Tino Münster

In vivo imaging using fluorescent antibodies to tumor necrosis factor predicts therapeutic response in Crohn's disease

As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohns disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this disease. Topical antibody administration in 25 patients with Crohns disease led to detection of intestinal mTNF+ immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF+ cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF+ cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohns disease and autoimmune or inflammatory disorders.

Modulation of transcription factor NF-κB by enantiomers of the nonsteroidal drug ibuprofen

The nonsteroidal drug ibuprofen exists as an R(−)‐ and S(+)‐enantiomer. Only the S(+)‐enantiomer is an effective cyclo‐oxygenase inhibitor, while the R(−)‐enantiomer is inactive in this respect. Thus the molecular mechanism by which R(−)‐ibuprofen exerts its anti‐inflammatory and antinociceptive effects remains unknown. In this study the effects of the enantiomers of ibuprofen on modulation of transcription factors have been examined with electrophoretic mobility‐shift assay (EMSA), transient transfection experiments, confocal immunofluorescence and nuclear import experiments, to determine their selectivity and potency as inhibitors of the activation of transcription factor nuclear factor‐κB (NF‐κB). R(−)‐ibuprofen (IC50: 121.8 μM) as well as the S(+)‐enantiomer (IC50: 61.7 μM) inhibited the activation of NF‐κB in response to T‐cell stimulation. The effect of ibuprofen was specific because, at concentrations up to 10 mM, ibuprofen did not affect the heat shock transcription factor (HSF) and the activation of NF‐κB by prostaglandin E2 (PGE2). Very high concentrations of ibuprofen (20 mM) did not prevent NF‐κB binding to DNA in vitro. Immunofluorescence and nuclear import experiments indicate that the site of ibuprofen action appeared to be upstream of the dissociation of the NF‐κB‐IκB‐complex. Our data raise the possibility that R(−)‐ibuprofen exerts some of its effects by inhibition of NF‐κB activation.

Onset and duration of mivacurium‐induced neuromuscular blockade in children with Charcot–Marie–Tooth disease. A case series with five children

Background:  The Charcot–Marie–Tooth (CMT) disorders are a group of hereditary motor and sensory neuropathies characterized clinically by peripheral muscle wasting and weakness. We hypothesized that unknown involvement of the muscle used for monitoring neuromuscular block may account for the conflicting reports about the effect of nondepolarizing neuromuscular agents in these patients. The aim of this study was to compare onset and recovery from mivacurium‐induced neuromuscular block on the adductor pollicis and orbicularis oculi muscles.

Mivacurium-induced neuromuscular block in adult patients suffering from Charcot-Marie-Tooth disease.

PurposeThe response to non-depolarizing neuromuscular blocking drugs is variable in patients with Charcot-Marie-Tooth (CMT) disease. We speculated that CMT involvement of the monitored muscle may be partially responsible for this inconsistency. We therefore investigated the response to a standard dose of mivacurium simultaneously assessed at adductor pollicis (AP) and orbicularis oculi (OO) muscles in five patients with CMT.Clinical featuresOver a period of one year, five adult patients with CMT scheduled for orthopedic surgery were studied. The right arm and the right supercilliary arch were prepared for acceleromyographic (AMG) neuromuscular monitoring. The AMG probes were attached at the distal interphalangeal joint of the right thumb and on the right upper eyelid to record the response of the AP and OO, respectively. The ulnar nerve and upper part of the facial nerve were stimulated supramaximally with repeated train-of-four stimuli (2 Hz, 0.2 msec) every 15 sec via applied surface electrodes. Following monitor calibration and induction of general anesthesia, mivacurium 0.2 mg·kg-1 iv was given, and the time course of relaxation and recovery were assessed. Times to spontaneous recovery of T1 to 25% were 15 ± 3 vs 12 ± 4 min in the AP and OO muscle groups respectively, whereas times to 90% recovery were 23 ± 5 vs 29 ± 10 min, respectively.ConclusionThe onset and recovery characteristics associated with mivacurium-induced neuromuscular block were similar at the AP and OO muscle groups. A near normal response to mivacurium was observed in this small series of patients with CMT disease.RésuméObjectifLa réaction aux curarisants non dépolarisants varie d’un patient à l’autre dans la maladie de Charcot-Marie-Tooth (CMT). En supposant qu’une atteinte du muscle sous observation et déjà atteint par la maladie MCT était partiellement responsable de cette variation, nous avons vérifié la réponse à une dose habituelle de mivacurium simultanément à l’adducteur du pouce (AP) et au muscle orbiculaire des paupières (OP) chez cinq patients atteints de CMT.Éléments cliniquesAu cours d’une année, cinq patients adultes atteints de CMT et opérés en orthopédie ont été étudiés. Le bras droit et l’arcade sourcilière ont été préparés pour un monitorage de la transmission neuromusculaire accéléromyographique (AMG). Les sondes d’AMG ont été fixées à l’articulation interphalangienne distale du pouce droit et à la paupière supérieure droite pour l’enregistrement des réponses respectives des AP et OP. Le nerf cubital et la partie supérieure du nerf facial ont été soumis à des stimuli supramaximaux en train-de-quatre (2 Hz, 0,2 ms) toutes les 15 s par les électrodes appliquées. Après le calibrage du moniteur et l’induction de l’anesthésie générale, 0,2 mg·kg-1de mivacurium iv ont été donnés et l’évolution du relâchement musculaire et de la récupération a été évaluée. Les temps de récupération spontanée de T1à 25 % ont été respectivement de 15 ± 3 vs 12 ± 4 min à l’AP et à l’OP, alors que les temps de récupération à 90 % ont été respectivement de 23 ± 5 vs 29 ± 10 min.ConclusionLes caractéristiques du délai d’installation et de la récupération associés au blocage neuromusculaire induit par le mivacurium ont été similaires pour les groupes musculaires AP et OP. Une réponse au mivacurium, près de la normale, a été observée chez cinq patients atteints de la maladie de CMT.

Postictal agitation after electroconvulsive therapy: incidence, severity, and propofol as a treatment option.

Objectives Postictal agitation (PIA) after electroconvulsive therapy (ECT) is a major medical problem. This observational study investigated the incidence and severity of PIA and evaluated propofol as a treatment option in a patient population. Methods The study included 14 patients that underwent a series of ECTs performed either with or without an approximately 0.5-mg/kg propofol bolus after the end of an electroencephalography (EEG) seizure. Among other values, we documented PIA incidence and severity as rated by a simple score; orientation to person, time, place, and situation; transfer times to the postanesthesia care (PACU) and inpatient unit; nurses’ and patients’ rating of recovery period, and others and tested for significant differences. Results Five minutes after the end of ECT, the patients showed moderate to severe PIA in 8 of 37 ECT sessions. Incidence was significantly lower when patients had received propofol (3/37). Transfer time to the PACU was longer, but transfer time to the inpatient unit was shorter after administration of propofol. The recovery period was rated significantly better after propofol administration by nurses and patients. Conclusions A single bolus of propofol administered after the end of the seizure reduced the incidence of post-ECT PIA. The PACU staff and patients rated the emergence period significantly better when propofol was administered.

Modulation of Somatosensory Profiles by Spinal Cord Stimulation in Primary Raynaud′s Syndrome

Background and Goal: Spinal cord stimulation (SCS) is an effective antinociceptive treatment for various neuropathic pain syndromes. Apart from antinociceptive action, it may modulate overall somatosensory perception. This case report targets the question of whether SCS may alter quantitative sensory testing (QST) in a patient with primary Raynaud′s syndrome.

Weak Inhibitors of Cyclooxygenases May Exert Their Antinociceptive Effect by Modulation of Transcription Factors

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain, fever and inflammation. For these agents inhibition of prostaglandin synthesis via inhibition of cyclooxygenases (COX) is considered to be their principle mode of action.1 However, inhibition of prostaglandin synthesis alone may not account for all effects of NSAIDs. There is no satisfying correlation between inhibition of prostaglandin synthesis and antinociceptive (analgesic) effects of some of these agents.2 Weak inhibitors of prostaglandin synthesis, e. g. salicylic acid exert potent antinociceptive effects.3 Such observations question the conventual concept that NSAIDs act exclusively by inhibiting prostaglandin synthesis. However, neither the cellular target nor cell signaling pathways possibly involved in the antinociceptive effect of weak prostaglandin inhibitors have been identified yet.

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn’s disease

Objective Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn’s disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy. Design Mucosal and blood cells were isolated from patients with Crohn’s disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS. Results Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4β7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R− cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23. Conclusions Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn’s disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn’s disease refractory to anti-TNF therapy.

Orphan anesthesia: an initiative of the scientific working group of pediatric anesthesia of the German society of anesthesiology

Anesthesia is often described as the best example of applied pharmacology. Indeed you probably cannot be a good anesthetist if you do not have a good grasp of pharmacology. A key aspect to a good anesthetic is the skill of exploiting the favorable pharmacodynamic interactions between agents. This superbly written and easily understood review by Hannan and Anderson helps demystify the complex science behind these interactions.

Anaesthesia and orphan disease: fragile X syndrome (Martin-Bell syndrome).

disturbances, have been reported; at autopsy, myocardial and valvular storage of lipopigments have been observed histologically and associated with hypertrophy and dilation of ventricles, degenerative myocardial changes, interstitial fibrosis and fatty replacement. Abundant accumulation of lipopigments and degeneration were seen in all components of the conduction system. Bradycardia, sinus arrest and severe supraventricular tachycardia during anaesthesia in patients with JNCL have also been reported. Some episodes of bradycardia were associated with hypothermia and were successfully treated with anticholinergics. Therefore, preoperative ECG and echocardiography in patients with NCL are considered essential.