Showing papers by "St Bartholomew's Hospital published in 2006"

Prevalence and correlates of personality disorder in Great Britain.

Abstract: Background Epidemiological data on personality disorders, comorbidity and associated use of services are essential for health service policy. Aims To measure the prevalence and correlates of personality disorder in a representative community sample. Method The Structured Clinical Interview for DSM–IVAxis II disorders was used to measure personality disorder in 626 persons aged 16–74 years in households in England, Scotland and Wales, in a two-phase survey. Results The weighted prevalence of personality disorder was 4.4% (95% CI 2.9–6.7).Rates were highest among men, separated and unemployed participants in urban locations. High use of healthcare services was confounded by comorbid mental disorder and substance misuse. Cluster B disorders were associated with early institutional care and criminality. Conclusions Personality disorder is common in the community, especially in urban areas. Services are normally restricted to symptomatic, help-seeking individuals, but a vulnerable group with cluster B disorders can be identified early, are in care during childhood and enter the criminal justice system when young. This suggests the need for preventive interventions at the public mental health level.

The Ectopic Adrenocorticotropin Syndrome: Clinical Features, Diagnosis, Management, and Long-Term Follow-Up

Abstract: Context: There are few large series of patients with ectopic, nonpituitary, corticotropin (ACTH) secretion (EAS). Objective: The objective of this study was to analyze the clinical, biochemical, and radiological features, management, and treatment outcome of patients with EAS. Design: This was a retrospective case-record study. Setting: The setting for this study was a tertiary referral hospital center. Patients: Forty patients with EAS were studied. Main Outcome Measures: Clinical, biochemical, and radiological features and response to therapy and survival were measured. Results: The median follow-up was 5 yr (range, 2–30 yr). None of the dynamic tests achieved 100% accuracy, but bilateral inferior petrosal sinus sampling showed an absent central gradient in all but one case (one of 12). Imaging correctly identified the lesion at first investigation in 65% of cases. Bronchial carcinoid tumors were the most common cause of EAS (n = 12; 30%), followed by other neuroendocrine tumors (n = 13, 32.5%). In 12.5...

Do corticosteroids damage the brain

Abstract: Corticosteroids are an essential component of the body's homeostatic system. In common with other such systems, this implies that corticosteroid levels in blood and, more importantly, in the tissues remain within an optimal range. It also implies that this range may vary according to circumstance. Lack of corticosteroids, such as untreated Addison's disease, can be fatal in humans. In this review, we are principally concerned with excess or disturbed patterns of circulating corticosteroids in the longer or shorter term, and the effects they have on the brain.

The impact of CT image integration into an electroanatomic mapping system on clinical outcomes of catheter ablation of atrial fibrillation.

Abstract: CT Image Integration for AF Ablation. Background: A detailed appreciation of left atrial/ pulmonary vein (LA/PV) anatomy may be important in improving the safety and success of catheter ablation (CA) for atrial fibrillation (AF). Objectives: The aim of this nonrandomized study was to determine the impact of computerized tomography (CT) image integration into a 3-dimensional (3D) mapping system on the clinical outcome of patients undergoing CA for AF. Methods: Ninety-four patients (age: 56 ± 10 years) with AF (paroxysmal 46, persistent 48) underwent wide encirclement of ipsilateral PV pairs using irrigated radiofrequency ablation with the endpoint of electrical isolation. Ablation was guided by 3D mapping alone (electroanatomic 24, noncontact 23) in 47 (3DM group) patients and by CT image integration (Cartomerge®) in 47 (CT group). In persistent AF, a combination of linear ablation and targeted ablation of complex fractionated electrograms was also performed. Results: Successful PV electrical isolation did not differ between the two groups. A significant reduction in fluoroscopy times was demonstrated in the CT group (49 ± 27 minutes vs 3DM group 62 ± 26 minutes, P = 0.03). Arrhythmia recurrence was reduced in the CT group (32% vs 51% in the 3DM group, P < 0.01). In 30 symptomatic patients (12 CT and 18 3DM), repeat procedures for AF (13 in 3DM and 5 CT, P < 0.10) and AT (5 in 3DM and 7 CT, P = NS) were performed. Overall success on 7-day monitor off antiarrhythmic drugs was achieved in 60% in the 3DM group when compared with 83% in the CT group (P < 0.05) at a follow-up of 25 ± 5 weeks. Conclusion: CA for AF guided by CT integration was associated with reduced fluoroscopy times, arrhythmia recurrence, and increased restoration of sinus rhythm. Improved visualization of complex LA geometries might improve the safety and success of CA for AF.

Number of CD4+ Cells and Location of Forkhead Box Protein P3–Positive Cells in Diagnostic Follicular Lymphoma Tissue Microarrays Correlates With Outcome

Abstract: Purpose To examine the immune microenvironment in diagnostic follicular lymphoma (FL) biopsies and evaluate its prognostic significance. Patients and Methods Immunohistochemistry was used to study numbers and location of cells staining positive for immune cell markers CD4, CD7, CD8, CD25, CD68, forkhead box protein P3 (FOXP3), T-cell intracellular antigen-1, and Granzyme B in tissue microarrays of paraffin-embedded, diagnostic lymph node biopsies taken from 59 FL patients who lived less than 5 years (short-survival group; n = 34) and more than 15 years (long-survival group; n = 25). Results CD4 and FOXP3 expression were significantly different between the two groups. Samples from the long-survival group were more likely than those from the short-survival group to have CD4+ staining cells and to have FOXP3-positive cells in a perifollicular location. Conclusion This study has identified differences in immune cell composition of the diagnostic FL lymph node immune microenvironment and these have the potenti...

Conventional pituitary irradiation is effective in lowering serum growth hormone and insulin-like growth factor-I in patients with acromegaly.

Abstract: Background: There has been recent controversy as to the effectiveness of conventional pituitary irradiation in reducing circulating GH levels to less than 2.5 ng/ml and/or normalization of serum IGF-I. Objectives: Our objectives were to determine the effects of conventional pituitary irradiation on 1) lowering of serum GH and IGF-I levels, 2) the proportion of patients who achieve a GH level less than 2.5 ng/ml and a normal age-corrected IGF-I and the time taken to achieve this, and 3) the incidence of hypopituitarism and other adverse effects. Design: We conducted retrospective data collection from 14 centers throughout the United Kingdom. Patients: We studied 1840 patients with acromegaly, of whom 884 had received conventional pituitary irradiation. Measurements: We assessed circulating GH and IGF-I levels and pituitary function at intervals after irradiation. Results: Mean GH levels declined from 13.5 to 5.3 ng/ml at 2 yr after irradiation, to 2.0 ng/ml by 10 yr, and to 1.1 ng/ml at 20 yr. Twenty-two p...

Insight into the nature of the CRP–coronary event association using Mendelian randomization

Abstract: BACKGROUND: It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded. METHODS: We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies). RESULTS: CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs. CONCLUSIONS: A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.

Does growth hormone cause cancer

Abstract: The ability of GH, via its mediator peptide IGF-1, to influence regulation of cellular growth has been the focus of much interest in recent years In this review, we will explore the association between GH and cancer Available experimental data support the suggestion that GH/IGF-1 status may influence neoplastic tissue growth Extensive epidemiological data exist that also support a link between GH/IGF-1 status and cancer risk Epidemiological studies of patients with acromegaly indicate an increased risk of colorectal cancer, although risk of other cancers is unproven, and a long-term follow-up study of children deficient in GH treated with pituitary-derived GH has indicated an increased risk of colorectal cancer Conversely, extensive studies of the outcome of GH replacement in childhood cancer survivors show no evidence of an excess of de novo cancers, and more recent surveillance of children and adults treated with GH has revealed no increase in observed cancer risk However, given the experimental evidence that indicates GH/IGF-1 provides an anti-apoptotic environment that may favour survival of genetically damaged cells, longer-term surveillance is necessary; over many years, even a subtle alteration in the environmental milieu in this direction, although not inducing cancer, could result in acceleration of carcinogenesis Finally, even if GH/IGF-1 therapy does result in a small increase in cancer risk compared to untreated patients with GH deficiency, it is likely that the eventual risk will be the same as the general population Such a restoration to normality will need to be balanced against the known morbidity of untreated GH deficiency

Palliative chemotherapy beyond three courses conveys no survival or consistent quality-of-life benefits in advanced non-small-cell lung cancer

Abstract: This randomised multicentre trial was conducted to establish the optimal duration of palliative chemotherapy in advanced non-small-cell lung cancer (NSCLC). We compared a policy of three vs six courses of new-generation platinum-based combination chemotherapy with regard to effects on quality of life (QoL) and survival. Patients with stage IIIB or IV NSCLC and WHO performance status (PS) 0–2 were randomised to receive three (C3) or six (C6) courses of carboplatin (area under the curve (AUC) 4, Chatelut's formula, equivalent to Calvert's AUC 5) on day 1 and vinorelbine 25 mg m−2 on days 1 and 8 of a 3-week cycle. Key end points were QoL at 18 weeks, measured with EORTC Quality of Life Questionnaire (QLQ)-C30 and QLQ-LC13, and overall survival. Secondary end points were progression-free survival and need of palliative radiotherapy. Two hundred and ninety-seven patients were randomised (C3 150, C6 147). Their median age was 65 years, 30% had PS 2 and 76% stage IV disease. Seventy-eight and 54% of C3 and C6 patients, respectively, completed all scheduled chemotherapy courses. Compliance with QoL questionnaires was 88%. There were no significant group differences in global QoL, pain or fatigue up to 26 weeks. The dyspnoea palliation rate was lower in the C3 arm at 18 and 26 weeks (P<0.05), but this finding was inconsistent across different methods of analysis. Median survival in the C3 group was 28 vs 32 weeks in the C6 group (P=0.75, HR 1.04, 95% CI 0.82–1.31). One- and 2-year survival rates were 25 and 9% vs 25 and 5% in the C3 and C6 arm, respectively. Median progression-free survival was 16 and 21 weeks in the C3 and C6 groups, respectively (P=0.21, HR 0.86, 95% CI 0.68–1.08). In conclusion, palliative chemotherapy with carboplatin and vinorelbine beyond three courses conveys no survival or consistent QoL benefits in advanced NSCLC.

Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity

Abstract: Purpose To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. Patients and Methods Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-α) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. Results Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to tr...

Acute pain management for opioid dependent patients

Abstract: Patients requiring acute pain management may be opioid dependent as a result of either recreational or therapeutic opioid use, including those in opioid addiction programmes. Pain in these patients is often under-estimated and under-treated. In addiction, drug-seeking behaviour differentiates it from simple dependence. With few randomised controlled trials, current evidence predominantly consists of guidelines based on case reports, retrospective studies and expert opinion. Consensus recommendations include maintaining regular provision of the patient's pre-existing opioid requirement, with additional analgesia, ideally multimodal, in appropriate combinations of short-acting opioid (as required), local anaesthesia, and adjuvant anti-inflammatory analgesics and paracetamol. Patient controlled analgesia with higher bolus doses and shorter lock-out intervals is a recommended strategy. Transdermal opioid patches and implantable pumps will continue to deliver opioid, to which non-opioid and short-acting opioids may be added. Re-exposure to opioid is ideally avoided in previously addicted patients, but if not feasible, opioid therapy should be prescribed.

Multicenter Phase II Trial of Immunotherapy With the Humanized Anti-CD22 Antibody, Epratuzumab, in Combination With Rituximab, in Refractory or Recurrent Non-Hodgkin's Lymphoma

Abstract: Purpose A multicenter, single-arm study examining efficacy and toxicity of epratuzumab combined with rituximab was conducted in patients with recurrent or refractory non-Hodgkin's lymphoma. Patients and Methods Sixty-five patients were enrolled; 34 patients with follicular lymphoma (FL), 15 patients with diffuse large B-cell lymphoma (DLBCL), and 16 patients with other lymphomas. The patients had received a median of two prior therapies (range, 1 to 4); 23% had received rituximab. Epratuzumab was given at 360 mg/m2 intravenously over 60 minutes followed by infusion of 375 mg/m2 rituximab, weekly for 4 consecutive weeks. Results Combination therapy was well tolerated without greater toxicity than rituximab alone. The objective response (OR) rate was 47% (30 of 64) in assessable patients (46%; 30 of 65 in all patients), being highest in FL (64%; 21 of 33) and DLBCL (47%; seven of 15), and with 24% (eight of 33) and 33% (five of 15) achieving complete response (CR) or complete response unconfirmed (CRu) in t...

Influence of an algal triacylglycerol containing docosahexaenoic acid (22 : 6n-3) and docosapentaenoic acid (22 : 5n-6) on cardiovascular risk factors in healthy men and women.

Abstract: The intake of long-chain n-3 PUFA, including DHA (22 : 6n-3), is associated with a reduced risk of CVD. Schizochytrium sp. are an important primary source of DHA in the marine food chain but they also provide substantial quantities of the n-6 PUFA docosapentaenoic acid (22 : 5n-6; DPA). The effect of this oil on cardiovascular risk factors was evaluated using a double-blind randomised placebo-controlled parallel-design trial in thirty-nine men and forty women. Subjects received 4 g oil/d for 4 weeks; the active treatment provided 1.5 g DHA and 0.6 g DPA. Active treatment increased plasma concentrations of arachidonic acid, adrenic acid, DPA and DHA by 21, 11, 11 and 88 mg/l respectively and the proportions of DPA and DHA in erythrocyte phospholipids by 78 and 27 % respectively. Serum total, LDL- and HDL-cholesterol increased by 0.33 mmol/l (7.3 %), 0.26 mmol/l (10.4 %) and 0.14 mmol/l (9.0 %) compared with placebo (all P < or =0.001). Factor VII (FVII) coagulant activity increased by 12 % following active treatment (P = 0.006). There were no significant differences between treatments in LDL size, blood pressure, plasma glucose, serum C-reactive protein, plasma FVII antigen, FVII activated, fibrinogen, von Willebrand factor, tocopherol or carotenoid concentrations, plasminogen activator inhibitor-1, creatine kinase or troponin-I activities, haematology or liver function tests or self-reported adverse effects. Overall, the oil was well tolerated and did not adversely affect cardiovascular risk.

Long-term outcome among men with conservatively treated localised prostate cancer.

Abstract: Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of 30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients.

Violence and psychiatric morbidity in the national household population of Britain: public health implications

Abstract: Background It is unclear whether psychiatric morbidity contributes to the small proportion of the population responsible for a large percentage of antisocial behaviour, including violence. Aims To measure associations between psychiatric morbidity and severity, chronicity and types of victims of violence in the national household population of Britain. Method Cross-sectional survey of persons in households ( n =8397).Data included self-reported location, victims and outcome of violence over the previous 5 years. Diagnoses were determined by computer-assisted interviews. Results Hazardous drinking was associated with over half of all incidents involving injury. Antisocial personality disorder conveyed an attributable risk of 24% of respondents reporting victim injuries, but screening positive for psychosis conveyed an attributable risk of only 1.2%. Conclusions The burden of care resulting from violence associated with hazardous drinking supports population interventions. Despite exceptional risks, half of respondents with antisocial personality disorder were not violent, indicating limitations in targeted interventions to detain high-risk individuals.

A comparison between objective and subjective image quality measurements for a full field digital mammography system.

Abstract: This paper presents pre-sampling modulation transfer function (MTF), normalized noise power spectrum (NNPS) and detective quantum efficiency (DQE) results for an amorphous selenium (a-Se) full field digital mammography system. MTF was calculated from the image of an angled 0.5 mm thick Cu edge, acquired without additional beam filtration. NNPS data were acquired at detector air-kerma levels ranging from 9.1 µGy to 331 µGy, using a standard mammography x-ray spectrum of 28 kV, Mo/Mo target/filter combination and 4 cm of PMMA additional filtration. Prior to NNPS estimation, the image statistics were assessed using a variance image. This method was able to easily identify a detector artefact and should prove useful in routine quality assurance (QA) measurements. Detector DQE, calculated from the NNPS and MTF data, dropped to 0.3 for low detector air-kerma settings but reached an approximately constant value of 0.6 above 50 µGy at the detector. Subjective image quality data were also obtained at these detector air-kerma settings using the CDMAM contrast-detail (c-d) test object. The c-d data reflected the trend seen in DQE, with threshold contrast increasing at low detector air-kerma values. The c-d data were then compared against predictions made using two established models, the Rose model and a standard signal detection theory model. Using DQE(0), the Rose model gave results within approximately 15% on average for all the detector air-kerma values studied and for detail diameters down to 0.2 mm. Similar agreement was also found between the measured c-d data and the signal detection theory results, which were calculated using an ideal human visual response function and a system magnification of unity. The use of full spatial frequency DQE improved the agreement between the calculated and observer results for detail sizes below 0.13 mm.

Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus?

Abstract: Pheochromocytomas can have a highly variable presentation, making diagnosis challenging. To think of the tumor represents the crucial initial step, but establishing the diagnosis requires biochemical evidence of excessive catecholamine production and imaging studies to localize the source. Currently, however, there exist no generally agreed upon guidelines based on which tests and testing algorithms should be used to confirm and locate or exclude a suspected pheochromocytoma. Choice of biochemical tests and imaging studies instead usually depends on institutional experience. At the First International Symposium on Pheochromocytoma (ISP2005), held in Bethesda in October 2005, a panel of experts and patient representatives discussed current problems and available options for tumor diagnosis and localization and formulated recommendations, which were subsequently agreed upon by those in attendance at the meeting. This article summarizes the discussion and recommendations derived from that session.

Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours.

Abstract: Summary Objective To investigate two patients with the hyperparathyroidism-jaw tumour (HPT-JT) syndrome and three patients with familial isolated hyperparathyroidism (FIHP), together with 31 parathyroid tumours (2 HPT-JT, 2 FIHP and 27 sporadic) for HRPT2 mutations. The HPT-JT syndrome and FIHP are autosomal dominant disorders that may be caused by abnormalities of the HRPT2 gene, located on chromosome 1q31.2. HRPT2 encodes a 531 amino acid protein, parafibromin, which interacts with human homologues of the yeast Paf1 complex. Design Leukocyte and tumor DNA was used with HRPT2-specific primers for polymerase chain reaction amplification of the 17 exons and their splice junctions, and the DNA sequences of the polymerase chain reaction products determined. Results Three heterozygous germline HRPT2 mutations, two in HPT-JT and one in FIHP patients, were identified. These consisted of one 1-bp duplication (745dup1bp), 1 nonsense (Arg234Stop) and 1 missense (Asp379Asn) mutation. One parathyroid tumour from an FIHP patient was demonstrated to harbour a germline deletion of 1 bp together with a somatic missense (Leu95Pro) mutation, consistent with a ‘two-hit’ model for hereditary cancer. The 27 sporadic benign parathyroid tumours did not harbour any HRPT2 somatic mutations. Six HRPT2 polymorphisms with allele frequencies ranging from 2% to 15% were detected. Conclusions Our results have identified three novel HRPT2 mutations (two germline and one somatic). The Asp379Asn mutation is likely to disrupt interaction with the human homologue of the yeast Paf1 complex, and the demonstration of combined germline and somatic HRPT2 mutations in a parathyroid tumour provide further evidence for the tumour suppressor role of the HRPT2 gene.

A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma

Abstract: Despite intensive therapy, multiple myeloma (MM) remains an incurable disease, and novel treatment approaches are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the U.S. Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory or relapsed MM following the failure of at least two prior lines of therapy. Recently, it also received approval from the FDA for use as a second-line agent. An expert panel of hematologists met at the Ninth Congress of the European Hematology Association to review clinical data and experience in the treatment of MM with bortezomib, including bortezomib-based combination therapy. The conclusions of this expert panel, together with updated clinical data from the American Society of Hematology 46th Annual Meeting, provide a practical update on the use of bortezomib in MM. Bortezomib has demonstrated significant antitumor activity as a single agent in refractory and/or relapsed MM, with a significantly longer survival than with dexamethasone (1-year overall survival rate of 80% vs. 66%) and a 78% longer median time to progression. In combination therapy, patient responses suggest the possibility of chemosensitization and synergy. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem cell therapy. Bortezomib is well tolerated; most side effects are only mild to moderate and are manageable. Information is given on the practical management of the most common adverse events, including peripheral neuropathy and thrombocytopenia, and the use of bortezomib in renal and hepatic impairment.

Adult leydig cell tumors of the testis caused by germline fumarate hydratase mutations.

Abstract: Context: Leydig cell tumors (LCTs) are the most common non-germ-cell neoplasms of the testis. LCTs are often hormonally active and can result in precocious virilization or in adult feminization. We identified an LCT in an affected individual from a kindred with hereditary leiomyomatosis and renal cell cancer (HLRCC) and a germline fumarate hydratase (FH) mutation (N64T). Objective: Our objective was to investigate the role of FH mutations in predisposition to LCTs. Design: We tested for pathogenic effects of the N64T mutation and screened an additional 29 unselected adult LCTs for FH alterations. We also tested these LCTs for mutations in two genes, the LH/choriogonadotropin receptor (LHCGR) and the guanine nucleotide-binding protein α (GNAS) that had been implicated in LCT tumorigenesis. Results: No mutations were found in GNAS, and one tumor had a LHCGR somatic substitution. In addition to the HLRCC case with the N64T germline FH mutation, we identified one other LCT with a previously unreported FH muta...

Comparison of DNA extraction methods for Aspergillus fumigatus using real-time PCR.

Abstract: Newer methods such as PCR are being investigated in order to improve the diagnosis of invasive aspergillosis. One of the major obstacles to using PCR to diagnose aspergillosis is a reliable, simple method for extraction of the fungal DNA. The presence of a complex, sturdy cell wall that is resistant to lysis impairs extraction of the DNA by conventional methods employed for bacteria. Numerous fungal DNA extraction protocols have been described in the literature. However, these methods are time-consuming, require a high level of skill and may not be suitable for use as a routine diagnostic technique. Here, a number of extraction methods were compared: a freeze-thaw method, a freeze-boil method, enzyme extraction and a bead-beating method using Mini-BeadBeater-8. The quality and quantity of the DNA extracted was compared using real-time PCR. It was found that the use of a bead-beating method followed by extraction with AL buffer (Qiagen) was the most successful extraction technique, giving the greatest yield of DNA, and was also the least time-consuming method assessed.

Unmasking of central hypothyroidism following growth hormone replacement in adult hypopituitary patients

Abstract: Summary Background The effect of GH replacement on thyroid function in hypopituitary patients has hitherto been studied in small groups of children and adults with conflicting results. Objective We aimed to define the effect and clinical significance of adult GH replacement on thyroid status in a large cohort of GH-deficient patients. Patients and method We studied 243 patients with severe GH deficiency due to various hypothalamo-pituitary disorders. Before GH treatment, 159 patients had treated central hypothyroidism (treated group) while 84 patients were considered euthyroid (untreated group). GH dose was titrated over 3 months to achieve serum IGF-1 concentration in the upper half of the age-adjusted normal range. Serial measurements of serum T4, T3, TSH and quality of life were made at baseline and at 3 and 6 months after commencing GH replacement. Results In the untreated group, we observed a significant reduction in serum T4 concentration without a significant increase in serum T3 or TSH concentration; 30/84 patients (36%) became hypothyroid and needed initiation of T4 therapy. Similar but lesser changes were seen in the treated group, 25 of whom (16%) required an increase in T4 dose. Patients who became hypothyroid after GH replacement had lower baseline serum T4 concentration, were more likely to have multiple pituitary hormone deficiencies and showed less improvement in quality of life compared with patients who remained euthyroid. Conclusion GH deficiency masks central hypothyroidism in a significant proportion of hypopituitary patients and this is exposed after GH replacement. We recommend that hypopituitary patients with GH deficiency and low normal serum T4 concentration should be considered for T4 replacement prior to commencement of GH in order to provide a robust baseline from which to judge the clinical effects of GH replacement.