The effect of ‘two hit’ neonatal and young-adult stress on dopaminergic modulation of prepulse inhibition and dopamine receptor density

Background and purpose:

A combination of early neurodevelopmental insult(s) and young-adult stress exposure may be involved in the development of schizophrenia. We studied prepulse inhibition (PPI) regulation in rats after an early stress, maternal deprivation, combined with a later stress, simulated by chronic corticosterone treatment, and also determined whether changes in brain dopamine receptor density were involved.

Experimental approach:

Rats were subjected to either 24 h maternal deprivation on postnatal day 9, corticosterone treatment from 8 to 10 weeks of age, or both. At 12 weeks of age, the rats were injected with 0.1, 0.3 or 1.0 mg·kg⁻¹ of apomorphine or 0.5 or 2.5 mg·kg⁻¹ of amphetamine and PPI was determined using automated startle boxes. Dopamine D₁ and D₂ receptor levels were assessed in the nucleus accumbens and caudate nucleus using receptor autoradiography.

Key results:

Young-adult treatment with corticosterone resulted in attenuated disruption of PPI by apomorphine and amphetamine. In some rats, maternal deprivation resulted in reduced baseline PPI which added to the effect of corticosterone treatment. There was no down-regulation of dopamine D₁ or D₂ receptors.

Conclusions and implications:

These results confirm and extend our finding of an inhibitory interaction of developmental stress on dopaminergic regulation of PPI. No corresponding changes in dopamine receptor density were observed in brain regions with a major involvement in PPI regulation, suggesting long-lasting desensitization of dopamine receptor signalling or indirect changes in PPI regulation.     

Features of the offensive subtype of Taijin-Kyofu-Sho in US and Korean patients with DSM-IV social anxiety disorder

Taijin-Kyofu-Sho (TKS), an East Asian syndrome of interpersonal fear and avoidance, that has been considered culture-bound, overlaps with social anxiety disorder to an unknown extent. The offensive subtype of TKS is characterized by two features considered atypical of social anxiety disorder: the belief that one displays physical defects and/or socially inappropriate behaviors (offensive TKS symptoms) and fear of offending others (allocentric focus), but no studies have systematically evaluated these two features in patients with social anxiety disorder. The purpose of this study was to assess offensive TKS symptoms and allocentric focus of fear in US (n = 181) and Korean (n = 64) patients with DSM-IV social anxiety disorder, using the newly developed TKS Questionnaire. Seventy-five percent of patients with social anxiety disorder in the US and Korea endorsed at least one of the five offensive TKS symptoms surveyed. The severity of features of offensive TKS was significantly associated with severity of social anxiety symptoms, depressive symptoms, and disability in both samples. These results suggest that features of the offensive subtype of TKS are not uncommon among US patients with social anxiety disorder and may not be as culturally specific as previously believed. They also suggest that Western clinicians should assess patients with social anxiety for features of offensive TKS, and they support further consideration of integrating TKS features into conceptualizations of social anxiety disorder.     

Cross-cultural study of conviction subtype Taijin Kyofu: proposal and reliability of Nagoya-Osaka diagnostic criteria for social anxiety disorder

Conviction subtype Taijin-Kyofu (c-TK) is a subgroup of mental disorder characterized by conviction and strong fear of offending others in social situations. Although the concept of c-TK overlaps with that of social anxiety disorder (SAD), patients with c-TK often may not be diagnosed as such within the current Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria. We propose the Nagoya-Osaka criteria to amend this situation. This study examined the cross-cultural interrater reliability of the proposed criteria. Eighteen case vignettes of patients with a variety of complaints focused around social anxieties were collected from 6 different countries, and diagnosed by 13 independent raters from various nationalities according to the original DSM-IV and the expanded criteria. The average agreement ratio for the most frequent diagnostic category in each case was 61.5% with DSM-IV and 87.6% with the modified DSM-IV with Nagoya-Osaka criteria (p < 0.001). These findings indicate that the Nagoya-Osaka criteria for SAD can improve interrater reliability of SAD.     

Critical incident monitoring in anaesthesia

PURPOSE OF REVIEW: Updates on developments in critical incident monitoring in anaesthesia, and assesses its role in improving patient safety. RECENT FINDINGS: Critical incident reporting has become more widely accepted as an effective way to improve anaesthetic safety, and has continued to highlight the importance of human errors and system failures. The establishment of an international database also improves critical incident reporting. Experiences from the national reporting and learning system in the UK have provided some solutions to the many problems and criticisms faced by the critical incident reporting technique. Direct observations to detect errors are more accurate than voluntary reporting of critical incidents, and may be a promising new approach. SUMMARY: Critical incident monitoring is a valuable tool in ensuring patient safety due to its low cost and the ability to provide a comprehensive body of detailed qualitative information. The qualitative information gathered can be used to develop strategies to prevent and manage existing problems, as well as to plan further initiatives for patient safety. Novel approaches should complement existing methods to achieve better results. The development of a culture which emphasises safety should go hand in hand with current audit activities.     

EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases

Objective

To develop evidence‐based recommendations for the management of systemic glucocorticoid (GC) therapy in rheumatic diseases.

Methods

The multidisciplinary guideline development group from 11 European countries, Canada and the USA consisted of 15 rheumatologists, 1 internist, 1 rheumatologist–epidemiologist, 1 health professional, 1 patient and 1 research fellow. The Delphi method was used to agree on 10 key propositions related to the safe use of GCs. A systematic literature search of PUBMED, EMBASE, CINAHL, and Cochrane Library was then used to identify the best available research evidence to support each of the 10 propositions. The strength of recommendation was given according to research evidence, clinical expertise and perceived patient preference.

Results

The 10 propositions were generated through three Delphi rounds and included patient education, risk factors, adverse effects, concomitant therapy (ie, non‐steroidal anti‐inflammatory drugs, gastroprotection and cyclo‐oxygenase‐2 selective inhibitors, calcium and vitamin D, bisphosphonates) and special safety advice (ie, adrenal insufficiency, pregnancy, growth impairment).

Conclusion

Ten key recommendations for the management of systemic GC‐therapy were formulated using a combination of systematically retrieved research evidence and expert consensus. There are areas of importance that have little evidence (ie, dosing and tapering strategies, timing, risk factors and monitoring for adverse effects, perioperative GC‐replacement) and need further research; therefore also a research agenda was composed.Since 1948, glucocorticoids (GCs) have been widely used in medicine.¹ Although GCs soon became associated with the occurrence of adverse effects (AEs), they are still the most frequently used anti‐inflammatory and immune‐suppressive drugs in rheumatic diseases. Recent studies have demonstrated the disease‐modifying potential of low‐dose GCs in rheumatoid arthritis (RA) and this has renewed the debate on the risk–benefit ratio of this treatment.² Current literature on the risk–benefit ratio of GCs is nevertheless inconsistent, and inappropriate use of GCs could lead to increased toxicity;³ this emphasises the need for clear statements on proper use of GCs. Hence, a EULAR task force on GCs, including a patient, was formed to develop evidence‐based recommendations, to provide a tool for the better use and management of GC‐therapy in rheumatic diseases.     

DNA-PKcs-dependent modulation of cellular radiosensitivity by a selective cyclooxygenase-2 inhibitor

PURPOSE: Inhibition of cyclooxygenase-2 has been shown to increase radiosensitivity. Recently, the suppression of radiation-induced DNA-dependant protein kinase (DNA-PK) activity by the selective cyclooxygenase-2 inhibitor celecoxib was reported. Given the importance of DNA-PK for repair of radiation-induced DNA double-strand breaks by nonhomologous end-joining and the clinical use of the substance, we investigated the relevance of the DNA-PK catalytic subunit (DNA-PKcs) for the modulation of cellular radiosensitivity by celecoxib. METHODS AND MATERIALS: We used a syngeneic model of Chinese hamster ovarian cell lines: AA8, possessing a wild-type DNK-PKcs; V3, lacking a functional DNA-PKcs; and V3/WT11, V3 stably transfected with the DNA-PKcs. The cells were treated with celecoxib (50 muM) for 24 h before irradiation. The modulation of radiosensitivity was determined using the colony formation assay. RESULTS: Treatment with celecoxib increased the cellular radiosensitivity in the DNA-PKcs-deficient cell line V3 with a dose-enhancement ratio of 1.3 for a surviving fraction of 0.5. In contrast, clonogenic survival was increased in DNA-PKcs wild-type-expressing AA8 cells and in V3 cells transfected with DNA-PKcs (V3/WT11). The decrease in radiosensitivity was comparable to the radiosensitization in V3 cells, with a dose-enhancement ratio of 0.76 (AA8) and 0.80 (V3/WT11) for a survival of 0.5. CONCLUSIONS: We have demonstrated a DNA-PKcs-dependent differential modulation of cellular radiosensitivity by celecoxib. These effects might be attributed to alterations in signaling cascades downstream of DNA-PK toward cell survival. These findings offer an explanation for the poor outcomes in some recently published clinical trials.     

Prevalence of anemia in clinic patients with heart failure and cost analysis of epoetin treatment

STUDY OBJECTIVES: To determine the prevalence of anemia in an outpatient heart failure clinic, describe the type of anemia in patients treated there, and evaluate the potential costs associated with epoetin therapy in this cohort. DESIGN: Single-center, retrospective cohort analysis (part 1) and a literature-based economic decision analysis (part 2). DATA SOURCE: Medical records from a multidisciplinary, outpatient, heart failure clinic, and published hospitalization and drug-use data. PATIENTS: We evaluated 170 adults with chronic heart failure who were enrolled in the clinic and for whom at least one complete blood count was recorded between January 1, 2003, and April 15, 2006. MEASUREMENTS AND MAIN RESULTS: In part 1, demographic and clinical data were extracted from electronic medical records. The overall prevalence of anemia was 47.6% or 47.1%, as based on World Health Organization or National Kidney Foundation definitions, respectively. Normocytic anemia was characterized in 75.0% of patients. In part 2, heart failure hospitalization rates and costs, drug acquisition, and drug administration were estimated by using the published literature. In a hypothetical cohort of 100 patients with heart failure and comorbid anemia, the costs associated with outpatient epoetin and intravenous iron therapy exceeded savings in hospitalization costs by $83,070. Results of 1-way sensitivity analyses generally confirmed robustness of the model. CONCLUSION: Anemia is a common comorbidity in patients with chronic heart failure treated in the outpatient clinic. Although the current evidence is insufficient to support the use of epoetin in this population, initial findings indicate that epoetin and intravenous iron therapy may be associated with positive clinical outcomes. From a pharmacoeconomic standpoint, however, a reduction in the cost of heart failure-related hospitalization does not offset the cost of epoetin and intravenous iron therapy.