Involvement of capsaicin-sensitive afferent nerves in the proteinase-activated receptor 2-mediated vasodilatation in the rat dura mater.

Neurogenic inflammation of the dura mater encephali has been suggested to contribute to the mechanisms of meningeal nociception and blood flow regulation. Recent findings demonstrated that the rat dura mater is innervated by trigeminal capsaicin-sensitive peptidergic nociceptive afferent nerves which mediate meningeal vascular responses through activation of the transient receptor potential vanilloid type 1 (TRPV1) receptor. The present work explored the functional significance of the capsaicin-sensitive subpopulation of dural afferent nerves via their contribution to the meningeal vascular responses evoked through activation of the proteinase-activated receptor 2 (PAR-2). The vascular responses of the dura mater were studied by laser Doppler flowmetry in a rat open cranial window preparation. Topical applications of trypsin, a PAR-2-activator, or Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH(2)), a selective PAR-2 agonist peptide, resulted in dose-dependent increases in meningeal blood flow. The SLIGRL-NH(2)-induced vasodilatation was significantly reduced following capsaicin-sensitive afferent nerve defunctionalization by prior systemic capsaicin treatment and by pretreatment of the dura mater with the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37). Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) an unspecific inhibitor of nitric oxide (NO) production, but not 1-(2-trifluoromethylphenyl) imidazole (TRIM), a neuronal NO synthase inhibitor, also inhibited the vasodilator response to SLIGRL-NH(2). The vasodilator responses elicited by very low concentrations of capsaicin (10 nM) were significantly enhanced by prior application of SLIGRL-NH(2). The present findings demonstrate that activation of the PAR-2 localized on capsaicin-sensitive trigeminal nociceptive afferent nerves induces vasodilatation in the dural vascular bed by mechanisms involving NO and CGRP release. The results indicate that the PAR-2-mediated activation and sensitization of meningeal capsaicin-sensitive C-fiber nociceptors may be significantly implicated in the pathophysiology of headaches.

[Job satisfaction of hospital doctors. Results of a study of a national sample of hospital doctors in Germany]. / Arbeitszufriedenheit bei Krankenhausärzten und -ärztinnen in Deutschland. Ergebnisse einer bundesweiten Erhebung im Herbst 2006.

AIMS: This paper presents the findings on the level of job satisfaction among hospital physicians in Germany and puts the results into relation to demographic variables and employment status. METHODS: Data were collected as part of the survey "Work Life, Lifestyle and Health among Hospital Doctors in Germany 2006" using anonymous self-reporting questionnaires. Job satisfaction was scored using the scale according to Warr et al. It consists of 10 items with a seven-point Likert scale (1=dissatisfaction; 7=satisfaction), so the sum score ranks between 10 and 70. The following variables were correlated to job satisfaction: demographic variables (gender, age), and employment status (specialty, geographical localisation of hospital, hospital type, level of seniority, working time pattern). RESULTS: The response rate was 58% (n=1917). Doctors reported an average job satisfaction of 44.3. Comparing different specialties, physicians in radiology had the highest (47.6) and in surgery (43.0) the lowest level of job satisfaction. Below-average job satisfaction could also be found in urology (43.5) and internal medicine (43.7). The regression analysis showed that the younger age group (B=-1.45; p=0.031) and those with a status as junior physician (B=-4.97; p=0.0001) were significantly dissatisfied. Out of the ten items assessed "working hours" (3.25), "payment" (3.59), "physical working conditions" (3.96) and "recognition for good work" (4.08) attained the lowest ratings. CONCLUSIONS: Hospital doctors in Germany are moderately satisfied with their jobs - less satisfied than their colleagues in England, New Zealand and Norway. Improvement of job satisfaction and working conditions should be achieved via effective regulation of working hours and improvement of recognition for medical work regarding monetary and non-monetary factors such as payment and positive feedback for good work.

Loss of capsaicin-induced meningeal neurogenic sensory vasodilatation in diabetic rats.

Neuropathic alterations of sensory nerves involved in the mediation of neurogenic inflammation of the meninges may contribute to the increased incidence of headaches in diabetics. In the rat, activation of capsaicin-sensitive nociceptors, which express the transient receptor potential vanilloid type 1 (TRPV1) receptor, induces meningeal vasodilatation, a significant component of neurogenic inflammation, through the release of calcitonin gene-related peptide (CGRP). This study examines the effects of streptozotocin-induced diabetes on TRPV1 receptor-mediated neurogenic sensory vasodilatation, CGRP release and nerve fiber density in the rat dura mater. In a cranial window preparation, epidural application of capsaicin (10(-7) M) produced distinct vasodilatory responses in control animals as measured by laser Doppler flowmetry. In diabetic rats, capsaicin-induced vasodilatation was reduced or even abolished 6, but not 2 or 4 weeks after diabetes induction. In contrast, vasoconstriction, a non-neurogenic response to capsaicin at a higher concentration (10(-5) M), was not altered in diabetic rats. The vasodilatory effects of histamine (10(-5) M), acetylcholine (10(-4) M) and CGRP (10(-5) M) were similar in control, diabetic and insulin-treated diabetic animals. In diabetic rats, a significant decrease in the capsaicin-evoked release of CGRP and reduction in the density of TRPV1-immunoreactive (IR) nerves were demonstrated. Treatment of the diabetic rats with insulin restored both the vasodilatory response and the capsaicin-induced CGRP release toward control values. In conclusion, this study revealed a marked impairment of meningeal TRPV1-IR nerves in streptozotocin diabetic rats by showing reduced neurogenic sensory vasodilatation, decreased capsaicin-evoked CGRP release and reduction in the number of TRPV1-IR nerve fibers of the dura mater. The findings suggest that capsaicin-sensitive afferents may play an important role in meningeal nociceptor function and their dysfunction, e.g. due to a limited removal of inflammatory mediators and/or tissue metabolites from the meningeal tissue, may contribute to the enhanced incidence of headaches in diabetics.

Time-limited phototherapy of term newborns in ABO hemolytic disease and hyperbilirubinaemia.

"Limited" phototherapy was used to treat full term babies with and without ABO-isoimmunization. Serum indirect bilirubin levels calling for irradiation during the first five days of life are summarized in a diagram (Fig. 1). Seperate indications were given for babies with different etiologies of jaundice, maturity (gestational age and birthweight) and indicational levels were correlated with the postnatal age (days and hours) of the infant. After a fall or harmless stagnation of bilirubin levels irradiation was stopped. Clinical assessment of the treatment of 17 babies with ABO-isiommunization, and 16 newborns without it and with hyperbilirubinemia is given in detail. Results were compaired with the outcome of treatment of 44 newborns who received the same care in every respect, but phototherapy. These control cases, selected by pairs, were similar. Exchange transfusion, based on identical indications was necessary in 13 of the 44 babies treated without and only 3 of the 33 infants treated with phototherapy. The billirubin levels of the treated babies were lower during the whole course of the irradiation. The difference in favor of the treated babies was significant on the second and third days of life incases of ABO-hemolytic disease, and from the 4th day of life in cases of hyperbilirubinemia. The values of standard deviations, important in view of the indication for exchange transfusion were also lower in the light treated babies. Successful irradiation required on average of 44 hours (30-72 hours) in cases of ABO-isoimmunization and 40 hours (18-50) in cases of hyperbilirubinemia, respectively. Re-elavation of the bilirubin level after finishing phototherapy was not observed.