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T R Graham

Publications and source records attributed to T R Graham.

At least 19 recordsLinked to original sources
PubMed1995

Sorting of yeast alpha 1,3 mannosyltransferase is mediated by a lumenal domain interaction, and a transmembrane domain signal that can confer clathrin-dependent Golgi localization to a secreted protein.

alpha 1,3 mannosyltransferase (Mnn1p) is a type II integral membrane protein that is localized to the yeast Golgi complex. We have examined the signals within Mnn1p that mediate Golgi localization by expression of fusion proteins comprised of Mnn1p and the secreted protein invertase. The N-terminal transmembrane domain (TMD) of Mnn1p is sufficient to localize invertase to the Golgi complex by a mechanism that is not saturable by approximately 15-20 fold overexpression. Furthermore, the TMD-mediated localization mechanism is clathrin dependent, as an invertase fusion protein bearing only the Mnn1p TMD is mislocalized to the plasma membrane of a clathrin heavy chain mutant. The Mnn1-invertase fusion proteins are not retained in the Golgi complex as efficiently as Mnn1p, suggesting that other signals may be present in the wild-type protein. Indeed, the Mnn1p lumenal domain (Mnn1-s) is also localized to the Golgi complex when expressed as a functional, soluble protein by exchanging its TMD for a cleavable signal sequence. In contrast to the Mnn1-invertase fusion proteins, overexpression of Mnn1-s saturates its retention mechanism, and results in the partial secretion of this protein. These data indicate that Mnn1p has separable Golgi localization signals within both its transmembrane and lumenal domains.

Amino Acid Sequence↗
PubMed1994

Left ventricular rupture associated with mitral valve replacement.

Rupture of the left ventricle during the immediate postoperative period is a serious, but uncommon complication of mitral valve replacement. This review article outlines the pathological findings, possible causative mechanisms and current management of this cardiac surgical catastrophe.

Aged↗
PubMed1994

Signal-mediated retrieval of a membrane protein from the Golgi to the ER in yeast.

The Saccharomyces cerevisiae Wbp1 protein is an endoplasmic reticulum (ER), type I transmembrane protein which contains a cytoplasmic dilysine (KKXX) motif. This motif has previously been shown to direct Golgi-to-ER retrieval of type I membrane proteins in mammalian cells (Jackson, M. R., T. Nilsson, and P. A. Peterson. 1993. J. Cell Biol. 121: 317-333). To analyze the role of this motif in yeast, we constructed a SUC2-WBP1 chimera consisting of the coding sequence for the normally secreted glycoprotein invertase fused to the coding sequence of the COOH terminus (including the transmembrane domain and 16-amino acid cytoplasmic tail) of Wbplp. Carbohydrate analysis of the invertase-Wbp1 fusion protein using mannose linkage-specific antiserum demonstrated that the fusion protein was efficiently modified by the early Golgi initial alpha 1,6 mannosyltransferase (Och1p). Subcellular fractionation revealed that > 90% of the alpha 1,6 mannose-modified fusion protein colocalized with the ER (Wbp1p) and not with the Golgi Och1p-containing compartment or other membrane fractions. Amino acid changes within the dily sine motif (KK-->QK, KQ, or QQ) did not change the kinetics of initial alpha 1,6 mannose modification of the fusion protein but did dramatically increase the rate of modification by more distal Golgi (elongating alpha 1,6 and alpha 1,3) mannosyltransferases. These mutant fusion proteins were then delivered directly from a late Golgi compartment to the vacuole, where they were proteolytically cleaved in a PEP4-dependent manner. While amino acids surrounding the dilysine motif played only a minor role in retention ability, mutations that altered the position of the lysines relative to the COOH terminus of the fusion protein also yielded a dramatic defect in ER retention. Collectively, our results indicate that the KKXX motif does not simply retain proteins in the ER but rather directs their rapid retrieval from a novel, Och1p-containing early Golgi compartment. Similar to observations in mammalian cells, it is the presence of two lysine residues at the appropriate COOH-terminal position which represents the most important features of this sorting determinant.

Amino Acid Sequence↗
PubMed1994

Clathrin-dependent localization of alpha 1,3 mannosyltransferase to the Golgi complex of Saccharomyces cerevisiae.

Posttranslational modification of yeast glycoproteins with alpha 1,3-linked mannose is initiated within a Golgi compartment analogous to the medial Golgi cisternae of higher eukaryotes. We have characterized the synthesis, posttranslational modification, and localization of the yeast alpha 1,3 mannosyltransferase (Mnn1p) using antibodies prepared against a segment of this protein expressed in bacteria. Mnn1p is initially synthesized as a 98.5-kD, type II integral membrane glycoprotein that is modified with both N- and O-linked oligosaccharides. It is subject to a slow, incremental increase in molecular mass that is dependent upon protein transport to the Golgi complex. Self-modification of Mnn1p with alpha 1,3 mannose epitopes, primarily on O-linked oligosaccharides, is at least partly responsible for the incremental increase in molecular mass. Mnn1p is a resident protein of the Golgi complex and colocalizes with guanosine diphosphatase to at least two physically distinct Golgi compartments by sucrose gradient fractionation, one of which may be a late Golgi compartment that also contains the Kex2 endopeptidase. Surprisingly, we found that a significant fraction of Mnn1p is mislocalized to the plasma membrane in a clathrin heavy chain temperature sensitive mutant while guanosine diphosphatase remains intracellular. A mutant Mnn1p that lacks the NH2-terminal cytoplasmic tail is properly localized to the Golgi complex, indicating that clathrin does not mediate Mnnlp Golgi retention by a direct interaction with the Mnn1p cytoplasmic tail. These results indicate that clathrin plays a broader role in the localization of Golgi proteins than anticipated.

Amino Acid Sequence↗
PubMed1994

Hepatic portal venous flow in patients undergoing tricuspid valve surgery.

OBJECTIVE: To determine the changes of flow in the hepatic artery and portal vein of patients undergoing tricuspid valve repair together with mitral valve replacement. DESIGN: Non-randomised parallel group study. SETTING: Tertiary referral centre. PATIENTS: 18 patients with mitral valve disease with or without tricuspid regurgitation (age range 46-73; six men) and six patients with coronary artery disease and normal left ventricular function (women age range 39-78; four men). INTERVENTIONS: Mitral valve replacement with or without modified De Vega repair of the tricuspid valve or coronary artery bypass surgery. MAIN OUTCOME MEASURES: Flow in the hepatic artery and portal vein as measured by duplex Doppler flowmetry before and two to four weeks after operation. RESULTS: Preoperative hepatic artery flow was less in patients with mitral valve disease than in patients with coronary artery disease (162.7(13.1) ml.min-1 v 242.5(6.6) ml.min-1, p < 0.05). Portal vein perfusion was significantly reduced only in patients with associated tricuspid regurgitation compared with (844(83) ml.min-1 v 1422(64) ml.min-1 p < 0.05). Hepatic perfusion was unaltered after operation in patients undergoing coronary artery bypass surgery (p > 0.05). Flow in the hepatic artery and portal vein was improved only in patients undergoing mitral valve replacement with associated tricuspid valve repair (p < 0.05). CONCLUSION: Abnormalities of hepatic perfusion can be measured non-invasively in all patients with mitral valve disease but especially in those with associated tricuspid regurgitation needing valve repair. These abnormalities improved two to four weeks after mitral valve surgery and tricuspid valve repair, suggesting that measurement of portal flow might be a useful means of assessing the severity of tricuspid regurgitation.

Adult↗
PubMed1994

Efficacy of urgent thoracotomy for trauma in patients attended by a helicopter emergency medical service.

Over a 12-month period the Helicopter Emergency Medical Service underwent 1084 missions attending casualties in the London area. Sixteen patients required an emergency thoracotomy for resuscitation, nine of which were performed at the scene and seven in the emergency department. The median injury severity score of these patients was 29.9 (SIR 11.8) of which 11 had suffered blunt injuries. Medical attention at scene was administered 16.2 min (SIR 4.0) following the London ambulance service receiving the emergency call. Significantly longer time was spent attending patients who had a scene thoracotomy (35.1 min SIR 16.4) compared with those in whom the thoracotomy was performed in the casualty department. No patient in this series survived resuscitative thoracotomy. It is suggested that scene thoracotomy be abandoned and emphasis placed upon the rapid transport of patients to an emergency facility. This enables other resuscitative measures in addition to thoracotomy to be applied effectively and concentrated over a brief period by a multidisciplinary team.

Adolescent↗
PubMed1994

Atrial fibrillation following myocardial revascularization.

Atrial fibrillation following coronary artery surgery is common, especially in elderly patients but despite numerous studies its pathophysiological basis is still incompletely understood. It is usually benign and self-limiting, but may be associated with haemodynamic compromise, prolonged hospitalization and embolic stroke. No risk factors (apart from age and preoperative beta-blocker withdrawal) have been shown to be associated with its occurrence. Conventional treatment is usually effective but no prophylactic regime has been identified. Until such a regime is found the incidence of atrial fibrillation following myocardial revascularization may only be reduced by continuing treatment in patients on beta-blockers in the preoperative period and re-establishing this therapy after surgery.

Aged↗
PubMed1993

Intrahepatic leiomyosarcoma of the inferior vena cava with extension into the right atrium.

We present a case of leiomyosarcoma of the intrahepatic inferior vena cava extending into the right atrium, that has been successfully palliated by removal of the obstructing tumour under conditions of full cardiopulmonary bypass and circulatory arrest. Lesions of this kind have previously thought not to be amenable to surgery. Although resection was incomplete, successful palliation may be achieved facilitating this technique.

Heart Atria↗
PubMed1992

Coronary artery bypass grafting nine years after cardiac transplantation.

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.

Coronary Angiography↗
PubMed1992

Paraoesophageal hiatal hernias: when to operate.

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.

Adult↗