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Biomedical subjects

L Hudson

Publications and source records attributed to L Hudson.

At least 19 recordsLinked to original sources

Decreased expression of AMPA receptor messenger RNA and protein in AIDS: a model for HIV-associated neurotoxicity.

HIV infection can cause extensive neuronal loss and clinically a severe dementia. The cause of the neurotoxicity remains unclear as neurons are not infected, but disturbance of glutamate-linked calcium entry has been implicated. In this study, we have shown a decrease in HIV-infected brain of the expression of mRNA and protein of the GluR-A flop subtype of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor in cerebellar Purkinje cells. Although Purkinje cells are relatively resistant to loss, the observed disturbance of AMPA receptors may contribute to the neurotoxic process in other vulnerable brain regions and clinically to the development of dementia.

AIDS Dementia Complex

Analysis of the anatomical distribution of GAD67 mRNA encoding truncated glutamic acid decarboxylase proteins in the embryonic rat brain.

During development of the central nervous system (CNS) the gene that encodes the 67 kDa form of glutamic acid decarboxylase (GAD) undergoes alternative splicing. The alternatively spliced variants include an exon (referred to as ES, for embryonic stop) that contains a premature stop codon. The detection of mRNA containing the ES exon in embryonic rat brain has been previously reported (Proc. Natl. Acad. Sci., 87 (1990) 8771-8775). We have used in situ hybridization to identify the anatomical distribution of ES mRNA in the embryonic rat brain during two stages of development, embryonic day 17 (E17) and E20. At E17, GAD67 mRNA was expressed in several CNS regions that were destined to contain GABAergic neurons when mature. ES transcripts were predominantly localized to ventricular zones and other regions associated with populations of proliferative cells at E17 and E20. At both ages, however, the alternatively spliced variants were also detected in regions of brain associated with migratory or post-mitotic neurons. GAD67 transcripts that did not include the ES exon were localized to anatomical areas that contained post-mitotic, and often post-migratory neurons. The temporal and spatial disappearance of mRNA containing the ES exon generally followed a caudal-to-rostral gradient which paralleled neuronal terminal mitosis and differentiation.

Animals

Report of the American-European consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination. The Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of non-hydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies carries a high morbidity, mortality (10-90%) and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those whose wish to know the true incidence and outcome on this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Clinical Protocols

Report of the American-European Consensus conference on acute respiratory distress syndrome: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Consensus Committee.

The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity rate, mortality rate (10% to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged and may be different in Europe. Part of the reason for these uncertainties is the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The European American Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Clinical Trials as Topic

The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination.

The acute respiratory distress syndrome (ARDS), a process of nonhydrostatic pulmonary edema and hypoxemia associated with a variety of etiologies, carries a high morbidity, mortality (10 to 90%), and financial cost. The reported annual incidence in the United States is 150,000 cases, but this figure has been challenged, and it may be different in Europe. Part of the reason for these uncertainties are the heterogeneity of diseases underlying ARDS and the lack of uniform definitions for ARDS. Thus, those who wish to know the true incidence and outcome of this clinical syndrome are stymied. The American-European Consensus Committee on ARDS was formed to focus on these issues and on the pathophysiologic mechanisms of the process. It was felt that international coordination between North America and Europe in clinical studies of ARDS was becoming increasingly important in order to address the recent plethora of potential therapeutic agents for the prevention and treatment of ARDS.

Americas

Maternal-fetal HLA sharing and risk of newborn encephalopathy and seizures: a pilot study.

A pilot case-control study was done to collect data on whether susceptibility to newborn encephalopathy and neonatal seizures is influenced by the degree of maternal-fetal sharing of HLA antigens. Cases included 13 infants with moderate or severe newborn encephalopathy and seven infants with neonatal seizures but no other signs of encephalopathy. Controls were neurologically normal infants matched to cases by date of birth, sex, race, and payment status. Infants and their mothers were typed for HLA-A, -B, -DR, and -DQ antigens. The observed frequency of sharing of maternal antigens was greater than expected (ie, 0.5) for cases compared to controls at the HLA-B, -DR, and -DQ loci but not for HLA-A. The risk of neurologic problems in the neonatal period was increased 6.3 times when there was more than one match at the HLA-DR or -DQ locus. Placental abnormalities were noted at delivery only among cases, and the mean placental weight in cases was 598 g versus 695 g in controls. Further studies with sample sizes sufficiently large to statistically test this hypothesis are needed.

Alleles

The pathology and nosology of primary progressive aphasia.

We present three cases of primary progressive aphasia (PPA) with Pick-variant pathology to support a hypothesis of an underlying nosologic relatedness. Neuropathologic examination demonstrated focal brain atrophy with corresponding neuronal loss and gliosis, accompanied by superficial spongiosis. Specific histologic findings were ballooned neurons (Pick cells) in the atrophic areas, and in two of the cases, Pick bodies. They were immunoreactive for tau. In contrast to classic Pick's disease, there were no Pick bodies in the hippocampus. The intense neurofilament immunoreactivity of the perikarya of the ballooned neurons greatly facilitated their recognition. Based on our cases and a critical review of the literature, we hypothesize that the common underlying pathology of PPA is a variant of Pick's disease. Furthermore, we propose the concept of "Pick complex" to include other neurodegenerative diseases characterized by focal cortical degeneration, such as PPA, frontal lobe dementia, ALS with PPA, and corticonigral and corticobasal ganglionic degenerations.

Aged

Plasticity in the adult human oligodendrocyte lineage.

Preoligodendrocytes have been described in cultures and tissue prints of adult human white matter (Armstrong et al., 1992). To characterize further these precursors of human oligodendrocytes, we have investigated whether they express genes playing a critical role in oligodendrocyte development. In the intact human brain, platelet-derived growth factor receptor alpha (PDGF alpha R) and myelin transcription factor 1 (MyTI) transcripts are expressed in 1-2% of cells of the oligodendrocyte lineage (OL), and clusters of such cells can be found in the periventricular region. Myelin basic protein transcripts containing exon 2 information (exon 2+ MBP), which are characteristic of the premyelinating stage, are detected in 15-20% of OL cells in vivo. When OL cells are separated from human white matter and allowed to regenerate in vitro, a much larger proportion of these cells express developmentally regulated genes, while exon 2- MBP and proteolipid protein (PLP) transcripts characteristic of mature OL cells appear transiently downregulated. Basic fibroblast growth factor (bFGF), even in the presence of PDGF, does not promote DNA synthesis in these cultured OL cells. Yet bFGF induces human oligodendrocytes to regenerate their processes rapidly in vitro and to express O4 antigens as well as exon 2+ MBP, MyTI, and PLP transcripts. While bFGF accelerates early regenerative processes, it also maintains high expression of exon 2+ MBP transcripts in OL cells for up to 2 weeks in vitro. In contrast, high levels of insulin in the absence of bFGF allow accumulation of exon 2- MBP and PLP transcripts in most OL cells at 2-3 weeks in vitro. We propose that the myelinated human brain harbors a small pool of precursors of oligodendrocytes and that growth factor-regulated phenotypic plasticity rather than mitogenic potential accounts for the regeneration of oligodendrocytes in the initial stages of demyelinating diseases such as multiple sclerosis.

Adolescent

Unexpected effects of a social drug.

At medical school we are taught that history is 90 per cent of the diagnosis. In general practice, with earlier presentation of illnesses it assumes an even greater role. This case illustrates the great importance of the history; to make the diagnosis, to reduce the cost of investigations and to increase patient rapport.

Adult

Functional loss of chemotactic factor inactivator in the adult respiratory distress syndrome.

The adult respiratory distress syndrome (ARDS) is often characterized by a neutrophilic alveolitis, which may be mediated in part by the neutrophil chemoattractant, C5a. Chemotactic factor inactivator (CFI) can decrease C5a-directed neutrophil chemotaxis. Thus, a loss of CFI activity in the ARDS lung could lead to an increased ability of C5a to attract neutrophils. Lung CFI levels were measured antigenically and functionally in bronchoalveolar lavage (BAL) fluid obtained from 29 patients with ARDS and in 14 normal control subjects. Antigenic levels of CFI were found to be markedly elevated in ARDS BAL fluid (1,855 +/- 437 ng/ml) compared with that in normal BAL (29 +/- 10 ng/ml, p less than 0.005), but, in contrast, CFI functional activity was markedly decreased in ARDS BAL fluid compared with that in normal BAL fluid (31 +/- 7% inhibition versus 76 +/- 5% inhibition, p less than 0.01). Furthermore, although purified CFI readily inhibited the ability of C5a to attract neutrophils (92% inhibition), this activity was decreased when BAL fluid from patients with ARDS was incubated with CFI (47 +/- 10%, p less than 0.01). These findings suggest that patients with ARDS are functionally deficient in CFI, leading to an increased ability of C5a to attract neutrophils.

Aminopeptidases

Monoclonal antibodies mediating viable immunofluorescence and protection against Trypanosoma cruzi infection.

Both humoral and cell mediated immunity have been associated with protection against Trypanosoma cruzi infection. Antibody mediated protection has been associated with a particular functional type of antibody, as detected by viable immunofluorescence (VIF), which is able to bind to living trypomastigotes, and is produced during infection but not following immunisation with killed parasites. We have generated B cell hybridomas from mice infected with T. cruzi and screened these hybridomas for VIF mediating antibodies. In this paper we describe two such monoclonal antibodies which are able to provide substantial protection when administered passively prior to challenge infection.

Animals

Comparison of safety and efficacy of inhaled pirbuterol with metaproterenol.

This multicenter study was performed to compare the safety and efficacy of a new beta-2 selective beta agonist, pirbuterol, with metaproterenol. The study followed a double-blind parallel design evaluating 133 asthmatic patients for 12 weeks. There were essentially no clinical differences between groups and no differences in onset of action, peak effect, side effects, or development of tolerance between these two agents. Our conclusion is that pirbuterol is at least as effective and safe under conditions of chronic administration to asthmatics as metaproterenol and therefore can be considered a suitable alternative for therapy.

Administration, Inhalation

cGMP immunocytochemistry in aorta, kidney, retina and brain tissues of the rat after perfusion with nitroprusside.

The distribution of cyclic guanosine 3',5' monophosphate (cGMP) producing cells in various organs of the rat were studied immunocytochemically using antibodies raised against formaldehyde-fixed cGMP. Sodium nitroprusside (SNP), a direct activator of guanylate cyclase and vasodilator, was used to enhance cGMP levels. In order to reach all organs optimally, whole body perfusion was performed using a modified Krebs-Ringer buffer at 37 degrees C, aerated with 5% CO2/95% O2, also containing isobutyl methyl xanthine (IBMX); a phosphodiesterase inhibitor. After 15-min pre-perfusion, SNP was added to the perfusate, followed by fast fixation with ice-cold 4% paraformaldehyde-phosphate buffer. After vehicle perfusion, only the retina showed cGMP immunoreactivity in the photoreceptor and ganglion layer, while other organs lacked cGMP immunoreactivity. After 15-min perfusion with SNP (10 microM), enhanced cGMP immunostaining was seen in smooth muscles of the aorta, amacrine-like cells in the retina, glomeruli of the kidney cortex, blood vessels in the dura mater, as well as cells in the pineal and in the median eminence. The results indicate that the distribution and the reactivity of cGMP producing cells, situated outside the blood brain barrier, can be studied by immunocytochemistry after pharmacological manipulations of the intact tissue with a nitrovasodilator using whole body perfusion.

Animals

Cloning and expression of a trypomastigote-specific 85-kilodalton surface antigen gene from Trypanosoma cruzi.

An 85-kDa trypomastigote-specific surface antigen gene from Trypanosoma cruzi has been identified by screening a genomic library in lambda gt10 with trypomastigote and epimastigote cDNA. The 1.3-kb genomic clone (pTt34) hybridizes to a single trypomastigote mRNA of 3.7 kb and to multiple bands in genomic Southern blots. Dot-blot experiments show that there are 5-10 copies of this sequence per haploid genome, and these are arranged in a non-tandem manner. pTt34 has been expressed as an anthranilate synthetase fusion protein in Escherichia coli, and inclusion bodies have been used to raise antiserum in rabbits. This antiserum immunoprecipitates a cell surface trypomastigote-specific protein of 85 kDa. The DNA and predicted amino acid sequences of pTt34 are given. Four further clones obtained from a PvuII/HpaI partial genomic library in pUC13 have extended the sequence of the 3' end of pTt34; each of these clones has regions of sequence divergence and each could represent a different member of the gene family.

Amino Acid Sequence

Atrial natriuretic factor-responding and cyclic guanosine monophosphate (cGMP)-producing cells in the rat hippocampus: a combined micropharmacological and immunocytochemical approach.

Atrial natriuretic factor (ANF)-responding, cyclic guanosine monophosphate (cGMP)-producing cells were visualized in the hippocampus of the rat applying cGMP immunocytochemistry to hippocampal tissue slices incubated in vitro. These cells were found scattered throughout the hippocampus with their highest density in the hilus fascia dentata. Staining with an antibody against glial fibrillary acidic protein showed a completely different pattern, suggesting a non-glial nature of the ANF-responding cells. cGMP accumulation assayed biochemically was observed already at 10 microM ANF and was sensitive to inhibition by Methylene blue. The immunocytochemical data were fully supported by the biochemical measurements of cGMP under these conditions. Our results show for the first time a response to ANF of individual, cGMP-producing cells in the CNS of the rat.

Animals

Longitudinal studies of the immune response of Colombian patients infected with Trypanosoma cruzi and T. rangeli.

Two groups of patients were examined for anti-Trypanosoma cruzi antibodies by immunofluorescence and ELISA (i) inhabitants of the village and surrounding rural area of Tibu, Norte de Santander, Columbia (n = 327) and (ii) employees of the Empresa Colombiana de Petroleos (ECOPETROL, n = 849). The latter group had a lower rate of positive serology (12 as compared to 29%) but the distributions of antibody titres were very similar in the two groups. A total of 119 serum samples (37 village and 82 ECOPETROL, including 25 seronegative controls) were analysed for their ability to immunoprecipitate the 7 major polypeptides of T. cruzi trypomastigotes of Mr greater than 72 kDa. Although 10 sera from positive patients showed no immunoprecipitation, all of the remaining positive sera contained antibodies which reacted with the 150, 90 and 85 kDa polypeptides. When the T. cruzi immunofluorescence positive, immunoprecipitation negative sera were retested by ELISA using GP90, all were negative thus suggesting that the patients had had a misdiagnosed T. rangeli infection. The new diagnosis was confirmed by immunofluorescence and ELISA with T. rangeli epimastigotes. Longitudinal studies were carried out on 19 patients from the ECOPETROL group for up to 3.5 years. Five seropositive patients showed a change in their anti-trypomastigote immunoprecipitation profiles over this period; one by loss of a previously recognized high molecular weight band and four others by conversion from a negative to a positive immunoprecipitation profile. These latter patients presented initially with uncomplicated T. rangeli infection but then acquired a T. cruzi superinfection. These patients represent the nucleus of a group in which prospective studies will identify the effect of T. rangeli infection on the course of subsequent South American trypanosomiasis and Chagas' disease.

Animals

Smoke inhalation.

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Acute Disease