Tryptase potentiates enteric nerve activation by histamine and serotonin: Relevance for the effects of mucosal biopsy supernatants from irritable bowel syndrome patients.

BACKGROUND: We previously showed that mucosal biopsy supernatants from irritable bowel syndrome patients activated neurons despite low concentrations of tryptase, histamine, and serotonin which individually would not cause spike discharge. We studied the potentiating responses between these mediators on excitability of enteric neurons. METHODS: Calcium-imaging was performed using the calcium-sensitive dye Fluo-4 AM in human submucous plexus preparations from 45 individuals. Histamine, serotonin, and tryptase were applied alone and in combinations to evaluate nerve activation which was assessed by analyzing increase in intracellular Ca2+ ([Ca2+ ]i ), the proportion of responding neurons and the product of both defined as Ca-neuroindex (NI). Protease activated receptor (PAR) 2 activating peptide, PAR2 antagonist and the serine protease-inhibitor FUT-175 were used to particularly investigate the role of proteases. KEY RESULTS: Histamine or serotonin (1 µmol/L each) evoked only few small responses (median NI [25%/75%]: 0 [0/148]; 85 [0/705] respectively). Their combined application evoked statistically similar responses (216 [21/651]). Addition of the PAR2 activator tryptase induced a significantly higher Ca-NI (1401 [867/4075]) compared to individual application of tryptase or to coapplied histamine and serotonin. This synergistic potentiation was neither mimicked by PAR2 activating peptide nor reversed by the PAR2 antagonist GB83, but abolished by FUT-175. CONCLUSIONS & INFERENCES: We observed synergistic potentiation between histamine, serotonin, and tryptase in enteric neurons, which is mediated by proteolytic activity rather than PAR2 activation. This explained neuronal activation by a cocktail of these mediators despite their low concentrations and despite a relatively small PAR2-mediated response in human submucous neurons.

Toca 511 gene transfer and 5-fluorocytosine in combination with temozolomide demonstrates synergistic therapeutic efficacy in a temozolomide-sensitive glioblastoma model.

Toca 511 (vocimagene amiretrorepvec), an amphotropic retroviral replicating vector (RRV), can successfully and safely deliver a functional, optimized cytosine deaminase (CD) gene to tumors in orthotopic glioma models. This agent, in conjunction with subsequent oral extended-release 5-fluorocytosine (5-FC) (Toca FC), is currently under investigation in patients with recurrent high-grade glioma . Temozolomide (TMZ) with radiation is the most frequently used first-line treatment for patients with glioblastoma, the most common and aggressive form of primary brain cancer in adults. However, subsets of patients with certain genetic alterations do not respond well to TMZ treatment and the overall median survival for patients who respond remains modest, suggesting that combinatorial approaches may be necessary to significantly improve outcomes. We show that in vitro TMZ delays but does not prevent RRV spread, nor interfere with Toca 511+5-FC-mediated cell killing in glioma tumor cells, and in vivo there is no significant hematologic effect from the combination of 5-FC and the clinically relevant dose of TMZ. A synergistic long-term survival advantage is observed in mice bearing an orthotopic TMZ-sensitive glioma after Toca 511 administration followed by coadministration of TMZ and 5-FC. These results provide support for the investigation of this novel combination treatment strategy in patients with newly diagnosed malignant glioma.

[Monoaminergic transmitters in the cerebrospinal fluid of patients with acute, chronic, and intermittent pain. Interface between pain and depression?]. / Monoaminerge Transmitter in der Zerebrospinalflüssigkeit von Patienten mit akuten, chronischen und episodischen Schmerzen. Schnittstelle zu depressiven Symptomen?

BACKGROUND AND STUDY PURPOSE: Pain and depression share similar neurobiological characteristics, and it is a common clinical observation that pain and depression may coincide in the same patient. They also appear to influence each other in the process of chronification. Furthermore, there is a complex coupling of pain and depression by monoaminergic transmitter system. PATIENTS AND METHODS: On the basis of these findings, norepinephrine (NE), epinephrine (E), dopamine (DOP), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and vanillylmandelic acid (VMA) concentrations were determined in the cerebrospinal fluid (CSF) in patients with acute (20), chronic (27), and episodic pain syndrome (44) in a prospective study. The biochemical parameters were correlated to self-assessment pain and depression scores. The control group consisted of 13 pain-free patients with diseases affecting the muscular system. RESULTS: Patients with chronic and episodic pain syndromes had significantly more depressive and psychovegetative symptoms compared to patients with acute pain. In patients with acute pain, DOP was significantly higher than in controls and chronic and episodic pain patients. In addition DOP was positively correlated to self-assessment pain score (p*<0.05). In patients with chronic and episodic pain, NE and 5-HIAA were positively correlated to the duration of disease and were significantly lower than in the control group. In neither of these two groups could significant correlations be established between these parameters and pain or depression self-assessment scores. In all groups, positive correlations were seen between the neurotransmitter and their metabolites. CONCLUSION: The pathological decrease of NE and 5-HIAA in the CSF points to the crucial role of noradrenergic and serotonergic transmitter systems in the generation, modulation, and perpetuation of chronic and episodic pain syndromes. It indicates that antidepressants are effective drugs in these diseases. However, a discriminative neurochemical pattern between pain and depression could not be established. The demonstration of polyvalent correlations between different neurotransmitters is indicative of complex neurobiological coupling between cortical, limbic, and hypothalamic neuronal networks on the one hand and the nociceptive descending system on the other hand in the genesis of pain and depression.

[Altered function of the hypothalamic-pituitary-adrenal axis in patients with acute, chronic and episodic pain]. / Funktionsstörung der hypothalamisch-hyphophysär-adrenalen Achse bei Patienten mit akuten, chronischen und intervallartigen Schmerzsyndromen.

INTRODUCTION: Complex disorders of the hypothalamic-pituitary-adrenal axis constitute phenomena whose etiopathogenetic significance is the subject of controversy. The frequent coincidence with depressive symptoms further complicates interpretation. PATIENTS AND METHODS: Daily variations in cortisol levels were measured in 20 patients with acute pain, 27 with chronic pain in the lumbar musculoskeletal system, and 44 with episodic forms of headache to determine the daily average and then correlated with differentiated algesimetric data. RESULTS: Patients with chronic and episodic pain had significantly higher scores on the McGill Pain Questionnaire and more affective items as an expression of depressive symptoms than patients with acute pain. The three groups did not however exhibit significant differences for the depression scale and list of "psychovegetative" disorders. In comparison to an age-matched pain-free control population (n=17), the average daily levels of cortisol were significantly higher in all three groups besides singularly elevated daily levels, but no correlations between the cortisol values and overall algesimetric data could be established. Chronic pain patients with high depression scores had significantly higher cortisol levels irrespective of pain intensity. DISCUSSION: Pain experiences cause increased plasma cortisol levels with significant elevation of the daily average. Whereas in cases of acute pain, a direct but unspecific stress reaction not connected with the pain seems to be likely, the underlying cause in cases of chronic and episodic pain appears to be a complex and enduring activation of the hypothalamic-pituitary-adrenal axis, likewise independent from pain, probably associated with concomitant depressive symptoms and disruption of the circadian rhythm of release controlled by the hypothalamus.

JNK2 and IKKbeta are required for activating the innate response to viral infection.

Viral infection or double-stranded (ds) RNA induce interferons (IFN) and other cytokines. Transcription factors mediating IFN induction are known, but the signaling pathways that regulate them are less clear. We now describe two such pathways. The first pathway leading to NF-kappaB depends on the dsRNA-responsive protein kinase (PKR), which in turn activates IKB kinase (IKK) through the IKKbeta subunit. The second viral-and dsRNA-responsive pathway is PKR independent and involves Jun kinase (JNK) activation leading to stimulation of AP-1. Both IKKbeta and JNK2 are essential for efficient induction of type I IFN and other cytokines in response to viral infection or dsRNA. This study establishes a general role for these kinases in activation of innate immune responses.

[Autonomic dysfunction in migraine und tension-type headache--pilot study]. / Autonome Regulationsstörung bei Migräne und Spannungskopfschmerz. Pilotstudie.

UNLABELLED: Autonomic nervous system (ANS) dysfunction in migraine has been hypothesized during the last years. However, the pathophysiological relevance of this dysfunction on the etiology and the maintenance of the headaches remains unclear. The aim of this study was to investigate connections between the ANS dysfunction and the clinical appearances of the pain and its processing in migraine and tension-type headache (TTH). METHODS: Ten migraine-patients (31,4+/-10,6 years) and ten TTH-patients (49,3+/-14,6 years) underwent a cardiovascular reflex testing during headache-free intervals. A questionnaire was obtained to determine the patients' clinical pain-symptoms. RESULTS: The ANS function testings showed sympathetic hypofunction in both groups of patients. In the migraine-group, there was a significant correlation between the pain-intensity and the extent of the autonomic dysfunction (r=0,82) In the TTH-group, we found a correlation between the results of the orthostatic test and the v. Zerssen-depression-scale (r=0.69). CONCLUSIONS: These results suggest a sympathetic dysfunction in both headache-syndromes and suggest that the ANS plays an important role on the pathophysiology and the maintenance of the headaches.