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.

The tyrosine phosphatase STEP: implications in schizophrenia and the molecular mechanism underlying antipsychotic medications.

Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is required for synaptic plasticity. Disruptions in glutamatergic signaling are proposed to contribute to the behavioral and cognitive deficits observed in schizophrenia (SZ). One possible source of compromised glutamatergic function in SZ is decreased surface expression of GluN2B-containing NMDARs. STEP(61) is a brain-enriched protein tyrosine phosphatase that dephosphorylates a regulatory tyrosine on GluN2B, thereby promoting its internalization. Here, we report that STEP(61) levels are significantly higher in the postmortem anterior cingulate cortex and dorsolateral prefrontal cortex of SZ patients, as well as in mice treated with the psychotomimetics MK-801 and phencyclidine (PCP). Accumulation of STEP(61) after MK-801 treatment is due to a disruption in the ubiquitin proteasome system that normally degrades STEP(61). STEP knockout mice are less sensitive to both the locomotor and cognitive effects of acute and chronic administration of PCP, supporting the functional relevance of increased STEP(61) levels in SZ. In addition, chronic treatment of mice with both typical and atypical antipsychotic medications results in a protein kinase A-mediated phosphorylation and inactivation of STEP(61) and, consequently, increased surface expression of GluN1/GluN2B receptors. Taken together, our findings suggest that STEP(61) accumulation may contribute to the pathophysiology of SZ. Moreover, we show a mechanistic link between neuroleptic treatment, STEP(61) inactivation and increased surface expression of NMDARs, consistent with the glutamate hypothesis of SZ.

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.

Urgent cholecystectomy for acute cholecystitis in a district general hospital - is it feasible?

INTRODUCTION: Laparoscopic cholecystectomy has become the gold standard for treatment of symptomatic gall stone disease. However, its place remains controversial in the management of acute cholecystitis due to a high reported incidence of bile leaks and conversion rate. Tertiary referral centres have reported good results. We present a series of cases after the introduction of an urgent cholecystectomy pathway in a district general hospital. PATIENTS AND METHODS: A practice of urgent cholecystectomy for acute cholecystitis was introduced by three consultant general surgeons. All prospective patients having an urgent laparoscopic cholecystectomy for acute cholecystitis, over an 8-month period were entered into a database. A dedicated ultrasound service was instituted to provide prompt diagnosis in these patients. Their demographic details, operative findings, laboratory results were recorded in a prospective database. Timing of ERCP, postoperative complications and conversion rate and hospital stay were also noted. RESULTS: There were 64 patients in the study with a median age of 51 years (range, 21-84 years). There were 21 males and 43 females. All patients underwent laparoscopic cholecystectomy during the index admission. Eleven patients had pre-operative ERCP and 12 patients had on-table cholangiogram. There were no conversions. Postoperative ERCP was required in six patients. The median time interval between admission and operation was 3 days (range, 2-7 days). There were two bile leaks but no common bile duct injury. There were two cases of superficial wound infection. One patient required re-operation for small bowel obstruction secondary to a port site hernia. CONCLUSIONS: Urgent laparoscopic cholecystectomy for acute cholecystitis is a feasible treatment option in a district general hospital. A safe practice can be ensured by adherence to a care pathway and a multidisciplinary, consultant-delivered service. Urgent cholecystectomy service can be provided safely in a district general hospital with outcomes comparable to previously published literature.

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.

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.

Arteriovenous fistulae complicating orthopaedic procedures.

Arterial injuries in general and arteriovenous fistulae in particular are uncommon complications of orthopaedic procedures. We report the case of a 75 year old patient who suffered an arteriovenous fistula following bone graft insertion for an un-united tibial fracture. Aetiology diagnosis and management of these potentially serious injuries are reviewed.

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.

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.

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.

Cystic carcinoma of the breast: a trap for the unwary.

Cystic breast masses are a common presentation to breast clinics. While the majority of cysts can be managed by simple aspiration, a small proportion are malignant. Histology records for a 10-year period have been examined to identify patients with cystic breast carcinomas. In all, 31 patients were identified. Of these, 18 had cystic degeneration of high-grade tumours, while 13 had intracystic papillary carcinoma. Both of these tumour types were diagnosed by a combination of cyst fluid cytology and breast imaging. The prognosis of high-grade tumours was poor, while that of intracystic papillary carcinomas was excellent. After cyst aspiration, bloodstained fluid should be sent for cytology and breast imaging arranged in all patients. Patients in whom a cyst refills within 2 week of aspiration require a careful re-evaluation. Cysts in postmenopausal women should be viewed with suspicion. Excision should be performed in patients with positive cytology or imaging.

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.

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.

Arteriovenous fistula complicating operative treatment of an ununited tibial fracture.

We report the case of a traumatic arteriovenous fistula of the peroneal vessels following a bone graft operation for an un-united tibial fracture. The fistula was recognised as a result of a bruit at the site of the fracture. The fistula was repaired and the fracture subsequently united.

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.

Randomized comparison of fine-needle aspiration cytology and Biopty-Cut needle biopsy after unsatisfactory initial cytology of discrete breast lesions.

In a minority of patients with a discrete breast lump the initial cytological assessment is either unsatisfactory or at variance with the results of other methods of diagnosis. A randomized comparison of repeat cytology and needle-core biopsy provided clinically useful information in 14 of 31 patients receiving repeat cytology and in 26 of 29 randomized to core biopsy. Nineteen patients had carcinoma: ten who received repeat cytology, which indicated malignancy in only three (diagnostic of malignancy in one, suspicious in two), while all nine patients who underwent core biopsy had a correct diagnosis (only suspicious of malignancy in one). The sensitivity for the definitive diagnosis of carcinoma on repeat cytology and core biopsy was 10 and 89 per cent respectively. Patients with a discrete breast lump and unclear cytology results require needle-core biopsy. This has more diagnostic value than repeat cytology.