Search PubMed⌕ Search

Biomedical subjects

M D Brown

Publications and source records attributed to M D Brown.

At least 73 records · Page 4Linked to original sources
PubMed1999

Mitochondrial DNA variation in human evolution and disease.

Analysis of mitochondrial DNA (mtDNA) variation has permitted the reconstruction of the ancient migrations of women. This has provided evidence that our species arose in Africa about 150000 years before present (YBP), migrated out of Africa into Asia about 60000 to 70000 YBP and into Europe about 40000 to 50000 YBP, and migrated from Asia and possibly Europe to the Americas about 20000 to 30000 YBP. Although much of the mtDNA variation that exists in modern populations may be selectively neutral, studies of the mildly deleterious mtDNA mutations causing Leber's hereditary optic neuropathy (LHON) have demonstrated that some continent-specific mtDNA lineages are more prone to manifest the clinical symptoms of LHON than others. Hence, all mtDNA lineages are not equal, which may provide insights into the extreme environments that were encountered by our ancient ancestor, and which may be of great importance in understanding the pathophysiology of mitochondrial disease.

Biological Evolution↗
PubMed1999

Bradycardia-induced coronary angiogenesis is dependent on vascular endothelial growth factor.

A marked coronary angiogenesis is known to occur with chronic bradycardia. We tested the hypothesis that vascular endothelial growth factor (VEGF), an endothelial cell mitogen and a major regulator of angiogenesis, is upregulated in response to low heart rate and consequential increased stroke volume. Bradycardia was induced in rats by administering the bradycardic drug alinidine (3 mg/kg body weight) twice daily. Heart rate decreased by 32% for 20 to 40 minutes after injection and was chronically reduced by 10%, 14%, and 18.5% after 1, 2, and 3 weeks of treatment, respectively. Arterial pressure and cardiac output were unchanged. Left ventricular capillary length density (mm/mm(3)) increased gradually with alinidine administration; a 15% increase after 2 weeks and a 40% increase after 3 weeks of alinidine treatment were documented. Left ventricular weight, body weight, and their ratio were not significantly altered by alinidine treatment. After 1 week of treatment, before an increase in capillary length density, VEGF mRNA increased >2-fold and then declined to control levels after 3 weeks of treatment. VEGF protein was higher in alinidine-treated rats than in controls after 2 weeks and increased further after 3 weeks of treatment. Injection of VEGF-neutralizing antibodies over a 2-week period completely blocked alinidine-stimulated angiogenesis. In contrast, bFGF mRNA was not altered by alinidine treatment. These data suggest that VEGF plays a key role in the angiogenic response that occurs with chronic bradycardia. The mechanism underlying this VEGF-associated angiogenesis may be an increase in stretch due to enhanced diastolic filling.

Acute Disease↗
PubMed1999

Myelin and collapsin-1 induce motor neuron growth cone collapse through different pathways: inhibition of collapse by opposing mutants of rac1.

Precise growth cone guidance is the consequence of a continuous reorganization of actin filament structures within filopodia and lamellipodia in response to inhibitory and promoting cues. The small GTPases rac1, cdc42, and rhoA are critical for regulating distinct actin structures in non-neuronal cells and presumably in growth cones. Collapse, a retraction of filopodia and lamellipodia, is a typical growth cone behavior on contact with inhibitory cues and is associated with depolymerization and redistribution of actin filaments. We examined whether small GTPases mediate the inhibitory properties of CNS myelin or collapsin-1, a soluble semaphorin, in chick embryonic motor neuron cultures. As demonstrated for collapsin-1, CNS myelin-evoked growth cone collapse was accompanied by a reduction of rhodamine-phalloidin staining most prominent in the growth cone periphery, suggesting actin filament disassembly. Specific mutants of small GTPases were capable of desensitizing growth cones to CNS myelin or collapsin-1. Adenoviral-mediated expression of constitutively active rac1 or rhoA abolished CNS myelin-induced collapse and allowed remarkable neurite extension on a CNS myelin substrate. In contrast, expression of dominant negative rac1 or cdc42 negated collapsin-1-induced growth cone collapse and promoted neurite outgrowth on a collapsin-1 substrate. These findings suggest that small GTPases can modulate the signaling pathways of inhibitory stimuli and, consequently, allow the manipulation of growth cone behavior. However, the fact that opposite mutants of rac1 were effective against different inhibitory stimuli speaks against a universal signaling pathway underlying growth cone collapse.

Actins↗
PubMed1999

Pregnancy outcomes in two commercial dairy herds following hormonal scheduling programs.

There are a number of options for hormonal management of post partum dairy cows; however, only a few studies have made direct comparisons of these programs in commercial herd settings. We compared reproductive management programs of 2 commercial dairy herds to evaluate the efficacy of prostaglandin-based treatment regimens on reproductive outcomes. Cows in Herd A were left untreated and served as the negative controls. Cows in Herd B were given PGF2alpha every 14 d until first insemination beginning 45 d post partum and served as the positive controls. Treatment 1 (Ovsynch), initiated randomly during the estrous cycle, consisted of sequential injections of GnRH, PGF2alpha, GnRH again and insemination 16 to 20 h later. Treatment 2 consisted of an Ovsynch protocol, as described above, which was begun 7 d post estrus (Ovsynch + 7). In Herd A, the number of days from parturition to conception (days open) for controls, for Ovsynch and for Ovsynch + 7 were 126, 112 and 102, respectively. In Herd B, respective days open were 102, 100 and 93 for controls, Ovsynch and Ovsynch + 7. Hormonal intervention reduced the number of days open in both herds.

Animals↗
PubMed1999

Emergency medicine in Eritrea: rebuilding after a 30-year war of independence.

Eritrea became a member of the United Nations in 1993, after a devastating 30-year war of independence with Ethiopia. Although Eritrea suffers from many of the problems beset by the developing world, the people are determined to rebuild their country. Emergency medical care and emergency services are in their infancy, yet the signs of progress are already visible in the capital city of Asmara. This report describes the current state of the prehospital system and emergency medical care in Eritrea.

Communicable Disease Control↗
PubMed1999

Stable antisense RNA expression neutralizes the activity of low-density lipoprotein receptor-related protein and promotes urokinase accumulation in the medium of an astrocytic tumor cell line.

Low-density lipoprotein receptor-related protein (LRP) binds and internalizes multiple ligands that are structurally and functionally diverse. However, the effects of LRP on cellular phenotype remain unclear. To study LRP in human astrocytic tumor cells, we designed LRP antisense RNA expression constructs in which the antisense cDNA fragment was expressed under the control of the cytomegalovirus (CMV) promoter. U-1242 MG astrocytic tumor cells were transfected with the antisense constructs and cloned from single cells to yield multiple cell lines with decreased LRP expression. Further studies were performed with two cell lines in which LRP antigen was completely eliminated (L(alpha)42) or substantially decreased (Lalpha47), as determined by Western blot analysis. Untransfected U-1242 MG cells and cells that were stably transfected with empty vector (pBK-CMV) bound activated alpha2-macroglobulin (alpha2M) in a specific and saturable manner. The Bmax was about 5000 receptors/cell. Lalpha42 cells did not bind alpha2M, and binding was decreased by >60% in Lalpha47 cells. Lalpha42 and Lalpha47 cells also demonstrated reduced susceptibility to the cytotoxin, Pseudomonas exotoxin A, and accumulated greatly increased levels of urokinase-type plasminogen activator (uPA) in conditioned medium. The accumulation of uPA demonstrates a major role for LRP in the catabolism of this protein in astrocytic tumor cells. The LRP-deficient cell lines, developed using antisense technology, represent a new model system for studying LRP function in astrocytes.

ADP Ribose Transferases↗
PubMed1999

Paraduodenal hernia presenting as unexplained recurrent abdominal pain.

We present a case of a 29-yr-old female nurse who presented with an 8-h history of abdominal pain. She had had similar episodes (twice/yr) over the last 5 yr, and the pain had usually resolved spontaneously. Prior investigations including laboratory studies, plain films of the abdomen, an abdominal and pelvic ultrasound, and a CT scan yielded no diagnosis. Her pain was previously considered to be either psychosomatic or a variant of irritable bowel syndrome. On this admission, an evaluation and subsequent enteroclysis revealed a left paraduodenal hernia. The importance of considering paraduodenal hernias in the differential diagnosis of unexplained intermittent abdominal pain is discussed here.

Abdominal Pain↗
PubMed1999

Large scale screening of the mitochondrial DNA reveals no pathogenic mutations but a haplotype associated with multiple sclerosis in Caucasians.

We report the first large-scale screening of mitochondrial (mt) DNA in 77 Caucasian patients with relapsing-remitting or secondary progressive form of multiple sclerosis (MS) and in 84 Caucasian controls by using the method of restriction site polymorphism and haplotype analysis. No pathogenic mtDNA mutation was found in association with MS. However, mtDNA haplotypes K* and J* defined by the simultaneous presence of Ddel restriction sites at nucleotides 10,394 and 14,798 of the mtDNA in haplogroups K and J showed association with MS at a P-value of 0.001. A relative increase of MS patients compared to controls either with the J* or with the K* haplotype (+10,394Ddel/+14,798Ddel in haplogroup J or K) also was detected (each with a P<0.05). No distinct phenotypic characteristics of MS were observed when clinical data of patients with haplotypes K* or J* were analyzed. In addition to previous complete sequencing in several MS patients, the population screening of mtDNA presented here suggests that mtDNA point mutations are not likely to be involved in the pathogenesis of typical forms of MS. However, the mitochondrial genetic background (haplotype K* and J*) may moderately contribute to MS susceptibility. The reported association between MS and Leber's hereditary optic nerve atrophy, a disease caused by mtDNA point mutations preferentially occurring in haplogroup J, may be at least in part related to the overlapping mitochondrial genetic background of the two diseases.

Adult↗
PubMed1999

Cardiovascular hemodynamics with increasing exercise intensities in postmenopausal women.

We sought to determine the cardiovascular responses to increasing exercise intensities in postmenopausal women with different physical activity levels and hormone replacement therapy (HRT) status. Forty-four women (11 sedentary, 19 physically active, 14 master athletes; 24 not on HRT, 20 on HRT) completed treadmill exercise at 40, 60, 80, and 100% of maximal oxygen consumption. Oxygen consumption, heart rate, blood pressure, and cardiac output, determined via acetylene rebreathing, were measured at each exercise intensity. HRT did not affect cardiovascular hemodynamics. Stroke volume (SV) decreased significantly between 40 and 100% of maximal oxygen consumption in all groups, and the decrease did not differ among groups. The greater oxygen consumption of the athletes at each intensity was due to their significantly greater cardiac output, which was the result of a significantly greater SV, compared with both of the less active groups. The athletes had significantly lower total peripheral resistance at each exercise intensity than did the two less active groups. There were no consistent significant hemodynamic differences between the physically active and sedentary women. These results indicate that SV decreases in postmenopausal women as exercise intensity increases to maximum, regardless of their habitual physical activity levels or HRT status.

Aged↗
PubMed1999

Eggshell sampling: quantitative or qualitative data?

This research evaluated the use of qualitative presence/absence data compared with quantitative real number counts of Aedes vigilax eggshell data to obtain information on the spatial distribution of eggshells in several salt marsh vegetation types. Eggshells were extracted by subsampling and flotation, a method that does not recover all eggshells. The results of the analysis of presence/absence data were compared with those of real numbers. The general conclusions were similar by either method, suggesting that presence/absence data may be sufficient to rapidly determine eggshell distribution patterns.

Aedes↗
PubMed1999

Green tea (Camellia sinensis) extract and its possible role in the prevention of cancer.

The American Cancer Society estimates that in the 1980s more than 4. 5 million Americans died of cancer. In addition, there were nearly nine million new cases and about 12 million people were under medical care for cancer. With cancer being the second most common cause of death in the United States population, the possibility that readily-available natural substances may be beneficial in the prevention of cancer warrants closer examination. A growing body of research has demonstrated green tea polyphenols to be powerful antioxidants with anticarcinogenic properties. These polyphenolic compounds, specifically the catechins epigallocatechin-3-gallate (EGCG), epigallocatechin (EGC), and epicatechin-3-gallate (ECG), which account for 30-40 percent of the extractable solids of green tea leaves, are believed to mediate many of the cancer chemopreventive effects. Mechanisms of action may include antioxidant and free-radical scavenging activity, and stimulation of detoxification systems through selective induction or modification of phase I and phase II metabolic enzymes. In addition, green tea may inhibit biochemical markers of tumor initiation and promotion, including the rate of cell replication and thus inhibition of the growth and development of neoplasms. Current studies are hopeful, as they show an inverse association between green tea consumption and cancer risk, supporting a possible chemopreventive effect of green tea. Based on the knowledge that green tea is inexpensive, non-toxic, and is a popular beverage consumed worldwide, clinical trials should be conducted to evaluate the in-vivo effectiveness of green tea polyphenols on the inhibition and chemopreventive treatment of cancer.

Catechin↗
PubMed1999

Epidermal growth factor differentially regulates low density lipoprotein receptor-related protein gene expression in neoplastic and fetal human astrocytes.

Low density lipoprotein receptor-related protein (LRP) is a multifunctional endocytotic receptor that may modify the biological activity of reactive astrocytes in neuroplasticity and neurodegeneration and of malignant astrocytes in brain invasion. In this study, the regulation of LRP by epidermal growth factor receptor (EGFR) ligands in both cultured human fetal astrocytes and astrocytic tumor cell lines (U-251 MG and U-1242 MG) was investigated. All astrocytic cell types expressed LRP, as determined by the binding of activated alpha2-macroglobulin (alpha2M*) on intact cells and by Western and Northern blot analyses of cell extracts. Primary cultured astrocytes expressed the highest levels of alpha2M*-binding capacity (Bmax = 30 fmol/mg protein). This was twofold higher than for the U-1242 MG astrocytoma cells (Bmax = 15 fmol/mg protein) and fourfold greater than for the glioblastoma U-251 MG cells (7.0 fmol/mg protein). Receptor affinity (K(D)) ranged from 0.25 to 0.6 nM in all the astroglial cell types. Functional LRP at the surface was down-regulated by EGF, compared with controls, as indicated by a reduction of both Bmax and LRP-mediated endocytosis by approximately 50% and 60%, respectively. In comparison, EGF treatment of primary astrocytes did not down-regulate LRP expression or LRP-mediated endocytosis. Treatment of the tumor cells with EGF or TGFalpha (25 ng/ml) significantly down-regulated total cellular LRP. Receptor-associated protein (RAP) mRNA expression was not affected by EGF in either tumor cells or primary astrocytes. The reduction of LRP in the tumor cells resulted from a specific decrease in LRP mRNA transcription, as determined by Northern blot and nuclear run-on experiments. These data suggest that EGF mediates a functional down-regulation of LRP endocytotic activity in astrocytic tumor cells and that LRP expression is differentially regulated in neoplastic and non-neoplastic astrocytes.

Astrocytes↗
PubMed1998

Papillomavirus vaccines.

The considerable morbidity and mortality associated with certain human papillomaviruses (HPV) has provided the impetus for HPV vaccine development. The design of such vaccines has evolved from an understanding of the nature of HPV infections and their consequences, together with evaluation of the efficacy of different approaches to vaccination in animal models. These studies have culminated in the production of several different vaccine preparations which are currently undergoing Phase I and II clinical trials. The justification for the widespread implementation of prophylactic HPV vaccines will depend on the outcome of larger scale studies of vaccine efficacy that take into account the epidemiology of HPV infections and associated disease. The usefulness of therapeutic HPV vaccines will require evidence that they can substantially augment or substitute for the effectiveness of currently available treatments.

Antigens, Viral↗