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Laura S Ward

Publications and source records attributed to Laura S Ward.

At least 19 recordsLinked to original sources
PubMed2006

Subclinical hypothyroidism increases the risk for depression in the elderly.

In order to determine if subclinical hypothyroidism is a risk factor for depression in the elderly, a total of 323 individuals over 60 years old were interviewed using the Structured Clinical Interview for Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for mood disturbances. Patients were divided into Group I: 252 patients (184 females, 68 males; median age: 67 years, range: 60-89 years) with elevated serum thyrotropin (TSH) levels and Group II: 71 patients (45 females, 26 males; median age: 67 years, range: 60-92 years) with diagnosis of depression. Serum TSH and free thyroxine (fT4) were measured by sensitive assays. Thyroid antibodies were determined by IRMA. Depression was observed in 24 (9.5%) Group I patients and was frequent in subclinical hypothyroidism patients (14/24 = 58.3%). On the other hand, elevated TSH levels were found in 22 (30.9%) Group II patients. Depression was observed more frequently among individuals with subclinical (74/149 = 49.7%) hypothyroidism than among individuals with overt hypothyroidism (21/125 = 16.8%) (p < 0.001). Indeed, subclinical hypothyroidism increased the risk for a patient to present depression more than four times (OR = 4.886; 95% confidence interval = 2.768-8.627). Our results demonstrate that subclinical hypothyroidism increases the risk for depression and emphasize the importance of thyroid screening tests in the elderly.

Aged↗
PubMed2006

Polymorphisms at exon 4 of p53 and the susceptibility to herpesvirus types 6 and 1 infection in renal transplant recipients.

In order to replicate their own genome in the host nucleus, herpesviruses have to overcome the barrier presented by p53 gene. Variants of codon 72 and codon 47 of exon four decrease the ability of p53 to induce apoptosis. In order to investigate the influence of this germline inheritance on the susceptibility to herpesvirus type 6 (HHV6) and 1 (HHV1) infection, we examined 78 renal transplant recipients and 151 controls. HHV6 infection was more frequent among the renal transplant patients (35.89%) than in the control population (11.25%) (P < 0.001). HHV1 infection rate was similar in renal transplant patients (7.28%) and controls (2.56%). HHV6-positive cases were more frequent among patients with codon 72 of p53 variants (60.71%) than among wild-type p53 patients (28.20%) (P = 0.001) despite the higher frequency of codon 72 of p53 wild-type variant in renal transplant patients compared with controls (64.1% vs. 36.4%; P < 0.001). The presence of a codon 72 of p53 germline variant genotype increased the risk for HHV6 infection more than five times (OR = 5.479; 95% CI = 1.992-15.069). Our data suggest that codon 72 of p53 polymorphism genotyping may be useful to screen for patients at higher risk for post-transplant infections hence identifying individuals that could benefit from preventive treatment.

Adult↗
PubMed2006

Prevalence of papillary microcarcinoma of the thyroid in Brazilian autopsy and surgical series.

In order to search for parameters to differentiate patients at low and high risk for development of thyroid cancer, we studied thyroids from 166 consecutive autopsies and 261 thyroids that were surgically resected for thyroid diseases in general. We found 32 papillary microcarcinomas, corresponding to 7.8% of autopsies and 7.2% of surgical material, with a higher incidence between 30 and 49 yr of age. Both genders were similarly affected: 9.3% of the men and 8.8% of the women in autopsy series, and 6.2% of the men and 7.3% of the women in surgical series, suggesting that hormonal factors may favor the subsequent development of clinical lesions in women. Although associated nodular goiter has been observed in 54% of autopsies and 26% of surgical specimens, while Hashimoto's thyroiditis only in surgical material (15% of the cases), we were not able to correlate risk of malignancy with any concomitant lesion. The smallest papillary microcarcinomas presented most frequently as nonencapsulated nonsclerosing tumors without inflammatory infiltrate or fibrosis, suggesting that they may represent the early stages of development. Our data show a relatively high and similar frequency of papillary microcarcinomas in surgical and autopsy series, but do not demonstrate risk factors for clinical evolution.

Autopsy↗
PubMed2006

[Low-risk differentiated thyroid carcinoma--literature review and management guidelines].

The trend of increasing thyroid cancer has been recognized in Brazil as well as all over the world for several decades. The large use of simple and effective diagnostic tools has significantly contributed to this trend. It is estimated that small carcinomas found at surgery for benign thyroid disorders and by ultrasonography will be identified at greater frequency in the further years. Part of these tumors occurs in low-risk patients that may benefit of less aggressive management strategies. However, the characterization of low-risk patient is still confusing and we lack adequate markers to tell apart patients that may present a troublesome progression of the disease. Furthermore, the use of new follow-up methods has recently changed some guidelines. A multidisciplinary team, including basic scientists, endocrinologists, nuclear medicine physicians, thyroid surgeons and endocrine pathologists reviewed the pertinent literature and, based on their experience, propose some management guidelines for Brazilian patients with low-risk thyroid carcinomas.

Carcinoma, Papillary↗
PubMed2006

Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1 allelic variants.

In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P=0.0147), reducing the risk for this type of cancer (odds ratio=0.564; 95% confidence interval=0.357-0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P=0.0385) and CYP1A1 germline inheritance (P=0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

Adult↗
PubMed2004

Human herpesvirus type 6 and type 1 infection increases susceptibility to nonmelanoma skin tumors.

In order to investigate herpesvirus (HHV) role in the susceptibility to skin cancer, we compared HHV6 and HHV1 incidence in DNA samples extracted from 120 lesions and 41 normal skin tissues. HHV6 (31.7%) and HHV1 (23.8%) were detected more frequently in skin cancer than in control individuals (14.6 and 5%, respectively) (P=0.0391 and P=0.00094, respectively). The risk of presenting basal cell carcinomas (BCC) was more than 3 times higher for HHV-6 infected patients (OR=3.182; 95% CI: 1.125-8.997). The risk for HHV-1 infected individuals of presenting BCC and squamous cell carcinomas was increased 8 and 6 times, respectively (OR=8.125; 95% CI: 1.735-38.043 and OR=6.290; 95% CI: 1.283-30.856, respectively).

Adolescent↗
PubMed2004

Epigenetic loss of the familial tumor-suppressor gene exostosin-1 (EXT1) disrupts heparan sulfate synthesis in cancer cells.

Germline mutations in the Exostoses-1 gene (EXT1) are found in hereditary multiple exostoses syndrome, which is characterized by the formation of osteochondromas and an increased risk of chondrosarcomas and osteosarcomas. However, despite its putative tumor-suppressor function, little is known of the contribution of EXT1 to human sporadic malignancies. Here, we report that EXT1 function is abrogated in human cancer cells by transcriptional silencing associated with CpG island promoter hypermethylation. We also show that, at the biochemical and cellular levels, the epigenetic inactivation of EXT1, a glycosyltransferase, leads to the loss of heparan sulfate (HS) synthesis. Reduced HS production can be reversed by the use of a DNA demethylating agent. Furthermore, the re-introduction of EXT1 into cancer cell lines displaying methylation-dependent silencing of EXT1 induces tumor-suppressor-like features, e.g. reduced colony formation density and tumor growth in nude mouse xenograft models. Screening a large collection of human cancer cell lines (n=79) and primary tumors (n=454) from different cell types, we found that EXT1 CpG island hypermethylation was common in leukemia, especially acute promyelocytic leukemia and acute lymphoblastic leukemia, and non-melanoma skin cancer. These findings highlight the importance of EXT1 epigenetic inactivation, leading to an abrogation of HS biosynthesis, in the processes of tumor onset and progression.

Animals↗
PubMed2004

Proline homozygosity in codon 72 of p53 is a factor of susceptibility for thyroid cancer.

A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro = 19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg = 36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%, Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR=9.714; CI: 2.334-40.436) and of PC (OR=5.299; CI: 2.334-40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer.

Adenocarcinoma, Follicular↗
PubMed2004

GST profiling may be useful in the screening for thyroid nodule malignancy.

Screening tools are of utmost necessity in order to identify individuals at risk for thyroid nodule cancer. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) system, plays an important role in the development of most human cancers. GSTP1 enzyme is the most important detoxification enzyme in human head and neck tissues. An aminoacid substitution (1105V) in the GSTP1 gene result in two genotypes, GSTP1AB and GSTP1BB. Those produce a variant enzyme with lower activity and less capability of effective detoxification of carcinogens than the wild type GSTP1AA. In order to look for the influence of GSTP1 enzymes inheritance pattern on thyroid cancer risk we used a PCR-SSCP-sequencing approach to compare the genotypes of 98 malignant nodules, including 77 papillary carcinomas (PC) and 21 follicular carcinomas (FC), to 44 benign nodules and to 157 healthy control individuals. Individuals with history of previous thyroid disease, exposure to radiation and antecedents of malignancy were excluded. Patients with PC and FC showed a significant over-representation of the variants of GSTP1 allele compared to the control population (p < 0.0001 The risk for thyroid cancer in individuals with the variant GSTP1 enzymes, after adjusting for gender, age, tobacco and drugs use, increased 7,092 (CI: 2,307-21,802) and 9,625 (CI: 2.484-37.291) times for PC and FC, respectively. We suggest that GST genotype may be associated with an increased susceptibility to thyroid cancer. GSTP1 profiling from peripheral blood may be a simple and useful tool in the screening for thyroid nodule malignancy. Glutathione-S-Transferase system; GSTP; Thyroid cancer; Screening.

Adenocarcinoma, Follicular↗
PubMed2004

A transcript finishing initiative for closing gaps in the human transcriptome.

We report the results of a transcript finishing initiative, undertaken for the purpose of identifying and characterizing novel human transcripts, in which RT-PCR was used to bridge gaps between paired EST clusters, mapped against the genomic sequence. Each pair of EST clusters selected for experimental validation was designated a transcript finishing unit (TFU). A total of 489 TFUs were selected for validation, and an overall efficiency of 43.1% was achieved. We generated a total of 59,975 bp of transcribed sequences organized into 432 exons, contributing to the definition of the structure of 211 human transcripts. The structure of several transcripts reported here was confirmed during the course of this project, through the generation of their corresponding full-length cDNA sequences. Nevertheless, for 21% of the validated TFUs, a full-length cDNA sequence is not yet available in public databases, and the structure of 69.2% of these TFUs was not correctly predicted by computer programs. The TF strategy provides a significant contribution to the definition of the complete catalog of human genes and transcripts, because it appears to be particularly useful for identification of low abundance transcripts expressed in a restricted set of tissues as well as for the delineation of gene boundaries and alternatively spliced isoforms.

Alternative Splicing↗
PubMed2004

[Thyroid cancer: prognostic factors and treatment].

Because most differentiated thyroid carcinomas have an excellent prognosis, some authors have claimed that these patients are suffering from over treatment. Grouping patient- and tumor-specific factors have been proposed for prognostic stratification, but no clinicopathologic staging was demonstrated to be useful at the present time. More recently, molecular genetic tools have been used to identify and understand how the primary tumor progresses and many molecular markers have been proposed in order to distinguish the subset of patients at risk of developing metastasis. Here we analyzed some of them, with emphasis on the expression of NIS, a determinant of prognosis since the functional integrity of the iodine transport is essential to assure an uptake of radioiodine high enough to detect and destroy any tumoral thyroid tissue. More recent observations on how some relevant molecular genetics aspects of thyroid cancer impact new potential therapeutic approaches are also discussed.

Adolescent↗
PubMed2004

Propylthiouracil reduces the effectiveness of radioiodine treatment in hyperthyroid patients with Graves' disease.

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.

Adolescent↗
PubMed2004

Impact of long-term administration of amiodarone on the thyroid function of patients with Chagas' disease.

The effect of long-term treatment with amiodarone on patients with Chagas' disease has seldom been reported. This nonrandomized observational study attempted to analyze the follow-up of patients with Chagas' disease regarding their clinical evolution, thyroid dysfunction, and goiter. We compared 72 patients with long-term use (11 +/- 5 years) of amiodarone, including 22 patients who developed goiter, to 33 patients who did not use amiodarone, followed-up for 2 to 20 years (7 +/- 11 years). Follow-up of 72 patients for 9 +/- 5.4 years with periodic cardiac and thyroid function evaluations showed that only 26 maintained normal serum thyrotropin (TSH) levels; 24 presented with elevated levels; 4 had low levels, and 18 patients presented with fluctuations of TSH level. Among the 22 patients with goiter, only 3 (14%) patients maintained normal TSH, 8 (36%) had elevated TSH, 2 (9%) had low TSH, and 9 (41%) patients presented with fluctuating serum TSH levels. Most individuals remained clinically euthyroid with no evidence of cardiac impairment that could be attributed to thyroid dysfunction and the arrhythmias were adequately controlled by amiodarone. We suggest that amiodarone treatment may be continued for patients with Chagas' disease with arrhythmias, even in those who develop thyroid function abnormalities or goiter.

Amiodarone↗
PubMed2004

Thyroid autoantibodies in autoimmune diseases.

Abnormalities in the thyroid function and thyroid autoantibodies have been frequently described in patients with autoimmune diseases but seldom in antiphospholipid syndrome patients. In order to determine the prevalence of thyroid function and autoimmune abnormalities, we compared serum thyrotropin (TSH, serum free thyroxine (T4) levels, thyroid antithyroglobulin (TgAb) and antithyroperoxidase (TPOAb) levels of 25 patients with systemic sclerosis, 25 patients with rheumatoid arthritis and 13 patients with antiphospholipid syndrome to a control group of 113 healthy individuals. Evaluation included a thorough clinical examination with particular attention to thyroid disease and a serologic immune profile including rheumatoid factor, antinuclear and anticardiolipin antibody measurements. Subclinical hypothyroidism (4.2<TSH<10 mU/L) was diagnosed in five patients (8%), and subclinical hyperthyroidism (undetectable<TSH<0.34 mU/L) in four patients (6%). Anti-thyroglobulin (TgAb) and/or anti-thyroperoxidase (tPOAb) antibodies were present in 21/63 (33%) of our patients: 13/25 (52%) of the systemic sclerosis cases, 8/25 (32%) of the rheumatoid arthritis patients, but 0 (0/13) of the antiphospholipid syndrome patients. In conclusion, our data confirm a high prevalence of silent autoimmune thyroid diseases in association with systemic sclerosis and rheumatoid arthritis (p<0.02), but not with antiphospholipid syndrome. Elevated antibody titres may reflect an epiphenomenon of the underlying autoimmune disorders and play an additive role in the development of the euthyroid sick syndrome in these patients, but our data suggest that the antiphospholipid syndrome presents a different pattern of response. Subclinical thyroid diseases should be considered when evaluating patients with autoimmune diseases.

Adult↗