Estrogen receptor α (ERα) regulates several physiological functions. In pathophysiological conditions, ERα is involved in the development and progression of estrogen-sensitive tumors. The ERα gene contains multiple 5′-untranslated exons and eight conventional coding exons and presents multiple isoforms generated by alternative promoter usage and alternative splicing. This gene also possesses non-conventional exons in the 3′- and intronic regions, and alternative use of cryptic exons contributes to further diversity of ERα mRNAs and proteins. Recently, the genomic organization of ERα genes and the splicing profiles of their transcripts were comparatively analyzed in humans, mice, and rats, and multiple ERα isoforms with distinct structures and functions were identified. These transcripts contain cryptic sequences that encode insertion-containing or truncated ERα proteins. In particular, alternative cryptic exons with in-frame stop codons yield transcripts encoding C-terminally-truncated ERα proteins. The C-terminally-truncated ERα isoforms lack part or all of the ligand-binding domain but possess an isoform-specific sequence. Some of these isoforms exhibit constitutive transactivation and resistance to estrogen receptor antagonists. Although numerous studies have reported conflicting results regarding their functions, the critical determinant for their gain-of-function has been identified structurally. Here we review recent progress in ERα variant research concerning the genomic organization of ERα genes, splicing profiles of ERα transcripts, and transactivation properties of ERα isoforms.

Background: We investigated the effect of subclinical hyperthyroidism and subclinical hypothyroidism on cognitive function in rats and the role of autophagy in this process. Methods: Forty Wistar rats were randomized into normal control (NC), hyperthyroidism (Hyper), hypothyroidism (Hypo), subclinical hyperthyroidism (sHyper), and subclinical hypothyroidism (sHypo) groups. Cognitive function (spatial learning and memory) was tested by the Morris water maze test. Hippocampal histopathology was analyzed by H&E staining, and expression levels of caspase-3 in hippocampal CA1 neurons were measured. In addition, immunoblot analysis was performed to detect hippocampal autophagy-related proteins. Results: Escape latency from day 1 to day 4 was significantly longer in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). In addition, the number of rats crossing the virtual platform was significantly lower in the Hypo, Hyper, and sHyper groups than in the NC group (P < 0.01). Compared with the NC group, all four groups had significantly lower residence time in the target quadrant (P < 0.05). Beclin-1 and LC3-II protein expression in hippocampal tissues was significantly higher in the Hyper and sHyper groups than in the NC group (P < 0.01). Beclin-1 and LC3-II protein expression in hippocampal tissues did not significantly differ between the sHypo group and NC group (P > 0.05). Conclusions: Subclinical thyroid dysfunction in rats might lead to cognitive impairment. Subclinical hyperthyroidism might be associated with excessive activation of autophagy and hippocampal neuron damage and necrosis.

Background: No compatibility tests are available for remdesivir other than 0.9% sodium chloride. In this study, we aimed to evaluate the physical compatibility of remdesivir with drugs used in palliative care and COVID-19 treatment. Methods: Remdesivir was tested for compatibility with 10 different drugs (fentanyl, morphine, hydromorphone, oxycodone, heparin, furosemide, octreotide, acetated Ringer's injection, 2-in-1 peripheral parenteral nutrition, and 2-in-1 total parenteral nutrition). Remdesivir was formulated to a final concentration of 1 mg/mL, and the other drugs were prepared at clinical concentrations. Three test solutions were used for compatibility testing, with remdesivir and the target drugs compounded in a 1:1 ratio. Appearance measurements, including Tyndall effect, turbidity, and pH, were performed immediately after mixing and at 1 h and 4 h after mixing. Changes in appearance, including the Tyndall effect, turbidity (turbidity change of ≥ 0.5 nephelometric turbidity unit [NTU] based on control solution for each test drug), and pH (a change of ≥ 10% based on the pH immediately after mixing) were used to determine physical compatibility. Results: All the drugs tested were compatible with remdesivir. The combination of remdesivir and furosemide produced the highest turbidity (0.23 ± 0.03 NTU) 1 h after mixing. The lowest and highest pH values were observed at 4 h after mixing for the combinations of remdesivir and morphine (3.23 ± 0.02) and remdesivir and furosemide (8.81 ± 0.06). Conclusions: The drugs tested in this study show Y-site physical compatibility with remdesivir.

Background: The preconditioning effects of dexmedetomidine and propofol on septic acute kidney injury (AKI) have been reported, but the postconditioning effects remain unknown. This study investigated the postconditioning effects of dexmedetomidine, midazolam, and propofol on septic AKI. Methods: Forty-eight male Wistar rats were intraperitoneally administered lipopolysaccharide (LPS; 8.3 mg kg^-1) or normal saline. Twenty-four hours later, rats were allocated to specific anesthetic groups (n=6 each) and exposed for 6 h, as follows: C, control (no anesthetic); D, dexmedetomidine (5 μg kg^-1 h^-1); M, midazolam (0.6 mg kg^-1 h^-1); or P, propofol (10 mg kg^-1 h^-1). Serum creatinine (Cr) and cystatin C (CysC) were measured at the end of anesthesia. Western blot and immunofluorescent analyses of kidney samples were performed. Results: Among LPS-treated groups, D group showed worsened renal dysfunction (L-C vs L-D: Cr, P=0.002, effect size (η²) =0.83; CysC, P=0.004, η²=0.71), whereas M group showed improved renal function (L-C vs L-M: Cr, P=0.009, η²=0.55). In immunofluorescent analysis of renal tubules, D group showed increased expression of nuclear factor κB (NFκΒ) (L-C vs L-D: NFκΒ, P=0.002, η²=0.75; phospho-NFκΒ, P=0.018, η²=0.66) and inhibitor of κ light polypeptide gene enhancer in B-cell kinase β (IKKβ) (L-C vs L-D: IKKβ, P=0.002, η²=0.59; phospho-IKKα/β, P=0.004, η²=0.59), whereas M group showed decreased NFκB expression (L-C vs L-M: NFκB, P=0.003, η²=0.55; phospho-NFκB, P=0.013, η²=0.46). Conclusions: Dexmedetomidine administration might worsen septic AKI, while midazolam might preserve kidney function via the NFκΒ pathway.

A metastatic thyroid tumor (MTT) arising from breast carcinoma (BC) is rare and sometimes difficult to diagnose. We present a case of MTT from BC; we suspected anaplastic thyroid carcinoma at initial presentation. The patient was a 58-year-old female with a hard nodule in the right anterior neck and a history of breast cancer. Computed tomography indicated tumors on both thyroid lobes, and ultrasonography (US) with shear wave measurement (SWM) showed malignant features. We performed fine needle aspiration cytology (FNAC), the results of which led us to strongly suspect MTT from BC. The surgically resected specimen was evaluated histopathologically, including by immunohistochemistry (IHC), and the diagnosis was confirmed. In addition to FNAC and IHC, SWM is useful to diagnose MTT from BC.

Nitrous oxide (N₂O) is readily available, and its abuse for recreational purposes has become a social problem. In Japan, where N₂O is strictly prohibited for non-medical use, abuse is often overlooked due to a lack of experience in the field. N₂O abuse causes various long-term symptoms, including vitamin B₁₂ deficiency, myelopathy, myeloneuropathy, subacute combined degeneration, mood changes, and psychosis. The diagnosis of N₂O abuse is difficult due to the compound's short half-life and rapid elimination through the lungs. This report describes a case of fever and impaired consciousness in a patient with a history of N₂O abuse.

Downhill varices are usually caused by superior vena cava (SVC) obstruction due to bronchogenic carcinoma or mediastinal tumors. These structures exhibit retrograde blood flow and are located in the proximal esophagus. Varices in the hypopharynx resulting from mediastinal thyroid tumor are extremely rare. A 70-year-old man with a 35-year history of a growing thyroid tumor on the right side of his neck visited a local hospital. Fine-needle aspiration cytology of the tumor revealed benign goiter. Contrast-enhanced computed tomography showed a huge tumor (13 × 10 × 5 cm) in the right to left lobe of the thyroid that extended into the mediastinum. A well-enhanced mass mimicking hypopharyngeal cancer was identified in the hypopharynx. Endoscopic examination showed varices in the postcricoid region, so biopsy was contraindicated. The preoperative diagnosis was adenomatous goiter and hypopharyngeal varices caused by obstruction of the internal jugular and brachiocephalic vein by the goiter. Total thyroidectomy was performed and the hypopharyngeal varices had disappeared by the next day. The histopathological diagnosis of the thyroid tumor was poorly differentiated carcinoma. Mediastinal thyroid tumor rarely causes downhill varices due to SVC obstruction. However, signs of SVC obstruction were absent in this case, and varices were present in the hypopharynx, not in the upper esophagus. Obstructed venous flow from the thyroid plexus might circulate via the superior laryngeal vein and cause varices in the postcricoid region. When a patient with a large mediastinal tumor has a tumor-like lesion in the hypopharynx, downhill varices should be considered before scheduling a biopsy.

Background: Rehabilitation therapy for patients with severe coronavirus disease 2019 (COVID-19) is crucial; however, studies regarding rehabilitation strategies for intensive care unit (ICU) patients with COVID-19 are limited. We report a case of severe COVID-19 in an ICU patient whose physical function and basic movement ability rapidly improved after the initiation of active aerobic exercise in the supine position. Case: A 70-year-old man with hypertension and obesity was admitted to the ICU and managed with a ventilator because of severe COVID-19. Physical therapy started on postadmission day 34. Problems encountered during physical therapy included low saturation of percutaneous oxygen (SpO₂; <90%), dyspnea with a light exercise load, advancing muscle weakness, and endurance decline. The rehabilitation program included getting out of bed and resistance training of the upper and lower limbs twice daily while maintaining SpO₂ at ≥90%. After ventilator weaning, we initiated aerobic training using a supine ergometer with varying load volume. On discharge from the ICU on postadmission day 45, the patient's physical function (handgrip strength, Medical Research Council score, and Borg scale) and basic movement ability (Functional Status Score for ICU) rapidly improved. Conclusion: Rehabilitation therapy involving aerobic cycling training based on a quantitative load setting may be effective in treating COVID-19.

Trisomy 21 (Down syndrome) is sometimes complicated by congenital heart disease; however, comorbid type I diabetes mellitus and diseases involving autoantibodies, such as Hashimoto disease and Graves disease, are not uncommon. Autoinflammatory diseases such as Kawasaki disease and systemic juvenile idiopathic arthritis are rare. We report a rare case of trisomy 21 with systemic juvenile idiopathic arthritis that responded well to the initial course of methylprednisolone pulse therapy but flared up and was complicated by macrophage activation syndrome (MAS). Subsequent methylprednisolone pulse therapy and cyclosporine resolved this condition. Cytokines were analyzed at several time points during the clinical course and revealed that interleukin-18, interleukin-6, and chemokine ligand 9 levels were elevated at MAS onset in the present patient, even though clinical symptoms had abated. Thus, early analysis of cytokine profiles should be performed to assess MAS risk and determine treatment intensity, even in T21 patients.