bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Testing in Pheochromocytoma
Authors: BORNSTEIN STEFAN R. , GIMENEZ‐ROQUEPLO ANNE‐PAULE
Published: November 2006

Abstract:  Hereditary pheochromocytomas and paragangliomas are caused by germline mutations in syndrome‐associated genes. This includes multiple endocrine neoplasia Type 2 (MEN 2) caused by mutations in the RET proto‐oncogene, von Hippel–Lindau (VHL) syndrome due to mutations of the VHL gene, neurofibromatosis Type I (NF1) caused by mutations of the NF1 gene, and pheochromocytoma/paraganglioma syndromes due to mutations in genes encoding the succinate dehydrogenase subunits D (SDHD) and B (SDHB). At the First International Symposium on Pheochromocytoma (ISP2005) organized by the National Institutes of Health, a panel of specialist clinicians and scientists from around the world addressed the topic of genetic testing in pheochromocytoma patients. This review summarizes the discussions and conclusions of the panel and provides a recommendation for evidence‐based management of genetic testing in these patients and their families. A pragmatic algorithm is presented, taking into account patient age, tumor location (extra‐adrenal, intra‐adrenal, unilateral, and bilateral), biochemical presentation, and financial costs. This was based on cumulative frequencies ranging from 7.5% to 29% for germline mutations in four genes (RET, VHL, SDHB, and SDHD) in patients with apparently sporadic pheochromocytomas. This algorithm will need to be validated by further genetic analysis, multicenter studies, and long‐term observations.
New Advances in the Genetics of Pheochromocytoma and Paraganglioma Syndromes
Authors: GIMENEZ‐ROQUEPLO ANNE‐PAULE
Published: November 2006

Abstract:  The discovery of the SDH genes in 2000/2001 dramatically changed the genetics of pheochromocytoma (PHEO) and paraganglioma (PGL). Five years on, it is widely accepted that all patients with PHEO/PGL, whatever their age, should undergo genetic testing, because 25–30% of PHEOs are caused by a germline mutation in one of the five PHEO susceptibility genes. However, genetic testing should be targeted according to family and clinical history. The identification of a causal mutation modifies the management and follow‐up of the patient and provides an opportunity for presymptomatic genetic testing for other family members. Moreover, the demonstration that the SDH genes, are tumor suppressor genes and that their inactivation is involved in the hypoxia‐angiogenic pathway activating the transcription factor hypoxia‐inducible factor (HIF) by inhibiting prolyl hydroxylases (PHDs) may lead to the identification of new therapeutic targets for these rare diseases. We discuss here these recent findings and their clinical consequences for the management of PHEO/PGL families and the future of research in this field.
Genetic and Clinical Investigation of Pheochromocytoma
Authors: BAUSCH BIRKE , BOEDEKER CARSTEN C. , BERLIS ANSGAR , BRINK INGO , CYBULLA MARKUS , WALZ MARTIN K. , JANUSZEWICZ ANDRZEJ , LETIZIA CLAUDIO , OPOCHER GIUSEPPE , ENG CHARIS , NEUMANN HARTMUT P.H.
Published: November 2006

Abstract:  Although deceptively simple, the etio‐pathogenesis of pheochromocytoma represents a clinical and molecular genetic investigative challenge. Here, we summarize, from a historical point of view, the 22‐year‐long studies initiated at the University of Freiburg, which developed from a local experience to a national and finally an international effort. All research activities are translational and clinical and hence, registry based and intended to improve the outcome of the patients, whether by improved detection, prevention, or treatment. Major clinical steps are the prospective study on hormone tests and imaging techniques for adrenal and extra‐adrenal abdominal tumors as well as the concept of organ sparing and endoscopic tumor resection. Further, we introduced 18‐fluoro‐dopa positron emission tomography. Population‐based registries were used in order to identify germline mutations in the susceptibility genes VHL, RET, SDHB, and SDHD in non‐syndromic pheochromocytoma. We differentiated distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Finally, we identified predictors and prevalence of paraganglioma syndromes associated with mutations of the SDHC gene.
Genetic Analyses of Apparently Sporadic Pheochromocytomas
Authors: KORPERSHOEK E. , VAN NEDERVEEN F. H. , DANNENBERG H. , PETRI B. J. , KOMMINOTH P. , PERREN A. , LENDERS J. W. , VERHOFSTAD A. A. , DE HERDER W. W. , DE KRIJGER R. R. , DINJENS W. N. M.
Published: November 2006

Abstract:  Pheochromocytomas (PCCs) are neuroendocrine tumors of chromaffin tissue that produce catecholamines. They are usually located in the adrenal medulla, although in about 10% the tumors arise from extra‐adrenal chromaffin tissue. The majority of PCCs arise sporadically, but PCCs occur also in the context of hereditary cancer syndromes. Familial PCC is inherited as an autosomal dominant trait alone or as a component of the multiple endocrine neoplasia Type 2 (MEN2) syndrome (RET gene), Von Hippel–Lindau (VHL) disease (VHL gene), neurofibromatosis Type 1 (NF1 gene), or familial pheochromocytoma–paraganglioma (PCC–PGL) syndrome (SDHD/B and C genes). It has been reported that 24% of apparently sporadic PCCs patients harbor germline mutations in these PCC‐causing genes. We investigated the contribution of the inherited PCC‐causing genes in a partly retrospectively and partly prospectively obtained series of 213 apparently sporadic PCCs. Mutation analysis was performed for RET (56 cases), VHL (136 cases), and SDHD (126 cases) and SDHB (47 cases). No germline RET mutations, six (4.4%) germline VHL mutations, two (1.5%) germline SDHD mutations, and one germline (1.6%) SDHB mutation were found. In total we found germline mutations in about 7.5% of the investigated apparently sporadic PCCs. Although 7.5% germline mutations in a series of apparently sporadic PCCs are far less than the more than 20% reported in the literature, the figure is significant enough to consider germline mutation testing for each patient with PCC.
SDH Mutations in Patients Affected by Paraganglioma Syndromes
Authors: MANNELLI M. , SIMI L. , ERCOLINO T. , GAGLIANÒ M.S. , BECHERINI L. , VINCI S. , SESTINI R. , GENSINI F. , PINZANI P. , MASCALCHI M. , GUERRINI L. , PRATESI C. , NESI G. , TORTI F. , CIPOLLINI F. , BERNINI G.P. , GENUARDI M.
Published: November 2006

Abstract:  Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest‐derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2‐1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3 + 1G>A) was associated with a malignant PHEO.
A Phenotypic Perspective on Mammalian Oxygen Sensor Candidates
Authors: BAYSAL BORA E.
Published: November 2006

Abstract:  Chronic hypoxic stimulation in mammals can induce several phenotypic changes, such as polycythemia, pulmonary vascular changes, pulmonary hypertension, and carotid body (CB) enlargement. These phenotypic alterations provide a tool to test whether an oxygen sensor candidate is involved in an organism's response to environmental hypoxia. Here I evaluate the phenotypic evidence for several commonly considered oxygen sensor candidates. Germline mutations in NADPH oxidase, mitochondrial complexes I, III, IV, and heme oxygenase 2 genes cause different phenotypic consequences, suggesting distinct physiological roles rather than oxygen sensing. Germline mutations in VHL and HIF1 prolyl hydroxylase 2 genes cause polycythemia consistent with their role in oxygen homeostasis. However, it is unclear whether environmental variations affecting oxygen availability modify their phenotype, as would be expected from a defect in an oxygen sensor. Succinate dehydrogenase (SDH); mitochondrial complex II) germline mutations cause CB paragangliomas and there is evidence that the severity and the population genetics of paragangliomas may be influenced by altitude. Thus, from a phenotypic perspective, succinate dehydrogenase (SDH) appears to be a well‐supported oxygen sensor candidate. It is suggested that a universal oxygen sensor candidate must be supported by evidence from multiple layers of biological complexity.
Expression of mRNAs for Succinate Dehydrogenase Subunits and Related Genes in Pheochromocytoma
Authors: ISOBE KAZUMASA , NISSATO SUMIKO , TATSUNO ICHIRO , YASHIRO TORU , TAKEKOSHI KAZUHIRO , KAWAKAMI YASUSHI
Published: November 2006

Abstract:  Mutations in the genes encoding succinate dehydrogenase (SDH) have been associated with susceptibility to pheochromocytoma. However, few reports have examined the level of SDH mRNAs expression. In this study, we examined the level of expression of mRNAs encoding SDHB, SDHC, and SDHD in pheochromocytoma, pheochromocytoma subgroups, and normal adrenal gland, and compared the expression of these genes to the level of expression of related genes in the same tissues. The mean relative level of expression of SDHB, SDHC, SDHD and VHL mRNA was 28.7 ± 6.2%, 16.6 ± 4.8%, 214 ± 47.5% and 25.9 ± 8.2%, respectively, in pheochromocytoma tissues compared to normal adrenal gland. Furthermore, the mean relative level of the RET proto‐oncogene mRNA was 707 ± 149% in pheochromocytoma compared to normal adrenal gland. The level of expression of the SDH genes was highly correlated in each individual sample (P < 0.0001). The level of expression of the SDH mRNAs correlated with the level of VHL mRNA (P < 0.0001), but not with the level of RET mRNA. The level of SDH mRNAs expression also correlated with the expression of phenylethanolamine N‐methyl transferase (PNMT), an adrenaline synthesizing enzyme (P < 0.01), which may explain the correlation between SDH expression and adrenaline content (P < 0.05). The level of SDH mRNAs expression correlated strongly with the expression of VEGF mRNA (P < 0.0001). In multiple endocrine neoplasia (MEN) 2a, the expression of the SDH genes and VHL mRNA was significantly higher than that observed in adrenal or extra‐adrenal pheochromocytoma. The expression of the corticotropin‐releasing hormone (CRH) mRNA was significantly higher in extra‐adrenal pheochromocytoma than in adrenal pheochromocytoma or MEN2a. Thus, tumor‐specific gene expression exists in pheochromocytoma, which may explain the characteristics of the tumor.
The Effects of Urotensin‐II on Proliferation of Pheochromocytoma Cells and mRNA Expression of Urotensin‐II and Its Receptor in Pheochromocytoma Tissues
Authors: ZENG ZHENG‐PEI , LIU GUO‐QIANG , LI HAN‐ZHONG , FAN XIN‐RONG , LIU DONG‐MEI , TONG AN‐LI , ZHENG XIN , LIU CHANG
Published: November 2006

Abstract:  This study was conducted to investigate the effects of urotensin‐II (UII) on the proliferation of pheochromocytoma cells and the mRNA expression of UII and its receptor G protein–coupled receptor 14 (GPR14) in normal adrenal and human pheochromocytoma tissues. The effects on the cell proliferation by different UII concentrations and at different time were observed with the MTT method in both rat pheochromocytoma cell line (PC12 cell) and human pheochromocytoma cells. The mRNA expression of UII and GPR14 was evaluated by RT‐PCR. UII had no significant effect on the proliferation in PC12 cells, but promoted the proliferation of human pheochromocytoma cells. The mRNA expression of UII and GPR14 in pheochromocytoma was lower than that in normal adrenal tissues. But mRNA expression of UII and GPR14 in adrenal pheochromocytomas was lower than that in extra‐adrenal pheochromocytomas. Thus, UII and its receptor GPR14 exert a possible effect in the pathogenesis of pheochromocytoma.
Role of DHEA and Growth Factors in Chromaffin Cell Proliferation
Authors: SICARD F. , KRUG A.W. , ZIEGLER C.G. , SPERBER S. , EHRHART‐BORNSTEIN M. , BORNSTEIN S.R.
Published: November 2006

Abstract:  Dehydroepiandrostreone (DHEA) is a neuroactive steroid produced by the inner layer of the adrenal cortex close to the adrenomedullary cells. Chromaffin cell growth and proliferation are under the control of insulin‐like growth factor II (IGF‐II) and basic fibroblast growth factor (bFGF). The aim of the present study was to examine the role of DHEA on chromaffin cell proliferation induced by IGF‐II and bFGF. In our model, DHEA significantly decreased IGF‐II‐induced proliferation by 48.7%, whereas it did not affect the proliferation induced by bFGF. These data suggest that DHEA exerts a paracrine function in the control of chromaffin cell growth.
Analysis of PTEN Mutation in Non‐familial Pheochromocytoma
Authors: PUC JANUSZ , PLACHA GRZEGORZ , WOCIAL BOZENNA , PODSYPANINA KATRINA , PARSONS RAMON , GACIONG ZBIGNIEW
Published: November 2006

Abstract:  PTEN, a tumor suppressor gene, is frequently mutated in a variety of human tumors. In mice, monoallelic inactivation of this gene predisposes animals to neoplasia of multiple organs. Interestingly, Pten heterozygous mice develop bilateral hyperplasia of the adrenal medulla. In this report we demonstrate that these neoplasms are hormonally active pheochromocytomas that secrete increased amounts of bioactive catecholamines: norepinephrine and epinephrine. To test a possibility that PTEN might be one of the genes responsible for human sporadic pheochromocytoma, we performed mutation analysis of DNA obtained from tumors of 29 patients. However, direct sequencing of all nine exons of the PTEN gene, including the splice junctions, revealed no mutations. Examination of protein expression by immunohistochemistry using 8 normal adrenals and 11 sporadic pheochromocytomas showed no decrease in the PTEN protein expression in the tumor tissue, but upregulation of insulin‐like growth factor II, a peptide implicated in growth of adrenal tissue, was observed in four cases (36%).
Diagnostic Value of Biochemical Parameters in the Differential Diagnosis of an Adrenal Mass
Authors: PETERSENN STEPHAN , UNGER NICOLE , WALZ MARTIN K. , MANN KLAUS
Published: November 2006

Abstract:  In patients with an adrenal mass, hormonally active tumors including pheochromocytomas as well as aldosterone‐ and cortisol‐secreting adenomas need to be considered. Several studies have demonstrated that metanephrines, which are the metabolites of catecholamines, are reliable parameters for the diagnosis of pheochromocytoma. In patients with an adrenal mass, we found plasma metanephrines, measured by a newly available radioimmunoassay, to be highly sensitive and specific for pheochromocytomas, with a better accuracy than any other biochemical parameter.The plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio is an established screening tool for primary hyperaldosteronism. However, determination of active renin concentration (ARC) in contrast to PRA may offer advantages in regard to processing and standardization. We found a PAC to ARC ratio of >62 in patients with PAC levels >200 ng/L to be a reliable screening method for primary hyperaldosteronism in patients with adrenal masses.The screening for hypercortisolism relies on excess urinary cortisol secretion, loss of the physiological feedback during dexamethasone challenge, and loss of the circadian rhythm. Because urinary‐free cortisol may not identify subclinical Cushing's syndrome, in which hypercortisolism is still mild, the 1‐mg dexamethasone suppression test has been recommended in all patients with incidentally detected masses. Alternatively, late‐night cortisol levels in saliva have been found to have a high sensitivity and specificity for the diagnosis of Cushing's syndrome. In summary, in patients with an adrenal mass, hormonally active adrenal tumors can be excluded with high certainty using a few highly reliable biochemical parameters.
Current Trends in Functional Imaging of Pheochromocytomas and Paragangliomas
Authors: SHULKIN BARRY L. , ILIAS IOANNIS , SISSON JAMES C. , PACAK KAREL
Published: November 2006

Abstract:  Most pheochromocytomas/paragangliomas should be evaluated with anatomical imaging (computed tomography or magnetic resonance imaging) followed by functional imaging (nuclear medicine modalities). Functional imaging assures that the tumor is indeed a pheochromocytoma/paraganglioma and enables more thorough localization, especially detecting as many lesions as possible (in particular for metastatic disease). Functional imaging for pheochromocytomas/paragangliomas, can use radiolabled ligands specific for pathways of synthesis, metabolism, and inactivation of catecholamines or nonspecific ligands. In an overview of the available nuclear medicine modalities, we summarize the accumulated experience and recommend when functional imaging should be applied to patients with pheochromocytoma/paraganglioma.
Management and Treatment of Pheochromocytomas and Paragangliomas
Authors: MANNELLI MASSIMO
Published: November 2006

Abstract:  Pheochromocytomas and paragangliomas are rare neural crest–derived tumors of sympathetic (generally catecholamine producing) or parasympathetic (rarely catecholamine producing) origin. Patients affected by these tumors present with a variable clinical picture, often making diagnosis troublesome. Surgery is the treatment of choice, but requires appropriate medical management before, during, and after tumor resection. Appropriate follow‐up of patients is particularly important to identify recurrences, remaining disease, or developing malignancy. Currently, however, no firm guidelines exist about what form follow‐up should take. There is also a general lack of prospective studies establishing the best approaches for management and treatment of the tumor. Choice of the many available different therapeutic options instead usually depends on institutional experience and clinical setting, which may vary for different groups of patients. At the First International Symposium on Pheochromocytoma (ISP2005), held in Bethesda in October 2005, a panel of experts addressed and discussed the many therapeutic options and problems associated with management and treatment of patients with pheochromocytoma, reporting their personal experience and sharing their opinions with those of patient representatives. The aim of this special Discussion Session was to reconcile differences of opinion and reach agreement about appropriate management and therapeutic options. This article summarizes the discussion and the recommendations derived from that session.
Aspects on Radionuclide Therapy in Malignant Pheochromocytomas
Authors: FORSSELL‐ARONSSON EVA , BERNHARDT PETER , WÄNGBERG BO , KÖLBY LARS , NILSSON OLA , AHLMAN HÅKAN
Published: November 2006

Abstract:  Malignant pheochromocytomas/paragangliomas (PCs/PGs) often have distant metastases to the skeleton, liver, and lungs. Radionuclide therapy is valuable for treatment of disseminated tumor disease and could be used as adjuvant therapy after surgery. Patients with local and/or distant metastases of PC/PG should be investigated preoperatively by scintigraphy using both 123I‐MIBG and 111In‐DTPA‐D‐Phe1‐octreotide, to evaluate the possibilities for radionuclide therapy (i.e., a dosimetric estimation of radiation dose to the tumor tissue versus critical normal tissues). Individual patient dose‐planning should be performed. For patients in whom positive therapeutic effects are anticipated radionuclide therapy can be applied. Therapy with both 131I‐MIBG and 177Lu‐octreotate might be favorable in individual patients with lesions visualized by both metaiodobenzylguanidine (MIBG) and octreotide scintigraphy with enhanced therapeutic effects and reduced side effects.
Courses of Malignant Pheochromocytoma
Authors: SISSON JAMES C. , SHULKIN BARRY L. , ESFANDIARI NAZANENE H.
Published: November 2006

Abstract:  Survival of patients with metastatic pheochromocytoma that have exceeded 30 years without therapy to reduce tumors have been reported. We reviewed the records of 38 patients with malignant pheochromocytoma who had received 131I‐metaiodiobenzylguanidine (131I‐MIBG) treatments between 1981 and 1996 to evaluate longevity. Survival from diagnosis to last follow‐up exceeded 5 years in 21 of 38 (55%) and ≥10 years in 50%. In 17 of 21, the interval from diagnosis to 131I‐MIBG therapy was greater than 5 years. Survival following 131I‐MIBG was ≥5 years in 12 of 17 and ≥10 years in 7 of 17 patients despite continued evidence of excessive circulating catecholamines. Objective responses to 131I‐MIBG therapy were seen in about 30% and were usually of a few years, duration, but one individual exhibited marked reductions in volume and function of tumors that have persisted for 21 years. No feature, including a remission of >5 years following surgical excision, was found to predict prolonged survival. In summary, many patients with malignant pheochromocytoma will follow a course extending over many years. The role of 131I‐MIBG therapy in longevity is uncertain, but this radiopharmaceutical reduces evidence of tumors in some patients. Criteria for selecting patients who will benefit from treatment remain to be determined.
Malignant Pheochromocytoma in a Population‐Based Study
Authors: WÄNGBERG BO , MUTH ANDREAS , KHORRAM‐MANESH AMIR , JANSSON SVANTE , NILSSON OLA , FORSSELL‐ARONSSON EVA , TISELL LARSERIK , AHLMAN HÅKAN
Published: November 2006

Abstract:  One hundred fifty‐four consecutive patients with pheochromocytoma (PC, n= 137) or paraganglioma (PG, n= 17) were treated at our unit. Twenty patients had MEN 2, 15 VRD, and 1 VHL tumors. Twelve had malignant tumors and were classified according to mode of presentation: (1) Distant metastases (n= 4); three underwent surgical debulking (with chemotherapy in one); and three had 131I‐MIBG therapy. Within 4 years two patients died of tumor progression. (2) Locally advanced disease (n= 4), all resected for cure. (3) Malignancy disclosed during follow‐up after adrenalectomy with “benign” histopathology (n= 4). All patients in groups 2 and 3 developed recurrence 9 (1–17) years after primary surgery; four underwent resection, one remains tumor‐free. The others were treated chronically with phenoxybenzamine, combined with 131I‐MIBG in one. These eight patients were observed 20 (5–35) years after primary surgery and 11 (1–19) years after recurrence. This series is population‐based and may better reflect the natural history of malignant PC/PG than the series from national referral centers. Active surgical treatment and phenoxybenzamine resulted in low tumor‐related mortality in groups 2 and 3; five patients died 8–30 years after diagnosis, four of PC/PG (three from group 2 and one from group 3
) and one of other causes. We propose tumor uptake studies (MIBG‐ and octreotide scintigraphy) in patients with nonresectable metastases; to select individual radionuclide therapy data on the expression of CA‐transporters/somatostatin receptors may be helpful. To diagnose PC/PG early, screening of adrenal incidentalomas has been suggested. In a regional population‐based prospective study, 503 incidentalomas were reported during 18 months, but only one patient with PG was identified.
Gene Expression Profiling of Benign and Malignant Pheochromocytoma
Authors: BROUWERS FREDERIEKE M. , ELKAHLOUN ABDEL G. , MUNSON PETER J. , EISENHOFER GRAEME , BARB JENNIFER , LINEHAN W. MARSTON , LENDERS JACQUES W.M. , DE KRIJGER RONALD , MANNELLI MASSIMO , UDELSMAN ROBERT , OCAL IDRIS T. , SHULKIN BARRY L. , BORNSTEIN STEFAN R. , BREZA JAN , KSINANTOVA LUCIA , PACAK KAREL
Published: November 2006

Abstract:  There are currently no reliable diagnostic and prognostic markers or effective treatments for malignant pheochromocytoma. This study used oligonucleotide microarrays to examine gene expression profiles in pheochromocytomas from 90 patients, including 20 with malignant tumors, the latter including metastases and primary tumors from which metastases developed. Other subgroups of tumors included those defined by tissue norepinephrine compared to epinephrine contents (i.e., noradrenergic versus adrenergic phenotypes), adrenal versus extra‐adrenal locations, and presence of germline mutations of genes predisposing to the tumor. Correcting for the confounding influence of noradrenergic versus adrenergic catecholamine phenotype by the analysis of variance revealed a larger and more accurate number of genes that discriminated benign from malignant pheochromocytomas than when the confounding influence of catecholamine phenotype was not considered. Seventy percent of these genes were underexpressed in malignant compared to benign tumors. Similarly, 89% of genes were underexpressed in malignant primary tumors compared to benign tumors, suggesting that malignant potential is largely characterized by a less‐differentiated pattern of gene expression. The present database of differentially expressed genes provides a unique resource for mapping the pathways leading to malignancy and for establishing new targets for treatment and diagnostic and prognostic markers of malignant disease. The database may also be useful for examining mechanisms of tumorigenesis and genotype–phenotype relationships. Further progress on the basis of this database can be made from follow‐up confirmatory studies, application of bioinformatics approaches for data mining and pathway analyses, testing in pheochromocytoma cell culture and animal model systems, and retrospective and prospective studies of diagnostic markers.
Expression of Connexins in Chromaffin Cells of Normal Human Adrenals and in Benign and Malignant Pheochromocytomas
Authors: WILLENBERG HOLGER S. , SCHOTT MATTHIAS , SAEGER WOLFGANG , TRIES ANNETTE , SCHERBAUM WERNER A. , BORNSTEIN STEFAN R.
Published: November 2006

Abstract:  Decrease in connexin (Cx) expression and loss of gap junctional intercellular communication (GJIC) have been associated with aberrant cell growth and enhanced neoplastic phenotype. We studied the expression of Cx26, Cx32, Cx43, and Cx50 in chromaffin cells of 10 normal human adrenal glands, 10 benign, and 13 malignant pheochromocytomas. Immunohistochemistry showed that Cx50 expression seemed to be the predominant form of Cx expressed in human chromaffin cells, whereas Cx43 immunoreactivity was the most prominent form found in the adrenal cortex. However, Western blotting revealed that nonphosphorylated and singly and doubly phosphorylated forms of Cx43 were present within the malignant adrenomedullary cells at the same time. Cx26 and Cx32 were distributed inhomogeneously with no emphasis of expression in the types of tissues studied. Cx50 expression was diminished in malignant pheochromocytomas. We conclude that there is a differential expression of Cx in human adrenals. Immunohistological testing for Cx expression does not however allow differentiation of benign from malignant pheochromocytomas.
Changing Patterns of Addiction and Public Aid Receipt: Tracking the Unintended Consequences of Welfare Reform
Authors: Schmidt Laura A. , Wiley James , Dohan Daniel , Zabkiewicz Denise , Jacobs Laurie M. , Henderson Stuart , Zivot Matthew
Published: November 2006

Sharp declines in welfare rolls since the passage of welfare reform legislation have led many to label it a social policy success. Using data from prereform and postreform samples of welfare applicants and recipients, as well as ethnographic data on welfare reform implementation, we examine three hypotheses based on concerns raised during the welfare reform debate about the possible effects of new policies on substance abusers and addicts: First, they would be “scared off,” or discouraged from applying to aid by welfare's new requirements surrounding work and treatment. Second, they might be “weeded out,” or face discrimination in the application process because of concerns about the difficulty of moving them successfully from welfare to work. Third, they might be “bumped down,” or shifted to local aid programs rather than moving from welfare to self-sufficiency. Our empirical analysis finds no evidence of scaring off or weeding out, and some evidence of bumping down. Using ethnographic data, we offer some possible explanations for these findings by placing them in the context of policy change and implementation in the years following welfare reform.
Does the silastic eustachian tube prosthesis improve eustachian tube function?
Authors: Lesinski S. George , Fox Joseph M. , Seid Allan B. , Bratcher Glenn O. , Cotton Robin
Published: November 2006

This clinical study attempts to evaluate the effectiveness of Eustachian tube function in 30 ears, 11–29 months after insertion of the Silastic® Eustachian tube prosthesis (SETP). Indications for the SETP were limited to persistent Eustachian tube dysfunction. Preoperatively, 13 patients had intact tympanic membranes with persistent serous otitis media. Seventeen patients underwent tympanoplasty and demonstrated persistent serous otitis media in the opposite ear.

Postoperatively, aeration of the middle ear was evaluated by tympanometry, microscopic examination, and myringostomy. Microphotographs demonstrate the state of the middle ear. Histology of the middle ear mucosa was obtained in a few cases.

Ninety‐six percent of the ears with an SETP demonstrated confirmed persistent Eustachian tube dysfunction beginning an average of six months after insertion. Complications were common.
Otosclerosis and vestibular dysfunction
Authors: Freeman Joseph
Published: November 2006

Vestibular dysfunction associated with otosclerosis has been observed for many years. In a recent clinical study of patients exhibiting progressive sensorineural hearing loss of unknown origin, it was demonstrated that approximately 50% of the cases had cochlear otosclerosis/otospongiosis as the most probable cause for the hypacusis. Of these, approximately 55% had vestibular symptoms. In the present study, the effect of sodium fluoride therapy in this group of patients is analyzed. It will be demonstrated that such therapy is beneficial not only in controlling the progressive sensorineural hearing loss but also the symptoms of vestibular dysfunction in patients with cochlear otosclerosis (otospongiosis).
Sacral Nerve Neuromodulation for the Treatment of Lower Bowel Motility Disorders
Authors: Kenefick Nicholas J
Published: November 2006

INTRODUCTION

Incontinence and constipation are common and cause a high degree of physical, social and psychological impairment. Maximal conservative therapy may improve some patients but many remain symptomatic. Surgical options are often unsatisfactory, with variable result and further options are limited. Sacral nerve stimulation uses electrical stimulation applied to the sacral nerves, eliciting a physiological effect on the lower bowel, anal sphincter and pelvic floor, resulting in clinical benefit. The objective of this study was to investigate whether sacral nerve neuromodulation can improve patients with disorders of bowel motility, when current maximal treatment has failed and to investigate the underlying physiological mechanism of action.

RESULTS

Incontinence: Nineteen patients, age 58 years (range, 37–71 years), with resistant incontinence for 6 years (range, 2–21 years) underwent stimulation. Continence improved in all at 24 months (range, 3–60 months), fourteen fully continent. Incontinent episodes decreased; 12 (range, 2–30) versus 0 (range, 0–4), P < 0.001. Urgency (P < 0.01) and quality of life improved (P < 0.05). Anal squeeze pressure (P = 0.001) and rectal sensation (P < 0.01) improved. Constipation: Four women, (aged 27–36 years) with resistant idiopathic constipation for 8–32 years underwent the first worldwide implants. Symptoms improved in all with temporary, and in three with permanent, stimulation at 8 months (range, 1–11 months). Bowel frequency increased: 1–5 versus 6–28 evacuations/3-weeks. Symptom scores and quality of life improved. Placebo effect: A double-blind, cross-over study was performed to examine placebo effect and efficacy. Once stimulation was removed, in a blinded manner, symptoms, physiological parameters and quality of life measures rapidly returned to baseline levels. Autonomic neuromodulation: Sixteen patients, median age 59 years (range, 38–71 years), were studied at 27 months (range, 2–62 years) using laser Doppler flowmetry. Chronic stimulation was at 2.8 V (range, 0.3–3.9 V). Median flux differed between none and chronic stimulation (P = 0.001). Step-wise increments caused an immediate, dose-dependent rise in flux (P < 0.0001) up to 1.0 V.

CONCLUSIONS

This research provides strong evidence that sacral nerve stimulation can improve patients with resistant incontinence and shows proof-of-concept for the treatment of constipation. The effect is unlikely to be due to placebo and the mechanism is rapidly reversible and involves a dose-dependent effect on the autonomic nerves.
Lymphoscintigraphy in Detection of the Regional Lymph Node Involvement in Gastric Cancer
Authors: Ozmen M Mahir , Zulfikaroglu Baris , Kucuk N Ozlem , Ozalp Necdet , Aras Gulseren , Koseoglu Tankut , Koç Mahmut
Published: November 2006

INTRODUCTION

Involvement of regional lymph node is a critical sign in prognosis of gastric cancer. Radiological techniques are commonly used to evaluate the extension of gastric cancer. But their sensitivity and specificity are low especially in the early stage. Our aim was to assess the value of gastric lymphoscintigraphy in identifying regional lymph node involvement in patients with gastric cancer, as compared to the abdominal ultrasonography, computed tomography and postoperative histopathological evaluation.

PATIENTS AND METHODS

50 patients (12 females) with a median age of 61 years (range, 35–73 years) were included in the study. Pre-operative staging in all cases included upper gastrointestinal endoscopy and biopsy, followed by ultrasound, computed tomography and lymphoscintigraphy. 148 MBq Technetium-99m lymphoscint was injected around the tumour during endoscopy and immediately after injection, anterior, lateral and posterior images were taken in 5-min intervals using a gamma camera. Findings were compared to the findings of other tests. The sensitivity, specificity, positive predictive value, and negative predictive value of each test were calculated and compared.

RESULTS

Histologically, 68% of cases (34/50) had metastasis in regional lymph nodes and all cases were accurately diagnosed by lymphoscintigraphy. Lymphoscintigraphy was significantly more sensitive for detecting lymph node involvement (P < 0.01). Both abdominal ultrasonography and CT had very low sensitivity in identifying lymph nodes.

CONCLUSIONS

Lymphoscintigraphy is a promising test in the identification of regional lymph nodes pre-operatively in patients with gastric cancer. It might help the surgeon to plan the extent of dissection before surgery which may decrease postoperative complications related to unnecessary extensive lymph node dissection.
Aggressive Management of Surgical Emergencies
Authors: Bengmark Stig
Published: November 2006

Increasing evidence suggests that two factors significantly influence outcome in a surgical emergency – premorbid health and the degree of inflammation during the first 24 h following trauma. Repeat observations suggest that the depth of post-trauma immunoparalysis reflects the height of early inflammatory response. Administration to surgical emergencies, as was routine in the past, of larger amounts of fluid and electrolytes, fat, sugar and nutrients seems counterproductive as it increases immune dysfunction, impairs resistance to disease and, in fact, increases morbidity. Instead, strong efforts should be made to limit the obvious superinflammation, which occurs during the first 24 h after trauma and, thereby, reduce the subsequent immuno-paralysis. paralysis. Several approaches show efficacy in limiting early superinflammation such as strict control of blood glucose, avoida nce of stored blood when possible, supply of antioxidants, live lactic acid bacteria and plant fibres. This review focuses mainly on use of live lactic acid bacteria and plant fibres, often called synbiotics. Encouraging experience is reported from clinical trials in liver transplantation, severe pancreatitis and extensive trauma. Immediate control of inflammation by enteral nutrition and supply of antioxidants, lactic acid bacteria and fibres is facilitated by feeding tubes, introduced as early as possible on arrival at the hospital.
Treating the whole patient
Authors: Coran Arnold
Published: November 2006

In this address given to the president and Diplomates on the presentation of his honorary membership to the College, Professor Coran looks back on a long and distinguished career in paediatric surgery. Central to his discussion are the privileges and responsibilities that come with the surgical career, and the globalisation of medicine.
The relaunch of the library's Adopta Book Scheme
Authors: Craig Tina
Published: November 2006

'As good almost kill a man as kill a good book: who kills a man kills a reasonable creature … but he who destroys a good book kills reason itself.'
Surgical skills work shop in Jamaica
Authors: Peach Chris , Hancock Laura
Published: November 2006

The Royal College of Surgeons of England has always had strong links with the Caribbean and in 2001 the formal College visit to Barbados stimulated the formation of the Caribbean College of Surgeons. Since that time, there has been a continued close association between the two colleges resulting in an invitation to attend the (2006) fourth annual conference of the Caribbean College of Surgeons in Jamaica, to participate in the scientific meeting and then to stage a surgical skills course and an advanced laparoscopic skills workshop in the capital, Kingston.
Affecting policy and practice: issues involved in developing an Argument Catalogue
Authors: Abrami Philip C. , Bernard Robert M. , Wade C. Anne
Published: November 2006

English

In this article we explore issues in developing an Argument Catalogue as a tool to compile evidence systematically on a topic of interest. A recent review is used to illustrate the steps in undertaking the development of an Argument Catalogue from multiple sources. An Argument Catalogue codebook, which provides categories and values that can be applied in order to classify conjectures, opinions, concerns and expert judgements, is also developed. Arguments are then compared and contrasted in two different ways: by quantifying the predictor and outcome variables described and by summarising qualitatively the major messages in each document.
Scotland’s national learning networks: coordinators’ reflections
Authors: Lowther Matthew , Gordon Jacki , Fraser Shirley
Published: November 2006

English

Scotland currently has four national health demonstration projects in the priority areas of child health, sexual health of young people, coronary heart disease and cancer. With the exception of the cancer project, each has a designated national learning network (and related network coordinator) designed to capture project learning, to blend this with the wider relevant evidence base and to disseminate it nationally to inform future policy and practice. This article describes the experiences of the three learning network coordinators. It attempts to tease out some of the challenges faced in coordinating a national learning network and offers some reflections on the process in the hope that future networks can learn from these experiences.
Teacher responses to bullying in relation to moral orientation and seriousness of bullying
Authors: Ellis Alicia A. , Shute Rosalyn.
Published: November 2006

Background. Little research has focused on factors influencing teachers' decisions about whether and how to intervene in bullying incidents. Such factors have the potential to influence the role of teachers as agents in counteracting bullying.

Aims. To examine: (a) whether moral orientation predicts teachers' responses to bullying, (b) the role of perceived seriousness of an incident in moderating responses to bullying and (c) factors that are important to teachers when deciding whether to intervene.

Sample. Primary, middle and high school teachers (N=127) were recruited during staff meetings at five schools.

Methods. Moral orientation was measured using a modified version of Caputo's (2000) Sanctioning Voice Index (SVI); other questionnaires were specifically designed for this study. Correlational and hierarchical multiple regression analyses examining how moral orientation and seriousness predict teachers' responses to bullying were performed.

Results. As anticipated, care moral orientation predicted a problem‐solving response, while justice orientation predicted a rules‐sanctions response. Care and justice orientations also interacted to predict rules‐sanctions, but not problem‐solving responses. However, seriousness of an incident accounted for the majority of variance (46% for rules‐sanctions and 40% for problem‐solving responses). Seriousness did not moderate the relationship between moral orientation and responses to bullying.

Conclusions. While teachers' moral orientation does impact upon the kinds of responses to bullying they choose, seriousness of the incident is more important. However, seriousness as perceived by teachers may not be consistent with impact on students. Implications for teacher education and policy are discussed.
Book Reviews
Authors: Pauley Gerard
Published: November 2006

Mindfulness and Psychotherapy (2005)

By Christopher K. Germer, Ronald D. Siegel and Paul R. Fulton London: Guilford Press. 2005. ISBN 1593851391
French wh-in-situ Questions and Syntactic Optionality: Evidence from Three Data Types
Authors: Adli Aria
Published: November 2006

The aim of this paper is to corroborate the assumption of syntactic optionality for French wh-questions. In terms of a broader basis of evidence three different data types are utilized: Firstly, a qualitative interview approach suggests that wh-in-situ does not show the syntactic restrictions postulated by Bošković (1998) and Cheng & Rooryck (2000), weakening the evidence in favor of the assumption of LF-movement. Secondly, a graded grammaticality judgment test reveals that even in terms of fine nuances an identical level of grammaticality exists between the wh-in-situ form and its counterpart with wh-movement. Given the fact that several crucial judgments in the literature on French wh-in-situ are doubtful, these approaches turn out to be particularly helpful for controlling undesirable interferences in the judgment process and for obtaining more reliable data. Thirdly, a reading time study shows that both variants have the same cognitive complexity in processing. These empirical studies come along with methodological work concerning the development and evaluation of the instruments. From a conceptual point of view the inherent contradiction to which optionality and economy lead within the minimalist framework will be addressed. I will largely follow the suggestion of Haider & Rosengren (2003), who assume optional movement to be exploited at the interface level of syntax. Concerning the latter, I point out that different registers partly correlate with different French wh-questions.
Crystal habits and magnetic microstructures of magnetosomes in coccoid magnetotactic bacteria
Authors: Lins Ulysses , McCartney Martha R. , Farina Marcos , Frankel Richard B. , Buseck Peter R.
Published: November 2006

We report on the application of off-axis electron holography and high-resolution TEM to study the crystal habits of magnetosomes and magnetic microstructure in two coccoid morphotypes of magnetotactic bacteria collected from a brackish lagoon at Itaipu, Brazil. Itaipu-1, the larger coccoid organism, contains two separated chains of unusually large magnetosomes; the magnetosome crystals have roughly square projections, lengths up to 250 nm and are slightly elongated along [111] (width/length ratio of about 0.9). Itaipu-3 magnetosome crystals have lengths up to 120 nm, greater elongation along [111] (width/length ~0.6), and prominent corner facets. The results show that Itaipu-1 and Itaipu-3 magnetosome crystal habits are related, differing only in the relative sizes of their crystal facets. In both cases, the crystals are aligned with their [111] elongation axes parallel to the chain direction. In Itaipu-1, but not Itaipu-3, crystallographic positioning perpendicular to [111] of successive crystals in the magnetosome chain appears to be under biological control. Whereas the large magnetosomes in Itaipu-1 are metastable, single-magnetic domains, magnetosomes in Itaipu-3 are permanent, single-magnetic domains, as in most magnetotactic bacteria.
Shallow gas accumulation in sediments of the Patos Lagoon, southern Brazil
Authors: Weschenfelder Jair , Corrêa Iran C.S. , Aliotta Salvador , Pereira Carla M. , Vasconcelos Vinicius E.B. de
Published: November 2006

A high resolution seismic survey was conducted in the Patos Lagoon, southern Brazil, aboard of the research vessel LARUS of the Fundação Universidade Federal do Rio Grande (FURG). Around 400 km of 3.5 kHz seismic profiles were collected, which provided acoustic signals of good penetration depth and resolution. Seismic anomalies, including turbidity and pocket gas, revealed that gas-charged sediments are common in several areas of the lagoon. The gas accumulations in the Patos Lagoon are controlled by the spatial distribution of the sedimentary facies. Either in 'curtains' or in 'acoustic turbid zones', the main gas accumulations occur in areas with paleotopographic lows related to fluvial channels and valleys developed in the Rio Grande do Sul coastal plain during regressive/transgressive events of the Quaternary.
Distribuição e freqüência de alelos e haplotipos HLA em brasileiros com diabetes melito tipo 1
Authors: Alves Crésio , Meyer Isadora , Vieira Nara , Toralles Maria Betânia P. , LeMaire Denise
Published: November 2006

A predisposição genética ao diabetes melito tipo 1 (DM1) é associada a múltiplos genes do sistema de histocompatibilidade humano (HLA) de classe II. Em caucasianos, os antígenos HLA-DR3 e -DR4 são associados à susceptibilidade e o -DR2, à proteção. No Brasil, um país constituído por grande miscigenação entre caucasianos europeus, índios nativos e negros africanos, a base genética do DM1 tem sido pouco estudada. O objetivo desse trabalho foi apresentar uma revisão crítica dos artigos indexados nos bancos de dados MEDLINE e LILACS-BIREME sobre a associação do HLA com DM1 em brasileiros. Todos os oito estudos encontrados foram realizados no sudeste do país. A susceptibilidade imunogenética para o DM1 em brasileiros foi associada com os alelos HLA-DRB1*03, -DRB1*04, -DQB1*0201, -DQB1*0302 e a proteção com os alelos -DQB1*0602 e -DQB1*0301 e os antígenos -DR2 e -DR7. Por ser o Brasil constituído por grande miscigenação, não se pode extrapolar para todo o país estudos realizados em apenas uma região. Faz-se necessário pesquisar populações de várias regiões, analisando sua diversidade alélica para identificar novas associações ou reforçar aquelas já existentes. Esse conhecimento contribuirá para futuras intervenções profiláticas e terapêuticas nos grupos de brasileiros com maior risco de desenvolver DM1.