Molecular dynamics study of water channels in natural and synthetic amyloid-ß fibrils.

We compared all-atom explicit solvent molecular dynamics simulations of three types of Aß(1-40) fibrils: brain-seeded fibrils (2M4J, with a threefold axial symmetry) and the other two, all-synthetic fibril polymorphs (2LMN and 2LMP, made under different fibrillization conditions). Fibril models were constructed using either a finite or an infinite number of layers made using periodic images. These studies yielded four conclusions. First, finite fibrils tend to unravel in a manner reminiscent of fibril dissolution, while infinite fibrils were more stable during simulations. Second, salt bridges in these fibrils remained stable in those fibrils that contained them initially, and those without salt bridges did not develop them over the time course of the simulations. Third, all fibrils tended to develop a "stagger" or register shift of ß-strands along the fibril axis. Fourth and most importantly, the brain-seeded, 2M4J, infinite fibrils allowed bidirectional transport of water in and out of the central longitudinal core of the fibril by rapidly developing gaps at the fibril vertices. 2LMP fibrils also showed this behavior, although to a lesser extent. The diffusion of water molecules in the fibril core region involved two dynamical states: a localized state and directed diffusion in the presence of obstacles. These observations provided support for the hypothesis that Aß fibrils could act as nanotubes. At least some Aß oligomers resembled fibrils structurally in having parallel, in-register ß-sheets and a sheet-turn-sheet motif. Thus, our findings could have implications for Aß cytotoxicity, which may occur through the ability of oligomers to form abnormal water and ion channels in cell membranes.

An ethical dilemma: malignant melanoma in a 51-year-old patient awaiting simultaneous kidney and pancreas transplantation for type 1 diabetes.

Malignant melanoma is a high-risk skin cancer that, in potential transplant recipients, is considered a substantial contraindication to solid organ transplantation due to significant risk of recurrence with immunosuppression. Current guidelines stipulate waiting between 3 and 10 years after melanoma diagnosis. However, in young patients with end-stage organ failure and malignant melanoma, complex ethical and moral issues arise. Assessment of the true risk associated with transplantation in these patients is difficult due to lack of prospective data, but an autonomous patient can make a decision that clinicians may perceive to be high risk. The national and worldwide shortage of available organs also has to be incorporated into the decision to maximize the net benefit and minimize the risk of graft failure and mortality. The incidence of malignant melanoma worldwide is increasing faster than that of any other cancer and continues to pose ethically challenging decisions for transplant specialists evaluating recipients for solid organ transplantation.

Low-energy (<10 meV) feature in the nodal electron self-energy and strong temperature dependence of the Fermi velocity in Bi{2}Sr{2}CaCu{2}O{8+δ}.

Using low photon energy angle-resolved photoemission, we study the low-energy dispersion along the nodal (π,π) direction in Bi{2}Sr{2}CaCu{2}O{8+δ} as a function of temperature. Less than 10 meV below the Fermi energy, the high-resolution data reveal a novel "kinklike" feature in the electron self-energy that is distinct from the larger well-known kink roughly 70 meV below E{F}. This new kink is strongest below the superconducting critical temperature and weakens substantially at higher temperatures. A corollary of this finding is that the Fermi velocity v{F}, as measured in this low-energy range, varies rapidly with temperature-increasing by almost 30% from 70 to 110 K. The behavior of v{F}(T) appears to shift as a function of doping, suggesting a departure from simple "universality" in the nodal Fermi velocity of cuprates.

Wrinkling and strain softening in single-wall carbon nanotube membranes.

The nonlinear elasticity of thin supported membranes assembled from length purified single-wall carbon nanotubes is analyzed through the wrinkling instability that develops under uniaxial compression. In contrast with thin polymer films, pristine nanotube membranes exhibit strong softening under finite strain associated with bond slip and network fracture. We model the response as a shift in percolation threshold generated by strain-induced nanotube alignment in accordance with theoretical predictions.

A simple kinetic model of polymer adsorption and desorption.

A model of the desorption and adsorption of a polymer layer at a planar surface indicates a transition from exponential kinetics at high temperatures to nonexponential kinetics (stretched exponential with index one-half) at lower temperatures where these processes are diffusion-limited. Measurements of polystyrene desorption through polyisoprene overlayers show this predicted transition. Corroborative results are obtained for polystyrene desorption through polymethylmethacrylate overlayers. This identification of two distinct kinetic regimes suggests a unifying perspective from which to analyze polymer and biopolymer mobility at surfaces.

Experimental setup for low-energy laser-based angle resolved photoemission spectroscopy.

A laser-based angle resolved photoemission (ARPES) system utilizing 6 eV photons from the fourth harmonic of a mode-locked Ti:sapphire oscillator is described. This light source greatly increases the momentum resolution and photoelectron count rate, while reducing extrinsic background and surface sensitivity relative to higher energy light sources. In this review, the optical system is described, and special experimental considerations for low-energy ARPES are discussed. The calibration of the hemispherical electron analyzer for good low-energy angle-mode performance is also described. Finally, data from the heavily studied high T(c) superconductor Bi(2)Sr(2)CaCu(2)O(8+delta) (Bi2212) is compared to the results from higher photon energies.

Dielectric study of the antiplasticization of trehalose by glycerol.

Recent measurements have suggested that the antiplasticizing effect of glycerol on trehalose can significantly increase the preservation times of proteins stored in this type of preservative formulation. In order to better understand the physical origin of this phenomenon, we examine the nature of antiplasticization in trehalose-glycerol mixtures by dielectric spectroscopy. These measurements cover a broad frequency range between 40 Hz to 18 GHz (covering the secondary relaxation range of the fragile glass-former trehalose and the primary relaxation range of the strong glass-former glycerol) and a temperature (T) range bracketing room temperature (220 K to 350 K). The Havriliak-Negami function precisely fits our relaxation data and allows us to determine the temperature and composition dependence of the relaxation time tau describing a relative fast dielectric relaxation process appropriate to the characterization of antiplasticization. We observe that increasing the glycerol concentration at fixed T increases tau (i.e., the extent of antiplasticization) until a temperature dependent critical "plasticization concentration" xwp is reached. At a fixed concentration, we find a temperature at which antiplasticization first occurs upon cooling and we designate this as the "antiplasticization temperature," Tant. The ratio of the tau values for the mixture and pure trehalose is found to provide a useful measure of the extent of antiplasticization, and we explore other potential measures of antiplasticization relating to the dielectric strength.

Heart transplantation in children with congenital heart disease.

OBJECTIVES: The aim of this study was to describe heart transplantation in children with congenital heart disease and to compare the results with those in children undergoing transplantation for other cardiac diseases. BACKGROUND: Reports describe decreased survival after heart transplantation in children with congenital heart disease compared with those with cardiomyopathy. However, transplantation is increasingly being considered in the surgical management of children with complex congenital heart disease. Present-day results from this group require reassessment. METHODS: The diagnoses, previous operations and indications for transplantation were characterized in children with congenital heart disease. Pretransplant course, graft ischemia time, post-transplant survival and outcome (rejection frequency, infection rate, length of hospital stay) were compared with those in children undergoing transplantation for other reasons (n = 47). RESULTS: Thirty-seven children (mean [+/- SD] age 9 +/- 6 years) with congenital heart disease underwent transplantation; 86% had undergone one or more previous operations. Repair of extracardiac defects at transplantation was necessary in 23 patients. Causes of death after transplantation were donor failure in two patients, surgical bleeding in two, pulmonary hemorrhage in one, infection in four, rejection in three and graft atherosclerosis in one. No difference in 1- and 5-year survival rates (70% vs. 77% and 64% vs. 65%, respectively), rejection frequency or length of hospital stay was seen between children with and without congenital heart disease. Cardiopulmonary bypass and donor ischemia time were significantly longer in patients with congenital heart disease. Serious infections were more common in children with than without congenital heart disease (13 of 37 vs. 6 of 47, respectively, p = 0.01). CONCLUSIONS: Despite the more complex cardiac surgery required at implantation and longer donor ischemic time, heart transplantation can be performed in children with complex congenital heart disease with success similar to that in patients with other cardiac diseases.

The influence of HLA-A, B, and DR matching on graft survival in primary cadaveric renal transplantation in Belfast.

HLA-DR matching has been shown in a retrospective study of 72 renal transplant patients to significantly enhance graft survival at 12 months. HLA-A and -B antigen matching also increased the graft survival rate significantly. Analysis of combined HLA-A, -B and -DR matching suggested an improvement in graft survival rate with better matching, but this did not attain statistical significance. It is now our policy to use HLA-DR matching prospectively and to ensure that all recipients receive a kidney with a maximum of 1 HLA-DR incompatibility and a minimum of 2 HLA-A and -B antigens shared.

Increased incidence of IgM class smooth muscle antibody in patients after renal transplantation.

Autoantibodies were examined in 70 patients with renal failure, before acceptance on a hemodialysis program, during the program, and up to 3 months after renal transplantation. Smooth muscle antibody (SMA) in the IgM class was detected in 76% of the patients after transplantation compared with 14% before transplantation. This increase was significant at the 5% level. Furthermore, two groups of patients were distinguished on the basis of a 4-fold or greater increase or no demonstrable increase in the titer of IgM SMA after transplantation. Rejection episodes occurred more frequently amongst patients from this former group (67%) compared with the latter group (35%).

Advantages of low dose steroid from the day after renal transplantation.

We have used a low dose of steroid (20 mg of prednisolone), commencing the day after transplantation, for 151 consecutive renal transplants in 141 patients. Five patients received grafts from living related donors, 146 received cadaver grafts. All patients received azathioprine for routine immunosuppression and the first 47 received a single dose of actinomycin C i.v. for treatment of rejection. No other immunosuppressive drugs were used. This treatment provided satisfactory immunosuppression as 109 of 151 grafts continue to function for periods of 3 months to 10 years and, of 42 grafts lost, only 17 failed from rejection. The cumulative survival of first cadaver grafts at 1 and 2 years in recipients of all ages (7 to 55 years) was 77.9 and 76.0%, respectively; in recipients 15 to 34 years old, 90.9 and 86.1%, respectively. Twenty-three patients died, no patient died from infection during the admission for transplantation, and infection played a part in the deaths of only four patients. The incidence of other complications was low; seven patients developed gastrointestinal complications, one died, four patients developed diabetes, all survived; only one patient developed avascular necrosis of bone.

Carcinogenicity testing of phthalate esters and related compounds by the National Toxicology Program and the National Cancer Institute.

Five phthalate ester and related compounds (phthalic anhydride, phthalamide, di(2-ethylhexyl) phthalate, di(2-ethylhexyl) adipate and butyl benzyl phthalate) have been tested for carcinogenic effects in standard lifetime rodent feeding studies. Groups of 50 male and female rats and mice were fed diets containing various concentrations of the test chemicals for 102-106 consecutive weeks. The dietary concentrations were estimated to be maximally tolerated doses and half maximally tolerated doses. All animals that died during the study and all survivors at the end of two years were examined grossly and microscopically for the presence of tumors. The incidences of animals with tumors at a specific anatomic site in the treated groups and the controls were compared statistically. Neither phthalamide nor phthalic anhydride increased tumor incidences in rats or mice. Di(2-ethylhexyl) phthalate increased the incidences of liver tumors in rats and mice of both sexes, while di(2-ethylhexyl) adipate caused liver tumors in male and female mice, only. Butyl benzyl phthalate did not cause tumors in male or female mice, but the incidence of myelomonocytic leukemia in butyl benzyl phthalate-treated female rats was significantly greater than that in the controls. Chemically induced early deaths in the butyl benzyl phthalate-treated male rats precluded an evaluation of carcinogenic potential in this sex. Under the conditions of these tests, di(2-ethylhexyl) adipate was considered to be carcinogenic in both rats and mice and di(2-ethylhexyl) adipate was considered to be carcinogenic in mice. The evidence for carcinogenic effects of butyl benzyl phthalate in female rats was judged to be equivocal because of the variable nature of the incidence of myelomonocytic leukemia in Fischer 344 rats. Phthalamide and phthalic anhydride did not exhibit carcinogenic effects in these studies.

Visual recovery in orbital vasculitis.

A 46-year-old woman with polyarteritis nodosa and chronic renal failure developed sudden loss of vision which was associated with orbital vasculitis. Treatment with cyclophosphamide produced rapid improvement in vision, which has been preserved with maintenance doses of cyclophosphamide and prednisolone.

Determination of anthranilic acid in plasma.

A simple, specific GLC method was developed for the determination of anthranilic acid in plasma. This method is based on extraction from a carefully controlled buffer followed by removal of solvent, silyation, and detection in the gas chromatograph. The procedure is quantitative in the 2-10 microgram/ml range.

Absorption, distribution, and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one in rats, dogs, and humans.

The absorption and metabolic fate of 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b)(1,3)-benzoxazin-9-one (I) was studied in rats, dogs, and humans. Orally administered I was readily absorbed by all species. In the rat, orally administered I was converted to its metabolite, 5-chlorosalicylic acid, by the intestinal wall. The half-lives of blood radioactivity, after the oral administration of I-9-14C, were about 18 and 12 hr in the rat and beagle hound, respectively. In human subjects, no intact I was detected in the bloodstream; however, the clearance of the metabolite, 5-chlorosalicylic acid, had a half-life of about 33 hr. Cleavage of the oxazine ring of I generated 5-chlorosalicylic acid, which was excreted both in the free form and conjugated with glycine and glucuronic acid. The isoxazole moiety was converted to beta-hydroxybutyric acid and its metabolites carbon dioxide and fumaric, citric, alpha-ketoglutaric, succinic, and malic acids. Binding of I to plasma proteins was extensive but was less than that of 5-chlorosalicylic acid.

Pre-transplantation immunological monitoring and graft survival in recipients of renal allografts.

Various immunological parameters were measured pre-transplantation in 82 renal transplant recipients. The results were compared with the clinical course of the recipient post-transplantation and with the results of 40 controls. Only one test C3 inactivation products (C3i) was associated with transplant outcome in that 0/30 patients with no rejection episodes had C3i whereas 9/38 patients with rejection episodes, including 3/12 patients whose graft failed, had C3i.

Mismatching for HLA-A, -B antigens and renal graft survival.

One hundred and seventy five recipients of a kidney graft were analyzed to see if mismatching for certain HLA-A, -B antigens was detrimental to graft survival. No association was found between graft survival and a specific mismatched HLA-A, -B antigen.

Isotope renography and long term follow-up of renal transplant patients.

Isotope renography was carried out in 64 kidney transplant patients attending a follow-up clinic. Graft survival in these patients ranged from two months to ten years. Forty-one patients had normal renograms and 98% of these had satisfactory function (creatinine clearance greater than 50 ml/min). Eighteen patients showed a major renogram abnormality and 50% of these had impaired function. Five of these 18 have been explored and found to have graft complications (obstructive disease in four, chronic pyelonephritis in one). Exploration has not been undertaken in the remaining 13 but nine show evidence suggestive of graft pathology (proteinuria, impaired creatinine clearance, elevated urinary enzymes, calyceal distortion on IVP). A successful kidney transplant should result in a normal isotope renogram, and a major abnormality of the renogram suggests the presence of a graft complication, even when the creatinine clearance is unimpaired. We feel renography is useful for identification of renal transplant patients who require further investigation or closer follow-up.

Critical properties and phase separation in lattice Boltzmann fluid mixtures.

Basic equilibrium properties of lattice Boltzmann (LB) fluid mixtures (coexistence curve, surface tension, interfacial profile, correlation length) are calculated to characterize the critical phenomena occurring in these model liquids and to establish a reduced variable description allowing a comparison with real fluid mixtures. We observe mean-field critical exponents and amplitudes so that the LB model may be useful for modeling high molecular weight polymer blends and other fluid mixtures approximated over a wide temperature range by mean-field theory. We also briefly consider phase separation under quiescent and shearing conditions and point out the strong influence of interacting boundaries on the qualitative form of the late-stage phase-separation morphology.