and high- (12 +/- 2 vs. 22 +/- 3 microU/ml) sodium diets compared with SR individuals. Similarly, there was a significant (P = 0.0002) group effect in regard to SI, with SS individuals having significantly higher SI on the low- (3.26 +/- 0.60 vs. 0.91 +/- 0.31 microU x 10(-4).min-1.ml-1) and high- (3.45 +/- 0.51 vs. 1.01 +/- 0.30 microU x 10(-4).min-1.ml-1) sodium diets compared with SR individuals. We conclude that SR individuals exhibit a greater degree of insulin resistance than SS individuals and that dietary sodium restriction fails to improve insulin sensitivity regardless of sodium sensitivity status.

Aged↗
PubMed1998

Alterations in small arterioles precede changes in limb skeletal muscle after myocardial infarction.

We tested the hypothesis that alterations in arterioles in locomotor skeletal muscles in rats with myocardial infarction (MI), but before development of congestive heart failure (CHF), precede structural and functional changes commonly observed in limb muscle in association with CHF. Resting diameters of third- (A3) and fourth-order arterioles (A4) in extensor digitorum longus (EDL) muscle were significantly smaller in rats with nonfailing small and medium-sized MI compared with control animals. Dilation of A4 in response to 10(-4) M adenosine was significantly attenuated in both groups (P < 0.05), whereas dilation of A3 was unaltered. Microvessels from both groups of infarcted rats constricted to all doses of acetylcholine (10(-9), 10(-8), and 10(-7) M) and showed a significantly exaggerated vasoconstrictor response to norepinephrine (10(-9), 10(-8), and 10(-7) M) compared with microvessels in control rats (P < 0.05). Peak isometric tension of combined tibialis anterior and EDL muscles and muscle fatigue (final/peak tension x 100), measured during 5-min isometric supramaximal twitch contractions at 4 Hz, were similar in control and MI rats (218 +/- 7 vs. 213 +/- 15 g/g muscle and 52 +/- 1 vs. 51 +/- 9%, respectively; n = 5 for both). There was also no difference with respect to the proportion of oxidative fibers or capillary-to-fiber ratios. Our results indicate that, in rats with left ventricular dysfunction but without failure, decreased diameter and perturbations in reactivity of small arterioles precede alterations in skeletal muscle performance often seen at a later date in association with CHF. These findings are consistent with the notion of aberrant endothelial and smooth muscle function and may contribute to the maintenance of blood pressure after MI but before CHF.

Acetylcholine↗
PubMed1998

Capillary growth in relation to blood flow and performance in overloaded rat skeletal muscle.

Rat extensor digitorum longus muscles were overloaded by stretch after removal of the synergist tibialis anterior muscle to determine the relationship between capillary growth, muscle blood flow, and presence of growth factors. After 2 wk, sarcomere length increased from 2.4 to 2.9 micrometers. Capillary-to-fiber ratio, estimated from alkaline phosphatase-stained frozen sections, was increased by 33% (P < 0.0001) and 60% (P < 0.01), compared with control muscles (1.44 +/- 0.06) after 2 and 8 wk, respectively. At 2 wk, the increased capillary-to-fiber ratio was not associated with any changes in mRNA for basic fibroblast growth factor (FGF-2) or its protein distribution. FGF-2 immunoreactivity was present in nerves and large blood vessels but was negative in capillaries, whereas the activity of low-molecular endothelial-cell-stimulating angiogenic factor (ESAF) was 50% higher in stretched muscles. Muscle blood flows measured by radiolabeled microspheres during contractions were not significantly different after 2 or 8 wk (132 +/- 37 and 177 +/- 22 ml. min-1. 100 g-1, respectively) from weight-matched controls (156 +/- 12 and 150 +/- 10 ml. min-1. 100 g-1, respectively). Resistance to fatigue during 5-min isometric contractions (final/peak tension x 100) was similar in 2-wk overloaded and contralateral muscles (85 vs. 80%) and enhanced after 8 wk to 92%, compared with 77% in contralateral muscles and 67% in controls. We conclude that increased blood flow cannot be responsible for initiating expansion of the capillary bed, nor does it explain the reduced fatigue within overloaded muscles. However, stretch can present a mechanical stimulus to capillary growth, acting either directly on the capillary abluminal surface or by upregulating ESAF, but not FGF-2, in the extracellular matrix.

Animals↗
PubMed1998

Acute toxicity of selected pesticides to the Pacific blue-eye, Pseudomugil signifer (Pisces).

Because the larvivorous fish Pseudomugil signifer is native to southeastern Queensland and is abundant in shallow estuarine habitats, intertidal marshes, wetland habitats, and freshwater streams, it was chosen as an indicator species for toxicologic studies with pesticides. Acute toxicity studies with 2 organophosphorus pesticides (pirimiphos-methyl and temephos) and 3 alternate compounds under evaluation for registration in Australia (Bacillus thuringiensis var. israelensis, s-methoprene, and pyriproxyfen), were tested in 96-h laboratory trials. Pirimiphos-methyl was the most toxic compound, with a median lethal concentration (LC50) of 0.091 ppm (0.3 times the estimated field concentration [EFC] for a 15-cm-deep pool). Temephos had an LC50 value of 0.594 ppm (9.9 times the EFC). Bacillus thuringiensis var. israelensis and pyriproxyfen produced LC50 values of 6.1 x 10(11) International Toxic Units (477 times the EFC) and 0.854 ppm (106 times the EFC), respectively. s-Methoprene was the least toxic compound, with no mortality recorded at 500 times the EFC.

Animals↗
PubMed1998

Laboratory and field evaluation of efficacy of VectoBac 12AS against Culex sitiens (Diptera: Culicidae) larvae.

Laboratory bioassay studies of the efficacy of VectoBac 12AS (active ingredient: 1,200 International Toxic Units [ITU]/mg Bacillus thuringiensis var. israelensis) against field-collected late 3rd/early 4th-instar larvae of Culex sitiens indicated excellent control potential. A 95% lethal concentration (LC95) value of 1.381 x 10(7) ITU was calculated, which equated to a dosage of 0.011 liters/ha. This dosage represented 1.8% of the recommended lowest dosage rate for the product. A field trial of VectoBac 12AS against late 3rd/early 4th-instar field specimens of Cx. sitiens in floating mesh cylinders was then conducted in salt-marsh pools near Coomera Marina, southeast Queensland, Australia. At a rate of 0.5 liters/ha, 100% mortality of Cx. sitiens larvae was recorded at 24 h posttreatment.

Animals↗
PubMed1997

Ancient mtDNA sequences in the human nuclear genome: a potential source of errors in identifying pathogenic mutations.

Nuclear-localized mtDNA pseudogenes might explain a recent report describing a heteroplasmic mtDNA molecule containing five linked missense mutations dispersed over the contiguous mtDNA CO1 and CO2 genes in Alzheimer's disease (AD) patients. To test this hypothesis, we have used the PCR primers utilized in the original report to amplify CO1 and CO2 sequences from two independent rho degrees (mtDNA-less) cell lines. CO1 and CO2 sequences amplified from both of the rho degrees cells, demonstrating that these sequences are also present in the human nuclear DNA. The nuclear pseudogene CO1 and CO2 sequences were then tested for each of the five "AD" missense mutations by restriction endonuclease site variant assays. All five mutations were found in the nuclear CO1 and CO2 PCR products from rho degrees cells, but none were found in the PCR products obtained from cells with normal mtDNA. Moreover, when the overlapping nuclear CO1 and CO2 PCR products were cloned and sequenced, all five missense mutations were found, as well as a linked synonymous mutation. Unlike the findings in the original report, an additional 32 base substitutions were found, including two in adjacent tRNAs and a two base pair deletion in the CO2 gene. Phylogenetic analysis of the nuclear CO1 and CO2 sequences revealed that they diverged from modern human mtDNAs early in hominid evolution about 770,000 years before present. These data would be consistent with the interpretation that the missense mutations proposed to cause AD may be the product of ancient mtDNA variants preserved as nuclear pseudogenes.

Alzheimer Disease↗
PubMed1997

Low density lipoprotein receptor-related protein is expressed early and becomes restricted to a somatodendritic domain during neuronal differentiation in culture.

Low density lipoprotein receptor-related protein (LRP) is a multi-functional receptor which mediates the endocytotic uptake of several ligands implicated in neuronal pathophysiology. In this study, LRP expression and localization, in cultured hippocampal neurons from 18-day-old rats, were examined by immunofluorescence microscopy. LRP was restricted to the cell bodies and dendrites of mature neurons, where it was uniformly distributed on both dendritic shafts and spines. Immunoreactive protein was detected within the first 24 h of culture and acquired a polarized distribution by the end of the first week. Expression of LRP mRNA by the cultured neurons was demonstrated by Northern blot analysis. Binding studies with the LRP ligand, activated alpha2-macroglobulin, confirmed that LRP was present and functional on the hippocampal neuron cell surface. These studies demonstrate that neuronal LRP undergoes selective compartmentation during neuronal maturation and suggest that LRP-mediated endocytosis is largely restricted to the somatodendritic compartment.

Animals↗
PubMed1997

MITOMAP: an update on the status of the human mitochondrial genome database.

We have continued to develop MITOMAP, a comprehensive database for the human mitochondrial DNA (mtDNA). MITOMAP uses the mtDNA sequence as the unifying element for bringing together information on mitochondrial genome structure and function, pathogenic mutations and their clinical characteristics, population associated variation and gene-gene interactions. As increasingly larger regions of the human genome are sequenced and characterized, the need for integrating such information will grow. Consequently, MITOMAP not only provides a valuable reference for the mitochondrial biologist, it will also provide a model for the development of comprehensive, multi-media information storage and retrieval systems for other components of the human genome. This paper is an update of the changes which have occurred to MITOMAP over the past year.

Base Sequence↗