The aim of the present study was to evaluate the effect of fibrinogen on number and function of osteoclasts (OC) consequently resulting in bone loss. It was hypothesized that the enhanced level of released fibrinogen due to loss of ovarian function caused bone loss by acting on OCs. Bone loss was induced by ovariectomy (OVX) in mice and analyzed by micro-CT. The effect of fibrinogen on OCs was evaluated by tartrate-resistant acid phosphatase, annexin V, actin staining, pit formation observed on dentine slices, and Western blotting. Exogenous fibrinogen increased OC survival, actin ring formation, and bone resorption in vitro. The effect of fibrinogen was dependent on ␤3-integrin, which is a marker for mature OCs. Fibrinogen induced the activation of transforming oncogene from Ak strain (Akt), Ras-related C3 botulinum toxin substrate 1 (Rac1), and Rho family of GTPase (Rho) and the degradation of the Bcl-2 interacting mediator of cell death (Bim) in a manner similar to macrophage colony-stimulating factor (M-CSF). OVX increased plasma fibrinogen and serum M-CSF together with elevated actin ring formation and bone loss. The increased fibrinogen level due to loss of ovarian function may contribute, at least partly, to bone loss through the enhanced number and activity of OCs. bone loss; osteoclast; ovariectomy ELEVATED PLASMA FIBRINOGEN is associated with metabolic syndrome, which is considered a chronic inflammation (11,33), suggesting that fibrinogen might act as a danger signal to the host. Plasma leakage is one of the characteristic features of inflammation. Gaps formed between endothelial cells within minutes of inflammation onset allow for the escape of plasma molecules, such as fibrinogen, into interstitial spaces. Fibrinogen deposition in tissues has been implicated as a major cause of disease such as atherosclerosis (3). A link between fibrinogen and cell-mediated inflammatory reactions is indicated by the observation that transient removal of fibrinogen from the circulation reduces the inflammation of joints in rheumatoid arthritis (5).Integrins are heterodimeric adhesion molecules that govern cell-matrix interactions. Members of three major families of integrins, ␣ 5 ␤ 1 , ␣ M ␤ 2 , and ␣ V ␤ 3, are expressed on leukocytes, and fibrinogen is known to engage all three family types (15).Specific interactions with leukocyte cell surface adhesion receptors account for the involvement of fibrinogen in inflammatory processes, although the molecular events involved have not been fully elucidated. Various extracellular matrix proteins, including vitronectin, osteopontin, bone sialoprotein, and fibrinogen, bind to integrins (15). The engagement of an extracellular ligand by an integrin not only provides a transmembrane mechanical link between the internal cytoskeleton of a cell and the extracellular matrix, but also initiates intracellular signaling that modulates the expression of proinflammatory molecules (15,24).Postmenopausal osteoporosis, characterized by the loss of bone mass and strength, is thought to be ...

polyuria polydipsia central diabetes insipidus familial diabetes insipidus AVP gene desmopressin a b s t r a c t Objective: Diabetes insipidus (DI) can be classified into 2 types: central/neurogenic DI and nephrogenic DI. Most cases of central DI occur after brain surgery, trauma, tumor, or infection. Here we report a rare case of familial central DI due to a heterozygous AVP gene mutation. Methods: A case of familial neurogenic DI has been described with thorough clinical, laboratory, and genetic workup. PubMed and Google scholar databases were used for literature discussion. Results: A 22-year-old man presented with polyuria and polydipsia. He drank about 4 gallons of water everyday and urinated large volumes very frequently. His physical examination was unremarkable. After 2 hours of water-deprivation, his serum sodium level was 147 mmol/L, serum osmolality was 302 mOsm/ kg with concurrent urine osmolality of 78 mOsm/kg, vasopressin level was <0.8 pg/mL, and copeptin level was <2.8 pmol/L, suggesting neurogenic DI. His brain magnetic resonance imaging revealed the absence of the posterior pituitary bright spot but a normal anterior pituitary gland. Genetic analysis revealed a nonfunctional heterozygous mutation in the AVP gene. Further questioning revealed that his mother also had the disease and that he had been treated with desmopressin as a child; however, it was later self-stopped. The patient was reinitiated on desmopressin, which improved his symptoms. Conclusion: Genetic mutations in the AVP gene represent a very rare etiology of DI, and patients with DI respond well to desmopressin treatment.

In diabetic ketoacidosis (DKA), hyponatremia is commonly observed due to hyperglycemia-induced water shift and osmotic diuresis. Thus, hypernatremia is rare and indicative of severe free water loss. We describe here a case of DKA with life-threatening hypernatremia. A 22-year-old type 1 diabetic male was admitted after experiencing polyuria and polydipsia, followed by nausea, vomiting, and lethargy for 2 weeks. On admission, plasma glucose was 1230 mg/dL and plasma sodium was 158 mEq/L. The patient developed acute kidney injury, lactic acidosis, and ketosis. Despite fluid resuscitation, sodium level continued to rise to 180 mEq/L. Tachycardia persisted and shock liver developed. After free water-deficit calculation, the patient was given more boluses of isotonic fluid in addition to 0.45% NaCl. Tachycardia began to improve, and hypernatremia and hyperglycemia were safely reduced. This case demonstrated how tedious volume evaluation and resuscitation helped the patient fully recover despite extreme hypernatremia, lethargy, and multiorgan failure.

Poor diet, low income, obesity and a lack of exercise are established lifestyle factors that are known to increase cancer burden and are often more prevalent in African American communities. As our understanding of tumor biology advances, it is becoming increasingly clear that these inter-related lifestyle factors have distinct molecular consequences on the biological make-up of tumors, altering cell signaling events and gene expression profiles to contribute to cancer disparity outcomes such as its earlier development or its progression to more aggressive disease. Sparse information exists about the genetic and biological factors that contribute to differential cancer survival and mortality rates observed in minority populations. A greater understanding of the interplay between risk factors and the molecular mechanisms associated with cancer disparity will significantly impact minority health. Advanced glycation end products (AGEs) are reactive metabolites produced as a by-product of sugar metabolism. Failure to remove these highly reactive metabolites can lead to protein damage, aberrant cell signaling, increased stress responses, and decreased genetic fidelity. Critically, AGE accumulation is also directly affected by our lifestyle choices such as poor diet, low income, obesity and a lack of exercise. We recently reported a potential mechanistic link between AGEs and prostate cancer which may provide a molecular consequence of our lifestyle choices that can directly impact tumor biology and contribute to cancer disparity. We examined circulating and intra-tumoral AGE metabolite levels in clinical specimens and identified a race specific, tumor dependent pattern of accumulation in prostate cancer serum and tumor. Further mechanistic studies in immortalized prostate cancer cell lines show that AGE treatment increases the expression of the receptor for AGEs (RAGE) to activate cancer-associated signaling cascades. Loss of function studies show that AGE mediated increases in cancer associated processes was dependent upon RAGE expression. Significantly, we show that AGEs are secreted into the tumor microenvironment by cancer cells and may function as signaling molecules to promote immune cell recruitment. These data implicate the AGE-RAGE signaling axis as a potential biological mechanism promoting prostate cancer and may represent a biological mechanism promoting prostate cancer disparity. AGE metabolites may have high potential impact as prognostic/diagnostic markers and/or as a novel area of potential therapeutic intervention to reduce cancer disparity. Citation Format: Danzell M. Smith, Dion Foster, Van Phan, Victoria J. Findlay, Lourdes M. Nogueira, Laura Spruill, Mahtabuddin Ahmed, Judith D. Salley, Marvella E. Ford, David P. Turner. Mechanistic implications of advanced glycation end-products to prostate cancer and racial disparity. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr C76.

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