Performance of Urinalysis Parameters in Predicting Urinary Tract Infection: Does One Size Fit all?

In a multi-hospital cohort study of 3392 patients, positive urinalysis parameters had poor positive predictive value for diagnosing urinary tract infection (UTI). Combined urinalysis parameters (pyuria or nitrite) performed better than pyuria alone for ruling out UTI. However, performance of all urinalysis parameters was poor in older women.

A Challenging Case of Diabetes in a Patient With XXYY Syndrome.

48 XXYY syndrome is a rare polyploidy often compared with Klinefelter syndrome because of shared features such as tall stature, neurocognitive diseases, hypogonadism, and cardiac malformations. This population is believed to be predisposed to type 2 diabetes because of the presence of hypogonadism and central adiposity. We present a patient with XXYY syndrome who had an atypical and difficult-to-manage diabetes presentation. The patient was nonadherent to medication regimen with poorly controlled diabetes and hemoglobin A1c ranging from 12% to 14% (16.5-19.6 mmol/L). He lacked history of diabetes ketoacidosis, raising the question of maturity-onset diabetes of the young. Workup was negative for glutamic acid decarboxylase-65 and pancreatic islet cell antibody testing. Genetic testing for 5-gene panel for maturity-onset diabetes of the young was also negative. Distinct parts of his presentation make an accurate diabetes diagnosis very challenging. Clinicians should be aware of diabetes associations in patients with XXYY syndrome for optimization of care.

Effectiveness of romosozumab in primary biliary cholangitis at half the recommended dose in an underweight patient.

Romosozumab (RSB) is a monoclonal antibody to sclerostin that is approved for post-menopausal osteoporosis at high fracture risk. It is administered as a monthly 210 mg subcutaneous injection for 12 months. We report the response to half the standard dose of RSB in an underweight patient with severe osteoporosis and primary biliary cholangitis (PBC). Using half dose RSB (approximately 3 mg/kg RSB), she demonstrated significant improvement in lumbar spine BMD, paralleling the results of phase III trials. This case highlights the effectiveness of RSB in a patient with concomitant PBC, in addition to its effectiveness at half the recommended dose in an underweight patient.

A Sweet Paradox: Severe Insulin Resistance and Hyperglycemia in Asymptomatic COVID-19 Infection.

There is a well-established association between hyperglycemia and severe coronavirus disease 2019 (COVID-19) infection, regardless of the diagnosis of diabetes prior to the infection. However, it is unusual for patients with a mild infection to present with severe hyperglycemia and insulin resistance requiring intravenous insulin therapy. Uncontrolled hyperglycemia is associated with worse outcomes in COVID-19, making it crucial to achieve optimal glycemic control, which occasionally requires IV insulin therapy. We report a patient with type 1 diabetes mellitus (T1DM), on hemodialysis, who presented with diabetic ketoacidosis (DKA) due to non-adherence to insulin. He was found to be incidentally positive for COVID-19 on admission. Although he was asymptomatic and did not require steroids for the treatment of COVID-19, he was noted to have persistent severe hyperglycemia requiring unusually high levels of intravenous insulin. This proposes that even a mild infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can trigger a systemic response that can lead to downstream manifestations including insulin resistance and severe hyperglycemia. Interestingly, our patient had three admissions within the past six months as well as another admission two weeks after the current presentation with DKA secondary to insulin non-compliance, all of which required IV insulin for <24 hours following which he was transitioned to a basal-bolus insulin regimen with well-controlled glucose levels.

Giant Prolactinoma Presenting With Facial Nerve Palsy and Hemiparesis.

BACKGROUND: Giant prolactinomas are an exceedingly uncommon type of pituitary adenomas that usually occur in men, and cause extremely high prolactin levels and mass-related symptoms. Rarely, patients may experience neurological deficits resembling ischemic events. METHODS: We describe an unusual case of a young man who presented with stroke-like symptoms and was found to have a giant prolactinoma. CLINICAL CASE: A 25-year-old man presented with left facial droop and gradually progressing upper and lower extremity weakness for evaluation of stroke. He reported recent weight gain and erectile dysfunction. Physical examination revealed left homonymous hemianopsia, left VII nerve palsy, and left hemiparesis. Magnetic resonance imaging of the brain showed an enormous mass in the sella turcica, which invaded the sphenoid sinus and right side of the skull base. Prolactin level was elevated at 13 580 ng/mL, and the testosterone level was low. The patient was started on cabergoline and had marked improvement in his symptoms in a few months. Fifteen months after starting treatment, he has had more than 90% reduction in tumor volume and a 93% reduction in prolactin level. CONCLUSION: Giant prolactinomas are uncommon and present with compressive symptoms that can be mistaken for a stroke. Our case is a unique report of a facial nerve palsy and hemiparesis secondary to giant prolactinoma in the absence of stroke or pituitary apoplexy.

Evaluation of Provider Screening Practices for Fracture Risk Assessment among Patients with HIV Disease.

People living with HIV are known to have greater risk of low bone mineral density than HIV-negative peers. The reasons for this disparity are multifactorial. To address this increased risk, the Infectious Diseases Society of America (IDSA) released fracture risk screening recommendations in 2015, which differ significantly from recommendations that apply to the general population. A study was conducted at the University of Connecticut to assess for provider awareness and adherence to these recommendations. Electronic surveys were sent to providers, and patients were also surveyed for risk factors and prevalence of low bone mineral density. The results of the provider survey showed low rates of awareness of the IDSA screening recommendations. A substantial proportion of patients surveyed met criteria for low BMD screening but did not have dual-energy X-ray absorptiometry (DXA) ordered by their provider. As an intervention, providers were sent information via e-mail regarding current screening recommendations, as well as notifications if their patient met criteria for DXA screening. A twelve-month follow-up survey showed increased provider knowledge of screening recommendations and improved screening practices. Additionally, the results of a logistic regression analysis of patient factors showed that increasing age and male sex were positively associated with fragility fracture risk. Increased duration of antiretroviral therapy use was associated with a lower likelihood of fragility fracture.

SUBLINGUAL VITAMIN D3 EFFECTIVE IN A PATIENT RESISTANT TO CONVENTIONAL VITAMIN D SUPPLEMENTATION.

OBJECTIVE: Vitamin D deficiency is prevalent worldwide and is usually treated with oral supplementation. Bioavailability of vitamin D may differ among individuals due to variable absorption and metabolism in the body. METHODS: A 66-year-old woman presented for evaluation of low 25-hydroxyvitamin D (25[OH]D) level. She had no known prior history of gastric or intestinal surgeries or malabsorptive conditions. She had previously been treated with oral vitamin D3 at 2,000 IU daily with poor response. She was then treated with oral vitamin D2 at 50,000 IU weekly, with persistently low 25(OH)D level at 14 ng/mL after 8 weeks of treatment. RESULTS: Celiac screen was negative and duodenal biopsy was normal. Due to demonstration of poor oral absorption, she was prescribed vitamin D2 at 50,000 IU sublingually for 8 weeks and then changed to over-the-counter vitamin D3 drops sublingually (1,000 IU/drop) at 4,000 IU twice daily due to suboptimal response with vitamin D2. 25(OH)D level improved gradually to 28 ng/mL after 12 weeks on this regimen and was at 37 ng/mL at 1 year. CONCLUSION: Sublingual vitamin D3 may be an effective alternative mode of vitamin D supplementation in patients who demonstrate poor oral vitamin D absorption despite adequate supplementation for various reasons.

Protease-Activated Receptor 1 Deletion Causes Enhanced Osteoclastogenesis in Response to Inflammatory Signals through a Notch2-Dependent Mechanism.

We found that protease-activated receptor 1 (PAR1) was transiently induced in cultured osteoclast precursor cells. Therefore, we examined the bone phenotype and response to resorptive stimuli of PAR1-deficient (knockout [KO]) mice. Bones and bone marrow-derived cells from PAR1 KO and wild-type (WT) mice were assessed using microcomputed tomography, histomorphometry, in vitro cultures, and RT-PCR. Osteoclastic responses to TNF-α (TNF) challenge in calvaria were analyzed with and without a specific neutralizing Ab to the Notch2-negative regulatory region (N2-NRR Ab). In vivo under homeostatic conditions, there were minimal differences in bone mass or bone cells between PAR1 KO and WT mice. However, PAR1 KO myeloid cells demonstrated enhanced osteoclastogenesis in response to receptor activator of NF-κB ligand (RANKL) or the combination of RANKL and TNF. Strikingly, in vivo osteoclastogenic responses of PAR1 KO mice to TNF were markedly enhanced. We found that N2-NRR Ab reduced TNF-induced osteoclastogenesis in PAR1 KO mice to WT levels without affecting WT responses. Similarly, in vitro N2-NRR Ab reduced RANKL-induced osteoclastogenesis in PAR1 KO cells to WT levels without altering WT responses. We conclude that PAR1 functions to limit Notch2 signaling in responses to RANKL and TNF and moderates osteoclastogenic response to these cytokines. This effect appears, at least in part, to be cell autonomous because enhanced osteoclastogenesis was seen in highly purified PAR1 KO osteoclast precursor cells. It is likely that this pathway is involved in regulating the response of bone to diseases associated with inflammatory signals.

PROINSULIN-PREDOMINANT PANCREATIC NEUROENDOCRINE TUMOR-INDUCED HYPOGLYCEMIA AFTER ROUX-EN-Y GASTRIC BYPASS SURGERY.

OBJECTIVE: To present a case of recurrent hypoglycemia following Roux-en-Y gastric bypass (RYGB) surgery whose etiology was determined to be a proinsulin-predominant pancreatic neuroendocrine tumor (a proinsulinoma). METHODS: A case report along with a brief discussion and review of the pertinent literature is presented. RESULTS: The patient is a 62-year-old female who presented with symptomatic hypoglycemia 11 years after RYGB surgery. Initial workup revealed low insulin levels with elevated proinsulin levels. A 72-hour fast confirmed the presence of proinsulin-induced hypoglycemia secondary to a pancreatic neuroendocrine tumor (PNET). She underwent distal pancreatectomy with splenectomy and a PNET tumor was successfully removed with resolution of her symptoms. CONCLUSION: Hypoglycemia after RYGB surgery is a well-established syndrome. While there are several etiologies for this, PNETs (including proinsulinomas) should be considered in the differential diagnosis in this population. Proinsulinomas are an increasingly recognized cause of hypoglycemia. Proinsulin levels must always be included as part of the workup of hypoglycemia in an adult.

Dried plum alleviates symptoms of inflammatory arthritis in TNF transgenic mice.

Dried plum (DP), a rich source of polyphenols has been shown to have bone-preserving properties in both animal models of osteoporosis and postmenopausal women. We evaluated if DP alleviated the destruction of joints in transgenic mice (TG) that overexpress human tumor necrosis factor (TNF), a genetic model of rheumatoid arthritis (RA). A four-week treatment of 20% DP diet in TG slowed the onset of arthritis and reduced bone erosions in the joints compared to TG on a regular diet. This was associated with fewer tartrate-resistant acid phosphatase (TRAP) positive cells, suggesting decreased osteoclastogenesis. A DP diet also produced significant protection of articular cartilage and reduction of synovitis. Cultures of human synovial fibroblast in the presence of TNF showed a significant increase in inflammatory interleukin (IL)-1ß, chemokines (monocyte chemoattractant protein-1: MCP1 & macrophage inflammatory protein-1 alpha: MIP1α), cartilage matrix metalloproteinases (MMP1&3), and an osteoclastogenic cytokine (receptor activator of nuclear factor-κB ligand: RANKL) compared to controls. Addition of neochlorogenic acid (NC), a major polyphenol in DP to these cultures resulted in down-regulation of these genes. In the cultures of mouse bone marrow macrophage, NC also repressed TNF-induced formation of osteoclasts and mRNA levels of cathepsin K and MMP9 through inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression and nuclear factor kappa B (NF-κB) activation. Our data suggested that dietary supplementation with DP inhibited TNF singling; leading to decreased erosions of bone and articular cartilage as well as synovitis.

Management of endocrine disease: Secondary osteoporosis: pathophysiology and management.

Osteoporosis is a skeletal disorder characterized by decreased mass and compromised bone strength predisposing to an increased risk of fractures. Although idiopathic osteoporosis is the most common form of osteoporosis, secondary factors may contribute to the bone loss and increased fracture risk in patients presenting with fragility fractures or osteoporosis. Several medical conditions and medications significantly increase the risk for bone loss and skeletal fragility. This review focuses on some of the common causes of osteoporosis, addressing the underlying mechanisms, diagnostic approach and treatment of low bone mass in the presence of these conditions.

Changes in bone sclerostin levels in mice after ovariectomy vary independently of changes in serum sclerostin levels.

We examined the effects that ovariectomy had on sclerostin mRNA and protein levels in the bones of 8-week-old mice that were either sham-operated (SHAM) or ovariectomized (OVX) and then euthanized 3 or 6 weeks later. In this model, bone loss occurred between 3 and 5 weeks postsurgery. In calvaria, ovariectomy significantly decreased sclerostin mRNA levels at 6 weeks postsurgery (by 52%) but had no significant effect at 3 weeks. In contrast, sclerostin mRNA levels were significantly lower in OVX femurs at 3 weeks postsurgery (by 53%) but equal to that of SHAM at 6 weeks. The effects of ovariectomy on sclerostin were not a global response of osteocytes because they were not mimicked by changes in the mRNA levels for two other relatively osteocyte-specific genes: DMP-1 and FGF-23. Sclerostin protein decreased by 83% and 60%, at 3 and 6 weeks postsurgery in calvaria, respectively, and by 38% in lumbar vertebrae at 6 weeks. We also detected decreases in sclerostin by immunohistochemistry in cortical osteocytes of the humerus at 3 weeks postsurgery. However, there were no significant effects of ovariectomy on sclerostin protein in femurs or on serum sclerostin at 3 and 6 weeks postsurgery. These results demonstrate that ovariectomy has variable effects on sclerostin mRNA and protein in mice, which are dependent on the bones examined and the time after surgery. Given the discrepancy between the effects of ovariectomy on serum sclerostin levels and sclerostin mRNA and protein levels in various bones, these results argue that, at least in mice, serum sclerostin levels may not accurately reflect changes in the local production of sclerostin in bones. Additional studies are needed to evaluate whether this is also the case in humans.

Management of bone disease in patients undergoing hormonal therapy for breast cancer.

Estrogen deficiency at menopause is associated with increased risk of bone loss and osteoporosis. Aromatase inhibitors (AIs) are increasingly being used for the treatment of postmenopausal hormone-sensitive breast cancer because of better disease-free survival compared with tamoxifen seen in clinical trials with AIs. This article reviews the effect of endocrine therapies of breast cancer on bone and the management of bone disease with these endocrine therapies. The effect of these therapies on bone mineral density and bone turnover along with possible interventions is discussed. AIs are also associated with skeletal-related events, which are not discussed.

Serum sclerostin levels negatively correlate with parathyroid hormone levels and free estrogen index in postmenopausal women.

CONTEXT: Sclerostin is a negative regulator of bone formation. OBJECTIVE: The aim of the study was to compare serum sclerostin levels in premenopausal and postmenopausal women and evaluate its relationship to estrogen, TH, bone turnover, and bone mass. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional observational study of healthy community-dwelling pre- and postmenopausal women. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURE(S): We compared serum sclerostin levels in pre- and postmenopausal women and correlated sclerostin levels with female sex hormones, calciotropic hormones, bone turnover markers, and bone mineral density. RESULTS: Premenopausal women were 26.8 yr old, and postmenopausal women were 56.8 yr old. Postmenopausal women had lower values for estradiol (30 +/- 23 vs. 10 +/- 4 pg/ml; P < 0.001), estrone (61 +/- 24 vs. 29 +/- 10 pg/ml; P <0.001), and free estrogen index (FEI) (6 +/- 4 vs. 3 +/- 2 pmol/nmol; P = 0.008) and significantly lower bone mineral density at all sites compared to premenopausal women, with no significant differences in levels of PTH, 25-hydroxy or 1,25-dihydroxy vitamin D levels. Postmenopausal women had significantly higher serum sclerostin levels (1.16 +/- 0.38 ng/ml vs. 0.48 +/- 0.15 ng/ml; P < 0.001). Because most of the premenopausal women were on oral contraceptives, subsequent analyses were limited to postmenopausal women. There were significant negative correlations between sclerostin and FEI and sclerostin and PTH in this group. Using multiple regression analysis, both FEI (beta = -0.629; P = 0.002) and PTH (beta = -0.554; P = 0.004) were found to be independent predictors of sclerostin levels in postmenopausal women. CONCLUSIONS: Our findings suggest that serum sclerostin levels are regulated by both estrogens and PTH in postmenopausal women. These findings need to be explored further in larger prospective studies.

Effects of estradiol and the angiotensin II receptor blocker irbesartan on vascular function in postmenopausal women.

OBJECTIVE: Estradiol and angiotensin receptor blockers have prominent effects on the renin-angiotensin-aldosterone system. The purpose of this study was to determine whether irbesartan, an angiotensin receptor blocker, has a greater effect on vascular function when combined with estradiol, compared with irbesartan alone, in hypertensive postmenopausal women. DESIGN: Fifty-one women were studied while off any antihypertensive medications or hormone therapy at baseline and after randomization to one of four treatment arms for 12 weeks: (1) irbesartan and estradiol, (2) irbesartan and placebo, (3) estradiol and placebo, and (4) placebo/placebo. Estradiol and placebo arms served as control groups. Blood pressure, brachial reactivity, aldosterone, insulin, glucose, 24-hour urinary catecholamines, urinary sodium, and creatinine were measured. Fisher's exact test was used for comparison of differences in blood pressure in the treatment arms. Paired t test and analysis of variance were also performed for within- and between-group analysis. RESULTS: A significantly larger number of women in the irbesartan and estradiol group had a decrease of 5 mm Hg or more in both systolic and diastolic blood pressures (P < 0.05) compared with irbesartan alone group. Forearm vascular reactivity was increased significantly compared with baseline (P < 0.05), and there was a significant decrease in the serum aldosterone level after treatment compared with baseline (P < 0.05) in the irbesartan and estradiol combination group. Fasting glucose and insulin, urinary sodium/creatinine ratio, and catecholamines were similar at each time point. CONCLUSIONS: The results suggest that irbesartan and estradiol, when used in combination, may cause a greater lowering of blood pressure in postmenopausal hypertensive women. This effect may be mediated via increased vasodilation and lower aldosterone levels. These results warrant further testing in larger clinical trials.

Bone health and aging: implications for menopause.

Osteoporosis is one major health condition that contributes to excess morbidity and mortality in women after menopause. In the past, hormone therapy (HT) was prescribed commonly for symptoms of menopause, and there was also evidence that HT protected against osteoporosis. Recently, however, the overall health risks have been reported to exceed benefits, with the beneficial effects seen only in the decreased incidence of hip fractures and colon cancer. The role of HT in menopausal women is unclear at this time, although many women may require it to reduce menopausal symptoms. Osteoporosis may be an area where the benefit of using HT may outweigh the risks in a select group of women. Further, because lower than usual doses of estrogen have been shown to reduce menopausal symptoms and to protect bone, additional research will likely expand physicians' current knowledge of the use of HT in menopausal women. This article reviews the use of low-dose estrogen to promote bone health in postmenopausal women.