A 48-Year-Old Man With a Hip Fracture and Skin Rash: A Case Report.

Background/Objective: Patients with systemic mastocytosis are at high risk of developing osteoporosis and fractures. Herein, we report a case of hip fragility fracture in a patient with indolent systemic mastocytosis and normal bone density. Case Report: A 48-year-old man experienced a left femoral neck fracture after a fall. After a dose of oxycodone/hydromorphone postoperatively, he developed an anaphylactic reaction. Previously, he experienced a few other episodes of flushing, dizziness, and syncope precipitated by stress and alcohol. His examination was notable for pink and brown macules on his chest, back, arms, and legs. His laboratory test revealed a markedly elevated tryptase level of 171 ng/mL (<11 ng/mL). Treatment including cetirizine, montelukast, and ranitidine controlled his symptoms. His bone density test result was normal. Ten months after hip surgery, his c-terminal telopeptide of collagen type 1 and bone-specific alkaline phosphatase levels significantly increased. The bone scan demonstrated diffusely increased radiotracer uptake throughout the osseous structures. Given high bone turnover and the prior hip fracture, he received zoledronic acid yearly for 3 years, and no further fractures have occurred. Discussion: The case is unusual as the fracture occurred despite normal bone density and significant osteosclerosis, which was previously considered protective against fractures. Additionally, rather than the spine, the fracture occurred in the hip, which is an uncommon site for mastocytosis-induced fractures. Conclusion: Mastocytosis is a rare cause of osteoporosis, and it is important to keep this condition in the differential diagnosis of osteoporosis, particularly when the fracture presentation is atypical.

Uveal Melanoma Metastasis to the Thyroid.

Background: Around 1.2 to 3.1% of thyroid malignancies are due to metastasis. Among them, cutaneous malignant melanomas constitute 4% of malignancy metastasized to the thyroid. Uveal melanoma is uncommon, and its metastasis to the thyroid has only rarely been reported. Hereby, we describe an unusual case of uveal melanoma metastasized to the thyroid and discuss the concept of correct diagnosis. Case Report. During a routine ophthalmological examination, an 86-year-old Caucasian female was found to have retinal detachment secondary to choroidal melanoma. She was treated with gamma knife which resulted in reduction of tumor size. Three months later, she was noted to have a goiter on physical examination. Follow-up thyroid ultrasonography demonstrated numerous vascularized nodules in both lobes. The fine needle aspiration (FNA) of the left dominant nodule was indeterminate the first time and nondiagnostic the second time. FNA of the right dominant nodule was nondiagnostic twice but showed malignant cells the third time. Subsequent immunohistochemistry staining of the FNA sample from the right thyroid nodule confirmed a profile consistent with malignant melanoma. Conclusion: It should be kept in mind that a thyroid nodule detected in a patient with a diagnosis of uveal melanoma can be metastasis and that uveal melanoma diagnosis should be taken into account for the examination of the thyroid tumors of these patients. It is important to employ immunohistochemical staining FNA examination of the patient with such tumors for markers associated with a patient's known malignancy to facilitate diagnosis.

Vanishing Adrenal Glands: Bilateral Adrenal Hemorrhage With Adrenal Insufficiency in COVID-19 Infection.

Coronavirus disease 2019 (COVID-19) has been associated with thrombotic and endocrine complications, including adrenal insufficiency in the setting of adrenal hemorrhage. We present a patient diagnosed with antiphospholipid syndrome (APLS) in the setting of COVID-19 infection resulting in bilateral adrenal hemorrhage, subsequently leading to adrenal insufficiency. Acute adrenal hemorrhage is an underrecognized cause of decompensation, multisystem failure, and death in severe illness. Reports of adrenal insufficiency in the setting of COVID-19 infection revealed microscopic infarction, which can increase the risk of hemorrhage. Other mechanisms include severe hyperinflammatory response and cytokine storm leading to endothelial dysfunction, vascular injury, adrenal parenchymal damage, and hemorrhage. COVID-19 infection can be associated with coagulopathy and thromboembolic events and can lead to adrenal hemorrhage. Adrenal insufficiency is life-threatening and needs to be recognized promptly. There can be a latent phase between hemorrhagic events and adrenal failure; hence, close monitoring and timely intervention are important.

Enhancing Patient Literacy on Calcium Supplementation: A Quality Improvement Initiative.

OBJECTIVE: This study aims to assess patients' knowledge and identify barriers in interpreting calcium on supplement and nutrition labels and to determine whether education would be beneficial. METHODS: Patients with conditions requiring calcium supplementation were included in this study. Participants were first given a 9-question pre-education survey. They were then taught how to read calcium on labels using the educational cards developed. This was followed by a 7-question posteducation survey. Endocrinologists were surveyed to assess their experience in treating patients who required calcium supplementation. RESULTS: Before education, 31 (33%) and 37 (40%) of the participants felt that the supplement and nutrition labels, respectively, were confusing. After education, only 2 (2%) and 6 (6%) of the participants, respectively, still felt the same. There was a significant improvement in the interpretation of calcium citrate (Citracal) and calcium carbonate (TUMS) labels, with a trend of improvement in reading a milk label. Of the 47 endocrinologists surveyed, only 5 (11%) felt that their patients often or always knew the correct amount of calcium to be taken. Two-thirds 30 (64%) of the endocrinologists always or often explained to their patients how to interpret calcium labels. About half 23 (49%) of the endocrinologists always or often needed to take time to look up the calcium content of supplements. For most endocrinologists 29 (62%), this took at least 2 to 4 minutes. CONCLUSION: Our patients had trouble interpreting calcium labels, and the use of educational cards was effective in improving calcium literacy.

Monitoring Endocrine Complications of Immunotherapy: A Screening Tool.

Introduction The advent of immunotherapy has revolutionized cancer therapy in recent years. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T-lymphocyte antigen 4 (CTLA)-4, has become a cornerstone in cancer therapy. However, due to the physiologic role of checkpoint molecules in preventing autoimmunity, immune-related adverse events (irAEs) have emerged as frequent complications. As the use of immunotherapy increases, a better understanding of irAEs and screening tools for timely diagnosis and management are needed. Materials and methods We surveyed oncology providers at our institution with 10 questions assessing their knowledge, and comfort levels in diagnosing and managing endocrine irAEs. We created an endocrine clinic referral order specifically for oncology-related endocrinopathies and created a screening tool for diagnosing these endocrinopathies. We met with our oncology providers in three different hour-long sessions. A post-intervention survey was sent out six months after our initial meeting to assess changes in the participants' knowledge and comfort levels. We also reviewed the electronic medical records system for the number of new referrals to endocrinology clinic. Results A total of 27 (N) participants responded to the initial survey and 14 (n) responded to the subsequent survey six months later. Based on the initial survey, only a minority (26%) of respondents were comfortable diagnosing and managing (15%) immunotherapy-related adrenal dysfunction whereas more respondents were comfortable diagnosing (55%) and managing (56%) thyroid dysfunction. The majority (67%) of the respondents knew which immunotherapies commonly are implicated in hypophysitis but only 42% of them were aware of the next steps of its management. We noted a significant increase in self-reported comfort levels in diagnosing (p < 0.05) and managing (p < 0.05) adrenal disorders post-intervention. There was also a trend of improvement in participants' comfort levels regarding diagnosing and managing thyroid dysfunction, management of hypophysitis, and immunotherapies implicated in thyroid dysfunction but the changes did not reach statistical significance. There was no significant change in their knowledge regarding immunotherapies implicated in hypophysitis and natural history of thyroid dysfunction in this setting. In the six months following our intervention, 30% (n=21) of the patients referred to the endocrine clinic were for immune-related endocrinopathies compared to 19% (n=7) of patients over a similar duration before the intervention. Data on the time between referral and endocrinology appointment was available for 16 out of the 21 patients and the mean (±SD) time to endocrine clinic appointment was 2.66 (±1.95) weeks. Nine (43%) of the 21 referred patients were seen in endocrinology clinic within two weeks. Conclusions Although immune-related endocrinopathies are rarely fatal, they have a significant impact on patients' quality of life. Endocrinopathies are typically manageable with prompt recognition and treatment. But the subtle and non-specific manifestations make the diagnostic process a challenge. Standardized and practical screening tools can help in diagnosing these adverse events promptly, seeking specialized care if needed and may also aid in reducing healthcare-related costs.

Two cases of malignant struma ovarii with metastasis to pelvic bone.

Histologically, malignant struma ovarii metastasizes rarely, and only a few cases reported bone metastasis. Here, we describe 2 cases of biologically malignant struma ovarii with pelvic bone metastasis. Case 1 is a 22-year-old female who was found to have a large left ovarian mass during routine prenatal ultrasound. Papillary thyroid cancer arising in struma ovarii was identified after laparoscopic salpingo-oophorectomy. After total thyroidectomy, radioactive iodine whole-body scan revealed extrathyroidal iodine uptake in left anterior pelvis. Subsequent I-131 treatment resolved the pelvic metastasis. Case 2 is a 49-year-old female who was diagnosed with malignant struma ovarii in 1996 and presented in 2007 with pelvic recurrence and extensive left hip metastasis. Treatment with resection of the pelvic tumor, total thyroidectomy, and multiple I-131 ablation led to eventual resolution of the abdominal and left hip foci. In conclusion, we present 2 rare cases of malignant struma ovarii, both with metastasis to the pelvic bone. This report makes pelvic bone the most frequent site for bone metastasis in malignant struma ovarii. It also emphasizes the importance of total thyroidectomy in allowing identification and treatment of bony metastasis with radioactive iodine.

Safety of vitamin D replacement in patients with primary hyperparathyroidism and concomitant vitamin D deficiency.

OBJECTIVE: To evaluate the safety of vitamin D replacement in patients with vitamin D deficiency and primary hyperparathyroidism. METHODS: Retrospective chart review of 35 patients from our endocrine clinic, age 22 to 89 years, diagnosed with primary hyperparathyroidism and vitamin D deficiency, and treated with either 1,000 to 2,000 international units (IU) of vitamin D daily or 50,000 IU of vitamin D weekly for 5 months. Data were collected before and after treatment on serum calcium, 25-hydroxyvitamin D (25-OH D), intact parathyroid hormone (iPTH), phosphorus, alkaline phosphatase, nephrolithiasis, fractures, and osteoporosis. RESULTS: 25-OH D increased significantly, from a baseline of 14.65 ± 6.57 ng/mL to 42.17 ± 12.98 ng/mL after weekly treatment with 50,000 IU of vitamin D (P<.0001), and from 22.42 ± 5.47 ng/mL to 33.33 ± 6.39 ng/mL following daily treatment with 1,000 to 2,000 IU of vitamin D (P<.0001). Pre- and posttreatment unadjusted serum calcium remained stable in the high-dose group (10.80 ± 0.43 mg/dL vs. 10.72 ± 0.67 mg/dL; P = .47), but decreased slightly in the low-dose group (10.76 ± 0.58 mg/dL vs. 10.11 ± 0.54 mg/dL; P = .0007). After adjusting for age, sex, vitamin D, and PTH levels, the small calcium difference in the low-dose group became statistically insignificant. Treatment with either high or low doses of vitamin D did not significantly change iPTH levels. Creatinine remained stable in all patients, and no new cases of nephrolithiasis were reported. CONCLUSION: Replacing vitamin D in mild primary hyperparathyroidism is safe, effective, and does not increase calcium to dangerous levels.

Pheochromocytoma presenting with arterial and intracardiac thrombus in a 47-year-old woman: a case report.

INTRODUCTION: Pheochromocytoma is a rare cause of hypertension but it could have severe consequences if not recognized and treated appropriately. The association of pheochromocytoma and thrombosis is even rarer but significantly increases management complexity, morbidity and mortality. To the best of our knowledge, this is the first report of a patient with pheochromocytoma presenting with left axillary arterial and intracardiac thrombus. CASE PRESENTATION: A 47-year-old Caucasian woman with a past medical history of hypertension presented for medical attention with left arm numbness. Doppler ultrasound showed an obstructing thrombus in her left axillary artery. She had symptom resolution after stent placement in her left axillary artery. A subsequent echocardiogram demonstrated a large intracardiac mass and abdominal computed tomography revealed a 7 cm mass between her spleen and left kidney. Labile blood pressure was noted during admission and she had very high levels of plasma and 24-hour urine catecholamines and metanephrines tests. A (123)I- metaiodobenzylguanidine scan showed intense uptake in the left abdominal mass. After adequate alpha blockage with phenoxybenzamine, laparoscopic tumor resection was performed without complications. She had normal metanephrines and complete symptom resolution afterwards. The intracardiac mass also disappeared with anticoagulation. All other endocrine laboratory abnormalities returned to normal after surgery. CONCLUSION: Arterial and ventricular thrombosis occurring in patients with pheochromocytoma is rare. A multi-disciplinary approach is necessary in caring for this type of patient. Catecholamines likely contributed to the development of thrombosis in our patient. Early recognition of pheochromocytoma is the key to improving outcome.

A novel missense mutation in the MEN1 gene in a patient with multiple endocrine neoplasia type 1.

OBJECTIVE: To describe a novel germline missense mutation in exon 2 of the MEN1 gene identified in a man with multiple endocrine neoplasia type 1 (MEN 1). METHODS: We describe the patient's clinical, laboratory, and genetic data, and we review the relevant literature. RESULTS: A 41-year-old man with a history of primary hyperparathyroidism and left lower parathyroidectomy presented with nausea, vomiting, and hematemesis. Laboratory data revealed an elevated gastrin level. Computed tomography of the abdomen demonstrated a 3.5-cm mass in the head of pancreas. A functional study with a somatostatin receptor scan showed increased uptake in the region of the pancreatic mass. The patient's symptoms promptly improved after the Whipple procedure, although he was also noted to have a markedly elevated calcium concentration along with inappropriately elevated parathyroid hormone levels. Sestamibi scan identified a hyperfunctioning right upper parathyroid gland. His calcium level normalized after parathyroidectomy, and results from pituitary hormone studies were all normal. Genetic testing of the MEN1 gene identified a novel mutation: Arg52Gly. The Arg52Gly mutation replaces the normal arginine residue (CGC) with a glycine residue (GGC) at position 52 of the resultant menin protein. This mutation was present in family members from 3 generations. CONCLUSIONS: We report a novel disease-causing germline missense mutation in exon 2 of the MEN1 gene in a patient with MEN 1. Nonconservative replacement of arginine, a small, neutral amino acid, with glycine, a bulky positively charged amino acid, could potentially have a deleterious effect on the menin protein.

Lowering low-density lipoprotein cholesterol: statins, ezetimibe, bile acid sequestrants, and combinations: comparative efficacy and safety.

Statins, ezetimibe, and bile acid-binding resins can be used individually or in combination for lowering low-density lipoprotein cholesterol (LDL-C) levels. Statins are the most potent drugs for lowering LDL-C and are well tolerated in most patients. The addition of a bile acid sequestrant or ezetimibe to a statin produces additional LDL-C reduction allowing many patients to reach LDL-C targets. This article discusses the efficacy and safety of available statins, bile acid sequestrants, and ezetimibe in the treatment of hyperlipidemia.

A case of severe neuropathy associated with hypertriglyceridemia.

OBJECTIVE: To describe a case of severe neuropathy associated with hypertriglyceridemia. METHODS: We describe the clinical and laboratory findings of the study patient and review the relevant literature. RESULTS: A 45-year-old woman presented to the emergency department with recurrent abdominal pain and severe peripheral neuropathy. Her laboratory data revealed elevated lipase and a very high triglyceride concentration (>10,000 mg/dL), consistent with a diagnosis of recurrent hypertriglyceridemia-induced pancreatitis. Workup for peripheral neuropathy showed normal concentrations of thyrotropin, fasting blood glucose, vitamin B(12), and creatinine, as well as a normal hemoglobin A(1c) level, serum protein electrophoresis, and urine protein electrophoresis. Rapid plasma reagin antibodies, antinuclear antibodies, and lyme antibodies were not detected. In the absence of other identifiable causes, hypertriglyceridemia was deemed the likely etiology of severe neuropathy in this patient. CONCLUSIONS: Peripheral nerve conduction abnormalities can be identified in patients with mild hypertriglyceridemia in the absence of symptoms. Early recognition and aggressive management of hypertriglyceridemia may prevent the complications of severe peripheral neuropathy.

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR alpha-chain CDR3 loop.

A significant fraction of CD1d-restricted T cells express an invariant T cell receptor (TCR) alpha-chain. These highly conserved invariant NKT (iNKT) populations are important regulators of a wide spectrum of immune responses. The ability to directly identify and manipulate iNKT cells is essential to understanding their function and to exploit their therapeutic potential. To this end, we sought monoclonal and polyclonal antibodies specific for iNKT cells by immunizing CD1d KO mice, which lack iNKT cells, with a cyclic peptide modeled after the TCRalpha CDR3 loop. One mAb (6B11) was specific for cloned and primary human but not rodent iNKT cells and the human invariant TCRalpha, as shown by transfection and reactivity with human invariant TCRalpha transgenic T cells ex vivo and in situ. 6B11 was utilized to identify, purify, and expand iNKT cells from an otherwise minor component of human peripheral blood lymphocytes and to specifically identify human iNKT cells in tissue. Thus, we report a novel and general strategy for the generation of mAb specific for the CDR3 loop encoded by the TCR of interest. Specifically, an anti-Valpha24Jalpha18 CDR3 loop clonotypic TCR mAb is available for the enumeration and therapeutic manipulation of human and non-human primate iNKT populations.

Defined culture conditions of human embryonic stem cells.

Human embryonic stem cells (hESCs) are pluripotent cells that have the potential to differentiate into any tissue in the human body; therefore, they are a valuable resource for regenerative medicine, drug screening, and developmental studies. However, the clinical application of hESCs is hampered by the difficulties of eliminating animal products in the culture medium and/or the complexity of conditions required to support hESC growth. We have developed a simple medium [termed hESC Cocktail (HESCO)] containing basic fibroblast growth factor, Wnt3a, April (a proliferation-inducing ligand)/BAFF (B cell-activating factor belonging to TNF), albumin, cholesterol, insulin, and transferrin, which is sufficient for hESC self-renewal and proliferation. Cells grown in HESCO were maintained in an undifferentiated state as determined by using six different stem cell markers, and their genomic integrity was confirmed by karyotyping. Cells cultured in HESCO readily form embryoid bodies in tissue culture and teratomas in mice. In both cases, the cells differentiated into each of the three cell lineages, ectoderm, endoderm, and mesoderm, indicating that they maintained their pluripotency. The use of a minimal medium sufficient for hESC growth is expected to greatly facilitate clinical application and developmental studies of hESCs.

Interleukin-12 and interleukin-2-induced invariant natural killer T-cell cytokine secretion and perforin expression independent of T-cell receptor activation.

Human invariant natural killer (iNK) T cells expressing an invariant Valpha24-Jalpha15 T-cell receptor (TCR) are thought to be important regulators of autoimmunity and tumour surveillance. Two major subsets of iNK T cells, CD4+ or CD4- CD8- are known to exist, but the in vivo importance of CD4 expression is unclear. Since interleukin-12 (IL-12) is a key iNK T-cell-activating cytokine, the effect of IL-12 plus or minus the T-cell growth factor IL-2 on a large panel of CD4+ versus CD4- CD8- iNK T-cell clones was examined. Strikingly, IL-12 and IL-2 significantly activated iNK T cells to secrete IL-4, interferon-gamma and granulocyte-macrophage colony-stimulating factor, and up-regulated perforin expression in the absence of TCR stimulation. Furthermore, IL-2 and IL-12 treatment resulted in a preferential increase in apoptosis of CD4- CD8- clones. Thus, independent of TCR activation, IL-2 and IL-12 can directly activate iNK T cells and provide a selective advantage to the CD4+ iNK T-cell population.

CD1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells.

CD1d-restricted T cells (NKT cells) are innate memory cells activated by lipid Ags and play important roles in the initiation and regulation of the immune response. However, little is known about the trafficking patterns of these cells or the tissue compartment in which they exert their regulatory activity. In this study, we determined the chemokine receptor profile expressed by CD1d-restricted T cells found in the peripheral blood of healthy volunteers as well as CD1d-restricted T cell clones. CD1d-restricted T cells were identified by Abs recognizing the invariant Valpha24 TCR rearrangement or by binding to CD1d-Fc fusion tetramers loaded with alpha-GalCer. CD1d-restricted T cells in the peripheral blood and CD1d-restricted T cell clones expressed high levels of CXCR3, CCR5, and CCR6; intermediate levels of CXCR4 and CXCR6; and low levels of CXCR1, CCR1, CCR2, and CX(3)CR1, a receptor pattern often associated with tissue-infiltrating effector Th1 cells and CD8+ T cells. Very few of these cells expressed the lymphoid-homing receptors CCR7 or CXCR5. CCR4 was expressed predominantly on CD4+, but not on double-negative CD1d-restricted T cells, which may indicate differential trafficking patterns for these two functionally distinct subsets. CD1d-restricted T cell clones responded to chemokine ligands for CXCR1/2, CXCR3, CXCR4, CXCR6, CCR4, and CCR5 in calcium flux and/or chemotaxis assays. These data indicate that CD1d-restricted T cells express a chemokine receptor profile most similar to Th1 inflammatory homing cells and suggest that these cells perform their function in peripheral tissue sites rather than in secondary lymphoid organs.

CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infection.

Invariant human natural killer T cells (NKT) express a restricted T-cell receptor (TCR) Valpha24Vbeta11 repertoire. These cells share both phenotypic and functional similarities between NK and T cells. Given the emerging role of NKT cells as critical cells in bridging the gap between innate and adaptive immunity, we examined their susceptibility to productive human immunodeficiency virus (HIV) infection by T-tropic, M-tropic, and primary isolates of HIV. We generated three human NKT cell clones (CA5, CA29, and CA31). Phenotypic characterization of these Valpha24+ Vbeta11+ clones indicated that they were predominately positive for CD4, CD161, HLA-DR, CD38, CD45RO, and CD95 expression. The NKT cell clones expressed significantly more surface CCR5 molecules/cell and lower CXCR4 molecules/cell than phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PBMC). Consistent with the surface expression of CCR5 and CXCR4, the NKT clones were also selectively susceptible to HIV M-tropic, T-tropic, and primary isolate infection, as evaluated by both HIV p24 enzyme-linked immunosorbent assay and intracellular staining of HIV proteins. The amount of p24 production was dependent on the NKT clone studied and the HIV strain used. Clones CA29 and CA31 were also susceptible to HIV IIIB infection. The virions produced by these clones were able to productively infect PHA-stimulated PBMCs with the same kinetics as for primary infection of CD4+ blast. Collectively, this data demonstrates that NKT cells can be a target for productive HIV infection but with a lag in the time to peak p24 production.

Loss of RecA function affects the ability of Escherichia coli to maintain recombinant plasmids containing a Ter site.

In the Escherichia coli chromosome, DNA replication forks arrested by a Tus-Ter complex or by DNA damage are reinitiated through pathways that involve RecA and numerous other recombination functions. To examine the role of recombination in the processing of replication forks arrested by a Tus-Ter complex, the requirements for recombination-associated gene products were assessed in cells carrying Ter plasmids, i.e., plasmids that contain a Ter site oriented to block DNA replication. Of the E. coli recombination functions tested, only loss of recA conferred an observable phenotype on cells containing a Ter plasmid, which was inefficient transformation and reduced ability to maintain a Ter plasmid when Tus was expressed. Given the current understanding of replication reinitiation, the simplest explanation for the restriction of Ter plasmid maintenance was a reduced ability to restart plasmid replication in a recA tus(+) background. However, we were unable to detect a difference in the efficiency of replication arrest by Tus in recA-proficient and recA-deficient cells, which suggests that the inability to restart arrested replication forks is not the cause of the restriction on growth, but is due to an additional function provided by RecA. Other explanations for restriction of Ter plasmid maintenance were examined, including plasmid multimerization, plasmid rearrangements, and copy number differences. The most likely cause of the restriction on Ter plasmid maintenance was a reduced copy number in recA cells that was detected when the copy number was measured in relation to an external control. Possibly, loss of RecA function leads to improper processing of replication forks arrested at a Ter site, leading to the generation of degradation-prone substrates.