Showing papers by "St Bartholomew's Hospital published in 2003"

Diagnosis and Complications of Cushing’s Syndrome: A Consensus Statement

Abstract: In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry

Abstract: Glycation of proteins forms fructosamines and advanced glycation endproducts. Glycation adducts may be risk markers and risk factors of disease development. We measured the concentrations of the early glycation adduct fructosyl-lysine and 12 advanced glycation endproducts by liquid chromatography with tandem mass spectrometric detection. Underivatized analytes were detected free in physiological fluids and in enzymic hydrolysates of cellular and extracellular proteins. Hydroimidazolones were the most important glycation biomarkers quantitatively; monolysyl adducts (N(epsilon)-carboxymethyl-lysine and N(epsilon)-1-carboxyethyl-lysine) were found in moderate amounts, and bis(lysyl)imidazolium cross-links and pentosidine in lowest amounts. Quantitative screening showed high levels of advanced glycation endproducts in cellular protein and moderate levels in protein of blood plasma. Glycation adduct accumulation in tissues depended on the particular adduct and tissue type. Low levels of free advanced glycation endproducts were found in blood plasma and levels were 10-100-fold higher in urine. Advanced glycation endproduct residues were increased in blood plasma and at sites of vascular complications development in experimental diabetes; renal glomeruli, retina and peripheral nerve. In clinical uraemia, the concentrations of plasma protein advanced glycation endproduct residues increased 1-7-fold and free adduct concentrations increased up to 50-fold. Comprehensive screening of glycation adducts revealed the relative and quantitative importance of alpha-oxoaldehyde-derived advanced glycation endproducts in physiological modification of proteins-particularly hydroimidazolones, the efficient renal clearance of free adducts, and the marked increases of glycation adducts in diabetes and uraemia-particularly free advanced glycation endproducts in uraemia. Increased levels of these advanced glycation endproducts were associated with vascular complications in diabetes and uraemia.

Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness.

Abstract: ObjectiveTo establish the prevalence, clinical characteristics, and electrophysiologic features of residual neuromuscular dysfunction after prolonged critical illness.DesignProspective follow-up study of survivors of prolonged critical illness.SettingA university hospital and two district general ho

Airway bacterial load and FEV1 decline in patients with chronic obstructive pulmonary disease

Abstract: Chronic obstructive pulmonary disease (COPD) is characterized by an accelerated decline in lung function and progressive airway inflammation. Bacteria have been isolated from the lower airway of stable COPD patients, and airway inflammation has been related to bacterial load and type. The relationship between bacterial colonization, airway inflammation, and lung function decline remains uncertain. We studied 30 patients with COPD, mean (SD) FEV1 0.947 (0.329), 34.8% (13.6%) predicted, for 12 months. Sputum collected at recruitment and the end of the study was analyzed for cytokines and for quantitative bacteriology. The decline in FEV1 was 57.6 (137.6) ml year-1. Bacterial growth was identified in all subjects, with an initial count of 107.47(0.91) cfu ml-1 rising to 107.93(0.81) cfu ml-1 at the end of the study (p = 0.019). FEV1 decline was related to this increase in airway bacterial load (r = 0.59, p = 0.001). FEV1 decline was greater in subjects who exhibited a change in the colonizing bacterial type compared with those with persistence of a single bacterial species over the study period (p = 0.017). Higher sputum interleukin (IL-8) was associated with greater declines in FEV1 (p = 0.03). Rising airway bacterial load and species changes are associated with greater airway inflammation and accelerated decline in FEV1. Bacterial colonization in COPD is an important factor in disease progression.

Exacerbations of Chronic Obstructive Pulmonary Disease

Abstract: Exacerbations of chronic obstructive pulmonary disease (COPD) cause morbidity, hospital admissions, and mortality, and strongly influence health-related quality of life. Some patients are prone to frequent exacerbations, which are associated with considerable physiologic deterioration and increased airway inflammation. About half of COPD exacerbations are caused or triggered primarily by bacterial and viral infections (colds, especially from rhinovirus), but air pollution can contribute to the beginning of an exacerbation. Type 1 exacerbations involve increased dyspnea, sputum volume, and sputum purulence; Type 2 exacerbations involve any two of the latter symptoms, and Type 3 exacerbations involve one of those symptoms combined with cough, wheeze, or symptoms of an upper respiratory tract infection. Exacerbations are more common than previously believed (2.5-3 exacerbations per year); many exacerbations are treated in the community and not associated with hospital admission. We found that about half of exacerbations were unreported by the patients, despite considerable encouragement to do so, and, instead, were only diagnosed from patients' diary cards. COPD patients are accustomed to frequent symptom changes, and this may explain their tendency to underreport exacerbations. COPD patients tend to be anxious and depressed about the disease and some might not seek treatment. At the beginning of an exacerbation physiologic changes such as decreases in peak flow and forced expiratory volume in the first second (FEV(1)) are usually small and therefore are not useful in predicting exacerbations, but larger decreases in peak flow are associated with dyspnea and the presence of symptomatic upper-respiratory viral infection. More pronounced physiologic changes during exacerbation are related to longer exacerbation recovery time. Dyspnea, common colds, sore throat, and cough increase significantly during prodrome, indicating that respiratory viruses are important exacerbation triggers. However, the prodrome is relatively short and not useful in predicting onset. As colds are associated with longer and more severe exacerbations, a COPD patient who develops a cold should be considered for early therapy. Physiologic recovery after an exacerbation is often incomplete, which decreases health-related quality of life and resistance to future exacerbations, so it is important to identify COPD patients who suffer frequent exacerbations and to convince them to take precautions to minimize the risk of colds and other exacerbation triggers. Exacerbation frequency may vary with the severity of the COPD. Exacerbation frequency may or may not increase with the severity of the COPD. As the COPD progresses, exacerbations tend to have more symptoms and take longer to recover from. Twenty-five to fifty percent of COPD patients suffer lower airway bacteria colonization, which is related to the severity of COPD and cigarette smoking and which begins a cycle of epithelial cell damage, impaired mucociliary clearance, mucus hypersecretion, increased submucosal vascular leakage, and inflammatory cell infiltration. Elevated sputum interleukin-8 levels are associated with higher bacterial load and faster FEV(1) decline; the bacteria increase airway inflammation in the stable patient, which may accelerate disease progression. A 2-week course of oral corticosteroids is as beneficial as an 8-week course, with fewer adverse effects, and might extend the time until the next exacerbation. Antibiotics have some efficacy in treating exacerbations. Exacerbation frequency increases with progressive airflow obstruction; so patients with chronic respiratory failure are particularly susceptible to exacerbation.

Characterization of adnexal mass lesions on MR imaging.

Abstract: OBJECTIVE. The aim of our study was to evaluate the accuracy of MR imaging in the detection and characterization of adnexal mass lesions and to determine which imaging features are predictive of malignancy.SUBJECTS AND METHODS. We prospectively performed MR imaging in 104 patients (age range, 19–87 years; mean age, 50 years) with clinically or sonographically detected complex adnexal masses. We used a 1.5-T unit to perform T1-, T2-, and fat-suppressed T1-weighted sequences before and after IV injection of gadolinium. The adnexal lesions were examined for several features including size, shape, character (solid–cystic), vegetation, signal intensity, and enhancement. Secondary signs such as ascites, peritoneal disease, and lymphadenopathy were noted. We compared the imaging features with the surgical and pathologic findings. Multiple logistic regression analysis was performed on all MR imaging features.RESULTS. A total of 163 lesions—94 benign and 69 malignant lesions—were examined. On MR imaging, 95% (155/...

An Intrapatient Comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPA-Octreotide for Diagnosis of Somatostatin Receptor-Expressing Tumors

Abstract: The aim of this study was to compare the imaging abilities of the recently developed somatostatin analog, 99mTc-hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC [99mTc-TOC]), with 111In-diethylenediaminepentaacetic acid-d-Phe1-octreotide (111In-OCT [Octreoscan]) in patients undergoing routine somatostatin receptor (SSTR) scintigraphy. Methods: Forty-one patients (20 men, 21 women; age range, 29–75 y; mean age, 56.7 y) with either histologically proven or biologically and clinically suspected endocrine tumors were enrolled in the study. Four groups were distinguished: (a) patients being evaluated for the detection and localization of neuroendocrine tumors (n = 6), (b) tumor staging (n = 19), (c) patients being investigated to determine the SSTR status of tumor lesions (n = 11), and (d) patient follow-up studies (n = 5). Each patient received a mean activity of 150 MBq 111In-OCT and 350–400 MBq 99mTc-TOC. Scintigraphy with 99mTc-TOC was performed 4 h after injection and scintigraphy with 111In-OCT was performed 4 and 24 h after injection. SPECT studies of areas of interest were performed 4 h after injection for both tracers as well as at 24 h after injection for 111In-OCT. The time interval between the studies using each tracer ranged from 2 to 22 d (mean interval, 9.3 d). Results:111In-OCT and 99mTc-TOC showed an equivalent scan result in 32 patients (78%), 9 cases showed discrepancies (22%), false-negative results with 111In-OCT were seen in 6 cases (14.6%), whereas 99mTc-TOC was false-positive in 2 cases (4.9%). 111In-OCT was true-negative in both cases. The false-positive findings of the 99mTc-TOC studies were caused by nonspecific uptake in the bowel. In 1 case, 99mTc-TOC correctly identified a metastasis in the lumbar spine but both scan results were false-positive because of an inflammatory process. In 21 patients with SSTR-expressing tumors, the semiquantitative region-of-interest analysis showed that 99mTc-TOC achieved higher tumor-to-normal tissue ratios than 111In-OCT. Conclusion: This study revealed a higher sensitivity of 99mTc-TOC as compared with 111In-OCT as an imaging agent for the localization of SSTR-expressing tumors. To avoid false-positive findings with 99mTc-OCT due to nonspecific tracer accumulation, additional scanning at 1–2 h after injection should be done.

Hepatic steatosis in Cushing's syndrome: A radiological assessment using computed tomography

Abstract: Objective: Hepatic steatosis may occur in association with insulin resistance and obesity, two features commonly seen in Cushing’s syndrome (CS). The aim of this report is to assess the prevalence of hepatic steatosis in patients with active CS using computed tomography (CT) and to identify any associations between hepatic steatosis, endocrine and biochemical variables and body fat distribution. Patients and measurements: We identified 50 patients with active CS in whom appropriate CT was available to allow measurement of liver and spleen attenuation. In 26 patients, abdominal fat measurements were also available. Serum markers of CS and liver function tests were recorded. Results: Ten of 50 patients had a liver-to-spleen CT attenuation ratio (L/S) of less than 1, indicating hepatic steatosis. There was a significant negative correlation between both liver attenuation and L/S ratio with total abdominal fat area, visceral fat area, the percentage of visceral fat and the visceral to subcutaneous fat ratio; the strongest negative correlation was found between visceral fat area and L/S ratio (r ¼ 2 0.638, P , 0.001, n ¼ 26). L/S ratio positively correlated with alkaline phosphatase levels (r ¼þ 0.423, P ¼ 0.044, n ¼ 23) but with no other serum marker of CS activity or liver enzyme. Conclusions: We have demonstrated hepatic steatosis on CT in 20% of patients with active CS. The presence of hepatic steatosis was significantly correlated with total abdominal fat area and visceral fat area.

Genome-wide analysis of acute myeloid leukemia with normal karyotype reveals a unique pattern of homeobox gene expression distinct from those with translocation-mediated fusion events.

Abstract: Gene expression profiles were determined from presentation peripheral blood and bone marrow samples of 28 patients with acute myeloid leukemia (AML). Hierarchical clustering sorted the profiles into separate groups, each representing one of the major cytogenetic classes in AML [i.e., t(8;21), t(15;17), inv(16), 11q23, and normal karyotype]. Statistical group comparison identified genes whose expression was strongly correlated with these chromosomal classes. Moreover, the normal karyotype AMLs were characterized by distinctive up-regulation of certain members of the class I homeobox A and B gene families, implying a common underlying genetic lesion. These data reveal novel diagnostic and therapeutic targets and demonstrate the potential of microarray-based dissection of AML.

Late adverse reactions to intravascular iodinated contrast media.

Abstract: Late adverse reactions to intravascular iodinated contrast media are defined as reactions occurring 1 h to 1 week after contrast medium injection. They have received increasing interest over the past decade, but their prevalence remains uncertain and their pathophysiology is not fully understood. The Contrast Media Safety Committee of the European Society of Urogenital Radiology decided to review the literature and to issue guidelines. An extensive literature search was carried out and summarized in a report. Based on the available information, simple guidelines have been drawn up. The report and guidelines were discussed at the 8th European Symposium on Urogenital Radiology in Genoa. Late adverse reactions after intravascular iodinated contrast medium include symptoms such as nausea, vomiting, headache, itching, skin rash, musculoskeletal pain, and fever. A significant proportion of these reactions is unrelated to the contrast medium; however, allergy-like skin reactions are well-documented side effects of contrast media with an incidence of approximately 2%. Late reactions appear to be commoner after non-ionic dimers. The majority of late skin reactions after contrast medium exposure are probably T-cell-mediated allergic reactions. Patients at increased risk of late skin reactions are those with a history of previous contrast medium reaction and those on interleukin-2 treatment. Most skin reactions are self-limiting and resolve within a week. Management is symptomatic and similar to the management of other drug-induced skin reactions.

Insulin sensitivity and glucose tolerance improve in patients with acromegaly converted from depot octreotide to pegvisomant.

Abstract: Aim and method: Insulin resistance leading, in some cases, to glucose intolerance is an important contributory factor to the cardiovascular morbidity and mortality associated with acromegaly. The aim of this study was to document changes in insulin sensitivity (IS) in a group of seven patients with acromegaly (three male, four female, mean^S.D. age 59^13 years) treated initially with a stable dose of depot octreotide (OT; median dose 30 mg four times weekly, range 10 – 30 mg) for a median of 18 months (range 16 – 19 months) and who were then transferred to treatment with pegvisomant (median dose 15 mg daily, range 10 – 20 mg) for a median of 8 months (range 7 – 9 months). IS was assessed by homeostatic model assessment (HOMA) using fasting glucose and insulin concentrations and by a short insulin tolerance test (sITT). Body composition was assessed by dual energy X-ray absorptiometry. Results: Mean^S.D. serum IGF-I concentrations during therapy with OT and with pegvisomant were not statistically different (283^119 ng/ml on OT vs 191^39 ng/ml on pegvisomant (P ¼ 0.4)). However, mean^S.D. fasting plasma glucose fell from 6.2^1.0 mmol/l on OT to 5.2^0.6 mmol/l on pegvisomant (P ¼ 0.017) and was lower on pegvisomant in all seven patients. In four patients, fasting plasma glucose fell from values diagnostic of diabetes mellitus or impaired fasting glucose on OT to within the normal range on pegvisomant. Mean^S.D. peripheral IS (by sITT) increased from 139^39mmol/l per min on OT to 169^59mmol/l per min on pegvisomant (P ¼ 0.037). Mean^S.D. IS (by HOMA %S) was unchanged over the course of the study (149.1^43.7% on OT vs 139.9^76.6% on pegvisomant, P ¼ 0.28). Mean^S.D. pancreatic b-cell secretory function (HOMA %B) improved significantly on pegvisomant compared with OT (49.4^19.2% vs 82.4^43.5%, P ¼ 0.01). No statistically significant change in total fat (P ¼ 0.3), % fat (P ¼ 0.28) or circulating non-esterified fatty acids (P ¼ 0.35) was observed. Conclusions: IS and glucose tolerance improved in patients converted from OT therapy to pegvisomant, without a change in body composition and even when serum IGF-I concentrations remained equally well controlled. This may be an important factor in the choice of medical therapy for patients with acromegaly.

Discriminatory value of the low-dose dexamethasone suppression test in establishing the diagnosis and differential diagnosis of Cushing's syndrome.

Abstract: Cushing's syndrome requires a screening test of high sensitivity, followed by biochemical evaluation of the source of the tumor when the cause is ACTH dependent. The high-dose dexamethasone suppression test is still in common use as an aid in differential diagnosis, although its value has been queried. We have routinely used the low-dose dexamethasone suppression test for many years in the diagnosis of Cushing's syndrome but noticed that patients with pituitary-dependent Cushing's syndrome or Cushing's disease, usually showed some degree of suppression of their serum cortisol, compared to those with the ectopic ACTH syndrome. We therefore analyzed retrospectively the serum cortisol responses during the low-dose dexamethasone suppression test and the high-dose dexamethasone suppression test in 245 patients with ACTH-dependent Cushing's syndrome and compared the diagnostic utility of each test either alone or in combination with a standard test using CRH. Evaluation of the serum cortisol response at 24 and 48 h during the low-dose dexamethasone suppression test correctly identified 98% of patients with ACTH-dependent Cushing's syndrome and distinguished between pituitary and ectopic causes with a sensitivity of 82% and a specificity of 79%. In the same patients, the serum cortisol response to the high-dose dexamethasone suppression test had a slightly higher sensitivity (91%) and specificity (80%). However, the combined criteria of a more than 30% suppression of serum cortisol during the low-dose dexamethasone suppression test and/or a more than 20% increase in the CRH test had a significantly higher sensitivity (97%) and specificity (94%) than either the high-dose dexamethasone or the CRH tests alone in the differential diagnosis of ACTH-dependent Cushing's syndrome. It produced equivalent information to that when high-dose and CRH test results were combined. We therefore conclude that in our patient series, the serum cortisol response during the low-dose dexamethasone suppression test is highly sensitive in diagnosing Cushing's syndrome and, combined with the results of the serum cortisol response to the CRH test, offered a safe and cost-effective test in the differential diagnosis of ACTH-dependent Cushing's syndrome. There does not appear to be any necessity for retaining the high-dose dexamethasone suppression test in this diagnostic work-up.

The GH-IGF-I axis and breast cancer.

Abstract: The growth hormone-insulin-like growth factor-I (GH-IGF-I) axis plays a fundamental role in the development of the breast. The maintenance of breast tissue architecture is aided by its effect on proliferation, differentiation and apoptosis. There has been increasing recognition of its role as a major determinant of breast cancer and, more recently, its involvement in the development of resistance to both tamoxifen and an important novel therapy for advanced disease, trastuzumab (Herceptin). Here, we discuss the influence of the GH-IGF-I axis in normal mammary development and homeostasis, its putative role in breast tumorigenesis and its interactions with estrogen signalling.

Ghrelin is released from rat hypothalamic explants and stimulates corticotrophin-releasing hormone and arginine-vasopressin.

Abstract: Ghrelin and synthetic growth hormone secretagogues have diverse effects on the hypothalamus including effects on appetite and the growth hormone axis as well as on the hypothalamus-pituitary-adrenal (HPA) axis. We previously studied the effect of synthetic growth hormone secretagogues on CRH and AVP release from rat hypothalami in vitro, and now report on the effects of ghrelin on CRH and AVP release. The ghrelin protein content and ghrelin output from rat hypothalamic explants was measured using a specific novel ghrelin enzyme immunoassay. The effect of 10(-8) M to 10(-6) M ghrelin on CRH and AVP release was studied in the rat hypothalamic explants, where stimulation with des-octanoyl ghrelin was used as control. The presence of both ghrelin mRNA and protein could be shown in the rat hypothalamus. Ghrelin output was detected in the incubation fluid of rat hypothalamic explants and could be stimulated with high potassium concentrations. Our data also demonstrated a dose-dependent effect of ghrelin on both CRH and AVP release, while des-octanoylated ghrelin showed no effect on either peptide. In summary, the current data suggest that ghrelin is expressed in the hypothalamus both at RNA and the protein levels. Ghrelin stimulates the HPA axis in the rat via stimulation of both CRH, and particularly, AVP release from the hypothalamus. The local autocrine/paracrine and endocrine effects of ghrelin in the hypothalamus could influence all the hormonal systems involved in ghrelin effects, including growth hormone release, the HPA axis and appetite.

Delayed puberty associated with inflammatory bowel disease.

Abstract: Delayed puberty frequently complicates the clinical course of young patients with inflammatory bowel disease, more often in Crohn's disease than ulcerative colitis. Undernutrition has been thought to be the main reason for delayed puberty in these patients. However, puberty may be delayed despite a normal nutritional status. Observations in patients with inflammatory bowel disease and in rats with experimental colitis suggest that inflammatory mediators may have a direct adverse influence, independent of undernutrition, on the onset and progression of puberty. Serum androgens are consistently reported to be reduced in patients with delayed puberty and inflammatory bowel disease. This reduction is not necessarily secondary to a reduction in gonadotrophins as serum concentrations of gonadotrophins have been reported to be normal or even increased in some studies. Management of delayed puberty involves calorie supplements to correct undernutrition and treatment of inflammation. Observations in boys with delayed puberty and controlled studies in experimental models of intestinal inflammation suggest that testosterone therapy can accelerate puberty.

Long-term experience with GH replacement therapy: efficacy and safety.

Abstract: Demonstration of the long-term efficacy of GH replacement in GH-deficient adults has depended on a combination of single-centre studies and data from large multinational databases, which, by virtue of their size, are likely to detect rare adverse events and also permit analysis of mortality rates. The Pharmacia International Metabolic Surveillance (KIMS) study (a pharmacoepidemiological survey of the safety and efficacy of GH replacement in adults, sponsored by Pharmacia) is currently the largest database, with information on over 8000 patients from a total of 27 countries. Abundant epidemiological evidence confirms that hypopituitarism is associated with premature mortality, with an increase in cardiovascular and cerebrovascular disease as a primary underlying cause. Central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus are common in adults with hypopituitarism. GH replacement is associated with improvements in central fat mass and mean reductions in serum total and low-density lipoprotein cholesterol which may be additive to those achieved with hydroxymethylglutaryl-coenzyme A reductase inhibitors. These beneficial effects are maintained for at least 2 Years after initiation of therapy, as are reductions in central adiposity, with similar benefits seen in men and women when the GH dose is titrated to achieve a serum IGF-I between the median and the upper end of the age-related reference range. Fasting plasma glucose and glycated haemoglobin increase, usually within the reference range, during prolonged GH replacement, but do not tend to rise further above baseline in subjects with pre-existing impaired glucose tolerance. Bone remodelling increases during GH replacement therapy, but indices tend to return to baseline within 5 Years of commencing treatment. Bone mineral density increases in men whereas, in women, improvement is limited to stabilisation of bone density. Data from the KIMS study demonstrate that prolonged GH replacement is associated with a reduction in the number of patients requiring assistance with daily living and a significant reduction in sick leave and hospital admissions. GH replacement therapy improves psychological well-being, particularly in those patients with the greatest deficit prior to treatment, with improvement maintained beyond 6 Months of therapy and sustained during long-term follow-up. Data from the KIMS population show that there is no increase in the overall occurrence of de novo neoplasia or the rate of regrowth of primary pituitary tumours. There is an apparent increase in intracranial neoplasia, which may be an artefact of comparing a surveillance population with general population data. Unlike mortality in untreated hypopituitary GH-deficient patients, mortality in the KIMS study is currently similar to that predicted for the normal population.

Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2

Abstract: CEBPA encodes the transcription factor C/EBPα and is specifically up-regulated during granulocytic differentiation. The gene is mutated in approximately 20% of patients with acute myeloid leukemia (AML) FAB type M2 and occurs in the absence of the t(8;21). In much the same way as specific translocations are associated with a particular AML FAB type, the identification of non-random associations of gene mutation with karyotype or FAB type may be helpful in elucidating the molecular basis of certain forms of leukemia. To confirm these initial findings, 99 patients with AML FAB type M1 or M2 were screened for CEBPA mutations by use of a PCR–single-strand conformational polymorphism and sequencing approach. Nine CEBPA mutations were identified in eight patients. The mutations were clustered toward the COOH terminal of the protein and occurred exclusively in the intermediate cytogenetic risk group (8/64, 12.5%). Two patients with biallelic mutation, one homozygous for 1137Ins (57 bp) and another with two CEBPA mutations, 1096Ins (27 bp) and 363Ins (GGCC), were observed. There was no evidence for deletion of this region in the other six mutated samples analyzed by fluorescence in situ hybridization with a BAC clone spanning the CEBPA locus. CEBPA mutation status was not demonstrated to be of prognostic importance in this patient group, although this may reflect the selection and size of the AML population studied. In conclusion, mutation of CEBPA is a recurrent finding in AML and appears specific to the intermediate cytogenetic risk group patients. © 2003 Wiley-Liss, Inc.

Epidemiology, public health and the problem of personality disorder

Abstract: Background The public health problem-solving paradigm is a comprehensive method not previously applied to preventive interventions for personality disorder. Aims To present an overview for clinical psychiatrists. Method Review of epidemiological research into DSM—IV Axis Il disorders and application to the paradigm. Results Personality disorder affects a substantial proportion of the population. Burdens on health care, social and criminal justice agencies have yet to be accurately quantified. Debates continue over case definition, but there is increasing information on prevalence using ‘broad’ definitions and aetiology. A conceptual framework, based on development, suggests preventive interventions should be targeted in childhood. The public health approach also requires monitoring of risk factors operating at the population level. Conclusions Services in England and Wales for persons with personality disorder are currently inadequate. The problem-solving paradigm suggests new preventive interventions. Psychiatrists should renegotiate their relationship with policy-makers and reconsider their preventive role.

Clinical features associated with survival of patients with lymphoma of the ocular adnexa.

Abstract: Purpose Although systemic or eyelid involvement by ocular adnexal lymphoma carries a worse prognosis, there have been few reports of the outcome in relation to clinical presentation The outcome of malignant ocular adnexal lymphoma was, therefore, related to presenting clinical symptoms and signs Design and Methods A retrospective, noncomparative case-note review of 326 patients treated in the Orbital Clinic at Moorfields Eye Hospital The associations between presenting symptoms or signs and three outcome measures (vi) were assessed by univariate and multiple variable regression together with Kaplan–Meier analysis Main Outcome Measures (i) Presence of extra-orbital disease at the time of presentation; (ii) development of systemic lymphoma after new presentation with solely ocular adnexal disease; and (iii) death attributable to widespread lymphoma Results Presentation with disseminated disease was rarer with over 1 year's ophthalmic symptoms (odds ratio (OR) 07; 95% CI 05–09) and much more frequent with bilateral adnexal disease (OR 58; 95% CI 30–112) With solely adnexal disease at presentation, subsequent extra-orbital lymphoma was more frequent and earlier with lacrimal gland disease (as compared to those without; hazard ratio (HR) 19; 95% CI 12–45) or with eyelid disease (compared to those without; HR 24; 95% CI 12–45), or with bilateral disease (compared to unilateral disease; HR 26; 95% CI 14–52) Prior or concurrent systemic disease was the most significant predictive factor for lymphoma-related death (HR 68; 95% CI 43–109), but tumour-related death was also commoner and earlier with bilateral disease (HR 24; 95% CI 14–40) or where a relative afferent papillary defect was present (HR 28; 95% CI 16–49) Similarly, the rate of tumour-related death was slightly less where symptoms had been present for more than a year (HR 08; 95% CI 07–10) and slightly greater in the elderly (HR 103; 95% CI 101–105) Conjunctival lymphoma had the lowest rate of extra-orbital spread and lymphoma-related death, the rate of these two events being sequentially greater for patients with predominantly deep orbital lymphoma, lacrimal gland lymphoma, or eyelid lymphoma Conclusion These data suggest that presenting symptoms and signs of patients with ocular adnexal lymphoma are significantly associated with the risk of systemic disease at orbital presentation, the rate of subsequent spread, and the rate of lymphoma-related death

Computed tomography assessment of fat distribution in male and female patients with Cushing's syndrome.

Abstract: Objective: Our aims were to describe the abdominal fat distribution in male patients with Cushing’s syndrome (CS) on computerised tomography (CT), to compare our findings with non-cushingoid patients, to validate previous reports of increased visceral fat in female patients with CS and to identify any correlations between fat distribution and biochemical findings. Design: Retrospective and observational. Patients: Appropriate CT scans were identified in 31 patients (seven male) with active CS. Measurements: Total, visceral and subcutaneous fat areas were obtained. The percentage of visceral fat and the visceral to subcutaneous fat ratio (V:S ratio) were calculated. Biochemical data were recorded. Control data of fat distribution were obtained from the literature. Results: There was a significant increase in the V:S ratio in male patients with CS when compared with non-cushingoid controls (1.175^0.59 vs 0.77^0.39, 95% confidence interval (CI) 0.0817 – 0.728). There was a significant increase in the V:S ratio in female patients with CS (0.845^0.53 vs 0.38^0.19, 95% CI 0.269 – 0.661). There was no difference in the V:S ratio between male and female patients with CS (1.175^0.59 vs 0.845^0.53, 95% CI 2 0.144 – 0.804). No significant correlations between fat distribution and glucose levels, circulating cortisol, ACTH or lipids were found. Conclusions: Our data demonstrate an increase in visceral fat distribution in both male and female patients with CS, with the abolition of the normal male to female difference in visceral fat. Increased visceral fat may increase the risk of the metabolic syndrome in this group of patients.

Membrane-permeable radical scavengers (tempol) for shock, ischemia-reperfusion injury, and inflammation.

Abstract: T empol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) is a water-soluble analogue of the spin label TEMPO, which is widely employed in electron spin resonance spectroscopy. Tempol is a stable piperidine nitroxide of low molecular weight (molecular weight, 172) that permeates biological membranes (Fig. 1). This article reviews the effects of tempol in animal models of shock, ischemiareperfusion injury, and inflammation. It should be noted that the effects of tempol in animal models of hypertension, diabetes, and vascular (endothelial cell) dysfunction are not subject of this review. In a separate section, the interactions of tempol with superoxide anions, hydrogen peroxide (H2O2), hydroxyl radicals, nitric oxide (NO), and peroxynitrite are discussed. Finally, this article highlights the potential therapeutic uses and side effects of tempol.

The Value of the Low-Dose Dexamethasone Suppression Test in the Differential Diagnosis of Hyperandrogenism in Women

Abstract: We studied 211 hyperandrogenic women with respect to clinical presentation, basal androgen levels, and the degree of cortisol and androgen suppression during a 48-h low-dose (2 mg) dexamethasone-suppression test (LDDST) to exclude ovarian and adrenal tumors. In 42 women with elevated testosterone levels, 21 of whom failed to suppress testosterone during the LDDST, the response of serum androgen levels during a 4-wk administration of 7.5 mg prednisolone in a reverse circadian regimen was also assessed. These results were compared with an additional 17 patients with histologically proven androgen-secreting tumors. Clinical presentation alone was suggestive of a virilizing tumor in 70% of patients with tumors. Serum testosterone, although occasionally only marginally elevated, was the sole androgen that was elevated in every patient with a tumor. After the LDDST, none of the patients with tumors obtained either a greater than 40% reduction or normalization of the previously elevated testosterone levels, whereas 88% of patients with nontumorous hyperandrogenism showed either normalization or suppression of more than 40%. With one exception, all of the patients with nontumorous hyperandrogenism who showed inadequate suppression of testosterone during the LDDST, and were treated with prednisolone, normalized the previously elevated androgens after 1 month of administration. In summary, in women presenting with hyperandrogenism, lack of testosterone suppression during the LDDST is associated with 100% sensitivity and 88% specificity in distinguishing patients with ovarian and adrenal androgen-secreting tumors from patients with nontumorous hyperandrogenism in this small series. The LDDST is an easy to perform screening test that can also identify causes of hyperandrogenism due to altered glucocorticoid secretion.

Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.

Abstract: BACKGROUND: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL). METHODS: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD. RESULTS: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex. CONCLUSION: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.

Family History is a Coronary Heart Disease Risk Factor in the Second Northwick Park Heart Study

Abstract: We have estimated the risk of coronary heart disease (CHD) from family history of CHD (FHCHD) in 2827 healthy European middle-aged men, and explored the extent to which this can be explained by classical and genetic risk factors. Men with FHCHD (obtained by questionnaire) had a hazard ratio of CHD of 1.73 (95% confidence interval: 1.30, 2.31) compared to those without FHCHD; after adjusting for classical risk factors this did not change substantially. Those with FHCHD had 2.3% lower Factor VIIc (p = 0.03) and 1.14% higher systolic and 1.21% higher diastolic blood pressure (p = 0.04 and p = 0.02), with evidence of interaction between blood pressure and FHCHD status on risk (p = 0.01). The risk for those with a positive family history who were also current smokers was 3.01 compared to non-smokers without FHCHD, which is greater than the risk posed by smoking or FHCHD alone (1.96 and 2.05 respectively compared to non-smokers without FHCHD), but not significantly different from a multiplicative model (p-value for interaction 0.33). Allele frequencies for 13 candidate gene variants were not significantly different between those with and without FHCHD. In those with FHCHD, current smokers who carried the APOE4 allele (e4+) had a hazard ratio of 5.66 compared to non-smokers who had no FHCHD and were not APOE4+, with a significant interaction between smoking and APOE4 in those with FHCHD p = 0.001. These data demonstrate the complex interaction between genetic and environmental factors in determining CHD risk, and suggest that the causes of the familial clustering of CHD remain largely unexplained.

Is ovarian and adrenal venous catheterization and sampling helpful in the investigation of hyperandrogenic women

Abstract: OBJECTIVE To audit our practice of performing ovarian and adrenal venous catheterization and sampling in hyperandrogenic women who fail to suppress their elevated androgen levels following a 48-h low-dose dexamethasone suppression test (LDDST). We considered the technical success rate of catheterization, the extra information obtained in addition to the standard biochemical tests and imaging findings, and the impact of sampling on management decisions. DESIGN A retrospective analysis of the results of all ovarian and adrenal venous catheterizations performed at St Bartholomew's Hospital, London, in the years 1980-1996. PATIENTS AND METHODS Baseline ovarian and adrenal androgens were measured in all women presenting with symptoms and signs of hyperandrogenism. Those patients who failed to suppress their elevated testosterone (T), androstenedione (A4) and/or dehydroepiandrosterone-sulphate (DHEAS) levels following a LDDST to within the normal range or to less than 50% of the baseline value were investigated further with adrenal computed tomography (CT), ovarian ultrasound, and ovarian and adrenal venous catheterization and sampling. RESULTS Results were available in 38 patients. The overall catheterization success rate was: all four veins in 27%, three veins in 65%, two veins in 87%. The success rate for each individual vein was: right adrenal vein (RAV) 50%, right ovarian vein (ROV) 42%, left adrenal vein (LAV) 87% and left ovarian vein (LOV) 73%. Eight patients were found to have tumours by means of imaging (adrenal CT and ovarian ultrasound), three adrenal and five ovarian, seven of which underwent operation. In six of these patients the clinical presentation was suggestive of the presence of a tumour; in addition, the combination of imaging findings allowed the detection of suspicious adrenal and ovarian masses in all eight cases. The five patients with ovarian tumours had serum testosterone levels > 4.5 nmol/l. In a further eight patients, laparotomy was performed based on a combination of diagnostic and therapeutic indications; in two of these patients the catheterization results were suggestive of an ovarian tumour. All these eight patients were shown histologically to have polycystic ovarian syndrome (PCOS), and no occult ovarian tumour was identified. None of the patients with nontumourous hyperandrogenism had a baseline testosterone level in excess of 7 nmol/l (median 4.4 nmol/l, range 2.5-7 nmol/l). CONCLUSIONS Our results suggest that ovarian and adrenal venous catheterization and sampling should not be performed routinely in women presenting with symptoms and signs of hyperandrogenism, even if they fail to suppress their elevated androgen levels to a formal 48-h LDDST. All patients presenting with symptoms and signs of hyperandrogenism and elevated androgen levels, and where the suspicion of an androgen-secreting tumour is high, should have adrenal CT and ovarian ultrasound imaging to detect such a tumour. Venous catheterization and sampling should be reserved for patients in whom uncertainty remains, as the presence of a small ovarian tumour cannot be excluded on biochemical and imaging studies used in this series alone. Its use should be restricted to units with expertise in this area.