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PLoS Pathogens Jun 2023Abnormal deposition of α-synuclein is a key feature and biomarker of Parkinson's disease. α-Synuclein aggregates can propagate themselves by a prion-like seeding-based...
Abnormal deposition of α-synuclein is a key feature and biomarker of Parkinson's disease. α-Synuclein aggregates can propagate themselves by a prion-like seeding-based mechanism within and between tissues and are hypothesized to move between the intestine and brain. α-Synuclein RT-QuIC seed amplification assays have detected Parkinson's-associated α-synuclein in multiple biospecimens including post-mortem colon samples. Here we show intra vitam detection of seeds in duodenum biopsies from 22/23 Parkinson's patients, but not in 6 healthy controls by RT-QuICR. In contrast, no tau seeding activity was detected in any of the biopsies. Our seed amplifications provide evidence that the upper intestine contains a form(s) of α-synuclein with self-propagating activity. The diagnostic sensitivity and specificity for PD in this biopsy panel were 95.7% and 100% respectively. End-point dilution analysis indicated up to 106 SD50 seeding units per mg of tissue with positivity in two contemporaneous biopsies from individual patients suggesting widespread distribution within the superior and descending parts of duodenum. Our detection of α-synuclein seeding activity in duodenum biopsies of Parkinson's disease patients suggests not only that such analyses may be useful in ante-mortem diagnosis, but also that the duodenum may be a source or a destination for pathological, self-propagating α-synuclein assemblies.
Topics: Humans; Parkinson Disease; alpha-Synuclein; Biopsy; Intestines; Duodenum
PubMed: 37390080
DOI: 10.1371/journal.ppat.1011456 -
European Journal of Pharmacology Sep 2023Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1...
Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1 expression have been identified in the gastrointestinal (GI) tract. GI mucosal functions remain largely undefined for TRPV1 and TRPA1 with side-dependence and regional differences in signalling unclear. Here we investigated TRPV1- and TRPA1-induced vectorial ion transport as changes in short-circuit current (ΔI), in defined segments of mouse colon mucosa (ascending, transverse and descending) under voltage-clamp conditions in Ussing chambers. Drugs were applied basolaterally (bl) or apically (ap). Capsaicin responses were biphasic, with primary secretory and secondary anti-secretory phases, observed with bl application only, which predominated in descending colon. AITC responses were monophasic and secretory, with ΔI dependent on colonic region (ascending vs. descending) and sidedness (bl vs. ap). Aprepitant (neurokinin-1 (NK1) antagonist, bl) and tetrodotoxin (Na channel blocker, bl) significantly inhibited capsaicin primary responses in descending colon, while GW627368 (EP4 receptor antagonist, bl) and piroxicam (cyclooxygenase inhibitor, bl) inhibited AITC responses in ascending and descending colonic mucosae. Antagonism of the calcitonin gene-related peptide (CGRP) receptor had no effect on mucosal TRPV1 signalling, while tetrodotoxin and antagonists of the 5-hydroxytryptamine-3 and 4 receptors, CGRP receptor, and EP1/2/3 receptors had no effect on mucosal TRPA1 signalling. Our data demonstrates the regional-specificity and side-dependence of colonic TRPV1 and TRPA1 signalling, with involvement of submucosal neurons and mediation by epithelial NK1 receptor activation for TRPV1, and endogenous prostaglandins and EP4 receptor activation for TRPA1 mucosal responses.
Topics: Mice; Animals; Transient Receptor Potential Channels; TRPA1 Cation Channel; Capsaicin; Tetrodotoxin; Colon; Mucous Membrane; TRPV Cation Channels
PubMed: 37394028
DOI: 10.1016/j.ejphar.2023.175897 -
World Journal of Surgical Oncology Jul 2023The diagnostic criteria and effect of persistent descending mesocolon (PDM) on sigmoid and rectal cancers (SRCs) remain controversial. This study aims to clarify PDM...
BACKGROUND
The diagnostic criteria and effect of persistent descending mesocolon (PDM) on sigmoid and rectal cancers (SRCs) remain controversial. This study aims to clarify PDM patients' radiological features and short-term surgical results.
METHOD
From January 2020 to December 2021, radiological imaging data from 845 consecutive patients were retrospectively analyzed using multiplanar reconstruction (MRP) and maximum intensity projection (MIP). PDM is defined as the condition wherein the right margin of the descending colon is located medially to the left renal hilum. Propensity score matching (PSM) was used to minimize database bias. The anatomical features and surgical results of PDM patients were compared with those of non-PDM patients.
RESULTS
Thirty-two patients with PDM and 813 patients with non-PDM were enrolled into the study who underwent laparoscopic resection. After 1:4 matching, patients were stratified into PDM (n = 27) and non-PDM (n = 105) groups. The lengths from the inferior mesenteric artery (IMA) to the inferior mesenteric vein (1.6 cm vs. 2.5 cm, p = 0.001), IMA to marginal artery arch (2.7 cm vs. 8.4 cm, p = 0.001), and IMA to the colon (3.3 cm vs. 10.2 cm, p = 0.001) were significantly shorter in the PDM group than those in the non-PDM group. The conversion to open surgery (11.1% vs. 0.9%, p = 0.008), operative time (210 min vs. 163 min, p = 0.001), intraoperative blood loss (50 ml vs. 30 ml, p = 0.002), marginal arch injury (14.8% vs. 0.9%, p = 0.006), splenic flexure free (22.2% vs. 3.8%, p = 0.005), Hartmann procedure (18.5% vs. 0.0%, p < 0.001) and anastomosis failure (18.5% vs. 0.9%, p = 0.001) were significantly higher in the PDM group. Moreover, PDM was an independent risk factor for prolonged operative time (OR = 3.205, p = 0.004) and anastomotic failure (OR = 7.601, p = 0.003).
CONCLUSION
PDM was an independent risk factor for prolonged operative time and anastomotic failure in SRCs surgery. Preoperative radiological evaluation using MRP and MIP can help surgeons better handle this rare congenital variant.
Topics: Humans; Colon, Sigmoid; Mesocolon; Operative Time; Retrospective Studies; Rectal Neoplasms; Anastomosis, Surgical; Sigmoid Neoplasms; Laparoscopy; Risk Factors; Mesenteric Artery, Inferior
PubMed: 37420246
DOI: 10.1186/s12957-023-03091-w