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Biomedical subjects

T Robertson

Publications and source records attributed to T Robertson.

At least 19 recordsLinked to original sources
PubMed1996

Initiation of impaired outer segment degradation in vivo using an antisense oligonucleotide.

This paper describes the first successful in vivo application of antisense DNA technology to induce the accumulation of photoreceptor outer segment derived debris in the retina. An antisense oligonucleotide (CatSC), which was previously demonstrated to be an effective tool to induce debris accumulation in vitro, was injected into the vitreous of pigmented and non-pigmented rats. The animals were euthanased 7 days after the injections. The number of inclusions significantly increased in the RPE layer of Long Evans and RCS-rdy + rats injected with 66 ug of CatSC to 96.2 +/- 13.6 (SD) (p < 0.0003) and 204.2 +/- 39.3 (SD) (p < 0.0001), respectively. The difference between the number of phagosome-like inclusions present in control saline, 6.6 ug of CatSC or 66 ug of sense oligonucleotide (S1) injected animals was not statistically significant. There were no abnormalities observed in the inner layers of the retina but the accumulation of phagosome-like inclusions was accompanied by disorganisation in the apices of outer segments. The large number of inclusions found in CatSC treated animals showed the characteristics of phagosomes containing stacks of undigested photoreceptor outer segment membranes which suggest that the lysosomal digestion process was halted or at least slowed down by the antisense oligonucleotide.

Animals↗
PubMed1995

Detection of mRNAs for urokinase-type plasminogen activator, its receptor, and type 1 inhibitor in giant cell tumors of bone with in situ hybridization.

Although giant cell tumor of bone (GCT) is generally considered to be an uncommon benign neoplasm, it can pursue an aggressive course with local recurrence and metastasis. Attempts to predict the biological behavior of GCT with histopathological parameters, however, have not been successful. The urokinase-type plasminogen activation system has been implicated in tumor invasion and metastasis and abnormalities of the components of this system have been found in several malignancies. In this study we postulated that the urokinase-type plasminogen activation system associated with bone destruction and local invasion is present in GCT. We therefore evaluated the mRNA levels for urokinase-type plasminogen activator (u-PA), urokinase-type plasminogen activator receptor (u-PAR), and plasminogen activator inhibitor type 1 (PAI-1) by using Northern blot analysis and in situ hybridization in four cases of GCT and spindle-shaped mononuclear cells at the 35th passage from a GCT. Our results showed that giant cell tumors of bone contained variable levels of u-PA, u-PAR, and PAI-1 mRNA, respectively, 2.3, 1.4, and 3.2 kb in size. In situ hybridization showed that u-PA, u-PAR, and PAI-1 mRNA were expressed in both the mononuclear cells and the osteoclast-like giant cells; the signal for u-PA mRNA in the spindle-shaped mononuclear cells was more intense than that in the osteoclast-like multinuclear giant cells. Some spherical mononuclear cells (macrophage-like cells) expressed high levels of PAI-1 mRNA in comparison with the spindle-shaped mononuclear cells. In addition, the 35th passaged spindle-shaped mononuclear cells were used to study the gene expression of u-PA during cell proliferation. The results showed that the level of u-PA mRNA increases after adding 10% fetal calf serum to quiescent cells. The induction was maximal at 16 hours and remained high during 48 hours of treatment. In conclusion, even though osteoclast-like cells are ultimately responsible for the bone resorption of GCT, the mononuclear neoplastic cells of GCT may also be involved in degradation of the extracellular matrix during invasive growth by facilitating the urokinase plasminogen activation system. In addition, our observation of upregulation of u-PA mRNA in spindle-shaped mononuclear cells after serum stimulation indicated that u-PA production may be linked to tumor growth.

Adult↗
PubMed1994

Dying in palliative care units and in hospital: a comparison of the quality of life of terminal cancer patients.

A comparison of the quality of life of terminal cancer patients in two palliative care units with that of those in a general hospital is reported here. Quality of life was considered as a multidimensional concept. It was assessed for the 182 patients by applying content analysis scales to transcripts of their responses to part of a standardized interview. A personal construct model of dying provided the specific hypotheses about differences in quality of life. Patients in specialized palliative care units were, as predicted, found to differ from those dying in hospital, showing less indirectly expressed anger but more positive feelings. They also reported more anxiety about death but less anxiety about isolation and general anxiety, and fewer influential and nonspecified shared relationships. Against prediction, the patients in the two specialized units were also found to differ from each other, those in the smaller unit showing more directly expressed anger and helplessness than those in the larger unit.

Attitude to Death↗
PubMed1994

Detection and possible functions of a cysteine protease involved in digestion of rod outer segments by retinal pigment epithelial cells.

PURPOSE: To investigate the presence and role of a recently cloned cysteine protease (cathepsin S) in the digestion of rod outer segments (ROS) by cultured retinal pigment epithelial (RPE) cells. METHODS: RPE cell cultures were established from eye bank donor eyes. Total RNA was extracted from freshly harvested cultures, and after reverse transcription, the cDNA was subjected to polymerase chain reaction (PCR). Cathepsin S (Cat S) mRNA translation was inhibited by antisense oligonucleotides, and the effect of inhibition on the accumulation of fluorescent debris was examined. The activity of cysteine and aspartic proteases in ROS-challenged RPE cell cultures was inhibited by leupeptin and pepstatin, respectively. The accumulation of autofluorescent debris within RPE cells was measured by a fluorophotometric flow cytometer. The presence of phagosomes in antisense DNA-inhibited and control cultures was demonstrated by electron microscopy. RESULTS: The expression of Cat S in RPE cells was demonstrated by RNA-PCR. Using antisense oligonucleotide-mediated-specific inhibition of Cat S, a significant ROS-derived increase in autofluorescence was detected within the RPE cells when they were compared with the unchallenged control cultures and cultures in the presence of ROS and sense oligonucleotides. Electron microscopy demonstrated the presence of a large number of phagosomes that enveloped structures similar to ROS. The accumulation of autofluorescent debris was also demonstrated in cysteine protease-inhibited, ROS-challenged RPE cultures, but it was not detected with aspartic protease inhibition. CONCLUSIONS: The expression of Cat S in RPE cells and the accumulation of an autofluorescent debris in cultures in which cysteine proteases or Cat S activity is inhibited suggest a key role for this enzyme, either in the ROS digestion process or in the activation of cathepsin D, the major lysosomal enzyme present in RPE cells.

Animals↗
PubMed1994

Gene expression of transforming growth factor-beta 1 and its type II receptor in giant cell tumors of bone. Possible involvement in osteoclast-like cell migration.

Giant cell tumor of bone (GCT) is a relatively rare skeletal neoplasm characterized by multinuclear giant cells (osteoclast-like cells) scattered in a mass of mononuclear cells. The currently favored hypothesis for the origin of cells within GCT is that the multinuclear giant cells are reactive osteoclasts, whereas the truly neoplastic cells are the major component of the mononuclear population. However, the pathological significance and the precise relationship of tumor cells and osteoclast-like cells in GCT have not been fully established. In this study, we evaluated two GCTs for the presence of transforming growth factor-beta 1 (TGF-beta 1) and TGF-beta type II receptor gene transcripts and attempted to establish a possible role for TGF-beta 1 in the interaction between tumor cells and osteoclast-like cells. By using in situ hybridization and Northern blot analysis, we have demonstrated that TGF-beta 1 mRNA transcript is consistently detected in both tumor mononuclear cells and osteoclast-like cells, whereas TGF-beta type II receptor gene transcript is only present in osteoclast-like cells. Moreover, isolated rat osteoclasts were tested for their ability to migrate in response to GCT-conditioned medium (GCTCM) in an in vitro chemotactic assay. Our results showed that GCTCM stimulates the migration of osteoclasts in a dose-dependent manner. Interestingly, only osteoclasts containing less than three nuclei can migrate through 12-mu pore filters. Addition of monoclonal antibody against TGF-beta significantly reduced but did not abolish the chemotactic activity of GCTCM. Moreover, TGF-beta type II receptor mRNA has been demonstrated in the normal rat osteoclasts and may be involved in the chemotactic action of TGF-beta 1. We concluded that TGF-beta 1, possibly in concert with other cytokines, is involved in the recruitment of osteoclast-like cells in GCT by acting in an autocrine or paracrine fashion.

Adult↗
PubMed1993

Baseline characteristics and therapeutic goals in the New Approaches to Coronary Intervention (NACI) registry.

BACKGROUND: The New Approaches to Coronary Intervention (NACI) voluntary registry was designed to study the use, safety, and efficacy of new percutaneous transluminal interventional devices including directional coronary atherectomy, the transluminal extraction catheter, the rotablator, the Palmaz-Schatz stent, the Gianturco-Roubin stent, the Advanced Interventional Systems (AIS) laser, and the spectranetics laser. METHODS: To date, more than 3800 consecutive patients treated for the first time with a new device at 41 centers have been entered into the registry. Complete detailed information about the patient, lesions, device characteristics, reasons for device selection, and procedural data, such as adjunctive use of conventional balloon angioplasty (PTCA), was available for the first 2835 patients. RESULTS: The registry shows that 88% of the 3233 attempts with a new device were intended as a definitive treatment of target lesions, frequently in combination with adjunctive PTCA. The remaining 12% of attempts with a new device were unplanned, prompted by unexpected complications, unsuccessful attempts, or suboptimal results with PTCA. Although there was some overlap in the indications for selecting a given interventional device, the variation from device to device was sufficiently large to caution users against any direct comparison of either safety or efficacy between devices without careful attention to the differences in baseline patient and lesion characteristics, treatment plans, and the circumstances of device use. CONCLUSION: This report provides the first comprehensive overview of how new interventional devices are currently being used in the treatment of coronary artery lesions at the 41 centers participating in the NACI registry.

Angina Pectoris↗
PubMed1992

Evidence for a viral aetiology of Jembrana disease in Bali cattle.

Jembrana disease is an acute infectious disease of Bali cattle (Bos javanicus) in Indonesia. High titres of the infectious agent are present in plasma during the febrile phase of the disease. The size of the agent determined by membrane filtration was between 50 and 100 nm, indicating it is a virus and not a rickettsia as previously proposed. Spherical virus-like particles of 75 to 130 nm diameter with a smooth membrane and frequently with an eccentric nucleoid were detected by electron microscopy in plasma from infected animals. The virus replicated in mononuclear cell cultures of peripheral blood origin but not in other cell cultures. The virus and the associated disease have characteristics consistent with viruses in the family Retroviridae.

Animals↗
PubMed1992

One-year results of the Thrombolysis in Myocardial Infarction investigation (TIMI) Phase II Trial.

BACKGROUND: The Thrombolysis in Myocardial Infarction (TIMI) Phase II Trial randomized 3,339 patients to either an invasive (INV, n = 1,681) or a conservative (CON, n = 1,658) strategy after intravenous recombinant tissue-type plasminogen activator (rt-PA) for acute myocardial infarction. METHODS AND RESULTS: The patients assigned to the INV strategy routinely underwent cardiac catheterization, and when anatomically appropriate, percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting 18-48 hours after infarction. CON patients had these procedures only in response to the occurrence of spontaneous or provoked ischemia. One-year follow-up data are available in 3,316 patients (99.3%). The primary trial end point, death and nonfatal reinfarction, occurred in 14.7% of INV patients and in 15.2% of CON patients (p = NS). When analyzed individually, there was no difference (p = NS) in death (INV, 6.9%; CON, 7.4%) or recurrent infarction (INV, 9.4%; CON, 9.8%) between the two groups. Anginal status at 1 year was also similar. Cardiac catheterization and PTCA were performed more often in INV (98.0% and 61.2%, respectively) compared with CON (45.2% and 20.5%, respectively) patients. At 1 year, the cumulative number of patients who underwent coronary bypass surgery (INV, 17.5%; CON, 17.3%) was similar in the two groups. CONCLUSIONS: The INV and CON strategies resulted in similar favorable outcomes at 1 year of follow-up. In particular, the rates of mortality and reinfarction were not different and were impressively low in both groups. One possible advantage of the INV strategy was detected in subgroup analyses. In patients with a history of myocardial infarction, the data are suggestive that 1-year mortality was lower in INV patients (10.3%) than in CON patients (17.0%) (p = 0.03).

Angioplasty, Balloon, Coronary↗
PubMed1991

The NACI Registry: an instrument for the evaluation of new approaches to coronary intervention. The NACI Investigators.

The New Approaches to Coronary Intervention (NACI) Registry was developed to collect in-depth data about patients whose coronary artery lesions are being treated with new interventional techniques such as atherectomy, stents, and laser devices. The NACI Registry database distinguishes among several possible "modes" for device use, such as preparatory, planned definitive, and bailout use. Common definitions are used for data collection across all devices, and device-specific forms are used to record procedural details. NACI's unique modular form design facilitates thorough data collection, even for the most complex treatment scenarios. The database structure allows for data analysis at the patient, procedure, lesion, and device levels, as required to perform in-depth analyses of the immediate and long-term success of new devices. Once adequate knowledge of basic device performance has been collected, the Registry structure can also allow expeditious planning and performance of randomized trials comparing a new device to conventional PTCA.

Angioplasty, Balloon, Coronary↗
PubMed1990

Analysis of possible triggers of acute myocardial infarction (the MILIS study).

Recent documentation of a circadian variation in acute myocardial infarction (AMI) suggests that AMI is not a random event, but may frequently result from identifiable triggering activities. The possible triggers reported by 849 patients enrolled in the Multicenter Investigation of Limitation of Infarct Size were analyzed. Possible triggers were identified by 48.5% of the population; the most common were emotional upset (18.4%) and moderate physical activity (14.1%). Multiple possible triggers were reported by 13% of the population. Younger patients, men and those without diabetes mellitus were more likely to report a possible trigger than were older patients, women and those with diabetes. The likelihood of reporting a trigger was not affected by infarct size. This study suggests that potentially identifiable triggers may play an important role in AMI. Because potential triggering activities are common in persons with coronary artery disease, yet infrequently result in AMI, further studies are needed to identify (1) the circumstances in which a potential trigger may cause an event, (2) the specific nature of potential triggering activites, (3) the frequency of such activities in individuals who do not develop AMI and (4) the presence or absence of identifiable triggers in various subgroups of patients with infarction.

Aged↗
PubMed1989

Pericarditis in acute myocardial infarction: characterization and clinical significance.

To determine the significance of pericarditis following acute myocardial infarction, the hospital course and 12-month follow-up were analyzed in 703 patients enrolled in the Multicenter Investigation of the Limitation of Infarct Size (MILIS). Pericarditis, defined by the detection of a pericardial rub, occurred in 20% of the patients (n = 141) and was more likely to follow Q wave than non-Q wave infarction (25% vs 9%, p less than 0.001). Patients with pericarditis experienced more serious myocardial damage compared to those without pericarditis, as evidenced by a larger infarct size (25 +/- 1 vs 17 +/- 1 MB-CK gm-Eq/m2, p less than 0.001), a lower admission left ventricular ejection fraction (42 +/- 1% vs 48 +/- 1%, p less than 0.001), and a higher incidence of congestive heart failure (47% vs 26%, p less than 0.001) and atrial tachyarrhythmias (16% vs 10%, p less than 0.05). When patients were classified by the presence of Q or non-Q wave infarction, these differences persisted although statistical significance was not always achieved due to smaller sample size. Mortality at 12-month follow-up for patients with pericarditis was 18% compared with 12% for patients without pericarditis (p = 0.055). This mortality difference could be accounted for in part by the lower ventricular ejection fraction in patients with pericarditis (p = 0.20 after adjustment).

Electrocardiography↗
PubMed1989

The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group.

Patients with diabetes mellitus experience a more adverse outcome after acute myocardial infarction compared with nondiabetic patients, although the mechanisms responsible for these findings are not clear. From the Multicenter Investigation of the Limitation of Infarct Size (MILIS) study, the course of acute infarction in 85 diabetic patients was compared with that in 415 nondiabetic patients, all of whom had serial assessments of left ventricular function. The diabetic patients experienced a more complicated in-hospital and postdischarge course than did the nondiabetic patients, including a higher incidence of postinfarction angina, infarct extension, heart failure and death, despite the development of a smaller infarct size and similar levels of left ventricular ejection fraction. Although diabetic patients had a worse profile of cardiovascular risk factors at the time of the index infarction, the increased incidence of adverse outcomes among them persisted despite adjustment for these baseline imbalances. Diabetic women had a poor baseline risk profile compared with the other groups categorized by gender and diabetic status, and experienced an almost twofold increase in cardiac mortality despite development of the smallest infarct size during the index event. The duration of diabetes and the use of insulin at the time of the index infarction were associated with a better in-hospital mortality rate, but the duration of diabetes did not exert a major influence on the outcome of the diabetic patients. The factors responsible for the increased incidence of adverse outcomes among diabetic patients may be related to an acceleration of the atherosclerotic process, diastolic left ventricular dysfunction associated with diabetic cardiomyopathy or other unidentified unfavorable processes.

Cardiovascular Diseases↗
PubMed1989

Research collaboration.

The complexity and cost of cardiovascular medical care dictate research to deliver high quality and cost-conscious cardiovascular care. This goal is aided by modeling medical decision making. To be useful, the modeling must be based on real data so that the results can serve as a guide to actual practice. It is suggested that a registry of randomized clinical trials and larger data bases in cardiovascular disease and health care delivery be established. The registry would be a resource for those desiring to model decision making. The registry would contain key words allowing retrieval by modelers accessing the registry and would contain contact information for consideration of possible collaborative work. The initiation of such a registry should contain plans for its evaluation to determine whether the registry itself is a cost-effective tool to encourage the needed research.

Clinical Trials as Topic↗
PubMed1989

Long-term follow-up of coronary angioplasty: the 1977-1981 National Heart, Lung, and Blood Institute registry.

Between September 1977 and September 1981, 1587 consecutive patients underwent a first coronary angioplasty (PTCA) at 16 clinical centres. After excluding patients with prior coronary bypass surgery (CABG) and left main or minimal vessel disease, 1390 were available for in-hospital and long-term follow-up. Mean duration of follow-up was 5.9 years (range 0-9.0 years). PTCA was successful (all attempted lesions reduced greater than or equal to 20%) in 882 patients (63.4%) and, overall, 624 patients (44.9%) had complete (COREV) and 766 (55.1%) incomplete (INCOREV) revascularization or a failed PtCA. In-hospital events included death in 0.7%, myocardial infarction (MI) in 5.0% and CABG in 24.0% of patients. Patients with COREV had significantly lower rates of these events than the INCOREV group. At 6 years, mortality in all registry patients was 6.5% and MI rate 15.0%; CABG was performed after the initial hospitalization in 15.5% of patients and repeat PTCA in 19.1%. All events, except repeated PTCA, were less frequent in the COREV than the INCOREV group. Among patients with a successful first PTCA, cumulative 6-year mortality was 5.8% and incidence of MI 10.8%; 16.9% underwent CABG and 24.7% repeat PTCA during follow-up. CABG was slightly more frequent in INCOREV than COREV patients with successful PTCA, but all other events were similar in the two groups, suggesting that INCOREV 'by intent' has a good prognosis. In patients with INCOREV, mortality and incidence of MI were higher during follow-up for patients with multivessel rather than single vessel disease. However, the incidence of CABG and repeat PTCA was similar in the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Morning increase in onset of ischemic stroke.

The time of onset of ischemic stroke was determined for 1,167 of 1,273 patients during the collection of data by four academic hospital centers between June 30, 1983, and June 30, 1986. More strokes occurred in awake patients from 10:00 AM to noon than during any other 2-hour interval. The incidence of stroke onset declined steadily during the remainder of the day and early evening. The onset of stroke is least likely to occur in the late evening, before midnight.

Acute Disease↗
PubMed1987

The neurotoxicity of high-dose cytosine arabinoside is age-related.

Fifteen patients with acute myeloid leukaemia were given a total of 17 courses of high-dose cytosine arabinoside (Ara-C). The median age of the patients was 37 years. Four patients developed severe irreversible neurotoxicity, three developed mild to moderate, reversible neurotoxicity, whereas eight patients had no toxicity. Of five patients over the age of 55 years given high dose Ara-C, four developed severe, irreversible neurotoxicity, but there were no severe episodes in nine patients aged 55 years or less. (P less than 0.01). At a dose of 3 g/m2 given intravenously every 12 hours for 3 days, three cases of severe irreversible neurotoxicity were noted in elderly patients. Neurotoxicity at this total dose has previously been considered unusual. Administration of high dose Ara-C at total doses of 18 g/m2 and over carries a risk of severe irreversible cerebellar toxicity that increases with age.

Activities of Daily Living↗