Effects of Denosumab,Alendronate, or Denosumab Following Alendronate on Bone Turnover,Calcium Homeostasis,Bone Mass and Bone Strength in Ovariectomized Cynomolgus Monkeys

Postmenopausal osteoporosis is a chronic disease wherein increased bone remodeling reduces bone mass and bone strength. Antiresorptive agents including bisphosphonates are commonly used to mitigate bone loss and fracture risk. Osteoclast inhibition via denosumab (DMAb), a RANKL inhibitor, is a newer approach for reducing fracture risk in patients at increased risk for fracture. The safety of transitioning from bisphosphonate therapy (alendronate; ALN) to DMAb was examined in mature ovariectomized (OVX) cynomolgus monkeys (cynos). One day after OVX, cynos (7–10/group) were treated with vehicle (VEH, s.c.), ALN (50 μg/kg, i.v., twice monthly) or DMAb (25 mg/kg/month, s.c.) for 12 months. Other animals received VEH or ALN for 6 months and then transitioned to 6 months of DMAb. DMAb caused significantly greater reductions in serum CTx than ALN, and transition from ALN to DMAb caused further reductions relative to continued ALN. DMAb and ALN decreased serum calcium (Ca), and transition from ALN to DMAb resulted in a lesser decline in Ca relative to DMAb or to VEH‐DMAb transition. Bone histomorphometry indicated significantly reduced trabecular and cortical remodeling with DMAb or ALN. Compared with ALN, DMAb caused greater reductions in osteoclast surface, eroded surface, cortical porosity and fluorochrome labeling, and transition from ALN to DMAb reduced these parameters relative to continued ALN. Bone mineral density increased in all active treatment groups relative to VEH controls. Destructive biomechanical testing revealed significantly greater vertebral strength in all three groups receiving DMAb, including those receiving DMAb after ALN, relative to VEH controls. Bone mass and strength remained highly correlated in all groups at all tested skeletal sites, consistent with normal bone quality. These data indicate that cynos transitioned from ALN to DMAb exhibited reduced bone resorption and cortical porosity, and increased BMD and bone strength, without deleterious effects on Ca homeostasis or bone quality. © 2014 American Society for Bone and Mineral Research.     

Donor‐Derived Strongyloides stercoralis Infection in Solid Organ Transplant Recipients in the United States, 2009–2013

Infection with Strongyloides stercoralis is typically asymptomatic in immunocompetent hosts, despite chronic infection. In contrast, immunocompromised hosts such as solid organ transplant recipients are at risk for hyperinfection syndrome and/or disseminated disease, frequently resulting in fatal outcomes. Infection in these recipients may result from reactivation of latent infection or infection through transmission from an infected donor. We describe the Centers for Disease Control and Prevention's experience with seven clusters of donor‐derived infection from 2009 to 2013. Six of the seven (86%) donors were born in Latin America; donor screening was not performed prior to organ transplantation in any of these investigations. Eleven of the 20 (55%) organ recipients were symptomatic, two of whom died from complications of strongyloidiasis. We also describe the New York Organ Donor Network (NYODN) experience with targeted donor screening from 2010 to 2013. Of the 233 consented potential donors tested, 10 tested positive for Strongyloides antibody; and 18 organs were transplanted. The majority (86%) of the donors were born in Central or South America. Fourteen recipients received prophylaxis after transplantation; no recipients developed strongyloidiasis. The NYODN experience provides evidence that when targeted donor screening is performed prior to transplantation, donor‐derived infection can be averted in recipients.     

Placental Hofbauer cells assemble and sequester HIV-1 in tetraspanin-positive compartments that are accessible to broadly neutralizing antibodies

Introduction

Within monocyte-derived macrophages, HIV-1 accumulates in intracellular virus-containing compartments (VCCs) that are inaccessible to the external environment, which implicate these cells as latently infected HIV-1 reservoirs. During mother-to-child transmission of HIV-1, human placental macrophages (Hofbauer cells (HCs)) are viral targets, and have been shown to be infected in vivo and sustain low levels of viral replication in vitro; however, the risk of in utero transmission is less than 7%. The role of these primary macrophages as viral reservoirs is largely undefined. The objective of this study is to define potential sites of viral assembly, accumulation and neutralization in HCs given the pivotal role of the placenta in preventing HIV-1 infection in the mother-infant dyad.

Methods

Term placentae from 20 HIV-1 seronegative women were obtained following caesarian section. VCCs were evaluated by 3D confocal and electron microscopy. Colocalization R values (Pearson''s correlation) were quantified with colocalization module of Volocity 5.2.1. Replication kinetics and neutralization studies were evaluated using p24 ELISA.

Results

We demonstrate that primary HCs assemble and sequester HIV-1_BaL in intracellular VCCs, which are enriched in endosomal/lysosomal markers, including CD9, CD81, CD63 and LAMP-1. Following infection, we observed HIV-1 accumulation in potentially acidic compartments, which stained intensely with Lysotracker-Red. Remarkably, these compartments are readily accessible via the cell surface and can be targeted by exogenously applied small molecules and HIV-1-specific broadly neutralizing antibodies. In addition, broadly neutralizing antibodies (4E10 and VRC01) limited viral replication by HIV-1-infected HCs, which may be mediated by FcγRI.

Conclusions

These findings suggest that placental HCs possess intrinsic adaptations facilitating unique sequestration of HIV-1, and may serve as a protective viral reservoir to permit viral neutralization and/or antiretroviral drug entry in utero.     

High grade endometrial stromal sarcoma on thinprep

High grade endometrial stromal sarcoma (HGESS) is an uncommon malignancy recently re‐defined in the new WHO classification of endometrial stromal tumors. In this article, we discuss the differential diagnoses of metastatic HGESS in a fine needle aspiration (FNA) of a lymph node and compare the cytomorphology of HGESS in ThinPrep [(TP), Hologic Inc., Boxborough, MA] to conventional smears (CS). The patient had a history of stage I HGESS, status‐post supracervical hysterectomy without regional lymph node metastases. Her post‐operative course was complicated by pelvic fluid collections and enlarging para‐aortic lymph nodes. Diff‐Quik (DQ)‐stained and Papanicolaou (Pap)‐stained smears from a para‐aortic lymph node FNA demonstrated a cellular specimen with monomorphic population of plump to oval cells with scant, wispy cytoplasm in aggregates and as single cells. The nuclei showed fine chromatin and small inconspicuous nucleoli. Compared to the CS, HGESS cells in the TP showed similar cytological features, with the exception that the nuclei were slightly smaller, hyperchromatic, and the chromatin pattern was attenuated. In the absence of prior clinical history, the cytomorphology of metastatic HGESS in a lymph node can be difficult to differentiate from a lymphoma, a variety of metastatic spindle cell tumors or metastatic carcinoma. Immunohistochemical analysis and comparison with the primary tumor can be useful in proving the nature of the malignant cells. The cytomorphology of HGESS on TP correlated well in both single cells and aggregates when compared to CS. The differences noted were decreased nuclear size, nuclear hyperchromasia, and slightly attenuated nuclear detail on TP. Diagn. Cytopathol. 2015;43:756–762. © 2015 Wiley Periodicals, Inc.     

Riedel thyroiditis: Fine needle aspiration findings of a rare entity

Riedel thyroiditis is a rare fibrosing disorder characterized by extension of the fibroinflammatory process beyond the thyroid capsule. Due to the nature of this lesion, fine‐needle aspiration often yields scant material and may be interpreted as non‐diagnostic. In this report, we describe cytologic features that allow the cytopathologist to favor a diagnosis of Riedel thyroiditis, thereby guiding appropriate further work‐up and management. Diagn. Cytopathol. 2015;43:747–750. © 2015 Wiley Periodicals, Inc.