Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked disorder arising from mutations in the SLC16A2 gene and resulting from dysfunctional thyroid hormone transport. This disorder is characterized by profound neurodevelopmental delay and motor disability due to a lack of thyroid hormone in the brain, and coexisting endocrinological symptoms, due to chronic thyrotoxicosis, resulting from elevated thyroid hormone outside the central nervous system (CNS). In February 2024, we reviewed the published literature to identify relevant articles reporting on the current unmet needs of patients with MCT8 deficiency. There are several main challenges in the diagnosis and treatment of MCT8 deficiency, with decreased awareness and recognition of MCT8 deficiency among healthcare professionals (HCPs) associated with misdiagnosis and delays in diagnosis. Diagnostic delay may also be attributed to other factors, including the complex symptomology of MCT8 deficiency only becoming apparent several months after birth and pathognomonic serum triiodothyronine (T3) testing not being routinely performed. For patients with MCT8 deficiency, multidisciplinary team care is vital to optimize the support provided to patients and their caregivers. Although there are currently no approved treatments specifically for MCT8 deficiency, earlier identification and diagnosis of this disorder enables earlier access to supportive care and developing treatments focused on improving outcomes and quality of life for both patients and caregivers.

Thyroid hormones (THs) are essential in neuronal and glial cell development and differentiation, synaptogenesis, and myelin sheath formation. In addition to nuclear receptors, TH acts through αvβ3-integrin on the plasma membrane, influencing transcriptional regulation of signaling proteins that, in turn, affect adhesion and survival of nerve cells in various neurologic disorders. TH exhibits protective properties during brain hypoxia; however, precise intracellular mechanisms responsible for the preventive effects of TH remain unclear. In this study, we investigated the impact of TH on integrin αvβ3-dependent downstream systems in normoxic and hypoxic conditions of pheochromocytoma PC12 cells. Our findings reveal that triiodothyronine (T3), acting through αvβ3-integrin, induces activation of the JAK2/STAT5 pathway and suppression of the SHP2 in hypoxic PC12 cells. This activation correlates with the downregulation of the expression palmitoyltransferase-ZDHHC2 and ZDHHC9 genes, leading to a subsequent decrease in palmitoylation and phosphorylation of Fyn tyrosine kinase. We propose that these changes may occur due to STAT5-dependent epigenetic silencing of the palmitoyltransferase gene, which in turn reduces palmitoylation/phosphorylation of Fyn with a subsequent increase in the survival of cells. In summary, our study provides the first evidence demonstrating the involvement of integrin-dependent JAK/STAT pathway, SHP2 suppression, and altered post-translational modification of Fyn in protective effects of T3 during hypoxia.

Obesity and its associated comorbidities place a substantial burden on public health. Given the considerable potential of brown adipose tissue in addressing metabolic disorders that contribute to dysregulation of the body\'s energy balance, this area is an intriguing avenue for research. This study aimed to assess the impact of various polymers, including collagen type I, fibronectin, laminin, gelatin, gellan gum, and poly-l-lysine (PLL), on the in vitro brown adipogenic differentiation of dedifferentiated fat cells within a fibrin gel matrix. The findings, obtained through RT-qPCR, immunofluorescent imaging, ELISA assay, and mitochondria assessment, revealed that PLL exhibited a significant browning-inducing effect. Compared to fibrin-only brown-like drops after two weeks of incubation in brown adipogenic medium, PLL showed 6 (±3) times higher UCP1 gene expression, 5 (±2) times higher UCP1 concentration by ELISA assay, and 2 (±1) times higher mitochondrial content. This effect can be attributed to PLL\'s electrostatic properties, which potentially facilitate the cellular uptake of crucial brown adipogenic inducers such as the thyroid hormone, triiodothyronine (T3), and insulin from the induction medium.

UNASSIGNED: Hypothyroidism is the result of impaired production and secretion of thyroid hormones. The cardiovascular system is affected by fluctuations in thyroid hormone levels. Stressful events or stressors can affect the hypothalamic-pituitary-thyroid (HPT) axis and psychological and physiological responses. Stress increases thyroid hormone levels while decreasing TSH levels, which exacerbates autoimmune thyroid disease.
UNASSIGNED: To evaluate the relationship between stress and primary hypothyroidism.
UNASSIGNED: A total of 77 newly diagnosed hypothyroid patients (TSH >5.0 mIU/L) and 77 healthy adults (TSH 0.5-5.0 mIU/L) were enrolled. During a brief general physical examination, the following values were measured: height, weight, blood pressure, pulse, and pulse rate. A brief systemic examination of the cardiovascular system and lungs was also performed to rule out systemic diseases. Heart rate variability (HRV) processing and analysis were performed using Pro LabChart (PowerLab 8Pro) data analysis software from AD Instrument.
UNASSIGNED: Mean Avg. RR was significantly higher, RM SSD and pRR50 were significantly lower in cases than in controls. Mean HF was significantly lower and LF/HF (frequency range) was significantly higher in cases than in controls. Mean PSS was significantly higher in cases (25.82 ± 2.83) than in controls (22.47 ± 2.10). The majority of cases (54.5%) had a high stress level. The TSH level showed a highly significant correlation with the LF/HF ratio and with the PSS score.
UNASSIGNED: The mean Avg. RR and HF were significantly higher, RM SSD and pRR50 and LF/HF (frequency range) were significantly lower in hypothyroid patients.

UNASSIGNED: Coronavirus diasease 2019 (COVID-19) can cause both pulmonary and systemic inflammation, potentially determining multi-organ dysfunction. The thyroid gland is a neuroendocrine organ that plays an important role in regulating immunity and metabolism. Low serum levels of thyroid hormones are common in critical disease situations. The association between low thyroid hormone levels and mortality in COVID-19 intensive care patients has yet to be studied.
UNASSIGNED: The aim of this study is to compare thyroid hormone levels between patients in the general intensive care unit (ICU) to patients in the COVID-19 ICU.
UNASSIGNED: This was a retrospective comparative study of 210 patients who were hospitalized at Ziv Medical Center in the general ICU and in the COVID-19 ICU. Clinical and demographic data were collected from patient\'s electronic medical records.
UNASSIGNED: Serum thyroid hormone levels of Thyroid Simulating Hormone (TSH), T4, and T3 were significantly lower in COVID-19 intensive care unit patients compared to the patients from the general intensive care unit (p < 0.05). The mortality rate in the COVID-19 ICU (44.4%) was higher compared to that in the general ICU (27.3%) (p < 0.05). No significant statistical difference was observed between the two groups in terms of gender and recorded comorbidities of diabetes mellitus, cerebral vascular accident, kidney disease, and cancer.
UNASSIGNED: Low serum thyroid hormone levels-T3, T4, and TSH-in COVID-19 ICU patients are associated with higher mortality and could possibly be used as a prognostic factor for mortality among COVID-19 ICU patients. Thyroid hormone levels should be a part in the routine evaluation of COVID-19 ICU patients.

OBJECTIVE: To characterize aspects of triiodothyronine (T3) induced chondrocyte terminal maturation within the molecular osteoarthritis pathophysiology using the previously established T3 human ex vivo osteochondral explant model.
METHODS: RNA-sequencing was performed on explant cartilage obtained from OA patients (n = 8), that was cultured ex vivo with or without T3 (10 ng/ml), and main findings were validated using RT-qPCR in an independent sample set (n = 22). Enrichment analysis was used for functional clustering and comparisons with available OA patient RNA-sequencing and GWAS datasets were used to establish relevance for OA pathophysiology by linking to OA patient genomic profiles.
RESULTS: Besides the upregulation of known hypertrophic genes EPAS1 and ANKH, T3 treatment resulted in differential expression of 247 genes with main pathways linked to extracellular matrix and ossification. CCDC80, CDON, ANKH and ATOH8 were among the genes found to consistently mark early, ongoing and terminal maturational OA processes in patients. Furthermore, among the 37 OA risk genes that were significantly affected in cartilage by T3 were COL12A1, TNC, SPARC and PAPPA.
CONCLUSIONS: RNA-sequencing results show that metabolic activation and recuperation of growth plate morphology are induced by T3 in OA chondrocytes, indicating terminal maturation is accelerated. The molecular mechanisms involved in hypertrophy were linked to all stages of OA pathophysiology and will be used to validate disease models for drug testing.

Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes.
We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation.
We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences.
Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3.
This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.

Innate immune cells, including macrophages, are functionally affected by thyroid hormone (TH). Macrophages can undergo phenotypical alterations, shifting between proinflammatory (M1) and immunomodulatory (M2) profiles. Cellular TH concentrations are, among others, determined by TH transporters. To study the effect of TH and TH transporters on macrophage polarization, specific proinflammatory and immunomodulatory markers were analyzed in bone marrow-derived macrophages (BMDMs) depleted of triiodothyronine (T3) and BMDMs with a knockout (KO) of Mct8 and Mct10 and a double KO (dKO) of Mct10/Mct8. Our findings show that T3 is important for M1 polarization, while a lack of T3 stimulates M2 polarization. Mct8 KO BMDMs are unaffected in their T3 responsiveness, but exhibit slight alterations in M2 polarization, while Mct10 KO BMDMs show reduced T3 responsiveness, but unaltered polarization markers. KO of both the Mct8 and Mct10 transporters decreased T3 availability and, contrary to the T3-depleted BMDMs, showed partially increased M1 markers and unaltered M2 markers. These data suggest a role for TH transporters besides transport of TH in BMDMs. This study highlights the complex role of TH transporters in macrophages and provides a new angle on the interaction between the endocrine and immune systems.

The hypothalamic-pituitary-thyroid (HPT) axis is fundamental to human biology, exerting central control over energy expenditure and body temperature. However, the consequences of normal physiologic HPT-axis variation in populations without diagnosed thyroid disease are poorly understood. Using nationally representative data from the 2007 to 2012 National Health and Nutrition Examination Survey, we explore relationships with demographic characteristics, longevity, and socio-economic factors. We find much larger variation across age in free T3 than other HPT-axis hormones. T3 and T4 have opposite relationships to mortality: free T3 is inversely related and free T4 is positively related to the likelihood of death. Free T3 and household income are negatively related, particularly at lower incomes. Finally, free T3 among older adults is associated with labor both in terms of unemployment and hours worked. Physiologic TSH/T4 explain only 1.7% of T3 variation, and neither are appreciably correlated to socio-economic outcomes. Taken together, our data suggest an unappreciated complexity of the HPT-axis signaling cascade broadly such that TSH and T4 may not be accurate surrogates of free T3. Furthermore, we find that subclinical variation in the HPT-axis effector hormone T3 is an important and overlooked factor linking socio-economic forces, human biology, and aging.

Atrial fibrillation (AF) is often accompanied by thyroid disease (THD). This study aimed to explore the relationship between THD and the occurrence of significant clinical outcomes in patients with AF. This post hoc analysis utilized data from the MISOAC-AF trial (NCT02941978), which enrolled hospitalized patients with AF. Patients were categorized based on their THD history into hyperthyroidism, hypothyroidism, or euthyroidism. Cox regression models were employed to calculate unadjusted and adjusted hazard ratios (aHRs). The primary outcomes of interest included all-cause mortality, cardiovascular death, and hospitalizations during the follow-up period. The study included 496 AF patients (mean age 73.09 ± 11.10 years) with available THD data, who were followed-up for a median duration of 31 months. Among them, 16 patients (3.2%) had hyperthyroidism, 141 (28.4%) had hypothyroidism, and 339 (68.4%) had no thyroid disease. Patients with hypothyroidism exhibited higher rates of hospitalization during follow-up (aHR: 1.57, 95% CI 1.12 to 2.20, p = 0.025) compared to the euthyroid group. Elevated levels of thyroid-stimulating hormone (TSH) were correlated with an increased risk of cardiovascular mortality (aHR: 1.03, 95% CI 1.01 to 1.05, p = 0.007) and hospitalizations (aHR: 1.06, 95% CI 1.01 to 1.12, p = 0.03). Conversely, lower levels of triiodothyronine (T3) were associated with higher risks of all-cause mortality (aHR: 0.51, 95% CI 0.31 to 0.82, p = 0.006) and cardiovascular mortality (aHR: 0.42, 95% CI 0.23 to 0.77, p = 0.005). Among patients with AF, hypothyroidism was associated with increased hospitalizations. Furthermore, elevated TSH levels and decreased T3 levels were linked to higher cardiovascular and all-cause mortality risks, respectively.