The appropriateness of current UK training in acute internal medicine.

Doctors training in Acute Internal Medicine (AIM) need to provide evidence that they can effectively manage 20 'top' and 40 'other important' acute medical presentations. However, the presentations considered important in the AIM curriculum do not have an empirical evidence base. This study compared real-life presentations against those in the AIM curriculum. Data on all presentations to the acute medical service at The Royal Free Hospital, London, were collected retrospectively for five non-consecutive weeks and prospectively for one week. Five frequently encountered presentations viz: cough, nausea and vomiting, dizziness, hyperglycaemia and lethargy were not amongst those listed as 'top' or 'other important' in the AIM curriculum. Hence, demonstration of competency in these presentations is currently not an explicit requirement.

Non-Convulsive Status Epilepticus as a cause for prolonged delirium: an under-diagnosed phenomenon?

Delirium is a common cause for acute hospital admissions. There are many potential causes for this presentation, including infection, polypharmacy and metabolic disorders. We present the case of a patient with hyponatraemia and prolonged delirium, in whom the diagnosis of non-convulsive status epilepticus (NCSE) was made following electroencephalography (EEG).

Implications of eosinophilia in the normal duodenal biopsy - an association with allergy and functional dyspepsia.

BACKGROUND: Allergy and functional gastrointestinal disorders have been associated with eosinophilia in duodenal mucosa. AIM: To assess the prevalence of eosinophilia in duodenal biopsies of patients attending for oesophogastroduodenoscopy and delineate associated clinical conditions. METHODS: A total of 155 patients (mean age 55 years, 59% women) with normal duodenal biopsies were randomly selected for audit from histopathology files. Eosinophil counts in five high power fields (HPFs) were assessed. Records were analysed for symptoms, diagnosis and medications; patients were divided into five groups based on upper gastrointestinal (UGI) symptom profiles, including a control group of those without predominant UGI symptoms. The prevalence of duodenal eosinophilia (defined as >22/5HPFs a priori) was calculated. RESULTS: In the control group, the mean duodenal eosinophil count was 15/5HPFs; prevalence of duodenal eosinophilia was 22.5%. In postprandial distress syndrome (PDS), both mean eosinophil counts (20.2/5HPF, P < 0.04) and prevalence of duodenal eosinophilia (47.3%, P < 0.04) were significantly higher. Duodenal eosinophilia was significantly associated with allergy (OR 5.04, 95% CI 2.12-11.95, P < 0.001). There was no association with irritable bowel syndrome or medications. CONCLUSIONS: Subtle duodenal eosinophilia is relatively common in routine oesophogastroduodenoscopy and previously overlooked; it is associated with allergy and may indicate a hypersensitivity mechanism in some patients with PDS including early satiety.

Magnetic resonance colonography versus colonoscopy as a diagnostic investigation for colorectal cancer: a meta-analysis.

AIMS: Magnetic resonance colonography (MRC) is emerging as a potential complementary investigation for the diagnosis of colorectal cancer (CRC) and also for benign pathology such as diverticular disease. A meta-analysis reporting the use of MRC is yet to be performed. The aim of this study was to evaluate the diagnostic accuracy of MRC compared with the gold-standard investigation, conventional colonoscopy (CC). METHODS: A literature search was carried out to identify studies containing comparative data between MRC findings and CC findings. Quantitative meta-analysis for diagnostic tests was performed, which included the calculation of independent sensitivities, specificities, diagnostic odds ratios, the construction of summary receiver operating characteristic (SROC) curves, pooled analysis and sensitivity analysis. The study heterogeneity was evaluated by the Q-test using a random-effect model to accommodate the cluster of outcomes between individual studies. RESULTS: In all, 8 comparative studies were identified, involving 563 patients. The calculated pooled sensitivity for all lesions was 75% (95% CI: 47% to 91%), the specificity was 96% (95% CI: 86% to 98%) and the area under the ROC curve was 90% (weighted). On sensitivity analysis, MRC had a better diagnostic accuracy for CRC than for polyps, with a sensitivity of 91% (95% CI: 97% to 91%), a specificity of 98% (95% CI: 66% to 99%) and an area under the ROC curve of 92%. There was no significant heterogeneity between the studies with regard to the diagnostic accuracy of MRC for CRC. CONCLUSION: This meta-analysis suggests that MRC is an imaging technique with high discrimination for cases presenting with colorectal cancer. The exact diagnostic role of MRC needs to be clarified (e.g. suitable for an elderly person with suspected CRC). Further evaluation is necessary to refine its applicability and diagnostic accuracy in comparison with other imaging methods such as computed tomography colonography.

Detection and quantitation of matrix metalloproteases by zymography.

Matrix metalloproteases (MMPs) are a family of structurally and functionally related endopeptidases. They have in common a zinc ion at the active site and are released as an inactive proform (zymogen). Proteolytic activation enables MMPs to degrade components of the extracellular matrix such as collagens, fibronectin, and laminin [for review see (1-4)].

Hypoxia inhibits macrophage migration.

The chemokine monocyte chemoattractant protein (MCP)-1 plays a role in regulating the lymphocyte and macrophage infiltrate in ovarian cancer, but macrophages also accumulate in necrotic areas of the tumors where there is little MCP-1 expression (Negus, R. P. M. et al., Am. J. Pathol. 1997. 150: 1723-1734). Necrotic regions are likely to be hypoxic. In this study we show that hypoxia inhibits MCP-1-induced migration of THP-1 monocytic cells and human macrophages. In contrast, lymphocytes from peripheral blood migrate normally to an MCP-1 gradient in hypoxic conditions. The inhibition of monocyte migration by hypoxia is rapid and reversible. At the exposure times studied (30-90 min) hypoxia does not affect expression of the MCP-1 receptor CCR2B and cells exposed to hypoxia still respond to MCP-1 with an elevation of intracellular calcium. Although hypoxia is known to modulate gene expression, the inhibition of migration reported here was not due to the production of soluble factors, and mRNA expression of macrophage migration inhibitory factor was unchanged. Hypoxia-induced inhibition of chemotaxis was not limited to MCP-1. Hypoxia also inhibited the chemotactic response to macrophage inflammatory protein-1alpha, RANTES and the chemoattractant N-formyl-met-leu-phe, but hypoxic cells were still able to phagocytose opsonized red blood cells. We suggest that inhibition of migration by hypoxia is not due to gene regulation but is a reflection of metabolic changes in the cell. Transient hypoxia may regulate the distribution of macrophages in tumors and other inflammatory conditions.

Hypoxia down-regulates MCP-1 expression: implications for macrophage distribution in tumors.

Monocyte chemoattractant protein 1 (MCP-1) is likely to contribute to the macrophage infiltrate in human ovarian carcinomas. Although MCP-1 is predominantly expressed by the tumor parenchyma, macrophages accumulate at highest density in necrotic regions, which are associated with low oxygen tensions. Tumor necrosis factor alpha (TNF-alpha) can stimulate MCP-1 production and is also present within ovarian carcinomas. We have investigated the effect of hypoxia both on MCP-1 expression in ovarian cancer cell lines and monocyte migration. Hypoxia down-regulated TNF-alpha-induced MCP-1 mRNA and protein production by ovarian cancer cells. The effect was mimicked by cobalt chloride and desferrioxamine, consistent with a specific oxygen-sensing mechanism. Unlike antioxidants, hypoxia did not inhibit nuclear factor KB mobilization. Monocyte migration in response to MCP-1 was also diminished under hypoxic conditions. Down-regulation of MCP-1 expression and the inhibition of monocyte migration are independent effects of hypoxia that may contribute to the distribution of macrophages within ovarian tumors.

Quantitative assessment of the leukocyte infiltrate in ovarian cancer and its relationship to the expression of C-C chemokines.

We have defined the host leukocyte infiltrate in epithelial ovarian tumors and related this to the expression of C-C chemokines. Immunohistochemical analysis of 20 paraffin-embedded biopsies showed that the infiltrate was primarily composed of CD68+ macrophages and CD8+/CD45RO+ T cells (median values, 3700 cells/mm3 and 2200 cells/mm3, respectively). Natural killer cells, B cells, and mast cells occurred in lower numbers (median values, 0 to 200 cells/mm3). Eosinophils were rarely seen and neutrophils were mainly confined to blood vessels. More infiltrating cells were found in stromal than in tumor areas. Only macrophages occurred in significant numbers in areas of necrosis (P < 0.0005). Using in situ hybridization to mRNA, we examined expression of the chemokines MCP-1, MIP-1 alpha, MIP-1 beta, and RANTES. MCP-1 and MIP-1 alpha were expressed by significantly more cells than MIP-1 beta and RANTES (P < 0.005). In tumor epithelial areas, the predominant chemokine was MCP-1. MCP-1 and MIP-1 alpha were the predominant stromal chemokines. A significant correlation was found between the total number of CD8+ T cells and the number of cells expressing MCP-1 (rs = 0.63 and P < 0.003, respectively) and between the CD8+ population and RANTES-expressing cells (rs = 0.6 and P < 0.003). A correlation was also found between CD68+ macrophages and the number of cells expressing MCP-1 (rs = 0.50 and P = 0.026). We suggest that MCP-1 may be responsible for the leukocyte infiltrate in ovarian carcinomas, but the expression of other chemokines may determine its exact nature.

A cytokine profile of normal and malignant ovary.

We defined a cytokine mRNA profile of 12 ovarian cancer biopsies, 10 normal/benign biopsies, six ovarian cancer cell lines and three ovarian cancer xenografts, using RT-PCR. The profile, based on screening for 25 cytokines and 12 receptor mRNAs, was rich in growth factors, pro-inflammatory cytokines and chemokines, but weak in lymphocyte-associated cytokines. The pattern was unique to ovarian tissue, but similar in normal, benign and malignant biopsies, with > 80% samples expressing 16 cytokines in common. Fourteen of these were also expressed by > 65% cell lines, but fewer were detected in xenografts. Potential autocrine loops existed for IL-1, IGF-1, M-CSF, GM-CSF and TNF-alpha. IL-4 and IFN-gamma receptors were expressed in absence of ligand. Chemokines RANTES, MIP-1 alpha and MIP-1 beta were expressed in biopsies, but were rarely detected in cell lines and absent from xenografts. IGF-1 and its receptor was expressed in every sample, as was IFN-gamma receptor. Another 10 cytokine mRNAs and six receptors were expressed in > 80% samples. These may contribute to key survival/growth loops. Similarities between normal and malignant biopsies suggest that analogous processes of remodelling and repair occur. RT-PCR proved a rapid, reproducible screen, but further assays are required to detect quantitative differences between normal and malignant tissues and tumour models.

Cytokines in tumour growth, migration and metastasis.

A wide variety of cytokines are involved at every stage of tumour growth and dissemination. Primary tumour growth is helped by growth factors and angiogenic factors. These may either be produced by tumour cells themselves or be provided by one of the infiltrating cell populations, such as vascular endothelium or leukocytes. The influx of these cells is, in turn, under the control of the chemokines, a chemoattractant subfamily of cytokines. Autocrine motility factors, in conjunction with cytokines that regulate the production and activity of proteases capable of breaking down components of the extracellular matrix, are involved in the dispersal of cells from primary tumours, leading to the formation of metastases. The development of metastases may also be under the control of circulating cytokines released from the primary tumour. The ways in which cytokines and allied growth factors regulate tumour growth and development are both complex and controversial. However, the study of this system will provide a more profound understanding of tumour biology and may lead the way for the development of novel therapeutic approaches.

Magnetic resonance angiography of renal artery stenosis.

Renal artery stenosis is a common cause of renal impairment which in many cases may be potentially reversible. The diagnosis and follow-up of this condition is commonly carried out using the relatively invasive technique of intra-arterial angiography. Magnetic resonance angiography (MRA) is emerging as a possible alternative technique to conventional angiography. We have studied 60 patients who were referred for investigation of possible renal artery stenosis using both 3-D phase contrast MRA techniques and conventional digital arteriography. Studies were assessed prospectively and conventional angiography was assumed to be the gold standard for the purposes of this study. Calculated sensitivity and specificity results were 84% and 91% respectively, for 3-D phase contrast MRA of the renal arteries. We conclude that 3-D phase contrast MRA is a very promising technique for the noninvasive investigation of renal artery stenosis with high sensitivity and specificity levels acting as a screening test in the future for patients with this potential diagnosis, diminishing the amount of conventional angiograms that are performed.

The detection and localization of monocyte chemoattractant protein-1 (MCP-1) in human ovarian cancer.

Chemokines may control the macrophage infiltrate found in many solid tumors. In human ovarian cancer, in situ hybridization detected mRNA for the macrophage chemokine monocyte chemoattractant protein-1 (MCP-1) in 16/17 serous carcinomas, 4/4 mucinous carcinomas, 2/2 endometrioid carcinomas, and 1/3 borderline tumors. In serous tumors, mRNA expression mainly localized to the epithelial areas, as did immunoreactive MCP-1 protein. In the other tumors, both stromal and epithelial expression were seen. All tumors contained variable numbers of cells positive for the macrophage marker CD68. MCP-1 mRNA was also detected in the stroma of 5/5 normal ovaries. RT-PCR demonstrated mRNA for MCP-1 in 7/7 serous carcinomas and 6/6 ovarian cancer cell lines. MCP-1 protein was detected by ELISA in ascites from patients with ovarian cancer (mean 4.28 ng/ml) and was produced primarily by the cancer cells. Human MCP-1 protein was also detected in culture supernatants from cell lines and in ascites from human ovarian tumor xenografts which induce a peritoneal monocytosis in nude mice. We conclude that the macrophage chemoattractant MCP-1 is produced by epithelial ovarian cancer and that the tumor cells themselves are probably a major source. MCP-1 may contribute to the accumulation of tumor-associated macrophages, which may subsequently influence tumor behavior.

Case report: extrathoracic herniation of the lung with a review of the literature.

A case of extrathoracic herniation of the lung is described together with the radiological findings in this condition including the role of computed tomography (CT) in its management. In addition a review of the literature is presented which outlines the incidence, classification and clinical features of lung herniae. Some reference is made to possible methods of treatment.

Magnetic resonance angiography of renal transplants.

Stenosis of the artery of transplanted kidneys is an important cause of graft dysfunction. Diagnosis and follow-up of this condition normally requires intra-arterial digital-subtraction angiography (IADSA), which is invasive and may cause complications. A possible alternative to IADSA is magnetic resonance angiography (MRA), and we have assessed this technique in 50 renal transplant patients who were referred for investigation of possible renal arterial stenosis. In every patient, MRA was compared prospectively with conventional IADSA. Compared with IADSA, MRA had a sensitivity of 83% and a specificity of 97%, and when all images were graded retrospectively for severity of stenosis, the two techniques showed a significant correlation (r = 0.74, p less than 0.001). MRA can provide an accurate image of the renal transplant artery in a non-invasive manner with a high sensitivity and specificity.

Renal transplant vein stenosis: demonstration and percutaneous venoplasty of a new vascular complication in the transplant kidney.

Stenosis of the renal transplant vein has been demonstrated in eight patients undergoing investigation for renal dysfunction arising 3 weeks to 3 years after transplantation. The stenoses were diagnosed by duplex Doppler ultrasound in three cases and by angiography in the presence of arterio-venous fistula in five cases. In four patients percutaneous venous dilatation was performed with technical success in three. In two patients this was repeated for recurrent stenosis but sustained improvement in renal function was not observed. Progression of the venous stenoses was documented with one patient suffering graft loss due to complete venous occlusion.

Tension hydrothorax and shock in a patient with a malignant pleural effusion.

A patient presented to the emergency department with a malignant pleural effusion associated with shortness of breath, and radiographic evidence of mediastinal shift and hypotension. Tube thoracostomy yielded serosanguinous pleural fluid under pressure and after 1 liter of fluid was drained, the patient's hemodynamic status stabilized. The entity of tension hydrothorax is rare but may be life threatening. The treatment should consist of prompt drainage and efforts to prevent recurrence. As physicians become more adept at prolonging the lives of patients with cancer, tension hydrothorax may become more common.

Bedside cerebrospinal fluid glucose analysis.

We studied the reliability and accuracy of a two-minute reagent strip (Chemstrip bG) and hand-held autoanalyzer (Accu-Chek IIR) for determining cerebrospinal fluid glucose. We found that both bedside methods were highly reliable (r = 0.93, Chemstrip bG: r = 0.95, Accu-Chek II) and were very accurate (89.7% and 96.6% accurate at +/- 15 and 20 mg/dL, respectively, for the Chemstrip bG: 91.7% and 95.8% accurate at +/- 15 and 20 mg/dL, respectively, for the Accu-Chek II) over a wide range of glucose values in 237 determinations. There was no significant difference between the two bedside methods. We conclude that these two methods of bedside glucose estimation are both highly reliable and accurate and could be used to quickly determine patients' cerebrospinal fluid glucose values.