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Biomedical subjects

D F Evans

Publications and source records attributed to D F Evans.

At least 19 recordsLinked to original sources

A prospective evaluation of the effect of tumor cell DNA content on recurrence in colorectal cancer.

Tumor cell DNA (ploidy) content was measured prospectively in samples from 320 patients resected for colorectal cancer with a minimum follow-up time of 2 years. All patients were followed and those with recurrence were investigated carefully. There was no correlation between tumors with an abnormal cellular DNA content (aneuploid or tetraploid) and patient age, sex, tumor site, pathologic stage, or histologic grade. In 236 patients who underwent potentially curative operations, 75 (32%) had local and/or distant recurrence. The recurrence rate was significantly higher (test statistic, 4.3; P = 0.04) for those patients with aneuploid tumors (52 of 142, 37%) compared with those with diploid tumors (23 of 94, 24%). The subgroups of patients where ploidy exerted an effect were in patients with Stage B tumors or mobile tumors and in patients over 65 years of age. Further analysis showed that there was a twofold increase in local recurrence and a threefold increase in distant recurrence in patients with aneuploid tumors, but no excess of patients who had both local and distant recurrence. Measurement of DNA ploidy can identify a group of patients undergoing curative surgery for colorectal cancer at high risk for recurrence. In combination with clinicopathologic factors, DNA ploidy may be useful in analyzing the results of trials and in planning adjuvant therapy.

Aged

Esophageal pH monitoring for gastroesophageal reflux: a United Kingdom study.

Esophageal pH monitoring is the accepted standard for the investigation of gastroesophageal reflux (GER) in adults. A postal questionnaire was sent to 912 United Kingdom paediatric physicians & surgeons. Five hundred forty-seven (61%) replied, with 124 (22.7%) currently using the technique, mostly in conjunction with barium swallow and/or esophagoscopy. The use of pH monitoring to quantify GER was also accepted in principal as being the best determinant of reflux by a further 186 (34%), but as yet was unavailable in their hospitals. Pediatricians were also questioned as to their management of children with GER. The majority were treated medically with a variety of antireflux medication, with only 237 (42%) referring cases for surgery.

Child

Correlation of the gastric emptying of nondisintegrating tablets with gastrointestinal motility.

The aim of the present study was to correlate the gastric emptying (GE) of nondisintegrating tablets with changes in gastrointestinal (GI) motility. Eight, healthy, male subjects each received 5 x 7-mm radiolabeled tablets, a radiolabeled meal, and a radiotelemetry capsule (RTC). Transit of the radiolabeled formulations was followed by gamma scintigraphy and the RTC detected contractile activity in the GI tract. The study demonstrated that 7-mm tablets can empty from the fed stomach, prior to the onset of interdigestive activity. Those tablets that were not emptied during fed activity were retained through the period of quiescence associated with the onset of the migrating myoelectric complex (MMC) and left the stomach during contractions associated with phase 2 and 3 activity. The RTC was retained in the stomach and was emptied only by large phase 3 contractions commonly termed the "housekeeper" wave. However, in one subject, the RTC was retained in the stomach for over 12 hr, during which time three distinct phase 3 complexes were monitored.

Adult

Characterisation of the in vivo behaviour of a controlled-release formulation of levodopa (Sinemet CR).

The gastrointestinal transit and systemic absorption of Sinemet CR (50-200) controlled-release tablets and standard Sinemet (25-100) immediate-release (IR) tablets have been studied in fasted and fed healthy human subjects. Both formulations were labelled with a gamma-emitting radionuclide and their gastric emptying, colon arrival and in vivo disintegration profiles monitored using gamma scintigraphy. The IR dosage forms were found to disperse soon after administration and to empty rapidly from both fasted and fed stomachs. Erosion of the CR system was independent of food or stomach pH. The CR tablet was observed to disintegrate fully in the gastrointestinal (GI) tract, resulting in complete release of levodopa over a 3-4 h time period. Considerable intersubject variation was found to exist for levodopa absorption. Absorption was more protracted with Sinemet CR than with standard Sinemet, due to the controlled release characteristics of the tablet matrix. There was no rapid initial absorption phase and instead, a gradual build-up in the absorption profile occurred.

Adult

Evaluation of an enteric-coated naproxen pellet formulation.

An enteric-coated, pellet formulation of naproxen has been evaluated in eight healthy subjects. Each volunteer was dosed with 153Sm-labelled, enteric-coated pellets on two occasions, once whilst fasted and once after breakfast. Gastrointestinal transit was followed using gamma scintigraphy and drug absorption compared with that from uncoated naproxen pellets dosed on a separate occasion. The pH in the stomach and intestines was monitored using radiotelemetry capsules. Gastric emptying was delayed by dosing after breakfast, but small intestinal transit of the enteric-coated formulation was the same on both occasions. The highest pH recorded from the stomach was 4.0 and in all subjects the pH rose to at least 7.3 in the small intestine. The onset of drug absorption was fastest from the uncoated formulation and slowest from the coated pellets taken after breakfast. The total amount of drug absorbed was the same on all three occasions.

Administration, Oral

An objective long-term evaluation of the Angelchik antireflux prosthesis.

This paper reports the long-term results of the Angelchik antireflux prosthesis (ACP) in Nottingham from October 1981 to December 1989 in 42 patients with gastrooesophageal reflux disease (GORD). Pre- and postoperative oesophagoscopy, pH monitoring, acid reflux provocation test (ARPT), manometry and symptom evaluation were documented to assess the benefits of the procedure. There were no operative complications, dysphagia was the commonest postoperative problem and necessitated the removal of four ACPs. In most patients, dysphagia resolved within 1 year of surgery. Recurrence of reflux symptoms resulted in revision surgery in two patients. In general, reflux control was good. We believe that the ACP is a good antireflux operation which gives good long-term reflux and symptom control in the majority of patients. The removal rate of 15% in our series is of some concern but may be due in part to operator skills. The long-term objective follow-up has shown a trend towards a return of GOR and this and the unknown long-term effects of implanted silicone may limit the use of this procedure to the more elderly patient.

Adult

Scanning tunneling microscopy of the enzymes of muscle glycogenolysis.

Scanning tunneling microscopy (STM) has been used to examine the structures of the skeletal muscle enzymes phosphorylase and phosphorylase kinase. The interaction of these two proteins represents the last step in the process of signal transduction which results in muscle glycogen being converted into metabolic energy for use in muscle contraction. Phosphorylase b has a molecular weight of 97,000 and the dimer is seen by STM to have dimensions of 11 X 5.7 nm. Phosphorylase b has a tendency to form linear arrays of dimers on the graphite surface used as the support for STM imaging. Phosphorylase kinase is imaged as a butterfly-like object with lateral dimensions of 36 X 27 nm. The molecular thicknesses given by scanning tunneling microscopy for these two non-conducting molecules is significantly less than expected. The height measurement in STM is dependent not only on the surface topology of the object being imaged, but also on the electronic work function of the object compared to that of the graphite surface on which it lies. In addition to the individual proteins, a complex between phosphorylase and phosphorylase kinase has been observed by scanning tunneling microscopy.

Animals

Direct visualization of phosphorylase-phosphorylase kinase complexes by scanning tunneling and atomic force microscopy.

In skeletal muscle the activation of phosphorylase b is catalyzed by phosphorylase kinase. Both enzymes occur in vivo as part of a multienzyme complex. The two enzymes have been imaged by atomic force microscopy and the results compared to those previously found by scanning tunneling microscopy. Scanning tunneling microscopy and atomic force microscopy have been used to view complexes between the activating enzyme phosphorylase kinase and its substrate phosphorylase b. Changes in the size and shape of phosphorylase kinase were observed when it bound phosphorylase b.

Animals

Cation radius effects on the helix-coil transition of DNA. Cryptates and other large cations.

Most polyelectrolyte theories of the effect of ions on the thermal melting of DNA assume that the predominant influence of the cations comes through their charge. Ion size and structure are treated, for analytic convenience, as negligible variables. We have examined the validity of this assumption by measuring the melting temperature of calf thymus DNA as a function of salt concentration with four univalent cations of different hydrated radii. These are K+ (3.3 A), (n-Pr)4N+ (4.5 A), (EtOH)4N+ (4.5 A), and C222-K+ (5 A). C222-K+ is a complex of cryptand C222 with K+. With K+ as the sole cation, Tm varies linearly with the log of ionic strength over the range 0.001-0.1 M. With all the K+ sequestered by an equimolar amount of C222, Tm is depressed by 10-20 degrees C and the slope of Tm vs. ionic strength is lower. At low ionic strength, an even greater reduction in Tm is achieved with (n-Pr)4N+; but the similar-sized (EtOH)4N+ gives a curve more similar to K+. Theoretical modeling, taking into account cation size through the Poisson-Boltzmann equation for cylindrical polyelectrolytes, predicts that larger cations should be less effective in stabilizing the double helix; but the calculated effect is less than observed experimentally. These results show that valence, cation size, and specific solvation effects are all important in determining the stability of the double-helical form of DNA.

Bridged Bicyclo Compounds

The influence of tumour cell DNA content on survival in colorectal cancer: a detailed analysis.

We have investigated the influence of tumour cell DNA content (ploidy) on survival of 416 patients undergoing excisional surgery for colorectal cancer. Two hundred and eleven (51%) tumours had an abnormal DNA content (aneuploid or tetraploid). There was no correlation between ploidy status, sex, age and pathological stage, histological grade, tumour site, local tumour extension or assessment of curability. Patients with tumours with an abnormal DNA content had a poorer survival 68/211 (32%) than patients with near normal (diploid) DNA content 88/205 (43%) (test statistic 5.0, P = 0.02). The patient subgroups in which DNA content exerted an influence on survival were: stage B tumours (P = 0.0058), moderately differentiated tumours (P = 0.004), rectal tumours (P = 0.02), and mobile tumours (P = 0.02). Multivariant analysis showed that pathological stage, local tumour extension and DNA ploidy were all independent prognostic indicators whereas histological grade, tumour site and assessment of 'curability' were not. The influence of pathological stage, however, was much greater than that of local tumor extension or DNA ploidy. Tumour cell DNA content together with pathological stage and local tumour extension may be used in a prognostic index and may be important in planning adjuvant therapy.

Adult

Viewing molecules with scanning tunneling microscopy and atomic force microscopy.

Two new microscopic techniques make it possible to obtain images of biologically interesting molecules directly in air, vacuum, or under water. Scanning tunneling microscopy and atomic force microscopy both have the capacity to visualize atoms on the surface of rigid structures and provide details of molecular structure for lipids, proteins, carbohydrates, and nucleic acids. In addition to providing visualizations of individual molecules, these scanning probe techniques allow direct imaging of complexes between molecules or between molecules and higher-order subcellular structures such as membranes and cytoskeletal components. Both microscopes can be operated under a variety of ambient conditions ranging from high vacuum to above atmospheric pressure. Specimens need not be dry; both techniques have been used to image molecules in aqueous media under nearly physiological conditions. It is proposed that as these techniques mature they will allow direct observation of many molecular interactions under physiological conditions or even in vivo while they are occurring within the cell.

Brain

Scanning tunneling microscopic images show a laminated structure for glycogen molecules.

Scanning tunneling microscopy (STM) has been used to examine glycogen molecules. Individual molecules were approximately ellipsoidal with dimensions in the 20- to 60-nm range. Images of the glycogen molecular surfaces have a laminar appearance. The layered features seen on the surfaces of the molecules suggest that glycogen may grow from one edge as a laminar structure to form an ellipsoid rather than originating at a central point with radial growth of the oligosaccharide chains to form a sphere. The results of these studies indicate that STM can be used to determine details of polysaccharide structures.

Animals

Gastrointestinal intraluminal pH in normal subjects and those with colorectal adenoma or carcinoma.

Recent evidence suggests that the production of colorectal carcinogens is facilitated when the pH of the colonic contents is alkaline. It follows that the colonic intraluminal pH of patients with colorectal neoplasms should be higher than in normal subjects. Gastrointestinal pH has been measured in 30 patients with colorectal cancer and 37 patients with benign colorectal adenomas (using a pH sensitive radiotelemetry capsule). These values have been compared with those recorded in 66 normal subjects. No differences in gastrointestinal pH were found and the results did not support the hypothesis that colonic pH plays a role in the aetiology of colorectal neoplasia.

Adenocarcinoma

Immunization against recombinant bovine inhibin alpha subunit causes increased ovulation rates in gilts.

Immunization of gilts in a commercial piggery against a fusion protein of the alpha subunit of bovine inhibin, produced by recombinant DNA methods, resulted in mean ovulation rate increases of 35% at the oestrus at which, under the piggery's management practices, they would have been mated. Sera from two immunized groups showed mean binding of 6.6% and 4.9% when assayed, at 1:800 final dilution, against iodinated bovine inhibin (Mr 31,000). Ovulation rates of immunized gilts were highly correlated with the ability of serum to bind iodinated native inhibin (r = 0.62; P less than 0.001), particularly when weight and age were included in the correlation (r = 0.72; P = 0.001), and inhibin binding accounted for 38% of the total variation in ovulation rate. Immunization caused no deleterious effects on growth rate or onset of oestrus. These results demonstrate the potential for use of such immunization to increase prolificacy in gilts and young sows.

Animals

Risk factors in patients with ischaemic rest pain of the lower limbs.

One hundred and three consecutive out-patients with ischaemic rest pain were studied. There were 77 men and 26 women with a mean (s.d.) age of 71 (10) years. Thirty-six (35.0%) patients had rest pain alone, 41 (39.8%) in association with an ischaemic ulcer and 26 (25.2%) with digital gangrene. A significantly increased risk of amputation was seen in those patients with an elevated serum cholesterol (greater than 5.2 mmol/l; P = 0.01), white blood cell count of greater than 10 x 10(9)/l (P = 0.05), fibrinogen greater than 4g/l (P = 0.04), and in women with elevated triglyceride levels (greater than 1.8 mmol/l; P less than 0.03). An increased risk of death for all patients was also associated with elevated triglyceride levels (P = 0.03). Few of the women smoked (P less than 0.0004), but they were more likely to have suffered a stroke (P = 0.01). They also had a significantly increased cholesterol level (P = 0.03) and tended to have a higher mortality rate than the men (P = 0.08). Surprisingly, smokers did not have a significantly higher amputation or death rate than non-smokers. Elevated plasma viscosity, packed cell volume, platelet count, haemoglobin and creatinine levels were not independent risk factors for any group. At 30 days after presentation the limb salvage rate was 73% (75/103), amputation was required in 15 (14.6%) cases and 13 (12.6%) patients died. Patients with ischaemic rest pain constitute a heterogeneous group with multiple diseases and risk factors. Early identification and treatment of risk factors may help to improve limb salvage and the mortality rate in this condition.

Aged

Direct observation of phosphorylase kinase and phosphorylase b by scanning tunneling microscopy.

The molecular structures of phosphorylase b and phosphorylase kinase have been visualized by scanning tunneling microscopy (STM). STM is a near field technique that can resolve structures at the nanometer level and thus can image individual molecules. Phosphorylase b can be seen in dimeric and tetrameric forms as well as linear and globular aggregates. The linear arrays consist of side by side dimers with the long axis of the dimer perpendicular to the aggregated chain. Individual molecules of phosphorylase kinase appear to be planar, bilobate structures with a 2-fold axis of symmetry and a central depression.

Animals