Is Stimulated Thyroglobulin Before Radioiodine Therapy a Useful Tool in Predicting Response to Initial Therapy in Patients with Differentiated Thyroid Carcinoma?

Thyroglobulin (Tg) is an important tool to evaluate the persistence and recurrence risk in differentiated thyroid cancer (DTC). We aimed to evaluate the correlation between pre-radioiodine therapy stimulated Tg (pre-RAI Tg) levels and the first response to treatment evaluation, and to establish a cut-off pre-RAI Tg threshold for predicting an initial excellent response. Retrospective cohort study of DTC patients who underwent total thyroidectomy and radioiodine therapy. Response to therapy was evaluated 6 to 24 months after initial therapy, and patients were classified as: excellent response (ER); indeterminate response (IndR) and incomplete response (IncR). Total patients: 166 among which 85.5% female with mean age of 47.6 ± 13 years. The ER had a significantly lower pre-RAI Tg in comparison to IndR (p<0.001) and IncR (p<0.001), and pre-RAI Tg were different between the IndR and IncR (p=0.02). A cut-off pre-RAI Tg value at 7.55ng/ml was obtained by receiver operating characteristics curve for differentiating ER from IndR and IncR. The area under curve was 0.832 (95% CI 0.76-0.91). In multivariate analysis, ATA low-risk (RR 1.61, 95% CI 1.06-2.43, p=0.025) and Tg below 7.55ng/ml (RR 2.17, 95% CI 1.52-3.10, p<0.001) were associated with ER. After a median of 7.4-year follow-up, 124 (74.7%) patients were allocated into ER, 22 (13.2%) into IndR, and 20 (12%) into IncR. In conclusion, pre-RAI Tg predicts first evaluation of treatment response. Pre-RAI Tg cut-off was a key predictor of initial excellent response to therapy and may be an important tool in the follow-up of DTC patients.

A subset of OPCs do not express Olig2 during development which can be increased in the adult by brain injuries and complex motor learning.

Oligodendrocyte precursor cells (OPCs) are uniformly distributed in the mammalian brain; however, their function is rather heterogeneous in respect to their origin, location, receptor/channel expression and age. The basic helix-loop-helix transcription factor Olig2 is expressed in all OPCs as a pivotal determinant of their differentiation. Here, we identified a subset (2%-26%) of OPCs lacking Olig2 in various brain regions including cortex, corpus callosum, CA1 and dentate gyrus. These Olig2 negative (Olig2neg ) OPCs were enriched in the juvenile brain and decreased subsequently with age, being rarely detectable in the adult brain. However, the loss of this population was not due to apoptosis or microglia-dependent phagocytosis. Unlike Olig2pos OPCs, these subset cells were rarely labeled for the mitotic marker Ki67. And, accordingly, BrdU was incorporated only by a three-day long-term labeling but not by a 2-hour short pulse, suggesting these cells do not proliferate any more but were derived from proliferating OPCs. The Olig2neg OPCs exhibited a less complex morphology than Olig2pos ones. Olig2neg OPCs preferentially remain in a precursor stage rather than differentiating into highly branched oligodendrocytes. Changing the adjacent brain environment, for example, by acute injuries or by complex motor learning tasks, stimulated the transition of Olig2pos OPCs to Olig2neg cells in the adult. Taken together, our results demonstrate that OPCs transiently suppress Olig2 upon changes of the brain activity.

A prospective comparison of ACR-TIRADS and EU-TIRADS in thyroid nodule assessment for FNA-US.

OBJECTIVE: Prospective data on the accuracy of ultrasound (US) classification systems in thyroid nodules are still scarce. The aim of this study is to compare the accuracy of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) and European (EU)-TIRADS classification systems. DESIGN AND PATIENTS: Consecutive patients with one or more thyroid nodule(s) who underwent fine-needle aspiration (FNA) under ultrasonographic guidance (FNA-US) were prospectively evaluated. MEASUREMENTS: Clinical evaluation and US data were collected. The reference standard used for this study was FNA-US cytology and histopathological diagnosis. RESULTS: A total of 186 thyroid nodules in 166 patients were evaluated, resulting in 168 nodules from 149 patients with conclusive benign or malignant results. Sensitivity, specificity, negative predictive value (NPV) and false negative (FN) were 100.0%, 28.7%, 100.0% and 0.0%, respectively, for ACR-TIRADS; and 90.0%, 19.1%, 96.8% and 9.1% (n = 1), respectively, for EU-TIRADS. The number of unnecessary FNA-US indicated by ACR-TIRADS was lower than EU-TIRADS (71.3% vs. 80.9%, p = .017), and the number of possibly avoided FNA-US was higher (26.7% vs. 17.8%). Using the same threshold of ACR-TIRADS to indicate FNA-US in EU-TIRADS 3 nodules (2.5 cm), there was an improvement in specificity (30.6%) and avoided FNA-US (28.6%). The best performance of both systems was demonstrated when FNA-US would be indicated only in highly suspicious nodules and/or in the presence of lymphadenopathy, with 85.7% and 89.3% of possibly avoided FNA-US for ACR-TIRADS and EU-TIRADS, respectively, without increasing FN. CONCLUSION: Both systems presented high sensitivity, but low specificity in selecting nodules for FNA-US. The use of nodular size for FNA-US selection is questioned.

Continuing Contributions of Field Epidemiology Training Programs to Global COVID-19 Response.

We documented the contributions of Field Epidemiology Training Program (FETP) trainees and graduates to global COVID-19 preparedness and response efforts. During February-July 2021, we conducted surveys designed in accordance with the World Health Organization's COVID-19 Strategic Preparedness and Response Plan. We quantified trainee and graduate engagement in responses and identified themes through qualitative analysis of activity descriptions. Thirty-two programs with 2,300 trainees and 7,372 graduates reported near-universal engagement across response activities, particularly those aligned with the FETP curriculum. Graduates were more frequently engaged than were trainees in pandemic response activities. Common themes in the activity descriptions were epidemiology and surveillance, leading risk communication, monitoring and assessment, managing logistics and operations, training and capacity building, and developing guidelines and protocols. We describe continued FETP contributions to the response. Findings indicate the wide-ranging utility of FETPs to strengthen countries' emergency response capacity, furthering global health security.

Cannabidiol Exerts a Neuroprotective and Glia-Balancing Effect in the Subacute Phase of Stroke.

Pharmacological agents limiting secondary tissue loss and improving functional outcomes after stroke are still limited. Cannabidiol (CBD), the major non-psychoactive component of Cannabis sativa, has been proposed as a neuroprotective agent against experimental cerebral ischemia. The effects of CBD mostly relate to the modulation of neuroinflammation, including glial activation. To investigate the effects of CBD on glial cells after focal ischemia in vivo, we performed time-lapse imaging of microglia and astroglial Ca2+ signaling in the somatosensory cortex in the subacute phase of stroke by in vivo two-photon laser-scanning microscopy using transgenic mice with microglial EGFP expression and astrocyte-specific expression of the genetically encoded Ca2+ sensor GCaMP3. CBD (10 mg/kg, intraperitoneally) prevented ischemia-induced neurological impairment, reducing the neurological deficit score from 2.0 ± 1.2 to 0.8 ± 0.8, and protected against neurodegeneration, as shown by the reduction (more than 70%) in Fluoro-Jade C staining (18.8 ± 7.5 to 5.3 ± 0.3). CBD reduced ischemia-induced microglial activation assessed by changes in soma area and total branch length, and exerted a balancing effect on astroglial Ca2+ signals. Our findings indicate that the neuroprotective effects of CBD may occur in the subacute phase of ischemia, and reinforce its strong anti-inflammatory property. Nevertheless, its mechanism of action on glial cells still requires further studies.

Cannabidiol Confers Neuroprotection in Rats in a Model of Transient Global Cerebral Ischemia: Impact of Hippocampal Synaptic Neuroplasticity.

Evidence for the clinical use of neuroprotective drugs for the treatment of cerebral ischemia (CI) is still greatly limited. Spatial/temporal disorientation and cognitive dysfunction are among the most prominent long-term sequelae of CI. Cannabidiol (CBD) is a non-psychotomimetic constituent of Cannabis sativa that exerts neuroprotective effects against experimental CI. The present study investigated possible neuroprotective mechanisms of action of CBD on spatial memory impairments that are caused by transient global cerebral ischemia (TGCI) in rats. Hippocampal synaptic plasticity is a fundamental mechanism of learning and memory. Thus, we also evaluated the impact of CBD on neuroplastic changes in the hippocampus after TGCI. Wistar rats were trained to learn an eight-arm aversive radial maze (AvRM) task and underwent either sham or TGCI surgery. The animals received vehicle or 10 mg/kg CBD (i.p.) 30 min before surgery, 3 h after surgery, and then once daily for 14 days. On days 7 and 14, we performed a retention memory test. Another group of rats that received the same pharmacological treatment was tested in the object location test (OLT). Brains were removed and processed to assess neuronal degeneration, synaptic protein levels, and dendritic remodeling in the hippocampus. Cannabidiol treatment attenuated ischemia-induced memory deficits. In rats that were subjected to TGCI, CBD attenuated hippocampal CA1 neurodegeneration and increased brain-derived neurotrophic factor levels. Additionally, CBD protected neurons against the deleterious effects of TGCI on dendritic spine number and the length of dendritic arborization. These results suggest that the neuroprotective effects of CBD against TGCI-induced memory impairments involve changes in synaptic plasticity in the hippocampus.

The gene expression of GPER1 is low in fresh samples of papillary thyroid carcinoma (PTC), and in silico analysis.

Papillary thyroid cancer (PTC), whose incidence has been increasing in the last years, occurs more frequently in women. Experimental studies suggested that estrogen could be an important risk factor for the higher female incidence. In fact, it has been demonstrated that 17ß-estradiol (E2) could increase proliferation and dedifferentiation in thyroid follicular cells. Genomic estrogen responses are typically mediated through classical estrogen receptors, the α and ß isoforms, which have been described in normal and abnormal human thyroid tissue. Nevertheless, effects mediated through G protein estrogen receptor 1 (GPR30/GPER/GPER1), described in some thyroid cancer cell lines, could be partially responsible for the regulation of growth in normal cells. In this study, GPER1 gene and protein expression are described in non-malignant and in papillary thyroid cancer (PTC), as well as its association with clinical features of patients with PTC. The GPER1 expression was lower in PTC as compared to paired non-malignant thyroid tissues in fresh samples of PTC and in silico analysis of GEO and TCGA databases. In PTC cases of TCGA database, low GPER1 mRNA expression was independently associated with metastatic lymph nodes, female gender, and BRAF mutation. Besides, GPER1 mRNA levels were positively correlated with mRNA levels of thyroid differentiation genes. These results support the hypothesis that GPER1 have a role in PTC tumorigenesis and might be a potential target for its therapy. Further studies are needed to determine the functionality of these receptors in normal and diseased thyroid.

Involvement of dopamine D2 and glutamate NMDA receptors in the antidepressant-like effect of amantadine in mice.

The present study investigated the pharmacological mechanisms of the antidepressant-like effects of amantadine in mice and their influence on hippocampal neurogenesis. To improve the translational validity of preclinical results, reproducibility across laboratories and replication in other animal models and species are crucial. Single amantadine administration at doses of 50 and 75 mg/kg resulted in antidepressant-like effects in mice in the tail suspension test (TST), reflected by an increase in immobility time. The effects of amantadine were seen at doses that did not alter locomotor activity. The tyrosine hydroxylase inhibitor α-methyl-ρ-tyrosine did not influence the anti-immobility effect of amantadine in the TST. Pretreatment with the α1 adrenergic receptor antagonist prazosin, ß adrenergic receptor antagonist propranolol, α2 adrenergic receptor antagonist yohimbine, and α2 adrenergic receptor agonist clonidine did not alter the antidepressant-like effect of amantadine. However, amantadine's effect was blocked by the dopamine D2 receptor antagonist haloperidol and glutamate receptor agonist N-methyl-D-aspartate (NMDA). Repeated amantadine administration (50 mg/kg) also exerted an antidepressant-like effect, paralleled by an increase in hippocampal neurogenesis. The present results demonstrate that the antidepressant-like effects of amantadine may be mediated by its actions on D2 and NMDA receptors and likely involve hippocampal neurogenesis.

Differential contribution of CB1, CB2, 5-HT1A, and PPAR-γ receptors to cannabidiol effects on ischemia-induced emotional and cognitive impairments.

An ever-increasing body of preclinical studies has shown the multifaceted neuroprotective profile of cannabidiol (CBD) against impairments caused by cerebral ischemia. In this study, we have explored the neuropharmacological mechanisms of CBD action and its impact on functional recovery using a model of transient global cerebral ischemia in mice. C57BL/6J mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min and received vehicle or CBD (10 mg/Kg) 0.5 hr before and 3, 24, and 48 hr after reperfusion. To investigate the neuropharmacological mechanisms of CBD, the animals were injected with CB1 (AM251, 1 mg/kg), CB2 (AM630, 1 mg/kg), 5-HT1A (WAY-100635, 10 mg/kg), or PPAR-γ (GW9662, 3 mg/kg) receptor antagonists 0.5 hr prior to each injection of CBD. The animals were evaluated using a multi-task testing battery that included the open field, elevated zero maze, Y-maze (YM), and forced swim test. CBD prevented anxiety-like behavior, memory impairments, and despair-like behaviors induced by BCCAO in mice. The anxiolytic-like effects of CBD in BCCAO mice were attenuated by CB1 , CB2 , 5-HT1A , and PPAR-γ receptor antagonists. In the YM, both CBD and the CB1 receptor antagonist AM251 increased the exploration of the novel arm in ischemic animals, indicating beneficial effects of these treatments in the spatial memory performance. Together, these findings indicate the involvement of CB1 , CB2 , 5-HT1A, and PPAR-γ receptors in the functional recovery induced by CBD in BCCAO mice.