Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial.

BACKGROUND: Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients' organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments. METHODS: In our parallel-group randomised trial, patients meeting Oxford criteria for chronic fatigue syndrome were recruited from six secondary-care clinics in the UK and randomly allocated by computer-generated sequence to receive specialist medical care (SMC) alone or with adaptive pacing therapy (APT), CBT, or GET. Primary outcomes were fatigue (measured by Chalder fatigue questionnaire score) and physical function (measured by short form-36 subscale score) up to 52 weeks after randomisation, and safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments. Primary outcomes were rated by participants, who were necessarily unmasked to treatment assignment; the statistician was masked to treatment assignment for the analysis of primary outcomes. We used longitudinal regression models to compare SMC alone with other treatments, APT with CBT, and APT with GET. The final analysis included all participants for whom we had data for primary outcomes. This trial is registered at http://isrctn.org, number ISRCTN54285094. FINDINGS: We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p = 0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p = 0·0003), but did not differ for APT (0·7 [-0·9 to 2·3] points lower; p = 0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p = 0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p = 0·0005), but did not differ for APT (3·4 [-1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p = 0·0027; GET p = 0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group. INTERPRETATION: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions.

Evaluating force field accuracy with long-time simulations of a ß-hairpin tryptophan zipper peptide.

We have combined graphics processing unit-accelerated all-atom molecular dynamics with parallel tempering to explore the folding properties of small peptides in implicit solvent on the time scale of microseconds. We applied this methodology to the synthetic ß-hairpin, trpzip2, and one of its sequence variants, W2W9. Each simulation consisted of over 8 µs of aggregated virtual time. Several measures of folding behavior showed good convergence, allowing comparison with experimental equilibrium properties. Our simulations suggest that the intramolecular interactions of tryptophan side chains are responsible for much of the stability of the native fold. We conclude that the ff99 force field combined with ff96 φ and ψ dihedral energies and an implicit solvent can reproduce plausible folding behavior in both trpzip2 and W2W9.

The TprK protein of Treponema pallidum is periplasmic and is not a target of opsonic antibody or protective immunity.

The finding that Treponema pallidum, the syphilis spirochete, contains 12 orthologs of the Treponema denticola outer membrane major sheath protein has engendered speculation that members of this T. pallidum repeat (Tpr) family may be similarly surface exposed. In this regard, the TprK protein was reported to be a target of opsonic antibody and protective immunity and subject to immunologically driven sequence variation. Despite these findings, results from our previous analyses of treponemal outer membranes in concert with computer-based predictions for TprK prompted us to examine the cellular location of this protein. TprK-alkaline phosphatase fusions expressed in Escherichia coli demonstrate that TprK contains a signal peptide. However, opsonophagocytosis assays failed to indicate surface exposure of TprK. Moreover, results from three independent methodologies, i.e., (a) indirect immunofluorescence analysis of agarose-encapsulated organisms, (b) proteinase K treatment of intact spirochetes, and (c) Triton X-114 phase partitioning of T. pallidum conclusively demonstrated that native TprK is entirely periplasmic. Consistent with this location, immunization with the recombinant protein failed to induce either protective immunity or select for TprK variants in the rabbit model of experimental syphilis. These findings challenge the notion that TprK will be a component of an efficacious syphilis vaccine.

Proteolysis by neutrophils. Relative importance of cell-substrate contact and oxidative inactivation of proteinase inhibitors in vitro.

Polymorphonuclear leukocytes have been implicated in connective tissue injury in a variety of disease processes. To gain insight into mechanisms by which neutrophils might degrade connective tissue macromolecules in the presence of proteinase inhibitors, we have used a model system that allows neutrophils to be held in vitro under physiologic conditions in close proximity to a very proteinase-sensitive substrate, (125)I-labeled fibronectin. We have found: (a) neutrophils spread rapidly on the fibronectin substrate; (b) fibronectin proteolysis by neutrophils is largely attributable to released elastase, and is linearly related to cell number over the range of 2,000 to 30,000 cells per assay; (c) oxidants released from neutrophils stimulated by opsonized zymosan or phorbol myristate acetate do not protect released elastase from inhibition by alpha(1)-proteinase inhibitor or alpha(2)-macroglobulin; (d) neutrophil myeloperoxidase and enzymatically generated superoxide anion render alpha(1)-proteinase inhibitor ineffective against fibronectin proteolysis when neutrophils are added 30 min later; and (e) alpha(1)-proteinase inhibitor and alpha(2)-macroglobulin incompletely inhibit fibronectin proteolysis by neutrophils (79.8+/-6.3 and 73.5+/-12.0%, respectively.) The data suggested that proteolysis due to neutrophils that are in contact with susceptible macromolecules may occur due to partial exclusion of inhibitors from the cell-substrate interface. Although confirming that alpha(1)-proteinase inhibitor is ineffective against neutrophil-derived proteolysis after exposure to oxidants, these studies did not support the hypothesis that oxidants released from stimulated neutrophils enhance activity of proteinases they release in the presence of alpha(1)-proteinase inhibitor. We anticipate that further studies with this test system will be helpful in defining conditions that modulate inflammatory connective tissue injury in diseases such as pulmonary emphysema and rheumatoid arthritis.

One-dimensional model of yeast prion aggregation.

Mammalian prion proteins (PrP) are of significant public health interest. Yeasts have proteins, which can undergo similar reconformation and aggregation processes to PrP, without posing a threat to the organism. These yeast "prions," such as SUP35, are simpler to experimentally study and model. Recent in vitro studies of the SUP35 protein found long aggregates, pure exponential growth of the misfolded form, and a lag time which depended weakly on the monomer concentration. To explain this data, we have extended a previous model of aggregation kinetics along with a stochastic approach. We assume reconformation only upon aggregation and include aggregate fissioning and an initial nucleation barrier. We find that for sufficiently small nucleation rates or seeding by a small number of preformed nuclei, the models achieve the requisite exponential growth, long aggregates, and a lag time which depends weakly on monomer concentration. The spread in aggregate sizes is well described by the Weibull distribution. All these properties point to the preeminent role of fissioning in the growth of misfolded proteins.

Cloning, expression, and tissue distribution of the rat nicotinamide adenine dinucleotide-dependent 11 beta-hydroxysteroid dehydrogenase.

A pcDNAI adult rat kidney complementary DNA (cDNA) library was screened using a sheep 11-hydroxysteroid dehydrogenase 2 (11 beta HSD-2) probe, and the isolated clones were sequenced. The 5'-end of the cDNA was determined by 5'-rapid amplification of cDNA ends. The rat 11 beta HSD-2 cDNA is 1864 base pair (bp) long. It consists of a 5'-untranslated region of 126 bp, an open reading frame of 1203 bp, and a 3'-untranslated region of 535 bp. The predicted protein contains 400 amino acid residues, with a calculated mol wt of 43,700. The rat 11 beta HSD-2 protein sequence is 85% homologous to human 11 beta HSD-2 and 76% to sheep 11 beta HSD-2. Expression of 11 beta HSD-2 messenger RNA by Northern blot and reverse transcription-polymerase chain reaction was high in kidney, distal colon, and adrenal and lower in the lung, hypothalamus, hippocampus, and midbrain. The rat 11 beta HSD-2 was transiently transfected into modified Chinese hamster ovary cells. Cells transfected with the 11 beta HSD-2 cDNA converted corticosterone into 11-dehydrocorticosterone. Conversion of corticosterone to 11-dehydrocorticosterone was NAD+ dependent and had a Km of 10.1 +/- 2.1 nM. In conclusion, we have cloned a rat NAD(+)-dependent 11 beta HSD with tissue distribution and kinetic characteristics suggesting that it could play a significant role in mineralocorticoid receptor selectivity.

Detection of estrogen receptor mRNA in human uterus.

We transcribed a cDNA clone of the human estrogen receptor (ER) with T7 RNA polymerase. The 32P-cRNA transcript complementary to ER mRNA was hybridized to poly(A)+ RNA from human uterus and revealed a single band of approximately 4.2 kilobases. No hybridization was seen with the cRNA probe of the opposite orientation. Hybridization of total RNA from calf and rat uterus yielded a single band at approximately 3.8 kilobases for both species. Total RNA from rat spleen did not hybridize. A 35S-labeled cRNA probe was prepared for in situ hybridization of ER mRNA in human uterus and spleen. Autoradiographic signal was present over endometrial epithelium, stromal cells of the lamina propria, and smooth muscle cells of the myometrium but was absent from sections of spleen. The ER mRNA hybridization label was located over cytoplasm and nuclei of uterine target cells.

Role of the nurse in the multidisciplinary team approach to care of liver transplant patients.

Nursing plays an important contributory role in the multidisciplinary team approach to patient care. The nurse who is responsible for the care of liver transplant patients requires special preparation to meet the patient's needs during the critical phases of the liver transplant process. In the hospital setting, a primary nursing-care delivery system enhances the nurse's role in supporting the goal of patient recovery. Primary nursing places the accountability and responsibility for planning, administering, and evaluating the care of the liver transplant patient with the primary nurse. The transplant nurse acts as a key link in the communication network within the multidisciplinary team, and effective communication is essential in the care of the liver transplant patient. For achievement of a life-style of independence after transplantation, the patient is assisted by the nurse, who provides instruction in such areas as diet, medications, monitoring of vital signs, and record keeping. Although the nurse is only one member contributing to the care of liver transplant patients, the nurse's role in the success of treatment is vital.

The sheep kidney contains a novel unidirectional, high affinity NADP(+)-dependent 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD-3).

The 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) enzymes convert corticosterone and cortisol to 11-dehydrocorticosterone and cortisone, and are thought to convey extrinsic specificity to the mineralocorticoid receptor by limiting access of the relatively more abundant glucocorticoids to it. Two different 11 beta-hydroxysteroid dehydrogenases (11 beta-HSD) have been described and cloned. The liver-type, NADP(+)-dependent 11 beta-HSD-1, has an affinity in the micromolar range and bidirectional activity. The NAD(+)-dependent 11 beta-HSD-2 has a higher affinity, in the nanomolar range, and exhibits only oxidase activity. 11 beta-HSD-2, because of its affinity and co-localization with the mineralocorticoid receptor, is likely to serve as the "gatekeeper" for the mineralocorticoid receptor in the kidney. Although the rat kidney expresses both isoforms, only the high-affinity, NAD(+)-dependent 11 beta-HSD-2 has been reported in the sheep kidney. We found both 11 beta-HSD NAD(+)- and NADP(+)-dependent activities in sheep kidney to be present. The NAD(+)-dependent activity exhibited a Km similar to that reported in the literature, 3.85 +/- 1.28 nM for corticosterone and 21.3 +/- 5.8 for cortisol, was distributed in approximately equal amounts between microsomes and nuclei, and was unidirectional, converting corticosterone to 11-dehydrocorticosterone. The enzyme exhibited prominent substrate inhibition. The NADP(+)-dependent activity had a Km for corticosterone of 4 +/- 1.3 nM for a Km for cortisol of 35.2 +/- 2 nM, 100-fold lower than that described for the 11 beta-HSD-1 in the liver of sheep and other species, and was more prevalent in the microsomes than the nuclei. This enzyme was not inhibited by its substrate. The NAD(+)-dependent activity was approximately 3-10 times greater than the NADP(+)-dependent activity when incubated with 5 nM corticosterone substrate, but had similar activity when incubated with 100 nM substrate concentrations. CHOP cells (a modified Chinese hamster ovary cell line) transiently transfected with the sheep 11 beta-HSD-2 plasmid exhibited a marked preference for NAD+ as co-factor. Oxidation of corticosterone by transfected cells in the presence of NADP+ was present, but minimal; NADP+ did not support the metabolism of cortisol, the primary glucocorticoid of sheep. These data suggest the existence of another NADP(+)-dependent enzyme, 11 beta-HSD-3, which, because of its high affinity and unidirectional oxidase activity, may play a physiological role in the modulation of glucocorticoid binding to both the mineralocorticoid and glucocorticoid receptors.

Anthelmintic activity of dioxapyrrolomycin.

Dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C2 produced by UC 11065 were evaluated as anthelmintics. Assays used to examine these compounds included effects on the free-living nematode Caenorhabditis elegans, ability to clear target nematodes (Haemonchus contortus and Trichostrongylus colubriformis) from jirds, and clearance of Haemonchus contortus from lambs. A crude extract of UC 11065 containing dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C2 was active against C. elegans and against H. contortus in the jird. Purified and/or synthetic samples of dioxapyrrolomycin, pyrrolomycin C, pyrrolomycin D, and piericidin C2 were tested in the jird model; only dioxapyrrolomycin exhibited appreciable activity against H. contortus (greater than or equal to 90.9% clearance at 0.33 mg/jird), while none of the compounds showed appreciable activity against T. colubriformis. Dioxapyrrolomycin cleared 99.9% of H. contortus from lambs at 12.5 mg/kg. An in vitro migration study using susceptible and closantel-resistant H. contortus showed there is cross-resistance between dioxapyrrolomycin and closantel. Dioxapyrrolomycin appears to be a narrow-spectrum anthelmintic which works through a closantel-like mode-of-action.

Concurrent infections with the ruminant nematodes Haemonchus contortus and Trichostrongylus colubriformis in jirds, Meriones unguiculatus, and use of this model for anthelmintic studies.

Haemonchus contortus- and Trichostrongylus colubriformis-infected jirds (Meriones unguiculatus) are useful for anthelmintic studies. With concurrent infections of these parasites established in the jird, questions of not only anthelmintic activity, but to some extent spectrum, could be assessed in a single model system. This report outlines a model using immunosuppressed (0.02% hydrocortisone in feed) jirds concurrently infected with H. contortus and T. colubriformis. Immunosuppressed jirds were inoculated with approximately 1,000 exsheathed infective larvae of each species, treated per os on day 10 postinoculation (PI), and killed on day 13 PI. Stomachs and small intestines were removed, opened longitudinally, incubated in distilled water at 37 C for 5 hr, fixed in formaldehyde solution, and stored for subsequent examination. Contents of both organs were examined using a stereomicroscope (15-45 x). Various standard anthelmintics were evaluated in the model; modern broad-spectrum ruminant anthelmintics (benzimidazoles, febantel, ivermectin, levamisole hydrochloride, and milbemycin D) are active uniformly and in most cases at doses comparable to those required for efficacy against these parasites in ruminants. This model, using worms of 2 genera living in distinct sites, allows preliminary evaluation of anthelmintic activity and spectrum for experimental compounds in a single cost- and resource-efficient experiment.

Gender-related therapist attributions in couples therapy: a preliminary multiple case study investigation.

Differential treatment by gender has been an ongoing area of concern and uncertainty both in society at large and in clinical research. In this investigation, therapist attributions over the course of therapy for three different couples were coded and analyzed to determine if cause for positive and negative events was assigned differentially to females and males. Additionally, the stability and globality dimensions of the therapist's attributions about the couples were examined for stereotypical gender-related patterns. Results indicate no gender differences in locus of causal attributions but some gender-related patterns in stability and globality dimensions. Implications for both couples therapy and gender bias in couples research are discussed.

Individual differences in visual discrimination of letters.

Research on the distinctive features of letters has been inconclusive. Investigators may have overlooked individual variations in their data which would have supported feature-extraction hypotheses but were concealed by analyses which averaged data into group means. Response latencies from a matching discrimination task with the 26 English capital letters were analyzed with INDSCAL, a multidimensional scaling procedure which weights individual contributions to a psychological space. Underlying a dimensions were linearity, curvature, angularity, and closure. The solution disclosed that individuals utilized these features differentially in the visual discriminations. The results suggest that future research in visual feature extraction will benefit from the examination of individual variations in the perceptual process.

Development of the Misener Nurse Practitioner Job Satisfaction Scale.

The purpose of this study was to construct a reliable and valid instrument to measure job satisfaction among nurse practitioners (NP). The methodological approach consisted of a literature review and modification of an extant instrument (Mueller/McCloskey, 1990) to reflect primary care, followed by augmentation and validation of the items suggested by nurse practitioner faculty members and Master's prepared nurse practitioners. A 77-item scale was developed and mailed to 413 NPs recognized by the state boards of nursing in two states. Usable returns were received from 342 (83%) NPs. Items were reviewed for validity prior to field-testing the instrument. The 77 items were subjected to exploratory factor analysis to support construct explication using the maximum likelihood method of extraction and a promax rotation. An eigenvalue cutoff of 1.0 and item-to-factor loadings of at least .35 were criteria that guided item retention. Thirty-three items were deleted. The resultant six factors were named: (a) intra-practice partnership/collegiality; (b) challenge/autonomy; (c) professional, social, and community interaction; (d) professional growth; (e) time; and (f) benefits. The six factors (subscales) produced internal consistency reliability estimates of .94, .89, .84, .86, .83, and .79, respectively. The 44 retained items were used to create the final version of the Misener Nurse Practitioner Job Satisfaction Scale (MNPJSS), with a possible maximum score of 264 using a 6-point Likert-type scale.

Sequence dependent electron transport in wet DNA: ab initio and molecular dynamics studies.

We combine molecular dynamics simulations and density functional theory to analyze the electrical structure and transmission probability in four different DNA sequences under physiological conditions. The conductance in these sequences is primarily controlled by interstrand and intrastrand coupling between low-energy guanine orbitals. Insertion of adenine-thymine base pairs between the guanine-cytosine rich domains acts as a tunneling barrier. Our theory explains recent length dependent conductance data for individual DNA molecules in water.

Correlated hybridization in transition-metal complexes.

We apply local orbital basis density functional theory (using SIESTA) coupled with a mapping to the Anderson impurity model to estimate the Coulomb assisted or correlated hybridization between transition-metal orbitals and ligand orbitals for a number of molecular complexes. We find remarkably high values which can have several physical implications including (i) renormalization of effective single-band or multiband Hubbard model parameters for the cuprates and, potentially, elemental iron, and (ii) spin polarizing molecular transistors.

Optical conductivity of wet DNA.

Motivated by recent experiments, we study the optical conductivity of DNA in its natural environment containing water molecules and counterions. Our density functional theory calculations (using Siesta) for four base pair B-DNA with order 250 surrounding water molecules suggest a thermally activated doping of the DNA by water states which generically leads to an electronic contribution to low-frequency absorption. The main contributions to the doping result from water near DNA ends, breaks, or nicks and are thus potentially associated with temporal or structural defects in the DNA.

Phase diagram of the two-channel kondo lattice model in one dimension.

Employing the density matrix renormalization group method and strong-coupling perturbation theory, we study the phase diagram of the SU(2)xSU(2) Kondo lattice model in one dimension. We show that, at quarter filling, the system can exist in two phases depending on the coupling strength. The weak-coupling phase is dominated by RKKY exchange correlations, while the strong-coupling phase is characterized by strong antiferromagnetic correlations of the channel degree of freedom. These two phases are separated by a quantum critical point. For conduction-band fillings of less than one-quarter, we find a paramagnetic metallic phase at weak coupling and a ferromagnetic phase at moderate to strong coupling.