Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels.

OBJECTIVE: Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. METHOD: We measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). RESULTS: Plasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. CONCLUSION: We suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

Taurine in plasma and CSF: a study in healthy male volunteers.

In order to explore the interrelationship between plasma and cerebrospinal fluid taurine concentrations, three consecutive 6-ml fractions of cerebrospinal fluid were drawn from 30 healthy male volunteers in the early morning after 8 h in the fasting condition. Repeated plasma samples were drawn over 24 h the day before lumbar puncture. Taurine in plasma and cerebrospinal fluid was determined by high performance liquid chromatography. The subjects were categorized as extensive or poor metabolizers with respect to the cytochrome P450 2D6 genotype. The taurine cerebrospinal fluid/plasma ratio at 8 a.m. was negatively influenced by the plasma taurine concentration at 4 p.m. the previous day. It was also negatively influenced by body mass index and positively by the intraspinal pressure. Three poor metabolizers of cytochrome P450 2D6 had higher plasma taurine areas under the curve than 27 extensive metabolizers. Hypothetically, cytochrome P450 2D6 influences the transport of taurine across the blood-brain barrier.

A national stroke quality register: 12 years experience from a participating hospital.

Registration of all hospitalized stroke patients is practiced in Sweden in order to assess care quality. Data in this register, Riks-Stroke (RS), may be biased due to incomplete registration. The purpose of this paper was to report changes in stroke outcome in relation to fluctuations in registration. Patients registered in RS at a hospital during the period 1994-2005 were analyzed. Case fatality at 28 days, living conditions, and activities of daily living (ADL) performance at 3 months were correlated to the number of patients registered and follow-up frequency. A total of 4994 stroke cases were registered during the period. A high annual registration rate was significantly correlated to a high case fatality ratio. A low annual follow-up rate was associated with a low proportion of patients living in their own home without any need of help. Quality parameters are sensible for selection bias, which make them difficult to compare over time and between hospitals. We suggest that by weighing outcome data against stroke severity, safer conclusions may be drawn. Additionally, hospitals considering setting up quality registers should make every effort to attain complete case ascertainment at all times, including patients managed outside the hospital, in order to avoid selection bias.

Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.

Stress and burnout in psychiatric professionals when starting to use dialectical behavioural therapy in the work with young self-harming women showing borderline personality symptoms.

The aim of the study was to investigate how starting to use dialectical behavioural therapy (DBT) in the work with young self-harming women showing symptoms of borderline personality disorder affected the psychiatric professionals (n = 22) experience of occupational stress and levels of professional burnout. The study was carried out in relation to an 18-month clinical psychiatric development project, and used a mix of quantitative and qualitative research methods [a burnout inventory, the Maslach burnout inventory-General Survey (MBI-GS), free format questionnaires and group interviews]. The result confirms previous reports that psychiatric health professionals experience treatment of self-harming patients as very stressful. DBT was seen as stressful in terms of learning demands, but decreased the experience of stress in the actual treatment of the patients. The teamwork and supervision were felt to be supportive, as was one particular facet of DBT, namely mindfulness training which some therapists felt also improved their handling of other work stressors not related to DBT. The inventory for professional burnout, the MBI-GS, showed no significant changes over the 18-month period, although there was a tendency for increased burnout levels at the 6-month assessment, which had returned to baseline levels at 18 months.

The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability.

BACKGROUND: The glycosaminoglycan hyaluronic acid (HA) is an important component of the extracellular matrix (ECM) in the brain. CD44 is a cell adhesion molecule that binds to HA in the ECM and is present on astrocytes, microglia and certain neurons. Cell adhesion molecules have been reported to be involved in anxiety and mood disorders. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in brain GWAS studies as a possible risk gene for suicidal behavior. METHOD: We measured the CSF levels of HA and the soluble CD44 (sCD44) in suicide attempters (n=94) and in healthy controls (n=45) using ELISA and electrochemiluminescence assays. We also investigated other proteins known to interact with CD44, such as osteopontin and the matrix metalloproteinases MMP1, MMP3 and MMP9. RESULTS: The suicide attempters had higher CSF levels of HA (p=.003) and MMP9 (p=.004). The CSF levels of HA correlated with BBB-permeability (rho=0.410, p<.001) and MMP9 correlated with sCD44 levels (rho=0.260, p=.005). LIMITATIONS: Other relevant biological contributors to suicidal behavior is not addressed in parallel to the specific role of CD44-HA signaling. The gender distribution of the patients from whom CSF was analyzed was uneven. CONCLUSIONS: Increased BBB-permeability and HA levels might be a results of increased neuroinflammation and can play a role in the pathobiology of suicidal behavior. The CD44 signaling pathway might be considered a novel target for intervention in mood disorders.

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation.

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

p57Kip2, a glucocorticoid-induced inhibitor of cell cycle progression in HeLa cells.

Glucocorticoids exert antiproliferative effects on a number of cell types, including the HeLa cervical carcinoma cell line. However, the mechanism responsible for the antiproliferative effect is poorly understood. In this report we have investigated the role of the recently identified cyclin-dependent kinase inhibitor (CDI) p57Kip2 in the antiproliferative effect conferred by glucocorticoids. When HeLa cells were treated with the synthetic glucocorticoid dexamethasone (DEX), the doubling time of exponentially growing cells increased 2-fold. Within 11 h of DEX treatment, this was accompanied by an accumulation of cells in the G1 phase of the cell cycle with a corresponding decreased proportion of cells in the S phase and decreased CDK2 activity. DEX treatment of the HeLa cells dramatically induced the protein and mRNA expression of the CDI p57Kip2. This induction was seen within 4 h of DEX treatment, preceding a major DEX-induced accumulation of cells in the G1 phase. DEX-induced mRNA expression of p57Kip2 did not require de novo protein synthesis, and the transcription of the p57Kip2 gene was increased as determined by a run-on transcription assay. Furthermore, DEX induction of p57Kip2 was not a consequence of the cell cycle arrest, since other growth inhibition signals did not result in strong p57Kip2 induction. Overexpression of p57Kip2 using HeLa cells stably transfected with a tetracycline-inducible vector showed that p57Kip2 is sufficient to reconstitute an antiproliferative effect similar to that seen in DEX-treated cells. Selective p57Kip2 expression by the tetracycline analog doxycycline to levels comparable to those observed on DEX induction resulted in a 1.7-fold increase in the doubling time and a shift of HeLa cells to the G1 phase as well as a decrease in CDK2 activity. Taken together, these results suggest that glucocorticoid treatment directly induces transcription of the p57Kip2 gene and that the p57Kip2 protein is involved in the glucocorticoid-induced antiproliferative effect.

Neutrophil recruitment, chemokine receptors, and resistance to mucosal infection.

Neutrophil migration to infected mucosal sites involves a series of complex interactions with molecules in the lamina propria and at the epithelial barrier. Much attention has focussed on the vascular compartment and endothelial cells, but less is known about the molecular determinants of neutrophil behavior in the periphery. We have studied urinary tract infections (UTIs) to determine the events that initiate neutrophil recruitment and interactions of the recruited neutrophils with the mucosal barrier. Bacteria activate a chemokine response in uroepithelial cells, and the chemokine repertoire depends on the bacterial virulence factors and on the specific signaling pathways that they activate. In addition, epithelial chemokine receptor expression is enhanced. Interleukin (IL)-8 and CXCR1 direct neutrophil migration across the epithelial barrier into the lumen. Indeed, mIL-8Rh knockout mice showed impaired transepithelial neutrophil migration, with tissue accumulation of neutrophils, and these mice developed renal scarring. They had a defective antibacterial defense and developed acute pyelonephritis with bacteremia. Low CXCR1 expression was also detected in children with acute pyelonephritis. These results demonstrate that chemokines and chemokine receptors are essential to orchestrate a functional antimicrobial defense of the urinary tract mucosa. Mutational inactivation of the IL-8R caused both acute disease and chronic tissue damage.

Management and prognostic features of intracerebral hemorrhage during anticoagulant therapy: a Swedish multicenter study.

BACKGROUND AND PURPOSE: Patients treated with oral anticoagulants (ACs) have an increased risk of intracerebral hemorrhage (ICH), which is more often fatal than spontaneous ICH. Options to reverse the AC effect include intravenous administration of vitamin K, plasma, and coagulation factor concentrate. However, the optimal management of AC-related ICH has not been determined in any randomized trial. In this study, the present management of AC-related ICH was surveyed, and determinants of survival were assessed. METHODS: We retrospectively reviewed the medical records of all AC-related ICHs at 10 Swedish hospitals during a 4-year period, 1993 to 1996. Survival status after the ICH was determined from the Swedish National population register. RESULTS: We identified 151 patients with AC-related ICH. Death rates were 53.6% at 30 days, 63.6% at 6 months, and 77.5% at follow-up (mean 3.5 years). The case fatality ratio at 30 days was 96% among patients unconscious on admission (n=27), 80% among patients who became unconscious before active treatment was started (n=15), 55% among patients in whom no special action was taken except withdrawal of AC treatment (n=42), and 28% among patients given active anti-coumarin treatment while they were still conscious (n=64). The case fatality ratio at 30 days was 11% in the group treated with plasma (n=18), 30% in the group treated with vitamin K (n=23), and 39% in the group treated with coagulation factor concentrate (n=23). Within the first 24 to 48 hours after admission, 47% of the patients deteriorated. Choice of therapy to reverse the AC effect differed substantially between the hospitals (P<0.0001), as did the time interval from symptom onset to start of treatment. Multiple logistic regression analysis showed only 2 factors (intraventricular extension of bleeding and ICH volume) that were independently related to case fatality at both 30 days and 6 months. The results were similar when the analysis was restricted to patients who were conscious on admission. CONCLUSIONS: In AC-related ICH, a progressive neurological deterioration during the first 24 to 48 hours after admission is frequent, and the mortality is high. Choice of therapy to reverse the AC effect differed considerably between the hospitals. There was no evidence that any treatment strategy was superior to the others. A randomized controlled trial is needed to determine the best choice of treatment.

Identification of a functional glucocorticoid response element in the promoter of the cyclin-dependent kinase inhibitor p57Kip2.

Glucocorticoids are known regulators of the cell cycle, normally exerting an anti-proliferative effect. We have previously shown that glucocorticoids stimulate expression of p57(Kip2), a member of the Cip/Kip family of cyclin-dependent kinase inhibitors which, in some cell types, may account for the anti-proliferative responses seen after glucocorticoid treatment. The induction of p57(Kip2) involves primary transcriptional effects where no de novo protein synthesis is necessary, suggesting a direct interaction of the glucocorticoid receptor with the p57(Kip2) gene. In this study we have identified a functional glucocorticoid response element (GRE), located 5 kilo bases (kb) upstream of the transcription start site in the human p57(Kip2) promoter. This GRE was functional also when isolated, suggesting a direct transcriptional effect of the glucocorticoid receptor. Furthermore, mutation of this GRE abolished glucocorticoid induction of the reporter gene, whereas mutation of a nearby Sp1 site did not. Using electrophoretic mobility shift assays, we have shown that the -5 kb p57(Kip2) promoter GRE was able to compete with a well-known GRE for glucocorticoid receptor binding. Sequence comparisons with the mouse genome showed that this GRE is highly conserved, further strengthening the biological importance of this site. All these data emphasize the involvement of this GRE in the glucocorticoid-mediated induction of p57(Kip2) expression.

Elevated number of cells secreting transforming growth factor beta in Guillain-Barré syndrome.

We used ELISPOT and cell ELISA to study secretion of IL-4, IFN-gamma, TGF-beta, IL-6, and TNF-alpha by circulating mononuclear cells during the course of Guillain-Barré syndrome (GBS). Compared to healthy controls, patients with GBS had higher numbers of TGF-beta-secreting cells and the number of individuals with myelin-peptide-induced IL-4 and TGF-beta secretion was higher in the GBS group. No significant differences were seen concerning the predominantly pro-inflammatory cytokines IFN-gamma, IL-6 or TNF-alpha. Our findings indicate a down-regulatory role for TGF-beta and IL-4 in GBS.

The host response to urinary tract infection.

The authors use the UTI model to identify basic mechanisms of disease pathogenesis, host response induction, and defense. Their studies hold the promise to provide a molecular and genetic explanation for susceptibility to UTI, and to offer more precise tools for diagnosis and therapy of these infections. There are few infections where the host response is understood in such detail and where pathologic host responses can be linked to distinct disease states. The susceptibility to UTI varies greatly in the population. The studies suggest that distinct molecular defects can cause the clinical entity of acute pyelonephritis with renal scarring, and suggest that the susceptibility to UTI in certain patient groups may have a genetic basis. In addition, the distinct signal transduction pathways explain the development of symptoms, and propose that defects in those signaling mechanisms may occur in patients with ABU. In the future, it may be useful to include these host response parameters in the diagnostic arsenal, to help in early detection of patients susceptible to recurrent UTI and renal scarring. These patients may then be offered therapies that strengthen their defense, and be offered close surveillance for recurrences and other complications.

T helper type 2 like cytokine responses to peptides from P0 and P2 myelin proteins during the recovery phase of Guillain-Barré syndrome.

T-lymphocytes are probably involved in the pathogenesis of Guillain-Barré syndrome (GBS). T-helper-1 (Th1) cytokines activate macrophages and induce a delayed type hypersensitivity (DTH) inflammatory response, consistent with the morphology of the demyelination in GBS. Th2 cytokines encourage antibody production and downregulate Th1 responses. To study the Th1/Th2 cytokines in relation to the clinical course of GBS an ELISPOT method for determination of single cells secreting interferon-gamma, IFN-gamma (Th1) or interleukin-4, IL-4 (Th2) was used. We serially investigated antigen-induced cytokine secretion from circulating T-cells stimulated with human peptides from the P0 and P2 proteins in seven patients and compared to results from seven serially investigated healthy controls. Most patients (five of seven) showed IL-4 responses during the plateau- or recovery-phase as compared to controls. One patient with a prolonged disease course, on the other hand, had an IFN-gamma dominated reactivity. We suggest that the IL-4 responses are beneficial in GBS, and may have a role in terminating the disease process in this self-limiting inflammatory disease.

Myopathy with respiratory failure and typical myofibrillar lesions.

16 patients representing 7 different pedigrees exhibited an unusual, adult onset limb-girdle myopathy with typical clinical hallmarks. In a majority of cases there was evidence of an autosomal dominant inheritance. A prominent early finding in all cases was respiratory muscle weakness, and in many of these an acute respiratory incapacity was the reason for the first neurological examination. Neck flexor and sometimes foot extensor weakness were other early symptoms. The clinical picture seems to be at variance with that of the more well known hereditary myopathies. Electrophysiological analysis confirmed a myopathy and serum muscle enzyme concentrations were normal or slightly elevated. Muscle biopsy findings revealed myofibrillar changes which, at the light microscopy level, included plaques that stained strongly with rhodamine-conjugated phalloidin, a specific marker for F-actin. At the ultrastructural level, these plaques were observed to be composed of moderately dense, thin filaments and were related to splitting of Z-discs or formed extensions from Z-discs. We believe that the muscle biopsy changes revealed by cytochemical and ultrastructural observations indicate defective myofibrillogenesis, and the possibility of defective actin polymerization is discussed. A conclusive answer requires further immunocytochemical and immunoelectrophoretic studies and possibly the application of molecular genetics.

Parental social support and child behaviour problems in different populations and socioeconomic groups: a methodological study.

In many research projects there is a need to apply a multifactorial approach. Practical reasons often make it necessary to use instruments that are not too time-consuming for each factor to be investigated. The Interview Schedule of Social Integration (ISSI) is proposed by Undén and Orth-Gomér as a suitable tool in measuring social support. It is increasingly used in Sweden. To further investigate its usefulness in measuring parental social support of importance for the children, an examination of the relation between the ISSI variables and Child Behaviour as well as Parental Psychopathology was undertaken, based on data from four studies: Psychosocial Factors and Child Diabetes, Single Parent Families in a child guidance clinic, a Clinical Child Psychiatric Ward Group and an Epidemiological Study of a Normal Swedish Population. The findings were that social support measured by ISSI had the expected associations to child behaviour as well as to parental psychopathology in the higher socioeconomic groups but not in the lower ones. The interpretation is made that ISSI does not measure qualitative aspects of social support but the sense of satisfaction with it. In the higher socioeconomic groups the sense of satisfaction may be a fairly good approximation of the actual quality even if it is probably confounded with personality trait factors. The same approximation cannot be made in lower socioeconomic groups and in psychiatric populations. In these cases there is a need to pay more attention to the actual quality of the social network.

Effects of timolol on terbutaline- and VIP-stimulated aqueous humor flow in the cynomolgus monkey.

The effects of timolol on terbutaline- and VIP-stimulated aqueous humor flow were investigated in cynomolgus monkeys, with a labeled albumin dilution method. The maximal increase in aqueous humor flow caused by intracameral (100 micrograms/ml) or intravenous (0.4 micrograms/kg/min) administration of terbutaline was about 100%. The effect of intravenously infused terbutaline was completely abolished by intracameral administration of timolol, 0.1 mg/ml. The same dose of timolol also abolished the effect of intravenously infused VIP, 50 ng/kg/min. Intravenous administration of timolol, 0.2 mg/kg, had no effect on VIP-stimulated aqueous humor flow, when VIP (90 micrograms) was given intracamerally, but abolished completely the effect of intracameral terbutaline, 100 micrograms/ml. The results suggest that the effect of intravenously infused VIP on aqueous humor flow is secondary to activation of the sympathetic nervous system, while the effect of intracameral administration of VIP is a direct effect on the ciliary epithelium. The maximal aqueous humor flow achieved with terbutaline is comparable to that in conscious cynomolgus monkeys.

CSF 5-HIAA predicts suicide risk after attempted suicide.

Suicide risk after attempted suicide, as predicted by cerebrospinal fluid (CSF) monoamine metabolite concentrations, was studied in a sample of 92 psychiatric mood disorder inpatients admitted shortly after attempting suicide. The potential of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the CSF to predict suicide risk within the first year after attempted suicide was studied by means of survival analysis after after median split subgrouping. Eleven patients (12%) committed suicide within 1 year after attempted suicide. Eight of these belonged to the below-the-median (< 87 nM) CSF 5-HIAA subgroup, that is, the suicide risk was 17% as compared with 7% among those with above-the-median CSF 5-HIAA. The cumulative number of survived patient-months during the first year after attempted suicide was significantly lower in the low CSF 5-HIAA subgroup. It was concluded that low CSF 5-HIAA predicts short-range suicide risk after attempted suicide in mood disorder psychiatric inpatients. These findings lend further support to the serotonin hypothesis of suicide risk.

Improving the interface between primary and secondary care: a statement from the European Working Party on Quality in Family Practice (EQuiP).

A group from the European Working Party on Quality in Family Practice (EQuiP), working with over 20 European colleges of primary care, has assessed what, in their view, is needed to improve the quality of care at the interface between general practice and specialists. Experiences and ideas from a wide range of people were gathered through focused group discussions. From these it was clear that, for real improvement at the interface of care, changes are needed in the system of care and in the ways that doctors view their roles and their performance. All providers of care need to be able to see the care system from the patients' perspective if they are to help their patients make sense of and benefit from an increasingly complex system. This paper outlines the EQuiP recommendations on how cooperation between general practitioners and specialists might be improved. This includes strategic perspectives and both targets for improvement and methods for teaching, training and development that are all independent of country and health care system. The 10 targets for development identified by the group are: leadership, initial shared care approaches, task division, mutual guidelines, patient perspective, informatics, education, team building, quality monitoring systems, and cost effectiveness. Working towards these targets could provide an effective approach to improving the cooperation between the interfaces of care. Getting effective leadership is a necessary first step as implementation of such a strategy will involve significant change. Responsibility lies primarily with the medical profession.