Colon cancer survival in the elderly without curative surgery.

INTRODUCTION: The aim of this study was to chart the natural history of elderly patients with colon cancer who are managed nonoperatively, with the primary outcome being life expectancy from diagnosis to death. METHODS: This was a retrospective analysis of patients aged 80 years and above diagnosed with colon cancer in a tertiary care referral hospital in England between 1 January 2012 and 31 December 2017. RESULTS: Thirty-two patients were diagnosed with non-metastatic colon cancer and managed non-operatively. The median age of patients in this study was 86 years. The group had a median Charlson Comorbidity Index of 7 (range 6-12) and the median frailty score was 6 (range 3-8). Progression to metastatic disease was identified in two patients; two further patients showed locoregional progression of cancer and therefore required palliative surgical intervention. Survival of these patients ranged from 105 to 1,782 days with a median life expectancy of 586 days. Place of death was identified in 15/31 patients: 4 (27%) died in hospital, 12 (38%) died at home and 15 (47%) died in a nursing or residential home; data were missing for 1 patient (3%). CONCLUSIONS: Nonoperative management of elderly patients with colon cancer yields reasonable life expectancy and a low risk of life-threatening local complications.

Long-term mental and physical quality of life outcomes following ileal pouch anal anastomosis surgery.

INTRODUCTION: This study presents the authors' experience over 14 years of performing restorative procto-colectomy with ileal pouch anal anastomosis (IPAA). The aim was to study the long-term quality of life outcomes and analyse the predictors of pouch function as well as physical and mental wellbeing. METHODS: This is a single-centre retrospective study conducted in a specialised colorectal surgery unit in the UK. The study included patients who underwent two- or three-staged panproctocolectomy with defunctioning ileostomy for ulcerative colitis (UC) or familial adenomatous polyposis between 2004 and 2018. Data were collected from a prospectively, surgeon-maintained database. Pouch function and quality of life scores were obtained via validated questionnaires. A multivariate analysis was utilised to explore predictors of quality of life and pouch function. RESULTS: The study reports 105 patients who underwent IPAA with a covering ileostomy. The majority of operations were performed for UC (97, 92.4%). The median age of patients was 36 years and the male to female ratio was 1:1. Thirty patients (28.5%) suffered early post-IPAA complications, while pouch failure rate was 11.4% (12/105). Late complications were reported at a rate of 45%. On long-term follow-up, the median Pouch Function Score was 7 (IQR 3-14). Both the physical and mental sections of the quality of life score were at a median indistinguishable from the normal population but had different predictors associated with them. CONCLUSION: Our findings recognise the complex interplay between physical and psychological wellbeing after pouch surgery and advise psychological counselling where appropriate.

Colorectal cancer outcomes determined by mode of presentation: analysis of population data in England between 2010 and 2014.

BACKGROUND: The purpose of this study was to investigate associations between mode of presentation; categorized as emergency, suspected cancer outpatient referral pathway (2-week wait or 2WW pathway), non-cancer suspected outpatient referral (non-2-week wait pathway) or following screening, and stage of diagnosis and survival in patients with colorectal cancer in England. METHODS: This was a retrospective cohort observational study of patients diagnosed with colorectal cancer between January 2010 and December 2014 in England using data from Public Health England collated from regional cancer registries. RESULTS: The most common route to diagnosis among 167,501 patients diagnosed with colorectal cancer was via the non-cancer suspect (non-2WW) outpatient referral pathway (35.1%) followed by the suspected cancer (2WW) referral pathway (31.6%), emergency presentation (22.8%) and most infrequently following screening (10.6%) (p < 0.01). Screening confers the greatest likelihood of early-stage diagnosis (61.6%) compared to other modes of presentation. The 5-year overall survival was 81.8%, 53.3%, 53.0% and 27.6% in those diagnosed via screening, 2WW, non-2WW pathway and emergency presentation, respectively. Patients from most deprived regions were more likely to be diagnosed following emergency presentation (27.7 vs 19.7%, p < 0.01) and less likely via screening (8.1 vs 12%, p < 0.01). CONCLUSIONS: Asymptomatic individuals diagnosed following screening have earlier stage cancers and better survival, the opposite was observed in those diagnosed following emergency presentation. Patients referred via the 2WW pathway do not have better survival outcomes when compared to those referred via the non-2WW pathway. In addition, this study has identified socio-economic groups that need to be targeted with public health campaigns to improve screening uptake.

Prognosis of non-operative management of non-metastatic colorectal cancer in octa- and nonagenarians.

INTRODUCTION: The aim of the study was to establish the natural history of elderly patients with non-metastatic colorectal cancer who underwent non-operative management in comparison with those who underwent operative management. MATERIALS AND METHODS: A retrospective analysis of patients aged 80 years and above diagnosed with colorectal cancer between 2007 and 2015 in a tertiary care hospital in the Southwest of England was done. Patients were divided into non-operatively managed and operatively managed groups. Clinical demographics, Charlson Comorbidity Index, location of the tumour and overall survival between the two groups were compared. RESULTS: A total of 407 patients were studied; 132 were treated non-operatively and 275 operatively. The non-operative group included fewer right-sided colon cancers (28.7% vs 54.9%), but significantly more rectal cancers were managed non-operatively (43.9 vs 23.6%, respectively). The two and five year overall survival was 38.9% and 11.3% respectively in the non-operative group, significantly lower than patients in the operative group where the two and five year survival was 78.9% and 59.6% respectively (p = .0001). The median Charlson Comorbidity Index was 7.99 for the non-operative group and 7.49 in the operative group (p = 0.109). Patients treated non-operatively were deemed unfit without objective frailty assessment and only 43/132(32.6%) had formal anaesthetic assessment before being deemed unfit for surgery. CONCLUSION: The survival of octa- and nonagenarians with non-metastatic colorectal cancer managed conservatively is significantly less than counterparts managed operatively. Our present strategy of deciding and denying treatment of the elderly patient with colorectal cancer is arbitrary, highlighting the need for robust geriatric and frailty assessment.

Calculation of the impulse response and phase noise of a high-current photodetector using the drift-diffusion equations.

We describe a procedure to calculate the impulse response and phase noise of high-current photodetectors using the drift-diffusion equations while avoiding computationally expensive Monte Carlo simulations. We apply this procedure to a modified uni-traveling-carrier (MUTC) photodetector. In our approach, we first use the full drift-diffusion equations to calculate the steady-state photodetector parameters. We then perturb the generation rate as a function of time to calculate the impulse response. We next calculate the fundamental shot noise limit and cut-off frequency of the device. We find the contributions of the electron, hole, and displacement currents. We calculate the phase noise of an MUTC photodetector. We find good agreement with experimental and Monte Carlo simulation results. We show that phase noise is minimized by having an impulse response with a tail that is as small as possible. Since, our approach is much faster computationally than Monte Carlo simulations, we are able to carry out a broad parameter study to optimize the device performance. We propose a new optimized structure with less phase noise and reduced nonlinearity.

A prospective randomized controlled trial comparing early postoperative complications in patients undergoing loop colostomy with and without a stoma rod.

AIM: A stoma rod or bridge has been traditionally placed under the bowel loop while constructing a loop colostomy. This is believed to prevent stomal retraction and provide better faecal diversion. However, the rod can cause complications such as mucosal congestion, oedema and necrosis. This single-centre prospective randomized controlled trial compared outcomes after creation of loop colostomy with and without a supporting stoma rod. The primary outcome studied was stoma retraction rate; other stoma-related complications were studied as secondary outcomes. METHOD: One hundred and fifty-one patients were randomly allotted to one of two arms, colostomy with or without a supporting rod. Postoperative complications such as retraction, mucocutaneous separation, congestion and re-exploration for stoma-related complications were recorded. RESULTS: There was no difference in the stoma retraction rate between the two arms (8.1% in the rod arm and 6.6% in the no-rod arm; P = 0.719). Stomal necrosis (10.7% vs 1.3%; P = 0.018), oedema (23% vs 3.9%; P = 0.001), congestion (20.3% vs 2.6%; P = 0.001) and re-admission rates (8.5% vs 0%; P = 0.027) were significantly increased in the arm randomized to the rod. CONCLUSION: The stoma rod does not prevent stomal retraction. However, complication rates are significantly higher when a stoma rod is used. Routine use of a stoma rod for construction of loop colostomy can be avoided.

Relations Between Self-Reported Adverse Events in Childhood and Hypersexuality in Adult Male Sexual Offenders.

Hypersexuality, or extreme normophilic sexual urges and behaviors, is a controversial construct that was recently considered as a candidate disorder for the DSM-5 and was rejected. It was also rejected for inclusion in Section III (Conditions for Further Study). Nonetheless, it has been found to be an important predictor of recidivism among sex offenders, and it continues to be discussed widely in the literature. In the present study, we investigated the developmental roots of this construct in a sample of 529 adult male sexual offenders, who were administered the Multidimensional Assessment of Sex and Aggression. Physical, psychological, and sexual abuse experiences were estimated using several scales of early development. Psychological abuse in childhood and adolescence, especially by a father, was found to be the most prominent predictor of subsequent hypersexual thoughts and behaviors. The accumulation of abuse types, however, was also associated with a monotonic increase in the latent trait of hypersexuality. The consequences of these results for conceptualizations of the construct are discussed.

Is Hypersexuality Dimensional or Categorical? Evidence From Male and Female College Samples.

The recent attempt to introduce hypersexual disorder into the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), has increased empirical scrutiny of the construct. Consensus on its definition and underlying structure remains elusive. Whereas some conceptualizations favor a categorical latent structure, others speculate that hypersexual behavior is dimensional. Research on the latent structure of hypersexual behavior, however, has been sparse. This is unfortunate, because determination of the latent structure can contribute to more accurate assessment, diagnosis, and understanding of etiological process. To date the only study on hypersexuality's latent structure found consistent evidence of a dimensional structure for males but less clear results for females. In the present study the Multidimensional Inventory of Development, Sex, and Aggression (MIDSA), a self-report, contingency-based inventory, was administered to 1,146 college students. Four indices of hypersexual behavior and six indices of sexual compulsivity were analyzed, using three taxometric methods (mean above minus below a cut [MAMBAC], maximum covariance [MAXCOV], and latent mode factor analysis [L-Mode]). Evidence supported a dimensional latent structure for hypersexuality in male and female samples. Future assessments of hypersexuality must focus on adequate reliability and discriminant validity across the continuum of sexual behavior rather than on attempts to differentiate between arbitrarily developed diagnostic categorizations.

Triiodothyronine regulates angiogenic growth factor and cytokine secretion by isolated human decidual cells in a cell-type specific and gestational age-dependent manner.

STUDY QUESTION: Does triiodothyronine (T3) regulate the secretion of angiogenic growth factors and cytokines by human decidual cells isolated from early pregnancy? SUMMARY ANSWER: T3 modulates the secretion of specific angiogenic growth factors and cytokines, with different regulatory patterns observed amongst various isolated subpopulations of human decidual cells and with a distinct change between the first and second trimesters of pregnancy. WHAT IS KNOWN ALREADY: Maternal thyroid dysfunction during early pregnancy is associated with complications of malplacentation including miscarriage and pre-eclampsia. T3 regulates the proliferation and apoptosis of fetal-derived trophoblasts, as well as promotes the invasive capability of extravillous trophoblasts (EVT). We hypothesize that T3 may also have a direct impact on human maternal-derived decidual cells, which are known to exert paracrine regulation upon trophoblast behaviour and vascular development at the uteroplacental interface. STUDY DESIGN, SIZE, DURATION: This laboratory-based study used human decidua from first (8-11 weeks; n = 18) and second (12-16 weeks; n = 12) trimester surgical terminations of apparently uncomplicated pregnancies. PARTICIPANTS/MATERIALS, SETTING, METHODS: Primary cultures of total decidual cells, and immunomagnetic bead-isolated populations of stromal-enriched (CD10+) and stromal-depleted (CD10-) cells, uterine natural killer cells (uNK cells; CD56+) and macrophages (CD14+) were assessed for thyroid hormone receptors and transporters by immunocytochemistry. Each cell population was treated with T3 (0, 1, 10, 100 nM) and assessments were made of cell viability (MTT assay) and angiogenic growth factor and cytokine secretion (immunomediated assay). The effect of decidual cell-conditioned media on EVT invasion through Matrigel(®) was evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Immunocytochemistry showed the expression of thyroid hormone transporters (MCT8, MCT10) and receptors (TRα1, TRß1) required for thyroid hormone-responsiveness in uNK cells and macrophages from the first trimester. The viability of total decidual cells and the different cell isolates were unaffected by T3 so changes in cell numbers could not account for any observed effects. In the first trimester, T3 decreased VEGF-A secretion by total decidual cells (P < 0.05) and increased angiopoietin-2 secretion by stromal-depleted cells (P < 0.05) but in the second trimester total decidual cells showed only increased angiogenin secretion (P < 0.05). In the first trimester, T3 reduced IL-10 secretion by total decidual cells (P < 0.05), and reduced granulocyte macrophage colony stimulating factor (P < 0.01), IL-8 (P < 0.05), IL-10 (P < 0.01), IL-1ß (P < 0.05) and monocyte chemotactic protein -1 (P < 0.001) secretion by macrophages, but increased tumour necrosis factor-α secretion by stromal-depleted cells (P < 0.05) and increased IL-6 by uNK cells (P < 0.05). In contrast, in the second trimester T3 increased IL-10 secretion by total decidual cells (P < 0.01) but did not affect cytokine secretion by uNK cells and macrophages. Conditioned media from first trimester T3-treated total decidual cells and macrophages did not alter EVT invasion compared with untreated controls. Thus, treatment of decidual cells with T3 resulted in changes in both angiogenic growth factor and cytokine secretion in a cell type-specific and gestational age-dependent manner, with first trimester decidual macrophages being the most responsive to T3 treatment, but these changes in decidual cell secretome did not affect EVT invasion in vitro. LIMITATIONS, REASONS FOR CAUTION: Our results are based on in vitro findings and we cannot be certain if a similar response occurs in human pregnancy in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Optimal maternal thyroid hormone concentrations could play a critical role in maintaining a balanced inflammatory response in early pregnancy to prevent fetal immune rejection and promote normal placental development through the regulation of the secretion of critical cytokines and angiogenic growth factors by human decidual cells. Our data suggest that there is an ontogenically determined regulatory 'switch' in T3 responsiveness between the first and second trimesters, and support the notion that the timely and early correction of maternal thyroid dysfunction is critical in influencing pregnancy outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study is funded by Wellbeing of Women (RG/1082/09 to S.Y.C., M.D.K., J.A.F., L.S.L., G.E.L.) and Action Medical Research - Henry Smith Charity (SP4335 to M.D.K., S.Y.C., L.S.L., J.A.F.). The authors have no conflicts of interest to disclose.

Manipulation of PBF/PTTG1IP phosphorylation status; a potential new therapeutic strategy for improving radioiodine uptake in thyroid and other tumors.

CONTEXT: The clinical effectiveness of ablative radioiodine treatment of thyroid tumors is limited by the availability of the sodium iodide symporter (NIS) at the plasma membrane (PM) for uptake of ¹³¹I. A significant proportion of well-differentiated thyroid tumors are unable to concentrate sufficient radioiodine for effective therapy, and in other tumor models such as breast tumors, where radioiodine uptake would be an attractive therapeutic option, uptake is insufficient. OBJECTIVE: Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is overexpressed in multiple cancers and significantly decreases NIS expression at the PM. The goal of this study was to identify a method by which PBF repression of NIS may be overcome in human tumors. RESULTS: Here, we identify PBF as a tyrosine phosphoprotein that specifically binds the proto-oncogene tyrosine protein kinase Src in mass spectrometry, glutathione S-transferase pulldown and coimmunoprecipitation assays. Src induction leads to phosphorylation at PBF residue Y174. Abrogation of this residue results in PM retention and a markedly reduced ability to bind NIS. The Src inhibitor PP1 inhibits PBF phosphorylation in multiple cell lines in vitro, including human primary thyroid cells. Of direct clinical importance to the treatment of thyroid cancer, PP1 stimulates iodide uptake by transfected NIS in TPC1 thyroid carcinoma cells and entirely overcomes PBF repression of iodide uptake in human primary thyroid cells. CONCLUSIONS: We propose that targeting PBF phosphorylation at residue Y174 via tyrosine kinase inhibitors may be a novel therapeutic strategy to enhance the efficacy of ablative radioiodine treatment in thyroid and other endocrine and endocrine-related tumors.

Expression and function of thyroid hormone transporters in the microvillous plasma membrane of human term placental syncytiotrophoblast.

The transplacental passage of thyroid hormones (THs) from mother to fetus in humans has been deduced from observational clinical studies and is important for normal fetoplacental development. To investigate the transporters that regulate TH uptake by syncytiotrophoblast (the primary barrier to maternal-fetal exchange, which lies in direct contact with maternal blood), we isolated the microvillous plasma membrane (MVM) of human term syncytiotrophoblasts. We have demonstrated that MVM vesicles express plasma membrane TH transporter proteins, including system-L (L-type amino acid transporter 1 and CD98), monocarboxylate transporters (MCTs) 8 and 10, organic anion-transporting polypeptides 1A2 and 4A1. We provide the first definitive evidence that the human syncytiotrophoblast MVM is capable of rapid, saturable T(4) and T(3) uptake at similar rates and in a Na(+)-independent manner. These two major forms of THs could not significantly inhibit each others' uptake, suggesting that each is mediated by largely different transporters. No single transporter was noted to play a dominant role in either T(4) or T(3) uptake. Using combinations of transporter inhibitors that had an additive effect on TH uptake, we provide evidence that 67% of saturable T(4) uptake is facilitated by system-L and MCT10 with a minor role played by organic anion-transporting polypeptides, whereas 87% of saturable T(3) uptake is mediated by MCT8 and MCT10. Our data demonstrate that syncytiotrophoblast may control the quantity and forms of THs taken up by the human placenta. Thus, syncytiotrophoblast could be critical in regulating transplacental TH supply from the mother to the fetus.

PTTG-binding factor (PBF) is a novel regulator of the thyroid hormone transporter MCT8.

Within the basolateral membrane of thyroid follicular epithelial cells, two transporter proteins are central to thyroid hormone (TH) biosynthesis and secretion. The sodium iodide symporter (NIS) delivers iodide from the bloodstream into the thyroid, and after TH biosynthesis, monocarboxylate transporter 8 (MCT8) mediates TH secretion from the thyroid gland. Pituitary tumor-transforming gene-binding factor (PBF; PTTG1IP) is a protooncogene that is up-regulated in thyroid cancer and that binds NIS and modulates its subcellular localization and function. We now show that PBF binds MCT8 in vitro, eliciting a marked shift in MCT8 subcellular localization and resulting in a significant reduction in the amount of MCT8 at the plasma membrane as determined by cell surface biotinylation assays. Colocalization and interaction between PBF and Mct8 was also observed in vivo in a mouse model of thyroid-specific PBF overexpression driven by a bovine thyroglobulin (Tg) promoter (PBF-Tg). Thyroidal Mct8 mRNA and protein expression levels were similar to wild-type mice. Critically, however, PBF-Tg mice demonstrated significantly enhanced thyroidal TH accumulation and reduced TH secretion upon TSH stimulation. Importantly, Mct8-knockout mice share this phenotype. These data show that PBF binds and alters the subcellular localization of MCT8 in vitro, with PBF overexpression leading to an accumulation of TH within the thyroid in vivo. Overall, these studies identify PBF as the first protein to interact with the critical TH transporter MCT8 and modulate its function in vivo. Furthermore, alongside NIS repression, PBF may thus represent a new regulator of TH biosynthesis and secretion.

The expression of thyroid hormone transporters in the human fetal cerebral cortex during early development and in N-Tera-2 neurodifferentiation.

Associations of neurological impairment with mutations in the thyroid hormone (TH) transporter, MCT8, and with maternal hypothyroxinaemia, suggest that THs are crucial for human fetal brain development. It has been postulated that TH transporters regulate the cellular supply of THs within the fetal brain during development. This study describes the expression of TH transporters in the human fetal cerebral cortex (7­20 weeks gestation) and during retinoic acid induced neurodifferentiation of the human N-Tera-2 (NT2) cell line, in triiodothyronine (T3) replete and T3-depleted media. Compared with adult cortex, mRNAs encoding OATP1A2, OATP1C1, OATP3A1 variant 2, OATP4A1, LAT2 and CD98 were reduced in fetal cortex at different gestational ages, whilst mRNAs encoding MCT8, MCT10, OATP3A1 variant 1 and LAT1 were similar. From the early first trimester, immunohistochemistry localised MCT8 and MCT10 to the microvasculature and to undifferentiated CNS cells. With neurodifferentiation, NT2 cells demonstrated declining T3 uptake, accompanied by reduced expressions of MCT8, LAT1, CD98 and OATP4A1. T3 depletion significantly reduced MCT10 and LAT2 mRNA expression at specific time points during neurodifferentiation but there were no effects upon T3 uptake, neurodifferentiation marker expression or neurite lengths and branching. MCT8 repression also did not affect NT2 neurodifferentiation. In conclusion, many TH transporters are expressed in the human fetal cerebral cortex from the first trimester, which could regulate cellular TH supply during early development. However, human NT2 neurodifferentiation is not dependent upon T3 or MCT8 and there were no compensatory changes to promote T3 uptake in a T3-depleted environment.

Differential triiodothyronine responsiveness and transport by human cytotrophoblasts from normal and growth-restricted pregnancies.

CONTEXT: Abnormal placentation in human pregnancy is associated with intrauterine fetal growth restriction (IUGR). Our group has previously reported the association between severe IUGR, lower fetal circulating concentrations of thyroid hormones (THs), and altered expression of TH receptors and TH transporters within human placental villi. We postulate that altered TH bioavailability to trophoblasts may contribute to the pathogenesis of IUGR. DESIGN AND OBJECTIVE: Cytotrophoblasts were isolated from normal and IUGR human placentae to compare their responsiveness to T(3) and their capability for T(3) transport. RESULTS: Compared with normal cytotrophoblasts, the viability of IUGR cytotrophoblasts (assessed by methyltetrazoleum assay) was significantly reduced (P < 0.001), whereas apoptosis (assessed using caspase 3/7 activity and M30 immunoreactivity) was significantly increased after T(3) treatment for 48 h (P < 0.001 and P < 0.01, respectively). The secretion of human chorionic gonadotropin was significantly increased by IUGR cytotrophoblasts compared with normal cytotrophoblasts (P < 0.001), independently of T(3) treatment. Net transport of [(125)I]T(3) was 20% higher by IUGR cytotrophoblasts compared with normal cytotrophoblasts (P < 0.001), and this was accompanied by a 2-fold increase in the protein expression of the TH transporter, monocarboxylate transporter 8, as assessed by Western immunoblotting (P < 0.01). CONCLUSIONS: IUGR cytotrophoblasts demonstrate altered responsiveness to T(3) with significant effects on cell survival and apoptosis compared with normal cytotrophoblasts. Increased monocarboxylate transporter 8 expression and intracellular T(3) accumulation may contribute to the altered T(3) responsiveness of IUGR cytotrophoblasts.

A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study.

CONTEXT: Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit. OBJECTIVE: Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function. DESIGN AND SETTING: We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care. PATIENTS: Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening. INTERVENTION: T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr). MAIN OUTCOME MEASURES: Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered. RESULTS: Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months. CONCLUSIONS: This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.

Older subjects with hyperthyroidism present with a paucity of symptoms and signs: a large cross-sectional study.

CONTEXT: The absence of classical symptoms and signs of hyperthyroidism often results in delayed diagnosis and treatment. OBJECTIVES: The objective of the study was to determine the prevalence of symptoms and signs of hyperthyroidism according to patients' age and gender as well as severity and type of hyperthyroidism. DESIGN, PARTICIPANTS AND SETTING: This was a cross-sectional study of 3049 consecutive patients with hyperthyroidism presenting to a single secondary/tertiary care clinic. MAIN OUTCOME MEASURES: Calculation of adjusted odds ratios for presence/absence of symptoms/signs of hyperthyroidism simultaneously analyzing the influence of patients' age/gender, disease etiology/severity, symptom duration, and smoking. RESULTS: The majority of patients older than 61 yr had two or more symptoms. The lowest proportion of subjects reporting five or more symptoms was found in those older than 61 yr. Increasing age was associated with reduced adjusted odds ratio for the presence of most classical symptoms except for weight loss and shortness of breath, independent of disease severity. Those with more severe hyperthyroidism and smokers had increased odds ratios for most symptoms. Older age, higher serum free T(4) concentrations at diagnosis, male gender, and toxic nodular hyperthyroidism were independently associated with risk of atrial fibrillation. Signs of ophthalmopathy were associated with increasing age, smoking, longer symptom duration, and female gender. CONCLUSIONS: Classical symptoms and signs of hyperthyroidism are significantly less prevalent in older patients and more prevalent in smokers and subjects with higher free T(4) concentrations. We propose a lower threshold for performing thyroid function tests in patients older than 60 yr, especially in those presenting with atrial fibrillation, weight loss, or shortness of breath.

Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction.

Thyroid hormones (TH) are important for the development of the human fetus and placenta from very early gestation. The transplacental passage of TH from mother to fetus and the supply of TH into trophoblasts require the expression of placental TH plasma membrane transporters. We describe the ontogeny of the TH transporters MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 in a large series (n = 110) of normal human placentae across gestation and describe their expression changes with intrauterine fetal growth restriction (IUGR n = 22). Quantitative RT-PCR revealed that all the mRNAs encoding TH transporters are expressed in human placenta from 6 weeks gestation and throughout pregnancy. MCT8, MCT10, OATP1A2 and LAT1 mRNA expression increased with gestation. OATP4A1 and CD98 (LATs obligatory associated protein) mRNA expression reached a nadir in mid-gestation before increasing towards term. LAT2 mRNA expression did not alter throughout gestation. Immunohistochemistry localised MCT10 and OATP1A2 to villous cytotrophoblasts and syncytiotrophoblasts, and extravillous trophoblasts while OATP4A1 was preferentially expressed in the villous syncytiotrophoblasts. Whilst MCT8 protein expression was increased, MCT10 mRNA expression was decreased in placentae from IUGR pregnancies delivered in the early 3rd trimester compared to age matched appropriately grown for gestational age controls. No significant change was found in the mRNA expression of the other transporters with IUGR. In conclusion, several TH transporters are present in the human placenta from early 1st trimester with varying patterns of expression throughout gestation. Their coordinated effects may regulate both transplacental TH passage and TH supply to trophoblasts, which are critical for the normal development of the fetus and placenta. Increased MCT8 and decreased MCT10 expression within placentae of pregnancies complicated by IUGR may contribute to aberrant development of the fetoplacental unit.

Monocarboxylate transporter 8 in neuronal cell growth.

Thyroid hormones are essential for the normal growth and development of the fetus, and even small alterations in maternal thyroid hormone status during early pregnancy may be associated with neurodevelopmental abnormalities in childhood. Mutations in the novel and specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) have been associated with severe neurodevelopmental impairment. However, the mechanism by which MCT8 influences neural development remains poorly defined. We have therefore investigated the effect of wild-type (WT) MCT8, and the previously reported L471P mutant, on the growth and function of human neuronal precursor NT2 cells as well as MCT8-null JEG-3 cells. HA-tagged WT MCT8 correctly localized to the plasma membrane in NT2 cells and increased T(3) uptake in both cell types. In contrast, L471P MCT8 was largely retained in the endoplasmic reticulum and displayed no T(3) transport activity. Transient overexpression of WT and mutant MCT8 proteins failed to induce endoplasmic reticular stress or apoptosis. However, MCT8 overexpression significantly repressed cell proliferation in each cell type in both the presence and absence of the active thyroid hormone T(3) and in a dose-dependent manner. In contrast, L471P MCT8 showed no such influence. Finally, small interfering RNA depletion of endogenous MCT8 resulted in increased cell survival and decreased T(3) uptake. Given that T(3) stimulated proliferation in embryonic neuronal NT2 cells, whereas MCT8 repressed cell growth, these data suggest an entirely novel role for MCT8 in addition to T(3) transport, mediated through the modulation of cell proliferation in the developing brain.

Prediction of cure and risk of hypothyroidism in patients receiving 131I for hyperthyroidism.

CONTEXT: There is little consensus regarding the most appropriate dose of radioiodine ((131)I) to be administered to patients with hyperthyroidism. OBJECTIVE: To compare the efficacy of fixed dose regimens of (131)I in curing hyperthyroidism and to define simple clinical and biochemical factors that predict outcome in individual patients. DESIGN: Consecutive series of hyperthyroid subjects treated with (131)I. SETTING: Single Secondary/Tertiary Care Hospital Clinic. PARTICIPANTS: A total of 1278 patients (1013 females and 262 males, mean age 49.7 years) presenting with hyperthyroidism between 1984 and 2006. INTERVENTION: Treatment with (131)I using a fixed dose regimen. MAIN OUTCOME MEASURES: Probability of cure and risk of development of hypothyroidism following a single dose of (131)I. RESULTS: Patients given a single dose of (131)I of 600 MBq (n = 485) had a higher cure rate (84.1%) compared with those receiving either 370 MBq (74.9%, P < 0.001) or those given 185 Bq (63%, P < 0.001). An increased incidence of hypothyroidism by 1 year was evident with higher doses (600 MBq: 60.4%; 370 MBq: 49.2%, P = 0.001; 185 Bq: 38.1%, P < 0.001). Binary logistic regression analysis identified a 600 Bq dose of (131)I [adjusted odds ratio, AOR 3.33 (2.28-4.85), P < 0.001], female gender [AOR 1.75 (1.23-2.47), P = 0.002], lower presenting serum free T4 concentration [AOR 1.01 (1.01-1.02), P < 0.001] and absence of a palpable goitre [AOR 3.33 (2.00-5.56), P < 0.001] to be independent predictors of cure. Similarly, a 600 MBq dose [AOR 3.79 (2.66-5.38), P < 0.001], female gender [AOR 1.46 (1.05-2.02), P = 0.02], younger age [AOR 1.03 (1.02-1.04), P < 0.001], absence of a palpable goitre [AOR 3.85 (2.38-5.88), P < 0.001] and presence of ophthalmopathy [AOR 1.57 (1.06-2.31), P = 0.02] were identified as independent factors predicting the probability of development of hypothyroidism at one year. Based on these findings, formulae to indicate probability of cure and risk of hypothyroidism for application to individual patients were derived. CONCLUSIONS: Simple clinical/biochemical criteria can be used to predict outcome after (131)I treatment. These factors determine that males, those with severe biochemical hyperthyroidism, and those with a palpable goitre require larger doses (600 MBq) in order to achieve cure.