Predictors of course and outcome in hypochondriasis after cognitive-behavioral treatment

Background. Predictors of treatment outcome were evaluated in a clinical sample suffering from hypochondriasis. Methods: The sample consisted of 96 patients with hypochondriacal disorder according to DSM-IV or high syndrome scores on the Illness Attitude Scales (IAS) or Whiteley Index (WI). After intense inpatient cognitive-behavioral treatment (CBT), 60% of the patients were classified as responders because of substantial improvements or recovery from hypochondriacal symptomatology. Results: Non-responders were characterized by a higher degree of pre-treatment hypochondriasis, more somatization symptoms and general psychopathology (SCL-90R), more dysfunctional cognitions related to bodily functioning, higher levels of psychosocial impairments, and more utilization of the health care system as indicated by the number of hospital days and costs for inpatient treatments and medication. No predictive value was found for sociodemographic variables, comorbidity with other mental disorders and chronicity. Multiple linear regression showed that pre-treatment variables significantly predicted IAS scores at post-treatment (R-2 = 0.59), changes during treatment (0.10), IAS scores at follow-up two years later (0.41) and changes between baseline and follow-up (0.25). Conclusions: The results demonstrate the relevance of various psychopathological variables and health care utilization as important indicators for outcome and further course of clinical hypochondriasis. Copyright (C) 2002 S. Karger AG, Basel

Stretching Single Domain Proteins: Phase Diagram and Kinetics of Force-Induced Unfolding

Single molecule force spectroscopy reveals unfolding of domains in titin upon stretching. We provide a theoretical framework for these experiments by computing the phase diagrams for force-induced unfolding of single domain proteins using lattice models. The results show that two-state folders (at zero force) unravel cooperatively whereas stretching of non-two-state folders occurs through intermediates. The stretching rates of individual molecules show great variations reflecting the heterogeneity of force-induced unfolding pathways. The approach to the stretched state occurs in a step-wise "quantized" manner. Unfolding dynamics depends sensitively on topology. The unfolding rates increase exponentially with force f till an optimum value which is determined by the barrier to unfolding when f=0. A mapping of these results to proteins shows qualitative agreement with force-induced unfolding of Ig-like domains in titin. We show that single molecule force spectroscopy can be used to map the folding free energy landscape of proteins in the absence of denaturants.Comment: 12 pages, Latex, 6 ps figure

Cognitive behavior therapy in panic disorder and comorbid major depression - A naturalistic study

Background: There is a lack of evidence about the effectiveness of cognitive behavior therapies (CBT) in settings of routine clinical care as well as in the treatment of panic and comorbid disorders. Methods: We investigated a group-oriented CBT approach for 80 patients with panic disorder including 35 patients with current comorbid major depression. Assessments took place 6 months before treatment, at the beginning and end of treatment, and 1 year later. Structured interviews and multiple clinical self-rating scales were used. Results: Panic patients with comorbid major depression showed higher anxiety-specific and nonspecific pathology. The most striking benefits were in reducing avoidance behavior, while improvements concerning catastrophic beliefs were smaller, but still significant. For most self-rating scale results, patients with and without comorbid depression improved to a comparable degree. However, the end-state functioning of patients with panic disorder and current comorbid depression at admission is significantly lower than for patients with panic disorder alone, Conclusions: The results point to the necessity to develop and improve treatment approaches for patients with comorbidity of panic disorder and current major depression. Copyright (C) 2000 S.Karger AG, Basel

In vitro and in vivo pharmacological activities of 14-o-phenylpropyloxymorphone, a potent mixed mu/delta/kappa-opioid receptor agonist with reduced constipation in mice

Pain, particularly chronic pain, is still an unsolved medical condition. Central goals in pain control are to provide analgesia of adequate efficacy and to reduce complications associated with the currently available drugs. Opioids are the mainstay for the treatment of moderate to severe pain. However, opioid pain medications also cause detrimental side effects, thus highlighting the need of innovative and safer analgesics. Opioids mediate their actions via the activation of opioid receptors, with the mu-opioid receptor as the primary target for analgesia, but also for side effects. One long-standing focus of drug discovery is the pursuit for new opioids exhibiting a favorable dissociation between analgesia and adverse effects. In this study, we describe the in vitro and in vivo pharmacological profiles of the 14-O-phenylpropyl substituted analog of the mu-opioid agonist 14-O-methyloxymorphone (14-OMO). The consequence of the substitution of the 14-O-methyl in 14-OMO with a 14-O-phenylpropyl group on in vitro binding and functional activity, and in vivo behavioral properties (nociception and gastrointestinal motility) was investigated. In binding studies, 14-O-phenylpropyloxymorphone (POMO) displayed very high affinity at mu-, delta-, and kappa-opioid receptors (Ki values in nM, mu:delta:kappa = 0.073:0.13:0.30) in rodent brain membranes, with complete loss of mu-receptor selectivity compared to 14-OMO. In guinea-pig ileum and mouse vas deferens bioassays, POMO was a highly efficacious and full agonist, being more potent than 14-OMO. In the [35S]GTPγS binding assays with membranes from CHO cells expressing human opioid receptors, POMO was a potent mu/delta-receptor full agonist and a kappa-receptor partial agonist. In vivo, POMO was highly effective in acute thermal nociception (hot-plate test, AD50= 0.7 nmol/kg) in mice after subcutaneous administration, with over 70- and 9000-fold increased potency than 14-OMO and morphine, respectively. POMO-induced antinociception is mediated through the activation of the mu-opioid receptor, and it does not involve delta- and kappa-opioid receptors. In the charcoal test, POMO produced fourfold less inhibition of the gastrointestinal transit than 14-OMO and morphine. In summary, POMO emerges as a new potent mixed mu/delta/kappa-opioid receptor agonist with reduced liability to cause constipation at antinociceptive doses

Procedure to Approximately Estimate the Uncertainty of Material Ratio Parameters due to Inhomogeneity of Surface Roughness

Roughness parameters that characterize contacting surfaces with regard to friction and wear are commonly stated without uncertainties, or with an uncertainty only taking into account a very limited amount of aspects such as repeatability of reproducibility (homogeneity) of the specimen. This makes it difficult to discriminate between different values of single roughness parameters. Therefore uncertainty assessment methods are required that take all relevant aspects into account. In the literature this is scarcely performed and examples specific for parameters used in friction and wear are not yet given. We propose a procedure to derive the uncertainty from a single profile employing a statistical method that is based on the statistical moments of the amplitude distribution and the autocorrelation length of the profile. To show the possibilities and the limitations of this method we compare the uncertainty derived from a single profile with that derived from a high statistics experiment.Comment: submitted to Meas. Sci. Technol., 12 figure

Different pathways in mechanical unfolding/folding cycle of a single semiflexible polymer

Kinetics of conformational change of a semiflexible polymer under mechanical external field were investigated with Langevin dynamics simulations. It is found that a semiflexible polymer exhibits large hysteresis in mechanical folding/unfolding cycle even with a slow operation, whereas in a flexible polymer, the hysteresis almost disappears at a sufficiently slow operation. This suggests that the essential features of the structural transition of a semiflexible polymer should be interpreted at least on a two-dimensional phase space. The appearance of such large hysteresis is discussed in relation to different pathways in the loading and unloading processes. By using a minimal two-variable model, the hysteresis loop is described in terms of different pathways on the transition between two stable states.Comment: 19 pages, 5 figure

Probing complex RNA structures by mechanical force

RNA secondary structures of increasing complexity are probed combining single molecule stretching experiments and stochastic unfolding/refolding simulations. We find that force-induced unfolding pathways cannot usually be interpretated by solely invoking successive openings of native helices. Indeed, typical force-extension responses of complex RNA molecules are largely shaped by stretching-induced, long-lived intermediates including non-native helices. This is first shown for a set of generic structural motifs found in larger RNA structures, and then for Escherichia coli's 1540-base long 16S ribosomal RNA, which exhibits a surprisingly well-structured and reproducible unfolding pathway under mechanical stretching. Using out-of-equilibrium stochastic simulations, we demonstrate that these experimental results reflect the slow relaxation of RNA structural rearrangements. Hence, micromanipulations of single RNA molecules probe both their native structures and long-lived intermediates, so-called "kinetic traps", thereby capturing -at the single molecular level- the hallmark of RNA folding/unfolding dynamics.Comment: 9 pages, 9 figure

A model for the force stretching double-stranded chain molecules

We modify and extend the recently developed statistical mechanical model for predicting the thermodynamic properties of chain molecules having noncovalent double-stranded conformations, as in RNA or ssDNA, and $\beta-$sheets in protein, by including the constant force stretching at one end of molecules as in a typical single-molecule experiment. The conformations of double-stranded regions of the chain are calculated based on polymer graph-theoretic approach [S-J. Chen and K. A. Dill, J. Chem. Phys. {\bf109}, 4602(1998)], while the unpaired single-stranded regions are treated as self-avoiding walks. Sequence dependence and excluded volume interaction are taken into account explicitly. Two classes of conformations, hairpin and RNA secondary structure are explored. For the hairpin conformations, all possible end-to-end distances corresponding to the different types of double-stranded regions are enumerated exactly. For the RNA secondary structure conformations, a new recursive formula incorporating the secondary structure and end-to-end distribution has been derived. Using the model, we investigate the extension-force curves, contact and population distributions and re-entering phenomena, respectively. we find that the force stretching homogeneous chains of hairpin and secondary structure conformations are very different: the unfolding of hairpins is two-state, while unfolding the latter is one-state. In addition, re-entering transitions only present in hairpin conformations, but are not observed in secondary structure conformations.Comment: 19 pages, 28 figure