Neurology residents' education in functional seizures.

We report a survey of neurology residency program directors (PDs) and recent neurology residency graduates about the education provided during residency on functional seizures (FS), a subtype of functional neurological disorder (FND). The purpose of our study was to assess the education gap for neurology residents about FS since patients with FS are frequently seen by neurologists, who typically conduct the evaluation and share the findings with the patient. A survey was sent to 93 Neurology residency program directors and 71 recent graduates. We obtained a low response rate of 17%. Results of the survey revealed that the most frequent settings for education on FS were within a clinical rotation in the Epilepsy Monitoring Unit (68.8% of PDs and 88.7% of recent graduate respondents) and via a single didactic lecture (81.3% of PDs and 80.3% of recent graduate respondents). The majority of programs did not provide a curriculum for training and feedback on best practices in communicating the diagnosis or on evidence-based treatments. Eighteen percent of neurology residents reported not learning how to communicate the diagnosis of FS to patients, while 77% responded that they were not taught about treatment. These results illustrate a curriculum gap in what neurology residents are taught about diagnosis and management of FS (and FND). We propose a standardized model that can be adapted in residencies.

The contributions of MRI-based measures of gray matter, white matter hyperintensity, and white matter integrity to late-life cognition.

BACKGROUND AND PURPOSE: GM volume, WMH volume, and FA are each associated with cognition; however, few studies have detected whether these 3 different types of MR imaging measurements exert independent or additive effects on cognitive performance. To detect their extent of contribution to cognitive performance, we explored the independent and additive contributions of GM atrophy, white matter injury, and white matter integrity to cognition in elderly patients. MATERIALS AND METHODS: Two hundred and 9 elderly patients participated in the study: 97 were CN adults, 65 had MCI, and 47 had dementia. We measured GM on T1-weighted MR imaging, WMH on FLAIR, and FA on DTI, along with psychometrically matched measures of 4 domains of cognitive performance, including semantic memory, episodic memory, executive function, and spatial abilities. RESULTS: As expected, patients with dementia performed significantly more poorly in all 4 cognitive domains, whereas patients with MCI performed generally less poorly than dementia patients, though considerable overlap in performance was present across groups. GM, FA, and WMH each differed significantly between diagnostic groups and were associated with cognitive measures. In multivariate models that included all 3 MR imaging measures (GM, WMH, and FA), GM volume was the strongest determinant of cognitive performance. CONCLUSIONS: These results strongly suggest that MR imaging measures of GM are more closely associated with cognitive function than WM measures across a broad range of cognitive and functional impairment.

R-spondin1 deficiency in mice improves glycaemic control in association with increased beta cell mass.

AIMS/HYPOTHESIS: Roof plate-specific spondin (R-spondin1; RSPO1) is a modulator of canonical Wg (wingless) plus Int1 (chromosomal integration site of mouse mammary tumour virus on mouse chromosome 15) (cWNT) signalling that induces cWNT target genes. We have demonstrated that Rspo1 is expressed in murine beta cells, and that it stimulates proliferation and insulin secretion, and inhibits cytokine-induced apoptosis, in mouse insulinoma (MIN6) and beta cells. We thus investigated the role of RSPO1 in beta cells in vivo using Rspo1 ( -/- ) mice. METHODS: The effects of Rspo1 deficiency were assessed by determination of cWNT signalling, glucose tolerance and beta cell mass. RESULTS: Rspo1 ( -/- ) mice demonstrated an 82% reduction in RSPO1 transcripts and a 61% reduction in the signal detected by an RSPO1 antibody, as well as a 47% decrease in islet cWNT signalling. Despite no differences in body and pancreatic weights or in fasting glycaemia and insulinaemia compared with Rspo1 (+/+) mice, Rspo1 ( -/- ) animals had improved glycaemic control after oral glucose challenge (p < 0.05), with no difference in insulin sensitivity, but an enhanced insulin response over 30 min (p < 0.05); glucagon responses were normal. Rspo1 deficiency also resulted in a twofold increase in beta cell mass (p < 0.05) in association with 2- and 12-fold increases in the number of beta cells positive for antigen identified by monoclonal antibody Ki67 (Ki67) (p < 0.01) and insulin-positive ductal cells (p < 0.05), respectively. No change in the number of TUNEL-positive beta cells was detected. Islets isolated from Rspo1 ( -/- ) animals displayed no differences in glucose-induced insulin secretion or in glucose suppression of glucagon. CONCLUSIONS/INTERPRETATION: The present study reveals an unexpected role for RSPO1 as a regulator of both beta cell proliferation and neogenesis in vivo, and reinforces the importance of cWNT signalling for the maintenance of normal pancreatic beta cell behaviour.

From cradle to grave: pancreatic beta-cell mass and glucagon-like peptide-1.

Type 2 diabetes mellitus and its clinical correlates, including impaired fasting blood glucose, obesity and insulin resistance, represent a significant public health issue worldwide, with the prevalence of these metabolic conditions increasing exponentially. Given the staggering financial costs and human suffering incurred by diabetes and its co-morbid conditions, any safe new therapeutic interventions that prove to have a beneficial effect in reducing the incidence of diabetes in susceptible individuals or in preventing progression of the disease would have major public health benefits. Studies on the regulation of beta-cell mass have demonstrated a remarkable plasticity, from fetal through adult life, as well as in response to a variety of stresses. These findings are considered in this review in the context of newer studies on the intestinal hormone, glucagon-like peptide-1, which not only enhances beta-cell function, but also stimulates beta-cell growth, neogenesis and survival.

Comparison of three stool antigen tests for Helicobacter pylori detection.

BACKGROUND: Active Helicobacter pylori infection can be diagnosed by invasive (biopsy based) or non-invasive methods, such as stool antigen testing. AIMS: To compare three stool antigen enzyme immunoassay kits--Premier Platinum Hp SA, FemtoLab Cnx, and Hp Ag--with biopsy based methods for the detection of H pylori in previously undiagnosed patients. METHODS: One hundred and eleven adults with dyspepsia referred for endoscopy provided a stool sample for testing and had biopsies taken. Patients were considered H pylori positive if two out of three invasive tests were positive or if culture alone was positive. RESULTS: The sensitivities and specificities of the Premier Platinum Hp SA, FemtoLab Cnx, and Hp Ag stool antigen kits when compared with biopsy based diagnosis were, 63.6%, 88.0%, and 56.0% and 92.6%, 97.6%, and 97.6%, respectively. CONCLUSIONS: FemtoLab Cnx may be considered as an alternative to urea breath testing in the initial diagnosis of patients with dyspepsia who do not require immediate endoscopy. Stool testing has the potential advantages of being simple to perform, relatively cheap, and samples can be submitted directly from primary care.

What proportion of dyspeptic patients having H. pylori breath test subsequently undergo endoscopy?

BACKGROUND: Helicobacter pylori (HP) testing in young patients with uncomplicated dyspepsia has been recommended. A test and treat strategy for dyspeptics positive for HP is recommended by the European H. pylori Study Group and the American Gastroenterology Association. OBJECTIVES: To assess the rates of re-referral for upper GI endoscopy (OGD) and outpatient (OPD) attendance in uncomplicated dyspeptic patients following assessment of HP status. METHODS: 190 patients under 50 years of age with uncomplicated dyspepsia (without alarm symptoms) referred from general practitioners (GPs) to the gastroenterology department underwent HP urea breath test (UBT). GPs were informed of the results of UBT and recommended eradication therapy if positive, and if negative advised symptomatic treatment with an acid suppressant with/without a prokinetic. The patients were analysed for subsequent attendance at OGD or OPD in the following two years. RESULTS: HP was present in 93 of 190 patients. Twenty of 190 (10.5%) patients subsequently were re-referred and underwent OGD for continuing dyspeptic symptoms; a further 6 were seen in OPD but not endoscoped as they have been judged to have uncomplicated gastro-oesophageal reflux disease. At time of OGD all patients were negative on Campylobacter-like organism (CLO) test for HP. Findings at OGD were normal (9), hiatus hernia (6), gastritis (4) and duodenitis (1). No case of peptic ulcer disease or gastric cancer has been identified. CONCLUSIONS: In this group of dyspeptic patients, adopting a test and treat policy after initial analysis of HP resulted in 10.5% being re-referred for subsequent OGD; findings in those endoscoped were normal or minimal. A test and treat strategy for H. pylori in uncomplicated dyspeptics therefore saves endoscopies and outpatient consultations without missing significant underlying pathology.

Hepatic sarcoidosis complicated by hepatocellular carcinoma.

A case of a 63-year-old man with a long-standing history of portal hypertension secondary to hepatic sarcoidosis who developed hepatocellular carcinoma is reported.

Tooth movement and vascularity of the dental pulp: a pilot study.

The effect of orthodontic tooth movement on the dental pulp was assessed histologically in twelve subjects. The participants in this study required the extraction of at least two maxillary first premolars for orthodontic treatment. They were asked to wear a maxillary removable appliance that acted to move a randomly determined premolar in a buccal direction. The appliance was designed to avoid contacting the contra-lateral tooth that was used as the matched control. The appliance was initially worn for a week to ensure patient comfort and cooperation. The appliance was then activated and the patient dismissed. After two weeks, the appliance was reactivated. Both the control and experimental teeth were extracted three weeks later, on the thirty-fifth day of activated appliance wear. The teeth were fixed, decalcified and sectioned. The sections were stained with haematoxylin and eosin for histological examination. This investigation demonstrated that orthodontic tooth movement did have an effect upon the dental pulp, causing vasodilation in the pulp of an orthodontically stressed tooth.

Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection.

Patients with chronic hepatitis C virus (HCV) infection are often asymptomatic with few clinical signs of liver disease. Recognition of the presence of fibrosis or cirrhosis is difficult without liver biopsy, but with the availability of effective treatments, such as interferon, and the potential for progression to hepatoma in some cases, an accurate measure of the stage of disease is important. Serum hyaluronic acid (HA) has been identified as a potential marker of fibrosis or cirrhosis in other settings. In a prospective study in 130 chronic HCV carriers therefore, serum HA concentrations were compared with conventional liver function tests (including alanine aminotransferase (ALT), a-glutathione-S transferase (GST) and serum HCV RNA in order to determine which identified the stage of liver fibrosis as assessed by liver biopsy most accurately. The median HA concentrations according to the stage of fibrosis 0, 1 & 2, 3 and 4 & 5 were 17 g l-1 (range 5-37), 17 g l-1 (5-80), 30 g l-1 (10-105) and 350 g l-1 (20-800) respectively. The median HA concentration in stage 4 & 5 was significantly greater than in stages 0, 1 & 2 or 3. Serum HA concentration rose with age, but even when adjusted for age the median HA at stage 4 & 5 was greater than all other groups (95% CI of difference between the medians exceeded 0). Thus, serum HA gave a sensitivity and specificity for stage 4 & 5 fibrosis of 85% and 88% respectively, exceeding those for ALT or GST. In contrast, serum ALT or GST levels were not correlated with the stage of fibrosis although ALT was significantly greater in the cirrhotic group when compared to the group with no fibrosis (stage 0). There was no correlation between serum HA and either the grade of inflammatory changes or serum HCV RNA. These results suggest that serum hyaluronic acid is a useful marker of liver fibrosis in patients with chronic HCV infection. It could therefore be used to monitor patients at risk of progressive fibrosis, in controlled clinical trials, as a measure of response to antifibrotic therapy and in those in whom liver biopsy is difficult or contraindicated.

Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C: 2 year follow up.

In 1994, an outbreak of hepatitis C virus (HCV) infection, genotype 1a, occurred in 30 hypogammaglobulinaemic patients in the UK from one batch of contaminated anti-HCV screened intravenous immunoglobulin. This study aimed to study prospectively the outcome of HCV in hypogammaglobulinaemic patients, and to assess the response to early treatment with interferon-alpha, 6 million units three times weekly for 6 months. Data were collected using standardized questionnaires. Five patients with secondary hypogammaglobulinaemia due to lymphoid malignancy were not treated and all have died of their primary malignancy. Of 25 patients with primary hypogammaglobulinaemia, one resolved HCV infection before treatment, 17 commenced on treatment, and seven declined or treatment was contra-indicated. Thirteen of 17 patients completed therapy and seven (54%) have a sustained response (normal transaminases, negative serum HCV RNA) at 6 and 12 months after treatment. Two of the 12 patients with primary hypogammaglobulinaemia, who were not treated or failed to complete treatment, have cleared the virus. Liver biopsy was performed in patients not clearing HCV and was abnormal in all. Four patients developed liver failure within 2 years, of whom three have died and one has been successfully transplanted. In conclusion, HCV can cause rapid severe liver disease in hypogammaglobulinaemic patients. Early treatment with high-dose interferon-alpha results in a high clearance of HCV.

The role for liver biopsy in haemophiliacs infected with the hepatitis C virus.

Assessment of chronic hepatitis C virus infection requires a liver biopsy in most circumstances. There is a reluctance to perform liver biopsy in haemophiliacs because of a perceived risk of haemorrhage, although with adequate factor concentrate replacement in patients without factor concentrate inhibitors it should be safe. We report a 4-year experience of liver biopsy in patients with haemophilia infected with chronic hepatitis C virus. Of 55 patients seropositive for anti-HCV, 35 have undergone liver biopsy; the median age of this group was 33 years (range 13-68). Seven patients had a normal liver. 22 had portal tract inflammation, four with lymphoid aggregates. Mild piece-meal necrosis was observed in only two and no bile duct injury was found. 11 patients had mild mixed micro- and macro-vesicular fat. 19 patients had no evidence of fibrosis despite an estimated median duration of disease of 20 years (range 8-43). In the remaining 16 patients the maximum degree of fibrosis achieved was stage III. Patients with more significant fibrosis could not be identified on the basis of ALT or HCV RNA. There were no complications of liver biopsy in this series. Liver biopsy following a well-defined protocol in chronic hepatitis C virus haemophiliac carriers is safe in the absence of factor concentrate inhibitors. In this young group of patients without HIV infection there was no evidence of significant liver disease despite a considerable duration of disease. Performing liver biopsy allows accurate information to be given to the patient and avoids unnecessary therapy. The relative youth of this group may be important in the light of the benign histology.

Hepatitis C virus genomic variability in untreated and immunosuppressed patients.

To investigate whether immune pressure enhances the genetic diversity of the hepatitis C virus (HCV) hypervariable region 1, nucleotide sequences were compared in multiple sera, collected longitudinally, from three untreated patients and four patients undergoing liver transplantation for HCV-related cirrhosis. A minor variant became dominant in three of three patients following transplantation and persisted unchanged for months. Compared with untreated HCV carriers, transplant recipients had fewer quasispecies, fewer nucleotide changes (1.61 and 2.58/month), fewer amino acid sequence changes (0.40 and 1.94/month), as well as higher ratio of transitional to transversional mutations (2.57 and 0.98, P < 0.02) and lower replacement to silent mutations (1.33 and 8.21, P < 0.01). The two patients with the least genomic variation died of HCV graft infection. The data suggest that HCV variants which infect the graft are selected by recipient immune pressure at the time of transplant and that preferential replication in the graft is enhanced by routine immunosuppression.

Treatment of corticosteroid-resistant ulcerative colitis with heparin--a report of 16 cases.

BACKGROUND: Heparin, a group of sulphated glycosaminoglycans, in addition to its anticoagulant activity, has a wide range of potentially anti-inflammatory effects. These include inhibition of neutrophil elastase and inactivation of chemokines. Previous reports of fortuitous improvement in ulcerative colitis patients treated with heparin for prophylaxis of venous thrombosis, prompted us to perform a pilot study in patients with corticosteroid-resistant ulcerative colitis. METHODS: Sixteen hospitalized patients in relapse from ulcerative colitis and unresponsive to high-dose corticosteroid therapy were treated with intravenous standard heparin (subcutaneous in two patients), the dose was adjusted to provide standard anticoagulant activity. Five patients continued with subcutaneous injections on discharge, with a gradual reduction in the frequency of doses. RESULTS: Within 1 week of starting heparin, 12/16 patients had shown a considerable reduction in stool frequency. After 2 weeks of heparin therapy median stool frequency had improved from 8.0/day (range 6.3-10.0) pre-treatment to 3.5/day (2.5-5.25) (P = 0.008), and by 4 weeks 12/16 achieved clinical remission, Four patients required elective colectomy. Three patients were treated with heparin on a second occasion during a relapse, two failed to respond and required subsequent colectomy. Nine remain well. No serious complications were seen due to the anticoagulant activity, apart from bruising at subcutaneous injection sites. CONCLUSION: The response to heparin in patients with ulcerative colitis resistant to standard therapy is encouraging and supports the previous uncontrolled evidence for a therapeutic effect. A controlled trial of heparin in ulcerative colitis is clearly indicated.

Fibrosis and other histological features in chronic hepatitis C virus infection: a statistical model.

AIMS: To study the inter-relation between hepatic fibrosis and other histological features of chronic hepatitis C virus (HCV) infection. METHODS: Liver biopsy specimens from 200 consecutive patients with chronic HCV infection were graded and staged separately for necro-inflammatory activity and for fibrosis. The interaction between fibrosis and other histological features was evaluated by univariate and multivariate analysis, followed by hierarchical log linear modelling. RESULTS: The most striking feature was the presence of portal tract inflammation in 177 (89%) of 200 samples. Lymphoid aggregates/follicles were observed either alone or as part of the general inflammatory infiltration of the portal tracts in 120 (60%) of 200 samples. Fatty change (macro- and microvesicular steatosis) was observed in 76 (38%) samples: mild to moderate in 60 (30%) and diffuse in 16 (8%). Bile duct damage was found in 30 (15%) of 200 specimens. Lobular activity was found in 154 (77%) of 200 samples and was significant in 44; piecemeal necrosis was present in 79 (40%). Thirty one (16%) patients had stage 0 liver fibrosis, 27 (14%) had stage 1, 69 (35%) had stage 2, 43 (22%) had stage 3, 16 (8%) had stage 4, and 12 (6%) had stage 5. On log linear analysis, piecemeal necrosis, lobular inflammation and steatosis were linked directly with fibrosis. Portal tract inflammation was linked directly and indirectly via piecemeal necrosis and lobular inflammation with fibrosis. The presence of lymphoid aggregates was associated with bile duct damage. CONCLUSIONS: Portal tract inflammation with lymphoid aggregates or follicles, together with fatty change, bile duct damage and/or lobular activity, are characteristic of chronic HCV infection, confirming previous reports. Piecemeal necrosis, lobular inflammation, portal inflammation, and steatosis are linked directly with fibrosis in this statistical model, suggesting a close inter-relation in the development of fibrosis/cirrhosis.

Incidence, character and clinical relevance of mixed cryoglobulinaemia in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection has been implicated in the pathogenesis of mixed cryoglobulinaemia. Several studies have shown the presence of anti-HCV antibodies and HCV-RNA in both sera and cryoglobulins of such patients. However, the prevalence and clinical significance of cryoglobulins remain uncertain in patients with chronic HCV infection. We have studied 113 consecutive patients referred for assessment because of the presence of anti-HCV antibody in serum for the presence of cryoglobulinaemia and ascertained their clinical relevance and immunochemical properties. Twenty-one of 113 (19%) had detectable cryoglobulins with a mean protein concentration of 0.38 g/l (range 0.15-3.34 g/l). Most of these patients were asymptomatic. The cryoglobulins were of type III in 19 (91%) and of type II in two patients (9%). The latter two patients had the highest concentration of cryoglobulins, subnormal C4 and C1q levels suggesting classical pathway activation and vasculitis with renal impairment. The cryoglobulin IgG subclasses were mainly IgG1 and IgG3. HCV-RNA was detected more frequently in the sera of cryoglobulin-positive patients than in cryoglobulin-negative patients. This study showed that mixed cryoglobulinaemia is common in chronic HCV infection, and is predominantly type III. Evidence of systemic or renal disease was rare except in those with type II cryoglobulinaemia, and this may reflect either the concentration of the cryoprecipitate or the presence of a monoclonal complement-activating IgM paraprotein. The detection of HCV-RNA in the majority of the cryoprecipitates further supports the important role of HCV in the etiopathogenesis of essential mixed cryoglobulinaemia, although the mechanism is at present unclear.

Selective regulation of the atrial natriuretic peptide gene by individual components of the activator protein-1 complex.

We used the human atrial natriuretic peptide (hANP) gene as a model to investigate the causal relationship between immediate early gene expression and the subsequent activation of the embryonic gene repertoire in cardiac hypertrophy. Using transient transfection analysis, we found that overexpression of individual Jun family members, alone or in combination, displayed unique activity that varied as a function of the promoter and the nature of the transfected myocyte populations under examination. In neonatal cardiac ventriculocytes, both c-jun and to a lesser extent, JunB stimulated hANP promoter activity (approximately 7- and 3- fold, respectively). When cotransfected together, a synergistic activation was observed (approximately 16-fold activation), a finding that stands in contrast to the behavior of JunB (i.e. neutral or inhibitory) with other 12-O- tetradeconoylphorbol 13-acetate response element-dependent promoters. In atriocytes, on the other hand, JunB did not itself activate the hANP promoter, and it antagonized c-jun- mediated transcription. JunD, a third member of this gene family, was devoid of activity in these transfected cultures. These findings suggest that the hANP gene promoter exhibits a broad range of responses to the individual products of the jun gene family. The response in any single situation is a function of the relative concentrations and subunit composition of the prevailing activator protein-1 complexes.

Buprenorphine and hepatic pruritus.

Pruritus in cholestatic liver disease can be difficult to treat. It may be related to impaired excretion of large opioid peptides. Buprenorphine, a drug with partial opiate antagonist properties, was used in a double-blind trial of five patients with uncontrollable itching. One patient improved clinically, one patient had good relief from pruritus and three had intolerable side-effects. Buprenorphine may be of limited use in intractable pruritus.