Stimulation of defecation: effects of coffee use and nicotine on rectal tone and visceral sensitivity

OBJECTIVE: Coffee and cigarette use is believed to induce bowel movements, although the literature is controversial and precise measurements of rectal tone and sensitivity with a barostat have never been performed. The aim of this study was to assess the effects of coffee and nicotine on rectal tone, compliance and sensitivity. MATERIALS AND METHODS: Sixteen healthy volunteers were recruited for the coffee (n = 8) and nicotine (n = 8) experiments. The experiments were randomly performed in a placebo-controlled crossover design on separate days. In the coffee experiment, 280 ml strong coffee or warm water was drunk and in the nicotine experiment, nicotine (2 mg) or placebo was given sublingually. A rectal barostat procedure was carried out. A flaccid bag, mounted on a catheter, was inserted in the rectum. Continuous pressure distension was exerted to register basal visceral sensitivity and compliance. After rectal adaptation, the stimulus was given. Rectal tone was measured for 1 h, after which continuous pressure distension was repeated. RESULTS: Rectal tone increased by 45% 30 min after coffee intake (p = 0.031) and by 30% after water intake (p = 0.032), but the effects of coffee and water were not significantly different. Rectal tone did not change significantly after administration of nicotine (7%) or placebo (10%). There was no difference in compliance and visceral sensitivity between coffee and water or nicotine and placebo. CONCLUSIONS: Both coffee and warm water have an effect on defecation by increasing rectal tone, but nicotine (2 mg) did not affect rectal tone. Coffee and nicotine did not influence sensitivity or compliance.     

Anorectal complications and function in patients suffering from inflammatory bowel disease: a series of patients with long-term follow-up

Aim

The aim of this study is to describe the long-term course of anorectal complains and function in a single centre cohort patients suffering from inflammatory bowel disease (IBD) with perianal lesions.

Methods

Between 1993 and 2000, 56 IBD patients (43 Crohn’s disease and 13 ulcerative colitis) with perianal complaints underwent anorectal function evaluation (AFE) (baseline). For follow-up, they were approached between 2010 and 2012 by sending questionnaires including Inflammatory Bowel Disease Quality of Life Questionnaire (IBDQ), Perianal Disease Activity Index (PDAI), faecal incontinence scale (Vaizey) and an invitation for AFE.

Results

At follow-up, 46 patients (82 %) were available, 9 (16 %) were lost and 1 (2 %) had died. Thirty patients returned the questionnaires of which 17 also underwent AFE. The remaining 16 patients were interviewed by phone and were only willing to mention their anorectal complaints. Median follow-up was 14 year. In 25 of the 46 patients (54 %), perianal complaints persisted faecal incontinence (n?=?7); soiling (n?=?13) and active fistula (n?=?5). Eighteen (39 %) patients had an active fistula at baseline and three persisted at follow-up. Two developed a new fistula. Mean IBDQ, Vaizey and PDAI were 178 (SD 29), 7 (SD 5) and 4.2 (SD 3.0), respectively. In 17 patients, who underwent AFE, anal endosonography showed healing in nine of the ten fistulas. Anal pressures as well as rectal capacity remained unaltered in the individual patient, but showed a large range within the group.

Conclusion

After 14 years, 54 % of the IBD patients with perianal lesions still have mild complaints. The quality of life remained moderate over a long period, which is concerning.     

Utilization of a rodent model to examine the neurological effects of early life adversity on adolescent pain sensitivity

All children experience pain, and although many recover quickly, some go on to develop chronic pain. Adolescent chronic pain is a growing epidemic. It is unknown why some adolescents recover without incident and others experience persistent pain. Although unexplored, early life adversity may contribute to the development and maintenance of chronic pain. This study investigated the effects and underlying neurobiological mechanisms of an early life stressor on nociceptive (pain) sensitivity and emotional function in male and female Sprague-Dawley rats. Using maternal separation (MS) as an established model of early life stress, we addressed two aims: investigation of the effects of MS on behavior (anxiety and pain sensitivity), and investigation of the effects of MS on mRNA and pathophysiological changes associated with an acutely painful stimulus. Our results indicate that MS increased anxiety-like behavior and altered nociceptive responsivity in adolescent rats, with decreased mechanical withdrawal thresholds indicative of heightened and prolonged pain-related behavior. The MS groups also demonstrated increased expression of genes involved in regulating the stress and fight-or-flight response, mood, and neuroplasticity; as well as increased levels of inflammatory markers. We conclude that nociception, both at the behavioral and molecular level, is altered in response to the MS stressor.     

Tim-3 mediates T cell trogocytosis to limit antitumor immunity

T cell immunoglobulin mucin domain-containing protein 3 (Tim-3) negatively regulates innate and adaptive immunity in cancer. To identify the mechanisms of Tim-3 in cancer immunity, we evaluated the effects of Tim-3 blockade in human and mouse melanoma. Here, we show that human programmed cell death 1–positive (PD-1⁺) Tim-3⁺CD8⁺ tumor-infiltrating lymphocytes (TILs) upregulate phosphatidylserine (PS), a receptor for Tim-3, and acquire cell surface myeloid markers from antigen-presenting cells (APCs) through transfer of membrane fragments called trogocytosis. Tim-3 blockade acted on Tim-3⁺ APCs in a PS-dependent fashion to disrupt the trogocytosis of activated tumor antigen–specific CD8⁺ T cells and PD-1⁺Tim-3⁺ CD8⁺ TILs isolated from patients with melanoma. Tim-3 and PD-1 blockades cooperated to disrupt trogocytosis of CD8⁺ TILs in 2 melanoma mouse models, decreasing tumor burden and prolonging survival. Deleting Tim-3 in dendritic cells but not in CD8⁺ T cells impeded the trogocytosis of CD8⁺ TILs in vivo. Trogocytosed CD8⁺ T cells presented tumor peptide–major histocompatibility complexes and became the target of fratricide T cell killing, which was reversed by Tim-3 blockade. Our findings have uncovered a mechanism Tim-3 uses to limit antitumor immunity.     

Who Is Lost to Followup?: A Study of Patients with Distal Radius Fractures

Distal radius fractures are the most common upper extremity fracture, representing one-sixth of all fractures treated in emergency departments nationwide. Beyond the initial reduction and immobilization of these fractures, providing proper followup to ensure maintenance of the reduction and identify complications is necessary for optimal recovery of forearm and wrist functions. We sought to identify the clinical and demographic factors that characterize patients with distal radius fractures who do not return for followup and to assess the underlying causes for their poor followup rates. Compared with patients who were compliant with followup, those lost to followup had lower Physical and Mental Health scores on the SF-36 forms, more often were treated nonoperatively, and more likely had not surpassed secondary education. However, we found no difference between these two groups based on age, gender, mechanism of injury, marital status, or hand dominance. Early identification of patients who potentially are noncompliant can result in additional measures being taken to ensure the patient’s return to the treating hospital and physicians. This in turn will prevent complications attributable to lack of followup and allow more accurate assessment of results, thereby improving patient outcomes.     

p53 alone or in combination with antisense cyclin D1 induces apoptosis and reduces tumor size in human melanoma

Melanoma incidence is growing at a faster rate than any other human malignancy. Wild-type (wt) p53 is important in both G(1) and G(2) cell cycle arrest, and cyclin D1 (CD1) is necessary for G(1)-->S progression in melanoma cells. We reported that an adenoviral vector containing wt p53 significantly reduced [(3)H]thymidine uptake in melanoma cells containing mutant but not wt p53. Subsequently we showed that CD1 decreased melanoma proliferation and increased apoptosis. We now extend these findings by evaluating the effect on preformed melanomas of (1) intratumoral therapy with wt p53 alone, (2) wt p53 in combination with antisense (AS) CD1, both short (< or =14 days) and longer term, and (3) doubling the dose or repeat doses of wt p53 or AS CD1. Two melanoma cells lines that metastasize in SCID mice (451 and 1205) were used, one containing a p53 mutation (451) and the other a normal p53 gene sequence (1205). Compared to injection with a control adenoviral vector containing beta-galactosidase (LacZ), intratumoral injection of wt p53 slowed the growth of tumors formed from 451 cells. Using 5 x 10(8) plaque forming units as our standard intratumoral dose, neither doubling the dose of LacZ, p53 or AS CD1, nor repeat doses of the vectors, was as effective as combined therapy with wt p53+AS CD1, which resulted in the shrinkage of all tumors treated and 4/7 (57%) tumors vanished. No tumors treated with wt p53 or AS CD1 alone vanished. Wt p53+AS CD1 treatment resulted in significantly more cells undergoing apoptosis compared to either therapy alone. In summary, combining the separately effective treatment vectors p53 and AS CD1 led to an enhanced growth-suppressive and apoptotic effect, supporting a role for combination gene therapy to treat human malignant melanoma.     

Photocarcinogenesis in human adult skin grafts.

It has been demonstrated previously that the exposure to 7,12-dimethyl[a]benzanthracene (DMBA) and UVB radiation leads to the development of epidermal cysts, squamous cell carcinomas (SCC), melanocytic hyperplasia and melanoma in human foreskins from newborns grafted to immunodeficient mice. Improved techniques in grafting full-thickness skin from adults have enabled us to study photocarcinogenesis in human skin from different body sites and from older donors. One hundred and fifty-five normal white skin specimens from the trunk and face of 53 adult individuals were grafted onto severe combined immunodeficient (SCID) and recombinase activating gene-1 (Rag-1) knockout mice and irradiated two to three times weekly with 40 mJ/cm(2) UVB or solar-simulated UV (SSUV) over a period of up to 10 months with or without one prior topical application of DMBA. Over an observation period of 2-22 months, histopathological and immunohistochemical analyses of 134 specimens revealed actinic keratoses in 30% of the DMBA- + UV-treated grafts, in 18% of the grafts exposed to SSUV only, and in 10% of the grafts exposed to UVB only. Actinic keratoses were absent in grafts treated with DMBA only. One SCC was found in an abdominal skin graft 3 months after exposure to DMBA followed by UVB. Point mutations in codon 61 of the human Ha-ras gene were detected in the SCC, five of six analyzed actinic keratoses and in non-lesional epidermis of DMBA- and UVB-treated grafts, indicating that DMBA as well as UVB alone can induce these mutations in human skin. In contrast to the previous experience with neonatal foreskin grafts, melanocytic lesions were not found except for mild hyperplasia in few cases. The data suggest that melanocytes from young individuals are more susceptible to the transforming effects of genotoxic agents than melanocytes from adults.     

Views of family medicine department Chairs about mentoring junior faculty

Mentoring can be a key component contributing to the success of faculty. We investigated the attitudes of family medicine department Chairs toward mentoring, with emphasis on mentoring female and minority faculty. This qualitative inquiry used semi-structured interviews with 13 Chairs of US departments of family medicine. Although most Chairs felt that mentoring had value, a minority of our sample had formal mentoring programs. Multiple mentors were suggested for female and minority faculty to meet both their personal career and content needs. Availability of senior faculty is a key resource. Until more senior women and minority faculty are available, cross-gender and cross-ethnicity mentoring will need to be utilized.