Showing papers by "St Bartholomew's Hospital published in 2001"

Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype

Abstract: OBJECTIVE: To analyze the association of polymorphisms in the tau gene with pathologically confirmed corticobasal degeneration (CBD). BACKGROUND: The authors previously described an extended tau haplotype (H1) that covers the human tau gene and is associated with the development of progressive supranuclear palsy (PSP). The authors now extend this analysis to CBD, a neurodegenerative condition with clinical and neuropathologic similarities to PSP. Like PSP, CBD is associated with accumulation of aggregates containing the 4-repeat isoforms of tau. Because of difficulty in diagnosis of CBD, the authors only analyzed cases with pathologically confirmed CBD. METHODS: The authors collected 57 unrelated, neuropathologically confirmed cases of CBD. Tau sequencing in these cases failed to show the presence of pathogenic mutations. Polymorphisms that spanned the tau gene were analyzed in all CBD cases and controls. RESULTS: Analyzing tau polymorphisms in CBD cases showed that the frequency of H1 and H1/H1 was significantly increased when analyzing all cases and when separating by country of origin. H1 frequency in all CBD cases was 0.921, compared with a control frequency of 0.766 (X(2) = 9.1, p = 0.00255 [1df], OR 3.56 [8.43 > CI 95% > 1.53]). The H1/H1 frequency was also significantly higher at 0.842 compared with 0.596 in age-matched controls (X(2) = 17.42, p = 0.00016, 2df), OR 3.61 [7.05 > CI 95% > 1.85]). CONCLUSIONS: The CBD tau association described here suggests that PSP and CBD share a similar cause, although the pathogenic mechanism behind the two diseases leads to a different clinical and pathologic phenotype.

Postoperative adhesions: ten-year follow-up of 12,584 patients undergoing lower abdominal surgery.

Abstract: PURPOSE: Postoperative adhesions are a significant problem after colorectal surgery. However, the basic epidemiology and clinical burden are unknown. The Surgical and Clinical Adhesions Research Study has investigated the scale of the problem in a population of 5 million. METHODS: Validated data from the Scottish National Health Service Medical Record Linkage Database were used to define a cohort of 12,584 patients undergoing open lower abdominal surgery in 1986. Readmissions for potential adhesion-related disease in the subsequent ten years were analyzed. The methodology was conservative in interpreting adhesion-related disease. RESULTS: In the study cohort 32.6 percent of patients were readmitted a mean of 2.2 times in the subsequent ten years for a potential adhesion-related problem. Although 25.4 percent of readmissions were in the first postoperative year, they continued steadily throughout the study period. After open lower abdominal surgery 7.3 percent (643) of readmissions (8,861) were directly related to adhesions. This varied according to operation site: colon (7.1 percent), rectum (8.8 percent), and small intestine (7.6 percent). The readmission rate was assessed to provide an indicator of relative risk of adhesion-related problems after initial surgery. The overall average rate of readmissions was 70.4 per 100 initial operations, with 5.1 directly related to adhesions. This rose to 116.4 and 116.5, respectively, after colonic or rectal surgery—with 8.2 and 10.3 directly related to adhesions. CONCLUSIONS: There is a high relative risk of adhesion-related problems after open lower abdominal surgery and a correspondingly high workload associated with these readmissions. This is influenced by the initial site of surgery, colon and rectum having both the greatest impact on workload and highest relative risk of directly adhesion-related problems. The study provides sound justification for improved adhesion prevention strategies.

Heterogeneity of type I diabetes: analysis of monozygotic twins in Great Britain and the United States.

Abstract: Aims. To determine the risk, hazard rate and factors affecting progression to diabetes in monozygotic twins of patients with Type I (insulin-dependent) diabetes mellitus. Methods. Prospective analysis was done of two cohorts of non-diabetic monozygotic twins of patients with Type I diabetes from Great Britain (n = 134) and the United States (n = 53). Results. The diabetes-free survival analysis was similar between both cohorts (p = 0.6). The combined survival analysis (n = 187, median follow-up = 17.7 years, range = 0.01–57) at 40 years of discordance estimated a 39 % probability of diabetes for the initially discordant twin. Survival analysis with left truncation of data estimated that probability to be 50 %. For twins who became concordant (n = 47), the median discordance time was 4.2 years (range 0.4 to 39), exceeding 15 years in 23.4 %. Twins of probands diagnosed at 24 years of age or younger had a 38 % probability of diabetes by 30 years of discordance, compared with 6 % for twins of probands diagnosed after 24 years of age (p = 0.004). The twins of probands diagnosed before 15 years of age had the highest diabetes hazard rate in the first discordance year, decreasing thereafter. By survival analysis, diabetes risk was higher in twins who were heterozygous for DR3-DQ2 and DR4-DQ8 than in twins with neither DR3-DQ2 nor DR4-DQ8 (p < 0.05). Conclusion/interpretation. Monozygotic twins of patients with Type I diabetes from two different countries had similar rates of progression to diabetes. Whereas most twins did not develop diabetes, 25 % of the twins who progressed did so after more than 14 years of discordance. An age-related heterogeneity was observed, with higher progression to diabetes for twins of patients diagnosed at a younger age. [Diabetologia (2001) 44: 354–362]

PTEN methylation is associated with advanced stage and microsatellite instability in endometrial carcinoma.

Abstract: Loss of heterozygosity and mutations in the PTEN (MMAC1) tumor suppressor gene are frequent in endometrial carcinoma. Promoter hypermethylation has recently been identified as an alternative mechanism of tumor suppressor gene inactivation in cancer, but its importance in the PTEN gene in endometrial carcinoma is unknown. The purpose of our study was to assess the frequency of promoter methylation of the PTEN gene and to determine its correlation with clinicopathologic variables in a prospective and population-based series of endometrial carcinomas with complete follow-up. Presence of PTEN promoter methylation was seen in 26 of 138 patients (19%). Methylation was significantly associated with metastatic disease (p = 0.01) and a microsatellite unstable phenotype (p = 0.006). In conclusion, we find that PTEN promoter methylation is relatively frequent in endometrial carcinoma. Its association with metastatic disease and microsatellite instability implicates its importance in the development of this tumor type.

Autoantibodies as predictors of disease

Abstract: Activation of the immune response is a major feature of many disease processes. Immune responses can be protective, as in infectious diseases, or destructive, as in autoimmune inflammatory diseases, or both. The immune response usually involves activation of both T and B cells, the latter producing antibodies that can be detected in the sera and can be used to guide the clinical management of certain diseases. Here, we focus on autoantibodies as predictive markers of disease. While the practical value of autoantibodies has been realized in some clinical conditions, it remains underutilized in the majority of diseases. Recognizing the clinical potential of autoantibodies and identifying appropriate populations to screen for such autoantibodies, we argue, could have rich practical rewards.

The Influence of Growth Hormone Deficiency, Growth Hormone Replacement Therapy, and Other Aspects of Hypopituitarism on Fracture Rate and Bone Mineral Density

Abstract: To assess the influence of factors affecting fracture risk and bone density in adult hypopituitary patients with growth hormone deficiency (GHD), data from a large-scale pharmacoepidemiological survey (the Pharmacia & Upjohn International Metabolic Database [KIMS]) were analyzed and compared with data from a control population (the European Vertebral Osteoporosis Study [EVOS]). The KIMS group consisted of 2084 patients (1112 men and 972 women) with various types of pituitary disease and EVOS consisted of 1176 individuals (581 men and 595 women). Fracture and bone mineral density (BMD) data were available from 2024 patients from the KIMS group and 392 patients from EVOS. The prevalence of fractures in patients with hypopituitarism was 2.66 times that in the non-GH-deficient EVOS population. Adult-onset hypopituitarism with GHD was associated with a higher fracture risk than childhood-onset disease, and patients with isolated GHD had a similar prevalence of fractures to those with multiple pituitary hormone deficiencies. Hormonal replacement therapy with L-thyroxine, glucocorticoids, and sex steroids did not affect the risk of fracture in KIMS patients. In addition, fracture rates in KIMS were independent of body mass index (BMI) and the country of origin. However, smoking was associated with a higher fracture rate in this group. In summary, this is the first large-scale analysis to support the hypothesis of an increased fracture risk in adult patients with hypopituitarism and GHD. This increased risk appears to be attributable to GHD alone, rather than to other pituitary hormone deficiencies or to their replacement therapy.

Comparison of Somatostatin Analog and Meta-Iodobenzylguanidine Radionuclides in the Diagnosis and Localization of Advanced Neuroendocrine Tumors

Abstract: A comparison has been made of [(123)I]meta-iodobenzylguanidine ([(123)I]MIBG) and [(111)In]pentetreotide scintigraphy in 54 patients with a variety of neuroendocrine tumors of whom 46 patients had metastatic disease. [(111)In]Pentetreotide scintigraphy was more sensitive in detecting metastatic lesions, as demonstrated on computed tomography and/or magnetic resonance scanning, than [(123)I]MIBG: 67% vs. 50% for carcinoid tumors (n = 24), 91% vs. 9% for pancreatic islet cell tumors (n = 12), 100% vs. 60% for medullary thyroid carcinomas (n = 5), and 75% vs. 100% for pheochromocytomas/paragangliomas (n = 4). In only 2 patients were lesions seen with [(123)I]MIBG scanning that were not apparent with [(111)In]pentetreotide. With the exception of pancreatic islet cell tumors, both radionuclides exhibited a similar sensitivity in detecting hepatic metastases, whereas in three patients the two radionuclides exerted a complementary role as different deposits exhibited uptake to only 1 or the other radionuclide. Hepatic metastases were the most important clinical predictor of a positive scan for both radionuclides. Neither elevated 5-hydroxyindoleacetic acid levels nor any other hormonal marker was predictive of a positive scan. In 8 patients with clinical and/or hormonal evidence of a neuroendocrine tumor but negative conventional radiology, [(111)In]pentetreotide scintigraphy was more sensitive than [(123)I]MIBG (37.5% vs. 12.5%) in detecting lesions. In conclusion, scintigraphy with [(111)In]pentetreotide detects more metastatic lesions than [(123)I]MIBG in patients with carcinoid and pancreatic islet cell tumors and medullary thyroid carcinomas; [(123)I]MIBG scintigraphy may be more sensitive for sympathoadrenomedullary tumors. The radionuclides may exert a complementary role in the detection and treatment of neuroendocrine tumors in occasional patients, as areas of different pattern of uptake were identified within the same patient. These data have implications not only for staging such tumors, but also for identifying patients who might benefit from treatment using either [(131)I]MIBG or radioactive somatostatin analogs.

Idiopathic gonadotrophin deficiency: genetic questions addressed through phenotypic characterization

Abstract: Summary OBJECTIVE The association of idiopathic hypogonadotrophic hypogonadism (IHH) with congenital olfactory deficit defines Kallmann’s syndrome (KS). Although a small proportion of IHH patients have been found to harbour defined genetic lesions, the genetic basis of most IHH cases remains to be elucidated. Genes currently recognized to be involved comprise KAL (associated with X-linkedKS), the GnRH receptor (associated with resistance to GnRH therapy), DAX 1 (associated with adrenohypoplasia congenita) and three loci also associated with obesity, leptin (OB), leptin receptor (DB) and prohormone convertase (PC1). Because of the rarity of the condition and the observation that patients are almost universally infertile without assistance, familial transmission of IHH is encountered infrequently and pedigrees tend to be small. This has constrained the ability of conventional linkage studies to identify other candidate loci for genetic IHH. We hypothesized that a systematic clinical evaluation of a large patient

Optimizing gh therapy in adults and children.

Abstract: Until the advent of modern neuroradiological imaging techniques in 1989, a diagnosis of GH deficiency in adults carried little significance other than as a marker of hypothalamo-pituitary disease. The relatively recent recognition of a characteristic clinical syndrome associated with failure of spontaneous GH secretion and the potential reversal of many of its features with recombinant human GH has prompted a closer examination of the physiological role of GH after linear growth is complete. The safe clinical practice of GH replacement demands a method of judging overall GH status, but there is no biological marker in adults that is the equivalent of linear growth in a child by which to judge the efficacy of GH replacement. Assessment of optimal GH replacement is made difficult by the apparent diverse actions of GH in health, concern about the avoidance of iatrogenic acromegaly, and the growing realization that an individual's risk of developing certain cancers may, at least in part, be influenced by cumulative exposure to the chief mediator of GH action, IGF-I. As in all areas of clinical practice, strategies and protocols vary between centers, but most physicians experienced in the management of pituitary disease agree that GH is most appropriately begun at low doses, building up slowly to the final maintenance dose. This, in turn, is best determined by a combination of clinical response and measurement of serum IGF-I, avoiding supraphysiological levels of this GH-dependent peptide. Numerous studies have helped define the optimum management of GH replacement during childhood. The recent requirement to measure and monitor GH status in adult life has called into question the appropriateness of simplistic weight- and surface area-based dosing regimens for the management of GH deficiency in childhood, with reliance on linear growth as the sole marker of GH action. It is clear that the monitoring of parameters other than linear growth to help refine GH therapy should now be incorporated into childhood GH treatment protocols. Further research will be required to define the optimal management of the transition from pediatric to adult GH replacement; this transition will only be possible once the benefits of GH in mature adults are defined and accepted by pediatric and adult endocrinologists alike.

Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium.

Abstract: BackgroundThe Toll protein in Drosophila regulates dorsal ventral patterning during embryogenesis, and participates in antibacterial and antifungal host defense. Mammalian homologues are termed Toll-like receptors and, to date, nine have been cloned (TLR1–9) in humans. They are characterized

Prevention of generalized reactions to contrast media: a consensus report and guidelines.

Abstract: The aim of this study was to document, using consensus methodology, current practice for prevention of generalized reactions to contrast media, to identify areas where there is disagreement or confusion and to draw up guidelines for reducing the risk of generalized contrast media reactions based on the survey and a review of the literature. A document with 165 questions was mailed to 202 members of the European Society of Urogenital Radiology. The questions covered risk factors and prophylactic measures for generalized contrast media reactions. Sixty-eight members (34%) responded. The majority indicated that a history of moderate and severe reaction(s) to contrast media and asthma are important risk factors. The survey also indicated that patients with risk factors should receive non-ionic contrast media. In patients at high risk of reaction, if the examination is deemed absolutely necessary, a resuscitation team should be available at the time of the procedure. The majority (91%) used corticosteroid prophylaxis given at least 11 h before contrast medium to patients at increased risk of reaction. The frequency of the dosage varied from one to three times. Fifty-five percent also use antihistamine Hl, mainly administered orally and once. Antihistamine H2 and ephedrine are rarely used. All essential drugs are available on the emergency resuscitation trolley. Patients with risk factors are observed up to 30 min by 48% and up to 60 min by 43% of the responders. Prophylactic measures are not taken before extravascular use of contrast media. Prophylactic drugs are given to patients with a history of moderate or severe generalized reaction to contrast media. In patients with asthma, opinion is divided with only half of the responders giving prophylactic drugs. Aspirin, beta-blockers, interleukin-2 and non-steroid anti-inflammatory drugs are not considered risk factors and therefore are not stopped before injection of contrast media. The survey showed some variability in rating of risk factors for generalized contrast medium reactions, and marked variability in the prophylactic measures used. There remain major areas of uncertainty, and there is insufficient data in the literature to guide practice. Some simple guidelines for prophylaxis of generalized contrast medium reactions are proposed.

Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG].

Abstract: Objective Meta-iodo-benzyl-guanidine labelled with 131-iodine [(131)I-mIBG] has been used extensively for imaging tumours originating from the neural crest but experience with its therapeutic use is limited, particularly for non-catecholamine secreting tumours. In order to assess the therapeutic response and potential adverse effects of the therapeutic administration of (131)I-mIBG, we have reviewed all patients who had received this form of treatment in our department. Design Retrospective analysis of the case notes of patients with neuroendocrine tumours who received treatment with (131)I-mIBG and were followed-up according to a defined protocol in a given time frame. Patients Thirty-seven patients (18 with metastatic carcinoid tumours, 8 metastatic phaeochromocytoma, 7 metastatic paraganglioma and 4 metastatic medullary carcinoma of the thyroid) treated with (131)I-mIBG over a 15-year period were included in this analysis. Measurements The symptomatic, hormonal and tumoural responses before and after (131)I-mIBG therapy over a median follow-up duration of 32 months (range 5-180 months) were recorded. Of the 37 patients (22 males; median age 51 years, range 18-81 years), 15 were treated with (131)I-mIBG alone whereas the other 22 received additional therapy. Results A total of 116 therapeutic (131)I-mIBG doses were administered [mean cumulative dose 592 mCi (21.9 GBq); range 200-1592 mCi (7.4-58.9 GBq)]. None of the patients showed a complete tumour response. However, 82% of patients treated with (131)I-mIBG alone and 84% who received additional therapy showed stable disease over the period of follow-up. Overall survival during the period of the study was 71%. The overall 5-year survival rate was 85% (95% confidence interval, 72-99%) for all patients and 78% (95% confidence interval, 55-100%) for the carcinoid group alone, according to Kaplan-Meier analysis. Symptomatic control was achieved in all the patients treated with (131)I-mIBG alone, and in 72% of those receiving additional therapy. Hormonal control was noted in 50% and 57% of patients, respectively. (131)I-mIBG therapy was safe and well tolerated. Serious side-effects necessitating the termination of (131)I-mIBG therapy were seen in only 2 of our patients. Conclusions (131)I-mIBG therapy produces symptomatic and hormonal improvement and moderate tumour regression/stabilization in patients with metastatic neuroendocrine tumours with minimal adverse effects. It may be a valuable alternative or additional therapeutic option to the currently available conventional treatment modalities.

Presence of ghrelin in normal and adenomatous human pituitary.

Abstract: Recently, an endogenous ligand has been described for the growth hormone secretagogue receptor (GHS-R), named ghrelin. It was originally isolated from the stomach, but it is also present in the hypothalamus, where the highest concentration of GHS-R has been detected. It is well established that synthetic GHSs exert their effects on the growth hormone (GH) axis principally via the hypothalamus, although they are also able to stimulate GH release directly from the pituitary. We have previously demonstrated the presence of GHS-R mRNA expression in normal and abnormal human pituitary. We have therefore now investigated the expression of the newly recognized endogenous ligand in rat as well as in human pituitary. We readily detected ghrelin mRNA message in normal rat pituitary using reverse transcriptase polymerase chain reaction with published primers. We then designed primers to the corresponding region on the human ghrelin sequence and successfully detected mRNA message in normal human pituitary, as well as in somatotroph, lactotroph, corticotroph, thyrotroph, and nonfunctioning adenomas. We confirmed the expected polymerase chain reaction product by direct sequencing. In conclusion, we suggest that in addition to the probable hypothalamic effects of ghrelin, the peptide is synthesized locally within the pituitary gland, where it may influence the release of GH in an autocrine or paracrine manner.

MRI of pancreatic neuroendocrine tumours

Abstract: Neuroendocrine tumours of the pancreas are rare and are frequently difficult to demonstrate. Several imaging modalities have been used to demonstrate these tumours, but recent reports have suggested that MRI may have an important role in their localization. We review the spectrum of MRI appearances of pancreatic neuroendocrine tumours.

General aspects of the cellular response to low- and high-LET radiation

Abstract: Radiobiological studies have shown for some time that the effects of ionising radiation on cells are mainly explained by modification of the DNA. Numerous studies over the past 50 years have accumulated clear evidence of the cause-effect relationship between damage to DNA and the cytotoxic and mutagenic effects of ionising radiation. However, the path from irradiation of the cells to the induction of biological effects comprises several complex steps. The first step involves interactions between the radiation and the cellular environment. These consist of physical and chemical reactions which produce ions, excited molecules and radical species. Excitations and ionisations are complete in about 10(-15) s, and are followed by a chemical thermal equilibrium of the species produced within 10(-12) s. These species then diffuse from their site of production and provoke alterations to a variety of cellular components. This damage is detected by cellular surveillance systems, which in turn activate signalling cascades, gene transcription and enzyme recruitment, which participate in the cellular response. In most cases, cell cycle arrest occurs, allowing, according to the biological relevance of the DNA damage, either a process of DNA repair or programmed cell death (apoptosis). The accuracy of the DNA repair which is performed depends on the complexity of the DNA lesion and on the DNA repair machinery fidelity itself. Improper DNA repair can lead to mutation, chromosome aberration, genetic instability, oncogenic transformation and, ultimately, cell death.

MR Imaging of Uterine Sarcomas

Abstract: OBJECTIVE. The MR imaging appearances of uterine sarcomas are not well described in the literature. We describe the MR imaging features of uterine sarcomas.MATERIALS AND METHODS. MR images from all patients with histologically proven uterine sarcomas scanned between 1993 and 2000 were reviewed. Tumor size, its relationship to the uterus, signal characteristics, and enhancement pattern after IV injection of gadolinium were noted.RESULTS. Twenty-five scans from 22 patients were reviewed. Findings from the scans included 11 leiomyosarcomas, five mixed mullerian tumors, two rhabdosarcomas, and four endometrial stromal sarcomas. Two patterns of disease were observed, including a characteristic large heterogenous pelvic mass (n = 17) and an endometrial mass indistinguishable from endometrial carcinoma (n = 8). On T2-weighted images, the large masses were characteristically of low or intermediate background signal intensity with pockets of very high T2 signal. The areas of high T2 signal corresponded to cystic n...

A randomized, double-blind, crossover comparison among cetirizine, levocetirizine, and ucb 28557 on histamine-induced cutaneous responses in healthy adult volunteers

Abstract: Background: Cetirizine is a highly efficacious and long-acting second-generation H1-receptor antagonist for the treatment of allergic diseases, such as allergic rhinitis and chronic idiopathic urticaria, in adults and children. Pharmacologic studies have demonstrated that cetirizine, a racemate mixture composed of equal amounts of two enantiomers, does not undergo hepatic metabolism to any significant level. The enantiomers are excreted mainly unchanged, predominantly in the urine and to a lesser extent in the faeces. Methods: The pharmacologic activity and potency of the two enantiomers of cetirizine in the management of allergic skin conditions were investigated by studying the effect of treatment with 5.0 mg cetirizine; 2.5 mg levocetirizine, the (R)-enantiomer; and 2.5 mg ucb 28557, the (S)-enantiomer, on histamine-induced wheal and flare response in 18 healthy volunteers. Each treatment was administered as a single oral dose in randomized, double-blind, and crossover manner, and the efficacy of treatment was assessed over a period of 32 h, as per cent inhibition of the histamine-induced wheal and flare areas before treatment. Blood and urine samples were collected in a time-dependent manner and analyzed for the total amounts of each study drug, to elucidate their pharmacokinetic profiles. Results: Both cetirizine and levocetirizine caused a marked inhibition of histamine-induced wheal and flare, whereas ucb 28557 was inactive in this model. Inhibition of the wheal response observed for cetirizine and levocetirizine was apparent by 1 h after dosage and lasted for mean durations of 24.4 and 28.4 h, respectively. In addition, the response for cetirizine and levocetirizine became maximal by 6 h after treatment, rising to 79.5% and 83.8%. Similarly, cetirizine and levocetirizine also markedly inhibited the histamine-induced flare response. This effect was evident for both drugs by 1 h after dosage and lasted over a mean period of 28.4 and 26.0 h, respectively, for cetirizine and levocetirizine. The inhibitory effect of these compounds on histamine-induced flare response was also maximal by approximately 6 h after dosage, peaking at 88.5% and 83.6%, respectively. Statistical evaluation showed that cetirizine and levocetirizine were equivalent for maximum inhibition of histamine-induced wheal and flare. However, levocetirizine was found to be superior to cetirizine when area under the curve was compared. In contrast, ucb 28557 was not found to inhibit histamine-induced wheal and flare responses at any time during the study period. Plasma concentrations of levocetirizine were found to be approximately double those of ucb 28557 at 4 and 8 h after dosing, and 50–60% of the drugs were excreted unchanged in urine over a period of 32 h. Conclusions: The finding that, in this model, levocetirizine 2.5 mg has comparable antihistaminic activity to cetirizine 5 mg, whereas its other enantiomer ucb 28557 has no pharmacodynamic effect, suggests that the antihistaminic properties of cetirizine observed in the management of allergic skin conditions are likely to be attributable to levocetirizine.

Frequency of the Bcl-2/IgH Rearrangement in Normal Individuals: Implications for the Monitoring of Disease in Patients With Follicular Lymphoma

Abstract: PURPOSE: To determine the incidence and frequency of the Bcl-2/IgH rearrangement in the peripheral blood of normal individuals to define the potential complication this may pose for the molecular monitoring of disease in patients with follicular lymphoma (FL). MATERIALS AND METHODS: The incidence and frequency of the major breakpoint cluster region rearrangement in DNA extracted from peripheral blood or lymphoblastoid cell lines from 481 normal individuals was determined using a TaqMan real-time polymerase chain reaction assay (PE Applied Biosystems, Foster City, CA). RESULTS: Twenty three percent of samples were positive for the Bcl-2/IgH rearrangement, with approximately 3% of these at levels of more than 1 in 104 cells. CONCLUSION: The presence of circulating Bcl-2/IgH+ cells, other than those derived from the malignant clone, could confound the detection and quantitation of minimal residual disease in patients with FL, particularly at low levels of tumor burden.

Antimicrobial effect of acidified nitrite on dermatophyte fungi, Candida and bacterial skin pathogens

Abstract: Aims: Nitric oxide is generated from sweat nitrite in the acidic environment of the skin surface and is thought to contribute to protection against infection. This study examined the sensitivity of Trichophyton mentagrophytes, T. rubrum, Candida albicans, Streptococcus pyogenes, Staphylococcus aureus and Propionibacterium acnes to acidified nitrite. Methods and Results: Organisms were cultured in varying concentrations of nitrite and pH for different lengths of time, before being transferred to recovery medium. With the exception of Strep. pyogenes, addition of nitrite increased the antimicrobial activity of acid solutions against all organisms tested. The rank order of sensitivity was: C. albicans < T. rubrum < T. mentagrophytes < Staph. aureus < P. acnes, with P. acnes being most sensitive. Conclusions: This work has shown that acidified nitrite is microbiocidal to common cutaneous pathogens. The concentrations of nitrite required to kill pathogenic fungi and bacteria in in vitro assays were higher than the concentrations of nitrite measured in sweat. However, additional co-factors in vivo and in sweat may potentiate the effect of acidified nitrite. Significance and Impact of the Study: Pharmacological preparations of acidified nitrite are novel antimicrobial agents. These data suggest skin organisms which may be sensitive to this treatment.

MIP-2 secreted by epithelial cells increases neutrophil and lymphocyte recruitment in the mouse intestine

Abstract: BACKGROUND—Invasion of the intestinal mucosa by leucocytes is a characteristic of intestinal inflammation but the role of the epithelium in orchestrating this recruitment has not been examined in vivo. Cultured intestinal epithelial cells secrete a wide variety of chemokines, often in response to agents present in the intestinal lumen. Macrophage inflammatory protein 2 (MIP-2) is a chemokine that attracts neutrophils, and its secretion from intestinal epithelial cells is enhanced by inflammatory stimuli such as interleukin 1β. We hypothesised that the production of MIP-2 by epithelial cells would increase leucocyte migration into the intestine. AIM—To study the effects of a chemokine secreted from intestinal epithelial cells in vivo. METHODS—MIP-2 was expressed in the mouse intestinal epithelium using an epithelial cell specific promoter from the gene encoding the intestinal fatty acid binding protein. The intestines of these transgenic mice were then analysed. RESULTS—Epithelial cells from transgenic mice expressed MIP-2 but wild-type mice did not. Neutrophil recruitment, examined by myeloperoxidase (MPO) staining and total MPO activity per unit weight of intestine, was significantly increased in transgenic mice in both the small intestine and proximal colon, and this was blocked by anti-MIP-2 antibody treatment. Both intraepithelial and lamina propria lymphocytes were also increased in transgenic mice. They showed chemotactic activity to MIP-2 in the Boyden chambers and expressed MIP-2 receptor (CXCR-2) mRNA confirmed by reverse transcription-polymerase chain reaction. CONCLUSION—These experiments are the first to show a functional role for epithelial chemokines in vivo and reveal an unexpected role for the neutrophil chemokine MIP-2 in controlling mucosal lymphocyte migration. Keywords: chemokines; epithelial cells; intestinal mucosa; leucocyte recruitment; transgenic mouse

Factors associated with self-disclosure of HIV serostatus to significant others.

Abstract: Objectives. To examine rates and patterns of self-disclosure of HIV serostatus amongst individuals attending an out-patient HIV clinic in East London. Design. A cross-sectional survey design was used. Methods. A volunteer sample of 95 out-patient HIV clinic attendees completed a self-report questionnaire examining patterns of disclosure to self-identified significant others, reasons for disclosure and non-disclosure, satisfaction with social support (SSQ6), quality of life (MOS-30) and anxiety and depression (HADS). Self-disclosure was examined in relation to cultural background, gender, satisfaction with social support, and medical and psychological variables. Results. Seventy-nine men and 16 women reported a mean disclosure rate of 68% to self-identified significant others. Five individuals had not disclosed their HIV status to anyone; 91% of individuals had informed their partner. Friends were more frequently informed (79%) than family (53%). Ethnicity (p <.001) and length of time since testing HIV seropositive (p<.05) emerged as significant predictors of disclosure. Global satisfaction with social support was negatively correlated with depression but was not associated with the total rate of HIV disclosure. Frequently reported reasons for non-disclosure included wanting to protect others from distress and fear of discrimination. Conclusions. Self-disclosure of HIV serostatus rates was highest for partners, followed by friends, and lowest for family members. Patterns of disclosure of HIV serostatus varied in relation to ethnicity. Fifteen years into the HIV epidemic, social stigma continues to contribute towards non-disclosure of diagnosis.

High-Dose Therapy and Autologous Stem-Cell Support for Chemosensitive Transformed Low-Grade Follicular Non-Hodgkin’s Lymphoma: A Case-Matched Study From the European Bone Marrow Transplant Registry

Abstract: PURPOSE: To assess the outcome of high-dose therapy with autologous stem-cell support in patients with histologic transformation of low-grade follicular non-Hodgkin’s lymphoma (NHL) and identify significant prognostic factors, as well as to compare survival of these patients with that of patients with matched low-grade and de novo high- or intermediate-grade NHL undergoing the same procedure. PATIENTS AND METHODS: Fifty patients with transformed low-grade NHL have been reported to the European Bone Marrow Transplant registry. Outcome from high-dose therapy and significant prognostic factors were analyzed. Their survival was also compared with that of 200 patients with matched low-grade NHL and 200 patients with matched de novo high- or intermediate-grade NHL by a case-matched analysis. RESULTS: The procedure-related death rate among the 50 transformed NHL patients was 18%. Overall survival (OS) and progression-free survival (PFS) rates were 51% and 30% at 5 years, respectively. Median PFS time was 13 mont...

Rigorous surveillance protocol increases detection of curable cancers associated with Barrett's esophagus.

Abstract: Esophageal adenocarcinoma is increasing in incidence and has a high mortality unless detected early. Barrett's esophagus is the only known risk factor for this cancer; however, whether endoscopic surveillance reduces morbidity and mortality is controversial. Endoscopic cancer surveillance programes for Barrett's esophagus are not routinely practiced in the UK, and this is the first study to examine whether a rigorous surveillance protocol increases the detection rate of early oesophageal cancer. All patients with a diagnosis of Barrett's esophagus or associated adenocarcinoma attending Havering Hospitals NHS Trust between 1992 and 1998 were included. A retrospective analysis was made of patients undergoing informal surveillance (96 patients, 1992-1997) and a prospective analysis was conducted following the implementation of a rigorous protocol (108 patients, 1997-1998). Over the same time periods Barrett's associated cancers diagnosed in patients not undergoing surveillance were analyzed (262 patients 1992-1997, 98 patients 1997-1998). From 1992 to 1997, one case of high-grade dysplasia was detected (N = 96, 1%). From 1997 to 1998, two cancers and three high-grade dysplasias were detected during rigorous surveillance (N = 108, 4.6%). Three of these patients have had curative esophagectomies (one high-grade dysplasia and two T1,N0,M0 tumors). In 1992-1997, 10 patients were found to have cancer in previously undiagnosed Barrett's esophagus (N = 262, 3.8%). Of 3/10 cancers treated surgically, one patient had a curative procedure (T1,N0,M0). In 1997-1998, nine patients were found to have de novo Barrett's esophagus cancer (N = 88, 10.2%) and three had curative resections (T1,N0,M0). Two of the patients with T1 lesions had no endoscopic evidence of cancer but were detected as a result of the multiple biopsy protocol. In conclusion, a rigorous biopsy protocol increases the detection of early cancer in Barrett's esophagus.

Effects of prior moderate exercise on exogenous and endogenous lipid metabolism and plasma factor VII activity.

Abstract: Moderate exercise reduces postprandial triacylglycerol concentrations, which are a risk marker for coronary heart disease. The present study sought to determine the qualitative nature of exercise-induced changes in lipid metabolism and their association (if any) with changes in factor VII activation. Eleven normotriglyceridaemic men, aged 51.7±6.1 years (mean±S.D.), participated in two oral fat tolerance tests after different pre-conditions: control (no exercise), and exercise (90 min of brisk walking the day before). Venous blood samples were obtained in the fasted state and for 8 h after ingestion of a high-fat meal (1.32 g of fat, 1.36 g of carbohydrate, 0.30 g of protein and 10 mg of [1,1,1-13C] tripalmitin·kg-1 body mass). Prior exercise reduced postprandial plasma triacylglycerol concentrations by 25±3% (mean±S.E.M.), with lower concentrations in the Svedberg flotation rate (Sf) 20–400 (very-low-density lipoprotein) fraction accounting for 79±10% of this reduction. There was no effect on plasma factor VII coagulant activity or on the concentration of the active form of factor VIIa. Prior exercise increased postprandial serum 3-hydroxybutyrate and plasma fatty acid concentrations, decreased serum postprandial insulin concentrations and increased exogenous (8 h 13C breath excretion of 15.1±0.9% of ingested dose compared with 11.9±0.8%; P = 0.00001) and endogenous postprandial fat oxidation. These data raise the possibility that reduced hepatic secretion of very-low-density lipoprotein plays a role in the attenuation of plasma triacylglycerol concentrations seen after exercise, although it is possible that increased triacylglycerol clearance also contributes to this effect.

Clinical features in women with polycystic ovaries: relationships to insulin sensitivity, insulin gene VNTR and birth weight.

Abstract: OBJECTIVE Polycystic ovaries are a common ultrasound finding, yet few of these women have many clinical features of polycystic ovary syndrome. Clinical presentation may relate to degree of insulin resistance, common polymorphism at the insulin gene VNTR, and birth weight. We therefore examined the relationship between insulin sensitivity, insulin gene VNTR genotype, birth weight and presence of polycystic ovaries/features of polycystic ovary syndrome in a normal population study. DESIGN AND PATIENTS In 224 young women recruited as normal volunteers, ovarian morphology was determined by transabdominal ultrasound and features of polycystic ovary syndrome were identified on clinical and biochemical examination. Insulin sensitivity was estimated from fasting glucose and insulin levels using the homeostasis model. Insulin gene VNTR genotypes were determined in women and their parents. MEASUREMENTS AND RESULTS Thirty-three per cent (74/224) had polycystic ovaries on ultrasound. These women had higher birth weights (P = 0·004), higher insulin sensitivity (P = 0·02) and higher leptin levels for body mass index (P = 0·04) than women with normal ovaries. However among women with polycystic ovaries, increasing severity of clinical phenotype (based on number of features of: menstrual irregularity, acne, hirsuitism, serum testosterone > 3 mmol/l and LH > 10 IU/l) was associated with decreasing insulin sensitivity (P < 0·0001) and related to paternally transmitted insulin gene VNTR class III alleles (P = 0·03). CONCLUSION Women with polycystic ovaries on ultrasound have increased insulin sensitivity and possible leptin resistance, which could predispose to future weight gain. However, in these women the appearance of clinical features of polycystic ovary syndrome is related to insulin resistance and insulin gene VNTR class III alleles.