Transmembrane signaling in chimeras of the Escherichia coli aspartate and serine chemotaxis receptors and bacterial class III adenylyl cyclases.

The Escherichia coli chemoreceptors for serine (Tsr) and aspartate (Tar) and several bacterial class III adenylyl cyclases (ACs) share a common molecular architecture; that is, a membrane anchor that is linked via a cytoplasmic HAMP domain to a C-terminal signal output unit. Functionality of both proteins requires homodimerization. The chemotaxis receptors are well characterized, whereas the typical hexahelical membrane anchor (6TM) of class III ACs, suggested to operate as a channel or transporter, has no known function beyond a membrane anchor. We joined the intramolecular networks of Tsr or Tar and two bacterial ACs, Rv3645 from Mycobacterium tuberculosis and CyaG from Arthrospira platensis, across their signal transmission sites, connecting the chemotaxis receptors via different HAMP domains to the catalytic AC domains. AC activity in the chimeras was inhibited by micromolar concentrations of l-serine or l-aspartate in vitro and in vivo. Single point mutations known to abolish ligand binding in Tar (R69E or T154I) or Tsr (R69E or T156K) abrogated AC regulation. Co-expression of mutant pairs, which functionally complement each other, restored regulation in vitro and in vivo. Taken together, these studies demonstrate chemotaxis receptor-mediated regulation of chimeric bacterial ACs and connect chemical sensing and AC regulation.

cGMP production in bacteria.

Production of cGMP in bacteria has been studied since the early 1970s. From the beginning on it proved to be a challenging topic. In Escherichia coli the cGMP levels were two orders of magnitude lower than the corresponding cAMP levels. Furthermore, no specific cGMP receptor protein was identified in the bacterium and a physiological role of cGMP in the bacterium was not substantiated. Consequently in 1977, compelling evidence was given that cGMP is a by-product of E. coli adenylate cyclase in vivo. This may be the reason why also work on cGMP in other bacteria like Bacillus licheniformis and Caulobacter crescentus was not pursued any further. However, recent study on cGMP and guanylate cyclase in the cyanobacterium Synechocysis PCC 6803 brought cGMP signaling in bacteria back to attention. In Synechocystis cGMP levels are of similar magnitude as those of cAMP and deletion of the cya2 gene markedly reduced the amount of cGMP without affecting cAMP. A few months ago the Cya2 gene product has been biochemically and structurally characterized. It behaves as a specific guanylate cyclase in vitro and a single amino acid substitution transforms the enzyme into a specific adenylate cyclase. These data point toward the existence of a true bacterial cGMP-signaling pathway, which needs to be explored and established by future experiments.

Does multidisciplinary assessment of long-term sickness absentees result in modification of sick-listing diagnoses?

AIMS: The aim was to study whether sick-leave diagnoses of long-term sickness absentees were modified after a multidisciplinary assessment and if modifications differed with type of medical specialty of the latest physician to sick-list the patient. METHODS: A sample of 635 long-term sickness absentees referred to a multidisciplinary assessment by Social Insurance Offices was included. Data were obtained through sickness certificates and medical records. Patients were examined by board-certified specialists in psychiatry, orthopaedic surgery, and rehabilitation medicine. Descriptive statistics were used. RESULTS: The multidisciplinary assessment resulted in an increase from 1-2 to 2-3 diagnoses for most patients. Forty-five per cent of the male and 47% of the female patients had only somatic diagnoses at referral. After the multidisciplinary assessment these percentages were 20% and 29%, respectively. The rate of women and men given both psychiatric and somatic diagnoses increased from 30% at referral to about 55%. The shift from either only psychiatric or only somatic diagnoses to having these diagnoses in combination was associated with type of specialty of the physician who had sick-listed the patient. CONCLUSIONS: The study indicates that many patients on long-term sick-leave with unclear diagnoses may suffer from unrecognized, and therefore probably untreated, medical disorders and co-morbidity.

Structure-function relationships in Escherichia coli adenylate cyclase.

Class I adenylate cyclases are found in gamma- and delta-proteobacteria. They play central roles in processes such as catabolite repression in Escherichia coli or development of full virulence in pathogens such as Yersinia enterocolitica and Vibrio vulnificus. The catalytic domain (residues 2-446) of the adenylate cyclase of E. coli was overexpressed and purified. It displayed a V(max) of 665 nmol of cAMP x mg(-1) x min(-1) and a K(m) of 270 microM. Titration of the metal cofactor Mg(2+) against the substrate ATP showed a requirement for free metal ions in addition to the MgATP complex, suggesting a two-metal-ion mechanism as is known for class II and class III adenylate cyclases. Twelve residues which are essential for catalysis were identified by mutagenesis of a total of 20 polar residues conserved in all class I adenylate cyclases. Five essential residues (Ser(103), Ser(113), Asp(114), Asp(116) and Trp(118)) were part of a region which is found in all members of the large DNA polymerase beta-like nucleotidyltransferase superfamily. Alignment of the E. coli adenylate cyclase with the crystal structure of a distant member of the superfamily, archaeal tRNA CCA-adding enzyme, suggested that Asp(114) and Asp(116) are the metal-cofactor-ion-binding residues. The S103A mutant had a 17-fold higher K(m) than wild-type, demonstrating its important role in substrate binding. In comparison with the tRNA CCA-adding enzyme, Ser(103) of the E. coli adenylate cyclase apparently binds the gamma-phosphate group of ATP. Consistent with this function, the S103A mutation caused a marked reduction of discrimination between ATP- and ADP- or AMP-derived inhibitors.

Outcome of multidisciplinary investigations of long-term sickness absentees.

OBJECTIVE: The aim was to investigate the results of multidisciplinary investigations of long-term sickness absentees regarding diagnoses, degree and prognoses of work incapacity, and need of rehabilitation measures and whether this was associated with socio-demographic factors. METHOD: A cross-sectional study of 545 long-term (>1 year) sickness absentees referred to multidisciplinary investigations by the Social Insurance Office. Data was obtained from questionnaires and medical records. The patients were examined by specialists in psychiatry, orthopaedic surgery, and rehabilitation medicine who afterwards agreed on diagnoses, work incapacity, time to return to work (RTW), and rehabilitation measures. Descriptive statistics and logistic regression were used for description and analyses of data. Data on age, country of birth, education, employment and marital status were included. RESULTS: The prevalence of psychiatric diagnoses was 72%, and 58% of the patients had that in combination with somatic diagnoses. Most patients were assessed to be capable of RTW within 6 - 24 months after further rehabilitation measures. Higher age was associated with a negative prognosis of RTW and those patients were less often recommended additional rehabilitation. CONCLUSION: Despite long-term sickness absence and high rates of psychiatric and somatic diagnoses in combination, RTW was considered possible for most patients after further rehabilitation measures.

The structure of the regulatory domain of the adenylyl cyclase Rv1264 from Mycobacterium tuberculosis with bound oleic acid.

The universal secondary messenger cAMP is produced by adenylyl cyclases (ACs). Most bacterial and all eukaryotic ACs belong to class III of six divergent classes. A class III characteristic is formation of the catalytic pocket at a dimer interface and the presence of additional regulatory domains. Mycobacterium tuberculosis possesses 15 class III ACs, including Rv1264, which is activated at acidic pH due to pH-dependent structural transitions of the Rv1264 dimer. It has been shown by X-ray crystallography that the N-terminal regulatory and C-terminal catalytic domains of Rv1264 interact in completely different ways in the active and inhibited states. Here, we report an in-depth structural and functional analysis of the regulatory domain of Rv1264. The 1.6 A resolution crystal structure shows the protein in a tight, disk-shaped dimer, formed around a helical bundle, and involving a protein chain crossover. To understand pH regulation, we determined structures at acidic and basic pH values and employed structure-based mutagenesis in the holoenzyme to elucidate regulation using an AC activity assay. It has been shown that regulatory and catalytic domains must be linked in a single protein chain. The new studies demonstrate that the length of the linker segment is decisive for regulation. Several amino acids on the surface of the regulatory domain, when exchanged, altered the pH-dependence of AC activity. However, these residues are not conserved amongst a number of related ACs. The closely related mycobacterial Rv2212, but not Rv1264, is strongly activated by the addition of fatty acids. The structure resolved the presence of a deeply embedded fatty acid, characterised as oleic acid by mass spectrometry, which may serve as a hinge. From these data, we conclude that the regulatory domain is a structural scaffold used for distinct regulatory purposes.

Evaluation of a multiprofessional rehabilitation programme for persistent musculoskeletal-related pain: economic benefits of return to work.

OBJECTIVE: The aim of this study was to evaluate the economic consequences of an 8-week multiprofessional rehabilitation programme for patients with persistent pain. SUBJECTS: A group of 67 patients following the programme and a comparison group of 322 patients. METHODS: The effect on return to work was estimated using 3 different methods: (i) a matched sample approach; (ii) regression analysis; and (iii) propensity score matching. The economic benefit of the programme was estimated as a reduction in production losses due to sick-leave. This benefit was compared with the actual cost of the programme. RESULTS: The benefit of the programme was estimated to be euro3,799-7,515 per treated patient and year. The total cost of the programme was estimated to be euro5,406 per patient. Based on these figures the total cost of the programme, including costs for patients remaining on sick-leave, had been recovered when the successfully rehabilitated patients had worked for 9-17 months. Any additional work after that yielded net economic benefits. CONCLUSION: Since other studies indicate that a large proportion of the patients working after one year also work after 3 and 6 years, we conclude that this multiprofessional rehabilitation programme for patients with persistent pain most likely generates substantial net economic gains.

Changes in purine specificity in tandem GAF chimeras from cyanobacterial cyaB1 adenylate cyclase and rat phosphodiesterase 2.

The C-terminal catalytic domains of the 11 mammalian phosphodiesterase families (PDEs) are important drug targets. Five of the 11 PDE families contain less well-characterized N-terminal GAF domains. cGMP is the ligand for the GAF domains in PDEs 2, 5, 6 and 11, and cAMP is the ligand for PDE10. Structurally related tandem GAF domains signalling via cAMP are present in the cyanobacterial adenylate cyclases cyaB1 and cyaB2. Because current high-resolution crystal structures of the tandem GAF domains of PDE2 and cyaB2 do not reveal how cNMP specificity is encoded, we generated chimeras between the tandem GAF domains of cyaB1 and PDE2. Both bind the ligand in the GAF B subdomains. Segmental replacements in the highly divergent beta1-beta3 region of the GAF B subdomain of cyaB1 by the corresponding PDE2 regions switched signalling from cAMP to cGMP. Using 10 chimeric constructs, we demonstrated that, for this switch in purine specificity, only 11% of the sequence of the cyanobacterial GAF B needs to be replaced by PDE2 sequences. We were unable, however, to switch the purine specificity of the PDE2 tandem GAF domain from cGMP to cAMP in reverse constructs, i.e. by replacement of PDE2 segments with those from the cyaB1 GAF tandem domain. The data provide a novel view on the structure-function relationships underlying the purine specificity of cNMP-binding GAF domains and indicate that, as potential drug targets, they must be characterized structurally and biochemically one by one.

The result of treatment on vestibular and general pain thresholds in women with provoked vestibulodynia.

OBJECTIVE: To correlate changes in vestibular pain thresholds to general pain thresholds in a subgroup of women with provoked vestibulodynia taking part in a treatment study. METHODS: Thirty-five women with provoked vestibulodynia were randomized to 4 months' treatment with either electromyographic biofeedback (n=17) or topical lidocaine (n=18). Vestibular and general pressure pain thresholds (PPTs) were measured and the health survey Short Form-36 (SF-36) was filled out before treatment and at a 6-month follow-up. Subjective treatment outcome and bodily pain were analyzed. Thirty healthy women of the same age served as controls for general PPTs and SF-36. RESULTS: No differences in outcome measures were observed between the 2 treatments. Vestibular pain thresholds increased from median 30 g before to 70 g after treatment in the anterior vestibule (P<0.001) and from median 20 to 30 g in the posterior vestibule (P<0.001). PPTs on the leg and arm were lower in the patients as compared with controls both before and at the 6-month follow-up. Patients reporting total cure were 3/35; 25/35 were improved. The number of patients who frequently reported of other bodily pain was reduced after the treatment. The patients had lower scores for SF-36 (General Health, Vitality) before treatment, which was restored at the 6-month follow-up. DISCUSSION: Treating provoked vestibulodynia by either topical lidocaine or electromyographic biofeedback increased vestibular pain thresholds, reduced dyspareunia, and improved bodily pain. The patients showed a general hypersensitivity to pressure pain compared with controls and in this study the hypersensitivity did not seem to be affected by treating the superficial dyspareunia.

The impact of pain and depression on assessment of rehabilitation need: a cross-sectional study in long-term sick-listed patients.

The aim of this study was to examine the relationship between pain extent, severity of depressive symptoms and recommended rehabilitation measures in long-term sick-listed patients. In this cross-sectional study, the medical records of 228 long-term sick-listed patients consecutively referred to a multidisciplinary setting were examined retrospectively. Three specialists in psychiatry, orthopaedic surgery and rehabilitation medicine had made joint rehabilitation recommendations into the four different groups: (i) back to work without rehabilitation; (ii) vocational rehabilitation or adjusted work; (iii) medical rehabilitation and (iv) sick pension. Each patient filled in a pain drawing as a measure of pain extent and the self-administered Montgomery-Asberg-Depression-Rating Scale for evaluating the severity of depressive symptoms. Ninety-five percent of the patients had ongoing pain and 53% had depression. No statistically significant difference was seen between the outcome groups regarding the pain extent. A statistically significant difference was seen between the back to work without any rehabilitation and vocational rehabilitation or adjusted work groups in Montgomery-Asberg-Depression-Rating Scale score versus the medical-rehabilitation and sick-pension groups [P<0.001 between groups (chi(2) test); P<0.05 within groups (Tukey-Kramer Honestly Significant Difference test)]. In conclusion, two-thirds of the patients were assessed to need medical rehabilitation. These patient groups could be separated from the ones who were assessed to be able to go back to work without medical rehabilitation by the severity of the ongoing depression, but not by the pain extent alone. It was found that the combination of severity of depression and pain extent provided more information than the severity of depression alone.

A 6-year follow-up study of 122 patients attending a multiprofessional rehabilitation programme for persistent musculoskeletal-related pain.

The aim of the study was to evaluate the outcome 6 years after completing a multiprofessional 8-week rehabilitation programme regarding the following objectives: (1) return to work, (2) level of activity and (3) pain intensity. Of 149 patients attending a rehabilitation programme, 122 were followed up after 6 years, through a structured telephone interview, and their present work situation, level of activity, sleeping habits, their estimated pain intensity and consumption of analgesics were recorded. The questions presented were the same as they had answered before entering the programme. The return-to-work rate was compared to 79 patients in a control group. At the 6-year follow-up, compared to before entering the programme, 52% had returned to work (P<0.001). In the control group the return-to-work rate was 13%. This difference was statistically significant (P<0.001). There was a statistically significant higher level of activity (P=0.037). A pain reduction was experienced by 58% of the patients (P<0.001) and 47% of the patients had decreased their consumption of analgesics (P<0.001). In conclusion, after completing the structured 8-week rehabilitation programme, the return-to-work rate was higher at a 6-year follow-up than in a control group. Furthermore, they had a higher level of activity and lower level of pain intensity than before entering the programme, indicating that the rehabilitation programme had a long-term positive effect on the return-to-work-rate, activity and pain as well as on the analgesic consumption.

Fatty acid regulation of adenylyl cyclase Rv2212 from Mycobacterium tuberculosis H37Rv.

Adenylyl cyclase Rv2212 from Mycobacterium tuberculosis has a domain composition identical to the pH-sensing isoform Rv1264, an N-terminal regulatory domain and a C-terminal catalytic domain. The maximal velocity of Rv2212 was the highest of all 10 mycobacterial cyclases investigated to date (3.9 micromol cAMP.mg(-1).min(-1)), whereas ATP substrate affinity was low (SC(50) = 2.1 mm ATP). Guanylyl cyclase side activity was absent. The activities and kinetics of the holoenzyme and of the catalytic domain alone were similar, i.e. in distinct contrast to the Rv1264 adenylyl cyclase, in which the N-terminal domain is autoinhibitory. Unsaturated fatty acids strongly stimulated Rv2212 activity by increasing substrate affinity. In addition, fatty acids greatly enhanced the pH sensitivity of the holoenzyme, thus converting Rv2212 to a pH sensor adenylyl cyclase. Fatty acid binding to Rv2212 was modelled by homology to a recent structure of the N-terminal domain of Rv1264, in which a fatty acid-binding pocket is defined. Rv2212 appears to integrate three cellular parameters: ATP concentration, presence of unsaturated fatty acids, and pH. These regulatory properties open the possibility that novel modes of cAMP-mediated signal transduction exist in the pathogen.

Adenylyl cyclase Rv0386 from Mycobacterium tuberculosis H37Rv uses a novel mode for substrate selection.

Class III adenylyl cyclases usually possess six highly conserved catalytic residues. Deviations in these canonical amino acids are observed in several putative adenylyl cyclase genes as apparent in several bacterial genomes. This suggests that a variety of catalytic mechanisms may actually exist. The gene Rv0386 from Mycobacterium tuberculosis codes for an adenylyl cyclase catalytic domain fused to an AAA-ATPase and a helix-turn-helix DNA-binding domain. In Rv0386, the standard substrate, adenine-defining lysine-aspartate couple is replaced by glutamine-asparagine. The recombinant adenylyl cyclase domain was active with a V(max) of 8 nmol cAMP.mg(-1).min(-1). Unusual for adenylyl cyclases, Rv0386 displayed 20% guanylyl cyclase side-activity with GTP as a substrate. Mutation of the glutamine-asparagine pair either to alanine residues or to the canonical lysine-aspartate consensus abolished activity. This argues for a novel mechanism of substrate selection which depends on two non-canonical residues. Data from individual and coordinated point mutations suggest a model for purine definition based on an amide switch related to that previously identified in cyclic nucleotide phosphodiesterases.

The class III adenylyl cyclases: multi-purpose signalling modules.

cAMP serves as a second messenger in virtually all organisms. The most wide-spread class of cAMP-generating enzymes are the class III adenylyl cyclases. Most class III adenylyl cyclases are multi-domain proteins. The catalytic domains exclusively work as dimers, catalysis proceeds at the dimer interface, so that both monomers provide catalytic residues to each catalytic center. Inspection of amino acid sequence profiles suggests a division of the class III adenylyl cyclases in to four subclasses, class IIIa-IIId. Genome projects and postgenomic analysis have provided novel aspects in terms of catalysis and regulation. Alterations in the canonical catalytic residues occur in all four subclasses suggesting a plasticity of the catalytic mechanisms. The vast variety of additional, probably regulatory modules found in class III adenylyl cyclases obviously reflects a large collection of regulatory inputs the catalytic domains have adapted to. The large versatility of class III adenylyl cyclase catalytic domains remains a major scientific challenge.

Adenylyl cyclases from Plasmodium, Paramecium and Tetrahymena are novel ion channel/enzyme fusion proteins.

In Paramecium, cAMP formation is stimulated by a potassium conductance, which is an intrinsic property of the adenylyl cyclase. We cloned a full-length cDNA and several gDNA fragments from Paramecium and Tetrahymena coding for adenylyl cyclases with a novel domain composition. A putative N-terminal ion channel domain contains a canonical S4 voltage-sensor and a canonical potassium pore-loop located C-terminally after the last transmembrane span on the cytoplasmic side. The adenylyl cyclase catalyst is C-terminally located. DNA microinjection of a green fluorescent protein (GFP)-tagged construct into the macronucleus of Paramecium resulted in ciliary localization of the expressed protein. An identical gene coding for an ion-channel adenylyl cyclase was cloned from the malaria parasite Plasmodium falciparum. Expression of the catalytic domain of the latter in Sf9 cells yielded an active homodimeric adenylyl cyclase. The occurrence of this highly unique subtype of adenylyl cyclase appears to be restricted to ciliates and apicomplexa.

The YHS-Domain of an Adenylyl Cyclase from Mycobacterium phlei Is a Probable Copper-Sensor Module.

YHS-domains are small protein modules which have been proposed to bind transition-metal ions like the related TRASH-domains. They are found in a variety of enzymes including copper-transporting ATPases and adenylyl cyclases. Here we investigate a class IIIc adenylyl cyclase from Mycobacterium phlei which contains a C-terminal YHS-domain linked to the catalytic domain by a peptide of 8 amino acids. We expressed the isolated catalytic domain and the full-length enzyme in E. coli. The catalytic domain requires millimolar Mn2+ as a cofactor for efficient production of cAMP, is unaffected by low micromolar concentrations of Cu2+ and inhibited by concentrations higher than 10 µM. The full-length enzyme also requires Mn2+ in the absence of an activator. However, 1-10 µM Cu2+ stimulate the M. phlei adenylyl cyclase sixfold when assayed with Mn2+. With Mg2+ as the probable physiological cofactor of the adenylyl cyclase Cu2+ specifically switches the enzyme from an inactive to an active state. Other transition-metal ions do not elicit activity with Mg2+. We favor the view that the YHS-domain of M. phlei adenylyl cyclase acts as a sensor for copper ions and signals elevated levels of the transition-metal via cAMP. By analogy to TRASH-domains binding of Cu2+ probably occurs via one conserved aspartate and three conserved cysteine-residues in the YHS-domain.

The actions of the social insurance agency regarding long-term sickness absentees before and after a medical assessment--a study of 384 case files.

PURPOSE: The purpose of this article is to investigate actions taken by the Social Insurance Agency (SIA) for long-term sickness absentees and possible associations of this with future sick leave or disability pension. METHOD: For 384 long-term sickness absentees who had had a multidisciplinary medical assessment (MMA) during 2001-2006, three types of data were obtained: (1) case file information about SIA actions, (2) suggested rehabilitation measures from the MMA and (3) sickness absence and disability pension data. RESULTS: Most individuals had been subject to a range of actions by the SIA. Sixty percent had been invited to a coordination meeting, and half of those who assessed by the MMA for vocational rehabilitation were approved to get it by the SIA. Few SIA actions were associated with full or partial return to work. CONCLUSIONS: Although the studied individuals had been on sick leave for a long time, the number of SIA actions related to vocational rehabilitation was limited and came late in the sick-leave spell. The information from the MMA was often not used as a basis for further SIA action and seldom resulted in return to work. The positive MMA views on the potential of vocational rehabilitation were not met by SIA actions. IMPLICATIONS FOR REHABILITATION: Suggestions on vocational rehabilitation from a medical assessment was in many cases not used by the social insurance agency in relationship to long-term sickness absentees. Active rehabilitation measures by the social insurance agency were few and came late in the sickness absence process. Few of the activities taken by the social insurance agency enhanced return to work.

Functional chimeras between the catalytic domains of the mycobacterial adenylyl cyclase Rv1625c and a Paramecium guanylyl cyclase.

The class IIIa adenylyl cyclase (AC) Rv1625c from Mycobacterium tuberculosis forms homodimers with two catalytic centres, whereas the Paramecium guanylyl and mammalian ACs operate as pseudoheterodimers with one catalytic centre. The functional and structural relationship of the catalytic domains of these related class III cyclases was investigated. Point mutations introduced into Rv1625c to engineer a forskolin-binding pocket created a single heterodimeric catalytic centre, yet did not result in forskolin activation. Chimerization of these Rv1625c point mutants with corresponding mammalian AC domains was impossible. However, it was successful using a complemental Paramecium guanylyl cyclase domain and resulted in an AC. The data signify a divergence of structural and functional evolution in class III Acs.

Depression predicts disability in long-term chronic pain patients.

PURPOSE: Investigators have examined factors that predict treatment outcome and disability status in chronic pain patients, including psychopathology and personality characteristics with equivocal results. The purpose of this study was to evaluate the usefulness of personality characteristics, depression, and personality disorders in predicting disability status in pain patients with long-term follow-up. The setting was a rehabilitation hospital in Southern Sweden. METHOD: Subjects were 184 pain patients (mean age = 43.4 (10.8) years; 72.8% female) who had no more than 365 sick leave days (Mean sick leave days = 132.7 (128.2)) prior to the baseline personality and psychiatric evaluation. The baseline evaluation consisted of a psychiatric interview that included the administration of the Structured Clinical Interview for DSM-IV Screen Questionnaire (SCID-II), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Karolinska Scales of Personality (KSP). Disability status was assessed by insurance record review a minimum of two-and-a-half years after baseline evaluation. RESULTS: Multivariate logistic regression suggests that age (OR = 1.09, 95% CI = 1.02-1.18; p = 0.013), number of sick leave days prior to evaluation (OR= 1.01, 95% CI= 1.01-1.02; p = 0.018), and baseline diagnosis of depression significantly predicted subsequent disability status (OR = 7.04, 95% CI = 1.15-42.93; p = 0.034). Baseline personality traits and the diagnosis of a personality disorder were not useful predictors of disability status in our sample. CONCLUSIONS: These data suggest that depression, but not personality disorders characteristics, was an important disability predictor in chronic pain patients with extended follow-up.

Relationship between sleep disturbance, pain, depression and functioning in long-term sick-listed patients experiencing difficulty in resuming work.

OBJECTIVE: To describe the frequency of reported sleeping, depression and pain problems, the severity of these problems and the degree of self-estimated difficulties in mental functions and activities in relation to the sleep disturbance and pain category group in patients on long-term sick-leave. DESIGN: Cross-sectional study. PATIENTS: A total of 1206 patients experiencing difficulty in resuming work. METHODS: Patient examinations by specialists in psychiatry, orthopaedic surgery and rehabilitation medicine. Validated questionnaires, including status regarding depression, sleep, pain and functioning were used. RESULTS: The prevalence of sleep disturbance was 83%; 74% of the patients with moderate/severe sleep disturbance also had moderate/severe pain problems and 26% had no/mild pain problems. Fifty-seven percent of the patients with no/mild sleep disturbance and 83% of the patients with moderate/ severe sleep disturbance also had depression. The degree of difficulty in performing the 6 selected International Classification of Functioning, Disability and Health activities and mental functions was higher for the category with moderate/severe sleep problems, compared with those with no/mild sleep problems. CONCLUSION: To optimize rehabilitation for patients on long-term sick-leave experiencing difficulties in returning to work, the results indicate a need also to focus attention on sleep problems and not only on pain and depression. This may entail the planning of measures to improve decision-making and concentration and alleviate lassitude, fatigability, sadness and pessimistic thoughts.