Angina and coronary artery disease. Manifestations and management.
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Aged↗
Biomedical subjects
D B Wilson
Publications and source records attributed to D B Wilson.
Transfer of a functional human immune system to mice with severe combined immunodeficiency.
The pressing need for a better experimental system for AIDS research has brought into sharp focus the shortcomings of available animal models and the practical and ethical limitations of studies of immune responses and viral pathogenesis in humans. Current studies of the human immune responses are limited to relatively restrictive in vivo experiments and several in vitro systems that, although useful, allow only short-term studies and support responses to a few antigens. Neither model is particularly amenable to studies of the pathogenesis of diseases of the immune system. We report here that injection of human peripheral blood leukocytes (PBL) can result in the stable long-term reconstitution of a functional human immune system in mice with severe combined immunodeficiency (SCID). Human PBL transplanted to SCID mice increase in number and survive for at least six months; reconstituted mice show spontaneous secretion of human immunoglobulin and a specific human antibody response is induced following immunization with tetanus toxoid. All of the major cell populations present in PBL are found in the lymphoid tissue and blood of SCID recipients, although the relative proportions of B cells, T-cell subsets and monocytes/macrophages in long-term recipients differ from those found in normal PBL and, in mice transplanted with 50 x 10(6) or more PBL from Epstein-Barr virus (EBV)-seropositive donors, EBV-positive B-cell lymphomas often develop. Our results suggest that xenogeneic transplantation of human lymphoid cells into SCID mice may provide a useful model for the study of normal human immune function, the response of the immune system to pathogenic agents and early events in lymphomagensis.
Animals↗
Hemodynamic effects of dopexamine hydrochloride infusions of 48 to 72 hours' duration for severe congestive heart failure.
Dopexamine hydrochloride, a new dopaminergic derivative with potent beta 2-agonist activity, was administered to 10 patients with severe congestive heart failure. Initially, the drug was infused at increasing dosage to achieve a maximal tolerated dose and then titrated to maintain acceptable clinical parameters over the next 48 to 72 hours. Cardiac index increased significantly during the initial titration and at peak effect. Tolerance over the duration of the study was noted in most patients, although further increases in cardiac index could usually be achieved by modest increases in the infusion rate. The peak hemodynamic effect was noted at an average infusion rate of 4.8 micrograms/kg/min. Both stroke volume and stroke work indexes increased during dopexamine hydrochloride infusion in association with decreases in mean arterial, right atrial, mean pulmonary artery and pulmonary capillary wedge pressures, systemic vascular resistance and pulmonary arteriolar resistance. Cardiac output increased by 60% during the infusion and this was out of proportion to the 12% increase in heart rate at peak effect. Most of the increase in cardiac index appeared to be due to the strong vasodilatory profile of the medication producing afterload reduction, with direct inotropic and chronotropic effects contributing to a lesser degree. Drug-related side effects occurred in 4 patients and were easily controlled by down-titration. Dopexamine hydrochloride is an effective and well-tolerated sympathomimetic agent that increases cardiac index while promoting vasodilatation.
Adult↗
The chief medical residency in Canada: comparison of opinions between physicians-in-chief and chief medical residents.
We conducted a survey of physicians-in-chief (PCs) and chief medical residents (CMRs) in training programs throughout Canada to determine their attitudes toward the need for and role of CMRs in Canada and to rate the importance of CMR duties and attributes. Forty-three hospitals with 5 to 126 house staff in all eight provinces with medical schools were surveyed; 36 PCs (84%) and 29 CMRs (67%) returned a completed questionnaire. Compared with the CMRs the PCs preferred more prior training (p less than 0.03), estimated as significantly less the time spent by CMRs in required duties (p less than 0.05) and rated as more important the responsibilities of faculty-house staff liaison, house staff leader, house staff role model and teaching house staff (p less than 0.05) and the attributes of clinical judgement, medical knowledge, clinician model and research interests (p less than 0.03). All of the PCs and 97% of the CMRs rated the position as somewhat to very necessary; 83% of the PCs and 66% of the CMRs would not alter the present CMR roles. A total of 92% of the PCs felt that the position was very or somewhat advantageous with respect to a future private practice, compared with 67% of the CMRs (p less than 0.02). Increased administrative and committee duties, decreased teaching and future reductions in house staff were identified as major but reversible threats to the unique quality of the CMR position. We conclude that the CMR has a necessary, important and highly regarded role in Canadian university hospitals that could possibly be improved by regular review by the PC and CMR at each hospital to avoid the identified problems.
Attitude of Health Personnel↗
Comparison of gated cardiac magnetic resonance imaging and two-dimensional echocardiography for the evaluation of right ventricular thrombi: a case report with autopsy correlation.
In a patient who died of complications of severe pulmonary hypertension, right ventricular failure, and sepsis, antemortem two-dimensional (2-D) echocardiography and magnetic resonance imaging (MRI) studies demonstrated a right ventricular mass which at autopsy proved to be thrombus. The diagnostic features of this mass as imaged by these two methods are compared. This case was complicated in that the patient had a history of right atrial myxoma that had been successfully removed three years previously, and a history of several prior pulmonary emboli. Gated MRI depicted the size, shape, and surface characteristics of the mass more clearly than 2-D echocardiography because MRI provided better contrast and spatial resolution. Both techniques were useful in localizing the mass and showing if it was fixed or mobile. Depiction of tumor attachment was unclear with echocardiography but very clear with MRI. MRI also showed a left pulmonary artery thrombus that was not visualized by 2-D echocardiography. Both techniques provided chamber dimension measurements showing enlargement of the right atrium and ventricle. This case demonstrates that gated MRI provides high-quality images of cardiac anatomy and masses. Gated cardiac MRI should be considered at least complementary and potentially superior to two-dimensional echocardiography in the evaluation of intracardiac masses in certain patients.
Adult↗
Closure of the posterior neuropore in the vl mutant mouse.
Alterations in the surface topography of cells in the apical neural folds of the posterior neuropore were analyzed by means of scanning electron microscopy in normal (+/+) and abnormal (vl/vl) embryos characterized by lumbosacral dysraphism. In early embryos (14-25 somites) surface features distinguishing the neuroepithelial cells, transitional zone cells, and surface ectoderm cells were similar in normal and abnormal embryos, as were the arrangement and configuration of filopodia and lamellipodia. However, in embryos with approximately 26-36 somites, the transitional zone of the abnormals showed a profusion of large blebs and excrescences along the entire length of the posterior neuropore. By 36 somites, the posterior neuropore was still variably open in the abnormals, in contrast to normal embryos in which no external opening could be detected. In view of the abnormalities associated with the transitional zone, it is possible that the underlying mechanism that results in lumbosacral spina bifida in this mutant may involve putative neural crest cells.
Animals↗
Potential opportunities and problems for genetically altered rumen microorganisms.
Rumen microbiologists are beginning to use genetic engineering techniques, and researchers should carefully consider both the potentials and limitations of using this technology to manipulate the rumen microbial ecosystem. Despite encouraging rhetoric, it is difficult to identify specific examples where genetic engineering would enhance ruminal performance. Many practical problems (lactic acidosis, deamination, etc.) might be better served by genetic engineering approaches that delete rather than add genes. The difficulty with this approach is that a highly selective means of preventing wild types from recolonizing the rumen would be needed. The addition of specific genes is confounded by 1) the fact that the rumen microorganisms are already adapted to the rumen, 2) the diversity of species inhabiting the rumen and 3) the complexity of interactions among these species. Aspects such as increased rates of cellulose digestion and changes in amino acid composition of the microflora are particularly sensitive to these biological constraints. Genetic engineering has, however, the potential to alleviate new limitations that humans have imposed on the rumen (detoxification, resistance to low pH, the digestion of novel feed materials, etc). A particular strategy of moving acid-resistant cellulose genes into noncellulytic, but acid-resistant, rumen bacteria is described.
Animals↗
Cytochemical analysis of neural dysraphism in the vl mutant mouse.
Closure of the posterior neuropore was analyzed by means of ultrastructural cytochemistry in ten-day dysraphic mouse embryos homozygous for the mutant gene vl, and comparisons were made with normal embryos in terms of convergence, apposition and fusion of the apices of the neural folds. In abnormal embryos, regional differences in the distribution of the surface coat were comparable to those in normal embryos. However, there was an abnormally acute medial bending of the neural folds, as well as a delay in closure of the posterior neuropore. In closed areas of the abnormal embryos the dorsum also showed an erratic knot of disorganized cells. Thus, the pathogenetic mechanism in this mutant appears to involve not only a failure in apposition in open areas, as well as an inappropriate association of cells in areas which do fuse, but possibly also a failure of proper alignment of neural fold apices prior to apposition and fusion.
Animals↗
Cloning of the Thermomonospora fusca Endoglucanase E2 Gene in Streptomyces lividans: Affinity Purification and Functional Domains of the Cloned Gene Product.
Thermomonospora fusca YX grown in the presence of cellulose produces a number of beta-1-4-endoglucanases, some of which bind to microcrystalline cellulose. By using a multicopy plasmid, pIJ702, a gene coding for one of these enzymes (E2) was cloned into Streptomyces lividans and then mobilized into both Escherichia coli and Streptomyces albus. The gene was localized to a 1.6-kilobase PvuII-ClaI segment of the originally cloned 3.0-kilobase SstI fragment of Thermomonospora DNA. The culture supernatants of Streptomyces transformants contain a major endoglucanase that cross-reacts with antibody against Thermomonospora cellulase E2 and has the same molecular weight (43,000) as T. fusca E2. This protein binds quickly and tightly to Avicel, from which it can be eluted with guanidine hydrochloride but not with water. It also binds to filter paper but at a slower rate than to Avicel. Several large proteolytic degradation products of this enzyme generated in vivo lose the ability to bind to Avicel and have higher activity on carboxymethyl cellulose than the native enzyme. Other smaller products bind to Avicel but lack activity. A weak cellobiose-binding site not observed in the native enzyme was present in one of the degradation products. In E. coli, the cloned gene produced a cellulase that also binds tightly to Avicel but appeared to be slightly larger than T. fusca E2. The activity of intact E2 from all organisms can be inactivated by Hg ions. Dithiothreitol protected against Hg inactivation and reactivated both unbound and Avicel-bound Hg-inhibited E2, but at different rates.
Journal Article↗
Transcription of the celE gene in Thermomonospora fusca.
The steady-state level of celE mRNA (coding for cellulase E5) in Thermomonospora fusca YX was measured by Northern (RNA blot) hybridization under conditions causing induction or repression of cellulase synthesis. A good correlation was found between the mRNA level and the level of cellulase E5, suggesting that the T. fusca celE gene is regulated at the level of mRNA and, most likely, at the level of transcription. The 5' and 3' ends of the celE gene transcription unit were determined by S1 mapping with single-stranded DNA probes. These results showed that there were three species of celE mRNA in T. fusca YX with closely spaced 5' ends and identical 3' ends. The size of each mRNA was about 1.5 kilobases, from both the Northern and S1 data. This size is only slightly longer than that required to code for the 45-kilodalton E5 protein. In Escherichia coli D318 (celE), the 5' ends of the celE mRNAs are identical to those in T. fusca, but the 3' ends are located ca. 300 base pairs upstream of the T. fusca 3' end. The region where the putative celE promoters were located had some interesting features, including a 60-base-pair A + T-rich sequence and sequences resembling sigma 60 promoters.
Base Sequence↗
Identification of a celE-binding protein and its potential role in induction of the celE gene in Thermomonospora fusca.
Thermomonospora fusca cellulase E5 is encoded by the celE gene. This gene appears to be regulated at the transcriptional level by both induction and repression, and three putative closely linked promoters have been located by S1 mapping. To study its regulatory mechanism, a gel retardation assay was used to identify a protein in T. fusca cell extracts that interacted specifically with the DNA fragment containing the celE promoters. It was found that the binding activity appeared only when cellulase synthesis was induced, and it therefore resembled an activator protein involved in cellulase induction. DNase I footprinting identified the target sequence for this protein as a 21-base-pair sequence downstream from the putative celE promoters. The level of this protein was measured in two cellulase constitutive mutants, and the results suggest a complex control for celE induction.
Bacterial Proteins↗
Quantitative aspects of growth hormone cell maturation in the normal and little mutant mouse.
Growth hormone (GH) cells were analyzed by means of ultrastructural morphometry in the pars distalis of pituitary glands from male adult and immature normal (C57BL) and homozygous little (lit/lit) mutant mice. Thin sections were exposed to anti-GH serum and processed immunocytochemically with the colloidal-gold technique. In the pars distalis of adult lit/lit mice, the mean volume density of GH cells/total tissue was 24% of the normal value, granules/GH cells was 58% of normal, and granules/total tissue was only 12% of normal. Deficits in all of these parameters likewise occurred in immature glands, though to a lesser extent than in the adults. The results indicate that the GH deficiency in this mutant reflects quantitative deficits in both the secretory granule content of GH cells, as well as the GH cell content of the gland, with the latter being the more severely affected.
Animals↗
Abnormal development of the notochord and perinotochordal sheath in duplicitas posterior, patch and tail-short mice.
Interest in developmental interactions involving the notochord and perinotochordal sheath led to a comparative investigation of these structures in three mouse mutants. Alcian blue or periodic acid-Schiff staining of 9 1/2-13 days' gestational age embryos revealed a supernumerary notochordal-like mass of cells or a deflected notochord in association with duplication of the neural tube in mice of the duplicitas posterior stock. The perinotochordal sheath and basement membrane of the accessory notochordal masses were frequently defective. Patch and Tail-short embryos were also utilized for study by means of light microscopy using Alcian blue staining. In Patch embryos, although the notochord was sometimes compressed dorso-ventrally, it had an intact perinotochordal sheath and a defined, but undulated, basement membrane. Mesenchymal cells between the notochord and neural tube were occasionally replaced by cell-free space. In contrast, in Tail-short embryos a poorly formed, lightly staining or totally absent notochordal sheath was revealed. Indeed, it was sometimes difficult to distinguish the notochord from surrounding mesenchymal cells. In both the Patch and Tail-short embryos the notochord was also deflected from its medial position. In the three mutants studied, the direct or indirect effect of gene action appeared to be on the notochord and perinotochordal sheath, and the important role of these structures in abnormal axial development was established.
Animals↗
Immunofluorescent analysis of somatotroph distribution in the adenohypophysis of developing lit/lit mice.
Regional and sexual patterns in the distribution and density of somatotroph cells exposed to anti-growth hormone serum were analysed by means of immunofluorescence histochemistry in adenohypophyses of normal C57BL mice and abnormal (lit/lit) mutant mice, which exhibit postnatal growth deficits. In adult (3-4 months) lit/lit mice, the regional distribution of somatotrophs both in males and females was normal; however, there was a sparsity of somatotrophs, relative to the normal condition, in the lateral wings of the pars distalis, and sexual differences in the concentration of immunoreactive cells were not as prominent as in the normal mice. In the midline region of the pars distalis a cranioventral zone virtually devoid of somatotrophs occurred in lit/lit as well as in normal mice, especially in the females, though it was not as well defined in lit/lit because of the overall sparsity of somatotrophs. In normal immature mice at 8 and 14 days after birth, the lateral wings did not show the striking sexual differences in density of somatotroph distribution as they did in the normal adults, and at 8 days they were more sparsely populated with somatotrophs than at 14 days. In 14 day lit/lit mice, the lateral wings were less densely populated with somatotrophs than their normal counterparts, but at 8 days these differences were not detectable. In both normal and abnormal 8 day mice, the medial and midline regions of the pars distalis contained less intensely immunoreactive somatotrophs than did the lateral wings.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Lymphocyte function-associated antigen 1 (LFA-1) and natural killer (NK) cell activity: LFA-1 is not necessary for all killer: target cell interactions.
A panel of five monoclonal antibodies detecting human lymphocyte function-associated antigen 1 (LFA-1) was generated and shown by competitive binding studies to react with at least four distinct epitopes on this molecule. The antibodies were then tested for their ability to inhibit the lytic activity of a variety of different human natural killer (NK) populations on a panel of four NK-susceptible target cells (K562, MOLT-4, HSB-2, and Jurkat). When heterogeneous NK populations derived from fresh peripheral blood and mixed-lymphocyte culture (MLC)-generated lines were used, these anti-LFA-1 monoclonal antibodies (MAbs) inhibited lysis of all four NK targets; this finding supports the notion that LFA-1 molecules play an important role in NK-mediated lysis. When tested on a cloned line of NK cells (NK 3.3), lysis of K562 was inhibited by these MAbs, but lysis of the other three targets was not affected. This represents an instance where a MAb specific for LFA-1 inhibits the lytic activity of NK cells against some but not all targets; thus the LFA-1 molecule cannot be considered under all circumstances to be an absolute requirement in NK-mediated lysis.
Antibodies, Monoclonal↗
The diagnosis of dementia.
The diagnosis of dementia in the elderly has important personal and social consequences, and a small proportion of cases initially diagnosed may be reversible. An understanding of the operating characteristics and cost-effectiveness of clinical signs and symptoms and of laboratory investigations in the diagnosis of dementia is needed to diagnose accurately yet contain costs. Using published criteria, we critically appraised the current scientific literature on the diagnosis of dementia. The articles that essentially satisfied our criteria suggested that duration and severity of dementia best predicted reversibility and the need for computed tomography of the head. A decision rule may be used to select among a number of investigations now advocated as routine in diagnosing dementia, with little or no risk of missing clinically significant diagnoses and with appreciable cost savings. The reversibility of dementia may not be as major an issue as previously believed, since most instances may be early, atypical presentations of Alzheimer-type dementia.
Aged↗
"Silent angina" in the elderly.
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Age Factors↗
Regulation of beta-1,4-Endoglucanase Synthesis in Thermomonospora fusca.
In Thermomonospora fusca YX, endocellulase synthesis varies over a 100-fold range depending on the carbon source used. This study shows that the variation is caused by two regulatory mechanisms: an induction mechanism that increases the rate of endocellulase synthesis about 20-fold and a growth rate-dependent repression mechanism that changes the rate of synthesis over a 6-fold range in both induced and noninduced cells. In T. fusca, endocellulase synthesis can be induced by cellulose, cellobiose, or cellodextrin. Cellulase is involved in inducer generation from cellulose. Growth rate-dependent repression can be reversed by limiting cultures for carbon, nitrogen, or, to a lesser extent, phosphorus. Further evidence for two separate regulatory mechanisms is provided by the isolation of mutants (CC-1 and CC-2) whose endocellulases are synthesized constitutively but are still sensitive to growth rate-dependent repression. These conclusions about total endocellulase synthesis were extended to the individual endocellulases by showing that three T. fusca endocellulases are coordinately regulated.
Journal Article↗