Transition to suicide ideation and attempt among emergency room patients.

BACKGROUND: Suicidal thoughts and behaviours (STB) represent a persistent and serious public health problem, and suicide is among the leading causes of death worldwide. We focus on predictors of transition rates and time courses through the STB spectrum among psychiatric emergency room (PER) patients. AIMS: We aimed to investigate (a) whether currently suicidal patients had prior referrals to the PER, (b) for which reason they were previously referred to the PER and (c) the timing of this referral. METHOD: We performed a retrospective study spanning 20 years with 24 815 PER referrals. Descriptive statistics of patients' sociodemographic and clinical characteristics are provided and expressed as weighted proportions and means. Logistic regression was used to identify risk profiles of patients who had a higher chance of being referred for reasons of STB given their PER history. Multiple imputation and data weighting techniques were implemented. RESULTS: STB among PER patients was persistent and led to repeated referrals (up to five times more likely), often within a short period (18% <1 month). Those previously referred for ideation/plan had 66% higher risk of making the transition to suicide attempt, with 25% making this transition within a month after previous referral. This is similar to the transition from depressed mood to suicide ideation/plan. CONCLUSIONS: STBs in PER patients are persistent and lead to repeated referrals, often within a short period, including transitions to more severe forms of STB.

Impact of job characteristics on return-to-work interval following arthroscopic partial meniscectomy.

The aim of this paper was to investigate whether job characteristics are associated with time interval for return to former professional activity (return to work, RTW) after arthroscopic partial meniscectomy (APM). A retrospective study was carried out in a sample of 63 patients in working age who underwent an APM between July 2018 and July 2020. The following preoperative characteristics were assessed: age at surgery, meniscal side, sex, physical job demands (white versus blue collar worker), telework and work status (salaried versus self- employed). A linear regression analysis was used to study the association between job characteristics and RTW interval adjusted for socio-demographic and medical (meniscal side) factors. Telework was most strongly associated with interval for RTW (p <0,001, adjusted R Square: 20,8). The results suggested that telework supports early RTW independently of sociodemographic and medical factors. This study supported the need for a tailormade approach in the prescription of sick leave.

Duplications of 17q12 can cause familial fever-related epilepsy syndromes.

OBJECTIVES: After we identified a 17q12 duplication cosegregating in a 4-generation family with genetic or generalized epilepsy with febrile seizures plus (GEFS+), we aimed to determine the frequency of 17q12 genomic rearrangements in GEFS+ and a wide spectrum of other epilepsy phenotypes. We furthermore describe seizure prevalence in previously reported patients with a 17q12 duplication or deletion. METHODS: We analyzed 433 patients with a broad range of epilepsy phenotypes. The 180k Cytosure ISCA v2 array was used for copy number variation screening in the index patient. Segregation analysis and follow-up studies were performed with the multiplex amplicon quantification technique. RESULTS: We identified 2 families in which a 17q12 duplication segregated with febrile-sensitive epilepsy. In the follow-up study, the mutation rate in familial febrile seizures (FS) and GEFS+ phenotypes was 1/222. No 17q12 deletions were detected. Two of the 6 mutation carriers in the initial GEFS+ family had mild intellectual disability, whereas all family members of the second family were of normal intelligence. In the literature, 4 of 43 individuals with a 17q12 duplication and 4 of 55 with the reciprocal deletion were described to have had seizures. CONCLUSIONS: Our study shows that 17q12 duplications are a rare cause of familial FS and GEFS+. Although some family members might have intellectual disability, seizures can be the sole clinical symptom. This is the first report on an inherited copy number variation in these self-limiting fever-sensitive epilepsy syndromes, potentially revealing a novel pathomechanism involved in familial FS and GEFS+.

EPHA4 is a disease modifier of amyotrophic lateral sclerosis in animal models and in humans.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons. Disease onset and progression are variable, with survival ranging from months to decades. Factors underlying this variability may represent targets for therapeutic intervention. Here, we have screened a zebrafish model of ALS and identified Epha4, a receptor in the ephrin axonal repellent system, as a modifier of the disease phenotype in fish, rodents and humans. Genetic as well as pharmacological inhibition of Epha4 signaling rescues the mutant SOD1 phenotype in zebrafish and increases survival in mouse and rat models of ALS. Motor neurons that are most vulnerable to degeneration in ALS express higher levels of Epha4, and neuromuscular re-innervation by axotomized motor neurons is inhibited by the presence of Epha4. In humans with ALS, EPHA4 expression inversely correlates with disease onset and survival, and loss-of-function mutations in EPHA4 are associated with long survival. Furthermore, we found that knockdown of Epha4 also rescues the axonopathy induced by expression of mutant TAR DNA-binding protein 43 (TDP-43), another protein causing familial ALS, and the axonopathy induced by knockdown of survival of motor neuron 1, a model for spinomuscular atrophy. This suggests that Epha4 generically modulates the vulnerability of (motor) neurons to axonal degeneration and may represent a new target for therapeutic intervention.

Clinical validation of a novel speckle-tracking-based ejection fraction assessment method.

BACKGROUND: The aim of this study was to determine the feasibility, accuracy, and reproducibility of a novel tracking-based echocardiographic ejection fraction (EF) assessment method in comparison with traditional methods based on magnetic resonance imaging and echocardiography. METHODS: In a prospective assessment, apical echocardiographic grayscale image loops from 81 patients were read in random order by four experienced readers, blinded to any data of the cases. In three separate sessions, EFs were estimated using biplane tracking-based assessment and according to the modified Simpson's rule, as well as by visual interpretation in three apical views. Data were compared with a reference EF derived from echocardiography and magnetic resonance imaging. RESULTS: On average, no significant difference was found between EF estimates of the different methods. Tracking-based EF assessments were possible in 90% of the patients. Tracking-based EF assessments showed slightly higher deviations from the reference EF than the modified Simpson's rule, while interobserver and intraobserver variability of tracking-based assessment were significantly better. Visual interpretation allowed the fastest EF assessment. Tracking-based EF assessment was approximately twice as fast as the modified Simpson's rule. CONCLUSIONS: Tracking-based EF assessment is feasible, has lower interobserver and intraobserver variability, and is faster than traditional echocardiographic EF quantification. Its minimal demand on user interaction makes it a favorable alternative to traditional echocardiographic approaches, with a particular clinical advantage when reliable follow-up measurements are needed.

Fluoxetine administration to pregnant rats increases anxiety-related behavior in the offspring.

RATIONALE: Fluoxetine (Prozac®) is the most frequently prescribed drug to battle depression in pregnant women, but its safety in the unborn child has not yet been established. Fluoxetine, a selective serotonin reuptake inhibitor, crosses the placenta, leading to increased extracellular serotonin levels and potentially neurodevelopmental changes in the fetus. OBJECTIVES: The purpose of this study was to elucidate the long-term consequences of prenatal fluoxetine in rats. METHODS: Pregnant rats were injected daily with 12 mg/kg fluoxetine or vehicle from gestational day 11 until birth, and the behavior of the offspring was monitored. RESULTS: Plasma fluoxetine transfer from mother to pup was 83%, and high levels of fluoxetine (13.0 µg/g) were detected in the pup brain 5 h after the last injection. Fluoxetine-treated dams gave birth to litters 15% smaller than usual and to pups of reduced weight (until postnatal day 7). Furthermore, prenatal fluoxetine exposure significantly increased anxiety in the novelty-suppressed feeding test, the footshock-induced conditioned place aversion test, and the elevated plus maze test (following footshock pre-exposure) during adulthood, and also significantly decreased components of social play behavior at 4 weeks of age, and a strong tendency for increased self-grooming and making less contact in adults. Behavioral despair, anhedonia, and sexual behavior were not different between treatment groups. Finally, the hypothermic response to the 5-HT(1A) agonist flesinoxan was observed at a lower dose in prenatally fluoxetine-exposed rats than in controls. CONCLUSIONS: Prenatal fluoxetine exposure in rats leads to detrimental behavioral outcomes in later life, which may partly be due to altered 5-HT(1A) receptor signaling.

Molecular mechanisms of chlorhexidine tolerance in Burkholderia cenocepacia biofilms.

The high tolerance of biofilm-grown Burkholderia cepacia complex bacteria against antimicrobial agents presents considerable problems for the treatment of infected cystic fibrosis patients and the implementation of infection control guidelines. In the present study, we analyzed the tolerance of planktonic and sessile Burkholderia cenocepacia J2315 cultures and examined the transcriptional response of sessile cells to treatment with chlorhexidine. At low (0.0005%) and high (0.05%) concentrations, chlorhexidine had a similar effect on both populations, but at intermediate concentrations (0.015%) the antimicrobial activity was more pronounced in planktonic cultures. The exposure of sessile cells to chlorhexidine resulted in an upregulation of the transcription of 469 (6.56%) and the downregulation of 257 (3.59%) protein-coding genes. A major group of upregulated genes in the treated biofilms encoded membrane-related and regulatory proteins. In addition, several genes coding for drug resistance determinants also were upregulated. The phenotypic analysis of RND (resistance-nodulation-division) efflux pump mutants suggests the presence of lifestyle-specific chlorhexidine tolerance mechanisms; efflux system RND-4 (BCAL2820-BCAL2822) was more responsible for chlorhexidine tolerance in planktonic cells, while other systems (RND-3 [BCAL1672-BCAL1676] and RND-9 [BCAM1945-BCAM1947]) were linked to resistance in sessile cells. After sessile cell exposure, multiple genes encoding chemotaxis and motility-related proteins were upregulated in concert with the downregulation of an adhesin-encoding gene (BCAM2143), suggesting that sessile cells tried to escape the biofilm. We also observed the differential expression of 19 genes carrying putative small RNA molecules, indicating a novel role for these regulatory elements in chlorhexidine tolerance.

Transcriptional response of Burkholderia cenocepacia J2315 sessile cells to treatments with high doses of hydrogen peroxide and sodium hypochlorite.

BACKGROUND: Burkholderia cepacia complex bacteria are opportunistic pathogens, which can cause severe respiratory tract infections in patients with cystic fibrosis (CF). As treatment of infected CF patients is problematic, multiple preventive measures are taken to reduce the infection risk. Besides a stringent segregation policy to prevent patient-to-patient transmission, clinicians also advise patients to clean and disinfect their respiratory equipment on a regular basis. However, problems regarding the efficacy of several disinfection procedures for the removal and/or killing of B. cepacia complex bacteria have been reported. In order to unravel the molecular mechanisms involved in the resistance of biofilm-grown Burkholderia cenocepacia cells against high concentrations of reactive oxygen species (ROS), the present study focussed on the transcriptional response in sessile B. cenocepacia J2315 cells following exposure to high levels of H2O2 or NaOCl. RESULTS: The exposure to H2O2 and NaOCl resulted in an upregulation of the transcription of 315 (4.4%) and 386 (5.4%) genes, respectively. Transcription of 185 (2.6%) and 331 (4.6%) genes was decreased in response to the respective treatments. Many of the upregulated genes in the NaOCl- and H2O2-treated biofilms are involved in oxidative stress as well as general stress response, emphasizing the importance of the efficient neutralization and scavenging of ROS. In addition, multiple upregulated genes encode proteins that are necessary to repair ROS-induced cellular damage. Unexpectedly, a prolonged treatment with H2O2 also resulted in an increased transcription of multiple phage-related genes. A closer inspection of hybridisation signals obtained with probes targeting intergenic regions led to the identification of a putative 6S RNA. CONCLUSION: Our results reveal that the transcription of a large fraction of B. cenocepacia J2315 genes is altered upon exposure of sessile cells to ROS. These observations have highlighted that B. cenocepacia may alter several pathways in response to exposure to ROS and they have led to the identification of many genes not previously implicated in the stress response of this pathogen.

In vitro activity of ceftazidime, ciprofloxacin, meropenem, minocycline, tobramycin and trimethoprim/sulfamethoxazole against planktonic and sessile Burkholderia cepacia complex bacteria.

OBJECTIVES: The goal of the present study was to obtain a comprehensive overview of the bacteriostatic and bactericidal effects of six commonly used antibiotics on planktonic as well as on sessile Burkholderia cepacia complex cells. METHODS: The bacteriostatic and bactericidal activities of ceftazidime, ciprofloxacin, meropenem, minocycline, tobramycin and trimethoprim/sulfamethoxazole were determined against 38 B. cepacia complex strains. MICs and minimal biofilm inhibitory concentrations (MBICs) were determined using a traditional broth microdilution method and a novel resazurin-based viability staining, respectively. The bactericidal effects of the investigated antibiotics (using antibiotic concentrations corresponding to 10 x MIC; except for tobramycin, for which a final concentration of 4 x MIC was tested) on stationary phase planktonic cultures and on 24-h-old biofilms were evaluated using conventional plate count methods. RESULTS: Our results confirm the innate resistance of B. cepacia complex organisms to six first-line antibiotics used to treat infected cystic fibrosis patients. All antibiotics showed similar bacteriostatic activities against exponentially growing B. cepacia complex planktonic cells and freshly adhered sessile cells (4 h). In addition, most of the antibiotics showed similar bactericidal effects on stationary phase planktonic cultures and on young and older biofilms. CONCLUSIONS: Despite the general assumption that sessile cells show a decreased susceptibility to antibiotics, our data indicate similar bacteriostatic and bactericidal activity of six selected antibiotics against planktonic and sessile B. cepacia complex bacteria.

Resistance of planktonic and biofilm-grown Burkholderia cepacia complex isolates to the transition metal gallium.

OBJECTIVES: The Burkholderia cepacia complex is a group of pathogens that can cause severe pulmonary infections in cystic fibrosis (CF) patients. The aim of the present study was to investigate the in vitro activity of gallium against planktonic and biofilm-grown B. cepacia complex isolates. METHODS: Six B. cepacia complex isolates (belonging to three different species) as well as Pseudomonas aeruginosa PAO1 were included in the present study. MICs of Ga(NO(3))(3) for planktonic cells were determined using a broth microdilution method. Biofilms were formed in 96-well microtitre plates, and the fraction of surviving cells following Ga(NO(3))(3) treatment was determined using resazurin as a marker for cell viability. The antimicrobial effect of Ga(NO(3))(3) was assessed in the presence (50 microM) and absence of Fe(3+). RESULTS: When tested against planktonic cells, the MICs of Ga(NO(3))(3) in the absence of Fe(3+) were 64 mg/L for all B. cepacia complex strains investigated. However, the addition of 50 microM Fe(3+) in the presence of 64 mg/L Ga(NO(3))(3) resulted in increased growth for all B. cepacia complex strains investigated. In sessile cells, resistance to Ga(NO(3))(3) and the extent of the protective effect of 50 microM Fe(3+) against Ga(NO(3))(3) appear to be strain-dependent: the Burkholderia cenocepacia strains investigated are insensitive to Ga(NO(3))(3) in the presence of 50 microM Fe(3+), whereas the presence of Fe(3+) has no protective effect for both Burkholderia multivorans strains investigated. CONCLUSIONS: As maximal tolerable Ga(3+) levels in plasma are estimated to be approximately 200 microM and considering the high levels of Fe(3+) in the lungs of people with CF, our data suggest that the added value of a Ga(NO(3))(3) treatment of B. cepacia complex-infected patients may be limited.

Comparison of multiple methods for quantification of microbial biofilms grown in microtiter plates.

In the present study six assays for the quantification of biofilms formed in 96-well microtiter plates were optimised and evaluated: the crystal violet (CV) assay, the Syto9 assay, the fluorescein diacetate (FDA) assay, the resazurin assay, the XTT assay and the dimethyl methylene blue (DMMB) assay. Pseudomonas aeruginosa, Burkholderia cenocepacia, Staphylococcus aureus, Propionibacterium acnes and Candida albicans were used as test organisms. In general, these assays showed a broad applicability and a high repeatability for most isolates. In addition, the estimated numbers of CFUs present in the biofilms show limited variations between the different assays. Nevertheless, our data show that some assays are less suitable for the quantification of biofilms of particular isolates (e.g. the CV assay for P. aeruginosa).

Platelet factor-4 variant chemokine CXCL4L1 inhibits melanoma and lung carcinoma growth and metastasis by preventing angiogenesis.

The platelet factor-4 variant, designated PF-4var/CXCL4L1, is a recently described natural non-allelic gene variant of the CXC chemokine platelet factor-4/CXCL4. PF-4var/CXCL4L1 was cloned, and the purified recombinant protein strongly inhibited angiogenesis. Recombinant PF-4var/CXCL4L1 was angiostatically more active (at nanomolar concentration) than PF-4/CXCL4 in various test systems, including wound-healing and migration assays for microvascular endothelial cells and the rat cornea micropocket assay for angiogenesis. Furthermore, PF-4var/CXCL4L1 more efficiently inhibited tumor growth in animal models of melanoma and lung carcinoma than PF-4/CXCL4 at an equimolar concentration. For B16 melanoma in nude mice, a significant reduction in tumor size and the number of small i.t. blood vessels was obtained with i.t. applied PF-4var/CXCL4L1. For A549 adenocarcinoma in severe combined immunodeficient mice, i.t. PF-4var/CXCL4L1 reduced tumor growth and microvasculature more efficiently than PF-4/CXCL4 and prevented metastasis to various organs better than the angiostatic IFN-inducible protein 10/CXCL10. Finally, in the syngeneic model of Lewis lung carcinoma, PF-4var/CXCL4L1 inhibited tumor growth equally well as monokine induced by IFN-gamma (Mig)/CXCL9, also known to attract effector T lymphocytes. Taken together, PF-4var/CXCL4L1 is a highly potent antitumoral chemokine preventing development and metastasis of various tumors by inhibition of angiogenesis. These data confirm the clinical potential of locally released chemokines in cancer therapy.

Biofilm formation by Propionibacterium acnes is associated with increased resistance to antimicrobial agents and increased production of putative virulence factors.

Propionibacterium acnes plays an important role in the pathogenesis of acne vulgaris, a common disorder of the pilosebaceous follicles. Recently, it was suggested that P. acnes cells residing within the follicles grow as a biofilm. In the present study, we tested the biofilm-forming ability of several P. acnes strains in a microtiter plate model. We also evaluated the resistance of biofilm-grown P. acnes towards antimicrobial agents commonly used in the treatment of acne and the production of putative virulence factors. Our results indicate that P. acnes can form biofilms in vitro. The results also show that sessile P. acnes cells are more resistant to various commonly used antimicrobial agents than planktonic cells. In addition, sessile cells produce more extracellular lipases as well as significant amounts of the quorum-sensing molecule autoinducer-2.

The links between the Adolescent Dissociative Experiences Scale (A-DES), fantasy proneness, and anxiety symptoms.

The purpose of this study was to further examine the psychometric properties of the Adolescent Dissociative Experiences Scale (A-DES). A sample of normal adolescents (N = 331) aged 12 to 18 years completed the A-DES and questionnaires measuring posttraumatic stress disorder (PTSD) symptoms, other anxiety disorder symptoms, and fantasy proneness. Factor analysis indicated that the A-DES, at least in nonreferred youths, is assessing a single dimension of dissociation. Furthermore, A-DES scores are not only significantly related to PTSD symptoms but also to other anxiety disorder symptoms (i.e., generalized anxiety disorder, obsessive-compulsive disorder, and panic disorder) and fantasy proneness. Theoretical and practical implications of these findings are briefly discussed.