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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder leading to progressive heterotopic ossifications (HO) of muscles, tendons, and ligaments, which can be induced by trauma or by surgery. Despite strong medical advice to the contrary, an FOP patient insisted on surgery to alleviate her complete trismus, which caused an unbearable impact on her quality of life (QOL). The entire trismus history of this FOP patient is presented. [18F]-NaF position emission tomography/computed tomography (PET/CT) scans were introduced as an imaging method for heterotopic bone formation activity. To place our findings into context, a systematic review on jaw surgery in FOP was performed. After falling down the stairs, a 9-year-old patient developed mobility impairment of her left-sided jaw. During the following 13 years bone scintigraphy showed persistent activity of the disease leading to progressive left-sided zygomatico-mandibular fusion by HO, resulting in complete trismus. Within 1 month after HO removal on the left side and a matching right coronoidectomy, [18F]-NaF PET/CT demonstrated a substantial flare-up activity followed by new HO in both masseter and temporalis muscles. Despite recurrent HO and trismus her QOL increased due to a stable increased interincisal opening of 5.5 mm. Although systematic review reveals a 100% risk of HO recurrence after jaw surgery, information on improved QOL is scarce. In conclusion, surgery in FOP may be beneficial for QOL despite new HO formation. Assessment of disease activity using [18F]-NaF PET/CT is possible before HO is evident on CT and may serve as a new and quantitative marker of the disease. © 2017 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

Previous work has established a robust relationship between impulsivity and addiction, and revealed that impulsive decision making predisposes the vulnerability to cocaine-seeking behavior in rats. An important next step is to assess whether elevated relapse vulnerability can be treated via the reduction of impulsive decision making. Therefore, this study explored whether subchronic atomoxetine treatment can reduce relapse vulnerability by reducing impulsive decision making. Rats were trained in the delayed reward task and were subjected to 3 weeks of cocaine self-administration. Following drug self-administration, animals were divided to different experimental groups and received the noradrenaline transporter inhibitor and attention-deficit/hyperactivity disorder drug atomoxetine or vehicle subchronically for 20 days. On days1 and 10 after treatment cessation, a context-induced reinstatement test was performed. Throughout the entire experiment, changes in impulsive decision making were continuously monitored. Subchronic treatment with atomoxetine reduced context-induced reinstatement both 1 and 10 days after treatment cessation, only in animals receiving no extinction training. Interestingly, neither subchronic nor acute atomoxetine treatments affected impulsive decision making. Our data indicate that the enduring reduction in relapse sensitivity by atomoxetine occured independent of a reduction in impulsive decision making. Nonetheless, repeated atomoxetine administration seems a promising pharmacotherapeutical strategy to prevent relapse to cocaine seeking in abstinent drug-dependent subjects.

Impulsivity is a risk factor for alcoholism, and long-term alcohol exposure may further impair impulse control in a manner that propels problematic alcohol use. The present study employed the rat 5-choice serial reaction time task (5-CSRTT) to measure behavioral inhibition and attentional capacity during abstinence from repeated 5-day cycles of alcohol liquid diet consumption. Task performance was not disrupted following the first cycle of alcohol exposure; however, evidence of impaired behavioral inhibition emerged following the third cycle of alcohol exposure. In comparison with controls, alcoholic rats exhibited deficits in inhibitory control during cognitively challenging 5-CSRTT tests employing variable intertrial interval (varITI). This behavioral disruption was not present during early abstinence (3 days) but was evident by 7 days of abstinence and persisted for at least 34 days. Interestingly, renewed alcohol consumption ameliorated these disruptions in impulse control, although deficient behavioral inhibition re-emerged during subsequent abstinence. Indices of increased impulsivity were no longer present in tests conducted after 49 days of abstinence. Alcohol-related impairments in impulse control were not evident in sessions employing highly familiar task parameters regardless of the abstinence period, and control experiments confirmed that performance deficits during the challenge sessions were unlikely to result from alcohol-related disruption in the adaptation to repeated varITI testing. Together, the current findings demonstrate that chronic intermittent alcohol consumption results in decreased behavioral inhibition in rats that is temporally similar to clinical observations of disrupted impulsive control in abstinent alcoholics performing tasks of behavioral inhibition. The present study employed the 5-Choice Serial Reaction Time Task (5-CSRTT) to evaluate the effects of prior chronic alcohol exposure on the impulsive-like behavior in rats. Alcohol-exposed rats exhibited deficits in inhibitory control and increased perseverative behavior during 5-CSRTT tests employing variable inter-trial intervals. These disruptions were not present during early abstinence (3d) but emerged by 7d abstinence and persisted for at least 34d. Renewed alcohol consumption ameliorated these disruptions, though deficient behavioral inhibition re-emerged during subsequent abstinence.

To investigate whether the disproportionate degradation of mandibular condyle cartilage in arthritic juvenile temporomandibular joint (TMJ) is related to distinctive responses of TMJ-derived cells to tumor necrosis factor-α (TNF-α), and whether mechanical loading affects this response. The effect of TNF-α (0.1–10 ng/ml) was tested on juvenile porcine TMJ cells isolated from the condyle, fossa, and disc, grown in 3D agarose gels. Expression of anabolic and catabolic factors was quantified by RT-qPCR and/or immunohistochemistry. Condylar cells were stimulated for 12 h with TNF-α (10 ng/ml), followed by 8 h of 6% cyclic tensile strain, and gene expression of MMPs was quantified. TNF-α (10 ng/ml) reduced the expression of the matrix proteins collagen types I and II after 6 h of incubation. Aggrecan gene expression was increased in the presence of 0.1 ng/ml TNF-α. The fossa and disc cells responded to TNF-α with an increased expression of the aggrecanase ADAMTS4. TNF-α enhanced MMP-13 gene and protein expression only by condylar cells. Mechanical loading reduced this effect. Cells isolated from the different cartilaginous structures reacted differently to TNF-α. Since the disc and fossa contain a very low level of proteoglycans in comparison to the condyle, the role played by ADAMTS4 in degradation of the fossa and disc might be limited. TNF-α induced MMP-13 expression by condylar cells might be involved in the degradation of the juvenile condyle. Since this expression was reduced by mechanical loading, functional loading with oral physiotherapy or orthodontic activators may help to reduce the catabolic effect of TNF-α. J. Cell. Physiol. 232: 1287–1294, 2017.

Osteoclasts are bone-degrading cells that are formed through fusion of their monocytic precursors. Three distinct subsets of monocytes have been identified in human peripheral blood: classical, intermediate, and non-classical monocytes. They are known to play different roles in physiology and pathology, but their capacity to differentiate into osteoclasts and whether inflammatory cytokines influence this differentiation is unknown. We hypothesized that classical, intermediate, and non-classical monocytes generate functionally different osteoclasts and that they respond in different ways to the inflammatory cytokine interleukin-17A (IL-17A). To investigate this, the different monocyte subsets were isolated from human peripheral blood and osteoclastogenesis was induced with the cytokines M-CSF and RANKL, with or without IL-17A. We found that all subsets are able to differentiate into osteoclasts in vitro, and that both osteoclastogenesis and subsequent bone resorption was distinctly affected by IL-17A. Osteoclastogenesis and bone resorption by osteoclasts derived from classical monocytes remained unaffected by IL-17A, while osteoclast formation from intermediate monocytes was inhibited by the cytokine. Surprisingly, bone resorption by osteoclasts derived from intermediate monocytes remained at similar levels as control cultures, indicating an increased bone resorbing activity by these osteoclasts. Limited numbers of osteoclasts were formed from non-classical monocytes on bone and no bone resorption was detected, which suggest that these cells belong to a cell lineage different from the osteoclast. By providing more insight into osteoclast formation from human blood monocytes, this study contributes to the possible targeting of specific osteoclast precursors as a therapeutic approach for diseases associated with inflammatory bone loss

Tobacco and alcohol dependence are characterized by continued use despite deleterious health, social and occupational consequences, implying that addicted individuals pay a high price for their use. In behavioral economic terms, such persistent consumption despite increased costs can be conceptualized as inelastic demand. Recent animal studies demonstrated that high-impulsive individuals are more willing to work for nicotine or cocaine infusions than their low-impulsive counterparts, indicating that this trait might be causally related to inelastic drug demand. By employing progressive ratio schedules of reinforcement combined with a behavioral economics approach of analysis, we determined whether trait impulsivity is associated with an insensitivity of nicotine or alcohol consumption to price increments. Rats were trained on a delayed discounting task, measuring impulsive choice. Hereafter, high- and low-impulsive rats were selected and trained to nose poke for intravenous nicotine or oral alcohol. Upon stable self-administration on a continuous reinforcement schedule, the price (i.e. response requirement) was increased. Demand curves, depicting the relationship between price and consumption, were produced using Hursh's exponential demand equation. Similar to human observations, nicotine and alcohol consumption in rats fitted this equation, thereby demonstrating the validity of our model. Moreover, high-impulsive rats displayed inelastic nicotine demand, as their nicotine consumption was less sensitive to price increments as compared with that in low-impulsive rats. Impulsive choice was not related to differences in alcohol demand elasticity. Our model seems well suited for studying nicotine and alcohol demand in rats and, as such, might contribute to our understanding of tobacco and alcohol dependence. © 2011 Society for the Study of Addiction.

Background and Objective: Inflammatory responses of host cells to oral pathogenic bacteria, such as Porphyromonas gingivalis, are crucial in the development of periodontitis. Host cells, such as periodontal ligament and gingival fibroblasts, from periodontitis patients may respond to P. gingivalis in a different manner compared with cells from healthy persons. The aim of this study was to investigate inflammatory responses to viable P. gingivalis by periodontal ligament and gingival fibroblasts from periodontitis patients and healthy control subjects.Material and Methods: Primary periodontal ligament and gingival fibroblasts from periodontitis patients (n = 14) and healthy control subjects (n = 8) were challenged in vitro with viable P. gingivalis. Gene expression of Toll-like receptors (TLRs) 1, 2, 4, 6, 7 and 9, CD14, nuclear factor-κB1 and its putative inhibitor NF-κB inhibitor-like protein 1, and of interleukin-1β, interleukin-6, interleukin-8, tumour necrosis factor-α, monocyte chemotactic protein-1 and regulated upon activation, normal T-cel expressed, and secreted, were assessed by real-time PCR.Results: Periodontal ligament fibroblasts from periodontitis patients had a higher mRNA expression of TLR1, TLR4, TLR7 and CD14, and a lower expression of NFKBIL1, both before and after P. gingivalis challenge. In contrast, gingival fibroblasts from periodontitis patients had stronger induction of TLR1, TLR2 and TLR7 by P. gingivalis. Cytokine responses were not different between patients and control subjects. Interestingly, periodontal ligament, but not gingival, fibroblasts from P. gingivalis culture-positive persons responded more strongly to P. gingivalis than periodontal ligament fibroblasts from P. gingivalis-negative persons.Conclusion: Periodontal ligament and gingival fibroblasts respond to P. gingivalis in a different manner and may play different roles in periodontitis. Both subsets of fibroblasts from patients appear more active in interaction with P. gingivalis. Moreover, periodontal ligament fibroblasts from P. gingivalis-positive donors are more responsive to an in vitro P. gingivalis challenge.

The objective of this study was to determine how different feeding methods may affect the learning of feeding, sorting, and competitive behavior of growing dairy heifers. We hypothesized that heifers previously fed a total mixed ration (TMR) would distribute their feeding time more evenly throughout the day, sort the new ration less, compete less for feed, maintain a more solid fecal consistency, and continue to grow rapidly compared with heifers previously fed a top-dressed ration (TDR). Thirty-two Holstein heifers (237.2 ± 21.9 d of age) were divided into 8 groups of 4 and exposed to 1 of 2 treatments for 13 wk: 1) TMR or 2) TDR, with each containing 65% grass/alfalfa haylage and 35% textured concentrate on a dry matter (DM) basis. Following this feeding period, all heifers were switched to an unfamiliar TMR containing 56.1% grass/alfalfa haylage, 21.0% corn silage, 21.0% high-moisture corn, and 1.9% mineral supplement (DM basis) for 7 wk. Group DM intakes were recorded daily throughout the experiment. Feeding behavior, recorded using time-lapse video, and sorting behavior were measured for 7 d during wk 1, 4, and 7 after the dietary change. Feeding competition was measured on d 2, 4, and 6 of each recording week. Sorting activity was determined through particle size analysis of the fresh feed and orts. The particle size separator separated feed into 4 fractions (long, medium, short, and fine). Sorting of each fraction was calculated as actual intake expressed as a percentage of predicted intake. Animals were scored for fecal consistency twice weekly, using a scale from 1 (liquid) to 4 (solid). Heifers were weighed every 2 wk. Neither DM intake (9.0 kg/d) nor average daily gain (1.2 kg/d) differed between treatments. Sorting also did not differ between treatments. Heifers tended to spend more time feeding if they had previously been fed a TDR (198.8 vs. 186.8 min/d). As they had done before the dietary change, heifers previously fed the TDR spent more time at the bunk in the 2 h following feed delivery (40.6 vs. 25.9 min/d). Heifers previously fed the TDR were displaced from the feed bunk more frequently than heifers previously fed the TMR (23.0 vs. 13.1 times/d), particularly during the 2-h period following feed delivery. Fecal scores were lower (more fluid in consistency) for heifers originally fed the TDR (3.2 vs. 3.7). The continued difference in feed bunk competition suggests that heifers previously fed the TDR had learned these patterns in the past, retaining them even when switched to an unfamiliar ration. Furthermore, lower fecal scores for heifers previously fed the TDR suggest altered rumen fermentation, possibly because of altered diurnal consumption patterns. These results show that feeding a TMR to replacement dairy heifers from a young age promotes a more even diurnal feeding pattern, minimizes feed bunk competition, and promotes a more solid fecal consistency.

Penguin feathers are highly modified in form and function, but there have been no fossils to inform their evolution. A giant penguin with feathers was recovered from the late Eocene (similar to 36 million years ago) of Peru. The fossil reveals that key feathering features, including undifferentiated primary wing feathers and broad body contour feather shafts, evolved early in the penguin lineage. Analyses of fossilized color-imparting melanosomes reveal that their dimensions were similar to those of non-penguin avian taxa and that the feathering may have been predominantly gray and reddish-brown. In contrast, the dark black-brown color of extant penguin feathers is generated by large, ellipsoidal melanosomes previously unknown for birds. The nanostructure of penguin feathers was thus modified after earlier macrostructural modifications of feather shape linked to aquatic flight.

The objective of this study was to determine the effects of feed delivery method on growth, feeding competition, feeding, and sorting behavior of dairy heifers. Thirty-two Holstein heifers (146.2 ± 21.9 d of age) were divided into 8 groups of 4 and exposed to 1 of 2 feed delivery treatments for 13 wk. The treatment rations contained 65% grass/alfalfa haylage and 35% textured concentrate (on a dry matter basis) fed as a 1) total mixed ration (TMR) or 2) top-dressed ration (TDR). Group dry matter intakes were recorded daily throughout the experiment. Feeding behavior, recorded using time-lapse video, and sorting behavior were measured for 7 d during each of wk 1, 5, 9, and 13. Sorting activity was determined through particle size analysis of the fresh feed and orts. The particle size separator separated feed into 4 fractions (long, medium, short, and fine). Sorting of each fraction was calculated as actual intake expressed as a percentage of predicted intake. Heifers were fecal scored for consistency of stool twice weekly using a scale from 1 (liquid) to 4 (solid); heifers were weighed every 2 wk. Neither dry matter intake (7.3 kg/d) nor average daily gain (1.3 kg/d) differed between treatments. Heifers fed the TDR tended to consume less neutral detergent fiber than heifers fed the TMR (4.77 vs. 4.91 kg/d). Heifers fed the TDR sorted against long particles (98.9 vs. 96.0%) and consumed short particles (100.3 vs. 101.1%) to a greater extent than did heifers fed the TMR. Daily feeding time did not differ between treatments (201.0 min/d), but heifers on the TDR did spend more time at the bunk in the 2 h following feed delivery (50.1 vs. 32.0 min/d). Heifers fed the TDR were displaced from the feed bunk more frequently than heifers fed the TMR (17.6 vs. 8.6 times/d), particularly during the 2-h period following feed delivery. Fecal scores were lower for heifers on the TDR (2.7 vs. 3.4). These results suggest that feeding a TMR to replacement dairy heifers may promote a more even diurnal feeding pattern, minimize feed sorting and feed bunk competition, and promote more solid fecal consistency.

Disequilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts is central to many bone diseases. Here, we show that dysregulated expression of translationally controlled isoforms of CCAAT/enhancer-binding protein beta (C/EBPbeta) differentially affect bone mass. Alternative translation initiation that is controlled by the mammalian target of rapamycin (mTOR) pathway generates long transactivating (LAP(*), LAP) and a short repressive (LIP) isoforms from a single C/EBPbeta transcript. Rapamycin, an inhibitor of mTOR signalling increases the ratio of LAP over LIP and inhibits osteoclastogenesis in wild type (WT) but not in C/EBPbeta null (c/ebpbeta(-/-)) or in LIP knock-in (L/L) osteoclast precursors. C/EBPbeta mutant mouse strains exhibit increased bone resorption and attenuated expression of MafB, a negative regulator of osteoclastogenesis. Ectopic expression of LAP and LIP in monocytes differentially affect the MafB promoter activity, MafB gene expression and dramatically affect osteoclastogenesis. These data show that mTOR regulates osteoclast formation by modulating the C/EBPbeta isoform ratio, which in turn affects osteoclastogenesis by regulating MafB expression.

The multinucleated osteoclast has a unique function: degradation of mineralized tissues. It is generally taken that all osteoclasts are alike, independent of the skeletal site where they exert their activity. Recent data, however, question this view as they show that osteoclasts at different bony sites appear to differ, for example in the machinery responsible for resorption. Support for the notion that there may be heterogeneity in osteoclasts is obtained from studies in which osteoclast activity is inhibited and from observations in osteopetrosis and inflammatory bone conditions. In this review we discuss the available evidence and propose the existence of bone-site-specific osteoclast heterogeneity.

Recent studies have implicated the endocannabinoid (eCB) system in the neuronal mechanisms underlying substance dependence. Here, we review results of studies using cannabinoid receptor subtype 1 (CB1) knockout mice as well as CB1 antagonists to elucidate the role of this neurotransmitter system in psychostimulant addiction. The overall picture is that CB1 receptors appear not to be involved in psychostimulant reward, nor in the development of dependence to such substances. In contrast, the eCB system appears to play a role in the persistence of psychostimulant addiction. In particular, CB1 receptors have been found to play a cardinal role in mediating reinstatement of previously extinguished drug-seeking behavior upon re-exposure to the drug or drug-associated cues. The anatomical loci as well as the neuronal mechanisms of the relapse-preventing effects of CB1 antagonists are still poorly understood, although interactions of the eCB system with afferent glutamatergic and possibly dopaminergic projections to the nucleus accumbens are most likely involved. In addition, CB1 receptors seem to modulate drug-related memories, in line with the hypothesized role of the eCB system in memory-related plasticity. Together, these findings suggest that modulators of the eCB system represent a promising novel type of therapy to treat drug addiction. © 2008 The Authors.

Glare laminates are materials that consist of alternating aluminium and glass prepreg layers especially designed for aeroplane structures. The result is a material that combines the properties of its constituents and the properties of a bonded structure. Some of the favourable characteristics of Glare are its fatigue, impact and fire resistance properties and the possibility to create tailored design solutions. After 25 years of development and extensive investigations within the aerospace environment, Glare is now ready to be applied for industrial production. It will be applied in large parts of the new Airbus A380 fuselage, which is planned to have its first flight in 2004. This research describes the behaviour of Glare with holes that are made within production and the behaviour when the material is damaged due to an impact like for example a bird strike or an engine seperationf what creates cracks. These holes and this damage are regarded as blunt and sharp notches respectively. The failure mechanisms that were observed are investigated and function as the basis for the development of engineering calculation methods for the blunt and sharp notch behaviour of arbitrary Glare laminates. Additional research concerning the behaviour of spliced Glare laminates in the presence of notches, the presence of a crack in a row of holes and the development of Glare with crack stoppers is presented.