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1.
Osteoporos Int ; 32(6): 1239-1244, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33624138

RESUMEN

Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. BMP1 variants have been reported in the rare OI type XIII, specifically referred to herein as BMP1-associated autosomal recessive (AR) OI. We report the clinical presentation and diagnostic evaluation of a patient found to have a novel homozygous variant in BMP1. We also provide an overview of reported BMP1 variants to date, with discussion focusing on the use of bisphosphonate therapy in these patients. A 7-year-old male with speech and motor delay sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6, he developed severe back pain after a fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3, and L5 were identified. Total hip BMD was generous (adjusted Z-score* = 1.76), and femoral neck BMD was high (adjusted Z-score* = 2.67). VCFs precluded assessment of lumbar spine BMD. Genetic analysis identified a homozygous missense variant in exon 4 of BMP1 (c.C505T; p.Arg169Cys). Unlike most forms of OI, patients with BMP1-associated AR OI may have normal or paradoxically increased BMD, making BMD and fracture risk correlation difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and underlying bone pathology, often in the setting of increased BMD, complicate management. HR-pQCT assessment of bone microarchitecture and quality may aid in the decision of BP therapy and subsequent monitoring. Evidence is limited with respect to the effectiveness of BP in this rare form of OI. *Z-score was adjusted for height Z-score.


Asunto(s)
Fracturas Óseas , Fracturas por Compresión , Osteogénesis Imperfecta , Fracturas de la Columna Vertebral , Densidad Ósea/genética , Niño , Preescolar , Difosfonatos/uso terapéutico , Humanos , Masculino , Mutación , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/tratamiento farmacológico , Osteogénesis Imperfecta/genética , Fenotipo , Fracturas de la Columna Vertebral/genética
2.
J Eur Acad Dermatol Venereol ; 31(7): 1223-1228, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28129487

RESUMEN

BACKGROUND: Growing evidence suggests that some individuals may exhibit symptoms of dependence on ultraviolet (UV) light, a known carcinogen, in the context of tanning; however, few studies have investigated predictors of tanning dependence (TD). OBJECTIVE: To identify predictors of TD. METHODS: Non-Hispanics of European ancestry who had previously participated in a case-control study of early-onset basal cell carcinoma completed an online survey to ascertain TD and other behaviours (alcohol dependence, nicotine dependence, seasonal affective disorder (SAD), exercise 'addiction' and depression). Information on host factors, such as skin and eye colour and history of sunbathing and indoor tanning, was obtained from a study in which the participants were previously enrolled. Lifetime TD was assessed using the modified Cut down, Annoyed, Guilty, Eye-opener (mCAGE) and the modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (mDSM-IV-TR) questionnaires. Participants were classified as 'TD' if positive on both questionnaires and not TD if negative on both questionnaires. RESULTS: In total, 499 individuals completed the online survey (81.9% participation rate), and 24.4% were classified as 'TD'. In the multivariate model, women were more likely to be TD [odds ratio (OR) 6.93; 95% confidence intervals (95% CI) (3.36-14.27)] than men. Alcohol dependence (OR 6.55: 95% CI 3.19-13.42), SAD (OR 2.77; 95% CI 1.26-6.09) and exercise 'addiction' (OR 5.47; 95% CI 1.15-26.06) were all significant predictors for TD. CONCLUSION: Increased knowledge of those at risk for TD will allow appropriate interventions to be designed.


Asunto(s)
Conducta Adictiva , Baño de Sol , Población Blanca , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino
3.
Regul Toxicol Pharmacol ; 72(1): 94-101, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25777839

RESUMEN

Regulatory agencies often utilize results from peer reviewed publications for hazard assessments. A problem in doing so is the lack of well-accepted tools to objectively, efficiently and systematically assess the quality of published toxicological studies. Herein, we evaluated the publicly available software-based ToxRTool (Toxicological data Reliability assessment Tool) for use in human health hazard assessments. The ToxRTool was developed by the European Commission's Joint Research Center in 2009. It builds on Klimisch categories, a rating system established in 1997, by providing additional criteria and guidance for assessing the reliability of toxicological studies. It also transparently documents the study-selection process. Eight scientists used the ToxRTool to rate the same 20 journal articles on thyroid toxicants. Results were then compared using the Finn coefficient and "AC1" to determine inter-rater consistency. Ratings were most consistent for high-quality journal articles, but less consistent as study quality decreased. Primary reasons for inconsistencies were that some criteria were subjective and some were not clearly described. It was concluded, however, that the ToxRTool has potential and, with refinement, could provide a more objective approach for screening published toxicology studies for use in health risk evaluations, although the ToxRTool ratings are primarily based on study reporting quality.


Asunto(s)
Sustancias Peligrosas/toxicidad , Evaluación del Impacto en la Salud/métodos , Evaluación del Impacto en la Salud/normas , Investigación/normas , Toxicología/métodos , Toxicología/normas , Humanos , Reproducibilidad de los Resultados , Programas Informáticos
4.
Br J Dermatol ; 171(6): 1451-7, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25059635

RESUMEN

BACKGROUND: Previous epidemiological studies of overall alcohol intake and basal cell carcinoma (BCC) are inconsistent, with some evidence for differences by type of alcoholic beverage. While alcohol may enhance the carcinogenicity of ultraviolet (UV) radiation, this has not been evaluated in existing epidemiological studies. OBJECTIVES: To evaluate alcohol intake in relation to early-onset BCC, and explore potential interactions with UV exposure. METHODS: Basal cell carcinoma cases (n = 380) and controls with benign skin conditions (n = 390) under 40 years of age were identified through Yale Dermatopathology. Participants provided information on lifetime alcohol intake, including type of beverage, during an in-person interview. Self-reported data on indoor tanning and outdoor sunbathing were used to categorize UV exposure. We calculated odds ratios (OR) and 95% confidence intervals (CIs) using unconditional multivariate logistic regression in the full sample and in women only. RESULTS: There was no statistically significant association between lifetime alcohol intake and early-onset BCC overall [above median intake vs. no regular alcohol intake (OR 1·10, 95% CI 0·69-1·73)] or in women only (OR 1·21, 95% CI 0·73-2·01). Similarly, intake of red wine, white wine, beer or spirits and mixed drinks was not associated with early-onset BCC. In exploratory analyses, we saw limited evidence for an interaction (P(interaction) = 0·003), with highest risk for high alcohol and high UV exposures, especially in women, but subgroup risk estimates had wide and overlapping CIs. CONCLUSIONS: Overall, we did not observe any clear association between lifetime alcohol intake and early-onset BCC.


Asunto(s)
Consumo de Bebidas Alcohólicas/efectos adversos , Carcinoma Basocelular/etiología , Neoplasias Cutáneas/etiología , Adulto , Edad de Inicio , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Baño de Sol/estadística & datos numéricos , Luz Solar/efectos adversos , Rayos Ultravioleta/efectos adversos
5.
Br J Cancer ; 98(2): 282-8, 2008 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-18219286

RESUMEN

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case-control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3' variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case-control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01-1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62-1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.


Asunto(s)
Carcinoma Endometrioide/genética , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/genética , Polimorfismo de Nucleótido Simple , Receptores de Progesterona/genética , Adulto , Anciano , Carcinoma Endometrioide/patología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Mutagénesis Insercional , Invasividad Neoplásica , Neoplasias Ováricas/clasificación , Neoplasias Ováricas/patología , Factores de Riesgo
6.
J Cutan Pathol ; 34(1): 65-70, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17214858

RESUMEN

BACKGROUND: Linear unilateral basal cell nevus represents a linear collection of macules and papules histologically similar to basal cell carcinoma but with benign clinical behavior. We describe a patient who initially presented at the age of 6 months with a unilateral linear basal cell nevus on the right flank. The differential diagnosis included the nevoid basal cell carcinoma syndrome. Constitutional PTCH mutations are causative of the nevoid basal cell carcinoma syndrome, and somatic PTCH mutations are found in the vast majority of basal cell carcinomas. Somatic SMO mutations have also been found in some basal cell carcinomas. METHODS: Histologic examination of the lesions is performed. Short tandem-repeat molecular analysis at the PTCH locus and sequencing of PTCH and SMO genes is performed. RESULTS: Histologic examination revealed features initially indistinguishable from basal cell carcinoma. Short tandem-repeat DNA analysis did not reveal loss of heterozygosity at the PTCH locus. DNA sequencing of both the PTCH and the SMO genes from the patient's lesions revealed neither inactivating mutations of PTCH nor activating mutations of SMO. CONCLUSION: Molecular examination indicates that the PTCH and SMO genes are not involved in the pathogenesis of the patients' congenital linear unilateral basal cell nevus. Furthermore, we discuss the relationship between linear basal cell nevus and basaloid follicular hamartoma.


Asunto(s)
Nevo/genética , Nevo/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Muslo , ADN de Neoplasias , Diagnóstico Diferencial , Humanos , Lactante , Pérdida de Heterocigocidad , Repeticiones de Microsatélite , Mutación , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G/genética , Neoplasias Cutáneas/congénito , Receptor Smoothened
7.
J R Nav Med Serv ; 91(2): 99-111, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-16196219

RESUMEN

BACKGROUND: This is the result of an observational study on 3,233 Gulf veterans who have attended our medical assessment programme. We wanted to determine as a result of in-depth interviews, full medical examination and appropriate investigations, whether there was any unique Gulf war related medical condition. METHODS: Over a period of 10 years, 3,233 veterans have been assessed. All diagnoses have been made according to ICD-10 classifications. All psychiatric diagnoses have been confirmed by consultant psychiatrists. FINDINGS: 75% of veterans were well. Of the 25% unwell, 83% of ill health was accounted for by a psychiatric disorder. 3% of veterans had organic conditions which could be linked to Gulf deployment. The most common of these were respiratory disorders, followed by digestive disorders, injuries and skin disorders. Only 11 of these cases could be linked to the use of medical countermeasures. A further, 51 cases (41 respiratory disorders, 6 infections, 2 skin disorders and 2 eye conditions) could be linked to environmental conditions. INTERPRETATION: All veterans seen with health problems could be identified as per ICD-10 classification of disease. We did not find any medically unexplained conditions. We found no evidence of a unique 'Gulf War Syndrome'.


Asunto(s)
Síndrome del Golfo Pérsico/epidemiología , Veteranos/estadística & datos numéricos , Adulto , Humanos , Clasificación Internacional de Enfermedades , Trastornos Mentales/epidemiología , Síndrome del Golfo Pérsico/diagnóstico , Reino Unido/epidemiología
8.
Neuroscience ; 130(1): 197-206, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15561435

RESUMEN

Toluene, a representative member of the large class of abused inhalants, decreases neuronal activity and depresses behavior in both animals and humans. The sites of action of toluene are not completely known but recent studies suggest that ion channels that regulate neuronal excitability may be particularly sensitive. Previous studies with recombinant receptors showed that toluene decreases currents carried by N-methyl-D-aspartate (NMDA)-glutamate receptors without affecting those gated by non-NMDA receptors. In addition, toluene increases currents generated by GABA and glycine receptors. In the present study, primary cultures of rat hippocampal neurons were used to investigate the effects of acute and chronic toluene exposure on native excitatory and inhibitory ligand-gated ion channels. Toluene dose-dependently inhibited NMDA-mediated currents (IC50 1.5 mM) but had no effect on responses evoked by the non-NMDA agonist kainic acid. Prolonged treatment of neurons with toluene (1 mM; 4 days) increased whole-cell responses to exogenously applied NMDA, reduced those evoked by GABA but did not alter responses generated by kainic acid. Immunoblot analysis revealed that prolonged toluene exposure increased levels of NR2A and NR2B NMDA receptor subunits with no change in NR1. Immunohistochemical analysis with confocal imaging showed that toluene-treated neurons had significant increases in the density of NR1 subunits as compared with control neurons. Toluene exposure increased the amplitude of synaptic NMDA currents and decreased those activated by GABA. The results from this study suggest that toluene induces compensatory responses in the functional expression of ion channels that regulate neuronal excitability.


Asunto(s)
Hipocampo/citología , Canales Iónicos/efectos de los fármacos , Neuronas/efectos de los fármacos , Tolueno/farmacología , Sistema de Transporte de Aminoácidos X-AG/farmacología , Animales , Animales Recién Nacidos , Bicuculina/farmacología , Western Blotting/métodos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas del GABA/farmacología , Proteínas de Transporte de Glutamato en la Membrana Plasmática , Ácido Glutámico/metabolismo , Hipocampo/efectos de los fármacos , Inmunohistoquímica/métodos , Activación del Canal Iónico/efectos de los fármacos , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/efectos de la radiación , Microscopía Confocal/métodos , Neuronas/efectos de la radiación , Técnicas de Placa-Clamp/métodos , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Solventes/farmacología , Simportadores/farmacología , Factores de Tiempo , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacología
9.
J R Army Med Corps ; 150(1): 14-9, 2004 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15149006

RESUMEN

OBJECTIVE: To determine whether the health of Porton Down volunteers (PDV) has suffered as a result of their participation in medical trials, during which they were exposed to single low dose concentrations of chemical warfare agents. METHODS: Data were obtained from a self-selected series of ex-Porton Down volunteers who attended the MOD's Porton Down Volunteers' Medical Assessment Programme (PDVMAP). One hundred and eleven men attended with a mean age of 62 (range 37-81) years. Information obtained was analysed to determine whether clinical diagnoses and symptoms reported had any relationship to chemical exposures. RESULTS: The diagnoses were not unusual for UK nationals with a mean age of 62 years. The majority of volunteers went to Porton Down in the 1950s and then had a mean age of 19. The mean time between volunteers attending Porton Down and coming to MAP was 42 years. We found no correlation between chemical exposures and later development of established diagnoses, a latent period of 30 years. CONCLUSION: On a clinical basis, no evidence was found to support the hypothesis that participation in Porton Down trials produced any long-term adverse health effects or unusual patterns of disease compared to those of the general population of the same age.


Asunto(s)
Sustancias para la Guerra Química/efectos adversos , Experimentación Humana , Personal Militar , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Enfermedad/clasificación , Enfermedad/etiología , Humanos , Masculino , Persona de Mediana Edad , Medición de Riesgo , Factores de Tiempo , Reino Unido
10.
J Dent Res ; 81(11): 757-60, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12407090

RESUMEN

The human patched gene (PTCH) functions in both embryologic development and tumor suppression. PTCH mutations have been found in odontogenic keratocysts. However, the expression and localization of the protein product of the gene have not been determined in odontogenic tumors and cysts. We investigated 68 odontogenic lesions by immunohistochemistry, and compared their PTCH expression with that in basal cell carcinomas. All odontogenic lesions, including two keratocysts with truncating mutations, were positive for PTCH. Different types of lesions had different amounts of staining. Lack of staining was noted in the majority of basal cell carcinomas. Taken together, these data suggest that odontogenic keratocysts arise with heterozygous mutations of the PTCH gene.


Asunto(s)
Proteínas de la Membrana/análisis , Proteínas de Neoplasias/análisis , Quistes Odontogénicos/genética , Tumores Odontogénicos/genética , Secuencia de Aminoácidos , Carcinoma Basocelular/química , Carcinoma Basocelular/genética , Genes Supresores de Tumor , Heterocigoto , Humanos , Técnicas para Inmunoenzimas , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Mutación , Proteínas de Neoplasias/genética , Quistes Odontogénicos/química , Tumores Odontogénicos/química , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular
11.
J R Army Med Corps ; 147(2): 153-60, 2001 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-11464406

RESUMEN

OBJECTIVE: To review the diagnoses made in the second 1000 veterans of the Gulf conflict 1990-91 seen in the Ministry of Defence's Gulf Veterans' Medical Assessment Programme and to determine the main conditions related to Gulf service. DESIGN: Case series of 1000 consecutive Gulf veterans who presented to the programme between 25 February 1997 and 19 February 1998. SUBJECTS: Gulf War veterans. MAIN OUTCOME MEASURES: Assessment of the patient's health status. Diagnosis of medical and psychiatric conditions using ICD-10. RESULTS: 204 patients were unwell. 309 patients had organic disease, of whom 248 were well, 252 had psychiatric conditions which remained active in 173. The remaining 79, now well, had had psychiatric disorders following Gulf service. The principal psychiatric diagnosis was post traumatic stress disorder and the majority arose as a result of Gulf service. CONCLUSION: 796 (80%) veterans were well. There were 309 (31%) patients with organic disease. 252 (25%) veterans had psychiatric conditions of which 173 (69%) had an active diagnosed disorder and post traumatic stress disorder was the predominant condition. The pattern of disease is similar to that seen in NHS practice. We found, like others, no evidence to support a unique Gulf War syndrome. Post conflict illnesses have many common features.


Asunto(s)
Grupos Diagnósticos Relacionados/estadística & datos numéricos , Estado de Salud , Morbilidad , Síndrome del Golfo Pérsico/epidemiología , Veteranos/estadística & datos numéricos , Guerra , Adulto , Distribución por Edad , Trastornos del Conocimiento/diagnóstico , Trastornos del Conocimiento/epidemiología , Grupos Diagnósticos Relacionados/clasificación , Fatiga/diagnóstico , Fatiga/epidemiología , Femenino , Cefalea/diagnóstico , Cefalea/epidemiología , Humanos , Infecciones/diagnóstico , Infecciones/epidemiología , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/epidemiología , Masculino , Medio Oriente , Enfermedades Musculoesqueléticas/diagnóstico , Enfermedades Musculoesqueléticas/epidemiología , Neoplasias/diagnóstico , Neoplasias/epidemiología , Síndrome del Golfo Pérsico/diagnóstico , Vigilancia de la Población , Distribución por Sexo , Factores Socioeconómicos , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/epidemiología , Reino Unido/epidemiología
12.
Hum Mol Genet ; 10(7): 757-62, 2001 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11257109

RESUMEN

Developmental pathways first elucidated by genetic studies in the fruit fly, Drosophila melanogaster, are conserved in vertebrates, and disruption of these pathways has been associated with various human congenital anomalies. Many developmental genes continue to play an important role in regulation of cell growth and differentiation after embryogenesis, and mutations in some of these genes can result in cancer. Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans. Although most BCCs are sporadic, in rare cases, individuals have a hereditary disease, Gorlin syndrome, that predisposes to multiple skin tumors as well as a variety of birth defects. Mutations in the human homolog of a Drosophila gene, patched, underlie Gorlin syndrome. Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in sporadic as well as hereditary BCCs, and inactivation of this gene is probably a necessary if not sufficient step for tumor formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for skin cancer and possibly other tumors.


Asunto(s)
Carcinoma Basocelular/genética , Proteínas/genética , Neoplasias Cutáneas/genética , Transactivadores , Animales , Síndrome del Nevo Basocelular/genética , Carcinoma Basocelular/terapia , Drosophila , Predisposición Genética a la Enfermedad , Proteínas Hedgehog , Humanos , Proteínas de la Membrana/genética , Modelos Biológicos , Mutación , Receptores Patched , Receptores de Superficie Celular , Neoplasias Cutáneas/terapia
13.
Methods Mol Med ; 49: 227-42, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-21370144

RESUMEN

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by the predisposition to develop both peptic ulcer disease and a wide variety of endocrine tumors usually in adolescence and adulthood. Specifically, hyperplasia and/or tumors (most often adenomas) of the parathyroid, pancreatic islet cells, anterior pituitary, and adrenal cortical glands are classically described in affected individuals who have MEN1 (1,2). MEN1 is a highly penetrant disorder whose onset is generally during adult life with the occurrence of at least one, but most often more than one, of the aforementioned tumors. The age-related penetrance of this disorder based on analysis in 63 unrelated kindreds is 7, 52, 87, 98, 99, and 100% by 10, 20, 30, 40, 50, and 60 yr, respectively (3). The disorder is estimated to occur in approx 1 in 30,000 to 1 in 50,000 individuals. Most cases are associated with a positive family history of the disorder, but new germline mutations have been identified in a small percentage of individuals having a negative family history of the disorder but classic features of MEN1 (3-7).

14.
Thyroid ; 10(11): 1001-7, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11128714

RESUMEN

OBJECTIVE: To note that a thyrotropin (TSH)-secreting macroadenoma may be part of the multiple endocrine neoplasia-1 (MEN-1) syndrome and to report the use of octreotide-LAR (OCT-LAR) to treat a TSH-secreting macroadenoma in a patient with MEN-1 with previous surgery for hyperparathyroidism and gastrinoma. METHODS: We present a patient with a TSH-secreting pituitary macroadenoma and report the results of her endocrine, genetic, radiologic, and nuclear medicine testing and her response to treatment with octreotide (OCT), octreotide-LAR, and estrogen. RESULTS: This patient's TSH-induced hyperthyroidism responded to octreotide for 5 months and octreotide-LAR for more than 11 months. Her hypercalcemia normalized while she was taking estrogen. Her genetic testing is reported to show a genetic defect that is typical of patients with MEN-1. CONCLUSION: This report describes: (1) The use of octreotide-LAR to treat both a TSH-secreting pituitary tumor and a gastrinoma over 12 months; (2) the importance of including these tumors into the MEN-1 syndrome with its attendant implications; and (3) a genetic defect, typical of patients with MEN-1, associated with this tumor.


Asunto(s)
Adenoma/tratamiento farmacológico , Hormonas/administración & dosificación , Neoplasia Endocrina Múltiple Tipo 1/tratamiento farmacológico , Octreótido/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Tirotropina/metabolismo , Adenoma/diagnóstico por imagen , Adenoma/metabolismo , Estrógenos/administración & dosificación , Femenino , Humanos , Hipercalcemia/etiología , Hipertiroidismo/diagnóstico por imagen , Hipertiroidismo/tratamiento farmacológico , Hipertiroidismo/etiología , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico por imagen , Cintigrafía , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/metabolismo
16.
J Dent Res ; 79(6): 1418-22, 2000 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-10890722

RESUMEN

An odontogenic keratocyst (OKC) is a benign cystic lesion of the jaws that occurs sporadically or in association with nevoid basal cell carcinoma syndrome (NBCCS). Recently, the gene for NBCCS was cloned and shown to be the human homologue of the Drosophila segment polarity gene Patched (PTCH), a tumor suppressor gene. The PTCH gene encodes a transmembrane protein that acts in opposition to the Hedgehog signaling protein, controlling cell fates, patterning, and growth in numerous tissues, including tooth. We investigated three cases of sporadic odontogenic keratocysts and three other cases associated with NBCCS, looking for mutations of the PTCH gene. Non-radioactive single-strand conformational polymorphism and direct sequencing of PCR products revealed a deletion of 5 base pairs (bp) in exon 3 (518delAAGCG) in one sporadic cyst as well as mutations in two cysts associated with NBCCS, a nonsense (C2760A) and a missense (G3499A) alteration. This report is the first to describe a somatic mutation of PTCH in sporadic odontogenic keratocysts as well as two novel mutations in cysts associated with NBCCS, indicating a similar pathogenesis in a subset of sporadic keratocysts.


Asunto(s)
Proteínas de la Membrana/genética , Mutación/genética , Quistes Odontogénicos/genética , Transactivadores , Adulto , Sustitución de Aminoácidos/genética , Síndrome del Nevo Basocelular/genética , Emparejamiento Base/genética , Codón sin Sentido/genética , Inducción Embrionaria/genética , Exones/genética , Femenino , Mutación del Sistema de Lectura/genética , Eliminación de Gen , Genes Supresores de Tumor/genética , Proteínas Hedgehog , Humanos , Masculino , Mutación Missense/genética , Receptores Patched , Receptor Patched-1 , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Proteínas/genética , Receptores de Superficie Celular , Análisis de Secuencia de ADN , Transducción de Señal/genética
17.
Hum Mutat ; 16(1): 89-90, 2000 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-10874314

RESUMEN

Medulloblastoma is the most common malignant embryonic tumors of the central nervous system. The nevoid basal cell carcinoma syndrome (NBCCS), which is caused by mutations of PTCH gene on chromosome 9q22, accounts for about 2% of all medulloblastomas. Previous studies of PTCH in sporadic medulloblastomas using single strand conformational polymorphism (SSCP) detected mutations in about 10% of the tumors. In this study, we directly sequenced the PTCH gene in 20 sporadic medulloblastoma DNA samples. A nonsense mutation (Q694X) and a splice site alteration (2875+1G>A) were identified in two of the samples. The mutations are predicted to result in a truncated PTCH protein and aberrant splicing, respectively. In both cases, only the mutant alleles were identified, indicating that the mutations were associated with loss of the wild-type PTCH allele in the tumor cells. Several novel variants, including 1653T>C, 1672C>T, and 2292C>T, were also found in these tumor samples. One of the two mutations detected in this study had been missed by SSCP, suggesting that the true rate of PTCH mutations in sporadic medulloblastomas may be underestimated by SSCP screening. Nevertheless, the frequency of mutations in this study did not differ from previous reports.


Asunto(s)
Neoplasias Cerebelosas/genética , Meduloblastoma/genética , Proteínas de la Membrana/genética , Mutación/genética , Humanos , Receptores Patched , Receptor Patched-1 , Receptores de Superficie Celular , Análisis de Secuencia de ADN/métodos , Células Tumorales Cultivadas
18.
Am J Surg ; 178(5): 360-1, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10612527

RESUMEN

BACKGROUND: This study was designed to determine if interpectoral nodes could be sentinel nodes for some breast cancers. METHODS: Thirty-five consecutive breast cancer patients undergoing axillary node dissection had a dissection of the interpectoral nodes. These were sent to pathology as a separate specimen. RESULTS: Three patients were identified with isolated interpectoral nodal metastasis. CONCLUSION: In upper quadrants or deep breast cancers the interpectoral nodes may be the earliest site of nodal metastasis. This may lead to false negative results in some sentinel node biopsies.


Asunto(s)
Neoplasias de la Mama/patología , Ganglios Linfáticos/patología , Estadificación de Neoplasias/métodos , Adulto , Anciano , Axila , Biopsia , Neoplasias de la Mama/cirugía , Reacciones Falso Negativas , Femenino , Humanos , Escisión del Ganglio Linfático , Metástasis Linfática , Persona de Mediana Edad , Sensibilidad y Especificidad
20.
J Pediatr ; 135(3): 327-31, 1999 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-10484798

RESUMEN

Two kindreds with familial medullary thyroid carcinoma (MTC) are described in which affected family members had variable clinical and pathologic manifestations. Genetic testing in 2 children from one kindred revealed a mutation in exon 10, codon 618 (TGC to AGC) in the extracellular cysteine-rich region of the RET gene. In this kindred an 11-year-old had microscopic evidence of MTC; however, a 17-year-old had no evidence of pathology on thyroidectomy. In a second kindred a rare mutation in exon 14, codon 804 (GTG to TTG) of the intracellular tyrosine kinase region of the RET gene was detected. In this kindred MTC has occurred in the 4th to 5th decades of life, with a clinical spectrum in mutation-positive family members ranging from no disease and C-cell hyperplasia to carcinoma with lymph node metastasis; a 7-year-old with the mutation and a normal response to provocative testing was also identified. Management recommendations in children from families with clearly defined familial MTC may be individualized to reflect emerging genotype-phenotype correlations.


Asunto(s)
Carcinoma Medular/diagnóstico , Carcinoma Medular/genética , Mutación de Línea Germinal/genética , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/genética , Adolescente , Adulto , Carcinoma Medular/cirugía , Niño , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas/métodos , Genotipo , Humanos , Persona de Mediana Edad , Linaje , Fenotipo , Neoplasias de la Tiroides/cirugía , Tiroidectomía
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