Hippocampal interactions with the motor system are often assumed to reflect the role of memory in motor learning. Here, we examine hippocampal connectivity with sensorimotor cortex during two tasks ...requiring paced movements, one with a mnemonic component (sequence learning) and one without (repetitive tapping). Functional magnetic resonance imaging activity was recorded from thirteen right-handed subjects; connectivity was identified from sensorimotor cortex correlations with psychophysiological interactions in hippocampal activity between motor and passive visual tasks. Finger movements in both motor tasks anticipated the timing of the metronome, reflecting cognitive control, yet evidence of motor learning was limited to the sequence learning task; nonetheless, hippocampal connectivity was observed during both tasks. Connectivity from corresponding regions in the left and right hippocampus overlapped extensively, with improved sensitivity resulting from their conjunctive (global) analysis. Positive and negative connectivity were both evident, with positive connectivity in sensorimotor cortex ipsilateral to the moving hand during unilateral movements, whereas negative connectivity was prominent in whichever hemisphere was most active during movements. Results implicate the hippocampus in volitional finger movements even in the absence of motor learning or recall.
Studies of the hippocampus use smaller voxel sizes and smoothing kernels than cortical activation studies, typically using a multivoxel seed with specified radius for connectivity analysis. This ...study identified optimal processing parameters for evaluating hippocampal connectivity with sensorimotor cortex (SMC), comparing effectiveness by varying parameters during both activation and connectivity analysis. Using both 3mm and 4mm isovoxels, smoothing kernels of 0-10mm were evaluated on the amplitude and extent of motor activation and hippocampal connectivity with SMC. Psychophysiological interactions (PPI) identified hippocampal connectivity with SMC during volitional movements, and connectivity effects from multivoxel seeds were compared with alternate methods; a structural seed represented the mean connectivity map from all voxels within a region, whereas a functional seed represented the regional voxel with maximal SMC connectivity. With few exceptions, the same parameters were optimal for activation and connectivity. Larger isovoxels showed larger activation volumes in both SMC and the hippocampus; connectivity volumes from structural seeds were also larger, except from the posterior hippocampus. Regardless of voxel size, the 10mm smoothing kernel generated larger activation and connectivity volumes from structural seeds, as well as larger beta estimates at connectivity maxima; structural seeds also produced larger connectivity volumes than multivoxel seeds. Functional seeds showed lesser effects from voxel size and smoothing kernels. Optimal parameters revealed topography in structural seed connectivity along both the longitudinal axis and mediolateral axis of the hippocampus. These results indicate larger voxels and smoothing kernels can improve sensitivity for detecting both cortical activation and hippocampal connectivity.
Abstract
Amiodarone is a class III antiarrhythmic drug containing 37% iodine by weight, with a structure similar to that of thyroid hormones. Deiodination of amiodarone releases large amounts of ...iodine that can impair thyroid function, causing either hypothyroidism or thyrotoxicosis in susceptible individuals reflecting ~20% of patients administered the drug. Not only the excess iodine, but also the amiodarone (or its metabolite, desethylamiodarone) itself may cause thyroid dysfunction by direct cytotoxicity on thyroid cells. We present an overview of the epidemiology and pathophysiology of amiodarone-induced thyroid disorders, with a focus on the various forms of clinical presentation and recommendations for personalized management of each form.
Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, ...about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.
Context:
More than two decades have passed since members from the American Thyroid Association (ATA), European Thyroid Association, and Japan Thyroid Association were surveyed on management practices ...for patients with hyperthyroidism due to Graves' disease (GD).
Objective:
We sought to document current practices in the management of GD and compare these results both to those documented in earlier surveys and to practice recommendations made in the 2011 ATA/American Association of Clinical Endocrinologists (AACE) hyperthyroidism practice guidelines. Lastly, we sought to examine differences in GD management among international members of U.S.-based endocrine societies.
Methods:
Members of The Endocrine Society (TES), ATA, and AACE were invited to participate in a web-based survey dealing with testing, treatment preference, and modulating factors in patients with GD.
Results:
A total of 730 respondents participated in the survey, 696 of whom completed all sections. Respondents included 641 TES members, 330 AACE members, and 157 ATA members. The preferred mode of therapy in uncomplicated GD was antithyroid drugs (ATDs) by 53.9% of respondents, radioactive iodine (RAI) therapy by 45.0%, and thyroid surgery in 0.7%. Compared with 1991, fewer U.S. (59.7 vs. 69%) and European (13.3% vs. 25%) respondents would use RAI therapy. Methimazole and carbimazole were the preferred ATDs, with only 2.7% of respondents selecting propylthiouracil. Patients with Graves' ophthalmopathy were treated with ATDs (62.9%) or surgery (18.5%) and less frequently with RAI plus corticosteroids (16.9%) or RAI alone (1.9%).
Conclusions:
Striking changes have occurred in the management of GD over the past two decades, with a shift away from RAI and toward ATDs in patients with uncomplicated GD. Apparent international differences persist but should be interpreted with caution. Current practices diverge in some areas from recently published guidelines; these differences should be assessed serially to determine the impact of the guidelines on future clinical practice.
A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to ...review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment.
Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force.
We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones.
We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.
Summary
Objective
Management of Graves' disease (GD) in Europe was published in 1987. Aim of this survey was to provide an update on clinical practice in Europe, and to compare it with a 2011 ...American survey.
Design
Members of the European Thyroid Association (ETA) were asked to participate in a survey on management of GD, using the same questionnaire of a recent American survey.
Results
A total of 147 ETA members participated. In addition to serum TSH and free T4 assays, most respondents would request TSH‐receptor autoantibody (TRAb) measurement (85·6%) and thyroid ultrasound (70·6%) to confirm aetiology, while isotopic studies were selected by 37·7%. Antithyroid drug (ATD) therapy was the preferred first‐line treatment (83·8%). Compared to the previous European survey, Europeans currently more frequently use TRAb measurement and thyroid ultrasound for diagnosis and evaluation, but first‐line treatment remains ATDs in a similar percentage of respondents. Current clinical practice patterns differ from those in North America, where isotopic studies are more frequently used, and radioiodine (RAI) still is first‐line treatment. When RAI treatment is selected in the presence of mild Graves' orbitopathy and/or associated risk factors for its occurrence/exacerbation, steroid prophylaxis is frequently used. The preferred ATD in pregnancy is propylthiouracil in the first trimester and methimazole in the second and third trimesters, similar to North America.
Conclusions
Significant changes in clinical practice patterns in Europe were noted compared to the previous European survey, as well as persisting differences in diagnosis and therapy between Europe and North America.
Sex dimorphism strongly impacts tumor biology, with most cancers having a male predominance. Uniquely, thyroid cancer (TC) is the only nonreproductive cancer with striking female predominance with ...three- to four-fold higher incidence among females, although males generally have more aggressive disease. The molecular basis for this observation is not known, and current approaches in treatment and surveillance are not sex specific.
Although TC has overall good prognosis, 6-20% of patients develop regional or distant metastasis, one third of whom are not responsive to conventional treatment approaches and suffer a 10-year survival rate of only 10%. More efficacious treatment strategies are needed for these aggressive TCs, as tyrosine kinase inhibitors and immunotherapy have major toxicities without demonstrable overall survival benefit. Emerging evidence indicates a role of sex hormones, genetics, and the immune system in modulation of both risk for TC and its progression in a sex-specific manner.
Greater understanding of the molecular mechanisms underlying sex differences in TC pathogenesis could provide insights into the development of sex-specific, targeted, and effective strategies for prevention, diagnosis, and management. This review summarizes emerging evidence for the importance of sex in the pathogenesis, progression, and response to treatment in differentiated TC with emphasis on the role of sex hormones, genetics, and the immune system.
In the present study, a total of 53 promising salt-tolerant genotypes were tested across 18 salt-affected diverse locations for three years. An attempt was made to identify ideal test locations and ...mega-environments using GGE biplot analysis. The CSSRI sodic environment was the most discriminating location in individual years as well as over the years and could be used to screen out unstable and salt-sensitive genotypes. Genotypes CSR36, CSR-2K-219, and CSR-2K-262 were found ideal across years. Overall, Genotypes CSR-2K-219, CSR-2K-262, and CSR-2K-242 were found superior and stable among all genotypes with higher mean yields. Different sets of genotypes emerged as winners in saline soils but not in sodic soils; however, Genotype CSR-2K-262 was the only genotype that was best under both saline and alkaline environments over the years. The lack of repeatable associations among locations and repeatable mega-environment groupings indicated the complexity of soil salinity. Hence, a multi-location and multi-year evaluation is indispensable for evaluating the test sites as well as identifying genotypes with consistently specific and wider adaptation to particular agro-climatic zones. The genotypes identified in the present study could be used for commercial cultivation across edaphically challenged areas for sustainable production.
Developmental differences in the neurocognitive networks for lexical processing were examined in 15 adults and 15 children (9-to 12-year-olds) using functional magnetic resonance imaging (fMRI). The ...lexical tasks involved spelling and rhyming judgments in either the visual or auditory modality. These lexical tasks were compared with nonlinguistic control tasks involving judgments of line patterns or tone sequences. The first main finding was that adults showed greater activation than children during the cross-modal lexical tasks in a region proposed to be involved in mapping between orthographic and phonologic representations. The visual rhyming task, which required conversion from orthography to phonology, produced greater activation for adults in the angular gyrus. The auditory spelling task, which required the conversion from phonology to orthography, also produced greater activation for adults in the angular gyrus. The greater activation for adults suggests they may have a more elaborated posterior heteromodal system for mapping between representational systems. The second main finding was that adults showed greater activation than children during the intra-modal lexical tasks in the angular gyrus. The visual spelling and auditory rhyming did not require conversion between orthography and phonology for correct performance but the adults showed greater activation in a system implicated for this mapping. The greater activation for adults suggests that they have more interactive convergence between representational systems during lexical processing.
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