Endogenous TNF␣ prevents the attainment of maximum achievable peak bone mass in vivo. In vitro, TNF␣ suppresses BMP-2-and TGF␤-mediated Smad activation through induction of NF-B. Consistently, pharmacological suppression of NF-B augments osteoblast differentiation and mineralization in vitro.Introduction: Osteoporosis is a major health threat. Traditional therapeutic strategies have centered on anti-catabolic drugs that block bone resorption. Recently focus has shifted to anabolic agents that actively rebuild lost bone mass. Future strategies may involve elevating peak bone mass to delay osteoporosis development. Recent in vitro studies show that TNF␣ represses osteoblast differentiation and mineralization; however, the mechanisms are poorly understood and the impact of basal TNF␣ concentrations on the acquisition of peak bone mass in vivo is unknown. Materials and Methods: We examined peak BMD, bone volume, and bone turnover makers in mice deficient in TNF␣ or its receptors. We further examined the effect of TNF␣ on Smad-induced signaling by TGF␤ and BMP-2 in vitro using a Smad responsive reporter. The effect of TNF␣-induced NF-B signaling on Smad signaling and on in vitro osteoblast mineralization was examined using specific NF-B inhibitors and activators, and effects of TNF␣-induced NF-B signaling on BMP-2-induced Runx2 mRNA were examined using RT-PCR. Results: Mice null for TNF␣ or its p55 receptor had significantly increased peak bone mass, resulting exclusively from elevated bone formation. In vitro, TNF␣ potently suppressed Smad signaling induced by TGF␤ and BMP-2, downregulated BMP-2-mediated Runx2 expression, and inhibited mineralization of osteoblasts. These effects were mimicked by overexpression of NF-B and prevented by pharmacological NF-B suppression. Conclusions: Our data suggest that TNF␣ and NF-B antagonists may represent novel anabolic agents for the maximization of peak basal bone mass and/or the amelioration of pathological bone loss.

The detection of viral dynamics and localization in the context of controlled HIV infection remains a challenge and is limited to blood and biopsies. We developed a method to capture total-body simian immunodeficiency virus (SIV) replication using immunoPET (antibody-targeted positron emission tomography). The administration of a poly(ethylene glycol)-modified, 64Cu-labeled SIV Gp120–specifc antibody led to readily detectable signals in the gastrointestinal and respiratory tract, lymphoid tissues and reproductive organs of viremic monkeys. Viral signals were reduced in aviremic antiretroviral-treated monkeys but detectable in colon, select lymph nodes, small bowel, nasal turbinates, the genital tract and lung. In elite controllers, virus was detected primarily in foci in the small bowel, select lymphoid areas and the male reproductive tract, as confirmed by quantitative reverse-transcription PCR (qRT-PCR) and immunohistochemistry. This real-time, in vivo viral imaging method has broad applications to the study of immunodeficiency virus pathogenesis, drug and vaccine development, and the potential for clinical translation.

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Postmenopausal osteoporosis stems from an imbalance in osteoclastic bone resorption with respect to osteoblastic bone formation, a consequence of estrogen deficiency. The nuclear factor-κB (NF-κB) signal transduction pathway is critical for osteoclast formation and resorption, and suppression of NF-κB activation has been shown to block bone resorption in vitro, and to ameliorate inflammatory bone loss in vivo. The use of NF-κB antagonists to blunt the bone loss associated with estrogen deficiency however, has not been previously reported. In this study, we investigated whether pharmacological suppression of NF-κB signaling protects mice against ovariectomy (ovx)-induced bone loss. Ovx mice were treated with the potent NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) for 4 weeks and bone mineral density (BMD) and indices of bone structure quantitated by dual-energy X-ray absorptiometry (DXA), and μ-computed tomography (μCT). In vivo indices of bone resorption were quantitated in mouse serum using the biochemical marker C-terminal telopeptide of collagen (CTx). Our data revealed that NF-κB suppression significantly prevented ovx-induced bone destruction by preventing the increase in ovx-induced osteoclastic bone resorption. Our data suggest that NF-κB inhibitors may represent novel anticatabolic therapeutic agents for the amelioration of postmenopausal bone loss.

ABSTRACT:A free-ranging adult male gray fox (Urocyon cinereoargenteus) with moderate diarrhea and thick ocular mucus discharge was examined postmortem. Microscopically, the fox had intranuclear inclusion bodies within hepatocytes. Canine adenovirus-1 was identified by polymerase chain reaction (PCR) and nucleotide sequencing. To our knowledge, this is the first report of clinical infectious canine hepatitis in a gray fox.

Certain arsenic and selenium compounds show a remarkable mutual cancelation of toxicities, where a lethal dose of one can be voided by an equimolar and otherwise lethal dose of the other. It is now well established that the molecular basis of this antagonism is the formation and biliary excretion of seleno bis-(S-glutathionyl) arsinium anion [(GS)2AsSe](-). Previous work has definitively demonstrated the presence of [(GS)2AsSe](-) in rabbit bile, but only in the presence of other arsenic and selenium species. Rabbits have a gall bladder, which concentrates bile and lowers its pH; it seems likely that this may be responsible for the breakdown of biliary [(GS)2AsSe](-). Since rats have no gall bladder, the bile proceeds directly through the bile duct from the hepatobiliary tree. In the present work we have shown that the primary product of biliary co-excretion of arsenic and selenium in rats is [(GS)2AsSe](-), with essentially 100% of the arsenic and selenium present as this species. The chemical plausibility of the X-ray absorption spectroscopy-derived structural conclusions of this novel arsenic and selenium co-excretion product is supported by density functional theory calculations. These results establish the biomolecular basis to further explore the use of selenium dietary supplements as a possible palliative for chronic low-level arsenic poisoning of human populations.

Retrograde ejaculation (RE) has been reported in humans and animals but RE with subsequent sperm calculi has rarely been reported. This report documents clinical and pathological findings of spontaneous sperm cystolithiasis in four rhesus macaques. While this condition has been associated with repeated electroejaculation, spontaneous sperm cystolithiasis is highly unusual. The animals presented with either stranguria, dysuria, hematuria, distended abdomen or lethargy. Ultrasound examination revealed several hyperechoic masses within the lumen of the urinary bladder. The animals were euthanized due to poor prognosis or study end points. Postmortem examination revealed multiple angular, amorphous, soft to firm, pale yellow to greenish-brown and variably sized calculi in the lumen of the urinary bladder or prostatic/penile urethra. Histologically, the calculi were composed of numerous sperm embedded in abundant brightly eosinophilic matrix. Based on gross and histologic findings, RE associated sperm cystolithiasis was diagnosed, with ulcerative urethritis as the major primary apparent etiology. To the authors’ knowledge, this is the first report of four spontaneous cases of sperm cystolithiasis in rhesus macaques.

Objective Uncertain biological consequences of titanium-magnet (Ti-mag) tongue implants constrain application of the Tongue Drive System (TDS), a brain-tongue-computer interface for individuals with severe physical impairment. Here we describe oromotor function and tongue tissue response following Ti-Mag implantation and explantation in the miniature pig, an animal model with a tongue similar in size to humans. Design A 1.8 × 6.2 mm Ti-mag tracer was implanted into the anterior tongue in five Yucatan minipigs. X-rays were taken immediately and >six days after implantation to evaluate tracer migration. In three minipigs, the tracer was explanted >16 days after implantation. Twenty-five days post-explantation, tongue tissue was harvested and processed for histological and immunohistochemical (IHC) markers of healing. In two minipigs tissue markers of healing were evaluated post-mortem following >12 days implantation. Drink cycle rate (DCR) was characterized to determine the impact of procedures on oromotor function. Results Neither implantation (N=5) nor explantation (N=3) changed DCR. X-rays revealed minimal tracer migration (N=4, 0–4 mm). By histology and IHC a robust capsule was present two weeks post-implantation with limited fibrosis. Explantation produced localized fibrosis and limited muscle remodeling. Conclusions These findings suggest the safety of Ti-mag anterior tongue implants for assistive technologies in humans.