bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in LRP5 cause primary osteoporosis without features of OI by reducing Wnt signaling activity
Authors: Korvala Johanna , Jüppner Harald , Mäkitie Outi , Sochett Etienne , Schnabel Dirk , Mora Stefano , Bartels Cynthia F , Warman Matthew L , Deraska Donald , Cole William G , Hartikka Heini , Ala-Kokko Leena , Männikkö Minna 
Published: April 2012

Abstract

Background
Primary osteoporosis is a rare childhood-onset skeletal condition whose pathogenesis has been largely unknown. We have previously shown that primary osteoporosis can be caused by heterozygous missense mutations in the Low-density lipoprotein receptor-related protein 5 (LRP5) gene, and the role of LRP5 is further investigated here.

Methods

LRP5 was analyzed in 18 otherwise healthy children and adolescents who had evidence of osteoporosis (manifested as reduced bone mineral density i.e. BMD, recurrent peripheral fractures and/or vertebral compression fractures) but who lacked the clinical features of osteogenesis imperfecta (OI) or other known syndromes linked to low BMD. Also 51 controls were analyzed. Methods used in the genetic analyses included direct sequencing and multiplex ligation-dependent probe amplification (MLPA). In vitro studies were performed using luciferase assay and quantitative real-time polymerase chain reaction (qPCR) to examine the effect of two novel and three previously identified mutations on the activity of canonical Wnt signaling and on expression of tryptophan hydroxylase 1 (Tph1) and 5-hydroxytryptamine (5-Htr1b).

Results
Two novel LRP5 mutations (c.3446 T > A; p.L1149Q and c.3553 G > A; p.G1185R) were identified in two patients and their affected family members. In vitro analyses showed that one of these novel mutations together with two previously reported mutations (p.C913fs, p.R1036Q) significantly reduced the activity of the canonical Wnt signaling pathway. Such reductions may lead to decreased bone formation, and could explain the bone phenotype. Gut-derived Lrp5 has been shown to regulate serotonin synthesis by controlling the production of serotonin rate-limiting enzyme, Tph1. LRP5 mutations did not affect Tph1 expression, and only one mutant (p.L1149Q) reduced expression of serotonin receptor 5-Htr1b (p < 0.002).

Conclusions
Our results provide additional information on the role of LRP5 mutations and their effects on the development of juvenile-onset primary osteoporosis, and hence the pathogenesis of the disorder. The mutations causing primary osteoporosis reduce the signaling activity of the canonical Wnt signaling pathway and may therefore result in decreased bone formation. The specific mechanism affecting signaling activity remains to be resolved in future studies.
Comparing risk factors of HIV among hijra sex workers in Larkana and other cities of Pakistan: an analytical cross sectional study
Authors: Altaf Arshad , Zahidie Aysha , Agha Ajmal 
Published: April 2012

Abstract

Background
In 2005, Pakistan was first labeled as a country with concentrated epidemic of Human Immunodeficiency Virus (HIV). This was revealed through second generation surveillance conducted by HIV/AIDS Surveillance Project (HASP). While injection drug users (IDUs) were driving the epidemic, subsequent surveys showed that Hijra (transgender) sex workers (HSWs) were emerging as the second most vulnerable group with an average national prevalence of 6.4%. An exceptionally high prevalence (27.6%) was found in Larkana, which is a small town on the right bank of river Indus near the ruins of Mohenjo-Daro in the province of Sindh. This paper presents the risk factors associated with high prevalence of HIV among HSWs in Larkana as compared to other cities of the country.

Methods
Data were extracted for secondary analysis from 2008 Integrated behavioral and biological survey (IBBS) to compare HSWs living in Larkana with those living in other cities including Karachi and Hyderabad in Sindh; Lahore and Faisalabad in Punjab; and Peshawar in Khyber Pakhtunkhwa provinces. After descriptive analysis, univariate and multivariate analyses were performed to identify risk factors. P value of 0.25 or less was used to include factors in multivariate analysis.

Results
We compared 199 HSWs from Larkana with 420 HSWs from other cities. The average age of HSWs in Larkana was 26.42 (±5.4) years. Majority were Sindhi speaking (80%), uneducated (68%) and unmarried (97%). In univariate analysis, factors associated with higher prevalence of HIV in Larkana included younger age i.e. 20–24 years (OR: 5.8, CI: 2.809–12.15), being unmarried (OR: 2.4, CI: 1.0–5.7), sex work as the only mode of income (OR: 5.5, CI: 3.70–8.2) and longer duration of being involved in sex work 5–10 years (OR: 3.3, CI: 1.7–6.12). In multivariate logistic regression the HSWs from Larkana were more likely to lack knowledge regarding preventive measures against HIV (OR 11.9, CI: 3.4–41.08) and were more prone to use of alcohol during anal intercourse (OR: 6.3, CI: 2.77–17.797).

Conclusion
Outreach programs focusing on safer sexual practices and VCT are urgently needed to address the upsurge of HIV among HSWs in Larkana.
Designing the ideal model for assessment of wound contamination after gunshot injuries: a comparative experimental study
Authors: von See Constantin , Rana Majeed , Stoetzer Marcus , Kokemueller Horst , Ruecker Martin , Gellrich Nils-Claudius 
Published: April 2012

Abstract

Background
Modern high-velocity projectiles produce temporary cavities and can thus cause extensive tissue destruction along the bullet path. It is still unclear whether gelatin blocks, which are used as a well-accepted tissue simulant, allow the effects of projectiles to be adequately investigated and how these effects are influenced by caliber size.

Method
Barium titanate particles were distributed throughout a test chamber for an assessment of wound contamination. We fired .22-caliber Magnum bullets first into gelatin blocks and then into porcine hind limbs placed behind the chamber. Two other types of bullets (.222-caliber bullets and 6.5 × 57 mm cartridges) were then shot into porcine hind limbs. Permanent and temporary wound cavities as well as the spatial distribution of barium titanate particles in relation to the bullet path were evaluated radiologically.

Results
A comparison of the gelatin blocks and hind limbs showed significant differences (p < 0.05) in the mean results for all parameters. There were significant differences between the bullets of different calibers in the depth to which barium titanate particles penetrated the porcine hind limbs. Almost no particles, however, were found at a penetration depth of 10 cm or more. By contrast, gas cavities were detected along the entire bullet path.

Conclusion
Gelatin is only of limited value for evaluating the path of high-velocity projectiles and the contamination of wounds by exogenous particles. There is a direct relationship between the presence of gas cavities in the tissue along the bullet path and caliber size. These cavities, however, are only mildly contaminated by exogenous particles.
The NAMPT inhibitor FK866 reverts the damage in spinal cord injury
Authors: Esposito Emanuela , Impellizzeri Daniela , Mazzon Emanuela , Fakhfouri Gohar , Rahimian Reza , Travelli Cristina , Tron Gian Cesare , Genazzani Armando A , Cuzzocrea Salvatore 
Published: April 2012

Abstract

Background
Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting.

Methods
We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI.

Results
Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity.
We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866.

Conclusions
Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.
Neovascularization of coronary tunica intima (DIT) is the cause of coronary atherosclerosis. Lipoproteins invade coronary intima via neovascularization from adventitial vasa vasorum, but not from the arterial lumen: a hypothesis
Authors: Subbotin Vladimir M 
Published: April 2012

Abstract
Background
An accepted hypothesis states that coronary atherosclerosis (CA) is initiated by endothelial dysfunction due to inflammation and high levels of LDL-C, followed by deposition of lipids and macrophages from the luminal blood into the arterial intima, resulting in plaque formation. The success of statins in preventing CA promised much for extended protection and effective therapeutics. However, stalled progress in pharmaceutical treatment gives a good reason to review logical properties of the hypothesis underlining our efforts, and to reconsider whether our perception of CA is consistent with facts about the normal and diseased coronary artery.

Analysis
To begin with, it must be noted that the normal coronary intima is not a single-layer endothelium covering a thin acellular compartment, as claimed in most publications, but always appears as a multi-layer cellular compartment, or diffuse intimal thickening (DIT), in which cells are arranged in many layers. If low density lipoprotein cholesterol (LDL-C) invades the DIT from the coronary lumen, the initial depositions ought to be most proximal to blood, i.e. in the inner DIT. The facts show that the opposite is true, and lipids are initially deposited in the outer DIT. This contradiction is resolved by observing that the normal DIT is always avascular, receiving nutrients by diffusion from the lumen, whereas in CA the outer DIT is always neovascularized from adventitial vasa vasorum. The proteoglycan biglycan, confined to the outer DIT in both normal and diseased coronary arteries, has high binding capacity for LDL-C. However, the normal DIT is avascular and biglycan-LDL-C interactions are prevented by diffusion distance and LDL-C size (20 nm), whereas in CA, biglycan in the outer DIT can extract lipoproteins by direct contact with the blood. These facts lead to the single simplest explanation of all observations: (1) lipid deposition is initially localized in the outer DIT; (2) CA often develops at high blood LDL-C levels; (3) apparent CA can develop at lowered blood LDL-C levels. This mechanism is not unique to the coronary artery: for instance, the normally avascular cornea accumulates lipoproteins after neovascularization, resulting in lipid keratopathy.

Hypothesis
Neovascularization of the normally avascular coronary DIT by permeable vasculature from the adventitial vasa vasorum is the cause of LDL deposition and CA. DIT enlargement, seen in early CA and aging, causes hypoxia of the outer DIT and induces neovascularization. According to this alternative proposal, coronary atherosclerosis is not related to inflammation and can occur in individuals with normal circulating levels of LDL, consistent with research findings.
Factoring-in agglomeration of carbon nanotubes and nanofibers for better prediction of their toxicity versus asbestos
Authors: Murray Ashley R , Kisin Elena R , Tkach Alexey V , Yanamala Naveena , Mercer Robert , Young Shih-Houng , Fadeel Bengt , Kagan Valerian E , Shvedova Anna A 
Published: April 2012

Abstract

Background
Carbon nanotubes (CNT) and carbon nanofibers (CNF) are allotropes of carbon featuring fibrous morphology. The dimensions and high aspect ratio of CNT and CNF have prompted the comparison with naturally occurring asbestos fibers which are known to be extremely pathogenic. While the toxicity and hazardous outcomes elicited by airborne exposure to single-walled CNT or asbestos have been widely reported, very limited data are currently available describing adverse effects of respirable CNF.

Results
Here, we assessed pulmonary inflammation, fibrosis, oxidative stress markers and systemic immune responses to respirable CNF in comparison to single-walled CNT (SWCNT) and asbestos. Pulmonary inflammatory and fibrogenic responses to CNF, SWCNT and asbestos varied depending upon the agglomeration state of the particles/fibers. Foci of granulomatous lesions and collagen deposition were associated with dense particle-like SWCNT agglomerates, while no granuloma formation was found following exposure to fiber-like CNF or asbestos. The average thickness of the alveolar connective tissue - a marker of interstitial fibrosis - was increased 28 days post SWCNT, CNF or asbestos exposure. Exposure to SWCNT, CNF or asbestos resulted in oxidative stress evidenced by accumulations of 4-HNE and carbonylated proteins in the lung tissues. Additionally, local inflammatory and fibrogenic responses were accompanied by modified systemic immunity, as documented by decreased proliferation of splenic T cells ex vivo on day 28 post exposure. The accuracies of assessments of effective surface area for asbestos, SWCNT and CNF (based on geometrical analysis of their agglomeration) versus estimates of mass dose and number of particles were compared as predictors of toxicological outcomes.

Conclusions
We provide evidence that effective surface area along with mass dose rather than specific surface area or particle number are significantly correlated with toxicological responses to carbonaceous fibrous nanoparticles. Therefore, they could be useful dose metrics for risk assessment and management.
Meiotic errors followed by two parallel postzygotic trisomy rescue events are a frequent cause of constitutional segmental mosaicism
Authors: Robberecht Caroline , Voet Thierry , Utine Gülen E , Schinzel Albert , de Leeuw Nicole , Fryns Jean-Pierre , Vermeesch Joris 
Published: April 2012

Abstract
Structural copy number variation (CNV) is a frequent cause of human variation and disease. Evidence is mounting that somatic acquired CNVs are prevalent, with mosaicisms of large segmental CNVs in blood found in up to one percent of both the healthy and patient populations. It is generally accepted that such constitutional mosaicisms are derived from postzygotic somatic mutations. However, few studies have tested this assumption. Here we determined the origin of CNVs which coexist with a normal cell line in nine individuals. We show that in 2/9 the CNV originated during meiosis. The existence of two cell lines with 46 chromosomes thus resulted from two parallel trisomy rescue events during postzygotic mitoses.
Enhanced generation of retinal progenitor cells from human retinal pigment epithelial cells induced by amniotic fluid
Authors: Sanie-Jahromi Fatemeh , Ahmadieh Hamid , Soheili Zahra-Soheila , Davari Maliheh , Ghaderi Shima , Kanavi Mozhgan Rezaei , Samiei Shahram , Deezagi Abdolkhalegh , Pakravesh Jalil , Bagheri Abouzar 
Published: April 2012

Abstract

Background
Retinal progenitor cells are a convenient source of cell replacement therapy in retinal degenerative disorders. The purpose of this study was to evaluate the expression patterns of the homeobox genes PAX6 and CHX10 (retinal progenitor markers) during treatment of human retinal pigment epithelium (RPE) cells with amniotic fluid (AF), RPE cells harvested from neonatal cadaver globes were cultured in a mixture of DMEM and Ham's F12 supplemented with 10% FBS. At different passages, cells were trypsinized and co-cultured with 30% AF obtained from normal fetuses of 1416 weeks gestational age.

Results
Compared to FBS-treated controls, AF-treated cultures exhibited special morphological changes in culture, including appearance of spheroid colonies, improved initial cell adhesion and ordered cell alignment. Cell proliferation assays indicated a remarkable increase in the proliferation rate of RPE cells cultivated in 30% AF-supplemented medium, compared with those grown in the absence of AF. Immunocytochemical analyses exhibited nuclear localization of retinal progenitor markers at a ratio of 33% and 27% for CHX10 and PAX6, respectively. This indicated a 3-fold increase in retinal progenitor markers in AF-treated cultures compared to FBS-treated controls. Real-time PCR data of retinal progenitor genes (PAX6, CHX10 and VSX-1) confirmed these results and demonstrated AF's capacity for promoting retinal progenitor cell generation.

Conclusion
Taken together, the results suggest that AF significantly promotes the rate of retinal progenitor cell generation, indicating that AF can be used as an enriched supplement for serum-free media used for the in vitro propagation of human progenitor cells.
Brazilian solar saltworks - ancient uses and future possibilities
Authors: De Medeiros Rocha Renato , Costa Diógenes FS , Lucena-Filho Milton A , Bezerra Rodolfo M , Medeiros David HM , Azevedo-Silva Antonio M , Araújo Cristian N , Xavier-Filho Lauro 
Published: April 2012

Abstract
Coastal solar saltworks of Brazil are exploited for sea salt, which becomes progressively concentrated by evaporation. This study aimed to review the current and new potential uses of these systems, in order to provide more dynamic for this activity. The first evaporation ponds are also used for artisanal fisheries, ensuring the livelihood of many families. All the brine rich in secondary salts (bittern) can be widely used by the chemical industry, while the Brazil shows an incipient production of "flower of salt", a salt with distinct characteristics with higher market value than sodium chloride. On the other hand, the saltponds have a high potential for management and obtaining of large populations of Artemia spp., purifying the brine through the action as biological filter. This microcrustacean occurs naturally in intermediate salinity ponds, being commonly used in aquaculture. Species of microalgae and halobacteria found in the saltworks are employed for extraction of beta-carotene and glycerol, used in an extensive list of products with high commercial value. These ecosystems represent refuge zones for many species of migratory birds, becoming imperative to promote the conservation of these hypersaline wetlands.
Antitumor Activity and Safety of Tivozanib (AV-951) in a Phase II Randomized Discontinuation Trial in Patients With Renal Cell Carcinoma
Authors: Nosov Dmitry A. , Esteves Brooke , Lipatov Oleg N. , Lyulko Alexei A. , Anischenko A. A. , Chacko Raju T. , Doval Dinesh C. , Strahs Andrew , Slichenmyer William J. , Bhargava Pankaj 
Published: April 2012

Purpose The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC). Patients and Methods In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS). Results Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). Conclusion Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC.
Long-Term Dynamics of Bone Mineral Density During Intermittent Androgen Deprivation for Men With Nonmetastatic, Hormone-Sensitive Prostate Cancer
Authors: Yu Evan Y. , Kuo Kevin F. , Gulati Roman , Chen Shu , Gambol Teresa E. , Hall Suzanne P. , Jiang Peter Y. , Pitzel Peggy , Higano Celestia S. 
Published: April 2012

Purpose To investigate changes in bone mineral density (BMD) and fracture risk in men who received intermittent androgen deprivation (IAD) for nonmetastatic, hormone-sensitive prostate cancer. Patients and Methods Men with prostate cancer who lacked radiographically detectable metastases were treated in a prospective trial of IAD. After 9 months of treatment with leuprolide and flutamide, androgen deprivation therapy (ADT) was stopped until prostate-specific antigen reached a threshold (1 ng/mL for radical prostatectomy; 4 ng/mL for radiation or primary ADT) for a new cycle. Dual-energy x-ray absorptiometry (DXA) scans were performed before starting ADT and subsequently with each change in therapy. At least two consecutive DXA scans were required for this analysis. Computed tomography, bone scintigraphy, and lumbar spine x-rays were performed at the beginning and end of each treatment period. Results Fifty-six of 100 patients met criteria for this analysis. The median age at study entry was 64.5 years (range, 49.8 to 80.9 years). The average percentage change in BMD during the first on-treatment period was −3.4% (P < .001) for the spine and −1.2% (P = .001) for the left hip. During the first off-treatment period (median, 37.4 weeks; range, 13.4 weeks to 8.7+ years), BMD recovery at the spine was significant, with an average percentage change of +1.4% (P = .002). Subsequent periods had heterogeneous changes of BMD without significant average changes. After a median of 5.5 years (range, 1.1 to 13.8+) years on trial, one patient (1.8%) had a compression fracture associated with trauma. Conclusion Patients experienced the greatest average change in BMD during early treatment periods of IAD with a smaller average change thereafter. Fractures were rare.