Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression.

BACKGROUND & AIMS: Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. METHODS: We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. RESULTS: Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.

Identifying risk factors using a skin cancer screening program.

BACKGROUND: The incidence of melanoma and nonmelanoma skin cancer continues to increase. To detect lesions at an earlier phase in their progression, skin cancer screening programs have been advocated by some. However, the effectiveness of skin cancer screening and the ideal population that these screenings should target have yet to be firmly established. This study details the relationship of a group of well-known risk factors with presumptive diagnoses in a large series of individuals self-referred for free skin cancer screening. METHODS: Data obtained during 2007 to 2010 from a descriptive cross-sectional study skin cancer screening program are presented. Participant history was recorded using standardized medical history forms prior to skin examination. Screeners conducted a skin examination varying from whole-body to limited areas (per participant preference) and recorded diagnoses. Diagnoses were assigned to the nonmelanoma cancer (NMC) or suspicious pigmented lesion group for analysis. RESULTS: A presumptive diagnosis of NMC was associated with male sex, age ≥ 50 years, personal history of skin cancer, lower skin phototype, increased sunscreen use, and increased chronic sun exposure (all P values ≤ .0001). After controlling for skin phototype, increased sunscreen use was not associated with a presumptive diagnosis of NMC (P = .96). Presumptive diagnosis of a suspicious pigmented lesion was associated with a reported history of "changing mole" (P < .0001) and negatively associated with age ≥ 50 years (P < .0001) and a personal history of skin cancer (P = .0119). CONCLUSIONS: Several known risk factors for nonmelanoma skin cancer correlated with a presumptive diagnosis of NMC. The yield of presumptive atypical pigmented lesions was increased in participants aged < 50 years, supporting the notion that this population may benefit from screening.

A qualitative study exploring access barriers to abortion services among Indigenous Peoples in Canada.

OBJECTIVE: This paper reports on findings from our exploratory qualitative study that aims to advance knowledge around access to and experiences with abortion services among Indigenous Peoples in Canada. STUDY DESIGN: We applied an Indigenous methodology to engage with 15 Indigenous Peoples across Canada utilizing a conversational interview method. Our study was informed by an Indigenous Advisory Committee consisting of front-line service providers working in the area of abortion service access and/ or support across Canada. RESULTS: We conducted conversations from September and November 2021. Participants identified with Métis, Cree, Dene, Inuit, Haudenosaunee, Anishinaabe, and Mi'kmaq nations, across nine provinces and territories. Participants spoke to six themes encompassing challenges and potential solutions around abortion access experiences among Indigenous Peoples in Canada. These included (1) logistical barriers, (2) poor treatment, (3) stigma, (4) impacts of colonialism on attitudes towards abortion, (5) traditional knowledge, and (6) follow-up care and support. CONCLUSIONS: Our study demonstrates that Indigenous Peoples experience abortion access barriers that are different than non-Indigenous Canadians, and that these barriers are closely linked to colonialism. IMPLICATIONS: Indigenous knowledges and practices that honor reproductive choice that pre-dates settler colonialism, must be brought forward into today to enhance the quality of abortion care.

"I would love for there not to be so many hoops ": recommendations to improve abortion service access and experiences made by Indigenous women and 2SLGTBQIA+ people in Canada.

Acknowledging the barriers in accessing sexual and reproductive health services that disproportionately impact Indigenous women and 2SLGTBQIA+ people, coupled with the lack of knowledge surrounding Indigenous peoples' experiences with abortion, we present qualitative findings from a pilot study investigating Indigenous experiences of accessing abortion services in Canada. We focus on findings related to participant recommendations for improving safety and accessibility of abortion services made by and for Indigenous people in Canada. Informed by an Indigenous Advisory Committee consisting of front-line service providers working in the area of abortion service access and/ or support across Canada, the research team applied an Indigenous methodology to engage with 15 Indigenous people across Canada utilising a conversational interview method, between September and November 2021. With representation from nine provinces and territories across Canada, participants identified with Anishinaabe, Cree, Dene, Haudenosaunee, Inuit, Métis and/ or Mi'kmaq Nations. Five cross-cutting recommendations emerged, including: (1) location, comfort, and having autonomy to choose where the abortion takes place; (2) holistic post-abortion supports; (3) accessibility, availability, and awareness of non-biased and non-judgemental information; (4) companionship, advocacy, and logistical help before and during the abortion from a support person; and (5) cultural safety and the incorporation of local practices and knowledges. Recommendations demonstrate that Indigenous people who have experienced an abortion carry practical solutions for removing barriers and improving access to abortion services in the Canadian context.

Shave biopsy is a safe and accurate method for the initial evaluation of melanoma.

BACKGROUND: Shave biopsy of cutaneous lesions is simple, efficient, and commonly used clinically. However, this technique has been criticized for its potential to hamper accurate diagnosis and microstaging of melanoma, thereby complicating treatment decision-making. STUDY DESIGN: We retrospectively analyzed a consecutive series of patients referred to the University of Florida Shands Cancer Center or to the Moffitt Cancer Center for treatment of primary cutaneous melanoma, initially diagnosed on shave biopsy to have Breslow depth < 2 mm, to determine the accuracy of shave biopsy in T-staging and the potential impact on definitive surgical treatment and outcomes. RESULTS: Six hundred patients undergoing shave biopsy were diagnosed with melanoma from extremity (42%), trunk (37%), and head or neck (21%). Mean (± SEM) Breslow thickness was 0.73 ± 0.02 mm; 6.2% of lesions were ulcerated. At the time of wide excision, residual melanoma was found in 133 (22%), resulting in T-stage upstaging for 18 patients (3%). Recommendations for additional wide excision or sentinel lymph node biopsy changed in 12 of 600 (2%) and 8 of 600 patients (1.3%), respectively. Locoregional recurrence occurred in 10 (1.7%) patients and distant recurrence in 4 (0.7%) patients. CONCLUSIONS: These data challenge the surgical dogma that full-thickness excisional biopsy of suspicious cutaneous lesions is the only method that can lead to accurate diagnosis. Data obtained on shave biopsy of melanoma are reliable and accurate in the overwhelming majority of cases (97%). The use of shave biopsy does not complicate or compromise management of the overwhelming majority of patients with malignant melanoma.