Tactics for mechanized reasoning: a commentary on Milner (1984) 'The use of machines to assist in rigorous proof'.

Robin Milner's paper, 'The use of machines to assist in rigorous proof', introduces methods for automating mathematical reasoning that are a milestone in the development of computer-assisted theorem proving. His ideas, particularly his theory of tactics, revolutionized the architecture of proof assistants. His methodology for automating rigorous proof soundly, particularly his theory of type polymorphism in programing, led to major contributions to the theory and design of programing languages. His citation for the 1991 ACM A.M. Turing award, the most prestigious award in computer science, credits him with, among other achievements, 'probably the first theoretically based yet practical tool for machine assisted proof construction'. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

Optical measures of thermally induced chain ordering and oxidative damage in polythiophene films.

Thermally induced chain ordering (aggregation) and oxidative damage in neat poly(3-hexylthiophene) (P3HT) films were assessed using multiple optical metrics (low-temperature photoluminescence (LT-PL), Raman, absorbance, and IR spectroscopies) and NMR through quantitative analysis of exciton/chromophore bandwidths, emission, vibronic line shapes, and changes in film chemistry. Polymer morphology is discussed in light of how absorbance and PL provide complementary information about physically and chemically related changes in conjugation due to chain alignment (kinking and torsion), π-stacking, crystallite domain growth, and photo-oxidation. LT-PL is shown to be sensitive to oxidation phenomena, while absorbance and Raman are not; in contrast, aggregation can be most easily evaluated via absorbance using a Franck-Condon-like model of vibronic excitation. IR and NMR reveal how hexyl side chains and thiophene units are attacked during annealing in O(2). We also demonstrate that competition exists between the "disordering" effect of photodegradation and the physical "ordering" effect of aggregation, each of which dominates under different processing conditions. Ultimately, it is shown that various optical metrics of film disorder must be considered collectively to understand how processing affects film morphology.

Reflection-mode, confocal, tip-enhanced Raman spectroscopy system for scanning chemical microscopy of surfaces.

A reflection-mode, confocal, tip-enhanced Raman spectroscopy system for nanoscale chemical imaging of surfaces is presented. The instrument is based on a beam-bounce atomic force microscope with a side-on Raman microscope with true confocal light illumination and collection. Localized vibrational (Raman) spectroscopy is demonstrated at length scales down to 20 nm on opaque samples. The design and validation of the instrument are discussed with quantitative emphasis on confocal microscope operation, plasmonic properties of the tip, point spectroscopy, and Raman imaging of SiGe nanowires.

Differential effects of nutritional folic acid deficiency and moderate hyperhomocysteinemia on aortic plaque formation and genome-wide DNA methylation in vascular tissue from ApoE-/- mice.

Low folate intake is associated with vascular disease. Causality has been attributed to hyperhomocysteinemia. However, human intervention trials have failed to show the benefit of homocysteine-lowering therapies. Alternatively, low folate may promote vascular disease by deregulating DNA methylation. We investigated whether folate could alter DNA methylation and atherosclerosis in ApoE null mice. Mice were fed one of six diets (n = 20 per group) for 16 weeks. Basal diets were either control (C; 4% lard) or high fat (HF; 21% lard and cholesterol, 0.15%) with different B-vitamin compositions: (1) folic acid and B-vitamin replete, (2) folic acid deficient (-F), (3) folic acid, B6 and B12 deficient (-F-B). -F diets decreased plasma (up to 85%; P < 0.05), whole blood (up to 70%; P < 0.05), and liver folate (up to 65%; P < 0.05) and hepatic SAM/SAH (up to 80%; P < 0.05). -F-B diets reduced plasma (up to 76%; P < 0.05), whole blood (up to 72%; P < 0.05), and liver B12 (up to 39%; P < 0.05) and hepatic SAM/SAH (up to 90%; P < 0.05). -F increased homocysteine 2-fold, while -F-B increased homocysteine 3.6- and 6.8-fold in the C and HF groups (P < 0.05). Plaque formation was increased 2-fold (P < 0.0001) in mice fed a HF diet. Feeding a HF-F diet increased lesion formation by 17% (P < 0.05). There was no change in 5-methyldeoxycytidine in liver or vascular tissue (aorta, periadventitial tissue and heart). These data suggest that atherogenesis is not associated with genome-wide epigenetic changes in this animal model.

Fermi surface of CeIn3 above the Néel critical field.

We report measurements of the de Haas-van Alphen effect in CeIn(3) in magnetic fields extending to approximately 90 T, well above the Néel critical field of mu(0)H(c) approximately 61 T. The unreconstructed Fermi surface a sheet is observed in the high magnetic field polarized paramagnetic limit, but with its effective mass and Fermi surface volume strongly reduced in size compared to that observed in the low magnetic field paramagnetic regime under pressure. The spheroidal topology of this sheet provides an ideal realization of the transformation from a "large Fermi surface" accommodating f electrons to a "small Fermi surface" when the f-electron moments become polarized.

Evidence of simultaneous double-electron promotion in F+ collisions with surfaces.

A high-flux beam of mass-filtered F+ at low energy (100-1300 eV) was scattered off Al and Si surfaces to study core-level excitations of F0 and F+. Elastic scattering behavior for F+ was observed at energies <300 (500) eV off Al (Si) for a 90 degrees lab angle. However, above this energy threshold, orbital mixing in the hard collision step results in electronic excitation of F via molecular orbital promotion along the 4f sigma (F-2p), significantly reducing the observed ion exit energy. In addition, despite the electronegativity of F, scattering at energies >450 (700) eV off Al (Si) produces F2+-behavior which is remarkably similar to Ne+ off the same surfaces. Inelasticities measured for single collision events agree well with the energy deficits required to form (doubly excited) F** and F+** states from F0 and F+, respectively; these excited species most likely decay to inelastic F+ and F2+ via autoionization.

Effects of tomato extract on human platelet aggregation in vitro.

Among all fruits tested in vitro for their anti-platelet property, tomato had the highest activity followed by grapefruit, melon, and strawberry, whereas pear and apple had little or no activity. Tomato extract (20-50 microl of 100% juice) inhibited both ADP- and collagen-induced aggregation by up to 70% but could not inhibit arachidonic acid-induced platelet aggregation and concomitant thromboxane synthesis under similar experimental conditions. The anti-platelet components (MW <1000 Da) in tomatoes are water soluble, heat stable and are concentrated in the yellow fluid around the seeds. The active fractions were separated using gel filtration and HPLC. The aqueous fraction (110 000 xg supernatant) of tomatoes containing anti-platelet activity was subjected to gel filtration column chromatography (Biogel P2 column). The activity was fractionated into two peaks, peak-3 and peak-4 (major peak). Subsequently, peak-4 was further purified by HPLC using a reversed-phase column. NMR and mass spectroscopy studies indicated that peak F2 (obtained from peak 4) contained adenosine and cytidine. Deamination of peak F2 with adenosine deaminase almost completely abolished its anti-platelet activity, confirming the presence of adenosine in this fraction. In comparison, deamination of peak-4 resulted in only partial loss of inhibitory activity while the activity of peak-3 remained unaffected. These results indicate that tomatoes contain anti-platelet compounds in addition to adenosine. Unlike aspirin, the tomato-derived compounds inhibit thrombin-induced platelet aggregation. All these data indicate that tomato contains very potent anti-platelet components, and consuming tomatoes might be beneficial both as a preventive and therapeutic regime for cardiovascular disease.

Clinical outcomes in reduction mammaplasty: a systematic review and meta-analysis of published studies.

This systematic review and meta-analysis were undertaken to determine whether reduction mammaplasty improves measurable outcomes in women with breast hypertrophy. A systematic review of the literature in 5 languages from 1985 until March 1999 was performed, and data were compared for meta-analysis. Eligible studies were both experimental and observational and involved women with preoperative physical and/or psychosocial signs and symptoms who underwent reduction mammaplasty for breast hypertrophy. Outcomes assessed were postoperative physical signs and symptoms such as shoulder pain, shoulder (bra strap) grooving, and quality-of-life domains, such as physical and psychological functioning, and were expressed primarily as risk differences (RDs). Twenty-nine studies of 4173 patients met all eligibility criteria. Reduction mammaplasty was associated with a statistically significant improvement in physical signs and symptoms involving shoulder pain (RD, 0.71 [95% confidence interval (CI), 0.62-0.80]); shoulder grooving (RD, 0.69 [95% CI, 0.60-0.78]); upper/lower back pain (RD, 0.59 [95% CI, 0.48-0.70]); neck pain (RD, 0.50 [95% CI, 0.37-0.64]); intertrigo (RD, 0.44 [95% CI, 0.34-0.54]); breast pain (RD, 0.36 [95% CI, 0.17-0.55]); headache (RD, 0.28 [95% CI, 0.11-0.46]); and pain/numbness in the hands (RD, 0.11 [95% CI, 0.04-0.18]). The quality-of-life parameter of physical functioning was also statistically significant (RD, 0.58 [95% CI, 0.44-0.71]), while psychological functioning was not significant (RD, 0.46 [95% CI, 0.00-1.00]). The evidence suggests that women undergoing reduction mammaplasty for breast hypertrophy have significant postoperative improvement in preoperative signs and symptoms, quality of life, or both.

Adverse drug reactions in hospitalized patients: A critique of a meta-analysis.

OBJECTIVE: To replicate and to critique a recently published meta-analysis[1] of the incidence of nonpreventable serious and fatal adverse drug reactions (ADRs) in hospitalized patients, to better understand its results and conclusions. METHODS: The published methods described in the meta-analysis of Lazarou and colleagues were followed.[1] This meta-analysis reviewed 30 original publications describing 39 prospective studies. In each study, the numbers of patients with nonpreventable ADRs, probably or definitely related to drugs, were sought to allow calculation of the incidence of "all-severities," serious and fatal, ADRs. In the original meta-analysis, these ADR incidences were then pooled to provide estimates of the incidence in all hospitalized patients. In our analysis, the original studies were examined by 2 investigators for consistency with the study search and inclusion criteria of the meta-analysis by Lazarou and colleagues, as well as accuracy and appropriateness of data extraction, meta-analysis, and conclusions. RESULTS: Multiple sources of heterogeneity among studies and data were found and include important differences in populations and hospital wards monitored, surveillance techniques, ADR definitions, determination of preventability of ADRs, distinguishing relationship to drugs, and in formats of reporting ADRs (by numbers of events or by patients). Imputations of event numerators made by the authors of the original meta-analysis were questionable and may overestimate the results of any individual study. With regard to fatal ADRs, the problem of small numbers of events is likely to introduce large errors in incidence estimates. Simple pooling of fatal event frequencies from only those studies specifically reporting the number of fatal ADRs, as was done in the meta-analysis of Lazarou and colleagues, is likely to dramatically overestimate the death rate. CONCLUSION: Meta-analysis was invalid because of heterogeneity of the studies. Most of these studies did not report the data needed for incidence calculations. The methodology used was seriously flawed, and no conclusions regarding ADR incidence rates in the hospitalized population in the United States should be made on the basis of the original meta-analysis.

Preferential distribution of long chain polyunsaturated fatty acids in phospatidyl ethanolamine fraction of guinea pig alveolar apical membranes.

We investigated the fatty acid distribution in guinea pig alveolar apical membranes at different developmental stages. Fatty acid composition of the purified membranes isolated from guinea pig fetuses (at 65 day, term=68 day), neonates (day 1) and adult males was determined. The levels of arachidonic acid (AA) and docosahexaenoic acid (DHA) were higher in the adult guinea pig alveolar apical membrane phosphatidylethanolamine (PE) fraction (9. 3+/-2.2 and 2.9+/-1.0%, respectively) while in other phospholipids (PL) fractions their levels were low or absent (P<0.01). Furthermore, levels of AA and DHA in the PE fraction of apical membrane increased significantly from fetal (6.6+/-3.0 and 0.8+/-0.4%, respectively) to neonatal life (10.3+/-1.5 and 3.0+/-0.8%, respectively). Increase in the level of DHA (almost four-fold) was much more pronounced than that of AA (P<0.05). As for guinea pig alveolar membranes, EPA and AA were mostly present in the PE fraction in pulmonary adenocarcinoma derived cells (A549 cells), a parallel model of type II pneumocytes, with the levels of AA around three-fold greater than that of EPA, Binding of radiolabelled fatty acids to A549 cells showed no significant differences between the maximum uptake achieved for different fatty acids (AA, 1.7+/-0.2, EPA, 2.3+/-0.3, LA, 1.7+/-0.2, OA, 2.0+/-0.2nmol/mg protein, P>0.5). Once the fatty acids were taken up by these cells AA was mostly identifiable in the monoacylglycerol (MAG) fraction, whereas EPA was equally distributed between the MAG and PL fractions. Oleic acid was mainly present in the triglyceride (TAG) fraction whereas LA was evenly distributed between the TAG, MAG, and PL fractions. Our data demonstrate a preferential distribution of AA and DHA in PE fractions of alveolar apical membranes during development.

Measurement of Gd-DTPA diffusion through PVA hydrogel using a novel magnetic resonance imaging method.

Polyvinyl alcohol-cryogel (PVA-C) is a hydrogel that is an excellent tissue mimic. In order to characterize mass transfer in this material, as well as to demonstrate in principle the ability to noninvasively measure solute diffusion in tissue, we measured the diffusion coefficient of the magnetic resonance (MR) contrast agent gadolinium diethylene triaminopentaacetic acid (Gd-DTPA) through PVA-C using a clinical MR imager. The method involved filling thick-walled rectangular PVA-C "cups" with known concentrations of Gd-DTPA solutions. Then by using a fast inversion recovery spin echo MR imaging protocol, a signal "null" contour was created in the MR image that corresponded to a second, known concentration of Gd-DTPA. By collecting a series of MR images through the PVA-C wall as a function of time, the displacement of this second known isoconcentration contour could be tracked. Application of Fick's second law of diffusion yielded the diffusion coefficient. Seven separate experiments were performed using various combinations of initial concentrations of Gd-DTPA within the PVA-C cups (3.2, 25.6, or 125 mM) and tracked isoconcentrations contours (0.096, 0.182, or 0.435 mM Gd-DTPA). The experimental results and the predictions of Fick's law were in excellent agreement. The diffusivity of Gd-DTPA through 10% PVA hydrogel was found to be (2.6 +/- 0.04) x 10(-10) m(2)/s (mean +/- s.e.m.). Separate permeability studies showed that the diffusion coefficient of Gd-DTPA through this hydrogel did not change with an applied pressure of up to 7.1 kPa. Accurate measurements could be made within 30 min if suitable Gd-DTPA concentrations were selected. Due to the excellent repeatability and fast data acquisition time, this technique is very promising for future in vivo studies of species transport in tissue.

Restoring hand function in patients with severe polyneuropathy: the role of electromyography before tendon transfer surgery.

Electromyography (EMG) was evaluated as a supplement to clinical examination and biomechanical considerations to optimize forearm donor muscle selection before tendon transfers to 4 functionless hands in 3 patients with slowly progressive polyneuropathies. Two patients had unusually severe Charcot-Marie-Tooth disease; the third patient had idiopathic mononeuropathy multiplex. Standard EMG parameters were used to devise an intuitive muscle grading system, including most importantly interference patterns and motor control, plus motor unit morphology and stability. Given our objective of restoring survivable function despite ongoing polyneuropathy, we found that EMG reveals prognostically important differences among partially denervated candidate muscles that cannot be detected by experienced clinical examiners. Opposition transfer was performed on one hand of each patient. After 39-, 39-, and 51-month follow-up durations, restored opposition was graded as good in these 3 hands. We conclude that EMG provides meaningful guidance in selecting optimal forearm muscles for tendon transfers to hands in the setting of slowly progressive polyneuropathies.

Identifying and overcoming barriers to providing sexuality information in the clinical setting.

While the scope of the clinician-patient relationship in rehabilitation includes the opportunity to provide information on sexuality, all too often this does not occur. This article identifies barriers to providing information on sexuality and makes suggestions for overcoming them. At a preconference workshop, "Sexuality After Spinal Cord Injury: Understanding the Effects of Knowledge and Attitude on Dissemination Practices," held during the Association of Rehabilitation Nurses 22nd Annual Educational Conference, participants explored barriers to providing sexuality information to their patients and ways for nurse managers and staff members to ameliorate their own discomfort and that of their patients. The barriers identified included lack of time, lack of knowledge, personal attitudes about sexuality, and patient lack of readiness. Approaches that can improve the comfort levels of nurse managers and staff include using educational films and written materials, conducting role playing to explore typical patient questions, and initiating conversation about sexuality with patients. Participants' suggestions for increasing patient comfort level included adopting an open and nonjudgmental listening mode, distinguishing between the physical and emotional aspects of sexual issues, and promoting peer counseling.

Inhibitory effect of Ginkgo biloba extract on human platelet aggregation.

The effect of pure flavonoids and Gingko biloba extract (GBE) on human platelet aggregation was investigated. Most of the flavonoids and vitamin E did not affect platelet aggregation in platelet-rich plasma (PRP); however some of these flavonoids inhibited platelet aggregation in gel-filtered platelets (GFP). GBE inhibited both ADP- and collagen-induced platelet aggregation in PRP, GFP and in whole blood in a dose-dependent manner. GBE at very low concentrations inhibited whole blood aggregation induced by ADP compared with those used for PRP or GFP. Flavonoids and GBE decreased the production of TxA(2) induced by collagen and ADP in PRP. However, no correlation was observed between the inhibition of platelet aggregation and the decrease of TxA(2) synthesis. GBE and flavonoids did not affect platelet membrane fluidity. However, the incubation of PRP with GBE increased cAMP levels in platelets, which is known to inhibit platelet activation by lowering intracellular Ca2+ levels. GBE is a mixture of many compounds, including flavonoids and gingkoglides, which affect metabolism of cAMP, TxA(2) and Ca2+ in platelets. It is effective in the inhibition of platelet aggregation, both in PRP and whole blood, and thus may be potentially used as an effective oral anti-platelet therapeutic agent.

Differential distribution and metabolism of arachidonic acid and docosahexaenoic acid by human placental choriocarcinoma (BeWo) cells.

The time course of incorporation of [14C]arachidonic acid and [3H]docosahexaenoic acid into various lipid fractions in placental choriocarcinoma (BeWo) cells was investigated. BeWo cells were found to rapidly incorporate exogenous [14C]arachidonic acid and [3H] docosahexaenoic acid into the total cellular lipid pool. The extent of docosahexaenoic acid esterification was more rapid than for arachidonic acid, although this difference abated with time to leave only a small percentage of the fatty acids in their unesterified form. Furthermore, uptake was found to be saturable. In the cellular lipids these fatty acids were mainly esterified into the phospholipid (PL) and the triacyglycerol (TAG) fractions. Smaller amounts were also detected in the diacylglycerol and cholesterol ester fractions. Almost 60% of the total amount of [3H]Docosahexaenoic acid taken up by the cells was esterified into TAG whereas 37% was in PL fractions. For arachidonic acid the reverse was true, 60% of the total uptake was incorporated into PL fractions whereas less than 35% was in TAG. Marked differences were also found in the distribution of the fatty acids into individual phospholipid classes. The higher incorporation of docosahexaenoic acid and arachidonic acid was found in PC and PE, respectively. The greater cellular uptake of docosahexaenoic acid and its preferential incorporation in TAG suggests that both uptake and transport modes of this fatty acid by the placenta to fetus is different from that of arachidonic acid.

Placental membrane fatty acid-binding protein preferentially binds arachidonic and docosahexaenoic acids.

To elucidate further the role of placental membrane fatty acid-binding protein (p-FABPpm) in preferential transfer of maternal plasma long chain polyunsaturated fatty acids (LCPUFA) across the human placenta, direct binding of the purified protein with various radiolabelled fatty acids (docosahexaenoic, arachidonic, linoleic and oleic acids) was investigated. Binding of these fatty acids to the protein revealed that p-FABPpm had higher affinities and binding capacities for arachidonic and docosahexaenoic acids compared with linoleic and oleic acids. The apparent binding capacities (Bmax) values for oleic, linoleic, arachidonic and docosahexaenoic acids were 2.0 +/- 0.14, 2.1 +/- 0.17, 3.5 +/- 0.11, 4.0 +/- 0.10 mol per mol of p-FABPpm whereas the apparent dissociation constant (Kd) values were 1.0 +/- .0.07, 0.73 +/- 0.04, 0.45 +/- 0.03 and 0.4 +/- 0.02 microM, respectively (n=3). In the case of human serum albumin, the Kd and Bmax values for all fatty acids were around 1 microM and 5 mol/mol of protein, respectively. These data provide direct evidence for the role of p-FABPpm in preferential sequestration of maternal arachidonic and docosahexaenoic acids by the placenta for transport to the fetus by virtue of its preferential binding of these fatty acids.

Interaction of free fatty acids with human leptin.

Relatively high concentrations of leptin are present in plasma and it is thought to play a major role in lipid homeostasis. Leptin is reported to lower tissue triglyceride content by increasing intracellular oxidation of free fatty acids (FFA). However very little is known regarding the interaction between leptin and plasma FFA. We studied the interaction of FFA with leptin using a direct radiolabelled fatty acid binding assay, a fluorescence assay, electrophoretic mobility and autoradiobinding. All these data indicate that binding of FFA with leptin is reversible and shows a positive co-operativity. The binding of FFA to leptin produces a change in the pI value of the leptin and also increased the electrophoretic mobility of the protein in native polyacrylamide gels. The change in leptin's electrophoretic mobility depends on the chain length and the number of double bonds of the fatty acid, as stearic acid, 18:0, had no effect whereas oleic acid, 18:1n-9, linoleic acid, 18:2n-6, arachidonic acid, 20:4n-6, and docosahexaneoic acid, 22:6n-3, affected leptin's mobility to different degrees. The physiological implication of leptin-FFA interaction is not known, however the interaction may depend on the plasma FFA composition and concentration which are known to vary in different pathological/physiological conditions.

Cutting the Gordian knot: a two-part approach to the evaluation and professional development of residents.

There is chronic dissatisfaction among both faculty and students about the process and effectiveness of resident performance evaluation. The author asserts that the source of this problem is the current practice of merging the two different purposes for evaluation: to monitor residents' meeting of performance standards and to provide guidance for residents' professional development. By attempting to meet both quality-control and guidance obligations using one set of objective data, most residency programs fall short in meeting one of these aims. The common preoccupation with psychometric precision, objectivity, and the statistical processing of forms frequently distracts users from making effective use of evaluation information. The proposed solution is to divide resident evaluation into two simpler, entirely separate and distinct systems--neither of which would look much like the current system. There would be a faculty-controlled, quality-control system focused on screening for minimal performance standards. This would use simple, qualitative measures for early warning and rapid follow-up. The second evaluation system would be a resident-controlled, guidance-oriented system focused on self-assessment, peer and faculty coaching, and reflection. The hypothesized benefits of this approach include an improvement in residents' motivation and performance, an increase in residents' self-direction, and an enhancement of communication between residents and faculty members.