Attitudes and training of research fellows in surgery: national questionnaire survey.
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Adult↗
Biomedical subjects
C R Wilson
Publications and source records attributed to C R Wilson.
Calcitonin gene-related peptide is not essential for the development of pressure overload-induced hypertrophy in vivo.
The regulatory neuropeptide calcitonin-gene related peptide (CGRP) has been shown to evoke a hypertrophic response in isolated cardiomyocytes in vitro, an effect which was attributed to PKC activation. Activation of PKC has previously been implicated in the development of cardiac hypertrophy. We therefore investigated the role of CGRP in pressure overload-induced hypertrophy in vivo, which has not previously been reported. Constriction of the ascending aorta of rats resulted in an increase in the heart weight to body weight ratio, increased myocyte diameter, re-expression of the fetal genes ANF, MHCbeta and skeletal alpha-actin, and decreased expression of the adult genes GLUT4 and SERCA2a. Treatment of neonatal rat pups (1-2 days old) with capsaicin (50 mg/kg), resulted in the permanent de-afferentation of small-diameter unmyelinated CGRP-containing sensory C-fibres. Such treatment caused a 68% decrease in the CGRP-like immunoreactivity of hearts isolated from 10 week old rats (p < 0.001). Contrary to expectations, aortic constriction of capsaicin treated rats had no effect on the development of hypertrophy at the trophic, morphometric or gene expression levels. The results suggest that the development of pressure overload-induced hypertrophy in vivo does not require the regulatory neuropeptide CGRP.
Actins↗
Mandibular and palatal tori, bone mineral density, and salivary cortisol in community-dwelling elderly men and women.
BACKGROUND: This investigation evaluated the relationship between the presence of tori and bone mineral density (BMD) and salivary cortisol levels. METHODS: A total of 230 healthy, community-dwelling elderly men (n = 129) and women (n = 101) aged 60 and older participated in this study. Forty-three women were on hormone replacement therapy (HRT). This was a component of a 5-year longitudinal study measuring subjects' body composition, hormone levels, physical activity, and diet every 6 months. Subjects were examined for the presence of tori by visual inspection and digital palpation. BMD at six sites was measured by dual-energy X-ray absorptiometry. Salivary cortisol levels were measured by radioimmunoassay. RESULTS: Twenty-three percent of all subjects had mandibular tori, 13% had palatal tori, and 12% had both mandibular and palatal tori. Mandibular tori were more common in men, and palatal tori were more common in women. The presence of mandibular tori was significantly correlated with BMD of the lumbar spine, femoral neck, trochanter, and Ward's triangle for all subjects, and with the femoral neck and trochanter of women not on HRT. Men with palatal tori had lower levels of salivary cortisol in the evening. CONCLUSIONS: This study documented the high prevalence of mandibular and palatal tori in a group of 230 elderly, community-dwelling subjects. Women not on HRT and all subjects taken as a group with mandibular tori had higher BMD. The presence of tori at young adulthood may be a marker of higher BMD in the future and of a lower risk for developing osteoporosis.
Aged↗
Engineering is preferred over physics as an undergraduate preparation for diagnostic and nuclear medical physicists.
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Engineering↗
Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids.
Malonyl-CoA decarboxylase (MCD) catalyzes the degradation of malonyl-CoA, an important modulator of fatty acid oxidation. We hypothesized that increased fatty acid availability would increase the expression and activity of heart and skeletal muscle MCD, thereby promoting fatty acid utilization. The results show that high-fat feeding, fasting, and streptozotocin-induced diabetes all significantly increased the plasma concentration of nonesterified fatty acids, with a concomitant increase in both rat heart and skeletal muscle MCD mRNA. Upon refeeding of fasted animals, MCD expression returned to basal levels. Fatty acids are known to activate peroxisome proliferator-activated receptor-alpha (PPARalpha). Specific PPARalpha stimulation, through Wy-14643 treatment, significantly increased the expression of MCD in heart and skeletal muscle. Troglitazone, a specific PPARgamma agonist, decreased MCD expression. The sensitivity of MCD induction by fatty acids and Wy-14643 was soleus > extensor digitorum longus > heart. High plasma fatty acids consistently increased MCD activity only in solei, whereas MCD activity in the heart actually decreased with high-fat feeding. Pressure overload-induced cardiac hypertrophy, in which PPARalpha expression is decreased (and fatty acid oxidation is decreased), resulted in decreased MCD mRNA and activity, an effect that was dependent on fatty acids. The results suggest that fatty acids induce the expression of MCD in rat heart and skeletal muscle. Additional posttranscriptional mechanisms regulating MCD activity appear to exist.
Animals↗
Mammalian recombination-repair genes XRCC2 and XRCC3 promote correct chromosome segregation.
Growth and development are dependent on the faithful duplication of cells. Duplication requires accurate genome replication, the repair of any DNA damage, and the precise segregation of chromosomes at mitosis; molecular checkpoints ensure the proper progression and fidelity of each stage. Loss of any of these highly conserved functions may result in genetic instability and proneness to cancer. Here we show that highly significant increases in chromosome missegregation occur in cell lines lacking the RAD51-like genes XRCC2 and XRCC3. This increased missegregation is associated with fragmentation of the centrosome, a component of the mitotic spindle, and not with loss of the spindle checkpoint. Our results show that unresolved DNA damage triggers this instability, and that XRCC2 and XRCC3 are potential tumour-suppressor genes in mammals.
Animals↗
Expression of Ku70 correlates with survival in carcinoma of the cervix.
Cervical carcinoma affects around 3400 women in the UK each year and advanced disease is routinely treated with radiation. As part of a programme to establish rapid and convenient methods of predicting tumour and patient responses to radiotherapy, we have examined the relationship between the pre-treatment expression of the Ku components of the DNA damage recognition complex DNA-PK and patient survival in cervical carcinoma. Using immunohistochemistry of formalin-fixed sections of tumour biopsies, antibodies to Ku70 and Ku80 stained identical regions of tumour and there was a high degree of correlation between the mean number of cells stained positive for the two components in 77 tumours (r = 0.82, P<0.001). In 53 tumours there was a borderline significant correlation between measurements of tumour radiosensitivity (surviving fraction at 2 gray: SF2) and Ku70 expression (r = 0.26, P = 0.057) and no correlation for Ku80 (r = 0.18, P = 0.19). However, all tumours with a low number of Ku70 or Ku80 positive cells were radiosensitive. Furthermore, using log-rank analysis there was significantly higher survival in the patients whose tumours had a low Ku70 expression (P = 0.046). This difference was also reflected with Ku80, but did not reach statistical significance (P = 0.087). The study suggests that lack of Ku protein leads to radiosensitivity in some tumours and that other factors are responsible for radiosensitive tumours with high Ku expression. It is likely that the most accurate prediction of treatment outcome will lie in assessing the expression of several proteins involved in the recognition and repair of DNA damage, one of which will be Ku.
Antigens, Nuclear↗
Effects of storage conditions and hemolysis on vitamin E concentrations in porcine serum and liver.
Vitamin E (alpha-tocopherol) is an antioxidant vitamin important in protecting unsaturated fatty acids in lipid membranes from peroxidation. Variation in collection, storage, and shipping conditions of samples can potentially lead to breakdown of vitamin E prior to analysis. Therefore, the purposes of this project were 1) to determine the stability of vitamin E in refrigerated and frozen porcine liver and serum and 2) to evaluate the effects of red blood cell (RBC) hemolysis on porcine serum vitamin E concentrations. Porcine liver and nonhemolyzed serum were collected and stored refrigerated or frozen. Samples were analyzed for vitamin E immediately or on days 2, 3, 7, or 14. In addition, porcine RBCs were added to normal serum at concentrations from 1 x 10(6) to 1 X 10(9) RBC/ml and hemolyzed by freeze-thaw prior to analysis for vitamin E or products of lipid peroxidation.
Animals↗
Multiphase hepatic CT with a multirow detector CT scanner.
OBJECTIVE: The aim of this study was to evaluate a new injection-acquisition technique performed using a multirow detector CT scanner for separation of three distinct hepatic circulatory phases (hepatic artery, portal venous inflow, hepatic venous) and to determine which of these phases is optimal for detecting hypervascular neoplasm. MATERIALS AND METHODS: Two sequential acquisitions were performed during a single breath-hold followed by a third acquisition beginning 60 sec after injection. Injection-to-scan delay for the first acquisition was the individual patient's circulation time, which was determined by a preliminary mini bolus. The mean attenuation of the upper abdominal aorta, portal vein, and hepatic parenchyma were determined for each imaging pass in 20 patients with cirrhosis and 20 patients without cirrhosis. Tumor-to-liver contrast for hypervascular primary and metastatic neoplasm was evaluated in a different set of 16 cirrhotic patients and nine noncirrhotic patients. Three-dimensional CT arteriograms were obtained from first-pass data. RESULTS: Three distinct circulatory phases (hepatic artery, portal vein inflow or late arterial, and hepatic venous) were seen in cirrhotic and noncirrhotic patients. Maximum tumor-to-liver contrast for hypervascular primary and metastatic neoplasm occurred during the second pass for both cirrhotic (p < 0.006) and noncirrhotic (p < 0. 001) patients. A three-dimensional hepatic-mesenteric CT arteriogram of normal or anomalous hepatic vessels without venous overlay was obtained from first-pass data in all patients. CONCLUSION: Rapid-sequence hepatic helical CT allows selection of the optimal time interval for hypervascular tumor detection. A new paradigm for rapid hepatic CT acquisition-namely, hepatic arterial, portal vein inflow, and hepatic venous phases-is recommended to replace hepatic artery dominant and portal venous phases.
Adult↗
Evaluating the effectiveness of 2 educational interventions in family practice.
BACKGROUND: Structured feedback of information can produce change in physician behaviour. The objective of this study was to assess the effectiveness of 2 educational interventions for improving the quality of care provided by family physicians in Ontario: the Practice Assessment Report (PAR) and the Continuing Medical Education Plan (CMEP) with a follow-up visit by a mentor. METHODS: The study was a randomized controlled trial. Physicians in the control group received only the PAR, whereas those in the experimental group received the PAR, CMEP and mentor interventions. The participants were 56 family physicians and general practitioners (27 in the PAR group and 29 in the CMEP group) in southern Ontario who agreed to participate in the interventions and provide data. A total of 2395 patients randomly sampled from the practices returned questionnaires and consented to have their medical records abstracted. The outcome measures were global scores in 4 areas--quality of care, charting, prevention and overall use of medications--and patient ratings of satisfaction with care and preventive practices. The measures were applied at the beginning (phase 1) and end (phase 2) of the study. RESULTS: The mean global scores at the end of the study for the PAR group were 70.1% for quality of care, 84.7% for prevention, 77.7% for charting and 82.2% for overall use of medications. The corresponding scores for the CMEP group were 68.3%, 82.1%, 76.4% and 83.2%. In the patient satisfaction component, the personal care scores at phase 2 were 93.6% for the PAR group and 94.6% for the CMEP group. Examples of the scores for prevention for the PAR group were 98.3% for children's current immunization, 96.6% for blood pressure measured within the previous 5 years, 79.4% for referral of women of the appropriate age for mammography within the previous 2 years, and 58.4% for discussion about alcohol use. The corresponding scores for the CMEP group were 95.8%, 97.6%, 77.6% and 64.6%. The changes in mean scores between phase 1 and phase 2 ranged from -1.9 to 2.3 points. There were no significant differences between the 2 groups in phase 1 or phase 2 scores or in change in scores. A total of 64.3% of the physicians rated the PAR as useful, 26.5% found the CMEP to be useful, and 41.0% considered the mentor strategy to be a useful form of continuing medical education. Although changes in practice related to the PAR, CMEP or mentor were reported by some physicians, they were not related to chart audit or patient scores. INTERPRETATION: Educational interventions based on quality-of-care assessments and directed to global improvements in quality of care did not result in improvements in the outcome measures. Educational interventions may have to be targeted to specific areas of the practice, with physicians being monitored and receiving ongoing feedback on their performance.
Education, Medical, Continuing↗
Non-chemical inhibition of respiratory motor output during mechanical ventilation in sleeping humans.
1. To determine the magnitude and time course of changes in respiratory motor output caused by non-chemical influences, six sleeping subjects underwent assist-control mechanical ventilation (ACMV) at increased tidal volume (VT). During ACMV, end-tidal PCO2 (PET,CO2) was either held at normocapnic levels (PET,CO2, 0.6-1.1 mmHg > control) by adding CO2 to the inspirate, or it was allowed to fall (hypocapnia). 2. Each sleeping subject underwent several repeat trials of twenty-five ACMV breaths (VT, 1.3 or 2.1 times control; peak flow rate, 30-40 l min-1; inspiratory time, +/- 0.3 s of control). The end-tidal to arterial PCO2 difference throughout normocapnic ACMV at raised VT was unchanged from eupnoeic levels during studies in wakefulness. 3. Normocapnic ACMV at both the smaller and larger increases in VT decreased the amplitude of respiratory motor output, as judged by decreased maximum rate of rise of mask pressure (Pm) (mean dPm/dtmax, 46-68% of control), reduced diaphragmatic EMG (to 55% of control) and reduced VT on the first spontaneous breath after ACMV (to 70% of control). Expiratory time (TE) was slightly prolonged (13-32% > control). This inhibition of amplitude of respiratory motor output progressed over the first five to seven ventilator cycles, was maintained over the remaining 18-20 cycles and persisted for three to five spontaneous breaths immediately following cessation of ACMV. 4. Hypocapnia did not further inhibit respiratory motor output amplitude beyond the effect of normocapnic ACMV at high VT, but did cause highly variable prolongation of TE when PET,CO2 was reduced by greater than 3 mmHg for at least five ventilator cycles. 5. These data in sleeping humans support the existence of a significant, non-chemical inhibitory influence of ACMV at increased VT and positive pressure upon the amplitude of respiratory motor output; this effect is manifested both during and following normocapnic mechanical ventilation.
Adult↗
Elevated salivary cortisol in the evening in healthy elderly men and women: correlation with bone mineral density.
BACKGROUND: Aging is associated with a loss of bone mineral density (BMD) in men and women. Loss of BMD can also be caused by hypercortisolemia in men or women at any age. This study measured salivary cortisol at 2300 h and 0700 h as indices of cortisol secretory activity in 228 elderly, community-dwelling subjects. Salivary cortisol results were correlated with BMD. We hypothesized that salivary cortisol is elevated at 2300 h in elderly people, and that salivary cortisol will correlate negatively with BMD. METHODS: Saliva was sampled at 2300 h (nadir in circadian rhythm) and 0700 h (peak in circadian rhythm) in 130 men (70.7 +/- 0.4 years old) and 98 women (70.0 +/- 0.4 years old); approximately half of the women were receiving hormone replacement therapy (HRT). BMD was measured by dual energy x-ray absorptiometry. RESULTS: Salivary cortisol at 2300 h was significantly elevated in men (2.3 +/- 0.1 nmol/L) and women (2.1 +/- 0.1 nmol/L) as compared to 73 younger controls (1.2 +/- 0.1 nmol/L; 37 +/- 1 year old). Salivary cortisol at 0700 h was not different between older subjects and younger controls. There was a significant negative correlation of lumbar (L2-4) BMD and 2300 h salivary cortisol in older women (r = -0.20, p = .05; n = 98); this correlation was significant only in women not on HRT. There was a highly significant negative correlation of lumbar (L2-4) BMD and 0700 h salivary cortisol in older men (r = -0.31, p = .0003). CONCLUSIONS: Salivary cortisol is a simple, nonstressful method for assessing activity of the hypothalamic-pituitary-adrenal (HPA) axis in the elderly population. A major finding was an elevation in the late night nadir in cortisol secretion. We also suggest that elevated cortisol secretion in elderly people may contribute to the age-related loss in bone mineral density and that this effect is prevented by HRT.
Aged↗
Plasma leptin and insulin levels in weight-reduced obese women with normal body mass index: relationships with body composition and insulin.
Obesity is a complex disease with multiple features that has confounded efforts to unravel its pathophysiology. As a means of distinguishing primary from secondary characteristics, we compared levels of fasting plasma leptin and insulin in a cohort of weight-reduced obese women who have attained and maintained a normal BMI for more than 1 year with the levels in cohorts of never-obese and currently obese women. Weight-reduced obese women showed decreased plasma concentrations of leptin and insulin compared with obese women, but these levels remained significantly higher than those of never-obese women. Plasma leptin levels were highly correlated with plasma insulin levels (r = 0.60, P < 0.001). To further explore relationships with body composition, total body fat was determined by dual-energy X-ray absorptiometry and body fat distribution by computed tomography in subsets of these groups. Weight-reduced obese women had a significantly greater percent body fat and subcutaneous abdominal fat mass than did the never-obese women, and these were highly correlated with plasma leptin (r = 0.90, P < 0.001, and r = 0.52, P < 0.001, respectively). In these weight-reduced obese women, visceral fat mass was similar to that of the never-obese. The insulin sensitivity index and first-phase insulin response were also comparable. These results demonstrate that higher leptin levels in weight-reduced obese women are related to the higher total fat and particularly the subcutaneous fat masses. Normalization of visceral fat mass in the weight-reduced obese was accompanied by normalization of insulin sensitivity index and first-phase insulin response. This study suggests that increases in plasma leptin and insulin in obesity are secondary features of the obese state.
Absorptiometry, Photon↗
An induced blood pressure rise does not alter upper airway resistance in sleeping humans.
Sleep apnea is associated with episodic increases in systemic blood pressure. We investigated whether transient increases in arterial pressure altered upper airway resistance and/or breathing pattern in nine sleeping humans (snorers and nonsnorers). A pressure-tipped catheter was placed below the base of the tongue, and flow was measured from a nose or face mask. During non-rapid-eye-movement sleep, we injected 40- to 200-microgram i.v. boluses of phenylephrine. Parasympathetic blockade was used if bradycardia was excessive. Mean arterial pressure (MAP) rose by 20 +/- 5 (mean +/- SD) mmHg (range 12-37 mmHg) within 12 s and remained elevated for 105 s. There were no significant changes in inspiratory or expiratory pharyngeal resistance (measured at peak flow, peak pressure, 0.2 l/s or by evaluating the dynamic pressure-flow relationship). At peak MAP, end-tidal CO2 pressure fell by 1.5 Torr and remained low for 20-25 s. At 26 s after peak MAP, tidal volume fell by 19%, consistent with hypocapnic ventilatory inhibition. We conclude that transient increases in MAP of a magnitude commonly observed during non-rapid-eye-movement sleep-disordered breathing do not increase upper airway resistance and, therefore, will not perpetuate subsequent obstructive events.
Adrenergic alpha-Agonists↗
Assessment of inspiratory flow limitation invasively and noninvasively during sleep.
To define the standard of airway flow limitation, pharyngeal pressure and flow rate were measured during wakefulness and sleep in seven habitual snorers with widely varying degrees of sleep-induced increases in upper airway resistance. Inspiratory pressure:flow relationships were used to group breaths into four categories of flow limitation, including linear (Level 1), mildly alinear (Level 2), constant flow rate with no pressure dependence (Level 3), and decreasing flow rate throughout significant portions of inspiration, i.e., negative pressure dependence (Level 4). These pressure:flow rate gold standards of flow limitation were used to evaluate a flow limitation index derived from the time profile (or "shape") of three noninvasive estimates of flow rate: (1) pneumotach flow rate, (2) differentiated sum respiratory inductance plethysmography (RIP), and (3) nasal pressure. A nonflow limited template for each of these noninvasive measurements was taken from awake breaths and the difference in area determined between the template breath and each of the noninvasive signals measured during nonrapid eye movement (NREM) sleep. The noninvasive flow limitation indices were found to be effective in differentiating severe types of inspiratory flow limitation, i.e., Level 1 versus Level 3 or Level 4 (sensitivity/specificity > 80%). On the other hand, these indirect indices were not able to consistently detect mild levels of flow limitation (Level 1 versus Level 2; sensitivity/specificity = 62 to 72%); nor were these noninvasive estimates of flow rate "shape" sensitive to breaths with a high but fixed resistance throughout inspiration. The area index derived from measurements of pressure at the nares (Pn) was the most sensitive, nonperturbing, noninvasive measure of flow rate and flow limitation, and we recommend its use for recognizing most of the common types of moderate to severe levels of airway flow limitation in sleeping subjects.
Adult↗
Potential radiation hazard associated with the unprotective use of mini C-arm fluoroscopy systems.
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Biophysical Phenomena↗
Biomechanical analysis of thoracolumbar interbody constructs. How important is the endplate?
STUDY DESIGN: A biomechanical study of human cadaveric thoracic vertebral bodies was conducted using several anterior fusion options subjected to axial loads. This study emphasized the contribution of the endplate to resistance of graft subsidence. OBJECTIVES: To determine the importance of the vertebral endplate in resisting subsidence of various constructs into the vertebral body; the relative efficacy of potential alternative graft constructs such as iliac crest, ribs, humerus, and titanium mesh cage; and the importance of bone mineral content, vertebral level, and cross-sectional graft area on construct subsidence. SUMMARY OF BACKGROUND DATA: As the fixation length of anterior and posterior spinal constructs is reduced, load sharing of the anterior column has become more important to reduce failure of the shorter devices. Several alternative graft constructs and surgical techniques have been used for reconstruction of the anterior column. There exist little comparative data as to whether any of these constructs are superior and whether the vertebral endplate contributes significantly to the integrity of the construct. METHODS: Sixty-three isolated human cadaveric vertebral bodies from T3 to T12 were used to test seven different constructs in direct axial load onto prepared endplates with an electrohydraulic testing device. These constructs were: 1) titanium mesh cage (17 x 22 mm) on intact endplate, 2) C-shaped humerus on intact endplate, 3) tricorticated iliac graft in "tee configuration" on intact endplate, 4) tricorticated iliac graft in cancellous trough, 5) triple rib strut graft, 6) single rib on endplate, and 7) single rib on cancellous body. Dual X-ray absorptiometry assessment of bone mineral content was performed. A uniaxial load was applied with force and displacement data collected to determine maximal load to "failure" of the vertebral body. RESULTS: Preservation of vertebral endplate did not significantly increase the resistance to graft subsidence. The titanium cage construct provided the greatest resistance to axial load. CONCLUSIONS: Preservation of the vertebral endplate may not offer a significant biomechanical advantage in reconstructing the anterior column. Several alternative constructs are mechanically equivalent.
Adult↗
Unusual ligand binding at the active site domain of an engineered mutant of subtilisin BL.
As an attempt to recruit the third calcium binding site of thermitase into subtilisin BL, a Bacillus lentus alkaline protease (BLAP), the amino acid sequence from position 50 to 60 and position 92 was modified to the equivalent amino acids in thermitase. The resulting protein, designated BLAPm109, exhibited unusual biochemical features. Peptide mapping and gel electrophoresis revealed that two protein species co-purify in a ratio of about 1:1. Form 1 consisted of a single polypeptide of 269 amino acid residues. Form 2 was the same protein but with an internal peptide bond cleavage at the C-terminus of position 54. On electropherograms a dimer of Form 1 and Form 2 was also detectable. A zymogram showed that all three molecular species were catalytically active. From this protein mixture, crystals suitable for X-ray analysis were nevertheless obtained. SDS-PAGE of protein recovered from a crystal revealed that only Form 2 appears. in the crystal. The space group for this crystal was P21 with unit cell dimensions of a=42 angstroms, b=58 angstroms, c=47 angstroms and beta = 106.3 degrees. Examination of the preliminary electron density map revealed that the "thermitase loop" from 50 to 60 departs from the surface of the protein and winds through the active site of a symmetry-related copy of the asymmetric unit.
Amino Acid Sequence↗