The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats

Calcitonin gene–related peptide (CGRP) is known to play a major role in the pathogenesis of pain syndromes, in particular migraine pain. Here we focus on its implication in a rat pain model of inflammation, induced by injection of complete Freund adjuvant (CFA). The nonpeptide CGRP receptor antagonist BIBN4096BS reduces migraine pain and trigeminal neuronal activity. Here we demonstrate that the compound reduces inflammatory pain and spinal neuronal activity. Behavioural experiments reveal a reversal of the CFA-induced mechanical hypersensitivity and monoiodoacetate (MIA)-induced weight-bearing deficit in rats after systemic drug administration. To further investigate the mechanism of action of the CGRP antagonist in inflammatory pain, in vivo electrophysiological studies were performed in CFA-injected rats. Recordings from wide dynamic range neurons in deep dorsal horn layers of the lumbar spinal cord confirmed a reduction of neuronal activity after systemic drug application. The same amount of reduction occurred after topical administration onto the paw, with resulting systemic plasma concentrations in the low nanomolar range. However, spinal administration of BIBN4096BS did not modify the neuronal activity in the CFA model. Peripheral blockade of CGRP receptors by BIBN4096BS significantly alleviates inflammatory pain.     

Work Ability Index Predicts Application for Disability Pension After Work-Related Medical Rehabilitation for Chronic Back Pain

Objective

To determine whether the Work Ability Index (WAI), a short 7-item self-report questionnaire addressing issues of perceived disability, impairment, and expectations for resuming work, predicts application for disability pension, recommendations for further treatment, and other adverse work-related criteria in patients with chronic back pain after rehabilitation.

Design

Cohort study with 3-month follow-up.

Setting

Seven inpatient rehabilitation centers.

Participants

Patients (N=294; 168 women; mean age, 49.9y) with chronic back pain.

Intervention

The WAI was completed at the beginning of rehabilitation. All patients were treated according to the German rehabilitation guidelines for chronic back pain and work-related medical rehabilitation.

Main Outcome Measure

Application for disability pension, as assessed by a postal questionnaire 3 months after discharge.

Results

Receiver operating characteristic curve analysis of the association between the WAI at baseline and subsequent application for disability pension revealed an area under the curve of .80 (95% confidence interval [CI], .62–.97). Youden index was highest when the WAI cutoff value was ≤20 points (sensitivity, 72.7%; specificity, 82.2%; total correct classification, 81.7%). After adjusting for age and sex, persons with a baseline WAI score of ≤20 points had 15.6 times (95% CI, 3.6–68.2) higher odds of subsequent application for disability pension, 4.9 times (95% CI, 1.5–16.8) higher odds of unemployment, and 6 times (95% CI, 2.4–15.2) higher odds of long-term sick leave at follow-up.

Conclusions

The WAI could help rehabilitation professionals identify patients with back pain with a high risk of a subsequent application for disability pension.     

Choi response criteria for prediction of survival in patients with metastatic renal cell carcinoma treated with anti-angiogenic therapies

Objective

Anti-angiogenic drugs cause a reduction in tumour density (Choi criteria) first and then in size [Response Evaluation Criteria In Solid Tumours (RECIST)]. The prognostic significance of changes in tumour density in metastatic renal cell carcinoma (mRCC) is unknown and was assessed in this study.

Methods

The prognostic significance of partial response (PR) as opposed to non-response [stable disease (SD) + progressive (PD)] to anti-angiogenic therapy was assessed in patients with mRCC separately for both criteria using the log-rank test and Cox regression models.

Results

Both criteria were applied to 35 patients. The response was identical for all eight patients with PR and most patients with PD (10/12) when using the RECIST and Choi criteria. Adding tumour density information, 14 patients with SD were re-categorised as having PR (7), SD (4), and PD (3). Patients with PR (Choi) were progression free significantly longer [hazard ratio (HR) 0.24; 95 % CI 0.10–0.57; P?=?0.001] and had better overall survival (HR 0.36; 95 % CI 0.15–0.89; P?=?0.026) compared to patients with SD or PD. The predictive value of PR according to RECIST was not statistically significant.

Conclusions

In mRCC, the Choi criteria separate prognostic groups better when compared with RECIST. This may allow early discrimination of patients benefiting from continued treatment.

Key Points

? CT is widely used to assess patients with metastatic renal cell carcinoma. ? Various algorithms can be applied for tumour therapy control in patients with mRCC. ? Follow-up should be based on evaluation of the tumour size and density. ? RECIST is based only on tumour shrinkage and might lead to wrong conclusions.     

Mucosal application of cationic poly(d,l-lactide-co-glycolide) microparticles as carriers of DNA vaccine and adjuvants to protect chickens against infectious bursal disease

Infectious bursal disease virus (IBDV) is an immunosuppressive virus of chickens. The virus protein (VP) 2 induces neutralizing antibodies, which protect chickens against the disease. The aim of this study was to develop a cationic poly(d,l-lactide-co-glycolide) (PLGA) microparticle (MP) based IBDV-VP2 DNA vaccine (MP-IBDV-DNA) for chickens to be delivered orally and by eye drop route. The tested IBDV-VP2 DNA vaccines were immunogenic for specific-pathogen-free chickens and induced an antibody response after intramuscular application. Co-inoculation with a plasmid encoding chicken IL-2 (chIL-2) or CpG-ODN did not significantly improve protection against IBDV challenge. However, the application of a MP-IBDV-DNA vaccine alone or in combination with a delayed oral and eye drop application of cationic MP loaded with CpG-ODN or chIL-2 improved protection against challenge. The MP-IBDV-DNA-vaccinated chickens showed less pathological and histopathological bursal lesions, a reduced IBDV antigen load as well as T-cell influx into the bursa of Fabricius (BF) compared to the other groups (p < 0.05). The addition of chIL-2 loaded MP improved challenge virus clearance from the BF as demonstrated by lower neutralizing antibody titers and reduced IL-4 and IFN-α mRNA expression in the bursa at 7 days postchallenge compared to the other challenged groups. Overall, the efficacy of the IBDV-DNA vaccine was improved by adsorption of the DNA vaccine onto cationic PLGA-MP, which also allowed mucosal application of the DNA vaccine.     

Ultraviolet irradiation induces apoptosis in human immature, but not in skin mast cells

As diverse pruritic cutaneous diseases respond to ultraviolet treatment, we have examined whether ultraviolet light is capable of inducing apoptosis in mast cells. Human mast cell line 1 (HMC1) derived from a patient with malignant mastocytosis and purified skin mast cells were irradiated with single doses of ultraviolet B or ultraviolet A1, or pretreated with 8-methoxypsoralen prior to ultraviolet A1 exposure. After 0 to 48 h of incubation, the percentage of apoptotic and dead cells was assessed. In HMC1 cells, morphologic features of apoptosis were further evaluated by electron microscopy. All ultraviolet treatment induced apoptosis of HMC1 cells in a time- and dose-dependent manner. Apoptosis was associated with activation of caspase-3, release of cytochrome C, cleavage of poly(ADP-ribose)-polymerase, and nuclear accumulation of p53. In contrast, resting skin mast cells were resistant to ultraviolet light induced apoptosis. After incubation with stem cell factor and interleukin-4 for 2 wk, however, slowly proliferating skin mast cells also underwent apoptosis in response to ultraviolet light. In conclusion, these data demonstrate that ultraviolet light directly affects mast cells, but mainly aims at the proliferating mast cells as found in mastocytosis and mast cell dependent pruritic diseases, where increased numbers are observed due to the recruitment mast cell precursors from the blood.     

Stärken‐ und Schwächen‐Analyse: Grundlage der Leistungsausrichtung im wettbewerbsorientierten Umfeld

Hospitals in the German health care system are confronted with increasing economic competition due to paradigm shifts in funding inpatient treatment. Major hospitals, such as university hospitals, will be under significantly greater pressure to keep up the ability to compete by uniform per case payment. The new hospital funding system based on a Diagnosis Related Group (DRG) system and the economic competition involved require analyses of organisational and locational factors. Cooperativeness and efficient utilisation of resources, properties and staff will be determining factors to secure existence. Adequate responses and strategies are essential to cope with the growing operating requirements. Carrying out an analysis identifying one's own strengths and weaknesses, opportunities and threats will help to focus activities and sustainable strategies into areas where the strengths and the greatest opportunities lie. An example of the process of strategic planning and positioning is shown for a university department of dermatology.     

Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas

Beta-blockers are a highly promising treatment modality for complicated infantile hemangiomas (IH). However, data on propranolol as first-line treatment, objective outcome measures and impact on hemodynamics in young infants is limited. We retrospectively evaluated a homogenous group of infants with proliferating complicated IH treated with propranolol (2 mg/kg/day). Outcome was assessed by blinded evaluation of clinical photographs by visual analogue scale (VAS), ultrasound examination and ophthalmological review (if appropriate). Tolerance and hemodynamic variables were recorded over time, including a 2-day in-patient observation at the initiation of therapy. Twenty-five infants (median age 3.6 (1.5–9.1) months) were included in the study. The median follow-up-time was 14 (9–20) months and 14 patients completed treatment at a median age of 14.3 (11.4–22.1) months, after a duration of 10.5 (7.5–16) months. In all patients, there was significant fading of colour (with a VAS of −9 (−6 to −9) after 7 months) and significant decrease in size of the IH (with a VAS of −8 (−3 to −10) after 7 months). Median thickness of the lesions assessed by ultrasound at baseline and after 1 month was 14 (7–28) mm and 10 (5–23) mm, respectively (p < 0.01). In children with periocular involvement, astigmatism and amblyopia resolved rapidly within 8 weeks. The overall tolerance of propranolol was good, and no relevant hemodynamic changes were noted. Conclusion: Our report supports the excellent effect and good tolerance of this novel therapy, and we propose the use of propranolol as first-line treatment for IH.