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H C Smith

Publications and source records attributed to H C Smith.

At least 55 records · Page 3Linked to original sources
PubMed1996

Base-modification mRNA editing through deamination--the good, the bad and the unregulated.

RNA editing is a co- or post-transcriptional process in which select nucleotide sequences in RNA are altered from that originally encoded in the genome. The mRNAs encoding apolipoprotein B and some glutamate receptor subunits of ionotropic membrane channels are edited by site-specific base-deamination systems. Although these editing systems differ markedly in their mechanism for RNA-substrate binding and in their catalytic subunits, recent results suggest potentially common solutions to the problem of editing-site selectivity. The data suggest that there are multiple editing complexes or 'editosomes', which manifest editing-site preferences due to their macromolecular composition.

Amino Acid Sequence↗
PubMed1996

Regulation of hepatic apolipoprotein B RNA editing in the genetically obese Zucker rat.

Hepatic apolipoprotein (apo) B RNA editing was examined in the genetically obese hyperinsulinemic and hypertriglyceridemic Zucker rat. In obese Zucker rats, apo B RNA editing was increased 42% relative to that in lean controls. Correspondingly, the proportion of serum triglyceride-rich lipoprotein containing apo B48 increased 4.7-fold in the obese Zucker rat. Quantification of hepatic total apo B mRNA showed no difference between obese Zucker and lean control rats. In contrast, the hepatic mRNA encoding APOBEC-1, the catalytic subunit of the RNA editing activity, demonstrated an increased abundance of 1.8-fold in obese Zucker rats versus lean controls.

APOBEC-1 Deaminase↗
PubMed1996

Cardiovascular disease in elderly patients.

OBJECTIVE: To provide an overview of the cardiovascular consequences of the normal aging process in humans and to review unique aspects of the diagnosis and management of heart disease in the elderly population. DESIGN: We reviewed relevant published articles and summarized the diagnostic approaches and treatment recommendations for congestive heart failure, coronary artery disease, cardiac valvular disease, and arrhythmias in elderly patients. RESULTS: The aging process is associated with predictable anatomic and physiologic alterations in the cardiovascular system. consequently, the manifestations of heart disease in the geriatric population differ from those found in younger patients. Additionally, outcomes of cardiac diseases and therapeutic options change with advancing age because of such factors as alterations in drug metabolism. CONCLUSION: Age-related changes in the cardiovascular system result from intrinsic cardiac aspects of human senescence, primary cardiac disease, and influence of comorbid conditions on the heart. The natural history of heart disease is generally adversely affected by age. Although many treatment strategies with demonstrated efficacy in younger patients are relevant in the elderly age-group, careful attention to the influence of concomitant illness, the unique physiologic and pharmacologic changes, and the assessment of the potential effect of therapy on survival and quality of life is essential in treating elderly patients.

Aged↗
PubMed1996

Determinants involved in regulating the proportion of edited apolipoprotein B RNAs.

Editing the apolipoprotein B (apoB) RNA involves deamination of cytidine by the catalytic subunit, APOBEC-1, as a component of an editosome. A tripartite sequence (editing motif) is essential for editosome assembly and site-specific editing. Current theory for the regulation of apoB RNA editing proposes that APOBEC-1 is rate limiting in cells and determines the proportion of edited apoB mRNAs. An evaluation of how the overexpression of APOBEC-1 increased the proportion of edited RNAs has led to the discovery of a paradox. McArdle cells edit a constant proportion of apoB RNA regardless of the total number of apoB RNAs expressed. Despite virtually identical editing motifs, apoB RNA transcripts from the endogenous gene and transfected, exogenous cDNA were edited with characteristic, but different efficiencies. This suggested that these RNAs were interacting with the editing machinery as distinct and noncompeting populations. We evaluated whether the presence of introns in the endogenous transcript may have distinguished it as a distinct population having reduced editing efficiency. The editing efficiency of chimeric splicing-editing RNA substrates was highest on fully processed RNA. Increased exon length improved utilization of the editing motif in these chimeric constructs. Taken together, the data suggest that the close proximity of introns can reduce apoB RNA editing efficiency. A population "gating" hypothesis is proposed wherein the proportion of edited RNAs in a population is determined my multiple cis- and trans-acting factors as RNAs pass through a nuclear restriction point.

APOBEC-1 Deaminase↗
PubMed1995

Outcome of cardiac surgery for carcinoid heart disease.

OBJECTIVES: The hypothesis was that cardiac surgery for symptomatic carcinoid heart disease in conjunction with adjunctive therapy could improve the long-term outlook of patients with carcinoid heart disease. BACKGROUND: Patients with carcinoid heart disease have a dismal prognosis; most die of progressive right heart failure within 1 year after onset of symptoms. Improved therapies for the systemic manifestations of the carcinoid syndrome have resulted in symptomatic improvement and prolonged survival in patients without heart disease. METHODS: Twenty-six patients with symptomatic carcinoid heart disease underwent valvular surgery. Preoperative clinical, laboratory, Doppler echocardiographic and hemodynamic factors were evaluated. The survival of the surgical group was compared with that of a control group of 40 medically treated patients. RESULTS: There were nine perioperative deaths (35%), primarily from postoperative bleeding and right ventricular failure. Of the 17 surgical survivors, 8 were alive at a mean of 28 months of follow-up. The postoperative functional class of the eight surviving patients was substantially improved. Late deaths were primarily due to hepatic dysfunction caused by metastatic disease. The only predictor of operative mortality (p = 0.03) was low voltage on preoperative electrocardiography (limb lead voltage < or = 5 mm). Predictors of late survival included a lower preoperative somatostatin requirement and a lower preoperative urinary 5-hydroxy-indoleacetic acid level. There was a trend toward increased survival for the surgical group compared with the control group. CONCLUSIONS: Because new therapies have improved survival in patients with the malignant carcinoid syndrome, cardiac involvement has become a major cause of morbidity and mortality. Valve surgery is the only definitive treatment. Although cardiac surgery carries a high perioperative mortality, marked symptomatic improvement occurs in survivors. Surgical intervention should therefore be considered when cardiac symptoms become severe.

Actuarial Analysis↗
PubMed1994

Only cytidines 5' of the apolipoprotein B mRNA mooring sequence are edited.

A 22 nucleotide 'cassette' containing three distinct sequence elements is required for efficient apolipoprotein B (apoB) RNA editing. One of the elements, the mooring sequence, has been proposed as the apoB RNA-recognition element in binding 66 and 44 kDa proteins during editosome assembly. We show here that editing can only take place on cytidines 5' of the mooring sequence; thereby providing further proof for the proposed orientation-specific assembly of editing factors at the editing site. We also provide direct evidence for the existence of a cryptic mooring sequence immediately downstream of the wild-type editing site (between nucleotides 6688-6710). When a cytidine is introduced 5' of this site (at nucleotide 6687), editing occurs at wild-type (nucleotide 6666) and cryptic sites. The cytidine to be edited is not involved in 66 and 44 kDa protein binding, and therefore, the data suggest that the cryptic mooring sequence binds these factors, and may facilitate factor recruitment to the wild-type editing site. These data may also explain why wild-type levels of editing on chimeric, RNA editing substrates can only be achieved when the 22 nucleotide editing cassette is flanked 3' by apoB RNA sequence.

Apolipoproteins B↗
PubMed1994

Specific 3' sequences flanking a minimal apolipoprotein B (apoB) mRNA editing 'cassette' are critical for efficient editing in vitro.

Apolipoprotein B (apoB) mRNA in mammalian intestine undergoes direct conversion of cytidine to uridine at nucleotide 6666, generating a UAA stop codon which defines the carboxyl-terminus of apoB48. We have identified three distinct sequence elements which are required for efficient apoB RNA editing in vitro and have defined a 20 nucleotide 'editing cassette' which will support efficient editing in the context of a variety of AT-rich apoB mRNA backgrounds. An important question remaining to be addressed is whether this cassette can support editing in a GC-rich background characteristic of other mRNAs. We demonstrate that the context into which the editing cassette is inserted may determine the efficiency of editing site utilization. When an editing cassette is placed in the context of human albumin mRNA sequence, editing is reduced 6-fold relative to a construct of similar length in which the cassette is surrounded by apoB mRNA sequence. Chimeric RNA substrates may be efficiently edited, however, when albumin sequence resides only 5' of the editing cassette. The data suggest that the proximal of an AT-rich, apoB-like, mRNA sequence is only required 3' of the editing cassette. These results should prove useful in evaluating the potential for editing on mRNAs where similar cassettes can be found.

APOBEC-1 Deaminase↗
PubMed1994

Herpes simplex myelitis as a cause of acute necrotizing myelitis syndrome.

We report a patient with herpes simplex virus (HSV) myelitis with a clinical history of rapidly progressive spinal cord dysfunction and extensive necrosis of the lumbosacral spinal cord at autopsy. The etiologic agent was HSV type 2. The close resemblance of the clinical features of this case to the syndrome of acute necrotizing myelitis emphasizes the need to recognize HSV myelitis as a cause of this syndrome, since it is diagnosable during life by culturing the CSF and is treatable.

Acute Disease↗
PubMed1993

Apolipoprotein B mRNA editing in vitro is a zinc-dependent process.

Apolipoprotein B mRNA editing involves the conversion of a cytidine at nucleotide 6666 to a uridine, thereby creating a translational stop codon from a glutamine codon. Recent evidence suggest that a cytidine deaminase is responsible for catalyzing the C to U conversion. All known nucleotide deaminases require zinc as part of their catalytic domain. Utilizing the selective chelator for zinc, 1,10-penanthroline, we demonstrate that in vitro editing activity in rat liver extracts is zinc dependent. These data, taken together with recent reports, strongly support a role for a cytidine deaminase and nucleotide conversion as the catalytic mechanism for apoB mRNA editing.

Animals↗
PubMed1993

Extract-specific heterogeneity in high-order complexes containing apolipoprotein B mRNA editing activity and RNA-binding proteins.

The mechanism for tissue-specific differences in apolipoprotein B (apoB) mRNA editing efficiency is not known. Structural data are presented which demonstrate tissue-specific, quantitative differences in the high order complexes containing apoB mRNA editing activity and RNA-binding proteins. The bulk of rat enterocyte extract editing activity sedimented at 11 S with an additional 5-10% at 60 S. Rat liver extract activity was less abundant and only sedimented at 60 S. Ultraviolet light cross-linking revealed two protein activities of approximately 66 and 44 kDa which specifically associated with apoB RNA substrates and cosedimented with editing activity. Extracts differed in the cross-linking yield of p66 and p44 and kinetically, enterocyte RNA-protein complexes reached maximum abundance more rapidly than those in liver extracts. Both 60 and 11 S forms of the editing activity redistributed to 27 S during in vitro editosome assembly. The redistribution of editing activities was accompanied by a corresponding redistribution of p66/p44 to 27 S. The data demonstrate that p66 and p44 are common to liver and enterocyte 27 S editosome assembly processes and suggest that differences in both the pre-editosomal assembly state of editing factors and their abundance may be mechanistically important for tissue-specific differences in editing efficiency.

Animals↗
PubMed1993

Apolipoprotein B mRNA editing: the sequence to the event.

Editing of the mRNA coding for apolipoprotein B involves a cytidine to uridine transition at nucleotide 6666 and enables translation of two protein variants. The development of in vitro editing systems has led to the identification of three sequence requirements in this process. The mechanism for C-->U editing requires specific sequences for editing site recognition, positioning of the catalytic activity and enhancement of catalytic efficiency. The dependence of in vitro editing on extract proteins has focused future research in this field on the identification of factors involved in apoB mRNA editing and the role of these factors in the assembly of ribonucleoprotein editosomes.

Animals↗
PubMed1993

Levels of five mycotoxins in grains harvested in Atlantic Canada as measured by high performance liquid chromatography.

An analytical protocol using high performance liquid chromatography (HPLC) was used to analyze samples of spring wheat, winter wheat, 2-row barley, and 6-row barley over a period of three years for the presence of five mycotoxins. These included deoxynivalenol, zearalenone, T-2 toxin, HT-2 toxin, and diacetoxyscirpenol. The protocol employed a single extraction step using acetonitrile-water and two cleanup procedures. One utilized a solid-phase extraction column and the other a charcoal-alumina column. Detection limits ranged from 0.02 to 0.15 micrograms of mycotoxin g-1 grain. Little T-2 toxin, HT-2 toxin, or diacetoxyscirpenol was found in the samples. Deoxynivalenol was detected in 53 to 62% of the samples tested and zearalenone in 25-29% of the samples. Several enzyme-linked immunosorbent assays were used for comparison purposes with deoxynivalenol, zearalenone, and T-2 toxin. These kits provided reliable qualitative, but not quantitative, data.

Canada↗
PubMed1993

Hypoxic stress induces reversible hypophosphorylation of pRB and reduction in cyclin A abundance independent of cell cycle progression.

The effect of hypoxic stress on the phosphorylation state of the product of retinoblastoma susceptibility gene (pRB) and cyclin A abundance was examined in CV-1P monkey kidney cells. Flow cytometric DNA histogram analysis and [3H]-thymidine incorporation assays demonstrated that hypoxia inhibited cell cycle progression and cell division. Within 6-12 h of hypoxia, pRB became hypophosphorylated and cyclin A abundance fell below detection limits. Hypophosphorylation of pRB and loss of cyclin A detection occurred without progression of cells through S-phase. These effects were found to be reversible by reoxygenation of the hypoxic cultures. Cells were shown to resume DNA synthesis within 12-16 h of reoxygenation concomitant with pRB hyperphosphorylation and an increase in cyclin A detection. These data demonstrate that hypoxic stress blocks the progression of these cells through the phases of the cell cycle and suggests that the effect might arise from the down regulation of key cell cycle controlling elements. The data also raise the possibility that maintaining pRB in a hyperphosphorylated state may be crucial for S-phase progression as well as S-phase entry.

Animals↗
PubMed1992

Three distinct RNA sequence elements are required for efficient apolipoprotein B (apoB) RNA editing in vitro.

Apolipoprotein B (apoB) mRNA is edited in rat liver and intestine to convert a CAA glutamine codon to a UAA translational stop codon by the direct conversion of cytidine to uridine at nucleotide 6666. We have proposed the 'mooring sequence' model for apoB RNA editing, in which editing complexes (editosomes) assemble on specific apoB mRNA flanking sequences to direct this site-specific editing event. One sequence element (approx. nts 6671-81, the presumed 'mooring sequence') has been previously identified as necessary for editing. We have identified two additional sequence elements which are necessary for efficient editing: (1) a 5' 'Regulator' region which modulates editing efficiency and (2) a 'Spacer' region between the editing site and the 3' mooring sequence, whose distance is critical for efficient editing. Utilizing this data, we have induced editing at a cryptic site and have defined a 22 nucleotide 'cassette' of specific apoB sequence which is sufficient to support wild-type levels of editing in vitro in a background of distal apoB RNA sequence.

Animals↗
PubMed1992

Prognosis in rupture of the ventricular septum after acute myocardial infarction and role of early surgical intervention.

Since 1944, 91 patients (50 men and 41 women, mean age 68 years [range 39 to 86]) with ventricular septal rupture after acute myocardial infarction were seen at the Mayo Clinic. Patients were divided into 4 groups according to therapy and timing of surgical intervention. Fourteen patients seen before 1965, when surgery was not performed for such a complication or not readily available, were excluded from the analysis. Group 1 (n = 22) had surgery within 48 hours of septal rupture, group 2 (n = 6) underwent operation between 2 and 14 days, group 3 (n = 24) had surgery after 14 days, and group 4 (n = 25) only received medical treatment. Short-term (30 days) survivors (45%, 35 of 77 patients) were compared with nonsurvivors. Using logistic regression, by univariate analysis, 3 variables were significantly associated with outcome: age (p less than 0.01), cardiogenic shock (p less than 0.00001), and long delay between ventricular septal rupture and surgical intervention (p less than 0.004). By multivariate analysis, however, only cardiogenic shock (p less than 0.00001) and age (p less than 0.007) correlated with an adverse outcome. In patients with cardiogenic shock after septal rupture, the prognosis was uniformly fatal unless patients undergo early surgery. None of the 23 patients in groups 2, 3 or 4 survived, whereas 5 of 13 patients (38%) who had surgery within 48 hours of septal rupture survived.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗