Inhibition of STEP61 ameliorates deficits in mouse and hiPSC-based schizophrenia models.

The brain-specific tyrosine phosphatase, STEP (STriatal-Enriched protein tyrosine Phosphatase) is an important regulator of synaptic function. STEP normally opposes synaptic strengthening by increasing N-methyl D-aspartate glutamate receptor (NMDAR) internalization through dephosphorylation of GluN2B and inactivation of the kinases extracellular signal-regulated kinase 1/2 and Fyn. Here we show that STEP61 is elevated in the cortex in the Nrg1+/- knockout mouse model of schizophrenia (SZ). Genetic reduction or pharmacological inhibition of STEP prevents the loss of NMDARs from synaptic membranes and reverses behavioral deficits in Nrg1+/- mice. STEP61 protein is also increased in cortical lysates from the central nervous system-specific ErbB2/4 mouse model of SZ, as well as in human induced pluripotent stem cell (hiPSC)-derived forebrain neurons and Ngn2-induced excitatory neurons, from two independent SZ patient cohorts. In these selected SZ models, increased STEP61 protein levels likely reflect reduced ubiquitination and degradation. These convergent findings from mouse and hiPSC SZ models provide evidence for STEP61 dysfunction in SZ.

Single hospital visit elective day-case laparoscopic cholecystectomy without prior outpatient attendance.

INTRODUCTION: Eighty percent of all UK elective laparoscopic cholecystectomies (LC) are performed as day-case procedures, but the pre-operative patient pathway has received little attention. In response to local patient feedback, we aimed to introduce a single hospital visit pathway for day-case LC. METHODS: A single hospital visit pathway for elective LC was piloted alongside standard services. Following telephone consultation, a pack containing procedure information, knowledge questionnaire and consent form were sent. Patients were not excluded on age, BMI or co-morbidity criteria, but recent ultrasonography and liver function tests were required. Patients were operated without attending any clinic or pre-operative service. There was no restriction on surgical or anaesthetic technique. Early surgeon-led telephone follow-up was made post-operatively and patient satisfaction assessed at 3 months. RESULTS: One hundred and sixty-six patients were referred with 92% transferred to day-case waiting lists following telephone consultation. One hundred and six patients underwent LC without previously visiting the hospital with 85% discharged the same day. Nine percent required post-operative primary care review primarily for wound reviews. Median patient-reported time to normal activities was 4 weeks (range 1-12). Ninety-nine percent reported being satisfied with the single-stop pathway. CONCLUSIONS: Single hospital visit LC is feasible, safe and acceptable for primary care referral patients with symptomatic gallstone disease without evidence of common bile duct or LFT abnormalities.

Single hospital visit day case laparoscopic hernia repair without prior outpatient consultation is safe and acceptable to patients.

BACKGROUND: For some common conditions, pre-operative clinic visits are often of little value to the patient or surgeon with transfer to the waiting list being predictable. In response to local patient feedback, we introduced a single hospital visit laparoscopic hernia surgery pathway with focus on informed consent, patient-reported outcomes and post-operative interaction with primary care services. METHODS: A single hospital visit service for elective hernia repairs was created. Patients were not excluded on age, BMI or co-morbidity. Following referral, patients were telephoned by a surgeon. If considered appropriate, a symptom assessment tool, procedure information and consent form were sent. All patients were operated without attending clinic or pre-operative assessment. Surgeon-led telephone follow-up was made at either 2 or 7 days post-operatively and patient satisfaction assessed at 3 months. RESULTS: A total of 517 patients were referred for single-stop surgery between 2012 and 2015. Median age was 58 (range 20-92), 91 % were male, and mean BMI was 25.6 (17.4-52.0). No patient refused the single-visit pathway. Single-stop patients had higher knowledge questionnaire scores (mean 16 vs. 10, p = 0.01) than patients who had attended clinic. Nine (1.7 %) were requested to attend clinic to confirm diagnosis, and three (0.8 %) were cancelled by their surgeon on the operative day. A total of 393 hernia repairs (331 TEP, 63 open) were performed under general anaesthetic. 92 % were discharged on day zero. Telephone follow-up day two rather than seven decreased attendance to primary care services (25 % vs. 57 %, p = 0.001). At 3 months, 95 % were satisfied and symptom scores were reduced (median 5-0, p < 0.0001). CONCLUSION: Single-visit surgery appears to extend the patient benefits of laparoscopy by reducing hospital visits without compromising safety. Single hospital visit hernia surgery for unselected primary care referrals is possible and acceptable to patients.

Clinical evaluation of a thin absorbent skin adhesive dressing for wound management.

OBJECTIVE: This article assesses the use of BeneHold Thin Absorbent Skin Adhesive (TASA) wound dressings in a large UK primary care organisation. These wound dressings are thin (0.12 mm), breathable, transparent, and are able to absorb and retain wound exudate. This non-comparative evaluation was undertaken to explore the clinical advantages this differentiated combination of physical properties offered. METHOD: The dressings are CE-marked medical devices, and were used on patients with acute and chronic wounds that were assessed and classified as light to moderately exuding. Clinical performance was evaluated with respect to the dressing's ease of use (application and removal, conformability, mould-ability, rolling and edge-lift), debridement, protection of the peri-wound, wear time, fluid handling, wound bed residue, visibility of the wound, and clinical acceptability. The evaluating clinicians used an agreed audit tool to collect data from case reports to document the progression of wounds of various aetiologies, including chronic and acute, for a maximum period of four weeks. Qualitative feedback on dressing performance was also collected at the evaluation's end, both from the clinicians' and patients' perspectives Results: Some 15 patients were assessed. The wear time was up to seven days in many cases, and on average was 3.9 days longer than their previous dressings. Clinicians perceived that wounds progressed toward healing in all but two cases, where the wounds remained unchanged. Out of five cases where wounds presented with necrosis, all underwent significant autolytic debridement underneath the new dressings. Transparency was a noted benefit from both the clinicians' and patients' perspectives because it enabled continuous monitoring of the full wound bed and peri-wound skin without the need to disrupt the dressing. CONCLUSION: The dressing was well-received by both clinicians and patients in all fifteen cases. The thin absorbent skin adhesive dressing was found to be a promising new technology that could offer significant advantages to improve the quality, cost, and convenience of wound care. Further work is underway to validate these findings in larger and more homogeneous patient groups.

Feasibility of a consultant-led, trainee-delivered urgent laparoscopic cholecystectomy service.

BACKGROUND: Urgent laparoscopic cholecystectomy has become the gold standard for the treatment of acute gallstone disease. Since 2005 we have implemented a consultant-delivered urgent surgical service for this condition. In an attempt to increase the capacity of this service, we have recently introduced a new policy of also allowing selected trainee surgeons to perform urgent laparoscopic cholecystectomy with consultant assistance available on request. The purpose of this study was to audit our initial experience of this new service. METHODS: Patients with acute gallstone disease had their surgery performed by a consultant or a trainee operating independently with consultant assistance available only on request. Allocation was based purely on surgeon availability. The clinical outcomes of 50 consecutive trainee and 50 consecutive consultant cases were compared and an attempt made to identify pre-operative predictors of technically-demanding trainee cases requiring consultant intervention. RESULTS: The mean operating time of trainees was significantly longer than consultants (80 +/- 5 mins vs 55 +/- 4 mins, p <0.001) although the conversion rates for trainees (4%) and consultants (2%) were similar. There were no significant differences between the groups with respect to postoperative morbidity. Of the 50 trainee cases, consultant intervention was required in 12 (24%) cases. There were no statistically significant pre-operative predictors of requirement for consultant assistance. CONCLUSIONS: Urgent laparoscopic cholecystectomy may be performed independently by appropriately skilled trainees within a consultant-led service. Although consultant intervention is often not required, the requirement for consultant assistance cannot be easily predicted based on pre-operative data.

Identification and partial characterization of an elastolytic protease in the amphibian pathogen Batrachochytrium dendrobatidis.

Batrachochytrium dendrobatidis (Bd) is a fungus that causes chytridiomycosis, a disease that has been implicated as a cause of amphibian population declines worldwide. Infected animals experience hyperkeratosis and sloughing of the epidermis due to penetration of the keratinized tissues by the fungus. These symptoms have led us to postulate that Bd produces proteases that play a role in the infection process. Here, we show that Bd is capable of degrading elastin in vitro, a protein found in the extracellular matrix of the host animal. Elastolytic enzyme activity was partially purified using ion exchange chromatography and size-exclusion filtration from cultures grown in inducing media. The elastolytic activity of the purified fraction had a pH optimum of 8, was strongly inhibited by EDTA and phenylmethylsulfonyl fluoride (PMSF), and was partially inhibited by an elastase-specific inhibitor. This activity was also enhanced by the presence of Mg2+ and Ca2+ but not Zn2+. An antiserum directed against Aspergillus fumigatus serine protease (Alp) was found to react with a polypeptide of approximately 110 kDa from the purified material. Using immunofluorescence, this antiserum was also observed to react with zoospores and sporangia grown on toad skin. These observations suggest that Bd may produce proteases similar to those produced by other pathogenic fungi that are capable of degrading proteins found in the extracellular matrix. The proteolytic activity exhibited in vitro might aid the organism in its ability to colonize and destroy the epidermis of its amphibian host.

A case of nodular fascitis of the breast and review of the literature.

Nodular fascitis is a benign condition commonly affecting the limbs. In the breast, however, it may mimic Breast Cancer clinically and radiologically. We report a case of nodular fascitis of the breast and its conservative management. With the use of cytology, core biopsy and imaging we were able to confidently diagnose nodular fascitis and, therefore, avoid surgical intervention. Recent literature is reviewed demonstrating the benign nature of this disease.

Tissue procoagulant activity may be important in sustaining metastatic tumour growth.

There is strong evidence for an association between the haemostatic system and malignancy. Thus, cancer may adversely affect the host coagulation system while the haemostatic system may play a role in the development of both primary and metastatic tumours. Metastatic growth is not dependent simply on haemodynamic factors, and properties of both the tumour cell and host organ are important determinants of the site of metastatic growth. Previous studies have demonstrated that some organs are preferred sites for metastasis while others are less preferred or resistant. We have measured the procoagulant activity (PCA) of normal rat and human tissues and correlated the results with the previously reported ability of these organs to support metastatic tumour growth. In addition, we determined changes in PCA in rat tissues during oral anticoagulant therapy, and following colonic anastomosis and partial hepatectomy, procedures which are known to affect experimental metastasis. In both rat and human studies, organs which are preferred sites for metastasis had significantly higher PCA than non-preferred organs (P less than 0.001). The PCA of adrenal, lung and colon was significantly reduced by administration of warfarin (P less than 0.001). PCA was significantly (P less than 0.001) increased in both colonic anastomoses and regenerating liver and followed a time course similar to that of the enhanced tumour growth usually seen in these situations. Although the exact source of the procoagulant activity remains to be determined, the results suggest that there is a broad correlation between tissue PCA and the ability of a tissue to support metastatic tumour growth.

Facilitation by partial hepatectomy of tumor growth within the rat liver following intraportal injection of syngeneic tumor cells.

The effects of both mechanical trauma and regeneration on the growth of intraportally injected tumor in the rat liver were investigated using two-thirds partial hepatectomy (PH). Tumor grew at the excision scar when PH was performed less than 2 days before tumor injection (34/34 animals). However, when the PH was performed 4-7 days before injection, tumor developed within the regenerating lobe, but not at the scar (50/51). Injecting the same cell dose into rats with intact livers caused few tumors to develop in 12/30 animals. Intraportally injected 51Cr-labelled tumor cells distributed uniformly in the liver irrespective of the time after PH. Patterns of tumor take seen at different times after PH were not due to selective trapping of the injected cells. Liver extracts showed that epidermal growth factor-like activity was unaltered by PH, while heparin-binding growth factor activity peaked at 2 days post-PH, before the incidence of tumor growth in the parenchyma increased. We observed two peaks of DNA synthesis at days 1 and 4 post-PH by pulse labeling with [125I]deoxyuridine and bromodeoxyuridine. Bromodeoxyuridine immunohistochemistry showed the first peak to be confined to hepatocytes. The second peak involved non-hepatocytes and coincided with the beginning of enhanced tumor take in the regenerating lobe.

Liver resection for colorectal liver metastases.

The management of patients with colorectal liver metastases is still controversial. Recent evidence suggests benefit for resection of localized metastases within a single lobe of the liver. A series of 49 patients undergoing liver resection for localized liver metastases is presented. Resection involved right hepatectomy (23), left hepatectomy (8) and segmental excision (18). The median age was 62 (range 40-77). Patients have been followed for a period of up to seven years. The overall median survival was 24 months. The actuarial 3-year survival was 57.9%. There was no significant correlation of survival with the degree of differentiation or Dukes staging of the primary tumour. This series adds further weight to the evidence supporting resection in selected patients with colorectal liver metastases.

Patterns of clinical metastasis in breast cancer: an analysis of 100 patients.

Many patients diagnosed with breast cancer will develop metastases and these have diverse presentations. We have reviewed 100 consecutive patients who have died with metastatic breast cancer, to determine the frequency, sites and mode of presentation of recurrent disease. The commonest site of failure was loco-regional (n = 61), this usually presented with a mass, but a minority of patients also complained of pain. Bone metastases developed in 60 patients and produced bone pain, pathological fracture (n = 6) or cord compression (n = 5). Pulmonary metastases producing shortness of breath were diagnosed in 34 patients and were asymptomatic in a further 10. Intra-abdominal metastases were found at some time in 23 patients, most commonly in the liver (n = 20) and the majority complained of epigastric pain (n = 17). Brain metastases occurred in 23 patients and produced a wide range of symptoms including those of a space-occupying lesion (n = 10), cranial nerve palsy (n = 7), diabetes insipidus (n = 3), focal limb weakness (n = 2) and meningitis (n = 1). Three patients had choroid metastases producing reduced visual acuity. Recurrent breast carcinoma can present in a variety of ways, therefore any new symptom or sign should be considered to represent recurrence until proved otherwise.

Which surgeons avoid a stoma in treating left-sided colonic obstruction? Results of a postal questionnaire.

There is now good evidence to indicate that the majority of patients with large bowel obstruction can be safely managed by resection and immediate anastomosis, but have surgeons embraced this policy? A postal survey has been performed to ascertain the opinions of consultant general surgeons within the Wessex region regarding the management of left-sided large bowel obstruction. Of 47 questionnaires sent, 42 replies could be analysed. In patients of good anaesthetic risk, 90% would perform resection with primary anastomosis if the lesion was at the splenic flexure, and 62% would adopt this policy for a rectosigmoid obstruction. In patients of higher anaesthetic risk these figures fell to 71% and 31%, respectively. Surgeons with a gastrointestinal interest were more likely to recommend resection with primary anastomosis. However, this trend reached statistical significance only for splenic flexure and descending colon lesions in good-risk patients. Most surgeons would avoid a stoma in the presence of liver metastases, and only three would be more likely to create a stoma in this situation.

Resection of liver metastases from a colorectal carcinoma does not benefit the patient.

This paper presents arguments for and against the motion that 'Resection of liver metastases from colorectal carcinoma does not benefit the patient'. The case for this proposition is summarised as follows: survival after resection of small metastases is not markedly different from the natural history of similar tumours; patients with metastases apparently localised to one area of the liver are uncommon, and thorough investigation further reduces the proportion of such patients; the operative mortality of liver resection has a significant adverse effect on survival after resection, and may cancel out the benefits of surgery, and finally the alternative non-operative methods of treating these patients may offer similar benefits to resection. The counter argument is simple: for a patient with liver metastases the only hope of eradication of liver disease lies in surgical resection. If this can be achieved then the prognosis is as good as for a similar primary tumour without liver metastases.

Pyogenic hepatic abscess after pancreatic resection for chronic pancreatitis.

Seventeen patients underwent surgery for alcohol-induced chronic pancreatitis. Three patients later presented with pyogenic liver abscess. The time interval between surgery and presentation with hepatic abscess varied from 6 weeks to 3.5 years. All patients were diabetic, the presentation was insidious and all made an uneventful recovery, two with percutaneous drainage and one with antibiotics alone. The aetiology of this uncommon complication is discussed.

Prospective randomised trial of two devices for suprapubic catheterisation in general surgical patients.

Compared with urethral catheterisation, suprapubic catheterisation is associated with a reduced incidence of urinary infection and urethral stricture and it facilitates a controlled trial of micturition. A prospective comparison of two types of suprapubic catheter was performed in 70 patients, using a specially designed catheter mounted on a trocar for insertion (Suprapubic Ingram Trocar), and a disposable trocar and cannula (Add-a-Cath) and standard Foley catheter. A suprapubic catheter was inserted successfully in 63 patients. Overall there was a low incidence of urinary tract infection (4.3%) and the only significant catheter-related problem was suprapubic leakage of urine, which was self-limiting in all but one patient. Although there is little objective difference between the systems tested, we prefer the Add-a-Cath system for its simplicity and economy. This trial provides further support for the more frequent use of suprapubic catheters in general surgical practice.

Anorectal physiology measurements are of no value in clinical practice. True or false?

This article examines whether there is any clinical value in anorectal physiology measurements. The function of the human rectum is poorly understood and the factors which affect function of the anal sphincters are complex. Several laboratories have reported results of anorectal physiology measurements, but there is extensive variation between normal values in different laboratories. It is argued that anorectal physiology measurements fail to meet the criteria of a useful clinical test: 1. It is not widely available to clinicians; 2. It is not possible to establish a reproducible normal range; 3. Abnormal measurements do not correlate with disease entities or explain symptoms; 4. The results are often unhelpful in diagnosis and management; 5. Clinical outcome after intervention does not correlate with alteration in the measurements obtained. On the other hand it can be argued that anorectal physiology measurements do provide information that assists in the management of conditions such as constipation, anismus, Hirschsprung's disease, faecal incontinence and tenesmus. Management based on biofeedback modification of physiological responses requires these techniques as part of the biofeedback system. There is evidence that this may be appropriate in anismus and solitary rectal ulcer syndrome. However, the assessment of these difficult conditions and the interpretation of the results are probably at present best confined to specialist units.

Management of ductal carcinoma in situ of the breast.

The advent of mammographic breast screening has increased the detection of ductal carcinoma in situ (DCIS), which now accounts for 15-20% of all breast cancer. While symptomatic DCIS has been treated satisfactorily by mastectomy, this may be an overtreatment of smaller screen-detected lesions. Although local excision, with or without radiotherapy, is associated with a significant risk of local recurrence of DCIS or invasive cancer, salvage surgery is usually successful. The long-term breast-specific mortality rate of treatment by mastectomy and local excision are similar. Whereas mastectomy is still appropriate for women with lesions > 30 mm in diameter or centrally placed and for those women who demand the best possible disease-free survival, local surgery should otherwise be considered.

Extended lymph node dissection (D2 resection) should now be performed routinely in the curative surgical treatment of gastric carcinoma.

Gastric cancer has a dismal prognosis in the Western world. In contrast, in Japan where extended lymphadenectomy is the rule in curative gastric cancer surgery, the prognosis is much better. The arguments for and against the adoption of this procedure in the West are presented. This procedure is safe in the hands of experienced surgeons and by improving locoregional control, may improve survival. However, in the absence of controlled data supporting a survival advantage, the excess morbidity and mortality of this extended procedure in the West may not be justified.

Prospective study of outcome in women presenting with nipple discharge.

In this study, 56 women who presented to the breast clinic with nipple discharge have been reviewed. Patients were selected for surgery by a triple assessment of clinical examination, discharge cytology and breast imaging. Surgical intervention was required in 17 women. Significant pathology was found in 11 cases including five with carcinoma (in situ or invasive). Those women who did not have carcinoma detected at their initial presentation have been reviewed after a minimum of 5 years. None has gone on to develop breast cancer. We conclude that women with nipple discharge, but no positive findings on triple assessment, are not at an increased risk of the development of carcinoma. In addition, nipple discharge spontaneously resolves in 73% of women over a 5 year period.

Management of fibroadenoma of the breast.

Fibroadenoma is a common cause of discrete breast lumps in young women. There is agreement that fibroadenomas can be diagnosed preoperatively with a high degree of confidence and that some of the lesions thus diagnosed will resolve, possibly obviating the need for excision. There is, however, wide disagreement over the proportion of fibroadenomas that resolve spontaneously and therefore the benefit that accrues from an expectant policy. The aim of this study was to audit the management of fibroadenomas on one unit and clarify their natural history over a 5-year period. A cohort of 70 women with 87 fibroadenomas diagnosed using a triple assessment of clinical examination, cytology and imaging (sonomammography) have been followed for a minimum of 5 years. In all, 53 of the 'fibroadenomas' have been excised. In four cases the histology revealed benign disease other than fibroadenoma; there were no neoplasms. The sensitivity of cytology and sonomammography for the diagnosis of fibroadenoma were 84% and 98% respectively. Thirty-four fibroadenomas have not been excised. Of 25 fibroadenomas that have been reassessed after at least 5 years of follow-up, 13 (52%) have reduced in size, 4 (16%) are unchanged in size and 8 (32%) have grown. No patient has developed a carcinoma at the site of the presumed fibroadenoma. This study confirms that an expectant management policy of fibroadenomas has not resulted in misdiagnosis of carcinomas. Further, since a significant proportion of fibroadenomas remain static or reduce in size over a 5-year period many women can avoid excision.