Aims Recent studies have identified neuroretinal abnormalities in persons affected by diabetes mellitus, before the onset of microvascular alterations. However, the role of glycemic variability (GV) on early retinal neurodegeneration is still not clarified. Methods To explore the relationship between glycemic control and neuroretinal characteristics, 37 persons with Type 1 diabetes mellitus (Type 1 DM) divided into two groups with no signs (noRD) and with mild non-proliferative diabetic retinopathy (NPDR) compared to 13 healthy control participants (C) were recruited. All persons underwent an optical coherence tomography with automatic segmentation of all neuroretinal layers. Measurements of mean of nasal (N)/temporal (T)/superior (S)/inferior (I) macular quadrants for individual layer were also calculated. Metabolic control was evaluated by glycated hemoglobin (HbA1c), and indexes of GV were calculated from continuous glucose monitoring. Results The difference among the three groups in terms of RNFL thickness was significantly dependent on quadrant (F(6;132) = 2.315; p = 0.037). This interaction was due to a specific difference in RNFL-N thickness, where both Type 1 DM groups showed a similar reduction versus C (−3.9 for noDR and −4.9 for NPDR), without any relevant difference between them (−1.0). Inner nuclear layer (INL) was increased in all quadrants in the two Type 1 DM groups compared to C (mean difference = 7.73; 95% CI: 0.32–15.14, p = 0.043; mean difference = 7.74; 95% CI: 0.33–15.15, p = 0.043, respectively). A negative correlation between RNFL-N and low blood glucose index (r = −0.382, p = 0.034) and positive correlation between INL and continuous overall net glycemic action −1, −2, −4 h (r = 0.40, p = 0.025; r = 0.39, p = 0.031; r = 0.41, p = 0.021, respectively) were observed in Type 1 DM patients. The triglycerides were positively and significantly correlated to INL (r = 0.48, p = 0.011), in Type 1 DM subjects. GV and triglycerides resulted both independent predictors of increased INL thickness. No correlation was found with HbA1c. Conclusions Early structural damage of neuroretina in persons with Type 1 DM patients is related to glucose fluctuations. GV should be addressed, even in the presence of a good metabolic control.

Myxedema coma and thyroid storm are among the most common endocrine emergencies presenting to general hospitals. Myxedema coma represents the most extreme, life‑threatening expression of severe hypothyroidism, with patients showing deteriorating mental status, hypothermia, and multiple organ system abnormalities. It typically appears in patients with preexisting hypothyroidism via a common pathway of respiratory decompensation with carbon dioxide narcosis leading to coma. Without early and appropriate therapy, the outcome is often fatal. The diagnosis is based on history and physical findings at presentation and not on any objective thyroid laboratory test. Clinically based scoring systems have been proposed to aid in the diagnosis. While it is a relatively rare syndrome, the typical patient is an elderly woman (thyroid hypofunction being much more common in women) who may or may not have a history of previously diagnosed or treated thyroid dysfunction. Thyrotoxic storm or thyroid crisis is also a rare condition, established on the basis of a clinical diagnosis. The diagnosis is based on the presence of severe hyperthyroidism accompanied by elements of systemic decompensation. Considering that mortality is high without aggressive treatment, therapy must be initiated as early as possible in a critical care setting. The diagnosis cannot be established based on laboratory tests alone, but several scoring systems are available. The usual clinical signs and symptoms of hyperthyroidism are present along with more exaggerated clinical manifestations affecting the cardiovascular, gastrointestinal, and central nervous systems. A multipronged approach has been recommended and has been associated with improved outcomes.

The nuclear-encoded subunit 4 of cytochrome c oxidase (COX4) plays a role in regulation of oxidative phosphorylation and contributes to cancer progression. We sought to determine the role of COX4 in differentiated (DTC) and medullary (MTC) thyroid cancers. We examined the expression of COX4 in human thyroid tumors by immunostaining and used shRNA-mediated knockdown of COX4 to evaluate its functional contributions in thyroid cancer cell lines. In human thyroid tissue, the expression of COX4 was higher in cancers than in either normal thyroid (p = 0.0001) or adenomas (p = 0.001). The level of COX4 expression correlated with tumor size (p = 0.04) and lymph-node metastases (p = 0.024) in patients with MTCs. COX4 silencing had no effects on cell signaling activation and mitochondrial respiration in DTC cell lines (FTC133 and BCPAP). In MTC-derived TT cells, COX4 silencing inhibited p70S6K/pS6 and p-ERK signaling, and was associated with decreased oxygen consumption and ATP production. Treatment with potassium cyanide had minimal effects on FTC133 and BCPAP, but inhibited mitochondrial respiration and induced apoptosis in MTC-derived TT cells. Our data demonstrated that metastatic MTCs are characterized by increased expression of COX4, and MTC-derived TT cells are vulnerable to COX4 silencing. These data suggest that COX4 can be considered as a novel molecular target for the treatment of MTC.

Background: Initiation of thyroid hormone replacement (THR) after a total thyroidectomy has traditionally relied on the weight of the patient, regardless of the patient's body mass index (BMI). Current literature suggests that THR in obese patients differs from nonobese patients. This can lead to overdosing of levothyroxine (LT4) and delay in achievement of euthyroid state. Methods: We retrospectively identified patients on THR after total thyroidectomy with a benign postoperative diagnosis. Patients who achieved euthyroidism with THR were included in the analysis. Patient demographic and THR dosing information was collected. Regression analysis was performed to identify appropriate THR dosing at varying BMIs. This study aimed to evaluate the appropriate dosing of THR in overweight and obese patients. Results: Our cohort consisted of 114 patients achieving euthyroidism while on THR. Mean age was 55 years (range 28–77 years) with 84% females. Of the 114 patients, the number of patients with a BMI less than 25, 25–29, 30–34, 35–39, and greater than 40 were 26 (23%), 33 (29%), 23 (20%), 19 (17%), and 13 (11%), respectively. Of the entire cohort, a mean of 50 weeks elapsed after surgery to achieve euthyroidism, with no significant difference between the BMI categories ( p = 0.58). In obese patients (BMI >30), 35% were overdosed with LT4 on initial dosing. The cohort lost a mean of 3 kg until euthyroidism was achieved, with no significant difference in the weight loss based on BMI category ( p = 0.61). Patients with a higher BMI did require a higher dose (mcg) of LT4 to achieve euthyroidism ( p < 0.01), but the dose was significantly lower in relation to their weight (mcg/kg) ( p < 0.01). The LT4 dose required to achieve euthyroidism based on the previously mentioned BMI categories were 1.76, 1.47, 1.42, 1.27, and 1.28 mcg/kg. Conclusion: The current weight-based dosing of THR inappropriately overdoses overweight and obese patients. A more appropriate formula for THR titration should consider both the weight and BMI of the patient.

We examined the utility of microfluidic digital PCR (dPCR) for detection of BRAF and TERT mutations in thyroid tumors. DNA extracted from 100 thyroid tumors (10 follicular adenomas, 10 follicular cancers, 5 medullary cancers, and 75 papillary thyroid cancer (PTC) were used for detection of BRAF and TERT mutations. Digital PCRs were performed using rare mutation SNP genotyping assays on QuantStudio 3D platform. In PTCs, BRAFV600E was detected by dPCR and Sanger sequencing in 42/75 (56%) and in 37/75 (49%), respectively. BRAFV600E was not detected in other tumors. The ratio of mutant/total BRAF alleles varied from 4.7% to 47.5%. These ratios were higher in classical PTCs (27.1%) as compared to follicular variant PTCs (9.4%) p = 0.001. In PTCs with and without metastases, the ratios of mutant/total BRAF alleles were 27.6% and 18.4%, respectively, (p = 0.03). In metastatic lesions percentages of mutant/total BRAF alleles were similar to those detected in primary tumors. TERTC228T and TERTC250T were found in two and one cases, respectively, and these tumors concomitantly harbored BRAFV600E. These tumors exhibited gross extra-thyroidal extension, metastases to lymph nodes, and pulmonary metastases (one case). Our results showed that dPCR allows quantitative assessment of druggable targets in PTCs and could be helpful in a molecular-based stratification of prognosis in patients with thyroid cancer.

The detection of rare mutational targets in plasma (liquid biopsy) has emerged as a promising tool for the assessment of patients with cancer. We determined the presence of cell-free DNA containing the BRAFV600E mutations (cfBRAFV600E) in plasma samples from 57 patients with papillary thyroid cancer (PTC) with somatic BRAFV600E mutation-positive primary tumors using microfluidic digital PCR, and co-amplification at lower denaturation temperature (COLD) PCR. Mutant cfBRAFV600E alleles were detected in 24/57 (42.1%) of the examined patients. The presence of cfBRAFV600E was significantly associated with tumor size (p = 0.03), multifocal patterns of growth (p = 0.03), the presence of extrathyroidal gross extension (p = 0.02) and the presence of pulmonary micrometastases (p = 0.04). In patients with low-, intermediate- and high-risk PTCs, cfBRAFV600E was detected in 4/19 (21.0%), 8/22 (36.3%) and 12/16 (75.0%) of cases, respectively. Patients with detectable cfBRAFV600E were characterized by a 4.68 times higher likelihood of non-excellent response to therapy, as compared to patients without detectable cfBRAFV600E (OR (odds ratios), 4.68; 95% CI (confidence intervals)) 1.26–17.32; p = 0.02). In summary, the combination of digital polymerase chain reaction (dPCR) with COLD-PCR enables the detection of BRAFV600E in the liquid biopsy from patients with PTCs and could prove useful for the identification of patients with PTC at an increased risk for a structurally or biochemically incomplete or indeterminate response to treatment.