Does a missed obstetric anal sphincter injury at time of delivery affect short-term functional outcome?

Introduction This study aimed to ascertain whether missed obstetric anal sphincter injury at delivery had worse functional and quality of life outcomes than primary repair immediately following delivery. Materials and methods Two to one propensity matching was undertaken of patients presenting to a tertiary pelvic floor unit with ultrasound evidence of missed obstetric anal sphincter injury within 24 months of delivery with patients who underwent primary repair at the time of delivery by parity, grade of injury and time to assessment. Outcomes compared included Birmingham Bowel, Bladder and Urinary Symptom Questionnaire (BBUSQ), Wexner Incontinence Score, Short Form-36, Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire and anorectal physiology results. Results Thirty-two missed anal sphincter injuries were matched two to one with sixty-two patients who underwent primary repair of an anal sphincter defect. Mean time to follow-up was 9.31 ± 6.79 months. Patients with a missed anal sphincter injury had suffered more incontinence, as seen in higher the Birmingham Bowel, Bladder and Urinary Symptom Questionnaire (BBUSQ; 30.56% ± 14.41% vs. 19.75% ± 15.65%, P = 0.002) and Wexner scores (6.00 ± 3.76 vs. 3.67 ± 4.06, P = 0.009). They also had a worse BBUSQ urinary domain score (28.25% ± 14.9% vs. 17.01 ± 13.87%, P = 0.001) and worse physical functioning as measured by the Short Form-36 questionnaire (P = 0.045). There were no differences in other outcomes compared, including anorectal physiology and sexual function. Discussion In the short-term, patients with a missed obstetric anal sphincter injury had significantly worse faecal incontinence and urinary function scores, however quality of life and sexual function were largely comparable between groups. Conclusions Longer-term follow-up is needed to assess the effects of missed obstetric anal sphincter injury over time.

Magnetic resonance defecography versus clinical examination and fluoroscopy: a systematic review and meta-analysis.

BACKGROUND: Magnetic resonance defecography (MRD) allows for dynamic visualisation of the pelvic floor compartments when assessing for pelvic floor dysfunction. Additional benefits over traditional techniques are largely unknown. The aim of this study was to compare detection and miss rates of pelvic floor abnormalities with MRD versus clinical examination and traditional fluoroscopic techniques. METHODS: A systematic review and meta-analysis was conducted in accordance with recommendations from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. MEDLINE, Embase and the Cochrane Central Register of Controlled Trials were accessed. Studies were included if they reported detection rates of at least one outcome of interest with MRD versus EITHER clinical examination AND/OR fluoroscopic techniques within the same cohort of patients. RESULTS: Twenty-eight studies were included: 14 studies compared clinical examination to MRD, and 16 compared fluoroscopic techniques to MRD. Detection and miss rates with MRD were not significantly different from clinical examination findings for any outcome except enterocele, where MRD had a higher detection rate (37.16% with MRD vs 25.08%; OR 2.23, 95% CI 1.21-4.11, p = 0.010) and lower miss rates (1.20 vs 37.35%; OR 0.05, 95% CI 0.01-0.20, p = 0.0001) compared to clinical examination. However, compared to fluoroscopy, MRD had a lower detection rate for rectoceles (61.84 vs 73.68%; OR 0.48 95% CI 0.30-0.76, p = 0.002) rectoanal intussusception (37.91 vs 57.14%; OR 0.32, 95% CI 0.16-0.66, p = 0.002) and perineal descent (52.29 vs 74.51%; OR 0.36, 95% CI 0.17-0.74, p = 0.006). Miss rates of MRD were also higher compared to fluoroscopy for rectoceles (15.96 vs 0%; OR 15.74, 95% CI 5.34-46.40, p < 0.00001), intussusception (36.11 vs 3.70%; OR 10.52, 95% CI 3.25-34.03, p = 0.0001) and perineal descent (32.11 vs 0.92%; OR 12.30, 95% CI 3.38-44.76, p = 0.0001). CONCLUSIONS: MRD has a role in the assessment of pelvic floor dysfunction. However, clinicians need to be mindful of the risk of underdiagnosis and consider the use of additional imaging.

Is robotic ventral mesh rectopexy better than laparoscopy in the treatment of rectal prolapse and obstructed defecation? A meta-analysis.

Ventral mesh rectopexy is an approach in the treatment of internal and external rectal prolapse and rectocele. Our aim was to assess whether robotic surgery confers any significant advantages over laparoscopy, and the associated complication rate. Two reviewers performed a literature search using MEDLINE and PubMed databases for studies comparing robotic versus laparoscopic surgery. Five prospective, non-randomised studies were identified and included. A total of 244 patients (101 robotic and 143 laparoscopic) were included in the analysis. Operative time was shorter with laparoscopic surgery, mean weighted difference 27.94 [confidence interval (CI) 19.30-36.57; p < 0.00001]. The conversion rate was not significantly different between groups. There was a trend towards a reduction in length of inpatient stay and early post-operative complications in the robotic group; however, these did not reach statistical significance. Recurrence rates were similar between groups (odds ratio 0.91, CI 0.32-2.63; p = 0.87). Functional results were comparable between groups. Early studies show that robotic ventral rectopexy is a safe option compared to the laparoscopic approach, with overall comparable results. There appeared to be a trend towards a reduction in length of inpatient stay and post-operative complications. These perceived benefits may offset the longer operative times and outlay costs. Larger randomised controlled trials are needed to further evaluate clinical value and cost-effectiveness.

A systematic review of sacral nerve stimulation for low anterior resection syndrome.

AIM: The efficacy of sacral nerve stimulation (SNS) in low anterior resection syndrome (LARS) is largely undocumented. A review of the literature was carried out to study this question. METHOD: Pubmed, Medline and Cochrane databases were searched for relevant articles up to August 2014. Studies were included if they evaluated the use of SNS following rectal resection and assessed at least one of the following end-points: bowel function, quality of life and ano-neorectal physiology. No restrictions on language or study size were made. RESULTS: Seven papers were identified including one case report and six prospective case series. These included 43 patients with a median follow-up of 15 months. After peripheral nerve evaluation definitive implantation was carried out in 34 (79.1%) patients. Overall, 32 (94.1%) of the 34 patients experienced improvement of symptoms which, based on intention to treat, was 32/43 (74.4%). CONCLUSION: The review suggests that SNS for faecal incontinence in LARS has success rates comparable to its use for other forms of faecal incontinence.

Gastric tube necrosis following minimally invasive oesophagectomy is a learning curve issue.

INTRODUCTION: Gastric tube necrosis following oesophagectomy is thought to have an increased association with a minimally invasive technique. Some suggest gastric ischaemic preconditioning may reduce ischaemic complications. We discuss our series of 155 consecutive minimally invasive oesophagectomies (MIOs), including a number of cases of gastric tube ischaemia, of which 4 (2.6%) developed conduit necrosis. METHODS: Data were collected prospectively of MIOs carried out by a single surgeon between 2005 and 2011. Cases of gastric tube necrosis were identified. RESULTS: Overall, 155 patients were identified. The inpatient mortality rate was 2.6%. Gastric tube necrosis occurred in four patients (2.6%). An ultrasonic dissector injury to the gastroepiploic arcade had occurred in two cases. In another case, the gastric tube was strangulated in the hiatus. In the remaining case, no clear mechanical cause was identified. All 4 cases occurred within the first 73 cases. The gastric tube necrosis rate of the first 50 cases versus cases 51-155 was 4% and 2% respectively (p=0.5948). The anastomotic leak rate in these two cohorts was 18% and 7% respectively (p=0.0457). There was a significant reduction in overall gastric tube complications from 22% to 10% following the learning curve of the initial 50 cases (p=0.0447). CONCLUSIONS: In our series, gastric tube necrosis appears to be a learning curve issue. Prophylactic measures such as ischaemic preconditioning become less relevant as the operating surgeon's experience increases. Instead, meticulous attention to preserving the gastroepiploic arcade, avoidance of tension in the tube and careful positioning of the gastric conduit through an adequately sized hiatus are key factors.

Signalling cascades in mechanotransduction: cell-matrix interactions and mechanical loading.

Mechanical loading of articular cartilage stimulates the metabolism of resident chondrocytes and induces the synthesis of molecules to maintain the integrity of the cartilage. Mechanical signals modulate biochemical activity and changes in cell behavior through mechanotransduction. Compression of cartilage results in complex changes within the tissue including matrix and cell deformation, hydrostatic and osmotic pressure, fluid flow, altered matrix water content, ion concentration and fixed charge density. These changes are detected by mechanoreceptors on the cell surface, which include mechanosensitive ion channels and integrins that on activation initiate intracellular signalling cascades leading to tissue remodelling. Excessive mechanical loading also influences chondrocyte metabolism but unlike physiological stimulation leads to a quantitative imbalance between anabolic and catabolic activity resulting in depletion of matrix components. In this article we focus on the role of mechanical signalling in the maintenance of articular cartilage, and discuss how alterations in normal signalling can lead to pathology.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet.

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR(betageo/+) mice were generated from embryonic stem (ES) cells with a gene trap integration of a beta-galactosidase-neomycin phosphotransferase (betageo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GR(betageo/+) mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin-aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GR(betageo/+) mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GR(betageo/+) mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.

NMDA receptor expression and activity in osteoarthritic human articular chondrocytes.

OBJECTIVE: Classical neuronal signalling molecules such as substance P and glutamate have been identified in cartilage and have roles in regulation of chondrocyte function. This study looks at expression and activity of the ionotropic glutamate NMDA (N-methyl-D-aspartic acid) receptor (NMDAR) in human osteoarthritic (OA) chondrocytes. METHOD: Chondrocytes were obtained from human knee joint arthroplasty specimens. NMDAR subunits and PSD-95 (postsynaptic density protein 95) expression were analysed by reverse transcription-polymerase chain reaction and Western blotting. Activity of NMDAR was assayed by radioactive calcium(45) uptake and changes in membrane potential in the presence and absence of NMDA and NMDAR antagonists and blockade of cell membrane ion channels. RESULTS: NMDAR 1, 2A, 2B and PSD-95 were detected in human OA chondrocytes whereas NR2B was absent from normal chondrocytes. NMDA induced calcium flux into OA chondrocytes and cell membrane depolarisation. These responses were blocked by NMDAR antagonists, removal of extracellular calcium, inhibition of nNOS (neuronal nitric oxide synthase) activity and uncoupling of NMDAR from PSD-95. Blockade of sodium channels by tetrodotoxin resulted in NMDA-induced membrane hyperpolarisation which was, in turn inhibited by apamin, a blocker of SK channels. NMDA-induced changes in cell membrane potential were not affected by l-type and stretch activated calcium channel inhibitors. CONCLUSIONS: Human OA and normal articular chondrocytes differ in the expression of NMDAR subunits. In OA chondrocytes NMDAR signalling requires extracellular calcium, association with PSD-95, and nNOS activity. Downstream signalling results in activation of tetrodotoxin sensitive sodium channels and SK channels, a response that differs from that of normal chondrocytes suggesting altered activity of NMDAR in OA.

Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney.

Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits (alpha, beta and gamma), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 microg/kg per day), dexamethasone (100 microg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaCalpha mRNA exceeded beta or gamma by approximately 1.75- to 2.8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in beta and gamma, and ENaCalpha decreased sharply ( approximately 50%) across the outer medulla. Expression of ENaCbeta and gamma (but not alpha) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaCbetagamma participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1.9- to 3.5-fold increase in ENaCalpha (particularly marked in outer medullary collecting duct), but changes for beta and gamma were minor and limited to the cortex. The results raise the possibility that medullary ENaCalpha upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role.

Auditing outcomes from a medicine for the elderly service.

Measurement of outcome and quality of health care is currently a subject of great interest, as clinicians aim to improve the service they provide to patients, and purchasers try to allocate resources wisely. Measurement of outcome and quality of health care is currently a subject of great interest, as clinicians aim to improve the service they provide to patients and purchasers try to allocate resources wisely. Details of outcomes from a Medicine for the Elderly service are presented and their relevance discussed.

An outbreak of fatal nosocomial infections due to group A streptococcus on a medical ward.

Group A streptococcus is an uncommon but important cause of nosocomial infections. Outbreaks of infection most often have occurred in surgical or obstetrical patients. We describe an outbreak of severe group A streptococcal infections that occurred on a medical unit of a community hospital. Within an 8-day period, three patients developed fatal nosocomial skin and soft-tissue infection due to group A streptococcus. Three nurses who had provided care to one or more of these patients subsequently developed streptococcal pharyngitis, and three other nurses were treated with antibiotics for pharyngitis (cultures not obtained). Patient isolates were serotype M-nontypeable, T-11, opacity factor-positive, and shared identical DNA profiles when typed by pulsed-field gel electrophoresis; staff isolates were not available for typing. To prevent further spread of infection, the ward was closed to new admissions, and symptomatic staff were treated with antibiotics and relieved of patient-care duties. This outbreak demonstrates the ability of group A streptococcus to spread rapidly in a hospital setting and to cause severe life threatening disease in hospitalized patients.

Effects of regular salmeterol on lung function and exercise capacity in patients with chronic obstructive airways disease.

BACKGROUND: The aim of this study was to evaluate the effects of single and chronic dosing with salmeterol on exercise capacity and lung function in patients with chronic obstructive pulmonary disease. METHODS: Twenty nine patients of mean (SE) age 64 (1.5) years, forced expiratory volume in one second (FEV1) 42(3)% of predicted, and 5-15% reversibility to salbutamol 200 micrograms were randomised to receive four weeks treatment with salmeterol 50 micrograms twice daily or placebo in a double blind crossover fashion with a one week washout period in between. Measurements of spirometric parameters, static lung volumes, and exercise capacity were made one and six hours after a single dose, and six hours after the final dose of salmeterol or placebo. RESULTS: Salmeterol produced a small increase in FEV1 at one and six hours after a single dose, and this was maintained after chronic dosing (mean difference and 95% CI versus placebo): single dosing at one hour 0.07 (95% CI 0.02 to 0.11) 1, single dosing at six hours 0.16 (95% CI 0.09 to 0.22) 1, chronic dosing at six hours 0.11 (95% CI 0.03 to 0.19) 1. The increase in forced vital capacity (FVC) was greater with salmeterol than with placebo six hours after single but not chronic dosing: single dosing at six hours 0.17 (95% CI 0.04 to 0.29) 1, chronic dosing at six hours 0.02 (95% CI -0.18 to 0.22) 1. Slow vital capacity was increased after treatment with salmeterol compared with placebo one and six hours after single but not after chronic dosing. There were no significant differences in static lung volumes or exercise capacity after single or chronic dosing with salmeterol compared with placebo. Patients reported a significantly lower Borg score for perceived exertion following the six minute walk after chronic treatment with salmeterol compared with placebo. CONCLUSIONS: Salmeterol produced a small improvement in spirometric values compared with placebo consistent with the degree of reversibility originally shown by the subjects to salbutamol 200 micrograms. This was not associated with improvements in static lung volumes or exercise capacity, but there was some symptomatic benefit in that patients were able to walk the same distance in six minutes with less perceived exertion.

Critical pathways as an effective tool to reduce cardiac transplantation hospitalization and charges.

A critical pathway is a component of managed care focusing on outcome-oriented, cost-effective care. This retrospective review of 74 cardiac transplants in 72 patients evaluated the influence of critical pathways on clinical management, length of hospitalization, and hospital charges. Transplant patients were divided into group 1 (n = 51), which received standard primary nursing care, and group 2 (n = 23), which received nursing case management using a critical pathway. The number of intensive care unit days for group 2 was significantly smaller than for group 1, as were duration of hospitalization and hospital charges. The critical pathway provided for systematic delivery of care and decreased length of hospitalization and charges without compromising safety or quality.

Incomplete arrest in the outer membrane sorts NADH-cytochrome b5 reductase to two different submitochondrial compartments.

The S. cerevisiae gene MCR1 encodes two mitochondrial isoforms of NADH-cytochrome b5 reductase. The primary translation product has an amino-terminal matrix-targeting signal, followed by a stretch of 21 uncharged amino acids. This precursor protein is inserted into the outer membrane, but only about one-third of the molecules become firmly anchored to the outer face of that membrane. The remaining molecules pass through the outer membrane into the inner membrane, are cleaved by inner membrane protease 1, and are released into the intermembrane space. Incomplete translocation arrest in the outer membrane is a novel mechanism by which the product of a single gene is sorted into different compartments of the same organelle.

Comparison of salmeterol with placebo in mild asthma: effect on peripheral blood phagocyte function and cytokine levels.

beta 2-Adrenergic agonists are widely prescribed for the symptomatic relief of asthma, but are not thought to alter the underlying pathogenesis. However, it has been suggested that salmeterol, a new beta-agonist with prolonged bronchodilatory action, may have anti-inflammatory properties. A double-blind crossover study of 4 weeks of inhaled salmeterol versus placebo was performed using a chemiluminescence assay to measure peripheral phagocyte function before and after each treatment period. Circulating cytokines [interleukin-1 beta (IL1 beta), IL4, IL6, IL2 receptor (IL2R)] were also measured. Although salmeterol caused a significant improvement in spirometry, there was no apparent modulation of phagocyte or cytokine activity. No evidence was obtained to support a clinically significant anti-inflammatory action of salmeterol.

Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.

The purpose of the present study was to assess the degree of protection of inhaled salmeterol against exercise-induced bronchoconstriction (EIB) after chronic compared with single dosing in patients with asthma. Twelve patients with exercise-induced asthma took part in a randomized double-blind crossover study to compare the duration of action of inhaled salmeterol 50 micrograms twice daily for 4 weeks with that of placebo. A standardized exercise test was performed at 6 h and 12 h after dosing on the first and last day of each treatment period. Salmeterol produced significant protection against EIB at 6 and 12 h after the first dose in comparison with placebo, whereas there was no significant attenuation of EIB after 4 weeks of chronic treatment with salmeterol. The percentage fall in FEV1 after exercise challenge at 6 h was (first dose): placebo 34.8 +/- 4.9% vs. salmeterol 11.9 +/- 2.8% (P < 0.05); (4 weeks): placebo 32.9 +/- 5.3% vs. salmeterol 24.0 +/- 4.4% (NS). These results suggest that tachyphylaxis may develop to the functional antagonism of salmeterol against EIB.

Functional cooperation of mitochondrial protein import receptors in yeast.

We have identified a 20 kDa yeast mitochondrial outer membrane protein (termed MAS20) which appears to function as a protein import receptor. We cloned, sequenced and physically mapped the MAS20 gene and found that the protein is homologous to the MOM19 import receptor from Neurospora crassa. MAS20 and MOM19 contain the sequence motif F-X-K-A-L-X-V/L, which is repeated several times with minor variations in the MAS70/MOM72 receptors. To determine how MAS20 functions together with the previously identified yeast receptor MAS70, we constructed yeast mutants lacking either one or both of the receptors. Deletion of either receptor alone had little or no effect on fermentative growth and only partially inhibited mitochondrial protein import in vivo. Deletion of both receptors was lethal. Deleting only MAS70 did not affect respiration; deleting only MAS20 caused loss of respiration, but respiration could be restored by overexpressing MAS70. Import of the F1-ATPase beta-subunit into isolated mitochondria was only partly inhibited by IgGs against either MAS20 or MAS70, but both IgGs inhibited import completely. We conclude that the two receptors have overlapping specificities for mitochondrial precursor proteins and that neither receptor is by itself essential.