A Case of Nonislet Cell Tumor Hypoglycemia Due to Metastatic Salivary Myoepithelial Carcinoma.

Background/Objective: Nonislet cell tumor hypoglycemia (NICTH) is an uncommon cause of hypoglycemia due to a relative surplus of insulin-like growth factor 2 (IGF-2) or its precursor molecule. The diagnosis is confirmed by an elevated ratio of IGF-2 to insulin-like growth factor 1 (IGF-1). Myoepithelial carcinoma (MECA) is a rare and aggressive salivary gland cancer that has not been previously associated with NICTH. Case Report: A 63-year-old female with a past medical history of metastatic salivary MECA, type 2 diabetes mellitus previously on metformin, hypertension, and hypothyroidism presented to her oncologist for chemotherapy and was found to have a serum glucose of 30 mg/dL (reference: 65-99). She was admitted for further diagnostic work-up which revealed an insulin level of <1 µU/mL (reference: 3-25), C-peptide <0.5 ng/mL (reference: 1.1-4.3), IGF-1 of 15 ng/mL (reference: 41-279), and IGF-2 of 147 ng/mL (reference: 180-580) with an IGF-2:IGF-1 molar ratio of 10, consistent with NICTH. The patient's hypoglycemia unfortunately was quite resistant to treatment, requiring a combination of corticosteroids, continuous dextrose infusion, and somatostatin injections. The patient died 3 weeks after presenting with hypoglycemia. Discussion: Salivary MRCAs commonly contain pleomorphic adenoma gene 1 oncogene rearrangements which are associated with increased IGF-2 production and may predispose patients to hypoglycemia. Conclusion: This case demonstrates that NICTH can be associated with metastatic salivary MECA. The hypoglycemia in this scenario is challenging to manage and is associated with poor prognosis.

Exaggerated Increases in the Serum Cortisol Level in a Woman Following Oral Contraceptive Treatment.

Background/Objective: Extreme hypercortisolemia in an otherwise healthy patient can be due to familial dysalbuminemia, generalized glucocorticoid resistance, and estrogen-containing medications. I report a woman who appeared to have an exaggerated increase in the serum cortisol level following oral contraceptive treatment. Case Report: A 50-year-old woman presented with extreme morning hypercortisolemia-cortisol levels of 61 and 55 mcg/dL (4 and 3 months before presentation, respectively; normal range, 8-25 mcg/dL)-found during workup of mildly increased white cell counts. The morning cortisol level had been 10 mcg/dL after administration of 1-mg dexamethasone. The 24-hour urine free cortisol level had been normal and only slightly increased after correction by creatinine. The patient was anxious about the extremely high cortisol levels but otherwise felt well. She took norgestimate-ethinyl estradiol contraceptive (0.18/0.215/0.25 mg - 35 mcg). Physical examination showed a well-appearing, lean female. The thyroid-stimulating hormone, total thyroxine, free thyroxine, total triiodothyronine, free triiodothyronine, androstenedione, dehydroepiandrosterone sulfate, aldosterone, and renin levels were normal. Morning total cortisol and cortisol-binding globulin (CBG) were tested before and after she held the oral contraceptive for 2 months. The total cortisol and CBG levels decreased from 50 to 26 mcg/dL and from 6.4 to 3.8 mg/dL (normal range, 1.7-3.1 mg/dL), respectively. Discussion: Increases in the serum cortisol-binding proteins are a well-recognized cause for increases in the serum cortisol levels. Conclusion: This case suggests that modern oral contraceptives with low to moderate estrogen activity can cause extreme increases in the serum cortisol levels due to marked increases in the CBG levels.

Plea to radiologists: Please consider Mahvash disease when encountering an enlarged pancreas.

Radiologists play a key role in establishing an early and accurate diagnosis, especially for rare diseases. Mahvash disease (OMIM 619290) is an autosomal recessive hereditary disease caused by inactivating mutations of the glucagon receptor and its main clinical consequences are pancreatic neuroendocrine tumors and in some cases, porto-sinusoidal vascular disease and portal hypertension. Untreated Mahvash disease can be lethal. The diagnosis of Mahvash disease has almost always been delayed in the past due to radiologists' unawareness of or unfamiliarity with the unique imaging features of Mahvash disease which are moderately to enormously enlarge pancreas with preserved pancreas contour and parenchyma without vascular involvement or lymphadenopathy. These features help differentiate Mahvash disease from other etiologies of diffusely enlarged pancreas such as diffuse pancreatic ductal carcinoma, diffuse pancreatic lymphoma, and autoimmune pancreatitis. Invoking Mahvash disease in the differential diagnosis of an enlarged pancreas has recently been shown to facilitate early diagnosis. To prevent missing the diagnosis of this significant disease, I sincerely ask radiologists to consider Mahvash disease in their differential diagnoses of diffusely enlarged pancreas.

Absence of PNET formation and normal longevity in a mouse model of Mahvash disease.

Mahvash disease, a rare autosomal recessive metabolic disorder characterized by biallelic loss-of-function mutations in the glucagon receptor gene (GCGR), induces significant pancreatic hyperglucagonemia, resulting in α-cell hyperplasia and occasional hypoglycemia. Utilizing CRISPR-Cas9 technology, we engineered a mouse model, designated as Gcgr V369M/V369M, harboring a homozygous V369M substitution in the glucagon receptor (GCGR). Although wild-type (WT) and Gcgr V369M/V369M mice exhibited no discernible difference in appearance or weight, adult Gcgr V369M/V369M mice, approximately 12 months of age, displayed a notable decrease in fasting blood glucose levels and elevated the levels of cholesterol and low-density lipoprotein-cholesterol. Moreover, plasma amino acid levels such as alanine (Ala), proline (Pro) and arginine (Arg) were elevated in Gcgr V369M/V369M mice contributing to α-cell proliferation and hyperglucagonemia. Despite sustained α-cell hyperplasia and increased circulating glucagon levels in Gcgr V369M/V369M mice, metabolic disparities between the two groups gradually waned with age accompanied by a reduction in α-cell hyperplasia. Throughout the lifespan of the mice (up to approximately 30 months), pancreatic neuroendocrine tumors (PNETs) did not manifest. This prolonged observation of metabolic alterations in Gcgr V369M/V369M mice furnishes valuable insights for a deeper comprehension of mild Mahvash disease in humans.

Diagnostic challenges from conflicting results of tests and imaging.

Accurate diagnosis is the foundation of clinical care but accurate diagnosis is not easily reached in some cases. In rare instances, even a sophisticated multidisciplinary team at an academic medical center cannot reliably reach an accurate diagnosis after extensive testing and imaging, and has to wait until histological diagnosis or even autopsy results are available. The underlying reason of challenging diagnoses is mostly conflicting data from history, tests, and imaging that point to different diagnoses. In this issue of World Journal of Clinical Cases, Huffaker et al reported such a challenging case of a tricuspid mass in a patient with Li-Fraumeni syndrome. The case by Huffaker et al powerfully illustrates the occasional diagnostic challenges inherent in our current diagnostic approach and the current technology. Clinicians should realize that in rare situations, agnosticism in diagnosis is unavoidable but a treatment has to be initiated so long as the principle of primum non nocere is upheld.

Trifluoroethanol promoted formal nucleophilic substitution of indol-2-yl diaryl methanol for the synthesis of tetraarylmethanes.

The synthesis of tetraarylmethanes has long been a challenge in the field of synthetic chemistry. In this study, a series of tetraarylmethanes were successfully synthesized through the formal nucleophilic substitution reaction of indol-2-yl diaryl methanol catalyzed by Brønsted acid. The key success of this study lies in suppressing the influence of water molecules by forming hydrogen bonds with the TFE solvent. This process leads to the formation of active 2-indole imine methide (2-IIM) intermediates, ensuring the successful synthesis of tetraarylmethanes. Furthermore, some of the products also exhibited potential anticancer activity.

Suicidal incidence and gender-based discrepancies in prolonged grief disorder: insights from a meta-analysis and systematic review.

Background: In the aftermath of bereavement, our research explores the subtleties of Prolonged Grief Disorder (PGD), focusing particularly on its correlation with suicidal behaviors and their variation across genders. This study seeks to elucidate the impact of gender on these behaviors among individuals suffering from PGD, thereby enhancing our understanding and facilitating the development of tailored therapeutic interventions. Methods: By November 24th, 2023, we had rigorously reviewed key databases such as PubMed, Web of Science, Cochrane Library, PsycINFO, and Embase. Independently, two researchers conducted detailed interviews and filled out questionnaires with participants to gather demographic information and record instances of prolonged grief disorder. The study also meticulously tracked occurrences of suicidal ideation, suicide attempts, suicide deaths, and self-injury among the participants. Results: The findings indicate that 22.34% of males reported suicidal ideation (95% CI: 21.33-23.35), a figure that rises to 26.84% among females (95% CI: 25.99-27.69). Notably, 12.11% of males attempted suicide (95% CI: 11.49-12.72), marginally surpassing the 9.60% observed in females (95% CI: 9.17-10.04). More striking disparities were observed in suicide deaths, with rates for males at 3.66% (95% CI: 3.32-4.00) compared to a notably higher 7.12% for females (95% CI: 6.44-7.81). Furthermore, the incidence of self-injury was lower among males, at 2.48% (95% CI: 2.03-2.94), than in females, who reported a rate of 5.09% (95% CI: 4.69-5.49). These patterns underscore the critical need for gender-specific interventions aimed at reducing these significant disparities. Conclusion: This study distinctly underscores the profound impact of gender on the manifestation of suicidal behaviors in individuals afflicted with prolonged grief disorder. It reveals that females are more prone to suicidal ideation, self-injury, and suicide deaths, while males predominantly exhibit a higher incidence of suicide attempts and risk-taking behaviors. These unmediated trends highlight the necessity for gender-specific clinical interventions tailored to address particular behaviors and modify prevalent patterns that typically resist conventional approaches. Systematic review registration: PROSPERO (york.ac.uk), identifier CRD42023480035.

[Types and colors of 1 374 chair-side CAD/CAM all-ceramic restorations].

PURPOSE: To analyse the types of chairside CAD/CAM all-ceramic restorations and the color range of all-ceramic materials used so as to provide reference for the application of clinical chairside all-ceramic restoration and the color selection of all-ceramic materials. METHODS: IPS e.max CAD prostheses and related data were collected from January 2021 to December 2021 from the Department of Prosthodontics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The number and type of restorations and the color of materials were investigated and analyzed by descriptive statistics. RESULTS: A total of 1 374 restorations were included, of which 624 were crown restorations, accounting for 45.41% of the total restorations. 516 cases were veneer, accounting for 37.55%; 219 were inlays, accounting for 15.94%; fixed bridges were all adhesive bridges, with the least number with only 15 cases, accounting for 1.09%. In terms of the selection of restoration materials, the use rate of low-transparent(LT) ceramic blocks was significantly higher than that of other transparent ceramic blocks. A was the most frequently used ceramic color. The most frequently used porcelain blocks for veneers were LTA2 and LTA1; for inlay were LTA3; for crowns were LTA2 and LTA3. The blocks used in the fixed bridges were all LT, and A3 color was the majority. CONCLUSIONS: Chairside CAD/CAM all-ceramic prostheses made of IPS e.max CAD materials have been widely used in clinical practice. The types of prostheses include veneer, inset, crown and fixed bridge. The most commonly used IPS e.max CAD blocks are LTA2, LTA3 and LTA1. These findings have certain guiding significance for the clinical restoration decision and the reserve of porcelain blocks in primary hospitals.

Predicting risk of preterm birth in singleton pregnancies using machine learning algorithms.

We aimed to develop, train, and validate machine learning models for predicting preterm birth (<37 weeks' gestation) in singleton pregnancies at different gestational intervals. Models were developed based on complete data from 22,603 singleton pregnancies from a prospective population-based cohort study that was conducted in 51 midwifery clinics and hospitals in Wenzhou City of China between 2014 and 2016. We applied Catboost, Random Forest, Stacked Model, Deep Neural Networks (DNN), and Support Vector Machine (SVM) algorithms, as well as logistic regression, to conduct feature selection and predictive modeling. Feature selection was implemented based on permutation-based feature importance lists derived from the machine learning models including all features, using a balanced training data set. To develop prediction models, the top 10%, 25%, and 50% most important predictive features were selected. Prediction models were developed with the training data set with 5-fold cross-validation for internal validation. Model performance was assessed using area under the receiver operating curve (AUC) values. The CatBoost-based prediction model after 26 weeks' gestation performed best with an AUC value of 0.70 (0.67, 0.73), accuracy of 0.81, sensitivity of 0.47, and specificity of 0.83. Number of antenatal care visits before 24 weeks' gestation, aspartate aminotransferase level at registration, symphysis fundal height, maternal weight, abdominal circumference, and blood pressure emerged as strong predictors after 26 completed weeks. The application of machine learning on pregnancy surveillance data is a promising approach to predict preterm birth and we identified several modifiable antenatal predictors.

Bone metastasis manifested 52 years after resection of an apparently benign paraganglioma: A case report.

Paraganglioma is derived from the paraganglia tissue in the neck, along the sympathetic trunk, and in the pelvis. Paraganglioma has malignant potential and can metastasize to remote organs such as the liver, lungs, and bones. Most metachronous metastases occur within several years after the initial diagnosis of paraganglioma. Here, we report the case of a 71-year-old male patient who developed bony metastasis 52 years after the resection of a large paraganglioma at the aortic bifurcation. The biopsy-proven paraganglioma metastasis to the lesser trochanter of left femur presented as an avulsion fracture. His normetanephrine level was elevated. DOTATATE PET (positron emission tomography) did not find any other metastatic lesions. The bony metastasis was treated with radiation therapy. We believe that the patient had one of the longest gaps ever reported, 52 years, between the initial diagnosis and metastasis of paraganglioma. This case highlights the importance of long-term surveillance of patients with paraganglioma for metastasis.

Polo-like kinase 4 promotes tumorigenesis and glucose metabolism in glioma by activating AKT1 signaling.

Glioblastoma (GBM) is an extremely aggressive tumor associated with a poor prognosis that impacts the central nervous system. Increasing evidence suggests an inherent association between glucose metabolism dysregulation and the aggression of GBM. Polo-like kinase 4 (PLK4), a highly conserved serine/threonine protein kinase, was found to relate to glioma progression and unfavorable prognosis. As revealed by the integration of proteomics and phosphoproteomics, PLK4 was found to be involved in governing metabolic processes and the PI3K/AKT/mTOR pathway. For the first time, this study supports evidence demonstrating that PLK4 activated PI3K/AKT/mTOR signaling through direct binding to AKT1 and subsequent phosphorylating AKT1 at S124, T308, and S473 to promote tumorigenesis and glucose metabolism in glioma. In addition, PLK4-mediated phosphorylation of AKT1 S124 significantly augmented the phosphorylation of AKT1 S473. Therefore, PLK4 exerted an influence on glucose metabolism by stimulating PI3K/AKT/mTOR signaling. Additionally, the expression of PLK4 protein exhibited a positive correlation with AKT1 phosphorylation in glioma patient tissues. These findings highlight the pivotal role of PLK4-mediated phosphorylation of AKT1 in glioma tumorigenesis and dysregulation of glucose metabolism.

Analysis of full and empty ratio of EV71 virus by using capillary zone electrophoresis.

Hand, foot, and mouth disease is a serious public health problem, and the main pathogen is enterovirus 71 (EV71). Its capsid assembly mechanism including capsid protein processing has been widely studied. Full and empty capsids have different immunological efficacy. Therefore, tracking full/empty capsid ratio throughout the EV71 production process is important to ensure consistent product quality and proper dosing response. The analysis of full/empty capsid ratio of intact virus has been widely reported as well. A variety of techniques have been employed to evaluate the full/empty capsid ratios. However, there has not been a rapid, reproducible, and robust assay to determine the full/empty capsid ratios of final and in-process products. In this study, a novel assay based on capillary zone electrophoresis was established. The separation of full and empty species could be achieved within 10 min and the ratio of peak areas was used to calculate the full/empty capsid ratio directly. The results showed good reproducibility and linearity for the determination of full/empty capsid ratios.

Artri King-induced Hypothalamic-pituitary-adrenal Axis Disruption: A Report of 3 Cases.

We present a case series of 3 patients who developed iatrogenic hypothalamic-pituitary-adrenal axis disruption while taking Artri King, an over-the-counter supplement marketed for joint pain that is reported to contain dexamethasone not listed on the supplement's label. Patient 1, a 58-year-old woman, presented with persistent hyponatremia, weight gain, proximal muscle weakness, dorsocervical fat pad, and new, red striae on her breast and abdomen in the setting of Artri King use. Her dexamethasone level was elevated (Table 1), confirming the suspicion of dexamethasone content in this supplement. Patient 2, a 55-year old woman, had presented with cushingoid features and a low morning cortisol level (Table 1) in the setting of Artri King use. Patient 3, a 59-year-old man, presented with poorly controlled diabetes in the setting of Artri King use and an elevated serum dexamethasone level. Supplements containing hidden glucocorticoids can cause not only iatrogenic Cushing syndrome, but also adrenal suppression, providing a diagnostic challenge for providers.

Sellar Mass in 2 Patients With Acute-Onset Headache and Visual Symptoms: Not Your Usual Pituitary Adenoma.

Background/Objective: Clinical diagnosis of rare aggressive sellar malignancies requires a high index of suspicion. The objective was to report 2 patients with primary sellar atypical teratoid (AT)/rhabdoid tumor (RT) who presented with acute-onset headache and visual symptoms. Case Report: Patient 1 was a 45-year-old woman who presented with 3 weeks of headache and 1 week of eye pain and diplopia. Magnetic resonance imaging (MRI) identified a 2.2-cm sellar mass. Pituitary hormone testing showed elevated prolactin and suppressed luteinizing hormone, follicle-stimulating hormone, and estradiol levels. Patient 2 was a 32-year-old woman who presented with 1 month of headache and 1 week of diplopia. MRI showed a 2.1-cm sellar mass. Hormonal test results were reportedly unremarkable. Both patients did not have a significant medical history. They each underwent transsphenoidal resection. Surgical histology and molecular studies were consistent with primary sellar AT/RT. After surgery, patient 1 developed bilateral blindness and was lost to follow-up. Patient 2 developed hypopituitarism; her visual symptoms improved temporarily but recurred 2 weeks later. Pituitary MRI showed sellar recurrence. She underwent further debulking, but the tumor recurred promptly again. Despite radiation therapy, she died 4 months after the original presentation. Discussion: AT/RT appears to be the most aggressive sellar malignancy. Conclusion: Based on the 2 cases presented and the literature, I conclude that rapidly progressive headache with subsequent visual impairment in women with large sellar masses is almost pathognomonic of sellar AT/RT.

Clinical Progression of a Paraganglioma Over Many Years in a Man With Congenital Heart Disease.

Background: Documented symptomatic progression of a paraganglioma (PGL) over many years is unusual. Our objective is to report a young man with such an occurrence. Case Report: A 27-year-old male presented with headache, sweating, and palpitation. He had a history of cyanotic congenital heart disease. Five years before presentation, he had 24-hour urine metanephrines 43 mcg/d (25-222), vanillylmandelic acid 3 mg/d (<6), and homovanillic acid 2.4 mg/d (1.6-7.5) levels and a 3.13 cm mass in the upper aortocaval space. Subsequent imaging showed slow growth of the mass. On admission, his blood pressure was 197/134 mm Hg, heart rate was 163 beats per minute, respiratory rate was 25 per minute, and oxygen saturation was 76% on room air. His 24-hour urine normetanephrine level was 2644 mcg/d (81-667) while metanephrine was 405 mcg/d (55-320). Plasma free metanephrine level was 0.92 nmol/L (0-0.49) and normetanephrine was 11.85 nmol/L (0-0.89). DOTATATE positron emission tomography-computed tomography revealed a 4.3 × 3.1 × 4.9 cm mass with activity in the right upper aortocaval space. He was treated with Prazosin. Two months later, he underwent resection of the mass. Pathology diagnosed a 4.9 cm PGL. He had improvement in metanephrine levels. Discussion: PGL is diagnosed by documenting excess catecholamines and identifying a lesion on imaging. False negative laboratory testing is rare but can occur. Patients with cyanotic congenital heart disease have a greater risk of developing PGL. Conclusion: It is crucial to evaluate a patient for PGL if clinical conditions suggest catecholamine excess, especially if a retroperitoneal tumor has grown or the patient has risk factors.

Liver Transplantation in a Woman with Mahvash Disease.

Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.

Metal-Free C(sp3)-H Bond Arylation of 3-Methylindole Derivatives via 3-Indole Imine Methides.

Direct arylation of the benzylic C(sp3)-H bond is one of the most straightforward strategies for the construction of multi-aryl methanes, owing to the extraordinary step and atom economy. In this paper, we developed the first metal-free arylation of the C(sp3)-H bond in 3-methylindoles, thereby providing rapid access to a range of diaryl- and triarylmethanes with two indole rings. Mechanistically, 3-indole imine methide serves as the key intermediate. Water plays a crucial role in this process, likely serving as a proton shuttle to facilitate the key 1,3-proton transfer step in this reaction and, thus, enhance the reaction efficiency.

Single-Cell RNA-Sequencing Provides Insight into Skeletal Muscle Evolution during the Selection of Muscle Characteristics.

Skeletal muscle comprises a large, heterogeneous assortment of cell populations that interact to maintain muscle homeostasis, but little is known about the mechanism that controls myogenic development in response to artificial selection. Different pig (Sus scrofa) breeds exhibit distinct muscle phenotypes resulting from domestication and selective breeding. Using unbiased single-cell transcriptomic sequencing analysis (scRNA-seq), the impact of artificial selection on cell profiles is investigated in neonatal skeletal muscle of pigs. This work provides panoramic muscle-resident cell profiles and identifies novel and breed-specific cells, mapping them on pseudotime trajectories. Artificial selection has elicited significant changes in muscle-resident cell profiles, while conserving signs of generational environmental challenges. These results suggest that fibro-adipogenic progenitors serve as a cellular interaction hub and that specific transcription factors identified here may serve as candidate target regulons for the pursuit of a specific muscle phenotype. Furthermore, a cross-species comparison of humans, mice, and pigs illustrates the conservation and divergence of mammalian muscle ontology. The findings of this study reveal shifts in cellular heterogeneity, novel cell subpopulations, and their interactions that may greatly facilitate the understanding of the mechanism underlying divergent muscle phenotypes arising from artificial selection.

Solid pseudopapillary neoplasm: Report of a case of primary ovarian origin and review of the literature.

Background: Solid pseudopapillary neoplasms (SPNs) are uncommon tumors of low malignancy with a generally favorable prognosis, mostly originating from the pancreas. To date, 12 cases of SPNs with a primary ovarian origin (SPN-Os) have been reported globally, and their detailed characteristics have not been fully elucidated. Case description: We reported the 13th SPN-O case, which occurred in a 52-year-old woman with an 18.5 cm left ovarian mass. Four imaging methods, including ultrasound, computed tomography, magnetic resonance imaging and positron emission tomography, were utilized before surgery. An elevated level of serum cancer antigen 125 was detected and a total hysterectomy plus bilateral salpingo-oophorectomy was performed. Microscopic examination revealed a typical solid pseudopapillary structure. The tumor cells were stained focally for pan-cytokeratin, synaptophysin, CD99 and CD10, while ß-catenin, vimentin and CD56 were diffusely expressed. The Ki-67 proliferation index was 3%, and immunohistochemical (IHC) staining for chromogranin-A, inhibin-a, and E-cadherin was negative. No evidence of recurrence or metastasis was observed by clinical and imaging data during a 5-month postoperative follow-up. Conclusion: This is a report of an unusual case of a primary ovarian SPN with an up-to-date review of SPN-Os. A minimum combination of imaging methods and IHC stains was proposed for SPN-Os, which may prove beneficial in clinical practice.