Incidental histopathologic patterns: possible evidence of 'field cancerization' surrounding skin tumors.
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Acantholysis↗
Biomedical subjects
D Scott
Publications and source records attributed to D Scott.
Interstitial pressure gradients around joints; location of chief resistance to fluid drainage from the rabbit knee.
The hypothesis has been advanced that synovium offers the main resistance to fluid escape from joints, even though it is under 20 microm thick. To test this, fluid was infused into the knee joint cavity of anaesthetised rabbits to set up a pressure gradient, then the profile of periarticular interstitial fluid pressure (P(if)) was measured by advancing a micropipette, connected to a servo-null pressure recorder, in steps through a periarticular tissue 'window' until the joint cavity was entered. With intra-articular pressure (P(j)) raised to 15 cmH(2)O (the pressure of an acute joint effusion) the pressure gradient dP(if) /dx (where x is distance) across the synovial lining was 0.47 +/- 0.04 cmH(2)O microm(-1) (n = 10 joints). This was 23.5-fold greater than the gradient in the subsynovium (0.02 +/- 0.01 cmH(2)O microm(-1); P < 0.0001, Student's t test), indicating that the hydraulic resistivity of the subsynovium is 4 % of that of the synovium. The pressure profile was not altered by circulatory arrest. To test the hypothesis further, the effect of a stab perforation of the synovial lining on fluid drainage rate ((.Q(s)) was studied. Perforation raised both.Q(s) and the conductance term d.Q(s)/dP(j) more than 10-fold (n = 6 joints; P < 0.0001, ANOVA). The results thus support the view that, despite its thinness, the synovial lining offers the main hydraulic resistance to fluid drainage from a synovial joint.
Animals↗
Foot length, an accurate predictor of nasotracheal tube length in neonates.
BACKGROUND: Existing guidelines for optimal positioning of endotracheal tubes in neonates are based on scanty data and relate to measurements that are either non-linear or poorly reproducible in sick infants. Foot length can be measured simply and rapidly and is related to a number of external body measurements. OBJECTIVES: To evaluate the relation of foot length to nasotracheal length in direct measurements at post mortem examinations, and then compare its clinical relevance with traditional weight based estimates in a randomised controlled trial. METHODS: The dimensions of the upper airway were measured at autopsy in 39 infants with median (range) postmenstrual age and birth weight of 32 (24-43) weeks and 1630 (640-3530) g. The regression equations with 95% prediction intervals were calculated to estimate the optimal nasotracheal length from foot length. In a randomised trial, 59 neonates were nasally intubated according to foot length and body weight based estimates to assess the achievement of "optimal" and "satisfactory" tube placements. RESULTS: In the direct measurements of the airway at autopsy, foot length was a better predictor of nasotracheal distances (r(2) = 0.79) than body weight, gestational age, and head circumference (r(2) = 0.67, 0.58, and 0.60 respectively). Measurement of foot length was easy and highly reproducible. In the randomised controlled trial, there were no significant differences between the foot length and body weight based estimates in the rates of optimal (44% v 56%) and satisfactory (83% v 72%) endotracheal tube placements. CONCLUSIONS: Foot length is a reliable and reproducible predictor of nasotracheal tube length and is at least as accurate as the conventional weight based estimation. This method may be particularly valuable in sick unstable infants.
Analysis of Variance↗
Monitoring service development through audit.
Comparative audits can be used as important tools for shaping service provision. Short stay facilities offer a more flexible and efficient approach to managing acute paediatric referrals. Users and providers views of the service are important. Children can be safely observed and discharged with parents empowered to continue care. Appropriate support systems should be in place in order to provide an ambulatory service.
Emergency Service, Hospital↗
Bimanual haptic workstation for laparoscopic surgery simulation.
Realistic laparoscopic surgical simulators will require real-time graphic imaging and tactile feedback. Our research objective is to develop a cost-effective haptic workstation for the simulation of laparoscopic procedures for training and treatment planning. The physical station consists of a custom-built frame into which laparoscopic trocars and surgical tools may be attached/inserted and which are continuously adjustable to various positions and orientations to simulate multiple laparoscopic surgical approaches. Instruments inserted through the trocars are attached to end effectors of two haptic devices and interfaced to a high speed PC with fast graphics capability. The haptic device transduces 3D motion of the two manually operated surgical instruments into slave maneuvers in virtual space. The slave instrument tips probe the simulated organ. Simulations currently in progress include: 1) Surface-only renderings, deformation, and haptic interactions with elements in the gall gladder surgical field; 2) Voxel-based simulations of the bulk manipulation of tissue; 3) laparoscopic herniorrhaphy. This system provides force feed-forward from the grasped tools to the contact tissue in virtual space, with deformation of the tissue by the virtual probe, and force feedback from the deformed tissue to the operator's hands.
Computer Graphics↗
Co-stimulation blockade, hemophilic inhibitors and tolerance.
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Animals↗
Early Permian bipedal reptile.
A 290-million-year-old reptilian skeleton from the Lower Permian (Asselian) of Germany provides evidence of abilities for cursorial bipedal locomotion, employing a parasagittal digitigrade posture. The skeleton is of a small bolosaurid, Eudibamus cursoris, gen. et sp. nov. and confirms the widespread distribution of Bolosauridae across Laurasia during this early stage of amniote evolution. E. cursoris is the oldest known representative of Parareptilia, a major clade of reptiles.
Animals↗
Action of polysaccharides of similar average mass but differing molecular volume and charge on fluid drainage through synovial interstitium in rabbit knees.
Hyaluronan (HA), an anionic polysaccharide of synovial fluid, attenuates fluid loss from joints as joint pressure is raised ('outflow buffering'). The buffering is thought to depend on the expanded molecular domain of the polymer, which causes reflection by synovial extracellular matrix, leading to flow-dependent concentration polarization. We therefore assessed the effects of polysaccharides of differing average molecular volume and charge. Trans-synovial fluid drainage( 8d s) was measured at controlled joint fluid pressure (Pj) in knees of anaesthetized rabbits. The joints were infused with polydisperse HA of weight-average mass 2100 kDa (4 mg x ml(-1), n = 17), with polydisperse neutral dextran of similar average mass (2000 kDa; n = 7) or with Ringer solution vehicle (n = 2). The role of polymer charge was assessed by infusions of neutral or sulphated dextran of average molecular mass 500 kDa (n = 6). When HA was present, 8d s increased little with pressure, forming a virtual plateau of approximately 4 microl x min(-1) from 10 to 25 cmH2O. Neutral dextran 2000 failed to replicate this effect. Instead, 8d s increased steeply with Pj, reaching eight times the HA value by 20 cmH2O (P = 0.0001, ANOVA). Dextran 2000 reduced flows in comparison with Ringer solution. Analysis of the aspirated joint fluid showed that 31 +/- 0.07 % (s.e.m.) of dextran 2000 in the filtrand was reflected by synovium, compared with > or = 79 % for HA. The viscometric molecular radius of the dextran, approximately 31 nm, was smaller than that of HA (101-181 nm), as was its osmotic pressure. Anionic dextran 500 failed to buffer fluid drainage, but it reduced fluid escape and synovial conductance d 8d s/dPj more than neutral dextran 500 (P < 0.0001, ANOVA). The anionic charge increased the molecular volume and viscosity of dextran 500. The results support the hypothesis that polymer molecular volume influences its reflection by interstitial matrix and outflow buffering. Polymer charge influences flow through an effect on viscosity and possibly electrostatic interactions with negatively charged interstitial matrix.
Animals↗
Activated murine endothelial cells have reduced immunogenicity for CD8+ T cells: a mechanism of immunoregulation?
The immunogenic properties of primary cultures of murine lung microvascular endothelial cells (EC) were analyzed. Resting endothelial cells were found to constitutively express low levels of MHC class I and CD80 molecules. IFN-gamma treatment of EC resulted in a marked up-regulation of MHC class I, but no change was observed in the level of CD80 expression. No CD86 molecules were detectable under either condition. The ability of peptide-pulsed EC to induce the proliferation of either the HY-specific, H2-K(k)-restricted CD8(+) T cell clone (C6) or C6 TCR-transgenic naive CD8(+) T cells was analyzed. Resting T cells were stimulated to divide by quiescent peptide-prepulsed EC, while peptide-pulsed, cytokine-activated EC lost the ability to induce T cell division. Furthermore, Ag presentation by cytokine-activated EC induced CD8(+) T cell hyporesponsiveness. The immunogenicity of activated EC could be restored by adding nonsaturating concentrations of anti-H2-K(k) Ab in the presence of an optimal concentration of cognate peptide. This is consistent with the suggestion that the ratio of TCR engagement to costimulation determines the outcome of T cell recognition. In contrast, activated peptide-pulsed EC were killed more efficiently by fully differentiated effector CD8(+) T cells. Finally, evidence is provided that Ag recognition of EC can profoundly affect the transendothelial migration of CD8(+) T cells. Taken together, these results suggest that EC immunogenicity is regulated in a manner that contributes to peripheral tolerance.
Animals↗
Role of hyaluronan chain length in buffering interstitial flow across synovium in rabbits.
1. Synovial fluid drains out of joints through an interstitial pathway. Hyaluronan, the major polysaccharide of synovial fluid, attenuates this fluid drainage; it creates a graded opposition to outflow that increases with pressure (outflow 'buffering'). This has been attributed to size-related molecular reflection at the interstitium-fluid interface. Chain length is reduced in inflammatory arthritis. We therefore investigated the dependence of outflow buffering on hyaluronan chain length. 2. Hyaluronan molecules of mean molecular mass approximately 2200, 530, 300 and 90 kDa and concentration 3.6 mg ml-1 were infused into the knees of anaesthetized rabbits, with Ringer solution as control in the contralateral joint. Trans-synovial drainage rate was recorded at known joint pressures. Pressure was raised in steps every 30-60 min (range 2-24 cmH2O). 3. With hyaluronan-90 and hyaluronan-300 the fluid drainage rate was reduced relative to Ringer solution (P < 0.001, ANOVA) but increased steeply with pressure. The opposition to outflow, defined as the pressure required to drive unit outflow, did not increase with pressure, i.e. there was no outflow buffering. 4. With hyaluronan-530 and hyaluronan-2000 the fluid drainage rate became relatively insensitive to pressure, causing a near plateau of flow. Opposition to outflow increased markedly with pressure, by up to 3.3 times over the explored pressures. 5. Hyaluronan concentration in the joint cavity increased over the drainage period, indicating partial reflection of hyaluronan by synovial interstitium. Reflected fractions were 0.12, 0.33, 0.25 and 0.79 for hyaluronan-90, -300, -530 and -2200, respectively. 6. Thus the flow-buffering effect of hyaluronan depended on chain length, and shortening the chains reduced the degree of molecular reflection. The latter should reduce the concentration polarization at the tissue interface, and hence the local osmotic pressure opposing fluid drainage. In rheumatoid arthritis the reduced chain length will facilitate the escape of hyaluronan and fluid.
Animals↗
Interaction of intraarticular hyaluronan and albumin in the attenuation of fluid drainage from joints.
OBJECTIVE: How is fluid volume regulated in joints? Fluid drainage rate is an important factor, both in normal joints and those with effusions. Hyaluronan and albumin, separately, are known to attenuate drainage, conserving synovial fluid volume in the presence of raised joint pressure. Hyaluronan and albumin normally coexist, however, in joint fluid. The objective was to determine their interactive effect on drainage. METHODS: The fluid escape rate from the joint cavity through synovium was measured at controlled intraarticular pressures using a rabbit knee model in vivo. One joint contained 4 mg/ml hyaluronan and the other contained 4 mg/ml hyaluronan plus 20 mg/ml albumin, as in normal synovial fluid. Hyaluronan-albumin interactions were assessed in vitro by viscometry and osmometry. RESULTS: Hyaluronan alone greatly attenuated fluid escape. Drainage rates plateaued at 4-5 microl/minute as pressure was raised, because the opposition to drainage increased with pressure. Addition of albumin to hyaluronan shifted the opposition-versus-pressure relation upward and further attenuated drainage by 22.5%, despite a small fall in the viscosity of the mixture. Osmometry showed a small synergistic interaction. Analysis of aspirates showed that < or =8% of albumin molecules in the draining fluid were reflected by the synovial lining (compared with 79% of hyaluronan molecules). CONCLUSION: Hyaluronan and albumin act together at normal concentrations to conserve synovial fluid in the presence of raised drainage pressures. Hyaluronan has the greater effect, acting osmotically by way of a concentration polarization boundary layer. Attenuation of this effect in arthritic effusions with low hyaluronan concentrations is one of several factors limiting fluid accumulation and, hence, the size of the effusion.
Albumins↗
Concentration dependence of interstitial flow buffering by hyaluronan in synovial joints.
Hyaluronan concentration in synovial fluid spans a 20-fold range, from as low as 0.2 mg ml(-1) in synovitis to as high as 4 mg ml(-1) in healthy joints. The aim was to determine the effect of this on fluid drainage from the joint cavity. The study extends the finding of P. J. Coleman, D. Scott, R. M. Mason, and J. R. Levick (1999, J. Physiol. 514, 265-282) that dissolved hyaluronan at 3.6-4.0 mg ml(-1) (the concentration in young human and rabbit joints) causes the opposition to interstitial fluid drainage to increase with pressure. Hyaluronan was infused into rabbit knees at 0, 0.2, 2.0, and 4.0 mg ml(-1) over a range of intraarticular pressures. Hyaluronan at 2 mg ml(-1) (as in healthy elderly joints and some osteoarthritis) greatly reduced drainage rates and generated a flattening (convex) pressure-flow relation, as observed previously with 4 mg ml(-1). Drainage rates were greater at 2 mg ml(-1) than at 4 mg ml(-1) hyaluronan (P < 0.0001, ANOVA, n = 7). The opposition to outflow (pressure required to drive unit outflow) increased with pressure, but less markedly than with 4 mg ml(-1) hyaluronan. Hyaluronan at 0.2 mg ml(-1) reduced outflow by approximately 50% relative to Ringer solution (P < 0.0001, ANOVA, n = 7) but the pressure-flow relation no longer flattened out with increasing pressure, because there was no significant increase in opposition to outflow with pressure. At 0 mg ml(-1) hyaluronan, outflow opposition decreased with pressure. Viscometry showed a marked transition in the hyaluronan state at >/=1.35 mg ml(-1), indicating that this is the critical concentration for molecular domain overlap and intermolecular coupling. The results broadly supported the concentration-polarization hypothesis, which predicts significant osmotic buffering of drainage at >/=1 mg ml(-1) hyaluronan; at 0.2 mg ml(-1) other factors may predominate. It is inferred that hyaluronan at physiological concentrations can conserve synovial fluid when pressures are raised (e.g., flexion): whereas dilution of hyaluronan, as in severe effusions, can effectively abolish buffering and thus facilitate fluid drainage.
Aged↗
Chromosomal radiosensitivity, cancer predisposition and response to radiotherapy.
AIM: This paper briefly summarizes the research on this topic, undertaken in the Department of Cancer Genetics, Paterson Institute for Cancer Research, Manchester, England, over the previous 6 years. PATIENTS AND METHOD: Patients with the recessively-inherited disease, ataxia-telangiectasia (A-T), who are cancer-prone and suffer severe reactions after radiotherapy, also have highly radiosensitive cells, particularly when chromosome damage is used as the measure of radiosensitivity. Enhanced chromosomal radiosensitivity is also a feature of many other cancer-prone disorders. We have investigated the possible role of such radiosensitivity as a marker of cancer predisposition and response to radiotherapy in the general population. RESULTS: We found that 42% (57/135) of breast cancer patients exhibit chromosomal radiosensitivity when lymphocytes are irradiated in the G2 phase of the cell cycle, compared with 6% (6/105) of healthy controls (Figure 1). These figures are much higher than the estimated frequencies of carriers of the ataxia-telangiectasia gene (heterozygotes) amongst breast cancer patients (< 5%) and controls (0.5%). We have also obtained evidence of heritability of G2 sensitivity by studying relatives of breast cancer cases (Figures 2 and 3). The pattern of inheritance is relatively simple and attributable to 1 or 2 genes segregating in each family (Figure 4). In a prospective study of 123 breast cancer patients, 9 (7%) had severe acute reactions to radiotherapy and their mean G2 sensitivity was significantly greater (p = 0.001) than that of the remaining patients (Figure 5). In 16 patients with adverse acute reactions we found no mutations of the ataxia-telangiectasia gene (ATM). Using another chromosomal assay (micronucleus induction in G0 lymphocytes) we found that the mean radiosensitivity of patients with severe late reactions was higher than that of normal reactors. For example, 8 patients with severe fibrosis were more sensitive (p = 0.055) than 39 patients with a normal response (Figure 6). However, the discriminatory power of these chromosomal assays is too low for them to be used alone in a clinical setting. CONCLUSION: Our results provide good evidence that genes other than ATM, that confer chromosomal radiosensitivity, are involved in low penetrance predisposition to breast cancer in a high proportion of cases and contribute to adverse reactions after radiotherapy.
Ataxia Telangiectasia↗
Gastric habitation by Helicobacter pylori: insights into acid adaptation.
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Animals↗
Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer.
BACKGROUND AND PURPOSE: There is a need for rapid and reliable tests for the prediction of normal tissue responses to radiotherapy, as this could lead to individualization of patient radiotherapy schedules and thus improvements in the therapeutic ratio. Because the use of cultured fibroblasts is too slow to be practicable in a clinical setting, we evaluated the predictive role of assays of lymphocyte chromosomal radiosensitivity in patients having radiotherapy for breast cancer. MATERIALS AND METHODS: Radiosensitivity was assessed using a micronucleus (MN) assay at high dose rate (HDR) and low dose rate (LDR) on lymphocytes irradiated in the G(0) phase of the cell cycle (Scott D, Barber JB, Levine EL, Burril W, Roberts SA. Radiation-induced micronucleus induction in lymphocytes identifies a frequency of radiosensitive cases among breast cancer patients: a test for predispostion? Br. J. Cancer 1998;77;614-620) and an assay of G(2) phase chromatid radiosensitivity ('G(2) assay') (Scott D, Spreadborough A, Levine E, Roberts SA. Genetic predisposition in breast cancer. Lancet 1994; 344: 1444). In a study of acute reactions, blood samples were taken from breast cancer patients before the start of radiotherapy, and the skin reaction documented. 116 patients were tested with the HDR MN assay, 73 with the LDR MN assay and 123 with the G(2) assay. In a study of late reactions, samples were taken from a series of breast cancer patients 8-14 years after radiotherapy and the patients assessed for the severity of late effects according to the'LENT SOMA' scales. 47 were tested with the HDR assay, 26 with the LDR assay and 19 with the G(2) assay. For each clinical endpoint, patients were classified as being normal reactors or 'highly radiosensitive patients' (HR patients (Burnet NG. Johansen J, Turesson I, Nyman J. Describing patients' normal tissue reactions: Concerning the possiblity of individualising radiotherapy dose presciptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer 1998;79:606-613)). RESULTS: The HR patients could be identified in some of the assays. For example, for acute skin reactions, 9/123 patients were judged as HR; they had significantly higher G(2) scores than normal reactors (P=0.004). For the late reactions, the mean HDR MN scores were higher for the 4/47 patients who had severe telangiectasia (P=0.042) and the 8/47 patients had severe fibrosis (P=0.055). However, there were no trends towards increased chromosomal radiosensitivity with the micronucleus scores at HDR or LDR, or with G(2) chromosomal radiosensitivity. CONCLUSIONS: While these results support the concept of using lymphocytes to detect elevated sensitivity to radiotherapy (as an alternative to fibroblasts), these assays are unlikely to be of assistance for the prediction of normal tissue effects in the clinic in their present form.
Adult↗
UreI-mediated urea transport in Helicobacter pylori: an open and shut case?
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Bacterial Proteins↗
Electronic telephone directory listings: preferred sampling frame for a population-based study of childhood cancer in Australia.
PURPOSE: We report our telephone-based system for selecting community control series appropriate for a complete Australia-wide series of Ewing's sarcoma cases. METHODS: We used electronic directory random sampling to select age-matched controls. The sampling has all listed telephone numbers on an up-dated CD-Rom. RESULTS: 95% of 2245 telephone numbers selected were successfully contacted. The mean number of attempts needed was 1.94, 58% answering at the first attempt. On average, we needed 4.5 contacts per control selected. Calls were more likely to be successful (reach a respondent) when made in the evening (except Saturdays). The overall response rate among contacted telephone numbers was 92.8%. Participation rates among female and male respondents were practically the same. The exclusion of unlisted numbers (13.5% of connected households) and unconnected households (3.7%) led to potential selection bias. However, restricting the case series to listed cases only, plus having external information on the direction of potential bias allow meaningful interpretation of our data. CONCLUSION: Sampling from an electronic directory is convenient, economical and simple, and gives a very good yield of eligible subjects compared to other methods.
Adolescent↗
Dendritic cells permit identification of genes encoding MHC class II-restricted epitopes of transplantation antigens.
Minor or histocompatibility (H) antigens are recognized by CD4+ and CD8+ T lymphocytes as short polymorphic peptides associated with MHC molecules. They are the targets of graft versus host and graft versus leukemia responses following bone marrow transplantation between HLA-identical siblings. Several genes encoding class I-restricted minor H epitopes have been identified, but approaches used for these have proved difficult to adapt for cloning class II-restricted minor H genes. We have combined the unique antigen-presenting properties of dendritic cells and high levels of episomal expression following transfection of COS cells to identify a Y chromosome gene encoding two HY peptide epitopes, HYAb and HYEk.
Amino Acid Sequence↗