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Biomedical subjects

D Brown

Publications and source records attributed to D Brown.

At least 91 records · Page 5Linked to original sources
PubMed2001

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Acetamides↗
PubMed2001

Massive gene decay in the leprosy bacillus.

Leprosy, a chronic human neurological disease, results from infection with the obligate intracellular pathogen Mycobacterium leprae, a close relative of the tubercle bacillus. Mycobacterium leprae has the longest doubling time of all known bacteria and has thwarted every effort at culture in the laboratory. Comparing the 3.27-megabase (Mb) genome sequence of an armadillo-derived Indian isolate of the leprosy bacillus with that of Mycobacterium tuberculosis (4.41 Mb) provides clear explanations for these properties and reveals an extreme case of reductive evolution. Less than half of the genome contains functional genes but pseudogenes, with intact counterparts in M. tuberculosis, abound. Genome downsizing and the current mosaic arrangement appear to have resulted from extensive recombination events between dispersed repetitive sequences. Gene deletion and decay have eliminated many important metabolic activities including siderophore production, part of the oxidative and most of the microaerophilic and anaerobic respiratory chains, and numerous catabolic systems and their regulatory circuits.

Animals↗
PubMed2001

Intra-endosomal pH-sensitive recruitment of the Arf-nucleotide exchange factor ARNO and Arf6 from cytoplasm to proximal tubule endosomes.

Kidney proximal tubule epithelial cells have an extensive apical endocytotic apparatus that is critical for the reabsorption and degradation of proteins that traverse the glomerular filtration barrier and that is also involved in the extensive recycling of functionally important apical plasma membrane transporters. We show here that an Arf-nucleotide exchange factor, ARNO (ADP-ribosylation factor nucleotide site opener) as well as Arf6 and Arf1 small GTPases are located in the kidney proximal tubule receptor-mediated endocytosis pathway, and that ARNO and Arf6 recruitment from cytosol to endosomes is pH-dependent. In proximal tubules in situ, ARNO and Arf6 partially co-localized with the V-ATPase in apical endosomes in proximal tubules. Arf1 was localized both at the apical pole of proximal tubule epithelial cells, but also in the Golgi. By Western blot analysis ARNO, Arf6, and Arf1 were detected both in purified endosomes and in proximal tubule cytosol. A translocation assay showed that ATP-driven endosomal acidification triggered the recruitment of ARNO and Arf6 from proximal tubule cytosol to endosomal membranes. The translocation of both ARNO and Arf6 was reversed by V-type ATPase inhibitors and by uncouplers of endosomal intralumenal pH, and was correlated with the magnitude of intra-endosomal acidification. Our data suggest that V-type ATPase-dependent acidification stimulates the selective recruitment of ARNO and Arf6 to proximal tubule early endosomes. This mechanism may play an important role in the pH-dependent regulation of receptor-mediated endocytosis in proximal tubules in situ.

ADP-Ribosylation Factor 6↗
PubMed2001

Early loss of dendritic spines in murine scrapie revealed by confocal analysis.

Confocal analysis of dye-filled neurons has revealed a significant early loss of dendritic spines in a murine scrapie model in which neuron loss occurs in the hippocampus. An 18% loss of spines was found at 109 days, > 50 days before neuron loss occurs, and by 126 days a 51% spine loss was found. Spine loss is concurrent with synapse loss, axon terminal degeneration and a decrease in long term potentiation in this model. Preceding these changes is the deposition of disease specific PrP at 70 days, which may initiate the damage to dendritic spines and the subsequent degeneration of synapses. We suggest that these changes underlie the development of clinical disease in the transmissible spongiform encephalopathies.

Animals↗
PubMed2001

The anterior/posterior polarity of somites is disrupted in paraxis-deficient mice.

Establishing the anterior/posterior (A/P) boundary of individual somites is important for setting up the segmental body plan of all vertebrates. Resegmentation of adjacent sclerotomes to form the vertebrae and selective migration of neural crest cells during the formation of the dorsal root ganglia and peripheral nerves occur in response to differential expression of genes in the anterior and posterior halves of the somite. Recent evidence indicates that the A/P axis is established at the anterior end of the presomitic mesoderm prior to overt somitogenesis in response to both Mesp2 and Notch signaling. Here, we report that mice deficient for paraxis, a gene required for somite epithelialization, also display defects in the axial skeleton and peripheral nerves that are consistent with a failure in A/P patterning. Expression of Mesp2 and genes in the Notch pathway were not altered in the presomitic mesoderm of paraxis(-/-) embryos. Furthermore, downstream targets of Notch activation in the presomitic mesoderm, including EphA4, were transcribed normally, indicating that paraxis was not required for Notch signaling. However, genes that were normally restricted to the posterior half of somites were present in a diffuse pattern in the paraxis(-/-) embryos, suggesting a loss of A/P polarity. Collectively, these data indicate a role for paraxis in maintaining somite polarity that is independent of Notch signaling.

Animals↗
PubMed2001

Therapeutic choices for patients with hemophilia and high-titer inhibitors.

Effective treatment of bleeding episodes in hemophilia with high titer inhibitors (HTI) remains a challenge, despite the fact that the therapeutic armamentarium has expanded considerably over the past few years. Treatment safety has improved with the availability of porcine factor VIII (FVIII) and bypassing products such as recombinant factor VIIa (rFVIIa), and plasma-derived activated Prothrombin Complex Concentrates (aPCCs) that are virally inactivated. The major drawbacks of rFVIIa and aPCCs are their unpredictable hemostatic effect, lack of laboratory assays to monitor efficacy and dosing frequency, and the risk of thrombosis. The proceedings of a one-day workshop of physicians who specialized in treating patients with hemophilia held in Vienna on May 13, 2000 have been summarized. In making a decision regarding the choice of product, physicians often consider the type of bleeding episode (life or limb threatening), age of the patient, volume of the reconstituted product, previous exposure to plasma derived products, cost, efficacy, and safety. For plasma naïve patients, to achieve rapid hemostasis a majority of the panelists used porcine FVIII (for patients who lack porcine inhibitory antibodies) or rFVIIa. For patients previously treated with plasma derived factors, in addition to the above concentrates, aPCCs were recommended. Although no data exists regarding safety and efficacy, switching products was routinely practiced either because of availability or cost. Furthermore, the panelists were uncertain about the efficacy of bypassing agents in the prevention of joint disease in inhibitor patients. The workshop participants felt that future research offers the best solution to resolve some of the dilemmas faced by clinicians and may help individualise treatment in a hemophilia patient with a high titer inhibitor.

Animals↗
PubMed2001

Assessing portal design skills in the radiation oncology interactive case management examination.

The American Board of Radiology is developing a computerized interactive case management examination to be used to evaluate the clinical skills of radiation oncologists. In the past, these skills have been evaluated by a pencil and paper written examination and an oral examination. With the increasing capabilities of computers, these skills can be easily, and perhaps even better, evaluated digitally. The aim is to develop an examination, which will be based on actual clinical cases, and be interactive so that it better mimics the clinical practice of a radiation oncologist than a written examination. It will also be less labor-intensive and less expensive than an oral examination. One of the most important skills of a radiation oncologist is the ability to design treatment portals that will encompass the entire cancer and yet minimize the irradiation of critical tissues and normal organs. Important parameters for radiation oncologists include the direction of the treatment beam, the size and shape of the portals, and the location of the margins of the field relative to patient anatomy and tumor location. In order to evaluate a physician's ability to design treatment portals, the computer-based examination has the capability to interactively construct field lines. The computer interface allows the candidate to draw field lines on a digitized x-ray image in a manner similar to practice. After the candidate illustrates the field lines, the evaluation of the response must be performed quickly to avoid interrupting the flow of the examination. The answer key is stored as a lossless compressed image. The key contains three regions consisting of (1) the must include region, which contains the tumor; (2) the must-exclude region, which contains tissues that if damaged would affect patient vitality and quality of life; and (3) the envelope of acceptable curves. Each region is assigned a unique byte code. The candidate's response is assigned a fourth byte code. Using basic logic operations, the response is swiftly evaluated. The scoring algorithm scores a candidate's action as correct if his/her drawn area encompasses all of the "must-include region" and is within the "envelope of acceptable curves." It scores a candidate's action as incorrect if his/her drawn area overlaps any part of the "exclude region" and/or exceeds at any point the "envelope of acceptable curves."

Algorithms↗
PubMed2001

Enhancers and core promoter elements are essential for the activity of a cryptic gene activation sequence from tobacco, tCUP.

Cryptic gene regulatory elements are sequences that are inactive at their native locations in the genome but have the ability to become functional when positioned adjacent to genes. We have recently isolated such a cryptic sequence from tobacco, tCUP, that can act as a promoter. A 135-bp fragment spanning extending from position -197 to -62, relative to the transcription start site, was found to promote GUS expression in all of the major organs of transgenic Arabidopsis plants. Furthermore, this 135-bp fragment complemented the -46 minimal promoter of CaMV 35S and conferred constitutive expression on transgenic Arabidopsis plants. An electrophoretic mobility-shift assay showed that nuclear proteins prepared from tobacco leaves interact with the 135-bp fragment. tCUP has a core promoter that lacks the TATA consensus sequence but addition of a TATA-box sequence increased the core promoter activity by three-fold. The sequence surrounding the transcription start site of tCUP has sequence similarity with the initiator element (Inr), and deletion of this sequence significantly reduced promoter activity, suggesting that an essential Inr element may exist in the tCUP core promoter. Fusion of the GCC-box enhancer element from pathogenesis-related genes to the core promoter elevated tCUP core promoter activity. Our study indicates that cryptic promoters are similar in composition and organization to promoters associated with expressed genes and that their promoter elements can be combined to create composite promoters that are fully functional. This data provides direct evidence that the expression pattern of plant genes can be influenced by cryptic gene regulatory elements when they are brought into juxtaposition with genes through DNA rearrangements.

Arabidopsis↗
PubMed2001

Predicted mercury concentrations in hair from infant immunizations: cause for concern.

Mercury (Hg) is considered one of the worlds most toxic metals. Current thinking suggests that exposure to mercury occurs primarily from seafood contamination and rare catastrophic events. Recently, another common source of exposure has been identified. Thimerosal (TMS), a preservative found in many infant vaccines, contains 49.6% ethyl mercury (EtHg) by weight and typically contributes 25 microg of EtHg per dose of infant vaccine. As part of an ongoing review, the Food and Drug Administration (FDA) announced in 1999 that infants who received multiple TMS-preserved vaccines may have been exposed to cumulative Hg in excess of Federal safety guidelines. According to the centers for disease control (CDC) recommended immunization schedule, infants may have been exposed to 12.5 microg Hg at birth, 62.5 microg EtHg at 2 months, 50 microg EtHg at 4 months, 62.5 microg EtHg at 6 months, and 50 microg EtHg at approximately 18 months, for a total of 237.5 microg EtHg during the first 18 months of life, if all TMS-containing vaccines were administered. Neurobehavioral alterations, especially to the more susceptible fetus and infant, are known to occur after relatively low dose exposures to organic mercury compounds. In effort, to further elucidate the levels of ethyl mercury resulting from exposure to vaccinal TMS, we estimated hair Hg concentrations expected to result from the recommended CDC schedule utilizing a one compartment pharmacokinetic model. This model was developed to predict hair concentrations from acute exposure to methymercury (MeHg) in fish. Modeled hair Hg concentrations in infants exposed to vaccinal TMS are in excess of the Environmental Protection Agency (EPA) safety guidelines of 1 ppm for up to 365 days, with several peak concentrations within this period. More sensitive individuals and those with additional sources of exposure would have higher Hg concentrations. Given that exposure to low levels of mercury during critical stages of development has been associated with neurological disorders in children, including ADD, learning difficulties, and speech delays, the predicted hair Hg concentration resulting from childhood immunizations is cause for concern. Based on these findings, the impact which vaccinal mercury has had on the health of American children warrants further investigation.

Forecasting↗
PubMed2001

Immunoneutralisation of GnRH-I, without cross-reactivity to GnRH-II, in the development of a highly specific anti-fertility vaccine for clinical and veterinary use.

In recent years, several forms of gonadotrophin releasing hormone (GnRH) molecules have been isolated from primate brain. These molecules are very similar in sequence and this raises the question of whether previously developed neutralisation vaccines based on GnRH (now termed GnRH-I) would remove other forms of GnRH (namely GnRH-II) as well. As the function of these other molecules has not yet been clearly defined, potential health risks could exist by their ablation. In view of the high sequence homology between the molecules, this paper describes the production of highly specific polyclonal antibodies against GnRH-I and GnRH-II, with negligible cross-reactivity. The ultimate aim of this is to develop an anti-fertility vaccine which does not present any inappropriate side-effects, caused by neutralisation of a GnRH molecule which may or may not be directly involved in reproduction. Several formulations were investigated, based on analogues of the following molecules, conjugated to tetanus toxoid: 1. GnRH-I pGlu-His-Trp-Ser-Try-Gly-Leu-Arg-Pro-Gly-NH2 and 2. GnRH-II pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2. The specificity of the antibodies produced was examined, together with effects on fertility and any inappropriate side-effects. Immunostaining of hypothalamic sections was carried out, using the generated antisera, to determine the regional distribution of GnRH-I and GnRH-II neurones, as well as to further evaluate the specificity of the antibodies.

Animals↗
PubMed2001

Genetic approaches to harvesting lichen products.

Lichens are symbiotic associations between fungi, green algae and/or cyanobacteria. They have a varied chemistry and produce many polyketide-derived compounds, including some, such as depsides and depsidones, that are rarely reported elsewhere. Although lichens have been appreciated in traditional medicines, their value has largely been ignored by the modern pharmaceutical industry because difficulties in establishing axenic cultures and conditions for rapid growth preclude their routine use in most conventional screening processes. Recently, molecular genetic techniques using PCR, genomic library construction and heterologous expression have provided an alternative approach to begin exploring the diversity of polyketide biosynthetic pathways in lichens. The techniques can be expanded to cover other pathway types and be integrated with conventional culture collection-based screening to provide a comprehensive search for novel chemical entities in these organisms.

Amino Acid Sequence↗
PubMed2001

The search for a new model structure of beta-factor XIIa.

We present the search for a new model of beta-factor XIIa, a blood coagulation enzyme, with an unknown experimental 3D-structure. We decided to build not one but three different models using different homologous proteins as well as different techniques and different modelers. Additional studies, including extensive molecular dynamics simulations on the solvated state, allowed us to draw several conclusions concerning homology modelling, in general, and beta-factor XIIa, in particular.

Amino Acid Sequence↗
PubMed2001

Treatment of congenital erythropoietic porphyria in children by allogeneic stem cell transplantation: a case report and review of the literature.

Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder of porphyrin metabolism in which the genetic defect is the deficiency of uroporphyrinogen III cosynthase (UIIIC). Deficiency of this enzyme results in an accumulation of high amounts of uroporphyrin I in all tissues leading to hemolytic anemia, splenomegaly, erythrodontia, bone fragility, exquisite photosensitivity and mutilating skin lesions. We describe the case of a 23-month-old boy who was cured of his CEP by a matched-sibling allogeneic bone marrow transplant, and review the published clinical experience regarding transplantation in this disease. He is alive and disease-free 15 months post transplant. All of his disease manifestations except for the erythrodontia have resolved. His UIIIC level and stool and erythrocyte porphyrin metabolites have almost completely corrected. He is the sixth child reported to be cured of this disease by stem cell transplantation, five cases being long-term survivors. If patients with this disease have an HLA-matched sibling, then stem cell transplantation should be strongly considered because this is currently the only known curative therapy.

Blood Donors↗
PubMed2001

Stronger proliferative response to membrane versus cell-wall Streptococcal proteins by peripheral blood T cells in chronic plaque psoriasis.

Proliferative responses of peripheral blood mononuclear cells (PBMC) to group A streptococcal (GAS) antigens have been studied in 24 patients with psoriasis and 15 disease controls. Extracts of cell wall (including M protein) from types M4 and M12 GAS, recombinant M6 protein, and both cell-wall and cell-membrane extracts from type M6 (M6+) GAS and its corresponding M gene deletion mutant (M6-) were tested. PBMC from psoriatic patients proliferated more strongly to cell-wall extracts from M12 versus M4 (P = 0.0348), and to M6+ versus M6- (P = 0.0019) GAS with, in most cases, moderate proliferation to recombinant M6 protein. The psoriatic response to M12 cell wall was significantly increased compared to the controls (P = 0.0032). In psoriatics, M6+ membrane extracts induced a markedly greater proliferation than those of cell wall (P = 0.0002); responses to M6+ (P = 0.0039) and M6- (P = 0.0114) membrane extracts were higher than those of the control PBMC. Both groups showed a decreased response to the M6- versus M6+ membrane extracts (P = 0.0030; P = 0.0181, respectively). This study has demonstrated that patients with psoriasis have a heightened circulating T-cell response to cell wall M protein and to non-M proteins present on the cell wall and membrane of GAS.

Adolescent↗