Differences in intraoperative and surgical outcomes between normotensive pheochromocytomas and sympathetic paragangliomas (PPGLs) and hypertensive PPGLs: results from the PHEO-RISK STUDY.

PURPOSE: To compare the intraoperative and surgical outcomes of normotensive pheochromocytomas and sympathetic paragangliomas (PPGLs), hypertensive PPGLs and non-PPGL adrenal lesions. METHODS: This a retrospective multicenter cohort study of patients with PPGLs from 18 tertiary hospitals. A control group of histologically confirmed adrenocortical adenomas (non-PPGL group) was selected to compare intraoperative and surgical outcomes with of the normotensive PPGLs. RESULTS: Two hundred and ninety-six surgeries performed in 289 patients with PPGLs were included. Before surgery, 209 patients were classified as hypertensive PPGLs (70.6%) and 87 as normotensive PPGLs. A higher proportion of normotensive PPGLs than hypertensive PPGLs did not receive alpha presurgical blockade (P = 0.009). When we only considered those patients who received presurgical alpha blockers (200 hypertensive PPGLs and 76 normotensive PPGLs), hypertensive PPGLs had a threefold higher risk of intraoperative hypertensive crisis (OR 3.0 [95% 1.3-7.0]) and of hypotensive episodes (OR 2.9 [95% CI 1.2-6.7]) than normotensive PPGLs. When we compared normotensive PPGLs (n = 76) and non-PPGLs (n = 58), normotensive PPGLs had a fivefold higher risk of intraoperative complications (OR 5.3 [95% CI 1.9-14.9]) and a six times higher risk of postoperative complications (OR 6.1 [95% CI 1.7-21.6]) than non-PPGLs. CONCLUSION: Although the risk of intraoperative hypertensive and hypotensive episodes in normotensive PPGLs is significantly lower than in hypertensive PPGLs, normotensive PPGLs have a greater risk of intraoperative and postoperative complications than non-PPGL adrenal lesions. Therefore, it is recommended to follow the standard of care for presurgical and anesthetic management of PPGLs also in normotensive PPGLs.

The IGF2 methylation score for adrenocortical cancer: an ENSAT validation study.

Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224-6.343; OR 1.467 95% CI 1.202-1.792, respectively; Hosmer-Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930-0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866-0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285-2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.

Impact assessment of agricultural inputs into a Mediterranean coastal lagoon (Mar Menor, SE Spain) on transplanted clams (Ruditapes decussatus) by biochemical and physiological responses.

The Mar Menor is a coastal lagoon threatened by the development of intensive agriculture in the surrounding areas. Large amounts of pesticides from these areas are discharged into El Albujón, a permanent watercourse flowing into the lagoon. We have used a multi-biomarker approach to assess the biological effects of agricultural pollution on a bivalve species. Biomarkers indicative of neurotoxicity (acetylcholinesterase, AChE), oxidative stress (catalase, CAT; glutathione reductase, GR and lipid peroxidation, LPO), phase II biotransformation of xenobiotics (glutathione S-transferase, GST) and physiological stress (scope for growth, SFG) were measured in clams transplanted to four sites of the lagoon (two reference sites and two sites affected by the dispersion of the effluent of the El Albujón), for exposure periods of 7 and 22 days. The hazards of this effluent were also examined by simultaneously measuring up to 83 contaminants (pesticides, PCBs, PAHs and others) in samples of fresh water from the watercourse mouth and seawater from the deployed sites, as well as the bioaccumulation of organochlorinated compounds and PAHs in the transplanted animals. Biomarker responses showed marked differences between reference and affected sites after 7 and 22 days. However it was only after 22 days that principal component analysis (PCA) of the biomarker responses distinguished between clams deployed in sites affected by the dispersion of the effluent of the watercourse and those from the reference sites. The chemical analysis of water showed high concentrations of pesticides close to El Albujón watercourse mouth, with the greatest input flux corresponding to the organophosphate chlorpyrifos, followed by pendimethalin and naphthalene, and at lower levels acenaphthene, terbuthylazine-desethyl and chlorpyrifos-methyl. In this regard, PCA analysis showed that the biological effects of the mixture of pesticides in caged clams after 22 days were reduced levels of AchE and SFG and increased levels of GR and phase II GST activity. An integrated biomarker response index was calculated from the combination of these biomarkers, proving useful for the assessment of the impact of agricultural pollution in caged clams.

Monocyte-derived dendritic cells from HCV-infected patients transduced with an adenovirus expressing NS3 are functional when stimulated with the TLR3 ligand poly(I:C).

Dendritic cells (DC) transfected with an adenovirus encoding hepatitis C virus (HCV) NS3 protein (AdNS3) induce potent antiviral immune responses when used to immunize mice. However, in HCV infected patients, controversial results have been reported regarding the functional properties of monocyte-derived DC (MoDC), a cell population commonly used in DC vaccination protocols. Thus, with the aim of future vaccination studies we decided to characterize MoDC from HCV patients transfected with AdNS3 and stimulated with the TLR3 ligand poly(I:C). Phenotypic and functional properties of these cells were compared with those from MoDC obtained from uninfected individuals. PCR analysis showed that HCV RNA was negative in MoDC from patients after the culture period. Also, phenotypic analysis of these cells showed lower expression of CD80, CD86, and CD40, but similar expression of HLA-DR molecules as compared to MoDC from uninfected individuals. Functional assays of MoDC obtained from patients and controls showed a similar ability to activate allogeneic lymphocytes or to produce IL-12 and IL-10, although lower IFN-alpha levels were produced by cells from HCV patients after poly(I:C) stimulation. Moreover, both groups of MoDC induced similar profiles of IFN-gamma and IL-5 after stimulation of allogeneic T-cells. Finally, migration assays did not reveal any difference in their ability to respond to CCL21 chemokine. In conclusion, MoDC from HCV patients are functional after transduction with AdNS3 and stimulation with poly(I:C). These findings suggest that these cells may be useful for therapeutic vaccination in chronic HCV infection.

Hereditary Melkersson-Rosenthal syndrome and multiple sclerosis.

UNLABELLED: The revision of MEDLINE from 1966 to 2003 did not report any association between multiple sclerosis (MS) and Melkersson-Rosenthal syndrome (MRS). This is a case report of a 51-year-old woman, with history of four recurrent Bell's palsies. In 1999 she developed a right facial paralysis due to a supranuclear pyramidal lesion with right monoparesis. The family history showed five relatives with recurrent Bell's paralysis and plicata tongue. PHYSICAL EXAMINATION: right Bell's paralysis, left supranuclear facial paralysis, furrowed tongue, right hemiparesis with pallor of the optic disks. Brain magnetic resonance imaging (MRI) demonstrated the typical lesions of MS and CSF oligoclonal bands. This is the first observation of a patient with hereditary MRS and MS. The link between both diseases is discussed.

Multiple endocrine neoplasia type 1 (MEN1): clinical heterogeneity in a large family with a nonsense mutation in the MEN1 gene (Trp471Stop).

OBJECTIVE: Familial multiple endocrine neoplasia type 1 (MEN1) is an hereditary dominant trait characterized by tumours of the parathyroids, anterior pituitary and endocrine pancreatic glands, among others. The MEN1 gene has recently been cloned, and MEN1-mutations have been identified in several families as well as in a number of sporadic cases. The aim of this study was to search for mutations in a large MEN1-family in order to define the clinical heterogeneity among mutation-carriers. We also analysed DNA from several tumour tissues in order to test the 'two hit' model for inactivation of the MEN1 gene. PATIENTS AND METHODS: We searched for mutations in the MEN1-gene in members of a large MEN1-family. A total of 11 affected and 4 healthy at risk individuals were analysed. DNA was obtained and exons 1 to 10 of the MEN1-gene were PCR-amplified and subjected to automated-direct sequencing. In addition, we isolated DNA from parathyroid tumours of two family members, and compared this DNA with that of the normal tissue counterpart to define if the normal copy of the MEN1-gene was deleted. RESULTS: G to A change at nucleotide 7640 (exon 10) that would convert Trp to Stop at codon 471 was found. This mutation was identified in eleven affected individuals, as well as in four healthy (asymptomatic) family members. These patients showed a wide spectrum of clinical symptoms and ages of presentation. Comparison of normal and tumour DNAs showed the loss of the normal (non-mutated) copy of MEN1 gene in the tumour tissue. CONCLUSION: The different ages of disease presentation and the heterogeneity of symptoms among carriers of the Trp471Stop mutation, which would lead to the synthesis of a truncated non-functional protein, suggest that clinical heterogeneity is a characteristic of MEN1 independent of the type of mutation. Finally, the lack of amplification of the normal MEN1-allele on DNA from parathyroid tumours of two family members indicates that MEN1 is a tumour suppressor gene, the second hit that inactivates the normal copy in mutation carriers being a deletion.

Multiple endocrine neoplasia type 1 (MEN1): LOH studies in a affected family and in sporadic cases.

Multiple endocrine neoplasia (Menl) is an autosomai dominant hereditary trait characterized by tumors of endocrine tissues. The MEN1 gene maps to chromosome llql3, has been recently isolated, and encodes a protein termed menin that is ubiquitously expressed. This gene is likely to be a tumor suppressor gene, with tumors developing after the inactivation of both copies of the gene in a single cell. In agreement with this, 11q-deletions (loss of heterozygosity) are frequently found in neoplasms from MEN1 patients. In this study, DNA from family-members was extracted and analysed for 10 microsatellites flanking the MEN1-gene on chromosome 11q. SSCP was used to determine the presence of MEN1-mutations in several patients. DNA was extracted from paraffin blocks containing tissue from 10 parathyroid tumors (4 familial and 6 sporadic) and 2 gastrinomas (both from patients of the Men1-family). LOH was determined by comparing the autoradiographic patterns of several markers between the normal tissue and the malignant tissue counterpart. All the affected individuals in the MEN1-family shared one haplotype, not present in the healthy individuals. We searched for mutations at the MEN1 gene (SSCP-analysis) in several affected members. An SSCP-mobility shift was found at exon 9, and direct sequencing showed that this corresponded to a common polymorphism at codon 418 (GAC/GAT), LOH, a genetic alteration characteristic of genomic regions containing tumor suppressor genes, was found in all the parathyroid tumors, but not in two gastrinomas. SSCP-analysis of the MEN1-exon 9 polymorphism showed that LOH included the MEN1-gene in the informative parathyroid tumors. In conclusion, LOH at 11q is frequent in Menl-parathyroid tumors, either sporadic or familial, and the deletion involves the MEN1-gene. In contrast, the two gastrinomas did not show LOH, indicating the existence of a second mutation other than the MEN1-deletion in these tumors. Our data suggest that the mechanism that drives tumorigenesis in Menl either familial or sporadic, is influenced by the tissue context.

Rhombomere-specific origin of branchial and visceral motoneurons of the facial nerve in the rat embryo.

The goal of this study was to localize selectively the facial nerve branchial and visceral motoneurons in the rat embryo hindbrain. This was achieved by injecting dextran amines into the peripheral facial nerve on embryos maintained in an artificial cerebrospinal fluid. Sprague-Dawley rat embryos 13, 14, and 15 days old (E13, E14, E15) were obtained by cesarean section. Branchial motoneurons were first labeled at E13. They were close to the midline and migrated from rhombomere (r) 4 toward r5 and r6. By E15, they had migrated caudally and ventrolaterally into the former location of r6. Most of them had reached their "adult" position by E15. Another group of motoneurons, the accessory facial nucleus, was found in r4 at E13 and in corresponding regions at later stages. Visceral motoneurons were labeled from the periphery at all stages. At E13, they were mainly in r5 but also in r2, r3, r4, and r6. At E14, most of them had migrated laterally, and, by E15, they were in the prospective parvocellular reticular formation. They could be divided into two subgroups: a more rostral one with fibers that made loops close to the midline and a more caudal one with fibers that went directly to the exit. The findings presented here show that most branchial and visceral motoneurons of the facial nerve are born in different and specific rhombomeres. Interestingly, developmental genes are expressed specifically in these rhombomeres and could be involved in the genesis of the facial and superior salivatory nuclei.

Neonatal tetanus mortality in Veracruz, Mexico, 1989.

This article describes a survey conducted in the State of Veracruz, Mexico, to estimate neonatal tetanus (NNT) mortality. The survey, which entailed visits to 72,720 households, collected data on 8,401 live births and 209 infant deaths occurring between April 1988 and May 1989. Twenty-six of the 209 fatalities conformed to a WHO standard case definition of death from neonatal tetanus. The estimated neonatal tetanus mortality was thus 3.1 deaths per 1,000 live births (95% confidence limits = 1.7, 4.5). Comparison of this rate to reported figures suggests that for every NNT death recorded in Veracruz during the study period, as many as 50 others went unreported. A case-control study nested within the survey was conducted to assess preventable NNT risk factors. Limited information on 13 NNT deaths and 217 controls showed an increased risk for neonates who were delivered at home and whose parents' ethnic background was Mexican Indian. Five of the 13 fatalities had their umbilical cords cut with a domestic or traditional cutting tool such as a reed cane, as compared to none of the 217 controls. The observed vaccine efficacy of 2+ doses of tetanus toxoid was 70% (95% confidence limits = 52, 100). Both the mothers of neonates who died of NNT and their controls missed an average of five opportunities to receive tetanus toxoid. These findings underscore the need to launch a perinatal health program serving Mexico's high-risk populations.

Evaluation of two cross-linked collagen gels implanted in the transected spinal cord.

In previous experiments, we have shown that spinal axons grow into a collagen matrix implanted between the stumps of a transected spinal cord. However, the matrix became denatured after 2 to 3 months. To improve the stability and the durability of the collagen gel implants, collagen was coprecipitated with chondroitin-6-sulfate (C-6-S) or chemically cross-linked with carbodiimide (CD). The spinal cords were taken out after 3 days, 1, 3, or 6 months and analyzed using different histological and tracing techniques. The cross-linked collagen matrices underwent major structural changes. Cross-linking treatments improved the stability of collagen implants which withstood at least 6 months. Axons revealed with DiI or silver staining crossed the proximal interface and grew into the bioimplants. Some axons were also followed across the distal bioimplant-spinal interface in DiI treated tissues. This study suggests that cross-linking the collagen hydrogel has improved the mechanical properties of the matrix, modified the normal scarring process, and favored axonal regeneration.

Tratamiento del hipertiroidismo con iodo radiactivo. Estudio de 35 casos / Hyperthyroidism treatment with radioactive iodine. Study of 35 cases

Se estudiaron 35 pacientes que presentaron hipertiroidismo, quienes habían sido tratados con diferentes dosis de radio isótopo en un período comprendido de 1 a 4 años. Se analizan los resultados y se encuentran 27 casos (77 porciento) eutiroideos, 7 casos (20 porciento) hipertiroideos y sólo un caso hipotiroideo. Se comparan sus resultados con los obtenidos por otros autores(AU)