Stepped-wedge randomized controlled trial of laparoscopic ventral mesh rectopexy in adults with chronic constipation.

BACKGROUND: The effectiveness of laparoscopic ventral mesh rectopexy (LVMR) in patients with defecatory disorders secondary to internal rectal prolapse is poorly evidenced. A UK-based multicenter randomized controlled trial was designed to determine the clinical efficacy of LVMR compared to controls at medium-term follow-up. METHODS: The randomized controlled trial was conducted from March 1, 2015 TO January 31, 2019. A stepped-wedge RCT design permitted observer-masked data comparisons between patients awaiting LVMR (controls) with those who had undergone surgery. Adult participants with radiologically confirmed IRP refractory to conservative treatment were randomized to three arms with different delays before surgery. Efficacy outcome data were collected at equally stepped time points (12, 24, 36, 48, 60, and 72 weeks). Clinical efficacy of LVMR compared to controls was defined as ≥ 1.0-point reduction in Patient Assessment of Constipation-Quality of Life and/or Symptoms (PAC-QOL and/or PAC-SYM) scores at 24 weeks. Secondary outcome measures included 14-day diary data, the Generalized Anxiety Disorder scale (GAD-7), the Patient Health Questionnaire-9 (PHQ-9), St Marks incontinence score, the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12), the chronic constipation Behavioral Response to Illness Questionnaire (CC-BRQ), and the Brief Illness Perception Questionnaire (BIPQ). RESULTS: Of a calculated sample size of 114, only 28 patients (100% female) were randomized from 6 institutions (due mainly to national pause on mesh-related surgery). Nine were assigned to the T0 arm, 10 to T12, and 9 to T24. There were no substantial differences in baseline characteristics between the three arms. Compared to baseline, significant reduction (improvement) in PAC-QOL and PAC-SYM scores were observed at 24 weeks post-surgery (- 1.09 [95% CI - 1.76, - 0.41], p = 0.0019, and - 0.92 [- 1.52, - 0.32], p = 0.0029, respectively) in the 19 patients available for analysis (9 were excluded for dropout [n = 2] or missing primary outcome [n = 7]). There was a clinically significant long-term reduction in PAC-QOL scores (- 1.38 [- 2.94, 0.19], p = 0.0840 at 72 weeks). Statistically significant improvements in PAC-SYM scores persisted to 72 weeks (- 1.51 [- 2.87, - 0.16], p = 0.0289). Compared to baseline, no differences were found in secondary outcomes, except for significant improvements at 24 and 48 weeks on CC-BRQ avoidance behavior (- 14.3 [95% CI - 23.3, - 5.4], and - 0.92 [- 1.52, - 0.32], respectively), CC-BRQ safety behavior (- 13.7 [95% CI - 20.5, - 7.0], and - 13.0 [- 19.8, - 6.1], respectively), and BIPQ negative perceptions (- 16.3 [95% CI - 23.5, - 9.0], and - 10.5 [- 17.9, - 3.2], respectively). CONCLUSIONS: With the caveat of under-powering due to poor recruitment, the study presents the first randomized trial evidence of short-term benefit of LVMR for internal rectal prolapse. TRIAL REGISTRATION: ISRCTN Registry (ISRCTN11747152).

Depressive symptoms in inflammatory bowel disease: an extraintestinal manifestation of inflammation?

Depressive symptoms are reported by more than 20% of people with inflammatory bowel disease (IBD), while sleep difficulties and fatigue are even more common. Co-morbid depressive symptoms predict a poor IBD course, including increased risk of relapse and surgery, which is inconsistently improved by psychological treatments. Rather than being distinct systems, there is compelling evidence for bidirectional communication between gut and brain, driven by neural, metabolic, endocrine and inflammatory mediators. An emerging concept is that depressive symptoms may be mechanistically linked to excess inflammation and dysregulation of the gut-brain axis. Given the close link between the intestinal microbiota and host immune responses, patients prone to shifts in their intestinal microbiome, including smokers, those with poor diet and early life stress, may be exposed to exaggerated immune responses. Excess inflammation is associated with brain changes (depressive symptoms, fatigue, sleep difficulties) and worsening gastrointestinal symptoms, which are exacerbated by psychological distress. Equally, treatments both for depressive symptoms and IBD provide opportunities to break this cycle by reducing the causes and effects of inflammation. As well as addressing potential risk factors such as smoking and diet, treatments to alter the microbiome may reduce depressive symptoms. Observational evidence suggests that anti-inflammatory treatments for IBD may improve co-morbid depressive symptoms correlating with reduction in inflammation. With a growing range of treatments targeting inflammation centrally, peripherally and in the gut, IBD provides a unique model to understand the interplay between brain and gut in the pathogenesis of depressive symptoms, both in IBD and in the whole population.

The Impact of System Factors on Quality and Safety in Arterial Surgery: A Systematic Review.

OBJECTIVE: A systems approach to patient safety proposes that a wide range of factors contribute to surgical outcome, yet the impact of team, work environment, and organisational factors, is not fully understood in arterial surgery. The aim of this systematic review is to summarize and discuss what is already known about the impact of system factors on quality and safety in arterial surgery. DATA SOURCES: A systematic review of original research papers in English using MEDLINE, Embase, PsycINFO, and Cochrane databases, was performed according to PRISMA guidelines. REVIEW METHODS: Independent reviewers selected papers according to strict inclusion and exclusion criteria, and using predefined data fields, extracted relevant data on team, work environment, and organisational factors, and measures of quality and/or safety, in arterial procedures. RESULTS: Twelve papers met the selection criteria. Study endpoints were not consistent between papers, and most failed to report their clinical significance. A variety of tools were used to measure team skills in five papers; only one paper measured the relationship between team factors and patient outcomes. Two papers reported that equipment failures were common and had a significant impact on operating room efficiency. The influence of hospital characteristics on failure-to-rescue rates was tested in one large study, although their conclusions were limited to the American Medicare population. Five papers implemented changes in the patient pathway, but most studies failed to account for potential confounding variables. CONCLUSIONS: A small number of heterogenous studies have evaluated the relationship between system factors and quality or safety in arterial surgery. There is some evidence of an association between system factors and patient outcomes, but there is more work to be done to fully understand this relationship. Future research would benefit from consistency in definitions, the use of validated assessment tools, measurement of clinically relevant endpoints, and adherence to national reporting guidelines.

Systematic review: interventions for abdominal pain management in inflammatory bowel disease.

BACKGROUND: Abdominal pain is frequently reported by people with inflammatory bowel disease (IBD), including in remission. Pain is an under-treated symptom. AIM: To systematically review evidence on interventions (excluding disease-modifying interventions) for abdominal pain management in IBD. METHODS: Databases (MEDLINE, EMBASE, PsycInfo, CINAHL, Scopus, Cochrane Library) were searched (February 2016). Two researchers independently screened references and extracted data. RESULTS: Fifteen papers were included: 13 intervention studies and two cross-sectional surveys. A variety of psychological, dietary and pharmacological interventions were reported. Four of six studies reported pain reduction with psychological intervention including individualised and group-based relaxation, disease anxiety-related Cognitive Behavioural Therapy and stress management. Both psychologist-led and self-directed stress management in inactive Crohn's disease reduced pain compared with controls (symptom frequency reduction index=-26.7, -11.3 and 17.2 at 6-month follow-up, respectively). Two dietary interventions (alcoholic drinks with high sugar content and fermentable carbohydrate with prebiotic properties) had an effect on abdominal pain. Antibiotics (for patients with bacterial overgrowth) and transdermal nicotine patches reduced abdominal pain. Current and past cannabis users report it relieves pain. One controlled trial of cannabis reduced SF-36 and EQ-5D pain scores (1.84 and 0.7, respectively). These results must be treated with caution: data were derived from predominantly small uncontrolled studies of moderate to low quality. CONCLUSIONS: Few interventions have been tested for IBD abdominal pain. The limited evidence suggests that relaxation and changing cognitions are promising, possibly with individualised dietary changes. There is a need to develop interventions for abdominal pain management in IBD.

The contribution of clinical and psychosocial factors to fatigue in 182 patients with inflammatory bowel disease: a cross-sectional study.

BACKGROUND: Fatigue is a frequently reported and predominant symptom experienced by patients with inflammatory bowel disease (IBD) and its impact has been associated with poorer quality of life (QoL). The complex interplay between disease-related variables and potentially modifiable psychosocial factors in IBD-fatigue has yet to be unravelled. AIM: To evaluate the contribution of clinical, sociodemographic and psychosocial factors to the severity and impact of IBD-fatigue and QoL. METHOD: In a cross-sectional study, 182 patients with IBD were recruited from three tertiary referral hospitals' out-patient clinics in London. Fatigue was assessed utilising the Inflammatory Bowel Disease-Fatigue Scale (IBD-F), the Multidimensional Fatigue Inventory (MFI); and QoL by the Inflammatory Bowel Disease Questionnaire (IBDQ). Patients completed self-report questionnaires evaluating emotional, cognitive and behavioural factors potentially correlated with fatigue. Sociodemographic data were collected. Disease-related and laboratory data were retrieved from patients' hospital electronic medical records. RESULT: In hierarchical regression models, disease activity was the only clinical factor consistently associated with severity and impact of fatigue and QoL (P = 0.01). More negative fatigue perceptions were significantly associated with greater IBD-F1 scores (P = 0.01). When controlling for clinical factors (disease activity and anti-TNF therapy), negative perceptions of fatigue, and all-or-nothing and avoidance behaviours explained an additional 41% of the variance in fatigue impact (IBD-F2). CONCLUSIONS: Apart from disease activity, emotional and behavioural factors and patients' negative fatigue perceptions may be key factors to be addressed. Further exploration of these factors in longitudinal and intervention studies may help to develop effective models of fatigue management.

Multicentre observational study of surgical system failures in aortic procedures and their effect on patient outcomes.

BACKGROUND: Vascular surgical care has changed dramatically in recent years with little knowledge of the impact of system failures on patient safety. The primary aim of this multicentre observational study was to define the landscape of surgical system failures, errors and inefficiency (collectively termed failures) in aortic surgery. Secondary aims were to investigate determinants of these failures and their relationship with patient outcomes. METHODS: Twenty vascular teams at ten English hospitals trained in structured self-reporting of intraoperative failures (phase I). Failures occurring in open and endovascular aortic procedures were reported in phase II. Failure details (category, delay, consequence), demographic information (patient, procedure, team experience) and outcomes were reported. RESULTS: There were strong correlations between the trainer and teams for the number and type of failures recorded during 88 procedures in phase I. In 185 aortic procedures, teams reported a median of 3 (i.q.r. 2-6) failures per procedure. Most frequent failures related to equipment (unavailability, failure, configuration, desterilization). Most major failures related to communication. Fourteen failures directly harmed 12 patients. Significant predictors of an increased failure rate were: endovascular compared with open repair (incidence rate ratio (IRR) for open repair 0·71, 95 per cent c.i. 0·57 to 0·88; P = 0·002), thoracic aneurysms compared with other aortic pathologies (IRR 2·07, 1·39 to 3·08; P < 0·001) and unfamiliarity with equipment (IRR 1·52, 1·20 to 1·91; P < 0·001). The major failure total was associated with reoperation (P = 0·011), major complications (P = 0·029) and death (P = 0·027). CONCLUSION: Failure in aortic procedures is frequently caused by issues with team-working and equipment, and is associated with patient harm. Multidisciplinary team training, effective use of technology and new-device accreditation may improve patient outcomes.

High pressure and temperature optical flow cell for near-infra-red spectroscopic analysis of gas mixtures.

A new optical flow cell with a new optical arrangement adapted for high pressures and temperatures using glass fibres to connect light source, cell, and spectrometer has been developed, as part of a larger project comprising new methods for in situ analysis of bio and hydrogen gas mixtures in high pressure and temperature applications. The analysis is based on measurements of optical, thermo-physical, and electromagnetic properties in gas mixtures with newly developed high pressure property sensors, which are mounted in a new apparatus which can generate gas mixtures with up to six components with an uncertainty of composition of as little as 0.1 mol. %. Measurements of several pure components of natural gases and biogases to a pressure of 20 MPa were performed on two isotherms, and with binary mixtures of the same pure gases at pressures to 17.5 MPa. Thereby a new method of analyzing the obtained spectra based on the partial density of methane was investigated.

Systematic review of tibial nerve stimulation to treat faecal incontinence.

BACKGROUND: Two forms of tibial nerve stimulation are used to treat faecal incontinence (FI): percutaneous (PTNS) and transcutaneous (TTNS) tibial nerve stimulation. This article critically appraises the literature on both procedures. METHODS: A systematic review was performed adhering to the PRISMA framework. A comprehensive literature search was conducted, with systematic methodological quality assessment and data extraction. Summary measures for individual outcome variables are reported. RESULTS: Twelve articles met eligibility criteria; six related to PTNS, five to TTNS, and one to both procedures. These included ten case series and two randomized clinical trials (RCTs). Case series were evaluated using the National Institute for Health and Care Excellence quality assessment for case series, scoring 3-6 of 8. RCTs were evaluated using the Jadad score, scoring 4 of a possible 5 marks, and the Cochrane Collaboration bias assessment tool. From one RCT and case series reports, the success rate of PTNS, based on the proportion of patients who achieved a reduction in weekly FI episodes of at least 50 per cent, was 63-82 per cent, and that of TTNS was 0-45 per cent. In an RCT of TTNS versus sham, no patient had a reduction in weekly FI episodes of 50 per cent or more, whereas in an RCT of PTNS versus TTNS versus sham, 82 per cent of patients undergoing PTNS, 45 per cent of those having TTNS, and 13 per cent of patients in the sham group had treatment success. CONCLUSION: PTNS and TTNS result in significant improvements in some outcome measures; however, TTNS was not superior to sham stimulation in a large, adequately powered, RCT. As no adequate RCT of PTNS versus sham has been conducted, conclusions cannot be drawn regarding this treatment.

The impact of stoma for bowel management after spinal cord injury.

STUDY DESIGN: Multi-centre, retrospective self-report postal survey. OBJECTIVES: To characterise spinal cord injured (SCI) individuals with a stoma, their stoma management and outcomes, to identify sources of information and support for decision making and to explore the impact of a stoma on life satisfaction. SETTING: Five UK spinal cord injury centres. METHODS: A study-specific questionnaire accompanied by self-concept, life satisfaction and mood measures, and three simple rating scales for satisfaction, impact and restriction on life were sent to all known ostomates at five participating centres. RESULTS: Respondents were 92 individuals, mean age 56 years, mean duration of injury 26 years, 91% with colostomy. Multiple sources of information were utilised in deciding on surgery; discussion with other SCI ostomates was important. Duration of bowel care, faecal incontinence, bowel-related autonomic dysreflexia, dietary manipulation and laxative use were all significantly reduced following surgery. Rectal mucous discharge was the most common and bothersome post-stoma problem. Satisfaction with stoma was high; provision of sufficient information preoperatively was important, those with ileostomy were more dependent and less satisfied. Life satisfaction and physical self-concept were both lower in this sample than in previously reported samples of SCI individuals without reported bowel difficulties or stoma. CONCLUSION: The findings of this study of self-selected respondents with a stoma for bowel management after SCI emphasised the benefits of stoma in selected individuals and the importance of timely intervention, the complexity of the associated decision-making and of preoperative counselling. The impact of bowel dysfunction on physical self-concept warrants investigation.

Can nurses manage gastrointestinal symptoms arising from pelvic radiation disease?

AIMS: About 17,000 patients receive radiotherapy for pelvic cancer in the UK annually. Up to 50% are left with altered bowel function affecting quality of life. The UK National Cancer Survivorship Initiative Vision acknowledges that the needs of cancer survivors are not being met and challenges professionals to develop new models of care. MATERIALS AND METHODS: A prospective, observational qualitative study was carried out to assess whether nurse-delivered care is feasible for patients with radiotherapy-induced bowel dysfunction. The experience of a senior nurse, directed by an algorithm of investigation with a comprehensive treatment pathway, is reported. RESULTS: Over 12 months, 59 new and 103 follow-up appointments were managed by the nurse. In total, 37 women and 73 men, with a median age of 69 years, were seen; 9 had been treated for gastrointestinal, 33 for gynaecological and 68 for urological cancers, 26 months (median) previously. Sixty minutes (new consultations) (median, range 35-80) and 40 minutes (follow-up consultations) (range 20-85) were required. Ordering investigations, treatment initiation, long-term care planning and discharge seemed to be manageable in 83% of patients. CONCLUSION: An experienced nurse, working within a defined scope of practice, with medical support can manage care in patients with mild or moderate symptoms arising after pelvic radiotherapy. An ongoing randomised controlled trial is assessing patient outcomes.

Systematic review of abdominal surgery for chronic idiopathic constipation.

AIM: Constipation is a common problem which increases in prevalence with age. Chronic constipation is complex and difficult to treat. Some patients will not respond to pharmacological therapy and therefore surgery may be considered. A systematic review of the literature was performed to determine the outcome of surgery. METHOD: Published papers were identified by a search of The Cochrane Library, MEDLINE, CINAHL and EMBASE. They were reviewed and the data were extracted. RESULTS: Forty-eight papers were identified, including 1443 patients. Eleven different procedures were described. There was inconsistency in reporting. In 65% of patients the mean frequency of defaecation increased from 1.1 to 19.7 evacuations per week. Where laxative usage was reported (971 patients), it was found that 88% of patients did not need them postoperatively. Early complications included ileus (0-16%), infection (0-13%) and anastomotic leakage (0-22%). Patient satisfaction and quality of life scores were high. Only 30% of studies included data on preoperative psychological assessment. CONCLUSION: Surgery improves constipation and is associated with a higher degree of patient satisfaction, but the quality of studies was very variable. Future controlled trials should examine the ideal therapeutic approach for different patient groups.

Predictors of the outcome of percutaneous nerve evaluation for faecal incontinence.

BACKGROUND: The aim was to identify patient-related and operative factors that might predict the outcome of percutaneous nerve evaluation (PNE). METHODS: Demographic data (age, sex, body mass index), primary cause of incontinence, number and type of incontinence episodes, results of endoanal ultrasonography and manometry, and operative factors from 244 patients who underwent PNE for faecal incontinence were reviewed. Each factor was assessed according to the outcome, and explored by univariable and multivariable analysis to identify predictors. RESULTS: Some 191 patients (78.3 per cent) had a successful PNE. A low amplitude of sensory threshold during PNE (odds ratio (OR) 0.69 (95 per cent confidence interval 0.59 to 0.81); P < 0.001) and lead placement anterior to the sacral cortex (OR 9.06 (4.70 to 17.45); P < 0.001) were positive predictive factors for successful outcome of PNE. Neither a defect nor an abnormality of either the external (OR 0.88 (0.39 to 1.97); P = 0.749) or internal (OR 0.62 (0.27 to 1.42); P = 0.255) anal sphincter was a negative predictive factor. Demographic variables, number of incontinence episodes and the motor response threshold did not predict outcome. CONCLUSION: No preoperative predictor of PNE outcome could be identified. Predictors were limited to operative lead placement and sensory response during PNE.

Investigation to predict faecal continence in patients undergoing reversal of a defunctioning stoma (Porridge enema test).

OBJECTIVE: A defunctioning stoma is often performed in cases of major anorectal surgery or sphincter injury. This study aimed to assess the Porridge enema (PE) test as a tool to evaluate function prior to stoma closure. METHOD: Thirty-eight patients underwent PE test at a median of 12.5 months after stoma formation prior to consideration of stoma closure. Outcome was assessed by immediate leakage after PE test on lying, standing, walking and the ability to hold the enema for 30 min. Patients available for follow-up were divided into two groups: group 1 (n = 20) patients with stoma closure performed and group 2 (n = 10) patients where the stoma remains. Eight patients were excluded from analysis as the stoma had not been reversed for reasons unrelated to continence. The results of other investigations performed in these patients were analysed. Finally, we studied the agreement in the interpretation of the test by two investigators blinded to the patient's group and each other's interpretation and to functional results after the stoma was reversed. RESULTS: Anorectal physiology testing and imaging assessment of the anal sphincters was not statistically different between the two groups. There was a significant difference in the percentage of patients in each group that had enema leakage in: lying position (P = 0.002), standing position (P = 0.013), walking (P = 0.002) and ability to defer for 30 min (P = 0.005). There was a good correlation in the interpretation of PE test results by two investigators. Among patients whose stoma was closed and who were evaluated functionally, 55% were fully continent. CONCLUSION: This report suggests that the PE test is a promising tool as part of evaluation of anorectal function prior to stoma reversal.

Subtotal scapulectomy as the treatment for scapular tumour in the dog: a report of six cases.

The medical records of six dogs treated by sub-total scapulectomy for tumours involving the scapula were reviewed. The mean age of dogs in this study was 8 years and 4 months. Clinical signs on presentation included lameness of the affected forelimb and a palpable mass over the scapular area on physical examination. Pre-operative chest and affected forelimb radiographs were taken in most cases in addition to a biopsy. Subtotal scapulectomy was performed, ensuring margins clear of neoplastic tissue of at least 2 cm, preservation of the glenoid cavity and thus retention of the scapulo-humeral joint. On histopathological examination the tumours where diagnosed as chondrosarcoma (one), haemangiosarcoma (two), anaplastic malignant neoplasia (one) and osteosarcoma (one). Limb function was found to be good in all cases postoperatively. Prognosis was related to histopathological diagnosis of the tumour, favourable with chondrosarcoma and poor with the other tumour types.

Drug treatment for faecal incontinence in adults.

BACKGROUND: Faecal incontinence is a common symptom which causes significant distress and reduction in quality of life. Available treatment options for faecal incontinence include conservative treatments (biofeedback, pelvic floor muscle training, dietary manipulation or drug therapy) or surgical treatments (e.g. sphincter repair, post anal repair, neosphincter). Drug treatment is often given either alone or in combination with other treatment modalities. OBJECTIVES: To assess the effects of drug therapy for the treatment of faecal incontinence. In particular, to assess the effects of individual drugs relative to placebo or other drugs, and to compare drug therapy with other treatment modalities. SEARCH STRATEGY: We searched the Cochrane Incontinence Group trials register (January 2003) and the reference lists of relevant articles. Date of the most recent search: January 2003. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials of the use of pharmacological agents for the treatment of faecal incontinence in adults. DATA COLLECTION AND ANALYSIS: Working independently, reviewers selected studies from the literature, assessed the methodological quality of each trial, and extracted data. MAIN RESULTS: Eleven trials were identified for inclusion in this review. Nine trials were of cross-over design. Seven trials included only people with faecal incontinence related to liquid stool (either chronic diarrhoea or following ileoanal pouch surgery). Three trials (total 58 participants) compared topical phenylephrine gel with placebo. Two trials (56 participants) compared loperamide with placebo. One trial (11 participants) compared loperamide oxide with placebo. One trial (15 participants) compared diphenoxylate plus atropine with placebo. One trial (17 participants) compared sodium valproate with placebo. One trial (30 participants) compared loperamide with codeine with diphenoxylate plus atropine. Two further trials (total 265 participants) assessed the use of lactulose in elderly people.No studies comparing drugs with other treatment modalities were identified. There was limited evidence that antidiarrhoeal drugs and drugs which enhance anal sphincter tone may reduce faecal incontinence in patients with liquid stools. However, the trials were small and of short duration. REVIEWER'S CONCLUSIONS: The small number of trials identified for this review assessed several different drugs in a variety of patient populations. The focus of most of the included trials was on the treatment of diarrhoea, rather than faecal incontinence. There is little evidence to guide clinicians in the selection of drug therapies for faecal incontinence. Larger, well-designed controlled trials, which include clinically important outcome measures, are required.

Environmental context and drug history modulate amphetamine-induced c-fos mRNA expression in the basal ganglia, central extended amygdala, and associated limbic forebrain.

The context in which amphetamine is administered modulates its ability to induce both behavioral sensitization and immediate early gene expression. When given in a novel test environment amphetamine produces greater levels of c-fos and arc mRNA expression in many brain regions relative to when it is given in the home cage. The purpose of the current study was to determine if environment and drug history interact to influence amphetamine-induced c-fos mRNA expression. Rats with a unilateral 6-hydroxydopamine lesion were treated for 7 days with saline or 0.5 mg/kg of d-amphetamine (i.v.) in a distinct and relatively novel test environment (Novel), or in their home cage (Home). Following a 10-12-day withdrawal period, a challenge injection of either saline or 0.5 mg/kg d-amphetamine was administered. In situ hybridization histochemistry was used to examine c-fos mRNA expression in several regions of the basal ganglia, the central extended amygdala, and limbic forebrain. In most brain regions amphetamine given in the Novel environment produced greater c-fos mRNA expression than when given it was given at Home, and drug history had no effect on amphetamine-induced c-fos mRNA expression. However, within the subthalamic nucleus, substantia nigra reticulata, and central nucleus of the amygdala prior experience with amphetamine in the Novel but not Home environment enhanced the effect of an amphetamine challenge injection on c-fos mRNA expression. In contrast, there was a decrease in c-fos mRNA expression in amphetamine-pretreated animals, regardless of environmental context, in the ventral portion of the far caudal striatum. Reexposure to an environment previously paired with amphetamine produced a conditioned increase in c-fos mRNA expression in portions of the caudate-putamen, the subthalamic nucleus, the nucleus accumbens shell and a conditioned decrease in c-fos mRNA expression in the central nucleus of the amygdala. We conclude that environmental context and drug history interact to alter the basal ganglia and central extended amygdala circuitry engaged by subsequent exposure to amphetamine, or exposure to an environment previously paired with amphetamine.

Amphetamine and cocaine induce different patterns of c-fos mRNA expression in the striatum and subthalamic nucleus depending on environmental context.

In the dorsal striatum, there are two major populations of medium spiny projection neurons. One population is positive for dynorphin mRNA (DYN+), and these cells project preferentially to the substantia nigra, forming the so-called 'direct pathway'. A second population is positive for enkephalin mRNA (ENK+), and these cells influence the substantia nigra indirectly, via the globus pallidus and subthalamic nucleus. Psychostimulant drugs, such as amphetamine and cocaine, are reported to induce immediate early genes (IEGs) in only one subpopulation of dorsal striatal projection neurons, DYN+ cells. However, this apparent selectivity appears to be a function of environmental context. We found that when given in the animal's home cage, amphetamine and cocaine increased expression of the IEG, c-fos, almost exclusively in DYN+ cells. However, when given in a novel environment, amphetamine and cocaine increased c-fos mRNA in both DYN+ and ENK+ cells. Furthermore, amphetamine and cocaine increased c-fos mRNA expression in the subthalamic nucleus when administered in the novel environment, but not when given at home. We conclude that the neural circuitry engaged by psychostimulant drugs, and their ability to induce specific patterns of gene expression, are determined by the environmental context in which they are experienced. This may be related to the ability of environmental novelty to facilitate psychostimulant drug-induced neuroplasticity.

Notch signaling is essential for vascular morphogenesis in mice.

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the role of the Notch4 gene, we generated Notch4-deficient mice by gene targeting. Embryos homozygous for this mutation developed normally, and homozygous mutant adults were viable and fertile. However, the Notch4 mutation displayed genetic interactions with a targeted mutation of the related Notch1 gene. Embryos homozygous for mutations of both the Notch4 and Notch1 genes often displayed a more severe phenotype than Notch1 homozygous mutant embryos. Both Notch1 mutant and Notch1/Notch4 double mutant embryos displayed severe defects in angiogenic vascular remodeling. Analysis of the expression patterns of genes encoding ligands for Notch family receptors indicated that only the Dll4 gene is expressed in a pattern consistent with that expected for a gene encoding a ligand for the Notch1 and Notch4 receptors in the early embryonic vasculature. These results reveal an essential role for the Notch signaling pathway in regulating embryonic vascular morphogenesis and remodeling, and indicate that whereas the Notch4 gene is not essential during embryonic development, the Notch4 and Notch1 genes have partially overlapping roles during embryogenesis in mice.

Functional outcome after restorative panproctocolectomy for ulcerative colitis decreases an otherwise enhanced quality of life.

BACKGROUND: Restorative panproctocolectomy is a favoured operation for ulcerative colitis, but altered bowel habit may adversely affect overall quality of life. METHODS: Specific and generic quality of life questionnaires and an instrument to award money for continuing disability based on government guidelines were sent to 103 patients who had curative surgery for ulcerative colitis between 1995 and 1997. Seventy-one patients returned completed questionnaires: 30 with an ileostomy (representing incontinence and abnormal body image), 11 with a Koch pouch (representing continence and abnormal body image) and 30 with a pelvic pouch (representing continence and normal body image). RESULTS: Patients valued the disability of having an ileostomy similar to that for a Koch pouch or a pelvic pouch: pound 40 000, pound 30 000 and pound 40 000 respectively (P = 0. 97). There was no sex difference. Body image measured with a visual analogue scale (least = 1, worst = 10) was worst with the ileostomy and Koch pouch (8 each) and best with a pelvic pouch (5) (P = 0.06). However, pelvic pouches scored significantly worse than an ileostomy with regard to altered bowel emptying (pelvic pouch, 8; Koch pouch, 7; ileostomy, 5) (P = 0.01). CONCLUSION: Poor function after pelvic pouch surgery offsets any advantage in body image over an ileostomy. Thus, overall quality of life and perceived monetary damage were the same for the two operations. Improved pelvic pouch function is likely to be reflected in better quality of life after restorative panproctocolectomy.

Long-term results of overlapping anterior anal-sphincter repair for obstetric trauma.

BACKGROUND: Anterior structural damage to the anal sphincter occurs in up to a third of women at first vaginal delivery, and of these a third have new bowel symptoms. The standard treatment for such structural damage is anterior overlapping anal-sphincter repair. We aimed to assess the long-term results of this operation. METHODS: We assessed the long-term results in 55 consecutive patients who had had repair a minimum of 5 years (median 77 months [range 60-96]) previously. Questionnaire and telephone interview assessed current bowel function and continence, restriction in activities related to bowel control, and overall satisfaction with the results of surgery. 42 of these patients had been continent of solid and liquid stool at a median of 15 months after the repair. FINDINGS: We were able to contact 47 (86%) of the 55 patients. One of these patients had required a proctectomy and end ileostomy for Crohn's disease. Of the remaining 46 patients, 27 reported improved bowel control without the need for further surgery, and 23 rated their symptom improvement as 50% or greater. Seven patients had undergone further surgery for incontinence and one patient had not had a covering stoma closed. Thus, the long-term functional outcome of the sphincter repair alone could be assessed in 38 patients. Of these patients, none was fully continent to both stool and flatus; only four were totally continent to solid and liquid stool; six had no faecal urgency; and eight had no passive soiling. Of the 38 patients, 20 still wore a pad for incontinence and 25 reported lifestyle restriction. 14 reported the onset of a new evacuation disorder after sphincter repair. 23 of the 46 patients contacted had a successful long-term outcome (defined as no further surgery and urge faecal incontinence monthly or less). INTERPRETATION: The results of overlapping sphincter repair for obstetric anal-sphincter damage seem to deteriorate with time. Preoperative counselling should emphasise that although most patients will improve after the procedure, continence is rarely perfect, many have residual symptoms, and some may develop new evacuation disorders.