Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Stimulated smooth muscle neosphincter in male intrinsic sphincter deficiency: Proof of principle studies in a rabbit model.

AIMS: Intrinsic sphincter deficiency (ISD) causes significant disability and impairment of quality of life despite a range of treatment options. We investigated a novel method to improve sphincter function that does not appear to have been previously attempted, that is, transplantation to create a smooth muscle cuff, that subsequently becomes innervated, around the urethra. METHODS: Bladder pressure and passage of urine were measured in conscious, sedated rabbits of three groups: 6 control (unoperated) rabbits, 8 rabbits rendered incontinent by incision of their urethral wall, and 12 lesioned rabbits treated by transplantation of a circumferential strip of autologous dartos muscle whose innervation was later stimulated electrically. Effects of stimulation were tested up to 6 months after surgery. RESULTS: Lesions of the proximal urethra caused the bladder to leak at filling volumes that previously caused no leak. The volume added to cause first leak was less than half the volume added to cause a voiding reflex in unoperated rabbits. Transplantation of dartos to the lesioned bladder neck did not affect urodynamic parameters. However, electrical stimulation of the innervation of the transplant increased the bladder volume necessary to cause voiding and restored voiding pressures and filling volumes towards normal. These effects were maintained for 6 months and were not related to spontaneous healing. CONCLUSIONS: Free transplants of smooth muscle that become innervated offer promise as a treatment for ISD that is unlikely to cause urethral erosion and will not require a pump to restore continence.

Static single channel and multichannel water perfusion pressure profilometry in a bench model of a urethra.

AIMS: To determine the catheter perfusion and withdrawal rate which generate the most repeatable single (SCPP) and multichannel pressure profilometry (MCPP) profiles in a bench model. METHODS: A bench model using a urethral substitute was developed in which SCPP and MCPP were performed using the Brown-Wickham method. One single channel and four multichannel catheters were tested using seven withdrawal rates and three perfusion rates. Repeatability was determined using spread of mean profile pressure, cross-correlation, Bland-Altman statistic, and a one-tailed Student's t-statistic. An artificial urinary sphincter (AUS) model was constructed to create a predictable intraluminal profile. MCPP data were used to generate three-dimensional (3D) images of the pressures exerted by the AUS model. RESULTS: A withdrawal rate of 0.5 mm/sec and perfusion rate 1 ml/min produced the most repeatable SCPP profiles with a spread of mean profile pressure ≤7 cmH(2)O. For MCPP, a 10 F 6-channel catheter using a withdrawal rate of 1 mm/sec and perfusion rate of 1 ml/min produced the most similar profiles (cross-correlation = 0.99). However, the spread of MCPP was large (spread ≤44 cmH(2)O per channel). Nevertheless MCPP was able to consistently demonstrate areas of high pressure as predicted by the AUS model. CONCLUSIONS: MCPP was not repeatable and is an unreliable measure of urethral pressure. MCPP and 3D images do demonstrate directional differences predicted from the AUS model. These may be of use for qualitative understanding and appreciation of relative relationships if not actual forces within the urethra and have application in understanding urethral function in vivo.

The effects of aviation-style non-technical skills training on technical performance and outcome in the operating theatre.

Unintended harm to patients in operating theatres is common. Correlations have been demonstrated between teamwork skills and error rates in theatres. This was a single-institution uncontrolled before-after study of the effects of "non-technical" skills training on attitudes, teamwork, technical performance and clinical outcome in laparoscopic cholecystectomy (LC) and carotid endarterectomy (CEA) operations. The setting was the theatre suite of a UK teaching hospital. Attitudes were measured using the Safety Attitudes Questionnaire (SAQ). Teamwork was scored using the Oxford Non-Technical Skills (NOTECHS) method. Operative technical errors (OTEs), non-operative procedural errors (NOPEs), complications, operating time and length of hospital stay (LOS) were recorded. A 9 h classroom non-technical skills course based on aviation "Crew Resource Management" (CRM) was offered to all staff, followed by 3 months of twice-weekly coaching from CRM experts. Forty-eight procedures (26 LC and 22 CEA) were studied before intervention, and 55 (32 and 23) afterwards. Non-technical skills and attitudes improved after training (NOTECHS increase 37.0 to 38.7, t = -2.35, p = 0.021, SAQ teamwork climate increase 64.1 to 69.2, t = -2.95, p = 0.007). OTEs declined from 1.73 to 0.98 (u = 1071, p = 0.009), and NOPEs from 8.48 to 5.16 per operation (t = 4.383, p<0.001). These effects were stronger in the LC group than in CEA procedures. The operating time was unchanged, and a non-significant reduction in LOS was observed. Non-technical skills training improved technical performance in theatre, but the effects varied between teams. Considerable cultural resistance to adoption was encountered, particularly among medical staff. Debriefing and challenging authority seemed more difficult to introduce than other parts of the training. Further studies are needed to define the optimal training package, explain variable responses and confirm clinical benefit.

Local recurrence after abdomino-perineal resection.

OBJECTIVE: Local recurrence of rectal cancer is a major cause of morbidity and mortality following curative resection. The published rates vary after abdomino-perineal resection (APR) from 5% to 47%. The aim of this study was to evaluate local recurrence following curative APR for low rectal cancer in our unit. METHOD: The medical notes of patients treated between 1st January 1996 and 31st December 2000 were retrieved. Local recurrence was defined as the presence of tumour within the pelvis confirmed by clinical findings, pathological specimen or radiological reports. A curative resection was defined as excision of tumour in the absence of macroscopic metastatic disease and whose resection margins were greater than 1 mm circumferentially and 10 mm distally. Outcomes and survival were compared using Fisher's exact test and Kaplan-Meier method. RESULTS: Two hundred consecutive cases with a diagnosis of rectal cancer were identified of which 139 underwent a curative resection (69.5%). Of these 40 patients (28%) underwent APR with curative intent. Two patients (5%) developed local recurrence at 18 and 24 months respectively. The overall local recurrence rate for all curative rectal cancer surgery, in the same period was 2.6%. Eleven patients have died in the follow-up period of which nine were cancer-related deaths. CONCLUSION: The local recurrence rates achieved with APR were not significantly different from those achieved with restorative operations. Tumours at the ano-rectal junction should not be dissected off the pelvic floor, but radically excised en bloc with the surrounding levator ani, as a cylinder, as originally described by Miles.

Cellular mechanism of the voltage-dependent change in slow potentials generated in circular smooth muscle of the guinea-pig gastric corpus.

The cellular mechanism of the voltage-dependent properties of slow potentials were investigated in single bundles of circular smooth muscle isolated from the gastric corpus of guinea-pig using conventional microelectrode recordings. Hyperpolarization of the membrane by current injection decreased the frequency and increased the amplitude of slow potentials linearly. At potentials negative of -80 mV, slow potential generation was abolished and a periodic generation of clustered unitary potentials was evident. Application of cyclopiazonic acid (CPA, 20 microM) or thapsigargin (1 microM; inhibitors of Ca(2+)-ATPase), carbonyl cyanide m-chlorophenyl hydrazone (CCCP, 0.1 microM; mitochondrial protonophore) or 2-aminoethoxydiphenyl borate (2-APB, 20 microM; inhibitor of IP(3) receptor-mediated Ca(2+) release) depolarized the membrane and reduced or inhibited the amplitude and frequency of slow potentials: repolarization of the membrane to the resting level by current injection resulted in a recovery of the amplitude of slow potentials in the presence of CPA or CCCP, but not 2-APB. The slow potentials abolished by thapsigargin did not recover upon membrane repolarization. The altered frequency of slow potentials by 2-APB, CPA or CCCP was not reversed by membrane repolarization to control potentials. Depolarization of the membrane by about 10 mV with high-potassium solution also reduced the amplitude and increased the frequency of slow potentials in a manner restored by repolarization to control potentials upon current injection, suggesting that membrane depolarization did not affect the voltage dependency of pacemaker activity. The results indicate that in corpus circular muscles the voltage dependency of the frequency and amplitude of slow potentials requires a functional Ca(2+) store and mitochondria.

Antenatal pelvic floor exercises: a survey of both patients' and health professionals' beliefs and practice.

The aim was to discover how often women perform pelvic floor exercises (PFE) in the antenatal period and how they wished to be taught. We compared this with the opinions of the health professionals looking after them. A total of 54 women attending the antenatal day assessment unit completed questionnaires. A total of 21 obstetricians, 29 midwives and 25 GPs returned similar questionnaires. Most women think they should be performing PFE daily but only 15% do so. Some 57% of the women wanted to be taught in the antenatal period. Over 50% of the women/midwives believed that PFE should be taught in an individual basis. Obstetricians/GPs favoured classes. A total of 76% of the women want midwives to teach them PFE and 57% of midwives agree. Most health professionals felt that they had not received adequate training on PFE. The midwife is felt to be the best placed person to teach PFE. Health professionals give PFE low priority.

Botulinum toxin B is not an effective treatment of refractory overactive bladder.

OBJECTIVES: To determine the efficacy and safety of botulinum toxin-B (BTX-B) in two groups of patients with urodynamically proven idiopathic detrusor overactivity (IDO) or neurogenic DO (NDO) refractory to conservative treatment. METHODS: This was a nonrandomized, prospective study. We diluted 5000 U of BTX-B in 20 mL of normal saline and injected it at 20 sites around the bladder, avoiding the trigone. The data collected at recruitment and 10 and 26 weeks postoperatively included number of incontinent episodes, frequency, and nocturia, King's Health Questionnaire score, and the urodynamic parameters of volume at the first overactive contraction and maximal cystometric capacity. RESULTS: A total of 25 patients were recruited, 20 with IDO and 5 with NDO. Only 7 patients, all with IDO, reported symptomatic improvement at the 10-week assessment. The symptoms had returned in these 7 patients at a median of 136 days (range 106 to 151) after injection. Of the remaining 20 patients, 16 (13 with IDO and 3 with NDO) thought an initial improvement had occurred but it had worn off or was wearing off by the first assessment. Two patients (both with NDO) reported no improvement. CONCLUSIONS: BTX-B had a limited duration of action, with most of its symptomatically beneficial effects wearing off by 10 weeks in most of our patients. The short duration of action for BTX-B suggests it is unlikely to gain widespread use in the treatment of DO.

Electrical events underlying organized myogenic contractions of the guinea pig stomach.

The stomach generates a characteristic pattern of coordinated activity whereby rings of contraction regularly start in the corpus and migrate slowly down the stomach to the duodenum. This behaviour persists after isolating the stomach and after blocking nervous activity; hence the response is myogenic, resulting from organized contractions of smooth muscle cells lying in the stomach wall. Each ring of contraction is triggered by a long lasting wave of depolarization, termed a slow wave. Slow waves are now known to be generated by sets of interstitial cells of Cajal (ICC), which intermingle with gastric smooth muscle cells. This article describes some studies which identify the roles played by ICC in the on-going generation of coordinated gastric movements. Intramuscular ICC in the corpus generate slow waves and these provide the dominant pacemaker frequency in the stomach. Corporal slow waves, in turn, activate a network of myenteric ICC, which starts in the antrum and slowly conducts waves of depolarization down the stomach. As these waves pass over bundles of circularly orientated muscle cells, they activate a set of intramuscular ICC which lie in the circular muscle layer: these generate slow waves that rapidly spread radially, so triggering each ring of contraction.

Identification of systems failures in successful paediatric cardiac surgery.

Patient safety will benefit from an approach to human error that examines systemic causes, rather than blames individuals. This study describes a direct observation methodology, based on a threat and error model, prospectively to identify types and sources of systems failures in paediatric cardiac surgery. Of substantive interest were the range, frequency and types of failures that could be identified and whether minor failures could accumulate to form more serious events, as has been the case in other industries. Check lists, notes and video recordings were employed to observe 24 successful operations. A total of 366 failures were recorded. Coordination and communication problems, equipment problems, a relaxed safety culture, patient-related problems and perfusion-related problems were most frequent, with a smaller number of skill, knowledge and decision-making failures. Longer and more risky operations were likely to generate a greater number of minor failures than shorter and lower risk operations, and in seven higher-risk cases frequently occurring minor failures accumulated to threaten the safety of the patient. Non-technical errors were more prevalent than technical errors and task threats were the most prevalent systemic source of error. Adverse events in surgery are likely to be associated with a number of recurring and prospectively identifiable errors. These may be co-incident and cumulative human errors predisposed by threats embedded in the system, rather than due to individual incompetence or negligence. Prospectively identifying and reducing these recurrent failures would lead to improved surgical standards and enhanced patient safety.

An electrical analysis of slow wave propagation in the guinea-pig gastric antrum.

This paper provides an electrical description of the propagation of slow waves and pacemaker potentials in the guinea-pig gastric antrum in anal and circumferential directions. As electrical conduction between laterally adjacent circular muscle bundles is regularly interrupted, anal conduction of pacemaker potentials was assumed to occur via an electrically interconnected chain of myenteric interstitial cells of Cajal (ICC(MY)). ICC(MY) were also connected resistively to serially connected compartments of longitudinal muscle. Circumferential conduction occurred in a circular smooth muscle bundle that was represented as a chain of electrically connected isopotential compartments: each compartment contained a proportion of intramuscular interstitial cells of Cajal (ICC(IM)) that are responsible for the regenerative component of the slow wave. The circular muscle layer, which contains ICC(IM), and the ICC(MY) network incorporated a mechanism, modelled as a two-stage chemical reaction, which produces an intracellular messenger. The first stage of the reaction is proposed to be activated in a voltage-dependent manner as described by Hodgkin and Huxley; the messenger altered the mean rate of discharge of depolarizing unitary potentials as a function of the concentration of messenger according to a conventional dose-effect relationship. A separate membrane conductance, scaled by the product of an independent voltage-sensitive reaction, was included in the ICC(MY) compartments; this was used to describe the primary component of pacemaker potentials and simulated a delay before the activation of this membrane current. The model generates pacemaker potentials and slow waves with propagation velocities similar to those determined in the physiological experiments described in the accompanying paper.

Propagation of slow waves in the guinea-pig gastric antrum.

Intracellular recordings were made from the circular layer of the intact muscular wall of the guinea-pig gastric antrum in preparations where much of the corpus remained attached. When two electrodes were positioned parallel to and near to the greater curvature, slow waves were first detected at the oral site and subsequently at the anal site: the oro-anal conduction velocity was found to be 2.5 mm s(-1). When one electrode was positioned near the greater curvature and the other at a circumferential location, slow waves were first detected near the greater curvature and subsequently at the circumferential site: the circumferential conduction velocity was 13.9 mm s(-1). When recordings were made from preparations in which the circular muscle layer had been removed, the oro-anal and the circumferential conduction velocities were both about 3.5 mm s(-1). When slow waves were recorded from preparations in which much of the myenteric network of antral interstitial cells (ICC(MY)) had been dissected away, slow waves were first detected near the region of intact ICC(MY) and subsequently at a circumferential location: the circumferential conduction velocity of slow waves in regions devoid of ICC(MY) was 14.7 mm s(-1). When the electrical properties of isolated single bundles of circular muscle were determined, their length constants were about 3 mm and their time constant about 230 ms, giving an asymptotic electrotonic propagation velocity of 25 mm s(-1). Oro-anal electrical coupling between adjacent bundles of circular muscle was found to vary widely: some bundles were well connected to neighbouring bundles whereas others were not. Together the observations suggest that the slow oro-anal progression of slow waves results from a slow conduction velocity of pacemaker potentials in the myenteric network of interstitial cells. The rapid circumferential conduction of slow waves results from the electrical properties of the circular muscle layer which allow intramuscular ICC (ICC(IM)) to support the radial spread of slow waves: regions of high resistance between bundles prevent the anally directed spread of slow waves within the circular layer.

Antegrade continence enema in the treatment of obstructed defaecation with or without faecal incontinence.

BACKGROUND: Obstructed defaecation and faecal incontinence are complex functional disorders that pose management challenges. In recent times, the antegrade continence enema (ACE) has been tried both as a primary procedure and as a final resort to avoid a colostomy in patients with a variety of functional problems. The purpose of this study was to evaluate the role of the ACE procedure as a treatment option for adult patients suffering from obstructed defaecation with or without faecal incontinence, some of whom also had slow transit constipation. METHODS: Twenty female patients underwent ACE as an appendicostomy (65%) or caecostomy (35%). The median age was 44 years (range, 20-65 years). The indications were obstructed defaecation with faecal incontinence (65%) and obstructed defaecation alone (35%). Fifteen of these patients were followed for 3-51 months (median, 6 months). Cleveland continence score, bowel score and quality of life score were recorded pre- and postoperatively along with post-procedure complications. RESULTS: Thirteen (65%) patients were satisfied with the outcome and recorded improvement in their scores while two (10%) remained the same and one (5%) was worse. This latter woman and another patient stopped using their ACE, whilst follow-up data was unavailable for three patients. Minor wound infections were noted in nine patients (45%), of whom one needed drainage of an abscess; the rest settled with antibiotics and dressings. Bowel and Cleveland continence scores improved postoperatively (p<0.001 and p=0.001, respectively) but SF36 scores did not. To date, no patient has had a colostomy following an ACE procedure. CONCLUSIONS: Colostomies can be avoided in patients with obstructed defaecation. There is, however, a need to minimise wound infections which seem to be the most troublesome complication.

Atypical slow waves generated in gastric corpus provide dominant pacemaker activity in guinea pig stomach.

When intracellular recordings were made from the circular layer of the intact muscular wall of the isolated guinea pig gastric corpus, an ongoing regular high frequency discharge of slow waves was detected even though this region lacked myenteric interstitial cells. When slow waves were recorded from preparations consisting of both the antrum and the corpus, slow waves of identical frequency, but with different shapes, were generated in the two regions. Corporal slow waves could be distinguished from antral slow waves by their time courses and amplitudes. Corporal slow waves, like antral slow waves, were abolished by buffering the internal concentration of calcium ions, [Ca2+]i, to low levels, or by caffeine, 2-aminoethoxydiphenyl borate or the chloride channel blocker DIDS. Corporal preparations demonstrated an ongoing discharge of unitary potentials, as has been found in all other tissues containing interstitial cells. The experiments show that the corpus provides the dominant pacemaker activity which entrains activity in other regions of the stomach and it is suggested that this activity is generated by corporal intramuscular interstitial cells.

Modulation of voltage-dependent Ba2+ currents in the guinea-pig gastric antrum by cyclic nucleotide-dependent pathways.

We have investigated whether the activation of cAMP- and cGMP-dependent pathways modifies the properties of voltage-dependent Ba(2+) currents (I(Ba)) recorded from guinea-pig gastric myocytes using patch-clamp techniques. All experiments were carried on single smooth muscle cells, dispersed from the circular layer of the guinea-pig gastric antrum. Both dibutyryl cAMP (db-cAMP, 0.1-1 mM), a membrane-permeable ester of cAMP, and isoproterenol, a selective beta-stimulant, inhibited I(Ba) in a concentration-dependent manner. Forskolin, but not dideoxy-forskolin, an inactive isomer of forskolin, inhibited the peak amplitude of I(Ba). In the presence of either Rp-cAMP or the PKA (cAMP-dependent protein kinase) inhibitor peptide 5-24 (PKA-IP), neither forskolin nor db-cAMP inhibited I(Ba). After establishing a conventional whole-cell recording, the peak amplitude of I(Ba) gradually decreased when the catalytic subunit of PKA was included in the pipette. The further application of Rp-cAMP reversibly enhanced I(Ba). Sodium nitroprusside (0.1-1 mM) and 8-Br-cGMP (0.1-1 mM) also inhibited I(Ba) in a concentration-dependent manner. The inhibitory effects of forskolin or db-cAMP on I(Ba) were not significantly changed by pretreatment with a cGMP-dependent protein kinase (PKG) inhibitor. Similarly, the inhibitory actions of 8-Br-cGMP on I(Ba) were not modified by PKA-IP. The membrane-permeable cyclic nucleotides db-cAMP and 8-Br-cGMP caused little shift of the voltage dependence of the steady-state inactivation and reactivation curves. Neither of the membrane-permeable cyclic nucleotides db-cAMP or 8-Br-cGMP had additive inhibitory effects on I(Ba). These results indicate that two distinct cyclic nucleotide-dependent pathways are present in the guinea-pig gastric antrum, and that both inhibited I(Ba) in an independent manner.

The role of rectocele repair in targeted patients with obstructed defaecation.

INTRODUCTION: Obstructed defaecation is a complex disorder that poses serious management challenges. The purpose of this study is to review the functional results of surgery in women undergoing rectocele repair for obstructed defaecation, and in a targeted subgroup in which the rectocele was the only identifiable cause of their symptoms. METHODS: All case notes were reviewed. Demographic details, preoperative symptoms, details of previous pelvic surgery, radiological and anorectal physiology results, operative procedure, post operative symptoms, length of follow-up and details of further pelvic reconstructive surgery were recorded. To enter the targeted group, patients (i) had not undergone previous pelvic surgery, (ii) had presented with obstructive defaecation, (iii) had a proctogram that demonstrated a rectocele with no or partial intrarectal intussusception and (iv) had no other functional abnormality in colonic transit studies, endoanal ultrasound or anorectal physiology. RESULTS: Eighty-two case notes were reviewed. All experienced obstructed defaecation. Forty-two women underwent a per-anal plication of the rectocele, 33 had a transperineal plication and levatorplasty and seven a mesh repair. A total of 63 (77%) women were pleased with the result, though symptoms later returned in 17 (27%) of them. 26 (31%) had further surgery in an attempt to improve their defaecatory difficulties. Sixteen women were eligible for the targeted group. All had a good early result though symptoms returned in three women. Two (12%) had further surgery. CONCLUSION: Careful preoperative patient selection is vital to improve outcomes. Preoperative counselling of all patients undergoing rectocele repair is of extreme importance, in particular explaining the evolving nature of pelvic floor dysfunction and the possible need for further reconstructive surgery.

An electrical description of the generation of slow waves in the antrum of the guinea-pig.

This paper provides an electrical description of the generation of slow waves in the guinea-pig gastric antrum. A short segment of a circular smooth muscle bundle with an attached network of myenteric interstitial cells of Cajal (ICC-MY) and longitudinal muscle sheet was modelled as three electrical compartments with resistive connexions between the ICC-MY compartment and each of the smooth muscle compartments. The circular smooth muscle layer contains a proportion of intramuscular interstitial cells of Cajal (ICC-IM), responsible for the regenerative component of the slow wave. Hence the equivalent cell representing the circular muscle layer incorporated a mechanism, modelled as a two stage reaction, which produces an intracellular messenger. The first stage of the reaction is proposed to be activated in a voltage-dependent manner as described by Hodgkin and Huxley. A similar mechanism was incorporated into the equivalent cell describing the ICC-MY network. Spontaneous discrete transient depolarizations, termed unitary potentials, are detected in records taken from either bundles of circular smooth muscle containing ICC-IM or from ICC-MY. In the simulation the mean rate of discharge of unitary potentials was allowed to vary with the concentration of messenger according to a conventional dose-effect relationship. Such a mechanism, which describes regenerative potentials generated by the circular muscle layer, also simulated the plateau component of the pacemaker potential in the ICC-MY network. A voltage-sensitive membrane conductance was included in the ICC-MY compartment; this was used to describe the primary component of the pacemaker potential. The model generates a range of membrane potential changes with properties similar to those generated by the three cell types present in the intact tissue.

Role of interstitial cells of Cajal in the control of gastric motility.

Most regions of the gastrointestinal tract generate spontaneous electrical and mechanical activity in the absence of stimulation. When electrical recordings are made from slow muscle cells lying in the gastrointestinal tract, a regular discharge of long lasting waves of depolarization, slow waves, is detected. It has recently become apparent that slow waves are generated by a specialized population of smooth muscle cells, known as interstitial cells of Cajal (ICC). ICC can be subdivided into at least two separate groups. In most regions of the gastrointestinal tract, one group of ICC form a network that generates pacemaker potentials, so producing rhythmical membrane potential changes in the adjacent muscle layers. The second group of ICC are distributed amongst the smooth muscle cells and are tightly electrically coupled to them. In some regions of the gut, the second group of ICC augment the waves of pacemaker depolarization, so ensuring that voltage-dependent calcium channels in the smooth muscles are activated during each slow wave cycle. In addition, the second group of ICC are densely innervated by inhibitory and excitatory nerve terminals. Thus intrinsic nerve terminals, rather than communicating directly with smooth muscle cells, selectively innervate ICC and release transmitters directly onto them. The signals that are generated in the ICC, by the neurally released transmitters, then alter the activity of surrounding smooth muscle cells.

Forty years of cancer modelling in the mouse.

Mouse models of human cancer have played an important role in formulating modern concepts of multistage carcinogenesis, and are providing us with a new armoury of tools for the testing of novel therapeutic approaches to cancer treatment. The development of inducible and conditional technologies provide us with greater opportunity to generate mouse models which faithfully recapitulate human tumorigenesis, in terms of both the biology and the genetics of this disease. It is now feasible to control, in time and space, the development of tumours in almost any mouse tissue, such that we now have available mouse models of all major human cancers. Moreover, novel non-invasive approaches to tumour imaging will enable us to follow tumour development and metastasis in vivo, as well as the effects of candidate therapeutic drugs. Such new generation tumour models, which accurately emulate the disease state in situ, should provide a useful platform with which to experimentally test drugs targeted to specific gene products, or combinations of genes that control rate-limiting steps of tumour development.