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Publications (150)745.48 Total impact
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ABSTRACT: We have previously shown that a (TC)n microsatellite in intron 5 of the Forkhead Box Protein 3 (FOXP3) gene was associated with a variant of the autoimmune polyglandular syndrome type 3 (APS3v), that is defined as the co-occurrence of type 1 diabetes (T1D) and autoimmune thyroiditis (AITD). Allele 10, containing 25 repeats of the microsatellite (long repeats), is preferentially transmitted to offspring with APS3v, while allele 2, containing 14 repeats of the microsatellite (short repeats), is protective. We hypothesized that the long repeats of the intron 5 microsatellite decrease FOXP3 splicing and function, thereby reducing regulatory T cell activity and promoting the development of APS3v. We cloned genomic DNA from two hemizygous males for the long and short repeats of the microsatellite on their X-chromosomes and transfected them into human embryonic kidney 293 (HEK 293) cells to perform direct splicing analysis. We identified a novel splice variant of FOXP3 lacking exon 6, and showed that it is expressed in human thymus and lymph node. However, the length of the repeats in the microsatellite did not significantly influence the expression of this FOXP3 splice variant in vitro. Interestingly, this splice variant was expressed in human regulatory T cells, suggesting that it may play a role in their function. In conclusion, we identified a novel splice variant FOXP3Δ6. The role of its expression in regulatory T cells in the development of autoimmunity remains to be determined. Copyright © 2014. Published by Elsevier B.V.Gene 12/2014; · 2.20 Impact Factor -
Article: ENDOPLASMIC RETICULUM STRESS AS A NOVEL MECHANISM IN AMIODARONE-INDUCED DESTRUCTIVE THYROIDITIS.
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ABSTRACT: Context: Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available, however, its use is limited by a serious side-effect profile, including thyroiditis. The precise mechanisms underlying AMIO thyroid toxicity have been elusive, thus, identification of novel approaches to protect thyroid cells is essential in patients with life-threatening arrhythmias. Objective: Our aim was to evaluate if AMIO treatment could induce Endoplasmic Reticulum (ER) stress in human thyroid cells, and the possible implications of this effect in AMIO-induced destructive thyroiditis. Results: Here, we reported that AMIO but not iodine, significantly induced the expression of ER stress markers such as immunoglobulin heavy chain-binding protein (BiP), phospho-eukaryotic translation initiation factor 2α (eIF2α), C/EBP homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO downregulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced downregulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1 cells and human primary thyrocytes with the chemical chaperone 4-phenylbutyric acid completely prevented the effect of AMIO on both ER stress induction and Tg downregulation. Conclusions: We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.Journal of Clinical Endocrinology & Metabolism 10/2014; · 6.31 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic-epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.Proceedings of the National Academy of Sciences 08/2014; · 9.81 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Context: Genetic and environmental factors play an essential role in the pathogenesis of Graves' disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults. Objective: The aim of the study was to identify susceptibility loci that predispose to GD in young age of onset (AO) GD patients. Design and Participants: One hundred and six patients with young AO GD (onset <30 years-old) and 855 healthy subjects were studied. Cases and controls were genotyped using the Illumina infinium immunochip, designed to genotype 196,524 polymorphisms. Case control association analyses were performed using the PLINK computer package. Ingenuity Pathway Analysis program was used to carry out pathway analyses. Results: Immunochip genetic association analysis identified 30 single-nucleotide polymorphisms in several genes that were significantly associated with young AO GD, including MHC class I and class II genes, BTNL2, NOTCH4, TNFAIP3, and CXCR4. Candidate gene analysis revealed that most of the genes previously shown to be associated with adult-onset GD were also associated with young AO GD. Pathway analysis demonstrated that antigen presentation, T-helper cell differentiation and B-cell development were the major pathways contributing to the pathogenesis of young AO GD. Conclusions: Genetic analysis identified novel susceptibility loci in young AO GD adding a new dimension to the understanding of GD etiology.The Journal of Clinical Endocrinology and Metabolism 03/2014; · 6.31 Impact Factor -
Article: DNA methylation profiles in type 1 diabetes twins point to strong epigenetic effects on etiology.
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ABSTRACT: Type 1 diabetes (T1D) shows ∼40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional annotation of the genes with distinct CpG methylation profiles in T1D samples showed differential DNAm of immune response and defense response pathways between affected and unaffected twins. Integration of DNAm data with GWAS data mapped several known T1D associated genes, HLA, INS, IL-2RB, CD226, which showed significant differences in DNAm between affected and unaffected of twins. Our findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D.Journal of Autoimmunity 11/2013; · 7.02 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.Journal of Autoimmunity 05/2013; · 7.02 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: CONTEXT:TSH receptor antibodies (TRAb) cause Graves' disease (GD) hyperthyroidism. Widely available TRAb measurement methods have been significantly improved recently. However, the role of TRAb measurement in the differential diagnosis of hyperthyroidism, the prediction of remission of GD hyperthyroidism, the prediction of fetal/neonatal thyrotoxicosis and the clinical assessment of Graves' ophthalmopathy (GO) is controversialEVIDENCE ACQUISITION:We reviewed and analyzed the literature reporting primary data on the clinical use of TRAb. We focused our analyses on clinical studies analyzing third generation TRAb assays.EVIDENCE SYNTHESIS:The performance of TRAb in the differential diagnosis of overt hyperthyroidism is excellent, with sensitivity and specificity in the upper 90%. TRAb can accurately predict short-term relapses of hyperthyroidism after a course of antithyroid drugs, but are less effective in predicting long-term relapses or remissions. Pregnancies in GD women with negative TRAb are highly unlikely to result in fetal hyperthyroidism, while high titers of TRAb in pregnancy require careful fetal monitoring. GD patients with GO frequently have high TRAb levels. However there is insufficient data to use the test to predict the clinical course of GO and response to treatment.CONCLUSIONS:Third generation TRAb assays are suitable in the differential diagnosis of hyperthyroidism. In GD, TRAb should be tested before deciding whether methimazole can be stopped. TRAb should be used in pregnant women with GD to assess the risk of fetal thyrotoxicosis. The use of TRAb in GO requires further studies.The Journal of Clinical Endocrinology and Metabolism 03/2013; · 6.31 Impact Factor -
Article: HLA Class I and II Alleles are Associated with Microvascular Complications of Type 1 Diabetes.
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ABSTRACT: Although HLA alleles are associated with type 1 diabetes, association with microvascular complications remains controversial. We tested HLA association with complications in multiplex type 1 diabetes families. Probands from 425 type 1 diabetes families from the Human Biological Data Interchange (HBDI) collection were analyzed. The frequencies of specific HLA alleles in patients with complications were compared with the frequencies in complications-free patients. The complications we examined were: retinopathy, neuropathy, and nephropathy. We used logistic regression models with covariates to estimate odds ratios. We found that the DRB1∗03:01 allele is a protective factor for complications (OR=0.58; p = 0.03), as is the DQA1∗05:01-DQB1∗02:01 haplotype found in linkage disequilibrium with DRB1∗03:01 (OR= 0.59; p = 0.031). The DRB1∗04:01 allele showed no evidence of association (OR=1.13; p = 0.624), although DRB1∗04:01 showed suggestive evidence when the carriers of the protective DRB1∗03:01 were removed from the analysis. The class II DQA1∗03:01-DQB1∗03:02 haplotype was not associated with complications, but the class I allele B∗39:06 (OR=3.27; P = 0.008) suggested a strong positive association with complications. Our results show that in type 1 diabetes patients, specific HLA alleles may be involved in susceptibility to, or protection from, microvascular complications.Human immunology 01/2013; · 2.55 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Background: Autoimmune and non-autoimmune thyroiditis frequently occur in persons with HCV infection. Treatment with interferon alpha (IFNα) is also associated with significant risk for the development of thyroiditis. To explore HCV-thyroid interactions at a cellular level, we evaluated whether a human thyroid cell line (ML1) could be infected productively with HCV in vitro. Methods and Results: ML1 cells showed robust surface expression of the major HCV receptor CD81. Using a highly sensitive, strand-specific RT-PCR assay, positive-sense and negative-sense HCV RNA were detected in ML1 cell lysates at days 3, 7, and 14 post-infection with HCV. HCV core protein was expressed at high levels in ML1 supernatants at days 1, 3, 5, 7, and 14 post-infection. The non-structural protein NS5A was also detected in ML1 cell lysates by Western Blot. HCV entry into ML1 cells was shown to be dependent on the HCV entry factors CD81 and Claudin-1 (CLA1), while IFNα inhibited HCV replication in ML1 cells in a dose-dependent manner. Supernatants from HCV-infected ML1 cells were able to productively infect fresh ML1 cells, suggesting that infectious virions could be transferred from infected to naïve thyroid cells in vivo. Additionally, HCV infection of ML1 cells led to increased expression of the pro-inflammatory cytokine IL-8. Conclusions: For the first time, we have demonstrated that HCV can infect human thyroid cells in vitro. These findings strongly suggest that HCV infection of thyrocytes may play a role in the association between chronic HCV infection and thyroid autoimmunity. Furthermore, the thyroid may serve as an extrahepatic reservoir for HCV viral replication, thus contributing to the persistence of viral infection and to the development of thyroid autoimmunity.Thyroid: official journal of the American Thyroid Association 12/2012; · 2.60 Impact Factor -
Article: Fine Mapping of Loci Linked to Autoimmune Thyroid Disease Identifies Novel Susceptibility Genes.
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ABSTRACT: Context:Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chromosomes 10q, 12q, and 14q that showed strong linkage with AITD, HT, and GD, respectively.Objectives:The objective of the study was to identify the AITD susceptibility genes at the 10q, 12q, and 14q loci.Design and Participants:Three hundred forty North American Caucasian AITD patients and 183 healthy controls were studied. The 10q, 12q, and 14q loci were fine mapped by genotyping densely spaced single-nucleotide polymorphisms (SNPs) using the Illumina GoldenGate genotyping platform. Case control association analyses were performed using the UNPHASED computer package. Associated SNPs were reanalyzed in a replication set consisting of 238 AITD patients and 276 controls.Results:Fine mapping of the AITD locus, 10q, showed replicated association of the AITD phenotype (both GD and HT) with SNP rs6479778. This SNP was located within the ARID5B gene recently reported to be associated with rheumatoid arthritis and GD in Japanese. Fine mapping of the GD locus, 14q, revealed replicated association of the GD phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively.Conclusions:Fine mapping of three linked loci identified novel susceptibility genes for AITD. The discoveries of new AITD susceptibility genes will engender a new understanding of AITD etiology.The Journal of Clinical Endocrinology and Metabolism 11/2012; · 6.31 Impact Factor -
Article: Genetically Driven Target Tissue Overexpression of CD40: A Novel Mechanism in Autoimmune Disease.
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ABSTRACT: The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.The Journal of Immunology 08/2012; 189(6):3043-53. · 5.36 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Objective: To report a case of apathetic thyrotoxicosis with an etiology of subacute thyroiditis.Methods: We describe the patient's clinical findings, laboratory findings, and clinical course.Results: An 85-year-old woman with no history of thyroid disease presented with severe obtundation and altered mental status. Laboratory testing documented elevated free thyroxine and free triiodothyronine concentrations and a suppressed thyrotropin concentration. Thyroid antibodies were absent. A radioactive iodine study revealed severely diminished uptake, suggestive of thyroiditis. After a short course of steroids, the patient's mental status returned to baseline. Follow-up laboratory testing showed normalizing thyroid function.Conclusion: Even in the absence of a history of thyroid disease, we recommend considering thyroid dysfunction in the differential diagnosis of patients who present with altered mental status, particularly in the elderly population.Endocrine Practice 05/2012; 18(5):e127-9. · 2.49 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, are among the commonest autoimmune disorders, affecting approximately 5 % of the population. Epidemiological data support strong genetic influences on the development of AITD. Since the identification of HLA-DR3 as a major AITD susceptibility gene, there have been significant advances made in our understanding of the genetic mechanisms leading to AITD. We have shown that an amino acid substitution of alanine or glutamine with arginine at position 74 in the HLA-DR peptide binding pocket is a critical factor in the development of AITD, and we are continuing to dissect these mechanisms at the molecular level. In addition to the MHC class II genes, there are now several other confirmed gene loci associated with AITD, including immune-regulatory (CD40, CTLA-4, PTPN22, FOXP3, and CD25) and thyroid-specific genes (thyroglobulin and TSHR). Mechanistically, it is postulated that susceptibility genes interact with certain environmental triggers to induce AITD through epigenetic effects. In this review, we summarize some of the recent advances made in our laboratory dissecting the genetic-epigenetic interactions underlying AITD. As shown in our recent studies, epigenetic modifications offer an attractive mechanistic possibility that can provide further insight into the etiology of AITD.Immunologic Research 03/2012; 54(1-3):204-13. · 3.53 Impact Factor - Journal of Autoimmunity 08/2011; 37(1):1-2. · 7.02 Impact Factor
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ABSTRACT: Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified an SNP (-1623A→G) that was associated with AITD in the Caucasian population (p = 0.006). We show that the nucleotide substitution introduced by SNP (-1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5' TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon α, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFNα) and genetic (TG) factors to trigger AITD.Journal of Biological Chemistry 07/2011; 286(36):31168-79. · 4.60 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Thyroglobulin (Tg) represents one of the largest known self-antigens involved in autoimmunity. Numerous studies have implicated it in triggering and perpetuating the autoimmune response in autoimmune thyroid diseases (AITD). Indeed, traditional models of autoimmune thyroid disease, experimental autoimmune thyroiditis (EAT), are generated by immunizing mice with thyroglobulin protein in conjunction with an adjuvant, or by high repeated doses of Tg alone, without adjuvant. These extant models are limited in their experimental flexibility, i.e. the ability to make modifications to the Tg used in immunizations. In this study, we have immunized mice with a plasmid cDNA encoding the full-length human Tg (hTG) protein, in order to generate a model of Hashimoto's thyroiditis which is closer to the human disease and does not require adjuvants to breakdown tolerance. Human thyroglobulin cDNA was injected and subsequently electroporated into skeletal muscle using a square wave generator. Following hTg cDNA immunizations, the mice developed both B and T cell responses to Tg, albeit with no evidence of lymphocytic infiltration of the thyroid. This novel model will afford investigators the means to test various hypotheses which were unavailable with the previous EAT models, specifically the effects of hTg sequence variations on the induction of thyroiditis.PLoS ONE 04/2011; 6(4):e19200. · 3.53 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: IFN-α is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-α is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-α treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-α under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-α involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.The Journal of Immunology 03/2011; 186(8):4693-706. · 5.36 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Autoimmune thyroid diseases (AITD) are postulated to develop as a result of a complex interplay between several genetic and environmental influences. The pathogenesis of AITD is still not clearly defined. However, among the implicated triggers (e.g. iodine, infections, medications), more recent data confirmed strong associations of AITD with the hepatitis C virus (HCV) infection and interferon-α (IFNα) therapy. Moreover, it is likely that HCV and IFN act in synergism to trigger AITD in patients. Indeed, approximately 40% of HCV patients develop either clinical or subclinical disease while receiving IFNα. Interferon induced thyroiditis (IIT) can manifest as non-autoimmune thyroiditis (presenting as destructive thyroiditis, or non-autoimmune hypothyroidism), or autoimmune thyroiditis [presenting with clinical features of Graves' disease (GD) or Hashimoto's thyroiditis (HT)]. Although not yet clearly understood, it is thought that IFNα can induce thyroiditis via both immune stimulatory and direct toxic effects on the thyroid. In view of the high frequency of IIT, routine screening and surveillance of HCV patients receiving IFNα is recommended to avoid the complications, such as cardiac arrhythmias, associated with thyrotoxicosis. In summary, IIT is a common clinical problem that can be readily diagnosed with routine thyroid function screening of HCV patients receiving IFN. The treatment of IIT consists of the standard therapy for differing clinical manifestations of IIT such as GD, HT, or destructive thyroiditis. However, anti-thyroid medications are not recommended in this setting since they can potentially be hepatotoxic.Journal of endocrinological investigation 02/2011; 34(1):78-84. · 1.65 Impact Factor - [Show abstract] [Hide abstract]
ABSTRACT: Significant progress has been made in our understanding of the mechanisms leading to autoimmune thyroid diseases (AITD). For the first time, we are beginning to unravel these mechanisms at the molecular level. AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune diseases affecting the thyroid. They have a complex etiology that involves genetic and environmental influences. Seven genes have been shown to contribute to the etiology of AITD. The first AITD gene discovered, HLA-DR3, is associated with both GD and HT. More recently, this association was dissected at the molecular level when it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide binding pocket is the specific sequence change causing AITD. Non-MHC genes that confer susceptibility to AITD can be classified into two groups: (1) immune-regulatory genes (e.g., CD40, CTLA-4, and PTPN22); (2) thyroid-specific genes-thyroglobulin and TSH receptor genes. These genes interact with environmental factors, such as infection, likely through epigenetic mechanisms to trigger disease. In this review, we summarize the latest findings on disease susceptibility and modulation by environmental factors.Clinical Reviews in Allergy & Immunology 01/2011; 41(2):190-7. · 4.73 Impact Factor -
Chapter: Genetics of Thyroid Autoimmunity
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ABSTRACT: Autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are the commonest autoimmune endocrine diseases, affecting up to 5% of the general population. Genetic factors play a major role in the etiology of AITD as evidenced by the strong familial aggregation of the AITD and the high concordance rates in monozygotic twins. The past decade has witnessed significant progress in our understanding of the genetic contribution to the etiology of AITD, and several major AITD susceptibility genes have been identified and characterized. Some susceptibility genes are specific to either Graves' disease or Hashimoto's thyroiditis, while others are common to both conditions. The first AITD susceptibility gene locus identified was the HLA-DR gene locus. Subsequently, five major non-HLA genes, including the CTLA-4, CD40, PTPN22, thyroglobulin, and TSH receptor (TSHR) gene, have been shown to contribute to the susceptibility to AITD; other putative genes are still being tested and confirmed. Excitingly, we are now beginning to unravel the mechanisms by which these AITD susceptibility genes confer risk for disease. Key WordsThyroid-Genes-Association-Linkage-Graves' disease-Hashimoto's thyroiditis-Autoimmune thyroiditis-HLA12/2010: pages 427-442;
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Boston Children's Hospital
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University of Cincinnati
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Mariners Mondays – Milestone Wins for King Felix
Mariners Mondays on ROOT SPORTS get started next week with a look back at two 2013 milestone wins for Mariners ace Felix Hernandez—an outstanding performance vs. Oakland on Opening Night, and his 100th career win against the Astros.
Last year's season opener (at Oakland) on April 1, was another impressive performance for Felix, even by his high standards. He pitched 7 2/3 scoreless innings, striking out eight, and retiring the first 10 batters in order. Franklin Gutierrez produced all the offense the Mariners needed with a two-run single in the 5th, giving the Mariners a 2-0 win over the A's.
A couple of starts later, Felix was on the mound in Houston for what would be his 100th career win. Felix pitched six scoreless innings and the Mariners offense backed him up with three home runs for the 7-1 win over the Astros. On that night, April 22, 2013, Felix joined Jamie Moyer and Randy Johnson as the only pitchers to reach 100 wins with the Mariners.
The first Mariners Mondays episode airs tonight on ROOT SPORTS beginning at 7:30 pm, right after Mariners All Access, which goes behind the scenes with manager Lloyd McClendon.
Mariners Mondays episodes will air on ROOT SPORTS for 12 weeks during the offseason and Spring Training, building to the March 31 season opener against the Los Angeles Angels.
Mariners Mondays – The King's Court x2
This week on Mariners Mondays on ROOT Sports a look back at two of Felix Hernandez's gems, including the remarkable Supreme Court Night, Felix's first home start after the perfect game.
Felix was in King's Court form at Yankee Stadium on August 4 for his third shutout of the season, a 1-0, two-hit win over the Yankees. It was Felix's second shutout in five starts at the new Yankee Stadium and it pushed his career ERA there to 1.13, the lowest of any pitcher with at least two starts there.
And of course, we all know that two starts later, Felix threw a perfect game at Safeco Field against the Tampa Bay Rays. Felix's next scheduled start at Safeco was to be just as memorable.
A sea of 39,000 yellow Supreme Court T-shirts greeted the King when he took the mound on August 21 against the Cleveland Indians. And although he wasn't perfect, Felix was still dominant with only one run and five strikeouts in 7 2/3 innings. A four-run 7th inning helped the Mariners to a 5-1 win over the Indians, the Mariners 7th straight victory.
Mariners Mondays looks back at both these great pitching performances tonight on ROOT SPORTS.
Mariners Mondays – Ichiro in Pinstripes
Tonight on Mariners Mondays on ROOT Sports a look back at last year's blockbuster trade that sent Ichiro to the New York Yankees.
With the Yankees in town for a three-game series, an emotional Ichiro met with media to talk about his storied career with the Mariners. A few hours later, he emerged from the visitor's dugout to the roar of the crowd. And, in typical Ichiro fashion, singled to center. The Yankees, who had just been swept by the Oakland A's, went on to win the game 4-1.
The next night had a different result (a Mariners 4-2 win) and a different dramatic story-line. Felix Hernandez was matched against former Mariners pitcher Freddy Garcia. Not as sharp as usual, Felix allowed a solo home run in the 1st inning and worked out of jams in 4th and 5th innings. Then he hit Ichiro, Derek Jeter and finally Alex Rodriguez, breaking A-Rod's hand with an 88 mph changeup that got away from him.
Mariners Mondays reviews the events of the emotional trade and the outcome of the next day's game tonight on ROOT SPORTS.
Mariners Mondays – Kuma handles the Angels
Tonight on Mariners Mondays on ROOT SPORTS a pair of starts by starting pitcher Hisashi Iwakuma in which he dominates the Angels in two late-seasons starts one month apart.
On Sunday, September 2, Iwakuma pitched 7 1/3 scoreless innings and Carols Peguero and Jesus Montero hit solo homers off the Angels ace Jered Weaver to give the Mariners a 2-1 win.
In the second game, October 2, Kuma was the happy recipient of some offensive support as the Mariners beat the Angels 6-1. Iwakuma allowed six hits and struck out seven, including Albert Pujols three times and won his third consecutive start. The offensive outburst was keyed by Kyle Seager's first inning solo home run, his 20th of the season.
Catch highlights of both games tonight on ROOT SPORTS Mariners Mondays (check your local listings).
Mariners Mondays – Dominating Yu
Tonight on Mariners Mondays on ROOT SPORTS – the Mariners have Yu Darvish's number.
The Rangers' star pitcher Yu Darvish was a 16-game winner in 2012, but the Mariners seem to have his number.
Darvish made his Major League debut against the Mariners on April 9, 2012. The Mariners welcomed him by scoring five runs in the first two innings. The Mariners wouldn't win that game, but they would come out on top in two other Darvish outings.
The first was May 21 with a dream match-up of Darvish vs. Felix Hernandez.
Darvish lasted just four innings, surrendering four runs and six walks, the shortest outing of his season. Felix, meantime, shut down the potent Texas offense for eight innings when Mitch Moreland hit a leadoff solo homer for the Rangers only run.
Ichiro greeted his countryman with a single and triple and two RBI, leading the Mariners to a 4-1 win.
A few months later, July 14, Darvish and Felix met again at Safeco Field with the same result.
Felix allowed only three hits and struck out 12 in the Mariners 7-0 win. Darvish had control problems from the start. Darvish's 33-pitch first inning went something like this: walk, hit batter, single, walk, E3, two-run single. The Mariners were up 4-0 after their first at-bat. Darvish lasted only 6 1/3 innings giving up eight hits, seven earned runs, four walks and four strikeouts.
In his first three starts against the Mariners last season, Darvish had a 9.00 ERA.
Mariners Mondays airs at 7:30 pm on ROOT SPORTS every Monday through March 25, one week before the season opener against the Oakland A's on April 1.
Mariners Mondays — Comebacks and Walk-offs Part 2
Tonight on Mariners Mondays on ROOT SPORTS – a look at four times the Mariners came back to win with late inning heroics.
On April 11, the Rangers took a 1-0 lead in the first inning. Pitchers Kevin Millwood and Colby Lewis were well matched until the Rangers hit back-to-back home runs off Steve Delebar in the 7th.
The Rangers tacked on another and it looked like they would cruise to the win. That was until the 8th inning when John Jaso tripled and then scored on a Dustin Ackley single, snapping a 23 inning scoreless streak.
In the 9th, Justin Smoak led off with a single, followed by Kyle Seager's double. Jesus Montero advanced the runners with a sacrifice fly and Michael Saunders scored two with an RBI double. Jaso again came through with a solid single that scored Saunders for the third run of the inning, capping a rally off Rangers closer Joe Nathan for the 4-3 win.
Rookie left-hander Lucas Luetge had two strikeouts in 1 1/3 innings for his first Major League victory.
Jaso's late inning heroics were on display again on May 7, when the Tigers came to town.
Starter Blake Beavan struggled early in the game and left the mound after getting hit on the elbow by a line drive in the 3rd inning. Tigers starter Doug Fister, the former Mariner pitcher, who was making his second start of the season, allowed just four hits, walked none, had three strike outs and looked to be on the way to his first win of the season.
That is until manager Jim Leyland lifted Fister for reliever Octavio Dotel, who lacked control from the beginning. He walked Brendan Ryan and Ichiro, advanced the runners on a wild pitch, then surrendered a two run double to Jesus Montero to tie the game. Jaso sacrificed Munenori Kawasaki in the bottom of the 9th, who scored the game winning run in the three-run comeback.
Another exciting walk-off came on August 14 against the Tampa Bay Rays (just one day before Felix would throw his perfect game), ending the Rays seven-game win streak.
Starter Kevin Millwood looked like he was off to a rocky start but regained his footing and gave up just two runs in seven innings and struck out a season-high eight. He was matched by Tampa Bay starter Matt Moore, who allowed one run on six hits and struck out nine.
Kyle Seager started the rally with a single off reliever Fernando Rodney, followed by a bunt base hit by Chone Figgins. Justin Smoak tied the game with a deep fly to center. Eric Thames, who had struck out in his first three at-bats, stepped up to the plate with two outs in the bottom of the ninth, facing one of the best closers in baseball. Thames was down to his final strike when he lined a changeup into short right, scoring Figgins, earning the Mariners a 3-2 win and receiving a beat-down from his teammates as he headed for 1st.
The final "last at-bat win" goes back to April 27th when the Mariners visited the Blue Jays in Toronto. Canada native Michael Saunders had spent the winter working on his hitting with a private instructor and it showed. Saunders had two home runs, including a grand slam in the 10th as the Mariners rallied to beat the Jays 9-5.
Relive the fun of those late-innings heroics on ROOT SPORTS tonight at 7:30 pm.
Mariner Mondays – Taking Two From the Angels
Tonight on Mariners Mondays on ROOT SPORTS, a couple of fun wins over a division rival when the Mariners beat the Los Angeles Angels by the same score, two nights apart.
Facing the Angels at Anaheim on June 4, the Mariners had an 8-4 lead heading into the 8th. After a passed ball and a couple of hits, the Angels had cut the lead to two runs with one out and Albert Pujols coming up to bat. But reliever Tom Wilhelmsen kept Pujols in the yard, caught John Hester in a rundown, struck out Mark Trumbo and then pitched a scoreless 9th to give the Mariners an 8-6 win.
And as for all that offense, the Mariners scored seven off starter Ervin Santana in 4 2/3 innings, and added another in the 8th on an Ichiro homer.
Two nights later, the Mariners won the series with another 8-6 game, this time on the strength of Michael Saunders three hits, another Ichiro homer and Kyle Seager's four RBI.
Reliever Stephen Pryor also shone when he stifled potential Angels rallies in the 6th and 7th innings with double-play balls.
Relive these intra-division victories on ROOT SPORTS tonight at 7:30pm.
Mariners Mondays – Two Felix Shutouts
Tonight on Mariners Mondays on ROOT SPORTS, Felix does what he does best – dominates unsuspecting hitters.
On June 28, the Red Sox were at Safeco Field, and for seven innings, Felix was evenly matched with Boston starter Franklin Morales. By the time Felix walked off the mound in after the top of the 9th, both teams had a handful of hits, but there was still no score.
Not wanting to spoil Felix's gem, John Jaso and Casper Wells stepped up. Wells lined a double into the gap in left-center. Justin Smoak was walked, and Skipper Eric Wedge lifted Miguel Olivo for pinch-hitter John Jaso, who at the time was leading the team with game-winning RBIs. He didn't waste any time, lignin a single to right, giving Wells just enough time to score on catcher Jarrod Saltalamacchia to give the Mariners a 1-0 win.
By August 27, Felix was on a roll. In 14 starts, he was 9-0 with a 1.40 ERA, 100 strikeouts, 17 walks and a perfect game. Facing the Twins in Minnesota, he was once again in top form, and although Felix needed just a single Mariners run to earn the victory, this time, the heroics came in the 8th on an Eric Thames homerun.
With Felix's 1-0 win over the Twins, he notched his 23rd career complete game and 9th shutout.
Relive these two (of many) Felix gems on ROOT SPORTS tonight at 7:30pm.
Mariners Mondays – Comebacks and Walk-offs
Tonight's Mariners Mondays on ROOT SPORTS features three games with late inning heroics that sent Mariners fans home happy.
June 2, the Mariners are at Chicago to take on the White Sox. The night before, a Mariners error in the 8th inning helped the Sox win their 9th in a row.
But with the help of a two homer game from Ichiro, a strong outing from the bullpen, the Mariners topped the White Sox 10-8 in 12 innings.
Ichiro led off the game with a homer (the 37th leadoff homer of his career). Justin Smoak went deep to open the second, and Ichiro homered again to start the third inning.
But by the 7th, the White Sox led 7-5. The Mariners came back with three runs in the top of the 8th to take the lead, only to see the White Sox tie it up with a solo homer in the bottom of the inning.
The score stayed tied until the top of the 12th when John Jaso doubled home the tiebreaking run and then scored the winning run courtesy of a Chone Figgins single. Mariners win 10-8.
Two weeks later, hosting the San Francisco Giants, Justin Smoak didn't need to cross home plate himself to help his team to victory. The Giants scored in the top of the first and the Mariners got a run in the bottom of the second for a 1-1 tie, and with starters Madison Bumgarner and Felix Hernandez on the mound, there the score remained.
Reliever Tom Wilhelmsen took over in the 9th. With the score still tied, the Giants loaded the bases with only one out. But Wilhelmsen struck out Melky Cabrera (then the National League's leading hitter) on three pitches, and got pinch-hitter Nate Schierholtz to ground out to end the threat.
The Mariners opened the bottom if the 9th with back-to-back singles, setting the stage for Smoak's dramatic game-winning single to left. Final score, 2-1 Mariners.
Two days later, at Arizona, Ichiro again starred with his 2,500th career hit and a 4-5 performance as the Mariners outlasted the Diamond Backs 12-9 in 10 innings.
Relive the fun of those late-innings heroics on ROOT SPORTS tonight at 7:30 pm.
Mariners Mondays – Offensive explosion in Texas
On this weeks edition of Mariners Mondays on ROOT SPORTS an offensive explosion in back-to-back games in Texas is featured. The Mariners won back-to-back games vs. the Rangers by a combined score of 31-11, including a 21-9 win on May 30.
That is until the next night, when the Mariners went on an offensive tear. Justin Smoak was the star, hitting two three-run homers. But everyone contributed with back-to-back eight-run innings in the second and third.
The 21 runs scored that night were only good enough for second-most in club history, equaling the 21-9 victory over the Los Angeles Angels on September 30, 2000.
The Rangers didn't go quietly, scoring five runs in the sixth and two in the seventh. But it wasn't enough to stop the Mariners juggernaut. Final score, 21-8.
Catch the highlights of those two very fun games from 7:30-10pm on ROOT SPORTS. Tune in at 6:30pm for back-to-back episodes of Mariners All Access with a tribute to Mariners Hall of Famers Randy Johnson and Dan Wilson and Felix's perfect game.

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- 20 Oct, 2014
Folsom's Quipt lets manufacturers control their online pricing
The Sacramento Bee: As consumers comb through online sites such as Amazon, Newegg andeBay for the lowest prices and e-tailers battle for sales, the race to the bargain basement can quickly eat away at manufacturers' profits.
- 20 Oct, 2014
El Dorado Hills' HomeZada raises $2.1 million in capital
The Sacramento Bee: El Dorado Hills startup HomeZada will announce Tuesday that it has closed its first round of financing, raking in $2.1 million in capital over the summer.
- 20 Oct, 2014
CalPERS has highest complexity, costs compared to other funds
Sacramento Business Journal: The California Public Employees' Retirement System had nearly double the pension administrative costs of four similar U.S. pension funds in 2012-13, according to a new comparison.
- 20 Oct, 2014
Moneta Ventures leads $2.1M financing round into HomeZada
Sacramento Business Journal: Digital home information company HomeZada is expected on Tuesday to close a $2.1 million seed financing round, much of it from local investors.
- 17 Oct, 2014
Workforce education grants may not dry up after this year
Sacramento Business Journal: Educators across the Sacramento region and California are embarking on an ambitious program this year to transform high schools into industry incubators that offer students technical training in sectors related to the local economy. The future of these programs is uncertain because the funding could run dry. But legislative Democrats are beginning to make a stand for permanent funding.
- 17 Oct, 2014
Patrons at Sacramento's Arcade Library get charge out of 3-D design, printing
The Sacramento Bee: The staff of Sacramento's Arcade Library never knows when lightning will strike at the Design Spot, a 3-D design and printing lab, but the charged atmosphere has led plenty of everyday people to become inventors.
- 17 Oct, 2014
Aerojet Rocketdyne chosen to help with new mission to Mars
Sacramento Business Journal: Aerojet Rocketdyne is on a mission to Mars. The rocket motor maker has a contract with NASA's Jet Propulsion Laboratory to make motors to help a Mars rover.
- 16 Oct, 2014
CalPERS, CalSTRS among biggest players in private equity
California's two major public pension funds rank among the giants in the world of private equity. A study by the Private Equity Growth Capital Council showed that CalPERS has more money invested in private equity, $32.3 billion, than any other public pension fund in the United States. The teachers' pension fund, CalSTRS, ranks No. 2 at $21.9 billion.
- 15 Oct, 2014
SARTA TechCon to feature entrepreneur pitchfest, speakers
Sacramento Business Journal: The Sacramento Regional Technology Alliance will bring together the region's various tech sectors at TechCon Sacramento in November.
- 15 Oct, 2014
LinkedIn offers Sacramento workshop on Thursday
Sacramento Business Journal: A representative from LinkedIn will be in Sacramento on Thursday to present a workshop designed to help users bolster their profiles on the social network. A representative from LinkedIn will be in Sacramento on Thursday to present a workshop designed to help users bolster their profiles on the social network.


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Jon Gosselin in Reading, Pa. (10/27)
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Please tell me he's not broke enough for this happen. Via InTouch:
According to former Cheaters producer Bobby Goldstein, Jon has agreed to star in a cheesy new reality show in which he'll date Octomom Nadya Suleman, who called Jon "hot" recently. "I heard that Nadya has an insatiable desire to sp...


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Ubisoft Unveiling Assassin's Creed II Short Films at Comic-Con
July 20, 2009 - SAN FRANCISCO = Today Ubisoft detailed a panel around Assassin's Creed II to be held on July 23, 2009 from 1:45-2:45 p.m. in Room 6A at Comic-Con in San Diego. The panel entitled "Assassin's Creed II: Video Games and Hollywood Converge" will touch on the evolution of entertainment creation and distribution while highlighting the bridge between video games and film. Featured panelists will be Yannis Mallat, chief executive officer at Ubisoft Montreal, and Pierre Raymond, founder and chief executive officer of Hybride Technologies, the visual effects studio behind 300 and Sin City, along with special guest Corey May, Assassin's Creed II video game scriptwriter.
Best of PC E3 2009 Awards
June 11, 2009 - As the conference unfolded at the Los Angeles Convention Center June 2-4, we kept a running tally of our favorite games on a big white board in our IGN E3 Command Center. When a new title blew us away, we wrote it down. When something surprised us, we wrote it down. When a behind-closed-doors demo made us want to get our wallets out and buy the game right then and there, we wrote it down.
Assassin's Creed II: Black Edition Revealed
June 11, 2009 - Ubisoft and special editions just about go hand in hand. That's why it should come as no surprised to anyone that they announced a limited edition sku for Assassin's Creed II.
Game Scoop! E3 2009 Wrap-up
June 5, 2009 - It's Daemon Hatfield, Hilary Goldstein, Levi Buchanan, Greg Miller, Jeremy Dunham, and an IGN reader this week. E3 has come and gone and we all agree it was one of the best shows we've been to. Join us and listen to our latest podcast for some polite dinner conversation over Hawaiian food as we discuss what we liked and loved this year.
E3 2009: Assassin's Creed 2 First Look
June 2, 2009 - A few years back, Ubisoft wowed many with the debut of Assassin's Creed. A large, fully scalable world with the promise of dynamic assassination missions was too good to be true. And as it turned out, the first Assassin's Creed didn't live up to expectations. Two years later, Ubisoft Montreal has learned from its mistakes and is ready to provide a better and more complete experience.
E3 2009: Monday Wrap-Up
June 1, 2009 - E3 2009 started up with a bang, with Microsoft making a lot of noise at the first conference of the show. Setting up shop at the Galen Center on the USC campus, a little way removed from the Los Angeles Convention Center where the main show takes place, the Xbox 360 manufacturer put on a show that focused on games, demoed some new motion-sensitive hardware, and made a few surprise announcements.
E3 2009: Assassin's Creed II Given Release Date
June 1, 2009 - During what was perhaps the longest press conference of all-time, Ubisoft snuck in a release date for Assassin's Creed II.
E3 2009: Ubisoft Live Blog
June 1, 2009 - The week of E3 has just begun, and already the industry is buzzing about announcements that have been made at earlier press conferences. Now that Microsoft and Electronic Arts have concluded, it's Ubisoft's turn to shine. The conference will officially start at 5pm Pacific Time. Our editors will report the news from the conference as soon as it becomes available, so make sure that you check back here frequently for all of the latest updates.
Ubisoft Planning Big Holiday Push
May 27, 2009 - As part of its fiscal year-end financial report today, publisher Ubisoft gave guidance on release dates for some of its upcoming games, including Assassin's Creed 2 and Splinter Cell: Conviction.
Pre-E3 2009: Ubisoft Details E3 Plans
May 7, 2009 - Ubisoft is planning an E3 blowout at the Los Angeles Theater next month to announce its Holiday 2009 game lineup.
The Big E3 List: 2009 Edition
May 1, 2009 - The 2009 Electronic Entertainment Expo has ditched its lower-key approach from previous years and is supposed to put the "big" back into the "big show" once again. Scheduled to run from June 2-4 at the Los Angeles Convention Center, E3 2009 showcases several of the year's hottest games from the industry's most powerful publishers and developers.
Editorial: Stop Teasing Me, Bro!
April 17, 2009 - Being called a "tease" is not a compliment. There's really nothing positive about calling someone a "teaser." And so it's only natural that anything labeled teaser trailer has a negative connotation attached. A pleaser trailer would be far more satisfying. Lately, we've been seeing an increase in videogame teaser trailers. It's sparked a heated debate in the IGN offices over their merit.
Assassin's Creed 2 Release Window Announced
April 16, 2009 - Though we've already seen the teaser, which is as good an announcement as any, Ubisoft today made the officially official announcement of Assassin's Creed II. While we already knew it was coming, one interesting bit of info is included within the text - a holiday 2009 release window on all current-generation systems, which reads to us like it's hitting the PS3, Xbox 360 and Wii (and probably the PC as well). Note that the first title never hit Nintendo's latest console.
Ubisoft Spills Assassin's Creed II Details
April 15, 2009 - This month's issue of Game Informer sports a rather dramatic pose by the new leading man of Assassin's Creed II, Ezio Auditore de Firenze, but it's what's inside that's truly interesting. Having listened to the cries of needless repetition besmirching what was an otherwise rather impressive debut for a new IP (it's apparently the fastest-growing new gaming franchise in history), Ubisoft is adding quite a bit more depth to the Renaissance Italy-based sequel.
Command Prompt Podcast, Episode 43
April 14, 2009 - Welcome to the half-hour edition of the Command Prompt podcast. That's because this week we were particularly busy on Tuesday, so we had to extract the goodness of a regular podcast and condense it down to a special 30-minute version. Just like frozen concentrated orange juice.
Command Prompt Podcast, Episode 42
April 7, 2009 - We're entering the doldrums that occurs between GDC and E3. With the industry's major press conference two months away, companies are either going into radio silence or they're starting to leak out info. Unfortunately, most publishers are opting for the former. Thankfully, Ubisoft and Funcom belong to the latter camp. Ubisoft released the first Assassin's Creed 2 trailer, while Funcom finally opened up about The Secret World a bit.
IGN AU's 2009 Hotlist
January 8, 2009 - Welcome to another 'most anticipated games of 2009' feature. It's a rite of passage in the videogame industry, but this year we're taking a selfish tack. Instead of detailing the 20 biggest or most important games of the year, we're simply going to list the ones we – the staff at IGN Australia - are most excited about playing. The caveat, as always, is that we don't have a crystal ball, so we're taking an educated guess as to what will come out this year. Some titles – such as Final Fantasy XIII - are likely to be wishful thinking, but hey, we really want it so in it goes. As you can no doubt imagine, it was very difficult narrowing our list down to only 20, so there are some cool titles that have missed the cut. Feel free to chip in with the reasons why they should be included in the comments!


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Our forefathers were strong, independent entrepreneurs, who made their own way and depended on no one to survive. These pioneers raised their own food, hunted or trapped the meat that they put on the tables and delivered their own babies. If they had extra vegetables or meat, they would trade for weapons, tools or cloth to make their clothing. Yes, life was tough, but these were proud, self-determined people.
If you've paid any attention to the financial news in the last few weeks, you're probably wondering what happened to the recovery we were told was under way.
Long-time readers will remember several years ago when I talked about a beautiful little lady I had met when she was just 2 years old and who possessed the most crystal blue eyes I had ever seen. Her name was Abby Smith and she was a knockout.
Last week, the Georgia Legislature convened into special session as a result of an official call issued by Gov. Nathan Deal.
A few months ago, Treasury Secretary Timothy Geithner predicted with unshakable confidence that there was "no risk" of a downgrade of U.S. debt. In fact, he argued, "things are better than they've been if you want to think about the prospects for improving our long-term fiscal position."
An annual survey of the nation's roads by the Reason Foundation reveals a lot about congestion in Georgia. The state is ranked 10th in the nation for spending on maintenance but 39th for capital spending. It was No. 1 for the condition of its interstates, but at 31 in the nation for the percent of urban congestion.
First, let's get the "well, they did it, too" argument out of the way.
"Georgia lawmakers return to the Gold Dome in Atlanta for a special legislative session primarily to deal with redistricting." This redistricting session comes up each decade following the completion of the census count.
Military retirement as we know it may be facing an uncertain future.
I would imagine that somewhere in the bowels of federally-funded research someone has examined the "power of suggestion" relative to over-eating and obesity. If not, then let me throw out some thoughts on the subject.
Justice may have been served Wednesday when Joseph Bozicevich was sentenced to life in prison without the possibility of parole for the September 2008 shooting deaths of Staff Sgt. Darris Dawson and Sgt. Wesley Durbin in Iraq. But even though the sentencing decision likely was what the families of the deceased had been hoping for, there clearly are no winners in this situation.
For the first time in history, the United States lost its highly rated position in the financial markets. Even China is scolding the United States for this mess because what we do financially affects the entire world, and they are suggesting that the world move away from the dollar as the world standard.
Last week was "Shark Week" on the Discovery Channel. They do this about twice a year. And when a varied assortment of seals had been killed and the one-armed surfers had told their stories and when all of the research had been discussed, the findings were about the same as they have been for many years.
There are serious problems with Georgia's ethics commission - or rather (excuse us), the Georgia Government Transparency and Campaign Finance Commission. The eligibility of its chairman is not among them.
The perception of arthritis is often that it typically affects the elderly or injured. However, it is worth noting that in Georgia alone, there are about 9,200 children younger than 16 suffering from the painful joint swelling and stiffness that plagues those with juvenile arthritis. According to The Arthritis Foundation, more than 300,000 children have been diagnosed nationwide.
Editor, There are a multitude of ads on TV these days from the American Society for the Prevention of Cruelty to Animals concerning homeless, injured, abused animals.
It happened a few months back. My father-in-law celebrated, to our great joy, his 88th birthday. There was no pomp or circumstance involved. He abhors that. Because he is among the most beautifully well-mannered people I have ever encountered, he politely took all the calls though he really wished we would just treat it as another day and leave him alone to watch the news channel.
The state of Georgia's Juvenile Justice System is going to the dogs. And that's a good thing.
As a member of the House Appropriations Committee, chairman of the Economic Development and Tourism Committee, and a member of the House's Ways and Means Committee, last week was a busy one for me. We gathered for four days of hearings at Gov. Nathan Deal's office, where the budget was presented. We also listened as state agencies offered input about budget needs and then asked questions regarding which programs worked well or were under- or over-funded.
In politics, you must take advantage of windows of opportunity. Sometimes good ideas are sidetracked by unfortunate events, a bad economy or even personality conflicts among political leaders. Given the risk of delaying decisions, Georgia needs to address its transportation shortfall quickly and practically.
My fellow Georgians: In order to keep my national certification as a modest and much-beloved columnist, it is required that I submit to you at the first of every year my State of the Column message. (Yay! Clap! Clap! Clap!) I do that gladly today. For one thing, this will be a lot shorter and less boring than the State of the Union address (Boooo!) and, also, we don't have to endure a bunch of fawning politicians trying to be seen on national television. (Yay! Ha! Ha! Ha!)
Editor, Since Georgia's own Sen. Johnny Isakson voted for discriminating against pre-9/11 veterans and later against ending this discrimination, I've penned and sent the following to then-Senate Veterans' Affairs Chairman Bernie Sanders, I-VT, who introduced the Caregivers Expansion and Improvement Act of 2013:
It happened the other day. It's funny how things so simple can remind us of things so meaningful, of those sweets that are tucked inside our hearts and unknowingly treasured.
Two weeks ago, my husband, daughter and I struggled to come up with a fun way to pass a Sunday afternoon. My mother-in-law had just been staying with us, and she left that morning to head back to Florida. Since I'd given our house a good, thorough "pre-mother-in-law-visit" cleaning before she arrived, I was completely caught up on chores and housework.
With major policy decisions on transportation, education, health care and tax reform on the legislative agenda, Georgia should think beyond the traditional approach of spending more money as the solution for every problem. Focusing on ways to enhance economic opportunity and empower individuals beats doubling down on the status quo.
Editor, On behalf of Bryan County Children's Fund, I would like to take this opportunity to extend our sincere appreciation to everyone who helped to support the program this year. We were able to provide Christmas gifts to over 400 disadvantaged children in our county. This would not have been possible without collaboration and assistance from local churches, businesses, schools, social-service agencies and many others. The communitywide response was overwhelming. We are exceptionally thankful to The Good Ol' Boys, who raised funds through the annual Santa Scramble Golf Tournament and to Pembroke Advanced Communication for use of their space ...
Editor, I read Mr. Bruce McCartney's letter to the editor regarding the Wounded Warrior Project. He is totally correct. The project is top-heavy with a greedy group of executives. The top 10 officers have a compensation package from $150,000 to $333,000 a year. The remaining funds are disbursed to over 40 distribution organizations with similar management configurations.
Allen Peake is a man on a mission. The five-term Republican state representative from Macon is the driving force behind proposed legislation to legalize medical marijuana in Georgia. He may succeed this year after suffering a setback in 2014 when the House and Senate got into a bit of political brinksmanship at the last minute and failed to pass his bill, which had sailed through the House with only four negative votes.
My parents, according to the world's definition of "cool," were not. Neither drank, nor did either ever possess a credit card. Groceries and clothing were paid for in cash, utilities paid by check, and the only monthly payments they ever allowed themselves were a mortgage for a house, a short-term loan for another farm, and a couple of cars bought, over time, and paid for quickly.
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Click here to print the obituary below
William P. "Mick" McManus
William P. 'Mick' McManus
of Lowell, decorated Marine Vet; 66
LOWELL -- William P. "Mick" McManus, age 66, died unexpectedly on Tuesday January 1, 2013, at his Lowell residence.
He was born in Lynn on October 27, 1946, a son of the late Francis and Ruth (Connors) McManus. Mick was educated in Lowell schools. Upon graduation from Lowell High School, he enlisted in the Marines. He served tours in Vietnam with the rank of Corporal where he received a
Purple Heart
When Mick was discharged from the Marines he began a career as a machine operator for Ideal Tape. He retired after more than 35 years of employment.
Mick enjoyed going to the beach but, most of all, he looked forward to spending time with his grandchildren.
Survivors include a son and daughter-in-law, Micah and Valerie McManus of Lowell; a daughter Melissa McManus of Lowell; 11 grandchildren, Corey, John, Cassidy, Dayme, Randy, Raymie, Micalie, Devin, Christian, Fernando and Angel "Baby Kevin"; and his best friend of 19 years, Lu.
McMANUS -- Relatives and friends may call at the McKENNA-OUELLETTE FUNERAL HOME, 327 Hildreth Street from 4 until 7 PM on Monday. Funeral Services and Burial will be private.
For condolences and directions, please visit
Funeral Home
McKenna-Ouellette Funeral Home
327 Hildreth St
Lowell, MA 01850
Published in Lowell Sun on Jan. 6, 2013


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Latest additionsAbstractJudicial and executive branches of government - a new partnership?Article by Lord Justice Thomas (Senior Presiding Judge, England and Wales) examining how the relationship between the two branches of government is to operate following the changes consequent upon the reform of the office of the Lord Chancellor. Published in Amicus Curiae - Journal of the Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London. Thomas, Lord Justice (2006) Judicial and executive branches of government - a new partnership? Amicus Curiae, 2006 (63). pp. 3-14. ISSN 1461-2097
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Rep. Robert Scott (D-VA) of the House Judiciary Committee speaks on the legal ramifications of President Bush's surveillance practices at a news briefing, on Capitol Hill in Washington on January 20, 2006. (UPI Photo/Kevin Dietsch)
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Latest Headlines
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1 year ago
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2 years ago
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To find that these relics of a heroic age are barely supported by Britain is just a little bit disappointing
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