TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon.

The transient receptor potential-melastatin 8 (TRPM8) is a non-selective Ca2+-permeable channel, activated by cold, membrane depolarization, and different cooling compounds. TRPM8 expression has been found in gut mucosal, submucosal, and muscular nerve endings. Although TRPM8 plays a role in pathological conditions, being involved in visceral pain and inflammation, the physiological functions in the digestive system remain unclear as yet. The aims of the present study were: (i) to verify the TRPM8 expression in human distal colon; (ii) to examine the effects of TRPM8 activation on colonic contractility; (iii) to characterize the mechanism of action. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used to analyze TRPM8 expression. The responses of human colon circular strips to different TRPM8 agonists [1-[Dialkyl-phosphinoyl]-alkane (DAPA) 2-5, 1-[Diisopropyl-phosphinoyl]-alkane (DIPA) 1-7, DIPA 1-8, DIPA 1-9, DIPA 1-10, and DIPA 1-12) were recorded using a vertical organ bath. The biomolecular analysis revealed gene and protein expression of TRPM8 in both mucosal and smooth muscle layers. All the agonists tested, except-DIPA 1-12, produced a concentration-dependent decrease in spontaneous contraction amplitude. The effect was significantly antagonized by 5-benzyloxytryptamine, a TRPM8 antagonist. The DIPA 1-8 agonist resulted in the most efficacious and potent activation among the tested molecules. The DIPA 1-8 effects were not affected by tetrodotoxin, a neural blocker, but they were significantly reduced by tetraethylammonium chloride, a non-selective blocker of K+ channels. Moreover, iberiotoxin, a blocker of the large-conductance Ca2+-dependent K+-channels, but not apamin, a blocker of small-conductance Ca2+-dependent K+ channels, significantly reduced the inhibitory DIPA 1-8 actions. The results of the present study demonstrated that TRPM8 receptors are also expressed in human distal colon in healthy conditions and that ligand-dependent TRPM8 activation is able to reduce the colonic spontaneous motility, probably by the opening of the large-conductance Ca2+-dependent K+-channels.

Workplace Aesthetic Appreciation and Exhaustion in a COVID-19 Vaccination Center: The Role of Positive Affects and Interest in Art.

BACKGROUND: Recently, workers employed in vaccination points around the world have been subjected to very high workloads to counter the progress of the COVID-19 epidemic. This workload has a negative effect on their well-being. Environmental psychology studies have shown how the physical characteristics of the workplace environment can influence employees' well-being. Furthermore, studies in the psychology of art show how art can improve the health of individuals. OBJECTIVES: The aim of this research was to test a moderated mediation model to verify how appreciation of workplace aesthetics can impact the level of exhaustion of staff working in a vaccination center, the mediating role of positive and negative affects, and the moderating role of interest in art. METHODS: Data were collected from a sample of 274 workers (physicians, nurses, reception, and administrative staff) working in the same vaccination center in Italy. Participants answered a self-report questionnaire during a rest break. We used a cross-sectional design. RESULTS: The results show that appreciation of workplace aesthetics impacts employees' level of exhaustion. This relationship is mediated by positive and negative affects, and interest in art moderates the relationship between positive affects and exhaustion. CONCLUSIONS: These findings indicate the central role of workplace aesthetics in influencing healthcare workers' well-being, and how interest in art can reduce exhaustion levels. Practical implications of the results are discussed.

Spasmolytic Effects of Aphanizomenon Flos Aquae (AFA) Extract on the Human Colon Contractility.

The blue-green algae Aphanizomenon flos aquae (AFA), rich in beneficial nutrients, exerts various beneficial effects, acting in different organs including the gut. Klamin® is an AFA extract particularly rich in ß-PEA, a trace-amine considered a neuromodulator in the central nervous system. To date, it is not clear if ß-PEA exerts a role in the enteric nervous system. The aims of the present study were to investigate the effects induced by Klamin® on the human distal colon mechanical activity, to analyze the mechanism of action, and to verify a ß-PEA involvement. The organ bath technique, RT-PCR, and immunohistochemistry (IHC) were used. Klamin® reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions. EPPTB, a trace-amine receptor (TAAR1) antagonist, significantly antagonized the inhibitory effects of both Klamin® and exogenous ß-PEA, suggesting a trace-amine involvement in the Klamin® effects. Accordingly, AphaMax®, an AFA extract containing lesser amount of ß-PEA, failed to modify colon contractility. Moreover, the Klamin® effects were abolished by tetrodotoxin, a neural blocker, but not by L-NAME, a nitric oxide-synthase inhibitor. On the contrary methysergide, a serotonin receptor antagonist, significantly antagonized the Klamin® effects, as well as the contractility reduction induced by 5-HT. The RT-PCR analysis revealed TAAR1 gene expression in the colon and the IHC experiments showed that 5-HT-positive neurons are co-expressed with TAAR1 positive neurons. In conclusion, the results of this study suggest that Klamin® exerts spasmolytic effects in human colon contractility through ß-PEA, that, by activating neural TAAR1, induce serotonin release from serotoninergic neurons of the myenteric plexus.

TAS-102 in metastatic colorectal cancer (mCRC): efficacy, tolerability, and quality of life in heavily pretreated elderly patients: a real-life study.

BACKGROUND: TAS-102 is an oral monotherapy, combining trifluridine and tipiracil hydrochloride, indicated for the treatment of pretreated metastatic colorectal cancer (mCRC). The aim of this real-life study is to evaluate the efficacy and safety of TAS-102 in heavily pretreated elderly patients with mCRC whose disease has progressed with standard therapies. METHODS: In this retrospective observational study, we enrolled 50 elderly patients >70 years of age (median age 78 years) with a diagnosis of mCRC who were previously treated or were not considered candidates for treatment with other available therapies. Patients aged >70 years with advanced colorectal cancer and with an ECOG performance status of grade 0 (n=18) or grade 1 (n=32) were included. Overall survival and progression-free survival were the primary endpoints, whereas objective response rate, tolerability, and quality of life were the secondary endpoints. RESULTS: Treatment with TAS-102 appeared to be well tolerated and side effects were generally mild, achieving disease control and a benefit on quality of life. The median overall survival was 6.7 (95% CI 5.7-11.3) and the median progression-free survival was 2.1 months (95% CI 1.2-3.2), estimated using the Kaplan-Meier method. CONCLUSION: TAS-102 represents a manageable and effective therapeutic opportunity and appeared to be well tolerated with generally mild side effects in elderly patients with mCRC who were heavily pretreated with standard therapies.

High-grade B-cell lymphoma arising in mucosa-associated lymphoid tissue of the duodenum.

Duodenal mucosa-associated lymphoid tissue lymphoma is a rare neoplasm. We report a case of a 70-year-old man with non-Hodgkin's lymphoma located in the descending duodenum that was not associated with Helicobacter pylori infection of the stomach. A surgical resection due to obstruction of the bowel lumen above the ligament of Treitz was performed. No invasion into the adjacent structure was confirmed at surgery. The pathological examination showed an infiltration of the duodenal mucosa and submucosa with B lymphocytes. Monoclonal proliferation of the lymphoid tissue was demonstrated by polymerase chain reaction. The histological appearance and the demonstration of monoclonality fulfilled the criteria for malignant high-grade B-cell lymphoma arising from mucosa-associated lymphoid tissue.