Botulinum Toxin Injection Plus Topical Diltiazem for Chronic Anal Fissure: A Randomized Double-Blind Clinical Trial and Long-term Outcome.

BACKGROUND: Chemical sphincterotomy avoids the risk of permanent incontinence in the treatment of chronic anal fissure, but it does not reach the efficacy of surgery and recurrence is high. Drug combination has been proposed to overcome these drawbacks. OBJECTIVE: This study aimed to compare the clinical, morphological, and functional effects of combined therapy with botulinum toxin injection and topical diltiazem in chronic anal fissure and to assess the long-term outcome after healing. DESIGN: This is a randomized, controlled, double-blind, 2-arm, parallel-group trial with a long-term follow-up. SETTINGS: This study was conducted at a tertiary care center. PATIENTS: A total of 70 consecutive patients were referred to the gastroenterology department of a hospital in Valencia, Spain. INTERVENTION: After botulinum toxin injection (20 IU), patients were randomly assigned to local diltiazem (diltiazem group) or placebo gel (placebo group) for 12 weeks. MAIN OUTCOME MEASURES: The primary outcome was fissure healing (evaluated by video register by 3 independent physicians). Secondary outcomes included symptomatic relief (30-day diary), effect on anal sphincters (manometry), safety, and long-term recurrence (24 months and 10 years). RESULTS: Healing was achieved per protocol in 13 of 25 (52%) patients of the diltiazem group and 11 of 30 (36.7%) patients of the placebo group (p = 0.25); on an intention-to-treat basis in 37.1% and 31.4% (p = 0.61). Both groups displayed significant reduction of anal pressures. Thirty percent reported minor and transitory incontinence, without differences between groups. Nine (69.2%) of the diltiazem group and 6 (54.5%) of the placebo group experienced a relapse at 24 months (p = 0.67). The overall recurrence rate at 10 years was 83.3% (20/24 patients). LIMITATIONS: This study was limited by the loss of patients during the trial. The low healing rate led to a small cohort to assess recurrence. CONCLUSIONS: Combined botulinum toxin injection and topical diltiazem is not superior to botulinum toxin injection in the treatment of chronic anal fissure. Both options offer suboptimal healing rates. Long-term recurrence is high (>80% at 10 years) and might appear at any time after healing. See Video Abstract at http://links.lww.com/DCR/B527. INYECCIN DE TOXINA BOTULNICA MS DILTIAZEM TPICO EN FISURA ANAL CRNICA UN ENSAYO CLNICO ALEATORIZADO DOBLE CIEGO Y RESULTADOS A LARGO PLAZO: ANTECEDENTES:La esfinterotomía química evita el riesgo de incontinencia permanente en el tratamiento de la fisura anal crónica, pero no alcanza la eficacia de la cirugía y la recurrencia es alta. Se ha propuesto la combinación de fármacos para superar estos inconvenientes.OBJETIVO:Comparar los efectos clínicos, morfológicos y funcionales de la terapia combinada con inyección de toxina botulínica y diltiazem tópico en fisura anal crónica y evaluar el resultado a largo plazo después de la cicatrización.DISEÑO:Ensayo aleatorizado, controlado, doble ciego, de dos brazos, de grupos paralelos con un seguimiento a largo plazo.ESCENARIO:Estudio realizado en un centro de atención terciaria.PACIENTES:Un total de 70 pacientes consecutivos referidos al servicio de gastroenterología de un hospital de Valencia, España.INTERVENCIÓN:Después de la inyección de toxina botulínica (20UI), los pacientes fueron asignados al azar a diltiazem local (grupo de diltiazem) o gel de placebo (grupo de placebo) durante 12 semanas.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la cicatrización de la fisura (evaluado por registro de video por tres médicos independientes). Los resultados secundarios incluyeron alivio sintomático (diario de 30 días), efecto sobre los esfínteres anales (manometría), seguridad y recurrencia a largo plazo (24 meses y 10 años).RESULTADOS:La curación se logró por protocolo en 13/25 (52%) en el grupo de Diltiazem y 11/30 (36,7%) en el grupo de Placebo (p = 0.25); por intención de tratar en el 37.1% y el 31.4%, respectivamente (p = 0.61). Ambos grupos mostraron una reducción significativa de las presiones anales. El 30% refirió incontinencia leve y transitoria, sin diferencias entre grupos. 9 (69.2%) del grupo de Diltiazem y 6 (54.5%) del grupo de placebo recurrieron a los 24 meses (p = 0.67). La tasa global de recurrencia a los 10 años fue del 83.3% (20/24 pacientes).LIMITACIONES:La pérdida de pacientes a lo largo del ensayo. La baja tasa de curación llevó a una pequeña cohorte para evaluar la recurrencia.CONCLUSIONES:La inyección combinada de toxina botulínica y diltiazem tópico no es superior a la inyección de TB en el tratamiento de la fisura anal crónica. Ambas opciones ofrecen tasas de curación subóptimas. La recurrencia a largo plazo es alta (> 80% a los 10 años) y puede aparecer en cualquier momento después de la curación. Consulte Video Resumen en http://links.lww.com/DCR/B527.

Nonplatinum-based therapy with Paclitaxel and Capecitabine for advanced squamous cell carcinomas of the anal canal: A population-based Danish anal cancer group study.

BACKGROUND: First-line platinum-based therapy for advanced squamous cell carcinomas of the anal canal (SCCA) implies a risk of substantial side effects, and data on second-line treatment options are limited. Paclitaxel and Capecitabine are a well-known regimen with a moderate toxicity profile, but its efficacy has not been evaluated. METHODS: We conducted a retrospective study using Danish Hospital Registers of patients treated with Paclitaxel and Capecitabine for inoperable, recurrent, or advanced metastatic SCCA in Denmark, between January 2000 and July 2018. RESULTS: A total of 52 patients met the eligibility criteria. Median age was 60.7 years (range 42-83). Efficacy was observed, with an overall response rate in patients receiving first-line (N = 28) and second-line (N = 23) Paclitaxel and Capecitabine of 39.3% (2 with complete responses) and 17.4%, respectively. Median progression-free survival (PFS) was 4.5 months (95% CI 3.3-5.9) and 3.8 months (95% CI 2.4-5.5) with OS of 6.7 months (95% CI 5.9-8.5) and 5.9 months (95% CI 3.9-14), respectively. Performance status ≥2 and neutrophil to lymphocyte ratio ≥4 were significantly associated with a short PFS. CONCLUSION: This study recognizes Paclitaxel and Capecitabine as a potential regimen for advanced SCCA, when recommended first-line therapy is not feasible or as a potential second-line treatment after failure of platinum-based chemotherapy.

Surgical Sphincter Saving Approach and Topical Nifedipine for Chronic Anal Fissure with Hypertonic Internal Anal Sphincter.

PURPOSE: The role of augmented internal anal sphincter (IAS) tone in the genesis of posterior chronic anal fissure (CAPF) is still unknown. Lateral internal sphincterotomy is the most employed surgical procedure, nevertheless it is burdened by high risk post-operative anal incontinence. The aim of our study is to evaluate results of sphincter saving procedure with post-operative pharmacological sphincterotomy for patients affected by CAPF with IAS hypertonia. Methods: We enrolled 30 patients, undergone fissurectomy and anoplasty with V-Y cutaneous flap advancement; all patients received topical administration of nifedipine 0.3% and lidocaine 1.5% ointment-based therapy before and for 15 days after surgery. The primary goal was patient's complete healing and the evaluation of incontinence and recurrence rate; the secondary goal included the evaluation of manometry parameters, symptom relief and complications related to nifedipine and lidocaine administration. Results: All wounds healed within 40 days after surgery. We didn't observe any de novo postoperative anal incontinence case. We reported 2 cases of recurrences, healed after conservative therapy. We didn't report any local complications related to the administration of the ointment therapy; with whom all patients reported a good compliance. Conclusions: Fissurectomy and anoplasty with V-Y cutaneous advancement flap and topical administration of nifedipine and lidocaine, is an effective treatment for CAPF with IAS hypertonia.

Analgesic injection of botulinum toxin in anal fissures is efficient and can be performed safely in patients actively receiving chemotherapy.

PURPOSE: Injection of botulinum toxin into the internal anal sphincter is a well-documented intervention to reduce anal hypertonia in the treatment of anal fissures. In patients receiving chemotherapy, painful anal conditions are frequent, secondary to change in bowel habits and reduced immunity. However, injection of botulinum toxin is often not offered due to fear of complications. METHODS: In this retrospective longitudinal observational study, performed in a tertiary hospital setting, we analysed patient characteristics, outcome and complication rates of botulinum toxin injection in patients actively receiving chemotherapy. RESULTS: Twenty-six patients were treated with 20-50 IU botulinum toxin while actively receiving chemotherapy because of intractable pain and hypertonia. The fissure was located dorsally in 69% (n = 18) and ventrally in 19% (n = 5), while in 3 patients (12%), no fissure was documented. The majority of the patients (88%, n = 23) had complete (54%, n = 14) or partial (35%, n = 9) relief of pain. In three patients, additional anal pathology developed in the weeks following botulinum toxin injection: thrombosis of grade IV haemorrhoids, perianal haematoma and an intersphincteric abscess. CONCLUSIONS: Injection of botulinum toxin in the anal sphincters is a safe and effective analgesic option in patients with anal fissure while actively receiving chemotherapy.

Gestational and pubertal exposure to low dose of di-(2-ethylhexyl) phthalate impairs sperm quality in adult mice.

Di-(2-ethylhexyl)-phthalate (DEHP) is a compound widely used as a plasticizer, which can leach from plastics into the environment and thus influence human health. The aim of this study was to analyze whether exposure to an environmentally relevant dose of DEHP during mice fetal development or puberty can cause long-lasting changes detectable month/s after the last exposure. We used a DEHP concentration relevant to a daily human intake of 2.4-3 µg/kg of body weight/day. CD1 outbred mice were treated either in utero or postnatally during puberty and analyzed in adulthood. Analyzing fertility parameters using morphometric, histologic, genomic and proteomic methods we showed that DEHP exposure leads to decreased sperm concentration and quality, in both experimental groups. Moreover, the changes in anogenital distance, seminal vesicle weight, and testicular gene expression suggest a disturbance of androgen signaling in exposed animals. In conclusion, we hereby present, that the prenatal and pubertal exposure to a low dose of DEHP negatively influenced reproductive endpoints in male mice, and some of the effects were persistent until adulthood.

Associations between intrauterine exposure to polychlorinated biphenyls on neonatal ano-genital distance.

Polychlorinated Biphenyls (PCBs) are widespread environmental contaminants. PCBs have endocrine disrupting properties which raises concerns regarding their effect on the developing fetus. This study aimed to examine the association between prenatal exposure to PCBs and anogenital distance (AGD) in newborns. Serum concentrations of PCB congeners -118, -138, -153 and -180 were measured in 175 pregnant women presenting to the delivery room. AGD was measured in their newborns. Regression models were used to estimate associations between maternal PCB exposure and infant anogenital measurements, controlling for possible confounding variables. Mean maternal serum concentrations were 2.95 ± 2.18 ng/g, 4.62 ± 3.54 ng/g, 7.67 ± 6.42 ng/g and 5.10 ± 3.91 ng/g for congeners -118, -138, -153 and -180, respectively. Higher maternal concentrations of PCBs were associated with reduced AGD measures in male infants. Higher maternal concentrations of PCB-138 and PCB-153 were associated with reduced ano-scrotal distances and higher maternal concentrations of all four PCB congeners were associated with reduced ano-penile distances. No significant associations were found between any PCB congener and any AGD measure in female newborns. This study demonstrates that intrauterine exposure to PCBs may be associated with reduced AGD in male newborns. More research is needed to reveal the implications for adult reproductive health.

Relief of hemorrhoid symptoms: pilot study of a new topical ally.

AIM: The pathogenesis of hemorrhoids involves vascular congestion, fragmentation of supporting tissues and, in many cases, increased resting anal pressure. A new ointment (Hemolen®) has been devised to control hemorrhoids symptoms acting on all the pathophysiologic mechanisms involved. METHODS: Pilot study on patients with grade I-III hemorrhoids. The ointment was applied twice daily for 30 days and follow-up visits were scheduled 7 days (T1), 14 days (T2) and 30 days (T3) after recruitment (T0). Signs and symptoms (bleeding, discomfort, itching, edema, thrombosis, congestion, inflammation, pain) were evaluated at each visit using dedicated scores and VAS scale. Resting anal pressure was measured at time T0, 1 hour after the first application and at T1. Use of painkiller was recorded. RESULTS: 48 patients (25 females; mean age 47±15.8 years) were enrolled; 52.1% of them had II degree hemorrhoids and 27.1% had III degree hemorrhoids. The severity scores significantly dropped from T0 to each scheduled visit and a significant reduction of resting anal pressure was observed from T0 to 1 hour after application (z=13.5; p<0.001) and from T0 to T1 (z=6; p<0.001). The comparison of the resting pressure among whole time series showed a significant reduction (Fr=124.4; p=<0.001). Use of pain-killers decreased significantly from T0 to T1 (p<0.001) and from T1 to T2 (p=0.001). CONCLUSION: The new ointment tested in the present study is safe and effective for the management of hemorrhoid symptoms in the early stages hemorrhoids, during the acute phases and in patients with more severe hemorrhoids awaiting surgery. Prospective, randomized controlled trials are needed to confirm these encouraging results.

Exposure to low doses of oxybenzone during perinatal development alters mammary gland morphology in male and female mice.

Oxybenzone (benzophenone-3) is an ultraviolet radiation filter commonly used in personal care products including sunscreens, textiles and inks, and food and beverage containers, among others. Due to its widespread use, human exposures to oxybenzone are widespread. Oxybenzone is considered an endocrine disrupting chemical due to its antiestrogenic and antiandrogenic properties. We evaluated the effects of oral exposures to oxybenzone on the growth and morphology of the mammary gland, body weight and anogenital distance in BALB/c mice exposed to 30, 212 or 3000 µg/kg/day in utero and during lactation. Developmental exposures to oxybenzone reduced the size and growth of mammary gland in males prior to and during puberty. In exposed females, oxybenzone reduced mammary cell proliferation, decreased the number of cells expressing estrogen receptor α, and altered mammary gland morphology in adulthood. These results suggest that even low doses of oxybenzone can disrupt hormone sensitive organs during critical windows of development.

Leuprolide Acetate, a GnRH Agonist, Improves the Neurogenic Bowel in Ovariectomized Rats with Spinal Cord Injury.

BACKGROUND: Electromyographic studies have shown that external anal sphincter activity is modified in response to distension in animals with spinal cord injury. Gonadotropin-releasing hormone and its agonist leuprolide acetate have neurotrophic properties in animals with spinal cord injury. AIM: This study was to determine the effects of leuprolide acetate treatment on electromyographic activity of the external anal sphincter and anorectal manometry in ovariectomized rats with spinal cord injury. METHODS: Adult ovariectomized rats were divided in three groups: (a) sham of spinal cord injury, (b) spinal cord injury treated with saline solution, and (c) spinal cord injury treated with leuprolide acetate. The spinal cord injury was induced by clamping at level T9. Leuprolide acetate dosage of 10 µg/kg was proctored intramuscular for 5 weeks, commencing the day after the lesion. Electromyography of the external anal sphincter, anorectal manometry, and volume of the cecum were evaluated in all groups. RESULTS: The electromyographic study of the external anal sphincter activity showed a significant improvement in injured rats treated with leuprolide acetate. Manometric analysis and cecum volume data obtained in animals with leuprolide acetate were very similar to those found in the sham group. CONCLUSIONS: These results demonstrate that leuprolide acetate treatment improves the neurogenic colon in ovariectomized rats with spinal cord injury.

In utero exposure to persistent and nonpersistent endocrine-disrupting chemicals and anogenital distance. A systematic review of epidemiological studies†.

Anti-androgenic endocrine-disrupting chemicals (EDCs) can cross the placenta to modify early offspring sexual dimorphic markers. These changes are linked to anogenital distance (AGD), which is an androgen-sensitive anthropometric parameter used as a biomarker of perineal growth and caudal migration of the genital tubercle. This review aimed to summarize strength of evidence for associations of in utero exposure to EDCs with AGD and to identify gaps and limitations in the literature so as to inform future research. We performed an electronic search of English literature in September 2019 in medical literature analysis and retrieval system online (MEDLINE), Web of Science and Toxline. We included epidemiological studies that examined in utero exposure to persistent and nonpersistent EDCs and considered AGD in offspring as an outcome. Our review contained 16 investigations examining exposure to persistent EDCs (nine studies) and nonpersistent EDCs (seven studies). Some individual studies reported an inverse association between exposure to bisphenol A (BPA), dioxins, perfluoroalkyl substances, and organochlorides and AGD in both male and female offspring. Meta-analysis of three studies found a small reduction of AGD in female offspring exposed to BPA. The number of studies per chemical is small, and number of subjects examined is limited; so, replication of these results is needed. To achieve more specificity and better replication of results, future studies should establish the association of nonpersistent EDCs using multiple urine samples, evaluate the cumulative impact of exposure to a mixture of anti-androgenic chemicals, and offer adequate consideration of more maternal- and children-related confounding factors.

ART is key to clearing oncogenic HPV genotypes (HR-HPV) in anal mucosa of HIV-positive MSM.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is one of the most frequent non-AIDS-defining neoplasias in HIV patients, mainly in MSM, and it has been associated with chronic infection with high-risk human papilloma virus (HR-HPV). Our main objective was to determine HR-HPV clearance and acquisition rates and related factors and their relationship with the incidence of HSILs and ASCC in anal mucosa of HIV+ MSM. PATIENTS AND METHODS: The study included consecutive HIV-infected MSM between May 2010 and December 2018. Data were gathered at baseline and annually on their sexual behavior, CD4 and CD8 levels, plasma HIV viral load, and results of anal cytology, HPV PCR, and high-resolution anoscopy. RESULTS: Out of the 405 patients studied, 34.9% of patients cleared oncogenic genotypes (IQR: 37-69) within 49 months, and 42.9% acquired new genotypes within 36 months (IQR:12-60). In multivariate analysis, clearance was only significantly influenced by the duration of antiretroviral therapy (ART) (OR: 1.016, 95% CI 1.003-1.030). The incidence of HSILs was 30.86/1,000 patient-years and that of ASCC was 81.22/100,000 patient-years; these incidences were not influenced by the acquisition (acquired: 14.9% vs. non-acquired: 10.4%; p = 0.238) or clearance (cleared 11.4% vs. non-cleared: 13.2%; p = 0.662) rates of these viruses. CONCLUSIONS: The duration of ART appears to positively affect oncogenic genotype clearance in the anal mucosa of HIV+ MSM, although this clearance does not affect the incidence of HSILs or ASCC. The reduction in HSIL+ rate observed in our patients may be attributable to the bundle of measures adopted at our center.

Botulinum toxin injections after surgery for Hirschsprung disease: Systematic review and meta-analysis.

BACKGROUND: A large proportion of patients with Hirschsprung disease experience persistent obstructive symptoms after corrective surgery. Persistent obstructive symptoms may result in faecal stasis that can develop into Hirschsprung-associated enterocolitis, a potential life-threatening condition. Important treatment to improve faecal passage is internal anal sphincter relaxation using botulinum toxin injections. AIM: To give an overview of all empirical evidence on the effectiveness of botulinum toxin injections in patients with Hirschsprung disease. METHODS: A systematic review and meta-analysis was done by searching PubMed, EMBASE and the Cochrane Library, using entry terms related to: (1) Hirschsprung disease; and (2) Botulinum toxin injections. 14 studies representing 278 patients met eligibility criteria. Data that were extracted were proportion of patients with improvement of obstructive symptoms or less enterocolitis after injection, proportion of patients with adverse effects and data on type botulinum toxin, mean dose, average age at first injection and patients with associated syndromes. Random-effects meta-analysis was used to aggregate effects and random-effects meta-regression was used to test for possible confounding factors. RESULTS: Botulinum toxin injections are effective in treating obstructive symptoms in on average 66% of patients [event rate (ER) = 0.66, P = 0.004, I 2 = 49.5, n = 278 patients]. Type of botulinum toxin, average dose, average age at first injections and proportion of patients with associated syndromes were not predictive for this effect. Mean 7 duration of improvement after one botulinum toxin injections was 6.4 mo and patients needed on average 2.6 procedures. There was a significant higher response rate within one month after botulinum toxin injections compared to more than one month after Botulinum toxin injections (ER = 0.79, vs ER = 0.46, Q = 19.37, P < 0.001). Botulinum toxin injections were not effective in treating enterocolitis (ER 0.58, P = 0.65, I 2 = 71.0, n = 52 patients). There were adverse effects in on average 17% of patients (ER = 0.17, P < 0.001, I 2 = 52.1, n = 187 patients), varying from temporary incontinence to mild anal pain. CONCLUSION: Findings from this systematic review and meta-analysis indicate that botulinum toxin injections are effective in treating obstructive symptoms and that adverse effects were present, but mild and temporary.

The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system.

BACKGROUND: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be "safe" (the US Acceptable Daily Intake - ADI - of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats. METHODS: Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups. RESULTS: In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup-treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure. CONCLUSIONS: The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female.

ACOG Practice Bulletin No. 210: Fecal Incontinence.

Fecal incontinence, or the involuntary leakage of solid or loose stool, is estimated to affect 7-15% of community-dwelling women (1). It is associated with reduced quality of life, negative psychologic effects, and social stigma (2), yet many women do not report their symptoms or seek treatment. Less than 3% of women who do self-report fecal incontinence will have this diagnosis recorded in their medical record (3). Obstetrician-gynecologists are in a unique position to identify women with fecal incontinence because pregnancy, childbirth, obstetric anal sphincter injuries (OASIS), and pelvic floor dysfunction are important risk factors that contribute to fecal incontinence in women. The purpose of this Practice Bulletin is to provide evidence-based guidelines on the screening, evaluation, and management of fecal incontinence to help obstetrician-gynecologists diagnose the condition and provide conservative treatment or referral for further work up and surgical management when appropriate. For discussion on fecal incontinence associated with OASIS, see Practice Bulletin No. 198, Prevention and Management of Obstetric Lacerations at Vaginal Delivery (4).

Botox treatment in patients with chronic functional anorectal pain: experiences of a tertiary referral proctology clinic.

BACKGROUND: Anorectal pain is a symptom which may have both structural and functional causes, and can, sometimes, develop into a chronic pain syndrome. Functional causes in particular are challenging to treat when conservative treatment measures fail. Botulinum toxin A (BTX-A) can be applied to relax the anal sphincter and/or levator ani muscle to break the vicious circle of pain and contraction. In our tertiary referral proctology clinic, we evaluated the outcome of patients treated with BTX-A for chronic functional anorectal pain. METHODS: Our electronic database was searched for patients who had BTX-A treatment for chronic functional anorectal pain from 2011 to 2016. All medical data concerning history, treatments, and clinical outcome were retrieved. The clinical outcome (resolution of pain) was scored as good, temporary, or poor. RESULTS: A total of 113 patients [47 (42%) males; age 51years, SD 13 years, range 18-88 years] with chronic functional anorectal pain were included. The outcome of BTX-A treatment was good in 53 (47%), temporary in 23 (20%), and poor in 37 (33%). To achieve this outcome, 29 (45%) patients needed a single treatment, 11 (44%) a second treatment, and 13 (54%) ≥ 3 treatments. CONCLUSIONS: Chronic functional anorectal pain can be treated successfully with BTX-A in 47% of patients who fail conservative management. Repeated injections may be needed to ensure complete cure in a subgroup of patients.

Distinct Transcriptional Profiles of the Female, Male, and Finasteride-Induced Feminized Male Anogenital Region in Rat Fetuses.

A short anogenital distance (AGD) in males is a marker for incomplete masculinization and a predictor of adverse effects on male reproductive health. For this reason, AGD is used to assess the endocrine disrupting potential of chemicals for risk assessment purposes. The molecular mechanisms underpinning this chemically induced shortening of the AGD, however, remains unclear. Although it is clear that androgen receptor-mediated signaling is essential, evidence also suggest the involvement of other signaling pathways. This study presents the first global transcriptional profile of the anogenital tissue in male rat fetuses with chemically induced short AGD, also including comparison to normal male and female control animals. The antiandrogenic drug finasteride (10 mg/kg bw/day) was used to induce short AGD by exposing time-mated Sprague Dawley rats at gestation days 7-21. The AGD was 37% shorter in exposed male fetuses compared with control males at gestation day 21. Transcriptomics analysis on anogenital tissues revealed a sexually dimorphic transcriptional profile. More than 350 genes were found to be differentially expressed between the 3 groups. The expression pattern of 4 genes of particular interest (Esr1, Padi2, Wnt2, and Sfrp4) was also tested by RT-qPCR analyses, indicating that estrogen and Wnt2 signaling play a role in the sexually dimorphic development of the anogenital region. Our transcriptomics profiles provide a stepping-stone for future studies aimed at characterizing the molecular events governing development of the anogenital tissues, as well as describing the detailed Adverse Outcome Pathways for short AGD; an accepted biomarker of endocrine effects for chemical risk assessment.

Anti-muscarinic drugs increase rectal compliance and exacerbate constipation in chronic spinal cord injury : Anti-muscarinic drug effect on neurogenic bowel.

STUDY DESIGN: Prospective cohort study OBJECTIVES: We hypothesized that anti-muscarinic agents alter rectal compliance in SCI patients and that altered rectal compliance relates to bowel symptomatology. Our primary aim was to compare rectal compliance before and after the institution of anti-muscarinics (solifenacin and tolterodine) and an adrenoceptor agonist (mirabegron) in these patients. Additionally, we wanted to evaluate if anorectal manometry differed before and after use of anti-muscarinic agents. SETTING: Tertiary neurogastroenterology clinic, London METHODS: Thirty-five patients with supraconal spinal cord injury (SCI) underwent anal manometry, assessment of rectoanal inhibitory reflex (RAIR) and rectal compliance before and after anti-muscarinic treatment (for overactive bladder) was started (mean follow-up 12 weeks). Patients were assessed identically, pre-and post-treatment (solifenacin n = 17, tolterodine n = 10, mirabegron n = 8). Doses used were as for non-SCI patients. RESULTS: Resting, squeeze and cough pressures were unchanged after anti-muscarinic treatment. Rectal compliance was significantly raised after anti-muscarinic treatment (p = 0.001). The percent amplitude of maximal sphincter relaxation of the RAIR was decreased (p < 0.001) and excitation latency was increased (p = 0.006). There was no significant change in the duration of recovery of the RAIR. There was a significant increase of the Wexner Constipation Score (p = 0.001) but no change in the Wexner Incontinence Score. There was a significant correlation between change in rectal compliance and change in Wexner Constipation Score (p = 0.001). Thus, increasing compliance of the rectum is associated with worsening of constipation after anti-muscarinic therapy. However, there were no changes in anorectal manometry or rectal compliance in those who received mirabegron. CONCLUSION: Anti-muscarinic therapy for overactive bladder increases compliance of the neurogenic rectum and alters anorectal reflex activity, with worsening of constipation.