Anti-PAD4 autoantibodies in rheumatoid arthritis: levels in serum over time and impact on PAD4 activity as measured with a small synthetic substrate

Isoform 4 of the human peptidylarginine deiminase (hPAD4) enzyme may be responsible for the citrullination of antigens in rheumatoid arthritis (RA) and has been shown to be itself the target of disease-specific autoantibodies. Here, we have tested whether the level of serum anti-hPAD4 antibodies in RA patients is stable over a period of 10 years and whether the antibodies influence hPAD4-mediated deimination of the small substrate N-α-Benzoyl-l-arginine ethyl ester. RA sera (n = 128) obtained at baseline and after 10 years were assessed for anti-hPAD4 antibodies by a specific immunoassay. For 118 RA patients, serum anti-hPAD4 IgG levels were stable over 10 years. Seven patients who were negative for anti-PAD4 IgG at baseline had become positive after 10 years. Further, total IgG from selected RA patients and controls were purified, and a fraction was depleted for anti-hPAD4 antibodies. Kinetic deimination assays were performed with total IgG and depleted fractions. The k _cat and K _m values of hPAD4-mediated deimination of N-α-Benzoyl-l-arginine ethyl ester were not affected by the depletion of the anti-hPAD4 antibodies from the total IgG pool. In conclusion, RA patients remain positive for anti-hPAD4 antibodies over time and some patients who are initially anti-hPAD4 negative become positive later in the disease course. The anti-hPAD4 antibodies did not affect the enzymatic activity of hPAD4 when the small substrate N-α-Benzoyl-l-arginine ethyl ester was used. However, this finding may not exclude an effect of these autoantibodies on citrullination of protein substrates in RA.     

Disease-stabilizing treatment with all-trans retinoic acid and valproic acid in acute myeloid leukemia: serum hsp70 and hsp90 levels and serum cytokine profiles are determined by the disease, patient age, and anti-leukemic treatment

Heat shock protein (HSP) 70 and HSP90 are released by primary human acute myeloid leukemia (AML) cells during stress-induced spontaneous in vitro apoptosis. The AML cells also show constitutive release of several cytokines and the systemic serum levels of several soluble mediators are altered in patients with untreated AML. In the present study, we have investigated serum levels of HSP70/HSP90 and the serum cytokine profiles of patients with untreated AML and patients receiving AML-stabilizing palliative treatment based on all-trans retinoic acid (ATRA) plus valproic acid. Patients with untreated AML showed increased HSP90 levels and a distinct serum cytokine profile when compared with healthy controls, and low pre-therapy HSP90 levels were associated with a prolonged survival during treatment with ATRA + valproic acid + theophyllin. Hierarchical cluster analysis showed a close association between HSP70, HSP90, IL-1 receptor antagonist (IL-1ra), and hepatocyte growth factor (HGF) levels. Furthermore, disease-stabilizing therapy altered the serum-cytokine profile, but the correlations between HSP70/HSP90/IL-1ra/HGF were maintained only when ATRA + valproic acid were combined with theophyllin but not when combined with cytarabine. We conclude that both HSP levels and serum cytokine profiles are altered and may represent possible therapeutic targets or prognostic markers in human AML.     

Parasuicide: The value of suicidal intent and various motives as predictors of future suicidal behaviour

Abstract

The main aim of the study was to examine whether various aspects of suicidal intent or various motives for an index parasuicide can predict nonfatal or fatal repetition of suicidal behaviour. 776 parasuicide patients from 5 Nordic regions participating in the WHO/EURO Multicentre Study on Parasuicide were followed for one year. The Suicide Intent Scale (SIS) and the Motives for Parasuicide Questionnaire (MPQ) were used as predictor variables. A low level of suicidal intent predicted nonfatal repetition. The motive “make things easier for someone” differentiated female repeaters From male repeaters. The report of an unclear motive was the only significant predictor of fatal repetition. Suicidal intent and various motives for a parasuicide have some value in predicting repetition of suicidal behaviour. but should, perhaps. in future studies be combined with other variables in order to increase the predictive value.     

Treatment needs, diagnoses and use of services for acutely admitted psychiatric patients in northwest Russia and northern Norway

Background

We compared demography, diagnoses and clinical needs in acutely admitted psychiatric hospital patients in northwest Russia and northern Norway.

Method

All acutely admitted psychiatric patients in 1 psychiatric hospital in north-west Russia and 2 in northern Norway were in a three months period assessed with HoNOS and a Norwegian form developed to study acute psychiatric services (MAP). Data from a total of 841 patients were analysed (377 Norwegian, 464 Russian) with univariate and multivariate statistics.

Results

Russian patients were more often males who had paid work. 2/3 were diagnosed with alcohol and organic disorders, and 70% reported problems related to sleep. Depression was widespread, as were problems associated with occupation. Many more Norwegian patients were on various forms of social security and lived in community supported homes. They had a clinical profile of affective disorders, use of drugs, suicidality and problems with activities involved of daily life. Slightly more Norwegian patients were involuntary admitted.

Conclusion

Acutely admitted psychiatric patients in North West Russia and Northern Norwegian showed different clinical profiles: alcohol, depression and organic disorders characterised Russian patients, affective disorders, suicidality and use of drugs characterised the Norwegians. Whereas Norwegian patients are mainly referred from GPs the Russians come via 1.line psychiatric services (“dispensaries”). Average length of stay for Russian patients was 2.5 times longer than that of the Norwegian.     

Simulation-assisted burn disaster planning

The aim of the study was to evaluate the Swedish medical systems response to a mass casualty burn incident in a rural area with a focus on national coordination of burn care. Data were collected from two simulations of a mass casualty incident with burns in a rural area in the mid portion of Sweden close to the Norwegian border, based on a large inventory of emergency resources available in this area as well as regional hospitals, university hospitals and burn centres in Sweden and abroad. The simulation system Emergo Train System^® (ETS) was used and risk for preventable death and complications were used as outcome measures: simulation I, 18.5% (n = 13) preventable deaths and 15.5% (n = 11) preventable complications; simulation II, 11.4% (n = 8) preventable deaths and 11.4% (n = 8) preventable complications. The last T1 patient was evacuated after 7 h in simulation I, compared with 5 h in simulation II. Better national coordination of burn care and more timely distribution based on the experience from the first simulation, and possibly a learning effect, led to a better patient outcome in simulation II. The experience using a system that combines both process and outcome indicators can create important results that may support disaster planning.     

Book Reviews

Abstract

Objective: Monitoring of ongoing psychotherapy is of crucial importance in improving the quality of mental health care by detecting therapies being off track, which requires that the instrument used is psychometrically sound. This study investigates the psychometric properties of the Norwegian version of the Outcome Questionnaire 45.2 (OQ-45) and situates the results in an international context.Method: Data from one non-clinical sample (N = 338) and one clinical sample (N = 560) were compared to international samples investigating reliability, cut-offs, and factor structure. Results: The results show adequate reliability and concurrent validity. Conclusions: The means, clinical cut-offs, and the reliable change index vary across countries. However, the means of the OQ-45 for nonclinical samples correlate highly with external values of national well-being, indicating that the OQ-45 is a valid instrument internationally. The factor analyses in the present study do not confirm the hypothesized factor structure of the OQ-45, but are similar to the results internationally.     

Penicillin G Treatment in Infective Endocarditis Patients – Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Penicillin G is frequently used to treat infective endocarditis (IE) caused by streptococci, penicillin‐susceptible staphylococci and enterococci. Appropriate antibiotic exposure is essential for survival and reduces the risk of complications and drug resistance development. We determined penicillin G plasma concentration [p‐penicillin] once weekly in 46 IE patients. The aim was to evaluate whether penicillin G 3 g every 6 hr (q6 h) resulted in therapeutic concentrations and to analyse potential factors that influence inter‐ and intra‐individual variability, using linear regression and a random coefficient model. [P‐penicillin] at 3 hr and at 6 hr was compared with the minimal inhibitory concentration (MIC) of the bacteria isolated from blood cultures to evaluate the following PK/PD targets: 50% fT > MIC and 100% fT > MIC. [P‐penicillin] varied notably between patients and was associated with age, weight, p‐creatinine and estimated creatinine clearance (eCLcr). Additionally, an increase in [p‐penicillin] during the treatment period showed strong correlation with age, a low eCLcr, a low weight and a low p‐albumin. Of the 46 patients, 96% had [p‐penicillin] that resulted in 50% fT > MIC, while 71% had [p‐penicillin] resulting in 100% fT > MIC. The majority of patients not achieving the 100% fT > MIC target were infected with enterococci. Streptococci and staphylococci isolated from blood cultures were highly susceptible to penicillin G. Our results suggest that penicillin G 3 g q6 h is suitable to treat IE caused by streptococci and penicillin‐susceptible staphylococci, but caution must be taken when the infection is caused by enterococci. When treating enterococci, therapeutic drug monitoring should be applied to optimize penicillin G dosing and exposure.