Below gap optical absorption in GaAs driven by intense, single-cycle coherent transition radiation.

Single-cycle terahertz fields generated by coherent transition radiation from a relativistic electron beam are used to study the high field optical response of single crystal GaAs. Large amplitude changes in the sub-band-gap optical absorption are induced and probed dynamically by measuring the absorption of a broad-band optical beam generated by transition radiation from the same electron bunch, providing an absolutely synchronized pump and probe geometry. This modification of the optical properties is consistent with strong-field-induced electroabsorption. These processes are pertinent to a wide range of nonlinear terahertz-driven light-matter interactions anticipated at accelerator-based sources.

Approach to critical illness polyneuropathy and myopathy.

A newly acquired neuromuscular cause of weakness has been found in 25-85% of critically ill patients. Three distinct entities have been identified: (1) critical illness polyneuropathy (CIP); (2) acute myopathy of intensive care (itself with three subtypes); and (3) a syndrome with features of both 1 and 2 (called critical illness myopathy and/or neuropathy or CRIMYNE). CIP is primarily a distal axonopathy involving both sensory and motor nerves. Electroneurography and electromyography (ENG-EMG) is the gold standard for diagnosis. CIM is a proximal as well as distal muscle weakness affecting both types of muscle fibres. It is associated with high use of non-depolarising muscle blockers and corticosteroids. Avoidance of systemic inflammatory response syndrome (SIRS) is the most effective way to reduce the likelihood of developing CIP or CIM. Outcome is variable and depends largely on the underlying illness. Detailed history, careful physical examination, review of medication chart and analysis of initial investigations provides invaluable clues towards the diagnosis.

Introduction of a new mobile-bearing total knee prosthesis: minimum three year follow-up of an RCT comparing it with a fixed-bearing device.

As part of the step-wise validation of a new prosthesis (TMK), we previously published the 1 year results of a randomised controlled trial in patients undergoing bilateral knee replacement [Price A., Rees J., Beard D., Juszczak E. et al. A mobile-bearing total knee prosthesis compared with a fixed-bearing prosthesis. JBJS B 2003;85-B-1:62-7.]. Forty patients had the new mobile-bearing prosthesis implanted in one knee and an established fixed-bearing device in the other (AGC). We now report the 3 year status of these patients and, in addition, review a separate multi-centre cohort of 172 patients who had undergone unilateral arthroplasty with the TMK. No significant differences were found in outcome (American Knee Society Score and Oxford Knee Score) between the two prostheses. The greater incidence of "clicking" in the mobile-bearing knee, reported in the previous review, persisted (TMK=48%, AGC=30%). The presence of this mechanical noise was found to have no relationship with outcome in either of the prostheses. The unilateral cohort study showed an acceptable complication rate for the new prosthesis, although some patients reported subjective instability. The method of controlled introduction of the TMK, of which this constitutes a further step, has allowed us to assess the significance of a reported problem (clicking) and to provide scientific data from which other surgeons can decide about use of the implant.

Development and clinical application of meniscal unicompartmental arthroplasty.

About one-third of osteoarthritic patients requiring knee replacement have focal lesions limited mainly to the medial compartment and can achieve excellent postoperative function after medial unicompartmental replacement. However, late failures of many unicompartmental prostheses require revision at a rate about twice that of total knee replacement. The use of a fully conforming mobile-bearing meniscal unicompartmental prosthesis in the hands of experienced surgeons can reduce revision rates to levels equivalent to the best results achieved with total knee replacement. The paper argues the case for such a prosthesis and demonstrates that the usual modes of failure of unicompartmental arthroplasty, most of them biomechanical, can thereby be avoided.

Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia.

OBJECTIVE: This work was undertaken to determine whether dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. BACKGROUND: Marine omega-3 fatty acids improve vascular function, but the underlying mechanism(s) are unclear. We studied the effects of marine omega-3 fatty acids on large artery endothelial function in subjects with hypercholesterolemia. METHODS: Hypercholesterolemic subjects with no other known cause for endothelial dysfunction were recruited to a prospective, placebo-controlled, randomized, double-blind, parallel-group study. Treatment with omega-3 fatty acids at a dose of 4 g/day (n = 15/group) was compared with placebo, at the beginning (day 0) and end (day 120) of a four-month treatment period. Endothelial function was assessed pre- and posttreatment by noninvasive ultrasonic vessel wall tracking of brachial artery flow-mediated dilation (FMD). RESULTS: Treatment with marine omega-3 fatty acids resulted in a significant improvement in FMD (0.05 +/- 0.12 to 0.12 +/- 0.07 mm, p < 0.05) and a significant reduction in triglycerides (2.07 +/- 1.13 to 1.73 +/- 0.95 mmol/liter, p < 0.05), whereas treatment with placebo resulted in no change in FMD (0.03 +/- 0.10 to 0.04 +/- 0.10 mm) or triglycerides (2.29 +/- 2.09 to 2.05 +/- 1.36 mmol/liter) (both p < 0.05 treated compared with control). Responses to sublingual glyceryl trinitrate were unchanged. CONCLUSIONS: Marine omega-3 fatty acids improve large artery endothelium-dependent dilation in subjects with hypercholesterolemia without affecting endothelium-independent dilation.

Distribution of solvent molecules around apolar side-chains in protein crystals.

We have analysed the distribution of solvent sites within 5.0 A of the apolar side-chains alanine, valine, leucine, isoleucine and phenylalanine based on experimental data from 24 high-resolution protein structures. Clustering of solvent molecules into specific regions can be seen superimposed on a broad background of sites. The non-random nature of these distributions is confirmed by quantitative analysis of the solvent sites according to a spherical polar (r, theta and phi) co-ordinate system with the apolar atom of interest at the centre. One of the general features of these solvent sites is that they peak at around 4.0 A from an apolar protein carbon atom. Preferences in orientation (theta and phi) are also seen in the solvent distributions especially around the alanine CB atom and the phenylalanine ring. Most (around 75%) of the solvent sites around apolar groups are also within hydrogen bonding distance of protein (main chain) polar groups which leads to a distribution dependent on the local secondary structure. The remaining 25% of solvent sites are referred to as "non-polar" water molecules and their crystallographic temperature factors are higher than average by between 15% to 28%. For alanine and phenylalanine there are enough data to show that water molecules not within hydrogen bonding distance of protein polar atoms also cluster into specific regions. However, the main conclusion appears to be that the hydrophobic hydration in protein crystals is correlated with hydration of polar groups and thus depends on the local environment as well as on the stereochemistry of the apolar atoms.

Adenine.methylthymine base-pairs enhance non-uniformity in DNA helices.

Nitroso compounds are known to induce mutations and cancer. Here we study the effect of methylation of O4 of thymine by nitroso compounds on the structure and dynamics of DNA helices. Four dodecamers, for which there exist experimental data obtained by NMR techniques, are studied using very long (approximately 1 ns) molecular dynamics simulations. The conformations obtained are in good agreement with the NMR data. A statistical analysis indicates that DNA in solution adopts conformations which are intermediate between those of the ideal DNA families, such as A and B-DNA. Also, the structures obtained in these molecular dynamics simulations possess a greater degree of non-uniformity than the crystal structures. Most importantly, the helices containing adenine.methylthymine base-pairs show a further enhancement in non-uniformity. A biological role for the enhanced nonuniformity is suggested.

Distributions of water around amino acid residues in proteins.

The atomic co-ordinates from 16 high-resolution (less than or equal to 1.7 A = 0.1 nm), non-homologous proteins have been used to study the distributions of water molecule sites around the 20 different amino acid residues. The proportion of residues whose main-chain atoms are in contact with water molecules was fairly constant (between 40% and 60%), irrespective of the nature of the side-chain. However, the proportion of residues whose side-chain atoms were in contact with water molecules showed a clear (inverse) correlation with the hydrophobicity of the residue, being as low as 14% for leucine and isoleucine but greater than 80% for asparagine and arginine. Despite the problems in determining accurate water molecule sites from X-ray diffraction data and the complexity of the protein surface, distinct non-random distributions of water molecules were found. These hydration patterns are consistent with the expected stereochemistry of the potential hydrogen-bonding sites on the polar side-chains. The water molecules around apolar side-chains lie predominantly at van der Waals' contact distances, but most of these have a primary, shorter contact with a neighbouring polar atom. Further analysis of these distributions, combined with energy minimization techniques, should lead to improved modelling of protein structures, including their primary shells of hydration.

Analysis of protein main-chain solvation as a function of secondary structure.

We have analysed the hydration of main-chain carbonyl and amide groups in 24 high-resolution well-refined protein structures as a function of the secondary structure in which these polar groups occur. We find that main-chain atoms in beta-sheets are as hydrated as those in alpha-helices, with most interactions involving "free" amide and carbonyl groups that do not participate in secondary structure hydrogen bonds. The distributions of water molecules around these non-bonded carbonyl groups reflect specific steric interactions due to the local secondary structure. Approximately 20% and 4%, respectively of bonded carbonyl and amide groups interact with solvent. These include interactions with carbonyl groups on the exposed faces of alpha-helices that have been correlated previously with bending of the helix. Water molecules interacting with alpha-helices occur mainly at the amino and carbonyl termini of the helices, in which case the solvent sites maintain the hydrogen bonding by bridging between residues i and i-3 or i-4 at the amino terminus and between i and i+3 or i+4 at the carbonyl terminus. We also see a number of solvent-mediated Ncap and Ccap interactions. The water molecules interacting with beta-sheets occur mainly at the edges, in which case they extend the sheet structure, or at the ends of strands, in which case they extend the beta-ladder. In summary, the solvent networks appear to extend the hydrogen-bonding structure of the secondary structures. In beta-turns, which usually occur at the surface of a protein, exposed amide and carbonyl groups are often hydrated, especially close to glycine residues. Occasionally water molecules form a bridge between residues i and i+3 in the turn and this may provide extra stabilization.

Folate improves endothelial function in coronary artery disease: an effect mediated by reduction of intracellular superoxide?

Homocysteine is a risk factor for coronary artery disease (CAD). Folic acid lowers homocysteine and may improve endothelial function in CAD, although the mechanism is unclear. We investigated the effect of folic acid on endothelial function, homocysteine, and oxidative stress in patients with CAD. We also examined the acute effect of 5-methyltetrahydrofolate (5-MTHF), the principal circulating folate, on endothelial function in vivo and on intracellular superoxide in cultured endothelial cells. A randomized crossover study of folic acid (5 mg daily) for 6 weeks was undertaken in 52 patients with CAD. Ten further patients were given intra-arterial 5-MTHF. Endothelial function was assessed by flow-mediated dilatation (FMD). Folic acid increased plasma folate (P<0.001), lowered homocysteine by 19% (P<0.001), and improved FMD (P<0.001). FMD improvement did not correlate with homocysteine reduction. Malondialdehyde and total plasma antioxidant capacity, markers of oxidative stress, were unchanged. 5-MTHF acutely improved FMD (P<0.001) without altering homocysteine (P=0.47). In vitro, 5-MTHF abolished homocysteine-induced intracellular superoxide increase (P<0.001); this effect was also observed with folic acid and tetrahydrobiopterin. Our data support the beneficial effect of folic acid on endothelial function in CAD but suggest that the mechanism is independent of homocysteine. Reduction of intracellular endothelial superoxide may have contributed to the effect.

Endothelial function is impaired in fit young adults of low birth weight.

OBJECTIVE: Non-insulin-dependent diabetes, hypertension and ischaemic heart disease, with insulin resistance, are associated with low birth weight (the 'Small Baby Syndrome'). Common to these adult clinical conditions is endothelial dysfunction. We tested the hypothesis that endothelial dysfunction could precede their development in those of low birth weight. METHODS: Endothelial function was measured by ultrasonic 'wall-tracking' of flow-related brachial artery dilatation in fit 19-20 year old subjects randomly selected (blind to the investigators throughout the study) from low (< 2.5 kg) and normal (3.0-3.8 kg) birth weight subjects in the 1975-7 cohort of the Cardiff Births Survey and with no known cause for endothelial dysfunction. RESULTS: Flow-related dilatation was impaired in low birth weight relative to normal birth weight subjects (median 0.04 mm [1.5%] [n = 22] cf. 0.11 mm [4.1%] [n = 17], p < 0.05; 0.04 mm [1.5%] [n = 15] cf. 0.12 mm [4.4%] [n = 12], p < 0.05 after exclusion of inadvertently included ever-smokers). CONCLUSION: The findings suggest that endothelial dysfunction is a consequence of foetal malnutrition, consistent with contributing to the clinical features of the 'Small Baby Syndrome' in later adult life.

Syndrome X and endothelial dysfunction.

OBJECTIVE: Syndrome X (angina, normal coronary arteriogram and positive exercise test) remains an enigma with unexplained features and apparent conflicts of evidence. The present study addressed whether (i) the Syndrome is characterised by generalised flow-related endothelial dysfunction, (ii) myocardial thallium201 defects reflect myocardial or microvascular dysfunction, (iii) endothelial dysfunction and its consequences can be improved by oral L-arginine. METHODS: Flow-mediated brachial artery dilatation was measured by ultrasonic 'wall-tracking' in 7 Syndrome X patients, further characterised as having thallium201 defects and no known cause of endothelial dysfunction, and a normal control group. Syndrome X patients entered a 4-week randomised double-blind placebo-controlled cross-over trial of oral L-arginine (7 g twice daily), with brachial artery studies, exercise tests and technetium99 tetrafosmin scans. RESULTS: Flow-mediated dilatation was absent in Syndrome X vs. normal. Stress technetium99 tetrafosmin and thallium201 scans showed similar defects. Flow-mediated dilatation, symptom-limited exercise duration and peak oxygen consumption (VO2max) were increased but rate-pressure-product (RPP) and radionuclide defects were unchanged after L-arginine vs. placebo. CONCLUSIONS: The study supports coronary microvascular rather than myocardial dysfunction and shows loss of flow-mediated dilatation in systemic arteries. Oral L-arginine improved flow-mediated dilatation, exercise capacity and VO2max (by ca. 17%) despite unchanged RPP. The findings support generalised endothelial dysfunction. The arginine effects imply NO-mediated improvement of skeletal muscle perfusion suggesting improved homogeneity of microvascular distribution.

Competing interactions contributing to alpha-helical stability in aqueous solution.

The stability of a 15-residue peptide has been investigated using CD spectroscopy and molecular simulation techniques. The sequence of the peptide was designed to include key features that are known to stabilize alpha-helices, including ion pairs, helix dipole capping, peptide bond capping, and aromatic interactions. The degree of helicity has been determined experimentally by CD in three solvents (aqueous buffer, methanol, and trifluoroethanol) and at two temperatures. Simulations of the peptide in the aqueous system have been performed over 500 ps at the same two temperatures using a fully explicit solvent model. Consistent with the CD data, the degree of helicity is decreased at the higher temperature. Our analysis of the simulation results has focused on competition between different side-chain/side-chain and side-chain/main-chain interactions, which can, in principle, stabilize the helix. The unfolding in aqueous solution occurs at the amino terminus because the side-chain interactions are insufficient to stabilize both the helix dipole and the peptide hydrogen bonds. Loss of capping of the peptide backbone leads to water insertion within the first peptide hydrogen bond and hence unfolding. In contrast, the carboxy terminus of the alpha-helix is stable in both simulations because the C-terminal lysine residue stabilizes the helix dipole, but at the expense of an ion pair.

Buried waters and internal cavities in monomeric proteins.

We have analyzed the buried water molecules and internal cavities in a set of 75 high-resolution, nonhomologous, monomeric protein structures. The number of hydrogen bonds formed between each water molecule and the protein varies from 0 to 4, with 3 being most common. Nearly half of the water molecules are found in pairs or larger clusters. Approximately 90% are shown to be associated with large cavities within the protein, as determined by a novel program, PRO_ACT. The total volume of a protein's large cavities is proportional to its molecular weight and is not dependent on structural class. The largest cavities in proteins are generally elongated rather than globular. There are many more empty cavities than hydrated cavities. The likelihood of a cavity being occupied by a water molecule increases with cavity size and the number of available hydrogen bond partners, with each additional partner typically stabilizing the occupied state by 0.6 kcal/mol.

Endothelial function and coagulant factors in growth hormone-treated hypopituitary adults receiving desmopressin.

Although GH deficiency may underlie the increased cardiovascular risk in adult hypopituitarism, other coexisting hormonal deficiencies and/or unphysiological hormone replacement may contribute. L-Deamino-8-D-arginine (DDAVP), when administered parenterally, potentiates hemostasis by increasing plasma procoagulant factors. We investigated whether chronic intranasal DDAVP therapy influences clotting factors (plasma fibrinogen, factor VIII, and von Willebrand factor antigen) and endothelial function (flow-mediated dilation of the brachial artery) in 30 GH-treated hypopituitary subjects, including both DDAVP-treated subjects (group A) (mean age, 46 +/- 11 yr) and vasopressin-sufficient subjects (group B) (mean age, 47 +/- 16 yr). Fifteen healthy controls (group C) (mean age, 48 +/- 12 yr) were also studied. All hypopituitary patients were receiving stable GH replacement (median duration, 19 months). Comparing the three groups, concentrations of fibrinogen (mean +/- SD) (A, 3.3 +/- 1.0 g/liter vs. B, 3.5 +/- 0.9 vs. C, 2.6 +/- 0.8, P < 0.05), factor VIII (A, 130% +/- 30% vs. B, 128% +/- 30% vs. C, 104% +/- 35%, P < 0.05) and von Willebrand factor antigen (A, 124% +/- 35% vs. B, 134% +/- 45% vs. C, 93% +/- 36%, P < 0.05) were higher in hypopituitary subjects, compared with controls. However, there were no differences in clotting factors between groups A and B. Flow-mediated dilation did not differ significantly between the two hypopituitary groups (A, 5.9% +/- 2.0% vs. B, 4.7% +/- 1.6%) and was similar to that in the control group (C, 5.7% +/- 2.1%). In conclusion, although endothelium-dependent vasodilation is intact in GH-treated hypopituitary adults, elevated concentrations of hemostatic markers suggest the persistence of a prothrombotic tendency and endothelial dysfunction. Intranasal DDAVP does not appear to influence this proatherogenic profile in hypopituitary adults with vasopressin deficiency.

Clinical evaluation of recombinant factor IX.

The pharmacokinetics, safety, and efficacy of recombinant factor IX (rFIX) have been evaluated in previously treated and untreated patients with hemophilia B. In a study of 56 previously treated patients, there was a total of 1,070 hemorrhages, which required 1,514 infusions of rFIX. Of the 1,070 episodes, 80% resolved after a single rFIX infusion. The majority of the remaining episodes requiring more than 1 infusion were either major or complicated hemorrhages. Eighty-seven percent of the 1,514 infusions were rated by the physicians or patients as providing an excellent or good response. These results are consistent with the efficacy data from other hemophilia product clinical trials. rFIX has also been administered as bolus doses or by continuous infusion in conjunction with 13 surgical procedures. Estimated blood loss during and after surgery was as expected when compared with blood loss for similar procedures in patients without hemophilia, and 97% of the clinical responses during and after surgery were rated by physicians or patients as excellent or good. Pharmacokinetic comparison of rFIX with one plasma-derived product showed a statistically significant lower recovery (28% less) of rFIX. The half-lives between the two products were comparable. Common adverse events associated with rFIX treatment have been comparable to other factor IX products. As expected, there has been no evidence of viral transmission by rFIX.

Is the fatty meal a trigger for acute coronary syndromes.

This hypothesis paper aims to illustrate the role of fatty meal ingestion has on the vascular endothelium and coagulation system. In particular highlighting the potential risk of fatty meal ingestion both as a trigger to an adverse factor in patients with acute coronary syndromes. We propose that as a result of ingesting fatty meals as a part of daily living, there occurs a constellation of changes in the vasculature that results in both a hypercoagulable and a provasoconstrictor state. These acute changes in response to a fatty meal on endothelial function, prothrombosis, and platelet activation can potentially trigger, facilitate and propagate the forces that drive acute coronary syndromes. In type 2 diabetes, adverse postprandial phenomena are exaggerated and prolonged and may therefore be expected to contribute significantly to the excess risk of acute coronary syndromes and atherosclerotic development in these subjects.

The incidence of ulcerative keratitis among aphakic contact lens wearers in New England.

We conducted a population-based incidence study in five New England states to quantify the risk of ulcerative keratitis associated with contact lens use among aphakic persons. All practicing ophthalmologists in the five-state area were surveyed to identify prospectively all new cases of ulcerative keratitis during a 4-month period. The number of aphakic persons using specific types of contact lenses was estimated through a telephone survey of 4178 households identified by random digit dialing. The annualized incidence of ulcerative keratitis among aphakic persons using contact lenses was estimated to be 52 cases per 10,000 aphakic contact lens wearers (95% confidence interval (CI), 31.1 to 86.9). The risk of ulcerative keratitis varied substantially by lens use, with extended wear having an estimated sevenfold greater risk relative to daily wear (95% CI, 1.6 to 30.2). Rates of ulcerative keratitis in aphakic persons using contact lenses were much greater than rates among cosmetic wearers of the same lens type: for daily-wear lenses, aphakic persons were estimated to have 6.3 times the risk of cosmetic wearers (95% CI, 1.9 to 21.0), and for extended-wear lenses, aphakic persons were estimated to have 8.7 times the risk of cosmetic wearers (95% CI, 3.5 to 21.9). These risks are useful in assessing the benefits and risks of contact lens wear as an alternative to other methods of aphakic correction.

Cardiovascular syndromes X, endothelial dysfunction and insulin resistance.

Cardiac Syndrome X (microvascular angina) and the more recently described metabolic Syndrome X (an epidemiological association between insulin resistance and atheroma, dyslipidaemia, and hypertension) may have more in common than the chance of their common sobriquet, in view of evidence that microvascular angina too is characterised by insulin resistance and endothelial dysfunction. The implications are discussed.

The biological implications of damage to DNA incorporating an 8-oxodeoxyguanine:cytosine basepair.

DNA damage produced by free radicals is probably the most frequent lesion encountered by cells (Wallace, S.S., Environmental and Molecular Mutagenesis 12, 431-477, 1988 (1)). One of the most common effects is the formation of 7-hydro-8-oxodeoxyguanine due to oxygen radicals interacting with the normal guanine base. Such chemical changes appear to be important in mutagenesis, cancer and aging. We have used computer simulation techniques to model the effect of inclusion of such a modified base within a duplex strand of DNA. We find that such modifications can be stabilized within a normal sequence. The conformation of the modified base relative to the sugar residue depends on many local interactions not accessible to the isolated nucleoside. We have also studied the essential dynamics of both normal and modified sequences and show that there are only subtle changes to the dynamics on inclusion of such a modification.