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D Johnstone

Publications and source records attributed to D Johnstone.

At least 19 recordsLinked to original sources
PubMed2005

Assessing proliferation, cell-cycle arrest and apoptotic end points in human buccal punch biopsies for use as pharmacodynamic biomarkers in drug development.

Easily accessible normal tissues expressing the same molecular site(s) of drug action as malignant tissue offer an enhanced potential for early proof of anticancer drug mechanism and estimation of the biologically effective dose. Studies were undertaken in healthy male volunteers to assess the tolerability of single and multiple (four in 24 h) 3 mm punch biopsies of the buccal mucosa, and to determine the feasibility of detecting and quantifying a range of proliferation, cell-cycle arrest and apoptosis markers by immunohistochemistry (IHC) for use as potential pharmacodynamic (PD) end points. The biopsy procedure was well tolerated with 100% of volunteers stating that they would undergo single (n = 10) and multiple (n = 12) biopsies again. Total retinoblastoma protein (pRb), phosphorylated pRb (phospho-pRb), total p27, phosphorylated p27 (phospho-p27), phosphorylated-histone H3 (phospho-HH3), p21, p53, Cyclin A, Cyclin E, Ki67 all produced good signal detection, but M30, cleaved caspase 3 and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling did not. Total pRb, phospho-pRb, total p27 and phospho-p27 were quantified further in a multiple biopsy study to allow components of variability to be addressed to inform future sizing decisions on intervention studies. Neither site of biopsy within the oral cavity, nor the nominal time of biopsy had any significant impact on any of the four markers expression levels. Inter- and intrasubject coefficients of variation (CVs) that could be used to size future intervention studies for pRb, phospho-pRb, total p27 and phospho-p27 were 14, 19, 18 and 16%; and 18, 29, 25 and 19%, respectively. In conclusion, quantitation of such markers in 3 mm buccal punch biopsies would be suitable to explore as PD end points within intervention studies of drugs acting on these pathways.

Adult↗
PubMed2003

Radiotherapy patterns of care study in lung carcinoma.

PURPOSE: For the first time, a lung Patterns of Care Study was conducted to determine the national patterns of radiation (RT) practice in patients treated for nonmetastatic lung cancer in 1998 to 1999. MATERIALS AND METHODS: A national survey of randomly selected RT institutions in the United States was conducted using two-stage cluster sampling, stratified by practice type. Patients with nonmetastatic lung cancer (Karnofsky performance score [KPS] > or = 60), who received RT as definitive or adjuvant therapy, were randomly selected. To determine national estimates, sample size was weighted by the relative number of institutions per strata and the number of patient records reviewed per the number of patients eligible. Accordingly, 42,335 patient records from 58 institutions were reviewed by trained research associates. The unweighted sample size (or number of patients) was 541. RESULTS: The histologies were small-cell lung cancer (SCLC) in 14.5% of patients versus non-small-cell lung cancer (NSCLC) in 85.5% of patients. The median age was 67 years (range, 29 to 92 years); 61% of patients were male, and 38% were current smokers. Bone scans and brain imaging were not obtained in 34% and 52% of clinical stage (CS) III NSCLC patients, respectively. Regarding treatment strategies, for SCLC and CS III NSCLC, chemotherapy plus RT was used significantly more than RT alone (P <.05); in CS I NSCLC, RT alone was the primary treatment (P <.05). Overall, 58% of patients received systemic therapy. On multivariate analysis, factors correlating with increased use of chemotherapy included younger age, histology (SCLC > NSCLC), increasing CS, increasing KPS, and lack of comorbidities. Only 3% of all patients were treated on prospective clinical trials. CONCLUSION: This study establishes the general patterns of care for lung carcinoma in RT facilities within the United States. As supported by clinical trials, patients with limited-stage SCLC and CS III NSCLC received chemotherapy plus RT more than they received RT alone. Further improvements in staging, smoking cessation, and increased accrual to clinical trials must be encouraged.

Adult↗
PubMed2002

Gastric colonisation, intestinal permeability and septic morbidity in acute pancreatitis.

INTRODUCTION: Bacterial translocation (BT) may represent an important cause of septic morbidity in patients with acute pancreatitis. We have previously demonstrated an association between BT, septic morbidity and colonisation of the proximal GI tract. Alterations in intestinal permeability (IP) may also predispose to BT. The aim of this study was to assess the extent of gastric colonisation, measure IP in patients with acute pancreatitis and relate these to both disease severity and septic complications. METHODS: Gastric colonisation was determined by culturing a sample of nasogastric aspirate, and IP was measured using a dual sugar probe technique (lactulose/rhamnose test). Disease severity was assessed according to the modified Glasgow (Imrie) criteria. All septic complications were recorded prospectively. RESULTS: A total of 59 patients were studied (M:F ratio 32:27, median age 66 years, range 18-89), 24 (31%) of whom had severe disease. A nasogastric aspirate was obtained in 56 patients. There was a significantly higher incidence of colonisation with potentially pathogenic enteric bacteria in patients with severe disease compared to those with mild disease (57 vs. 6%, p < 0.001). Septic morbidity occurred in 29% of severe patients and 11% mild patients (p = 0.17). 33% of patients colonised with enteric organisms developed sepsis, compared to 16% with no enteric bacteria in the NG aspirate (p = 0.34). Enteric bacteria caused 77% of the septic complications. Intestinal permeability was neither associated with disease severity nor was it predictive of septic morbidity. CONCLUSIONS: There is significantly higher incidence of gastric colonisation with enteric bacteria in patients with severe acute pancreatitis, but no difference in IP. Enteric bacteria were implicated in the majority of septic complications. These findings support the gut origin of sepsis hypothesis in acute pancreatitis.

Acute Disease↗
PubMed2002

An investigation into the sensitivities of translocating bacteria to a prophylactic antibiotic regimen.

INTRODUCTION: It is well established that bacterial translocation is associated with a significant increase in septic morbidity. The purpose of this study was to determine the antibiotic sensitivities of translocating bacteria on the basis that this information may influence antibiotic prophylaxis in surgical patients. METHODS: Routine microbiological techniques were used to assess the antibiotic sensitivities of those bacteria cultured from a mesenteric lymph node harvested at laparotomy in a large series of patients. RESULTS: Culture of the mesenteric lymph nodes yielded growth in 51 out of a total of 447 patients studied (11.4%). The isolates from 40 patients, a total of 60 organisms, were available for sensitivity testing. The most common species grown was Escherichia coli (48% of isolates). Thirty-three patients (83%) grew organisms sensitive to the antibiotic prophylaxis used, but there was no significant difference in the incidence of postoperative septic complications between these patients and those in whom resistant bacteria were grown (39% versus 29%, P = 0.64 Fisher's Exact test mid P). CONCLUSIONS: The majority of translocating bacteria are sensitive to the prophylactic antibiotics commonly used in patients undergoing laparotomy. However, the occurrence of postoperative septic morbidity is independent of this variable.

Aged↗
PubMed2001

Reduction of cardiovascular risk by regression of electrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril.

BACKGROUND: Electrocardiographic markers of left ventricular hypertrophy (LVH) predict poor prognosis. We determined whether the ACE inhibitor ramipril prevents the development and causes regression of ECG-LVH and whether these changes are associated with improved prognosis independent of blood pressure reduction. METHODS AND RESULTS: In the Heart Outcomes Prevention Evaluation (HOPE) study, patients at high risk were randomly assigned to ramipril or placebo and followed for 4.5years. ECGs were recorded at baseline and at study end. We compared prevention/regression and development/persistence of ECG-LVH in the two groups and related these changes to outcomes. At baseline, 676 patients had LVH (321 in the ramipril group and 355 in the placebo group) and 7605 patients did not have LVH (3814 in the ramipril group and 3791 in the placebo group). By study end, 336 patients in the ramipril group (8.1%) compared with 406 in the placebo group (9.8%) had development/persistence of LVH; in contrast, 3799 patients in the ramipril group (91.9%) compared with 3740 in the placebo group (90.2%) had regression/prevention of LVH (P=0.007). The effect of ramipril on LVH was independent of blood pressure changes. Patients who had regression/prevention of LVH had a lower risk of the predefined primary outcome (cardiovascular death, myocardial infarction, or stroke) compared with those who had development/persistence of LVH (12.3% versus 15.8%, P=0.006) and of congestive heart failure (9.3% versus 15.4%, P<0.0001). CONCLUSIONS: The ACE inhibitor ramipril decreases the development and causes regression of ECG-LVH independent of blood pressure reduction, and these changes are associated with reduced risk of death, myocardial infarction, stroke, and congestive heart failure.

Aged↗
PubMed2000

The Galactic Worm GW 123.4-1.5: A Mushroom-shaped H i Cloud.

The Dominion Radio Astrophysical Observatory's Synthesis Telescope provides the highest resolution data (1&arcmin; and 0.82 km s-1) to date of an H i worm candidate. Observed as part of the Canadian Galactic Plane Survey, mushroom-shaped GW 123.4-1.5 extends only a few hundred parsecs, contains approximately 105 M middle dot in circle of neutral hydrogen, and appears unrelated to a conventional shell or chimney structure. Our preliminary Zeus two-dimensional models use a single off-plane explosion with a modest ( approximately 1051 ergs) energy input. These generic simulations generate, interior to an expanding outer blast wave, a buoyant cloud whose structure resembles the morphology of the observed feature. Unlike typical model superbubbles, the stem can be narrow because its width is not governed by the pressure behind the blast wave or the disk scale height. Using this type of approach, it should be possible to more accurately model the thin stem and other details of GW 123.4-1.5 in the future.

Journal Article↗
PubMed1999

Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity.

AIMS: To investigate the "gut origin of sepsis" hypothesis. METHODS: Prospective controlled study of 279 surgical patients in which cultures of nasogastric aspirates were compared with those obtained from mesenteric lymph nodes taken at laparotomy and the organisms cultured from subsequent septic complications. Bacterial translocation was confirmed if positive cultures were obtained from mesenteric lymph nodes. Postoperative sepsis was defined as any positive culture in the postoperative period. Bacterial species obtained in gastric microflora, mesenteric lymph nodes, and postoperative septic complications were compared. RESULTS: Only 85/279 patients (31%) had a sterile nasogastric aspirate; the most frequently identified organism was Candida spp. (54%) and the most common enteric organism cultured was E coli (20%). Multiple organisms were isolated in 39% and occurred more frequently in patients aged over 70 years, those undergoing non-elective surgery, and in those requiring proximal gastrointestinal surgery. Postoperative sepsis was more common in these patients. Bacterial translocation occurred in 21% and was significantly more frequent in those with multiple organisms in their nasogastric aspirates. E coli was the commonest organism isolated from the lymph node specimens (48%) and septic foci (53%). Fungal translocation did not occur. An identical genus was identified in the nasogastric aspirate and the septic focus in 30% of patients, in the nasogastric aspirate and the lymph node in 31%, and in the lymph node and a postoperative septic focus in 45%. CONCLUSIONS: Proximal gut colonisation is associated with both increased bacterial translocation and septic morbidity. The commonality of organisms identified supports the gut origin of sepsis hypothesis.

Adolescent↗
PubMed1998

Microbiology of bacterial translocation in humans.

BACKGROUND: Gut translocation of bacteria has been shown in both animal and human studies. Evidence from animal studies that links bacteria translocation to the development of postoperative sepsis and multiple organ failure has yet to be confirmed in humans. AIMS: To examine the spectrum of bacteria involved in translocation in surgical patients undergoing laparotomy and to determine the relation between nodal migration of bacteria and the development of postoperative septic complications. METHODS: Mesenteric lymph nodes (MLN), serosal scrapings, and peripheral blood from 448 surgical patients undergoing laparotomy were analysed using standard microbiological techniques. RESULTS: Bacterial translocation was identified in 69 patients (15.4%). The most common organism identified was Escherichia coli (54%). Both enteric bacteria, typical of indigenous intestinal flora, and non-enteric bacteria were isolated. Postoperative septic complications developed in 104 patients (23%). Enteric organisms were responsible in 74% of patients. Forty one per cent of patients who had evidence of bacterial translocation developed sepsis compared with 14% in whom no organisms were cultured (p < 0.001). Septic morbidity was more frequent when a greater diversity of bacteria resided within the MLN, but this was not statistically significant. CONCLUSION: Bacterial translocation is associated with a significant increase in the development of postoperative sepsis in surgical patients. The organisms responsible for septic morbidity are similar in spectrum to those observed in the mesenteric lymph nodes. These data strongly support the gut origin hypothesis of sepsis in humans.

Adolescent↗
PubMed1998

Outcomes of coronary artery bypass surgery in elderly people.

OBJECTIVES: To document the impact of coronary artery bypass (CABG) surgery on quality of life in elderly people three months after surgery; to compare quality of life measures; to examine predictors of poor quality of life; and to assess the predictive validity of global clinical rating scales. STUDY DESIGN: Prospective cohort study with postoperative, three-month and one-year follow-up. SETTING: A 700-bed tertiary care teaching hospital in Halifax, Nova Scotia. PATIENTS: One hundred of 200 consecutive patients, 75 years and older, undergoing CABG. MEASURES: Demographic information, clinical data and global clinical ratings were collected at baseline to assess risk for adverse outcome (death, stroke, functional impairment) at each follow-up. Quality of life three months post-CABG was documented using the RAND 36-Item Health Survey and the Seattle Angina Questionnaire. MAIN RESULTS: Perioperative deaths occurred in four patients, disabling strokes in six and postoperative complications in seven. Three additional deaths occurred by the three-month follow-up and nine more by one year. On average, important improvements in quality of life were observed at three months' follow-up, using both assessments of quality of life. CONCLUSIONS: Many elderly patients do well after CABG surgery, but a higher proportion than is seen in younger patients have complications leading to death and disability. A global clinical measure by the attending cardiologist at baseline did not identify patients at a higher risk. Follow-up studies are needed to assess long term outcomes of older patients at higher risk of death or a poor quality of life after CABG surgery.

Aged↗
PubMed1997

Effects of an inhibitor of cathepsin L on bone resorption in thyroparathyroidectomized and ovariectomized rats.

The process of bone resorption by osteoclasts involves the dissolution of mineral salts and enzymatic degradation of the mainly collagenous extracellular matrix. Cysteine proteinases, which can efficiently degrade collagen at acidic pH, have been suggested to play an important role in the bone resorptive process. The cysteine proteinase cathepsin L is secreted by osteoclasts, and inhibitors of this enzyme can prevent bone resorption in vitro. The activity of acetyl-leu-leu-norleucinol (ALLN), a selective inhibitor of cathepsin L, was investigated in two models of bone resorption in vivo. In the first study, the ability of ALLN to inhibit bone resorption was investigated in Ro-13-6298 (arotinoid)-treated thyroparathyroidectomized (TPTX) rats. ALLN [100 mg/kg, intraperitoneally (i.p.)] inhibited hypercalcemia by 62.8% acutely (p < 0.001), compared to 94.9% (p < 0.001) inhibition by salmon calcitonin (sCT) (10 IU/kg, subcutaneously). In rats treated for 3 days with ALLN, arotinoid-induced reduction in cortical bone mineral density measured by peripheral quantitative computed tomography (pQCT) was inhibited by 86.4% (p < 0.05) in rats treated with ALLN 100 mg/kg, i.p., and by 82% in rats treated with 50 mg/kg, i.p. (p < 0.05). In a second study, the efficacy of ALLN was tested in a longitudinal study in ovariectomized (ovx) rats. Bone loss, measured by pQCT, was unaffected by treatment with ALLN. The bisphosphonate alendronate, however, inhibited bone loss in this model. These data demonstrate the ability of a cathepsin L inhibitor to inhibit bone resorption in arotinoid-treated TPTX rats, a process which may be dependent on the activity of cathepsin L-like cysteine proteinases. In contrast to its effects in TPTX rats, ALLN had no inhibitory activity on bone resorption in ovx rats. It is possible that in chronic bone resorption in ovx rats, the activity of other enzymes such as cathepsins OC-2 or K allows the process of resorption to continue even when cathepsin L is inhibited by ALLN. Further studies are required to determine why the activity of ALLN varies between different animal models. These data indicate that there may be variations in the effects of drugs in different animal models of bone resorption which should be considered when investigating novel antiresorptive therapies.

Animals↗
PubMed1996

Effect of ovariectomy on magnetic resonance T2* in rat femur.

Measurements have been made in the rat femur in vivo and ex vivo by using an asymmetric spin echo technique of T2(1), the susceptibility contribution to T2*. The trabecular spacing in this study in rat bone is considerably less than in previous studies in the human. A significant increase in T2(1) was seen in vivo 3 mm proximal to the growth plate with ovariectomy (a model of osteopenia), from 8.1 +/- 0.7 to 10.0 +/- 0.6 ms. Parallel changes in trabecular bone mineral density measured by quantitative computed tomography were found. T2(1) was higher in living bones than in the same bones measured post mortem.

Absorptiometry, Photon↗