Evoked responses to rhythmic visual stimulation vary across sources of intrinsic alpha activity in humans.

Rhythmic flickering visual stimulation produces steady-state visually evoked potentials (SSVEPs) in electroencephalogram (EEG) recordings. Based on electrode-level analyses, two dichotomous models of the underpinning mechanisms leading to SSVEP generation have been proposed: entrainment or superposition, i.e., phase-alignment or independence of endogenous brain oscillations from flicker-induced oscillations, respectively. Electrode-level analyses, however, represent an averaged view of underlying 'source-level' activity, at which variability in SSVEPs may lie, possibly suggesting the co-existence of multiple mechanisms. To probe this idea, we investigated the variability of SSVEPs derived from the sources underpinning scalp EEG responses during presentation of a flickering radial checkerboard. Flicker was presented between 6 and 12 Hz in 1 Hz steps, and at individual alpha frequency (IAF i.e., the dominant frequency of endogenous alpha oscillatory activity). We tested whether sources of endogenous alpha activity could be dissociated according to evoked responses to different flicker frequencies relative to IAF. Occipitoparietal sources were identified by temporal independent component analysis, maximal resting-state alpha power at IAF and source localisation. The pattern of SSVEPs to rhythmic flicker relative to IAF was estimated by correlation coefficients, describing the correlation between the peak-to-peak amplitude of the SSVEP and the absolute distance of the flicker frequency from IAF across flicker conditions. We observed extreme variability in correlation coefficients across sources, ranging from -0.84 to 0.93, with sources showing largely different coefficients co-existing within subjects. This result demonstrates variation in evoked responses to flicker across sources of endogenous alpha oscillatory activity. Data support the idea of multiple SSVEP mechanisms.

Prognostic value of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression in glioblastoma excluding nontumour cells from the analysis.

AIMS: It is important to predict response to treatment with temozolomide (TMZ) in glioblastoma (GBM) patients. Both MGMT protein expression and MGMT promoter methylation status have been reported to predict the response to TMZ. We investigated the prognostic value of quantified MGMT protein levels in tumour cells and the prognostic importance of combining information of MGMT protein level and MGMT promoter methylation status. METHODS: MGMT protein expression was quantified in tumour cells in 171 GBMs from the population-based Region of Southern Denmark (RSD)-cohort using a double immunofluorescence approach. Pyrosequencing was performed in 157 patients. For validation we used GBM-patients from a Nordic Study (NS) investigating the effect of radiotherapy and different TMZ schedules. RESULTS: When divided at the median, patients with low expression of MGMT protein (AF-low) had the best prognosis (HR = 1.5, P = 0.01). Similar results were observed in the subgroup of patients receiving the Stupp regimen (HR = 2.0, P = 0.001). In the NS-cohort a trend towards superior survival (HR = 1.6, P = 0.08) was seen in patients with AF-low. Including MGMT promoter methylation status, we found for both cohorts that patients with methylated MGMT promoter and AF-low had the best outcome; median OS 23.1 and 20.0 months, respectively. CONCLUSION: Our data indicate that MGMT protein expression in tumour cells has an independent prognostic significance. Exclusion of nontumour cells contributed to a more exact analysis of tumour-specific MGMT protein expression. This should be incorporated in future studies evaluating MGMT status before potential integration into clinical practice.

Manometry based randomised trial of endoscopic sphincterotomy for sphincter of Oddi dysfunction.

BACKGROUND: Endoscopic sphincterotomy for biliary-type pain after cholecystectomy remains controversial despite evidence of efficacy in some patients with a high sphincter of Oddi (SO) basal pressure (SO stenosis). AIM: To evaluate the effects of sphincterotomy in patients randomised on the basis of results from endoscopic biliary manometry. METHODS: Endoscopic biliary manometry was performed in 81 patients with biliary-type pain after cholecystectomy who had a dilated bile duct on retrograde cholangiography, transient increases in liver enzymes after episodes of pain, or positive responses to challenge with morphine/neostigmine. The manometric record was categorised as SO stenosis, SO dyskinesia, or normal, after which the patient was randomised in each category to sphincterotomy or to a sham procedure in a prospective double blind study. Symptoms were assessed at intervals of three months for 24 months by an independent observer, and the effects of sphincterotomy on sphincter function were monitored by repeat manometry after three and 24 months. RESULTS: In the SO stenosis group, symptoms improved in 11 of 13 patients treated by sphincterotomy and in five of 13 subjected to a sham procedure (p = 0.041). When manometric records were categorised as dyskinesia or normal, results from sphincterotomy and sham procedures did not differ. Complications were rare, but included mild pancreatitis in seven patients (14 episodes) and a collection in the right upper quadrant, presumably related to a minor perforation. At three months, the endoscopic incision was extended in 19 patients because of manometric evidence of incomplete division of the sphincter. CONCLUSION: In patients with presumed SO dysfunction, endoscopic sphincterotomy is helpful in those with manometric features of SO stenosis.

Hierarchies and cliques in the social networks of health care professionals: implications for the design of dissemination strategies.

Interest in how best to influence the behaviour of clinicians in the interests of both clinical and cost effectiveness has rekindled concern with the social networks of health care professionals. Ever since the seminal work of Coleman et al. [Coleman, J.S., Katz, E., Menzel, H., 1966. Medical Innovation: A Diffusion Study. Bobbs-Merrill, Indianapolis.], networks have been seen as important in the process by which clinicians adopt (or fail to adopt) new innovations in clinical practice. Yet very little is actually known about the social networks of clinicians in modern health care settings. This paper describes the professional social networks of two groups of health care professionals, clinical directors of medicine and directors of nursing, in hospitals in England. We focus on network density, centrality and centralisation because these characteristics have been linked to access to information, social influence and social control processes. The results show that directors of nursing are more central to their networks than clinical directors of medicine and that their networks are more hierarchical. Clinical directors of medicine tend to be embedded in much more densely connected networks which we describe as cliques. The hypotheses that the networks of directors of nursing are better adapted to gathering and disseminating information than clinical directors of medicine, but that the latter could be more potent instruments for changing, or resisting changes, in clinical behaviour, follow from a number of sociological theories. We conclude that professional socialisation and structural location are important determinants of social networks and that these factors could usefully be considered in the design of strategies to inform and influence clinicians.

Small bowel dysmotility in patients with postcholecystectomy sphincter of Oddi dysfunction.

Postcholecystectomy patients (N = 27) with severe recurrent biliary-like pain who had no evidence of organic disease were subdivided into those with and those without objective evidence of sphincter of Oddi dysfunction (SOD) based on two separate criteria: (1) clinical criteria-elevated liver function tests and/or amylase with pain, and/or a dilated bile duct, and/or delayed drainage at ERCP (N = 14, SOD classes I and II); and (2) abnormal biliary manometry (N = 19). Prolonged (24-48 hr) ambulant recording of duodenojejunal motor activity was performed in all patients and interdigestive small bowel motor activity compared between patient subgroups and a healthy control group. Phase II motor abnormality was more frequent in patients with, compared to those without, objective clinical criteria of SOD (7/14 vs 0/13, P = 0.003). Phase III abnormality also tended to be more frequent in these patients (7/14 vs 2/13, P = 0.06). In addition, both phase III (P = 0.03) and phase II (P = 0.03) motility index (MI) was higher in patients with sphincter dyskinesia compared to controls; phase II MI was also higher in patients with sphincter stenosis (P = 0.005). Disturbances of small bowel interdigestive motor activity are more prevalent in postcholecystectomy patients with, compared to those without, objective evidence of SOD, and especially in patients with SO dyskinesia. Postcholecystectomy SOD in some patients may thus represent a component of a more generalized intestinal motor disorder.

Discordance of pressure recordings from biliary and pancreatic duct segments in patients with suspected sphincter of Oddi dysfunction.

It remains controversial whether manometric parameters recorded from the pancreatic and biliary segment of the sphincter of Oddi (SO) differ. We therefore studied 48 consecutive patients (40 women, 43 +/- 11 years) with suspected SO dysfunction, in 33 of whom successful dual-duct SO manometry was obtained. Measures of concordance between the two duct segments were moderate for basal sphincter pressure (K = 0.31) and for contractile frequency (0.35), and were low for peak pressure (0.15) and for proportion of retrograde propagation (-0.19). There was also low concordance (-0.13) for the overall manometric diagnosis, and in 48% (CI 31-66%) of patients a conflicting diagnosis (normal/abnormal) was obtained from the two ducts. There was no evidence of a differential motor effect of CCK on either duct, nor were there significant differences in the rate of manometric abnormality according to the order of initial duct cannulation. These results indicate that, if technically feasible, dual-duct manometry of the sphincter of Oddi is required for diagnostic precision.

Abnormal sphincter of Oddi response to cholecystokinin in postcholecystectomy syndrome patients with irritable bowel syndrome. The irritable sphincter.

Standard biliary manometry, including cholecystokinin (CCK) provocation, was performed on 42 consecutive patients (36 F, 6 M, median age 45 years) with postcholecystectomy syndrome (PCS) who had no evidence of organic disease but who had objective clinical features suggesting sphincter of Oddi dysfunction (SOD) (classes I and II). Patients were subdivided into those with (N = 14) and without (N = 28) irritable bowel syndrome (IBS) using a validated symptom questionnaire based on the modified Rome criteria. Resting sphincter of Oddi (SO) motor parameters (basal pressure, contractile amplitude and frequency, and proportion of retrograde contractions), the presence of abnormal manometry, and the presence of an abnormal response to CCK were compared in the two groups. No significant differences in resting parameters of SO motor activity between patients with and without IBS were observed, and abnormal biliary manometry as a whole was not more prevalent in either group (8/13 and 18/27, respectively). An abnormal response to CCK (failure of complete inhibition of phasic contractions), however, was demonstrated in five of 12 patients with IBS compared with only one of 23 patients without IBS (P = 0.01). In patients with postcholecystectomy SOD, an abnormal response of the SO to CCK thus appears to be an important feature of the subset of patients with concomitant IBS.

Randomised trial of endoscopic stenting versus surgical bypass in malignant low bileduct obstruction.

The development of non-surgical techniques for the relief of malignant low bileduct obstruction has cast doubt on the best way of relieving jaundice, particularly in patients fit for surgery whose life expectancy is more than a few weeks. We did a randomised prospective controlled trial comparing endoscopic stent insertion and surgical biliary bypass in patients with malignant low bileduct obstruction. 204 patients were randomised (surgery 103, stent 101); 3 subsequently proved to have benign disease and were excluded, leaving 101 surgical and 100 stented patients for assessment. Technical success was achieved in 94 surgical and 95 stented patients, with functional biliary decompression obtained in 92 patients in both groups. In stented patients, there was a lower procedure-related mortality (3% vs 14%, p = 0.01), major complication rate (11% vs 29%, p = 0.02), and median total hospital stay (20 vs 26 days, p = 0.001). Recurrent jaundice occurred in 36 stented patients and 2 surgical patients. Late gastric outlet obstruction occurred in 17% of stented patients and 7% of the surgical group. Despite the early benefits of stenting there was no significant difference in overall survival between the two groups (median survival: surgical 26 weeks; stented 21 weeks; p = 0.065). Endoscopic stenting and surgery are effective palliative treatments with the former having fewer early treatment-related complications and the latter fewer late complications.

Flucloxacillin induced liver disease: histopathological findings at biopsy and autopsy.

The histological appearances of liver biopsies of 13 patients who developed cholestasis following courses of flucloxacillin are presented. In most of the cases jaundice and pruritus were protracted and in nearly all cases liver function tests are yet to return to normal after mean follow-up of 18 mths. One patient died after 7 mths of jaundice and another shows clinical evidence of secondary biliary cirrhosis. Biopsies typically showed hepatocellular and canalicular bile stasis with minimal or no hepatitis. Mild portal fibrosis and a patchy portal lymphocytic infiltrate were usually present. In 4 cases bile ducts were reduced in number and in 6 cases reduced in size. Bile duct epithelium showed degenerative changes but only occasional infiltration by inflammatory cells. Ductular proliferation was quite variable and in some cases--most noticeably the fatal case--was inconspicuous despite depletion of bile ducts. The appearances suggested damage not only of hepatocytes but also of bile ducts and proliferating ductules. This may explain the prolonged and occasionally irreversible hepatic disease associated with the use of flucloxacillin. Flucloxacillin should be included amongst the causes of vanishing bile duct syndrome.

Morphological changes and alterations in regional intrarenal blood flow induced by graded renal ischemia.

A model of renal ischemia was used to study morphological changes and alterations in intrarenal blood flow. Renal artery blood flow was reduced from 120 to 20 ml./minute (normal 172 +/- 14) for 3 weeks. Morphological changes were assessed histologically, and by electronmicroscopy. Intrarenal blood flow was determined using microspheres. Flow rates less than 80 ml./minute resulted in a progressive loss of renal volume with arterial thrombosis and renal infarction at 20 ml./minute. Histological changes included loss of glomerular volume, tubular dilatation (60 ml./minute), tubular cast formation (50 ml./minute) tubular atrophy, interstitial fibrosis, arteriolar thickening (40 ml./minute) and glomerular hyalinization (30 ml./minute). Electronmicroscopy changes at 60 ml./minute (loss of glomerular microvasculature, unfolding of glomerular vascular tuft, appearance of blind ending vessels) progressed to disruption of glomerular architecture noted at 30 ml./minute. Narrowing of medullary blood vessels (60 ml./minute) and neovascularisation (40 ml./minute) was observed. Progressive ischemia decreased medullary, inner cortical and outer cortical blood flow (5.9 to 2.1 ml./minute/gm.) p less than 0.01, with a compensatory increase to the opposite kidney.

Endoscopic therapy for bile duct stones in a geriatric population.

During the 5 year period to May 1988, 137 consecutive patients (age range, 65-102 years; median 84 years) with a diagnosis of choledocholithiasis, were referred to The Middlesex Hospital Geriatric Department. Endoscopic sphincterotomy was successful in 96.2% of cases and immediate biliary drainage was achieved in all but one of these patients. Stones were cleared endoscopically in 73.3% and surgically in 4.7% of cases. Long-term stenting was employed in 14.3% of patients. The 30 day mortality after endoscopic or surgical treatment was 4.7% (six deaths), although death was probably unrelated to therapy in half the cases. Deaths were due to procedural cardiorespiratory arrest (1), pancreatitis (1), pneumonia (2) and cerebrovascular accident (2). Endoscopic treatment is effective even in a high-risk geriatric population. After sphincterotomy patients with intact gall bladders should be managed expectantly.

A 10 year single centre experience of percutaneous and endoscopic extraction of bile duct stones with T tube in situ.

A non-randomised single centre study of 226 consecutive patients referred over 10 years with retained common bile duct stones and a T tube in situ or a cholecystostomy tube are reported. Percutaneous extraction was attempted in 204 and endoscopic extraction in 68 patients. Percutaneous clearance was achieved in 158 (77.5%) patients and endoscopic clearance in 52 (76.5%) patients. Six of 153 (3.9%) patients followed after percutaneous treatment suffered major complications (pancreatitis, cholangitis, or tract perforation). Three of 67 (44%) patients followed after endoscopic treatment suffered major complications (pancreatitis, cholangitis, or bleeding). When the initial method of treatment failed, the alternative was used, resulting in an overall success rate of bile duct clearance of 94.3%. It is concluded that percutaneous and endoscopic methods of bile duct clearance in patients with a T tube in situ are equally effective, carrying similar complication rates. This study has helped to clarify the indications and efficacy of these alternative treatments.

Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion.

For four years up to December 1987, 190 patients (median age 73 years) with proximal malignant biliary obstruction were treated by endoscopic endoprosthesis insertion. Altogether 101 had cholangiocarcinoma, 21 gall bladder carcinoma, 20 local spread of pancreatic carcinoma, and 48 metastatic malignancy. Fifty eight patients had type I, 54 type II, and 78 type III proximal biliary strictures (Bismuth classification). All patients were either unfit or unsuitable for an attempt at curative surgical resection. A single endoprosthesis was placed initially, with a further stent being placed only if relief of cholestasis was insufficient or sepsis developed in undrained segments. The combined percutaneous-endoscopic technique was used to place the endoprosthesis when appropriate, after failed endoscopic endoprosthesis insertion or for second endoprosthesis placement. Full follow up was available in 97%. Thirteen patients were still alive at the time of review and all but one had been treated within the past six months. Initial endoprosthesis insertion succeeded technically at the first attempt in 127 patients, at the second in 30, and at a combined procedure in a further 13 (cumulative total success rate 89% - type I: 93%; type II: 94%; and type III: 84%). There was adequate biliary drainage after single endoprosthesis insertion in 152 of the 170 successful placements, giving an overall successful drainage rate of 80%. Three patients had a second stent placed by combined procedure because of insufficient drainage, giving an overall successful drainage rate of 82% (155 of 190). The final overall drainage success rates were type I: 91%; type II: 83%; and type III: 73%. The early complication rates were type I: 7%; type II: 14%; and type III: 31%. The principle early complication was clinical cholangitis, which occurred in 13 patients (7%) and required second stent placement in five. The 30 day mortality was 22% overall (type I: 14%; type II: 15%; and type III: 32%) but the direct procedure related mortality was only 3%. Median survival overall for types I, II, and III strictures were 21, 12, and 10 weeks respectively but survival was significantly shorter for metastatic than primary malignancy (p<0.05). Endoscopic insertion of a single endoprosthesis will provide good palliation of proximal malignant biliary obstruction caused by unresectable malignancy in 80% of patients. Second stents should be placed only if required. Extensive structuring because of metastatic disease carries a poor prognosis and careful patient selection for treatment is requires.

Occult carcinoma in an adult choledochal cyst.

The complications of choledochal cyst are avoidable if diagnosed early, and adequate resection undertaken. This case report describes the long history of right subcostal pain in a young man of 26 who had a squamous carcinoma in a choledochal cyst diagnosed after serial section of the excised cyst. Subsequent resection of the head of the pancreas showed histological residual tumour from which he died 4 months later. This case illustrates the need for complete early excision of a choledochal cyst to prevent this complication.

Needle knife papillotomy: how safe and how effective?

Between January 1986 and July 1988 needle knife papillotomy was attempted in 103 patients after failure of conventional access for endoscopic sphincterotomy (96 cases) or diagnostic cholangiography (seven cases). Access was obtained at the same session in 36 cases and at a subsequent attempt within 2 to 5 days in a further 43, an overall success rate of 77%. The procedure related morbidity and mortality in the therapeutic group were 5.2% and 2.0% respectively. There were no deaths or complications in the diagnostic group. Needle knife papillotomy is a valuable adjunct to conventional techniques of biliary access.

Villous adenoma of the common hepatic duct: the role of ultrasound in management.

A case of villous adenoma of the common hepatic duct causing obstructive jaundice, where the diagnosis was made by ultrasound guided percutaneous biopsy is reported. At surgery ultrasonography was used to define the extent and operability of the tumour.