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 α4ß7, 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.

Intravenous theophylline is the most effective intervention to prolong EEG seizure duration in patients undergoing electroconvulsive therapy.

BACKGROUND: Seizure duration in electroconvulsive therapy (ECT) is positively related with patients' outcome. This study sought to investigate the impact of anesthetic management on seizure duration, and the impact of selected drugs (theophylline, remifentanil, S-ketamine) on seizure duration. METHODS: Retrospective analysis of all patients undergoing ECT at our institution from January 2011 to April 2012 was performed based on electronic medical chart and review of existing quality improvement data. Patient data (N = 78), including gender, age, height, weight, and administered drugs, energy levels, and electroencephalic seizure duration were analyzed. Statistical analysis was performed using a generalized linear model. RESULTS: A total of 78 patients (male = 39, female = 39, age 51 ± 12 years) were included. Average number of session was 10 ± 6 (1-30). In our patient population, theophylline administration was the only parameter, which significantly prolonged seizure duration, whereas S-ketamine, remifentanil, thiopental, age, sex, session or energy level had no significant effect. CONCLUSION: Theophylline can be a useful adjunct for patients with inadequate seizure duration. If there is a concomitant beneficial effect on patients' outcome needs to be investigated in further studies.

Anatomical location of the vocal cords in relation to cervical vertebrae: A new predictor of difficult laryngoscopy?

BACKGROUND: Several anatomical factors, such as prognathism, sex, short thyromental distance and others are known to make direct laryngoscopy difficult. OBJECTIVE: We investigated the hypothesis that the anatomical position of the vocal cords in relation to the cervical vertebrae correlates with difficult laryngoscopy. Existing MRI was used to identify the position of the vocal cords relative to the cervical spine in patients with and without difficult laryngoscopy. DESIGN: Observational study with adaptive enrichment. SETTING: University hospital. PATIENTS: A total of 142 adult patients, 91 with easy (Cormack-Lehane class 1 or 2) and 51 with difficult (Cormack-Lehane class 3 or 4) laryngoscopy. MAIN OUTCOME MEASURES: Position of the vocal cords relative to cervical vertebrae in patients with easy vs. difficult laryngoscopy. RESULTS: In patients with difficult laryngoscopy, we found a higher incidence of cranial position of the vocal cords in relation to the cervical spine compared with patients with easy laryngoscopy (P < 0.001). CONCLUSION: Anaesthesiologists should take advantage of existing imaging of the cervical spine when assessing the patient's airway.

Effects of Different Anesthetics on Pain Processing in an Experimental Human Pain Model.

OBJECTIVE: After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus. METHODS: Forty-eight healthy volunteers underwent conditioning noxious stimulation (CS) over 5 days. On day 2, the volunteers were randomized into 4 groups: control group (no anesthesia) and 3 groups receiving anesthesia before CS in anesthetic doses: propofol (P), propofol/remifentanil (PR), and propofol/remifentanil/S-ketamine (PRK). Quantitative sensory testing was performed on days 1 through 5 and on day 22. RESULTS: In every group, CS was associated with short- and long-term habituation to the electrical stimulus. Repetitive CS resulted in unmodified short-term sensitization with stable areas of hyperalgesia. Although the PR group showed a trend toward increased areas of hyperalgesia on day 2, no significant differences were detectable between the groups. In contrast, anesthesia resulted in decreased intensity of the electrically evoked pain on day 2. Finally, the mechanical pain threshold before CS on day 5 was increased in all groups and remained elevated 3 weeks after the first CS, consistent with a long-term antinociceptive effect after CS. CONCLUSIONS: The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems.

Characterization of somatosensory profiles in patients with Crohn's disease.

BACKGROUND: Crohn's disease (CD) is a painful chronic inflammatory bowel disease. It primarily affects terminal ileum, but the involvement of large and small intestines or extraintestinal manifestations is very common. CD may go along with neurogenic inflammation, mediated by substance P and CGRP, which are also key players in pain transmission. This may in turn contribute to hyperalgesia and altered somatosensory function in CD. METHODS: One hundred and three (103) patients with CD and 80 healthy volunteers were enrolled. Patient characteristics and disease history were documented. We used quantitative sensory testing (QST) to investigate the somatosensory profile in patients and volunteers. We also calculated z-scores for the QST results of the patients with CD based on the data of our control group. A 2-step cluster analysis, using all QST data, was performed to find subgroups within patients and volunteers. RESULTS: Thresholds of warm detection, mechanical pain, and vibration detection did significantly differ between patients with CD and volunteers. Z-scores indicated a general trend of sensory loss in CD patients with a significant relationship between patients with a sensory loss for cold and warm detection. In the hyposensitive cluster of the CD cohort, patients were more frequently male, had a higher incidence of extraintestinal manifestations, and suffered longer from CD. CONCLUSIONS: Our findings are consistent with the presence of a subclinical small fiber neuropathy. The group of CD patients with pronounced neuropathy findings were predominantly males, had a higher incidence of extraintestinal manifestations, and tended to have a longer history of disease duration.

Catheter-based distal sciatic nerve block in patients with Charcot-Marie-Tooth disease.

BACKGROUND: The use of peripheral nerve blocks in patients with Charcot-Marie-Tooth (CMT) disease is scarcely reported; however, when performed it has proven to be effective for postoperative pain control. METHODS: A distal catheter-based sciatic nerve block for postoperative pain control was offered to 27 consecutive CMT patients scheduled for elective foot surgery. 18 of the 27 CMT patients consented to the offered sciatic nerve block. Localization of the sciatic nerve was guided by a nerve stimulator. The threshold current required to generate a motor response was assessed and a catheter inserted. Postoperative pain was assessed by recording the dose of analgesics to maintain visual analog score < 3 the next 48 hours. On demand patients received boluses of ropivacaine (2 mg/mL) via the catheter and/or analgesics in case of insufficient pain relief. Total postoperative ropivacaine dosage and analgesic consumption were recorded. About one year after the block patients were contacted to report their actual status by self-assessment. RESULTS: In 17 patients a catheter could be placed. In 7 patients placement of the catheter was difficult (several attempts, high electrical impedance). Patients with nerve block had lower analgesics consumption compared to patients without a block. Surprisingly, the 7 patients with "difficult" catheter-placement had the overall lowest ropivacaine and analgesics consumption compared to all other patients with or without peripheral block. No anesthesia related complications were reported by the questionnaire. CONCLUSIONS: In our small series catheter-based distal sciatic block within CMT patients had safely been used for pain relief up to three days. The infusion of local anesthetics via a catheter was not associated with any complication.

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. MATERIALS AND METHODS: We report on a 44-year-old female patient with primary Raynaud's syndrome who had SCS via cervical and lumbar electrodes. QST was performed in a standardized manner assessing cold detection threshold (CDT) and warm detection threshold (WDT), cold pain threshold (CPT) and heat pain threshold (HPT), mechanical detection threshold (MDT) and mechanical pain threshold (MPT) thresholds, and vibration detection threshold (VDT) and pressure pain thresholds (PPT). We tested at the dorsum of the right/left hand of the patient with engaged and disengaged SCS. Test results were compared with a control group of 80 subjects. RESULTS: Without SCS, the patient showed a sensory decrease in CDT, MDT, MPT, and VDT. SCS influenced the perception of cold, warm, and tactile detection thresholds, whereby CDT, WDT, and VDT were impaired and MDT was improved. CONCLUSION: SCS significantly modulated the somatosensory profile in a patient with primary Raynaud's syndrome. These effects were pronounced in qualities involving Aß, C, and A∂ nerve fibers. Further investigations may help to understand the mechanisms of action of SCS.

General Anesthesia in the First 36 Months of Life.

BACKGROUND: Experimental data have shown that the developing brain is especially vulnerable to exogenous noxious substances. The potential effects of anesthetic drugs on brain growth and development are a matter of concern. Clinical studies of children who underwent general anesthesia in their earliest years can make a major contribution to our understanding of the effects of anesthetic drugs on infants and toddlers (i.e., children under age 5). METHODS: Children born at term during the years 2007-2011 who were exposed to general anesthesia before their third birthday were included in the study. Data on general anesthesia were retrospectively evaluated, and the overall intelligence quotient (IQ) was determined prospectively as the primary target parameter. Children who had not been exposed to general anesthesia were recruited as a control group. The non-inferiority threshold was set at a difference of 5 IQ points out of a consideration of clinical relevance. RESULTS: 430 complete data sets were available from exposed children and 67 from members of the control group. The exposed group achieved a mean IQ score of 108.2, with a 95% confidence interval of [107; 109.4]; the corresponding values in the control group were 113 [110; 116.1]. Both groups achieved a mean score that was higher than the expected 100 points. After adjustment for age, socioeconomic status, and sex, the difference between the two groups was 2.9 points [0.2; 5.6], indicating a significantly better outcome in the control group than in the exposed group. The non-inferiority threshold of 5 IQ points was within the confidence interval; thus, non-inferiority was not demonstrated. CONCLUSION: The fact that both groups achieved a higher IQ score than the expected 100 points may be attributable, at least in part, to the restriction of the study to children born at term. The results indicate that general anesthesia in early childhood is not associated with markedly reduced intelligence in later years, although noninferiority could not be demonstrated.

Evaluation of a Humor Training for Patients with Chronic Pain: A Randomized Clinical Trial.

BACKGROUND: Humor and laughter are positively associated with psychological as well as with physical well-being. As there is little research examining to what extent patients suffering from chronic pain could benefit from a humor intervention, the goal of this study was to develop a pain-specific humor training and to evaluate its feasibility and effectiveness as component of regular, multimodal pain therapy. PATIENTS AND METHODS: Patients from inpatient treatment groups for chronic pain in a German hospital were randomly assigned to the training group (final n = 62) and the control group (final n = 65). The training consisted of four sessions that were implemented in the usual therapy throughout two weeks. Outcomes were divided into primary (perceived current pain intensity and depression) and secondary ones (quality of life impairment by pain, cheerfulness, and self-enhancing humor) and were assessed prior to and after intervention. RESULTS: Results showed improvements in all outcomes for both groups. For primary outcomes, a trend for a greater reduction in current pain intensity was found for the training group compared to the control group (p = 0.060, η 2 p = 0.02), as well as, for secondary outcomes, a trend for greater reduction of quality of life impairment by pain (p = 0.079, η 2 p = 0.02) and a trend for greater increase in self-enhancing humor (p = 0.086, η 2 p = 0.02). Depression and cheerfulness remained unaffected. Feedback indicated feasibility of the training within multimodal therapy, showing overall acceptance as well as providing specific suggestions for improvement. CONCLUSION: As the first study evaluating a specific humor training for patients with chronic pain within a randomized controlled trial, its results are promising regarding an additional contribution that humor interventions can make towards multimodal pain therapy.

Transient receptor potential ankyrin 1 promoter methylation and peripheral pain sensitivity in Crohn's disease.

BACKGROUND: Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract associated with abdominal pain and diarrhea. Pain caused by Crohn's disease likely involves neurogenic inflammation which seems to involve the ion channel transient receptor potential ankyrin 1 (TRPA1). Since the promoter methylation of TRPA1 was shown to influence pain sensitivity, we asked if the expression of TRPA1 is dysregulated in patients suffering from Crohn's disease. The methylation rates of CpG dinucleotides in the TRPA1 promoter region were determined from DNA derived from whole blood samples of Crohn patients and healthy participants. Quantitative sensory testing was used to examine pain sensitivities. RESULTS: Pressure pain thresholds were lower in Crohn patients as compared to healthy participants, and they were also lower in females than in males. They correlated inversely with the methylation rate at the CpG - 628 site of the TRPA1 promoter. This effect was more pronounced in female compared to male Crohn patients. Similar results were found for mechanical pain thresholds. Furthermore, age-dependent effects were detected. Whereas the CpG - 628 methylation rate declined with age in healthy participants, the methylation rate in Crohn patients increased. Pressure pain thresholds increased with age in both cohorts. CONCLUSIONS: The TRPA1 promoter methylation appears to be dysregulated in patients suffering from Crohn's disease, and this effect is most obvious when taking gender and age into account. As TRPA1 is regarded to be involved in pain caused by neurogenic inflammation, its aberrant expression may contribute to typical symptoms of Crohn's disease.

Postoperative pain in small-for-gestational age infants after hernia repair, orchidopexy and urethral reconstruction surgery: A pilot study.

BACKGROUND: Small-for-gestational-age (SGA) birth bears an enhanced risk of developing hypertension, obesity, insulin resistance and mental health disorders in later life as a consequence of adaptive processes in utero. Only a small number of studies on pain perception in SGA infants exist. These are indicative of a blunted stress response to pain in SGA newborns. AIM: We initiated a pilot study investigating differences in postoperative pain perception between SGA and appropriate-for-gestational-age (AGA) infants. METHODS: Pain and alertness levels of 10 formerly SGA and 14 AGA infants at the age 0.5-2 years were evaluated by the FLACC scale, Steward and Aldrete Scores following hernia repair, reconstructive surgery of hypospadia and orchidopexy. In addition, the postoperative consumption of non-steroidal anti-inflammatory drugs was compared between SGA and AGA. RESULTS: Postoperative pain and alertness levels were not significantly different in SGA and AGA children. We did not observe significant group differences regarding the consumption of non-steroidal anti-inflammatory drugs. CONCLUSION: While previous studies were suggestive of a suppressed stress response to pain in SGA newborns, these findings did not fully translate into an altered response to pain beyond the newborn age. Further studies in a larger cohort seem necessary to verify this finding.

Epigenetic divergence in the TRPA1 promoter correlates with pressure pain thresholds in healthy individuals.

The expression pattern of important transduction molecules in nociceptive sensory neurons is likely to dictate pain sensitivity. While this notion is well established for increased pain sensitivities under conditions like inflammation and neuropathy, less is known as to which molecules are defining interindividual differences in pain sensitivity in healthy subjects. A genome-wide methylation analysis on monozygotic twins found that methylation of a CpG dinucleotide in the promoter of transient receptor potential ankyrin 1 (TRPA1) is inversely associated with the threshold for heat-induced pain. Several in vitro studies also suggest that TRPA1 mediates mechanical sensitivity of sensory afferents, thus potentially mediating pressure-evoked pain. In the present study, we therefore investigated the epigenetic predisposition for pressure pain by analyzing the methylation status of 47 CpG sites in the promoter region of TRPA1. Using DNA from whole-blood samples of 75 healthy volunteers, we found that the same CpG site previously found to affect the threshold for heat-evoked pain is hypermethylated in subjects with a low threshold for pressure pain. We also found gender differences, with females displaying higher methylation rates combined with higher pressure pain sensitivities as compared with males. In conclusion, our findings support the notion that epigenetic regulation of TRPA1 seems to regulate thermal and mechanical pain sensitivities.