Biomedical subjects
Publications and source records attributed to T R Graham.
Angina and increasing exertional dyspnea developed in a 53-year-old man 9 years after cardiac transplantation. Left heart catheterization revealed severe proximal triple coronary artery disease, and he underwent surgical revascularization. Now 18 months after the operation he continues to be free of symptoms.
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Between 1979 and 1988, 29 cases of paraoesophageal hernia presented to one surgeon (F.D.S.). There were 23 women and six men and the mean(s.e.m.) age was 66.3(4.1) years. All were symptomatic and 13 hernias (45%) were complicated by gastric volvulus, haemorrhage or perforation. Ten (34%) had evidence of gastro-oesophageal reflux, suggesting a sliding component in these cases. Operation, mostly transthoracic, consisted of hernial reduction, crural repair and, if indicated, an antireflux procedure. There were three deaths. Two occurred as a result of spontaneous, intrathoracic perforation of the hernia. The third followed dilatation of a benign stricture 2 months after surgery. The only major complication was a pulmonary embolus with full recovery. The mean(s.e.m.) follow-up time was 47.6(7.8) months and there were no recurrences. This series confirms that symptomatic paraoesophageal hernias warrant early repair because of the frequency and severity of associated complications. Although debate continues as to whether this policy should be extended to asymptomatic paraoesophageal hernias, we suggest that this should be so.
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The sec18 and sec23 secretory mutants of Saccharomyces cerevisiae have previously been shown to exhibit temperature-conditional defects in protein transport from the ER to the Golgi complex (Novick, P., S. Ferro, and R. Schekman, 1981. Cell. 25:461-469). We have found that the Sec18 and Sec23 protein functions are rapidly inactivated upon shifting mutant cells to the nonpermissive temperature (less than 1 min). This has permitted an analysis of the potential role these SEC gene products play in transport events distal to the ER. The sec-dependent transport of alpha-factor (alpha f) and carboxypeptidase Y (CPY) biosynthetic intermediates present throughout the secretory pathway was monitored in temperature shift experiments. We found that Sec18p/NSF function was required sequentially for protein transport from the ER to the Golgi complex, through multiple Golgi compartments and from the Golgi complex to the cell surface. In contrast, Sec23p function was required in the Golgi complex, but only for transport of alpha f out of an early compartment. Together, these studies define at least three functionally distinct Golgi compartments in yeast. From cis to trans these compartments contain: (a) An alpha 1----6 mannosyltransferase; (b) an alpha 1----3 mannosyltransferase; and (c) the Kex2 endopeptidase. Surprisingly, we also found that a pool of Golgi-modified CPY (p2 CPY) located in a compartment distal to the alpha 1----3 mannosyltransferase does not require Sec18p function for final delivery to the vacuole. This compartment appears to be equivalent to the Kex2 compartment as we show that a novel vacuolar CPY-alpha f-invertase fusion protein undergoes efficient Kex2-dependent cleavage resulting in the secretion of invertase. We propose that this Kex2 compartment is the site in which vacuolar proteins are sorted from proteins destined to be secreted.
Saccharomyces cerevisiae strains carrying vps18 mutations are defective in the sorting and transport of vacuolar enzymes. The precursor forms of these proteins are missorted and secreted from the mutant cells. Most vps18 mutants are temperature sensitive for growth and are defective in vacuole biogenesis; no structure resembling a normal vacuole is seen. A plasmid complementing the temperature-sensitive growth defect of strains carrying the vps18-4 allele was isolated from a centromere-based yeast genomic library. Integrative mapping experiments indicated that the 26-kb insert in this plasmid was derived from the VPS18 locus. A 4-kb minimal complementing fragment contains a single long open reading frame predicted to encode a 918-amino-acid hydrophilic protein. Comparison of the VPS18 sequence with the PEP3 sequence reported in the accompanying paper (R. A. Preston, H. F. Manolson, K. Becherer, E. Weidenhammer, D. Kirkpatrick, R. Wright, and E. W. Jones, Mol. Cell. Biol. 11:5801-5812, 1991) shows that the two genes are identical. Disruption of the VPS18/PEP3 gene (vps18 delta 1::TRP1) is not lethal but results in the same vacuolar protein sorting and growth defects exhibited by the original temperature-sensitive vps18 alleles. In addition, vps18 delta 1::TRP1 MAT alpha strains exhibit a defect in the Kex2p-dependent processing of the secreted pheromone alpha-factor. This finding suggests that vps18 mutations alter the function of a late Golgi compartment which contains Kex2p and in which vacuolar proteins are thought to be sorted from proteins destined for the cell surface. The Vps18p sequence contains a cysteine-rich, zinc finger-like motif at the COOH terminus. A mutant in which the first cysteine of this motif was changed to serine results in a temperature-conditional carboxypeptidase Y sorting defect shortly after a shift to nonpermissive conditions. We identified a similar cysteine-rich motif near the COOH terminus of another Vps protein, the Vps11/Pep5/End1 protein. Preston et al. (Mol. Cell. Biol. 11:5801-5812, 1991) present evidence that the Vps18/Pep3 protein colocalizes with the Vps11/Pep5 protein to the cytosolic face of the vacuolar membrane. Together with the similar phenotypes exhibited by both vps11 and vps18 mutants, this finding suggests that they may function at a common step during vacuolar protein sorting and that the integrity of their zinc finger motifs may be required for this function.
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Intercostal tubes are inserted to treat several intrathoracic calamities. As these conditions may present to any hospital specialty, every doctor should be capable of placing a drain successfully. Equal importance must be attached to the subsequent care of the drain. This report outlines the correct procedure for managing intercostal drains and describes the complications that may occur.
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Mechanical circulatory support devices are currently being developed. The indications for their use are presently following acute myocardial infarction; in post cardiac-surgical cardiogenic shock; and as a mechanical 'bridge' to cardiac transplantation. Devices are being developed for permanent implantation in patients with end-stage left ventricular failure who are unacceptable for or denied transplantation. Intensive care nurses are required to care for patients who receive such mechanical support. These patients need intensive physical care with extensive nursing intervention and psychological support. The following case study describes the care of a patient who received an implantable left ventricular assist device (LVAD). The study illustrates the nursing care required in the management of such patients.
Implantable left ventricular assist systems are being developed for long term clinical use. Prototype devices are currently used as extended mechanical bridges to cardiac transplantation. The Thermo Cardiosystems Inc. (TCI) pneumatic pusher plate left ventricular assist device (LVAD) features textured blood contacting surfaces to encourage the formation of an adherent fibrin-cellular coagulum. This serves as the foundation for the development of a neo-intimal lining. The TCI LVAD was implanted in 6 male patients (age range 22-53 years) between 1986 and 1988. The duration of implantation ranged from 1-41 days. No clinical thromboembolic events or pump-related thromboembolism occurred and none was evident at necropsy. The six device linings have been fully evaluated. Explanted devices were free of thrombus and calcification. Lining samples for light and electron microscopy were collected from areas of the diaphragm identical for flex and blood shear conditions and from high and low shear areas on the static housing. Islands of collagenous tissue were deposited on the static housing amongst compact fibrin. By day 13, cells populated the surface of the developing neo-intima overlying the diaphragm. By 41 days, the surface cell density increased and the cells became spindle shaped and relatively orientated in the high shear/flex area. Immunohistochemical techniques suggest that these cells are of mesenchymal origin. Textured blood contacting surfaces appear satisfactory in the preliminary clinical use of this device.
A TCI1 rough surface left ventricular assist device (LVAD) was implanted in a 47-year-old man who had sustained a recent massive myocardial infarction complicated by ventricular failure which remained unresponsive to intra-aortic balloon pump therapy and which was further complicated by irreversible ventricular fibrillation. Following implantation of the device and while awaiting a suitable donor organ for transplantation, further extension of the previous infarct resulted in left ventricular rupture and massive haemorrhage which led to his death. We report the successful use of the device in providing haemodynamic support, but caution against inordinate delay in bridging to transplantation patients who are at risk of extension of infarction.
Toward a detailed understanding of protein sorting in the late secretory pathway, we have reconstituted intercompartmental transfer and proteolytic maturation of a yeast vacuolar protease, carboxypeptidase Y (CPY). This in vitro reconstitution uses permeabilized yeast spheroplasts that are first radiolabeled in vivo under conditions that kinetically trap ER and Golgi apparatus-modified precursor forms of CPY (p1 and p2, respectively). After incubation at 25 degrees C, up to 45% of the p2CPY that is retained in the perforated cells can be proteolytically converted to mature CPY (mCPY). This maturation is specific for p2CPY, requires exogenously added ATP, an ATP regeneration system, and is stimulated by cytosolic protein extracts. The p2CPY processing shows a 5-min lag period and is then linear for 15-60 min, with a sharp temperature optimum of 25-30 degrees C. After hypotonic extraction, the compartments that contain p2 and mCPY show different osmotic stability characteristics as p2 and mCPY can be separated with centrifugation into a pellet and supernatant, respectively. Like CPY maturation in vivo, the observed in vitro reaction is dependent on the PEP4 gene product, proteinase A, which is the principle processing enzyme. After incubation with ATP and cytosol, mCPY was recovered in a vacuole-enriched fraction from perforated spheroplasts using Ficoll step-gradient centrifugation. The p2CPY precursor was not recovered in this fraction indicating that intercompartmental transport to the vacuole takes place. In addition, intracompartmental processing of p2CPY with autoactivated, prevacuolar zymogen pools of proteinase A cannot account for this reconstitution. Stimulation of in vitro processing with energy and cytosol took place efficiently when the expression of PEP4, under control of the GAL1 promoter, was induced then completely repressed before radiolabeling spheroplasts. Finally, reconstitution of p2CPY maturation was not possible with vps mutant perforated cells suggesting that VPS gene product function is necessary for intercompartmental transport to the vacuole in vitro.
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Preoperative nutritional assessment was carried out on 39 consecutive patients with bronchial carcinoma who underwent thoracotomy. For 18 patients the body mass index and triceps and subscapular skinfold thickness fell below the 25th centile. In 23 patients the creatinine height index was less than 80% of the predicted value. The mean (SEM) serum albumin concentration was 40.3 (0.57) g/l (reference range 35-50 g/l) and mean (SEM) serum transferrin 1.77 (0.1) g/l (reference range 2.0-3.0 g/l). Although only three patients were hypoalbuminaemic, transferrin concentrations were depressed in 26 patients. There was a significant fall in the serum concentrations of both prealbumin and transferrin in the first postoperative week. Nutritional insufficiency was particularly severe in the four patients who developed an early bronchopleural fistula. It is concluded that protein-energy malnutrition is common in patients with operable bronchial carcinoma and that routine postoperative feeding does not prevent further depletion of circulating proteins. A larger prospective study is needed to examine the relation between preoperative nutritional state and outcome.