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Find video protocols related to scientific articles indexed in Pubmed.
A comparative study of different dose fractionations schedule of thoracic radiotherapy for pain palliation and health-related quality of life in metastatic NSCLC.
Lung India
PUBLISHED: 11-08-2014
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To investigate the effect of different hypo fractionated thoracic radiotherapy schedules in relation to thoracic pain relief, overall survival and post radiotherapy HRQOL in metastatic NSCLC.
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Transport in two-dimensional disordered semimetals.
Phys. Rev. Lett.
PUBLISHED: 10-27-2014
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We theoretically study transport in two-dimensional semimetals. Typically, electron and hole puddles emerge in the transport layer of these systems due to smooth fluctuations in the potential. We calculate the electric response of the electron-hole liquid subject to zero and finite perpendicular magnetic fields using an effective medium approximation and a complementary mapping on resistor networks. In the presence of smooth disorder and in the limit of a weak electron-hole recombination rate, we find for small but finite overlap of the electron and hole bands an abrupt upturn in resistivity when lowering the temperature but no divergence at zero temperature. We discuss how this behavior is relevant for several experimental realizations and introduce a simple physical explanation for this effect.
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Pentoxifylline Plus Prednisolone versus Pentoxifylline Only for Severe Alcoholic Hepatitis: A Randomized Controlled Clinical Trial.
Ann Med Health Sci Res
PUBLISHED: 10-21-2014
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Prednisolone and pentoxifylline (PTX) have been shown to be individually useful in severe alcoholic hepatitis with Maddrey discriminant function (MDF) score ?32. Previous report suggests that PTX is probably superior to prednisolone alone. However the efficacy of PTX and prednisolone combination over PTX alone in the management of acute alcoholic hepatitis (MDF score ?32) is yet unrevealed.
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Lifestyle Health Behaviors of Hong Kong Chinese: Results of a Cluster Analysis.
Asia Pac J Public Health
PUBLISHED: 10-10-2014
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Sociodemographics affect health through pathways of lifestyle choices. Using data from a survey of 467 Hong Kong Chinese, this study aims to examine the prevalence of their lifestyle behaviors, identify profiles based on their sociodemographic and lifestyle variables, and compare differences among the profile groups. Two-step cluster analysis was used to identify natural profile groups within the data set: only 37% of the participants engaged in regular physical exercises, and less than 50% monitored their dietary intake carefully. The analysis yields 2 clusters, representing a "healthy" and a "less-healthy" lifestyle group. The "less-healthy" group was predominantly male, younger, employed, and had high-to-middle levels of education. The findings reveal the lifestyle behavior patterns and sociodemographic characteristics of a high-risk group, which are essential to provide knowledge for the planning of health promotion activities.
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[Lignans isolated from stems of Sambucus williamsii and their proliferation effects on UMR106 cells].
Zhongguo Zhong Yao Za Zhi
PUBLISHED: 10-03-2014
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The present study aims to investigate the lignan constituents from Sambucus williamsii and their proliferation effects on osteoblast-like UMR106 cells. Seven compounds were isolated and purified by macroporous resin D101, silica gel, Sephadex LH-20, Toyopearl HW-40, ODS column chromatographies and Preparative HPLC(C-18). Their structures were elucidated by spectroscopic methods as threo-guaiacylglycerol-beta-0-4'-conifery ether (1), lirioresinol A (2), 1-hydroxypinoresinol (3), 5-methoxybalanophonin (4), balanophonin (5), 5-methoxy-trans-dihydrodehydrodiconiferyl alcohol (6), and p-hydroxybenzaldehyde (7). Compounds 3-7 were obtained from this genus for the first time. The proliferation effects of all isolated compounds on osteoblast-like UMR106 cells were determined. Compounds 1-7 (1 x 10(-12)-1 x 10(-7) mol x L(-1)) increased UMR106 cell proliferation to some extent.
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Cognitive Aspects of Regularity Exhibit When Neighborhood Disappears.
J Psycholinguist Res
PUBLISHED: 10-01-2014
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Although regularity refers to the compatibility between pronunciation of character and sound of phonetic component, it has been suggested as being part of consistency, which is defined by neighborhood characteristics. Two experiments demonstrate how regularity effect is amplified or reduced by neighborhood characteristics and reveals the regularity effect without the confounding of neighboring characters. Experiment 1 examined the regularity effects of characters with more than one neighboring character, the results of which indicated that the consistency of irregular characters decides the patterns of regularity effects. Experiment 2 included characters without neighboring characters and measured the interaction of character frequency and regularity effect. The interactions of the characters with neighboring characters were reduced by the neighborhood characteristics of irregular characters, but a marginal interaction was found for characters without neighboring characters. The theoretical implication that regularity is acquired from lexical knowledge of phonetic components rather than accumulated from neighboring characters is discussed.
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Latent vitellointestinal duct sinus presenting with massive lower gastrointestinal bleeding in an adolescent.
BMJ Case Rep
PUBLISHED: 09-18-2014
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A 12-year-old boy with a history, at birth, of a weeping pink fleshy lesion after his umbilical cord detached, requiring repeated chemical cauterisation, presented with massive lower gastrointestinal bleeding and required resuscitation and blood transfusion. Augmented Tc99m nuclear medicine scan confirmed ectopic gastric mucosa. The lateral view suggested its attachment behind the umbilicus. At exploration, a latent vitellointestinal duct sinus with ectopic gastric mucosal mass was found. Segmental resection of the sinus and mass excision with primary anastomosis and incidental appendicectomy was curative. Pink fleshy mass discharging coloured fluid at the umbilicus following detachment of umbilical cord should be considered a remnant of vitellointestinal duct unless proved otherwise. A pink lesion with yellowish discharge resistant to chemical cauterisation should raise the suspicion of embryonic structures. Latent vitellointestinal sinus is a new lesion in the spectrum of umbilical anomalies. Lateral view of the nuclear medicine scan is helpful in locating the site.
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Association between Screen Viewing Duration and Sleep Duration, Sleep Quality, and Excessive Daytime Sleepiness among Adolescents in Hong Kong.
Int J Environ Res Public Health
PUBLISHED: 08-16-2014
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Screen viewing is considered to have adverse impacts on the sleep of adolescents. Although there has been a considerable amount of research on the association between screen viewing and sleep, most studies have focused on specific types of screen viewing devices such as televisions and computers. The present study investigated the duration with which currently prevalent screen viewing devices (including televisions, personal computers, mobile phones, and portable video devices) are viewed in relation to sleep duration, sleep quality, and daytime sleepiness among Hong Kong adolescents (N = 762). Television and computer viewing remain prevalent, but were not correlated with sleep variables. Mobile phone viewing was correlated with all sleep variables, while portable video device viewing was shown to be correlated only with daytime sleepiness. The results demonstrated a trend of increase in the prevalence and types of screen viewing and their effects on the sleep patterns of adolescents.
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Ethanolic extract of rhizome of Ligusticum chuanxiong Hort. (chuanxiong) enhances endothelium-dependent vascular reactivity in ovariectomized rats fed with high-fat diet.
Food Funct
PUBLISHED: 08-11-2014
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The rhizome of Ligusticum chuanxiong Hort. (LC), also known as chuanxiong, is a very common herb widely used to treat cardiovascular and cerebrovascular diseases. It is also used as a major ingredient in soups for regular consumption to promote good health. To study the protective effect of LC ethanolic extract (LCEE, 600 mg per kg per day, p.o.) on the integrity of the vascular system, ovariectomized (OVX) rats were fed with a high-fat diet (HFD) plus LCEE for 12 weeks. The animal model was used to mimic the dyslipidemic condition seen in postmenopausal women. LCEE was found significantly to reduce the body weight gain, improve serum lipid profiles (by lowering total cholesterol and low density lipoprotein cholesterol but raising high density lipoprotein cholesterol) and protect vascular endothelium in the HFD-fed OVX rats. It is postulated that LCEE could exert its vascular protective effect through multiple targets by (1) improving serum lipid profiles to reduce the detrimental effects of cholesterol; (2) reducing the ROS level in the body via enhancing the hepatic anti-oxidative activity or antioxidant level to scavenge the reactive oxygen species generated in the postmenopausal hypercholesterolemic condition; (3) stimulating eNOS-derived nitric oxide production; (4) counteracting the up-regulation of inflammatory cytokine (TNF-?, VCAM-1 and ICAM-1) expressions so as to reduce endothelium damage.
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Vanillic acid exerts oestrogen-like activities in osteoblast-like UMR 106 cells through MAP kinase (MEK/ERK)-mediated ER signaling pathway.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 08-05-2014
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Sambucus williamsii Hance (SWH) has been used for treatment of bone and joint disease in China for thousands of years. Our previous study showed that SWH extract and its bioactive fraction could effectively prevent oestrogen-deficiency induced bone loss in ovariectomized mice. The present study aimed to study the bone protective effects of vanillic acid (VA), a phenolic acid isolated from the bioactive fraction of SWH, and to characterize the signaling pathways that mediated its actions in rat osteoblast-like UMR 106?cells. VA significantly stimulated proliferation, alkaline phosphatase (ALP) activities as well as significantly altered the mRNA expression of genes involved in osteoblast functions and osteoclastogenesis in UMR 106?cells. Co-treatment of UMR 106?cells with 10(-6)M ICI182,780 (a specific oestrogen receptor (ER) antagonist) abolished the stimulatory effects of VA on osteoblast proliferation and ALP activities, suggesting the role of ER in mediating its actions. However, VA (10(-12) to 10(-6)M) failed to bind to ER? or ER? and did not activate oestrogen response element (ERE)-luciferase activities via ER? or ER? in UMR 106?cells. In contrast, 10(-10) and 10(-8)M of VA induced the phosphorylation of MEK 1/2, ERK1/2 and ER? at Ser118 residue in UMR 106?cells, suggesting that MAP kinase-mediated pathway is involved in mediating its actions. Taken together, our results indicated that VA is a bioactive compound in SWH that exerts stimulatory effects in osteoblast-like cells via non-genomic, but not classical, ER signaling pathway.
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VAS: a convenient web portal for efficient integration of genomic features with millions of genetic variants.
BMC Genomics
PUBLISHED: 07-15-2014
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High-throughput experimental methods have fostered the systematic detection of millions of genetic variants from any human genome. To help explore the potential biological implications of these genetic variants, software tools have been previously developed for integrating various types of information about these genomic regions from multiple data sources. Most of these tools were designed either for studying a small number of variants at a time, or for local execution on powerful machines.
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The incremental treatment of ESRD: a low-protein diet combined with weekly hemodialysis may be beneficial for selected patients.
BMC Nephrol
PUBLISHED: 06-29-2014
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Infrequent dialysis, namely once-a-week session combined with very low-protein, low-phosphorus diet supplemented with ketoacids was reported as a useful treatment schedule for ESRD patients with markedly reduced residual renal function but preserved urine output. This study reports our findings from the application of a weekly dialysis schedule plus less severe protein restriction (standard low-protein low-phosphorus diet) in stage 5 CKD patients with consistent dietary discipline.
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Chinese herbal medicine for bone health.
Pharm Biol
PUBLISHED: 06-25-2014
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Chinese herbal medicine (CHM) has been widely used in clinical practice to treat bone disease for thousands of years. They are cost-effective with fewer side effects and are more suitable for long-term use compared with chemically synthesized medicines.
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Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications.
Eur. J. Hum. Genet.
PUBLISHED: 06-19-2014
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Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, only larger-sized (8-21?Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935?kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.European Journal of Human Genetics advance online publication, 15 October 2014; doi:10.1038/ejhg.2014.217.
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Role of PSA density in diagnosis of prostate cancer in obese men.
Int Urol Nephrol
PUBLISHED: 06-19-2014
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To compare the performance of prostate-specific antigen (PSA) density in the diagnosis of prostate cancer in obese and non-obese Chinese men.
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The Influence of Secondary Processing on the Structural Relaxation Dynamics of Fluticasone Propionate.
AAPS PharmSciTech
PUBLISHED: 06-11-2014
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This study investigated the structural relaxation of micronized fluticasone propionate (FP) under different lagering conditions and its influence on aerodynamic particle size distribution (APSD) of binary and tertiary carrier-based dry powder inhaler (DPI) formulations. Micronized FP was lagered under low humidity (LH 25 C, 33% RH [relative humidity]), high humidity (HH 25°C, 75% RH) for 30, 60, and 90 days, respectively, and high temperature (HT 60°C, 44% RH) for 14 days. Physicochemical, surface interfacial properties via cohesive-adhesive balance (CAB) measurements and amorphous disorder levels of the FP samples were characterized. Particle size, surface area, and rugosity suggested minimal morphological changes of the lagered FP samples, with the exception of the 90-day HH (HH90) sample. HH90 FP samples appeared to undergo surface reconstruction with a reduction in surface rugosity. LH and HH lagering reduced the levels of amorphous content over 90-day exposure, which influenced the CAB measurements with lactose monohydrate and salmeterol xinafoate (SX). CAB analysis suggested that LH and HH lagering led to different interfacial interactions with lactose monohydrate but an increasing adhesive affinity with SX. HT lagering led to no detectable levels of the amorphous disorder, resulting in an increase in the adhesive interaction with lactose monohydrate. APSD analysis suggested that the fine particle mass of FP and SX was affected by the lagering of the FP. In conclusion, environmental conditions during the lagering of FP may have a profound effect on physicochemical and interfacial properties as well as product performance of binary and tertiary carrier-based DPI formulations.
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Genetic diagnosis of autism spectrum disorders: the opportunity and challenge in the genomics era.
Crit Rev Clin Lab Sci
PUBLISHED: 05-30-2014
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A genetic etiology for autism spectrum disorders (ASDs) was first suggested from twin studies reported in the 1970s. The identification of gene mutations in syndromic ASDs provided evidence to support a genetic cause of ASDs. More recently, genome-wide copy number variant and sequence analyses have uncovered a list of rare and highly penetrant copy number variants (CNVs) or single nucleotide variants (SNVs) associated with ASDs, which has strengthened the claim of a genetic etiology for ASDs. Findings from research studies in the genetics of ASD now support an important role for molecular diagnostics in the clinical genetics evaluation of ASDs. Various molecular diagnostic assays including single gene tests, targeted multiple gene panels and copy number analysis should all be considered in the clinical genetics evaluation of ASDs. Whole exome sequencing could also be considered in selected clinical cases. However, the challenge that remains is to determine the causal role of genetic variants identified through molecular testing. Variable expressivity, pleiotropic effects and incomplete penetrance associated with CNVs and SNVs also present significant challenges for genetic counseling and prenatal diagnosis.
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Uncoupled continuous-time random walk model: Analytical and numerical solutions.
Phys Rev E Stat Nonlin Soft Matter Phys
PUBLISHED: 05-28-2014
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Solutions for the continuous-time random walk (CTRW) model are known in few cases. In this work, the uncoupled CTRW model is investigated analytically and numerically. In particular, the probability density function (PDF) and n-moment are obtained and analyzed. Exponential and Gaussian functions are used for the jump length PDF, whereas the Mittag-Leffler function and a combination of exponential and power-laws function is used for the waiting time PDF. The exponential and Gaussian jump length PDFs have finite jump length variances and they give the same second moment; however, their distribution functions present different behaviors near the origin. The combination of exponential and power-law function for the waiting time PDF can generate a crossover from anomalous regime to normal regime. Moreover, the parameter of the exponential jump length PDF does not change the behavior of the n-moment for all time intervals, and for the Gaussian jump length PDF the n-moment also indicates a similar behavior.
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Paediatric giant cervicomediastinal thymolipoma.
BMJ Case Rep
PUBLISHED: 05-23-2014
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We report a case of a 11-year-old boy who presented with a massive soft tissue right cervical painless and progressive lesion displacing trachea to the left and extending into the anteriosuperior mediastinum which was diagnosed to be a lipomatous mass on chest CT scan. Subsequent biopsy and total excision proved it to be a giant cervicomediastinal thymolipoma. It was successfully excised with excellent prognosis and long-term results. A giant paediatric cervicomediastinal thymolipoma is a rare, benign, mediastinal mass of thymic origin. It may remain asymptomatic despite massive size and up to 50% in some series are associated with autoimmune disease. CT scan gives fat density and encapsulated benign nature and biopsy usually establishes the diagnosis. Preoperative tissue diagnosis is important as now the availability of thoracoscopic option is best suited to reduce morbidity. Treatment of choice is total excision using open surgical, minimal invasive techniques or robotic surgery and the prognosis is excellent.
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Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders.
Am. J. Hum. Genet.
PUBLISHED: 05-15-2014
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New human mutations are thought to originate in germ cells, thus making a recurrence of the same mutation in a sibling exceedingly rare. However, increasing sensitivity of genomic technologies has anecdotally revealed mosaicism for mutations in somatic tissues of apparently healthy parents. Such somatically mosaic parents might also have germline mosaicism that can potentially cause unexpected intergenerational recurrences. Here, we show that somatic mosaicism for transmitted mutations among parents of children with simplex genetic disease is more common than currently appreciated. Using the sensitivity of individual-specific breakpoint PCR, we prospectively screened 100 families with children affected by genomic disorders due to rare deletion copy-number variants (CNVs) determined to be de novo by clinical analysis of parental DNA. Surprisingly, we identified four cases of low-level somatic mosaicism for the transmitted CNV in DNA isolated from parental blood. Integrated probabilistic modeling of gametogenesis developed in response to our observations predicts that mutations in parental blood increase recurrence risk substantially more than parental mutations confined to the germline. Moreover, despite the fact that maternally transmitted mutations are the minority of alleles, our model suggests that sexual dimorphisms in gametogenesis result in a greater proportion of somatically mosaic transmitting mothers who are thus at increased risk of recurrence. Therefore, somatic mosaicism together with sexual differences in gametogenesis might explain a considerable fraction of unexpected recurrences of X-linked recessive disease. Overall, our results underscore an important role for somatic mosaicism and mitotic replicative mutational mechanisms in transmission genetics.
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Combating against methicillin-resistant Staphylococcus aureus - two fatty acids from Purslane (Portulaca oleracea?L.) exhibit synergistic effects with erythromycin.
J. Pharm. Pharmacol.
PUBLISHED: 04-22-2014
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The aims of this study were to identify the active ingredients from Portulaca oleracea?L. (PO) that could provide synergism with antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) and their possible mechanisms of resistance inhibition.
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Anthropometric factors and ovarian cancer risk: A systematic review and nonlinear dose-response meta-analysis of prospective studies.
Int. J. Cancer
PUBLISHED: 04-11-2014
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In the World Cancer Research Fund/American Institute for Cancer Research report from 2007 the evidence relating body fatness to ovarian cancer risk was considered inconclusive, while the evidence supported a probably causal relationship between adult attained height and increased risk. Several additional cohort studies have since been published, and therefore we conducted an updated meta-analysis of the evidence as part of the Continuous Update Project. We searched PubMed and several other databases up to 20th of August 2014. Summary relative risks (RRs) were calculated using a random effects model. The summary relative risk for a 5-U increment in BMI was 1.07 (95% CI: 1.03-1.11, I(2) = 54%, n = 28 studies). There was evidence of a nonlinear association, pnonlinearity ?
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Er-xian Decoction exerts estrogen-like osteoprotective effects in vivo and in vitro.
Am. J. Chin. Med.
PUBLISHED: 04-09-2014
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Er-xian Decoction (EXD), containing Herba epimedii Maxim (HEP) and Curculigo orchioides Gaertn (XM) as principal drugs, is a traditional Chinese medicine (TCM) formula prescribed for the treatment of postmenopausal osteoporosis. In the present study, the in vivo anti-osteoporosis effects of EXD, HEP and XM on four-month-old ovariectomized (OVX) Sprague-Dawley rats were investigated. Micro-computed tomography analysis showed that EXD could significantly improve the micro-architectural parameters (BMD, BV/TV, Tb.N, Tb.Th, and Tb.Sp) of trabecular bone in the distal femur and proximal tibia in OVX rats (p < 0.05). The biomechanical parameters of the distal femur in rats treated with EXD were also improved significantly (p < 0.05 vs. OVX group). The in vivo efficacy of EXD was found to be superior to HEP or XM alone in improving the bone properties of OVX rats. Treatment of rat osteoblastic-like UMR-106 cells with EXD, HEP, and XM significantly promoted the cell proliferation rate (p < 0.05) with the most promising effects observed in cells treated with EXD (p < 0.001). The proliferative effect in UMR-106 cells induced by EXD, HEP, and XM were abolished in the presence of the estrogen antagonist, ICI182780, suggesting that their effects were mediated by estrogen receptor (ER). Additionally, EXD could activate ER-? and ER-? mediated estrogen-response element (ERE)-dependent luciferase activity as well as phosphorylate ER-? at serine 118 in UMR-106 cells. Taken together, EXD offered better osteoprotective effects than its single principal herb, and the beneficial effects of EXD in preventing bone deteriorations are, at least partially, through the ER signaling pathway.
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Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor ? agonist in clinical trials for the treatment of dyslipidemia.
J. Med. Chem.
PUBLISHED: 04-08-2014
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The beneficial effects of thyroid hormone (TH) on lipid levels are primarily due to its action at the thyroid hormone receptor ? (THR-?) in the liver, while adverse effects, including cardiac effects, are mediated by thyroid hormone receptor ? (THR-?). A pyridazinone series has been identified that is significantly more THR-? selective than earlier analogues. Optimization of this series by the addition of a cyanoazauracil substituent improved both the potency and selectivity and led to MGL-3196 (53), which is 28-fold selective for THR-? over THR-? in a functional assay. Compound 53 showed outstanding safety in a rat heart model and was efficacious in a preclinical model at doses that showed no impact on the central thyroid axis. In reported studies in healthy volunteers, 53 exhibited an excellent safety profile and decreased LDL cholesterol (LDL-C) and triglycerides (TG) at once daily oral doses of 50 mg or higher given for 2 weeks.
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Does selective dorsal rhizotomy improve bladder function in children with cerebral palsy?
Int Urol Nephrol
PUBLISHED: 03-27-2014
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To investigate the efficacy of selective dorsal rhizotomy (SDR) on urinary symptoms and bladder function in cerebral palsy children.
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Efficacy of Physical Exercise in Preventing Falls in Older Adults With Cognitive Impairment: A Systematic Review and Meta-Analysis.
J Am Med Dir Assoc
PUBLISHED: 03-19-2014
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Numerous studies have reported the prevention of falls through exercise among cognitively healthy older people. This study aimed to determine whether the current evidence supports that physical exercise is also efficacious in preventing falls in older adults with cognitive impairment.
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6q22.1 microdeletion and susceptibility to pediatric epilepsy.
Eur. J. Hum. Genet.
PUBLISHED: 03-04-2014
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Genomic copy-number variations (CNVs) constitute an important cause of epilepsies and other human neurological disorders. Recent advancement of technologies integrating genome-wide CNV mapping and sequencing is rapidly expanding the molecular field of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 by linkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelated cases narrowed this region to ?5?Mb on 6q22.1q22.31. We sought to further narrow the critical region on chromosome 6q22. Array CGH analysis was used in genome-wide screen for CNVs of a large cohort of patients with neurological abnormalities. Long-range PCR and DNA sequencing were applied to precisely map chromosomal deletion breakpoints. Finally, real-time qPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patients and narrowed the critical region to a ?250-kb segment at 6q22.1 that includes NUS1, several expressed sequence tags (ESTs) that are highly expressed in the brain, and putative regulatory sequences of SLC35F1. Our findings indicate that dosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmental phenotype associated with 6q22 deletion, including epilepsy and tremors.European Journal of Human Genetics advance online publication, 14 May 2014; doi:10.1038/ejhg.2014.75.
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Flavonoids from Herba epimedii selectively activate estrogen receptor alpha (ER?) and stimulate ER-dependent osteoblastic functions in UMR-106 cells.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 02-24-2014
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Total flavonoids in Herba epimedii (HEP) have been demonstrated to protect against bone loss and bone deterioration associated with estrogen deficiency without exerting any uterotrophic effects. However, it is unclear how flavonoids in HEP exert their protective effects on bone and if different flavonoids exert estrogenic actions in bone cells via similar mechanism of actions. The present study aims to investigate the bone anabolic effects of four major flavonoids isolated from HEP, namely icariin, baohuoside-I, epimedin B and sagittatoside A as well as the mechanism involved in mediating their estrogenic actions in rat osteoblastic-like UMR-106 cells. All tested compounds significantly stimulated the cell proliferation rate, alkaline phosphate (ALP) activity and osteoprotegerin (OPG)/receptor activator of nuclear factor ?-B ligand (RANKL) mRNA expression in UMR-106 cells and their effects could be abolished by co-incubation with 10(-6)M ICI 182,780. None of the flavonoids exhibited binding affinities toward ER? and ER?. However, sagittatoside A selectively activated estrogen response element (ERE)-luciferase activity via ER?. In addition, icariin and sagittatoside A induced ER? phosphorylation at serine 118 residue. Taken together, our results indicated that all four flavonoids from HEP stimulated ER-dependent osteoblastic functions in UMR-106 cells, but only two of them appeared to exert their actions by ligand-independent activation of ER?. Our study provides evidence to support the hypothesis that the estrogen-like protective effects on bone by flavonoids are mediated via mechanisms that are distinct from the classical actions of estrogen.
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Discovery of camphor-derived pyrazolones as 11?-hydroxysteroid dehydrogenase type 1 inhibitors.
Bioorg. Med. Chem. Lett.
PUBLISHED: 02-20-2014
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Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11?HSD1.
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Phosphate levels in patients treated with low-flux haemodialysis, pre-dilution haemofiltration and haemodiafiltration: post hoc analysis of a multicentre, randomized and controlled trial.
Nephrol. Dial. Transplant.
PUBLISHED: 02-20-2014
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Whether convective therapies allow better control of serum phosphate (P) is still undefined, and no data are available concerning on-line haemofiltration (HF). The objectives of the study are to evaluate the effect of convective treatments (CTs) on P levels in comparison with low-flux haemodialysis (HD) and to evaluate the correlates of serum phosphate in a post hoc analysis of a randomized clinical trial.
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Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.
ACS Med Chem Lett
PUBLISHED: 02-13-2014
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The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.
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Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action.
Nat. Med.
PUBLISHED: 02-02-2014
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Despite the fact that genitourinary defects are among the most common birth defects in newborns, little is known about their etiology. Here we analyzed children born with congenital genitourinary tract masculinization disorders by array-comparative genomic hybridization, which revealed in 1.35% of cases the presence of de novo copy number gains at Xq28 encompassing the VAMP7 gene, which encodes a vesicle-trafficking protein that is part of the SNARE complex. Transgenic mice carrying a bacterial artificial chromosome encoding human VAMP7 mimicked the defective urogenital traits observed in boys with masculinization disorders such as cryptorchidism, urethral defects and hypospadias. Transgenic mice also exhibited reduced penile length, focal spermatogenic anomalies, diminished sperm motility and subfertility. VAMP7 colocalized with estrogen receptor ? (ESR1) in the presence of its cognate ligand, 17?-estradiol. Elevated levels of VAMP7 markedly intensified ESR1-potentiated transcriptional activity by increasing ESR1 protein cellular content upon ligand stimulation and upregulated the expression of estrogen-responsive genes including ATF3, CYR61 and CTGF, all of which have been implicated in human hypospadias. Hence, increased gene dosage of VAMP7, and thus higher expression levels of its protein product, enhances estrogen receptor action in male genitourinary tissues, affects the virilization of the reproductive tract and results in genitourinary birth defects in humans.
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Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27.
Eur. J. Hum. Genet.
PUBLISHED: 01-29-2014
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Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype-phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7?Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies.European Journal of Human Genetics advance online publication, 16 April 2014; doi:10.1038/ejhg.2014.51.
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Beliefs and knowledge about vaccination against AH1N1pdm09 infection and uptake factors among Chinese parents.
Int J Environ Res Public Health
PUBLISHED: 01-28-2014
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Vaccination against AH1N1pdm09 infection (human swine infection, HSI) is an effective measure of preventing pandemic infection, especially for high-risk groups like children between the ages of 6 months and 6 years. This study used a cross-sectional correlation design and aimed to identify predicting factors of parental acceptance of the HSI vaccine (HSIV) and uptake of the vaccination by their preschool-aged children in Hong Kong. A total of 250 parents were recruited from four randomly selected kindergartens. A self-administered questionnaire based on the health belief framework was used for data collection. The results showed that a number of factors significantly affected the tendency toward new vaccination uptake; these factors included parental age, HSI vaccination history of the children in their family, preferable price of the vaccine, perceived severity, perceived benefits, perceived barriers, and motivating factors for taking new vaccines. Using these factors, a logistic regression model with a high Nagelkerke R2 of 0.63 was generated to explain vaccination acceptance. A strong correlation between parental acceptance of new vaccinations and the motivating factors of vaccination uptake was found, which indicates the importance of involving parents in policy implementation for any new vaccination schemes. Overall, in order to fight against pandemics and enhance vaccination acceptance, it is essential for the government to understand the above factors determining parental acceptance of new vaccinations for their preschool-aged children.
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ECplot: an online tool for making standardized plots from large datasets for bioinformatics publications.
Bioinformatics
PUBLISHED: 01-24-2014
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We have implemented ECplot, an online tool for plotting charts from large datasets. This tool supports a variety of chart types commonly used in bioinformatics publications. In our benchmarking, it was able to create a Box-and-Whisker plot with about 67 000 data points and 8 MB total file size within several seconds. The design of the tool makes common formatting operations easy to perform. It also allows more complex operations to be achieved by advanced XML (Extensible Markup Language) and programming options. Data and formatting styles are stored in separate files, such that style templates can be made and applied to new datasets. The text-based file formats based on XML facilitate efficient manipulation of formatting styles for a large number of data series. These file formats also provide a means to reproduce published figures from raw data, which complement parallel efforts in making the data and software involved in published analysis results accessible. We demonstrate this idea by using ECplot to replicate some complex figures from a previous publication.
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Differential ER?-mediated rapid estrogenic actions of ginsenoside Rg1 and estren in human breast cancer MCF-7 cells.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 01-17-2014
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Recent studies indicated that both estren and Rg1 appear to be able to activate mitogen-activated protein kinase (MAPK) pathway in estrogen responsive cells. Rg1 could lead to MAPK activation through ligand-independent activation of estrogen receptor (ER), while estren could activate the Src-MAPK pathway in an ERE-independent manner. Thus, it is important to understand the mechanistic insights on the difference in transcriptional activation between estren and Rg1. The present study also addressed the differential abilities of Rg1 and estren in terms of the ability to activate ER and the ability to induce ER translocation in MCF-7 cells. Our data indicated that Rg1 could increase pS2 gene expression, and could recruit the co-activator steroid receptor co-activator-1 (SRC-1) to the pS2 promoter. Rg1 could also induce ER? nuclear translocation as well as ER? phosphorylation at Ser118 principally in the cytoplasm in MCF-7 cells. We deduced that estren induced ERE-dependent transcriptional activity and activated ER? at Ser118 occurred in the nucleus of MCF-7 cells. However, it was found to decrease pS2 gene expression and failed to induce the recruitment of SRC-1 to the pS2 promoter in MCF-7 cells. Our results suggest that the abilities of Rg1 and estren to regulate pS2 gene expression, to recruit co-activators as well as to induce sub-cellular distribution of ER? are dramatically different.
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Discovery of pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists.
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-14-2014
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We designed and synthesized a novel series of phenylamino- and phenoxy-substituted pyrazolo[3,4-d]pyrimidine derivatives as GPR119 agonists. SAR studies indicated that electron-withdrawing substituents on the phenyl ring are important for potency and full efficacy. Compound 26 combined good potency with a promising pharmacokinetic profile in mice, and lowered the glucose excursion in mice in an oral glucose-tolerance test.
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Parenting approaches and digital technology use of preschool age children in a Chinese community.
Ital J Pediatr
PUBLISHED: 01-09-2014
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Young children are using digital technology (DT) devices anytime and anywhere, especially with the invention of smart phones and the replacement of desktop computers with digital tablets. Although research has shown that parents play an important role in fostering and supporting preschoolers' developing maturity and decisions about DT use, and in protecting them from potential risk due to excessive DT exposure, there have been limited studies conducted in Hong Kong focusing on parent-child DT use. This study had three objectives: 1) to explore parental use of DTs with their preschool children; 2) to identify the DT content that associated with child behavioral problems; and 3) to investigate the relationships between approaches adopted by parents to control children's DT use and related preschooler behavioral problems.
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New lignans from the bioactive fraction of Sambucus williamsii Hance and proliferation activities on osteoblastic-like UMR106 cells.
Fitoterapia
PUBLISHED: 01-09-2014
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Four new lignans (1, 7-9), together with nine known ones, were isolated from the anti-osteoporosis fraction of the extract of Sambucus williamsii Hance which was eluted by 50% and 95% aqueous ethanol over D101 macroporous resin column. Their structures were elucidated by NMR spectroscopic analyses, and the absolute configurations of all compounds were determined by application of circular dichroism method. All the compounds were reported for the first time from the Sambucus genus and firstly studied for their proliferation effects on osteoblastic-like UMR 106 cell. The data showed that compounds 2-9 significantly promoted cell proliferation in some dose, especially compounds 2, 3, 4, 5, and 7 increased osteoblastic cell numbers by 31.3%, 28.3%, 25.6%, 25.1% and 26.0% at 10(-10) M, 10(-10) M, 10(-7) M, 10(-10) M and 10(-10) M, respectively, which suggested that lignans were the components accounting for the bone protective effects of SWH.
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Correlates of Protective Motivation Theory (PMT) to adolescents' drug use intention.
Int J Environ Res Public Health
PUBLISHED: 01-08-2014
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Early onset and increasing proliferation of illicit adolescent drug-use poses a global health concern. This study aimed to examine the correlation between Protective Motivation Theory (PMT) measures and the intention to use drugs among adolescents. An exploratory quantitative correlation design and convenience sampling were adopted. A total of 318 students completed a self-reported questionnaire that solicited information related to their demographics and activities, measures of threat appraisal and coping appraisal, and the intention to use drugs. Logistic regression analysis showed that intrinsic and extrinsic rewards were significant predictors of intention. The odds ratios were equal to 2.90 (p < 0.05) and 8.04 (p < 0.001), respectively. The logistic regression model analysis resulted in a high Nagelkerke R2 of 0.49, which suggests that PMT related measures could be used in predicting drug use intention among adolescents. Further research should be conducted with non-school adolescents to confirm the application.
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The influence of weather on health-related help-seeking behavior of senior citizens in Hong Kong.
Int J Biometeorol
PUBLISHED: 01-07-2014
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It is believed that extreme hot and cold weather has a negative impact on general health conditions. Much research focuses on mortality, but there is relatively little community health research. This study is aimed at identifying high-risk groups who are sensitive to extreme weather conditions, in particular, very hot and cold days, through an analysis of the health-related help-seeking patterns of over 60,000 Personal Emergency Link (PE-link) users in Hong Kong relative to weather conditions. In the study, 1,659,716 PE-link calls to the help center were analyzed. Results showed that females, older elderly, people who did not live alone, non-subsidized (relatively high-income) users, and those without medical histories of heart disease, hypertension, stroke, and diabetes were more sensitive to extreme weather condition. The results suggest that using official government weather forecast reports to predict health-related help-seeking behavior is feasible. An evidence-based strategic plan could be formulated by using a method similar to that used in this study to identify high-risk groups. Preventive measures could be established for protecting the target groups when extreme weather conditions are forecasted.
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Anti-Atherogenic Effect of Hydrogen Sulfide by Over-Expression of Cystathionine Gamma-Lyase (CSE) Gene.
PLoS ONE
PUBLISHED: 01-01-2014
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Hydrogen sulfide (H2S) is an important gaseous signaling molecule that functions in physiological and pathological conditions, such as atherosclerosis. H2S dilates vessels and therefore has been suggested as an anti-atherogenic molecule. Since cystathionine gamma-lyase (CSE) enzyme is responsible for producing H2S in the cardiovascular system, we hypothesized that up-regulation of CSE expression in vivo with preservation of H2S bioactivity can slow down plaque formation and, can serve as a therapeutic strategy against atherosclerosis. In this study, C57BL/6 wild type mice (WT), ApoE knockout mice (KO) and transgenic ApoE knockout mice overexpressing CSE (Tg/KO) at four weeks of age were weaned. They were then fed with either normal or atherogenic diet for 12 weeks. At week 16, serial plasma lipid levels, body weight, and blood pressure were measured prior to euthanization of the mice and the size of atherosclerotic plaques at their aortic roots was measured. Tg/KO mice showed an increase in endogenous H2S production in aortic tissue, reduced atherosclerotic plaque sizes and attenuation in plasma lipid profiles. We also showed an up-regulation in plasma glutathionine peroxidase that could indicate reduced oxidative stress. Furthermore, there was an increase in expression of p-p53 and down regulation of inflammatory nuclear factor-kappa B (NF-?B) in aorta. To conclude, alteration of endogenous H2S by CSE gene activation was associated with reduced atherosclerosis in ApoE-deficient mice. Up-regulation of CSE/H2S pathway attenuates atherosclerosis and this would be a potential target for therapeutic intervention against its formation.
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A multidimensional risk factor model for suicide attempts in later life.
Neuropsychiatr Dis Treat
PUBLISHED: 01-01-2014
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Elderly suicide is a public health problem worldwide, and the risk factors are multidimensional. Chronic mental health problems, personality traits, stressful life events, comorbid medical conditions, social isolation, unemployment, and poverty are associated with higher risk for suicide in later life. There was a relative paucity of data on the neurobiological markers of elderly suicide.
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Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1.
PLoS ONE
PUBLISHED: 01-01-2014
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Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1?47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
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Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation.
J. Exp. Med.
PUBLISHED: 12-23-2013
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We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21-mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell-derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.
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Baseline Demographic Profile and General Health Influencing the Post-Radiotherapy Health Related Quality-of-Life in Women with Gynaecological Malignancy Treated with Pelvic Irradiation.
Indian J Palliat Care
PUBLISHED: 12-19-2013
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Cancer specific survival and quality-of-life (QOL) assessment are important in evaluating cancer treatment outcomes. Baseline demographic profiles have significant effects on follow-up health related QOL (HRQOL) and affect the outcome of treatments.
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A systematic review on biological activities of prenylated flavonoids.
Pharm Biol
PUBLISHED: 11-21-2013
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Abstract Context: Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plants self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized. Objective: The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids. Methods: PubMed and WEB OF KNOWLEDGE® were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure-activity relationship between prenylated flavonoids and their bioactivities. Results: It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids. Conclusion: The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure-activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.
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Sociodemographic and substance use correlates of repeated relapse among patients presenting for relapse treatment at an addiction treatment center in Kolkata, India.
Afr Health Sci
PUBLISHED: 11-20-2013
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In India, substance abuse has infiltrated all socio-cultural and economic strata causing loss of productivity. Prevention of relapse is crucial for its control.
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In Vivo Emergence of a Novel Mutant L159F/L320F in the NS5B Polymerase Confers Low-Level Resistance to the HCV Polymerase Inhibitors Mericitabine and Sofosbuvir.
J. Infect. Dis.
PUBLISHED: 10-23-2013
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Background.?Resistance to mericitabine (prodrug of HCV NS5B polymerase inhibitor PSI-6130) is rare and conferred by the NS5B S282T mutation.Methods.?Serum HCV RNA from patients who experienced viral breakthrough, partial response, or nonresponse in 2 clinical trials in which patients received mericitabine plus peginterferon alfa-2a (40KD)/ribavirin were analyzed by population and clonal sequence analysis as well as phenotypic assay for assessment of in vivo mericitabine resistance.Results.?Among 405 patients treated with mericitabine plus peginterferon alfa-2a/ribavirin in PROPEL and JUMP-C, virologic breakthrough or nonresponse were not observed; 12 patients experienced a partial response. The NS5B S282T resistance mutation was not observed in any patient. A number of treatment-associated NS5B changes were observed and characterized. A novel double mutant (L159F/L320F) with impaired replication capacity was detected in one HCV genotype 1b-infected patient. Introduction of double mutant L159F/L320F into genotype 1a (H77) and 1b (Con-1) replicons, respectively, increased the EC50 for mericitabine by 3.1- and 5.5-fold and the EC90 by 3.1- and 8.9-fold. The double mutant also decreased susceptibility to sofosbuvir (GS-7977) and GS-938 but not setrobuvir, relative to wild-type.Conclusions.?A novel and replication-deficient double mutation (L159F/L320F) confers low-level resistance to mericitabine and cross-resistance to both sofosbuvir and GS-938.Clinical Trials Registration.?NCT00869661, NCT01057667.
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Estrogen deficiency-induced Ca balance impairment is associated with decrease in expression of epithelial Ca transport proteins in aged female rats.
Life Sci.
PUBLISHED: 09-05-2013
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The study is designed to determine whether estrogen and vitamin D endocrine systems interact to regulate calcium (Ca) balance as well as changes in mRNA expression of epithelial Ca transport proteins involved in intestinal and renal Ca transport in aging animals in response to ovariectomy and low dietary Ca intake.
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Fusion of large-scale genomic knowledge and frequency data computationally prioritizes variants in epilepsy.
PLoS Genet.
PUBLISHED: 09-01-2013
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Curation and interpretation of copy number variants identified by genome-wide testing is challenged by the large number of events harbored in each personal genome. Conventional determination of phenotypic relevance relies on patterns of higher frequency in affected individuals versus controls; however, an increasing amount of ascertained variation is rare or private to clans. Consequently, frequency data have less utility to resolve pathogenic from benign. One solution is disease-specific algorithms that leverage gene knowledge together with variant frequency to aid prioritization. We used large-scale resources including Gene Ontology, protein-protein interactions and other annotation systems together with a broad set of 83 genes with known associations to epilepsy to construct a pathogenicity score for the phenotype. We evaluated the score for all annotated human genes and applied Bayesian methods to combine the derived pathogenicity score with frequency information from our diagnostic laboratory. Analysis determined Bayes factors and posterior distributions for each gene. We applied our method to subjects with abnormal chromosomal microarray results and confirmed epilepsy diagnoses gathered by electronic medical record review. Genes deleted in our subjects with epilepsy had significantly higher pathogenicity scores and Bayes factors compared to subjects referred for non-neurologic indications. We also applied our scores to identify a recently validated epilepsy gene in a complex genomic region and to reveal candidate genes for epilepsy. We propose a potential use in clinical decision support for our results in the context of genome-wide screening. Our approach demonstrates the utility of integrative data in medical genomics.
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Continuous time random walk with linear force applied to hydrated proteins.
J Chem Phys
PUBLISHED: 08-17-2013
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An integro-differential diffusion equation with linear force, based on the continuous time random walk model, is considered. The equation generalizes the ordinary and fractional diffusion equations. Analytical expressions for transition probability density, mean square displacement, and intermediate scattering function are presented. The mean square displacement and intermediate scattering function can fit well the simulation data of the temperature-dependent translational dynamics of nitrogen atoms of elastin for a wide range of temperatures and various scattering vectors. Moreover, the numerical results are also compared with those of a fractional diffusion equation.
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Ligusticum chuanxiong prevents ovariectomy-induced liver and vascular damage in rats.
Am. J. Chin. Med.
PUBLISHED: 07-31-2013
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Post-menopause, there is an increase in body weight, visceral adiposity, and risk of developing non-alcoholic fatty liver disease (NAFLD), which leads to various cardiovascular diseases (CVDs). Some natural products have proven useful for counteracting the detrimental effects of menopause. The rhizome of Ligusticum chuanxiong Hort. (LC) is a well-known medicinal herb widely used in Chinese communities for the treatment of CVDs. The hepatic and vascular protective effects of LC ethanolic extract under postmenopausal conditions were investigated on ovariectomized (OVX) rats supplemented with or without LC ethanolic extract (600 mg/kg body weight/day, p.o.) or 17?-estradiol (1 mg/kg body weight/day, p.o.) for 12 weeks. The current findings demonstrated that consumption of LC ethanolic extract could reduce the body weight gain, improve serum lipid profile (lowering low density lipoprotein cholesterol but raising high density lipoprotein cholesterol), combat NAFLD, and protect vascular endothelium in the OVX rats. The beneficial effects of LC may be associated with its antioxidant or vasorelaxant compounds, which enhance the levels of hepatic antioxidant enzymes and up-regulate endothelial nitric oxide synthase mRNA expression, respectively. Taken together, LC may be a promising natural supplement for postmenopausal women to prevent NAFLD and CVDs.
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MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.
Hum. Mol. Genet.
PUBLISHED: 06-16-2013
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Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.
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Aqueous extract of danshen (Salvia miltiorrhiza Bunge) protects ovariectomized rats fed with high-fat diet from endothelial dysfunction.
Menopause
PUBLISHED: 06-01-2013
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Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in postmenopausal women. Danshen, the dried root of Salvia miltiorrhiza Bunge, has been used clinically in China to treat CVD and dyslipidemia in postmenopausal women, and its major active ingredients have been found to have an estrogenic effect. The aim of this study was to elucidate the underlying mechanism of danshens protective effects on vascular function in an ovariectomized (OVX) hyperlipidemic rat model.
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"Stainomics": identification of mitotracker labeled proteins in mammalian cells.
Electrophoresis
PUBLISHED: 03-27-2013
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Organelle-specific cell-permeable fluorescent dyes are invaluable tools in cell biology as they reveal intracellular dynamics in living cells. Mitrotracker is a family of dyes that strongly label the mitochondrion, a key organelle associated with many crucial cellular functions. Despite the popularity of these dyes, little is known about the molecular mechanism behind their staining specificity. Here, we aimed to identify the protein targets of one member of this dye family, mitotracker red (MTR), by 2DE and MS. MTR bound to cellular proteins covalently, and its fluorescence persisted even after cell lysis, protein solubilization, denaturation, and electrophoresis. This enabled us to display MTR-labeled proteins by 2DE. The MTR-specific fluorescent signals on the gel revealed the spots that contained MTR-conjugated proteins. These spots were analyzed by MS, resulting into the identification of ten proteins. We discovered that one major target is the mitochondrial protein HSP60 and that MTR staining could induce production of HSP60, predisposing cells to heat shock-like responses. The identification of the molecular targets of biological dyes, or "stainomics," can help correlate their intracellular staining properties with biochemical affinities. We believe this approach can be applied to a wide range of fluorescent probes.
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Involvement of IGF-I receptor and estrogen receptor pathways in the protective effects of ginsenoside Rg1 against A??????-induced toxicity in PC12 cells.
Neurochem. Int.
PUBLISHED: 03-20-2013
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Ginsenoside Rg1 is the main pharmacologically active compound of ginsenosides and has demonstrated pharmacological effects in the cardiovascular system, central nervous system and immune system. The involvement of insulin-like growth factor-I receptor (IGF-IR)-dependent pathway and estrogen receptor (ER)-dependent pathway in the biological effect of ginsenoside Rg1 have been demonstrated in our previous study. The present study tested the hypothesis that the protective effects of Rg1 against A?25-35-induced toxicity involved activation of the IGF-IR and ER signaling pathways in PC12 cells. Treatment with A?25-35 decreased the cell viability in a dose-dependent manner in PC12 cells. Rg1 pretreatment resulted in an enhancement of survival and the maximum protection occurred at the concentration of 1?M. Co-treatment with IGF-IR antagonist JB-1 or ER antagonist ICI182,780 could completely block the protective effect of Rg1. The decreased Bcl-2 mRNA expression induced by A?25-35 could be restored by Rg1 pretreatment. Rg1 pretreatment could also restore the decreased mitochondrial membrane potential induced by A?25-35 and these effects could be completely blocked by JB-1 or ICI182,780. In addition, Rg1 treatment alone could significantly increase the phosphorylation level of MEK and ERK in a time-dependent manner and the functional transactivation of ER? in PC12 cells. The functional transactivation of ER? by Rg1 could be completely blocked by JB-1 or ICI182,780. Taken together, our results suggest that IGF-IR and ER signaling pathways might be involved in the protective effect of Rg1 against A?25-35-induced toxicity in PC12 cells.
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Bioequivalence for locally acting nasal spray and nasal aerosol products: standard development and generic approval.
AAPS J
PUBLISHED: 03-19-2013
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Demonstrating bioequivalence (BE) for nasal spray/aerosol products for local action has been very challenging because the relationship between the drug in systemic circulation and the drug reaching the nasal site of action has not been well established. Thus, the current BE standard for these drug/device combination products is based on a weight-of-evidence approach, which contains three major elements: equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition, formulation sameness and device similarity are evidences to support BE. This paper presents a comprehensive review of the scientific rationale of the current BE standard and their development history for nasal spray/aerosol products, as well as the Food and Drug Administrations review and approval status of generic nasal sprays/aerosols with the application of these BE standard.
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TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.
Am. J. Hum. Genet.
PUBLISHED: 03-14-2013
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White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
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A mosaic 2q24.2 deletion narrows the critical region to a 0.4 Mb interval that includes TBR1, TANK, and PSMD14.
Am. J. Med. Genet. A
PUBLISHED: 02-26-2013
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Interstitial deletions involving 2q24 have been associated with a wide range of phenotypes including intellectual disability and short stature. To date, the smallest common region among reported cases of deletions in this region is approximately 2.65 Mb and contains 15 genes. In the present case report, we describe an 18-year-old male with mild intellectual disability, short stature, and mosaicism for a 0.422 Mb deletion on 2q24.2 that was diagnosed by comparative genomic hybridization and confirmed with fluorescent in situ hybridization (FISH). This deletion, which is present in approximately 61% of cells, includes three genes: TBR1, TANK, and PSMD14. The findings suggest that the critical region for intellectual disability and short stature in 2q24.2 can be narrowed to a 0.422 Mb segment. TBR1, a transcription factor involved in early cortical development, is a strong candidate for the intellectual disability phenotype seen in our patient and in patients with larger deletions in this region of the genome.
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Gender preference and awareness regarding sex determination among antenatal mothers attending a medical college of eastern India.
Scand J Public Health
PUBLISHED: 02-22-2013
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There are many women "missing" due to an unfavourable sex ratio in India, which has strong patriarchal norms and a preference for sons. Female gender discrimination has been reported in health care, nutrition, education, and resource allocation due to man-made norms, religious beliefs, and recently by ultrasonography resulting in lowered sex ratio.
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Design of libraries targeting protein-protein interfaces.
ChemMedChem
PUBLISHED: 02-21-2013
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TARGETING PPIS: A novel strategy for designing libraries targeting protein-protein interfaces enabled us to identify diverse chemical entry points to interact with therapeutic targets for which conventional screening libraries delivered no or only few hit structures. The concept was experimentally validated by early hit evaluation in biochemical screens and early ADMET profiling.
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SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
Nature
PUBLISHED: 02-20-2013
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Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.
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Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs.
Bioorg. Med. Chem. Lett.
PUBLISHED: 02-20-2013
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Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4-aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation.
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Trabecular bone deterioration at the greater trochanter of mice with unilateral obstructive nephropathy.
Asian J. Androl.
PUBLISHED: 01-31-2013
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Our previous study showed the early molecular responses of bone in response to obstructive nephropathy in a unilateral ureteral obstruction (UUO) mouse model. Here, we addressed the changes in trabecular bone properties at greater trochanter, the proximal and the distal metaphysis of femur in UUO mice. The male mice were subjected to UUO (n=10) or sham operation (n=10). All mice were killed on day 7 after the surgical operation. The micro-computed tomography (micro-CT) analysis for different femoral trabecular bone sites demonstrated pathological alterations of trabecular bone mass and micro-networks at greater trochanter as shown by decreases in bone mineral density/bone volume (P<0.05) and trabecular number (P<0.05) and increases in trabecular separation (P<0.01) and bone surface/bone volume (P<0.05) in UUO mice. The present study demonstrates that UUO-induced unilateral obstructive nephropathy has markedly detrimental effects on the trabecular trochanter of the femur.
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Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes.
J. Bone Miner. Metab.
PUBLISHED: 01-27-2013
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There are contradictory results about the effect of angiotensin-converting enzyme inhibitors (ACEIs) on bone. This study was performed to address the skeletal renin-angiotensin system (RAS) activity and the effects of the ACEI, captopril, on the bone of streptozotocin-induced type 1 diabetic mice. Histochemical assessment on bone paraffin sections was conducted by Safranin O staining and tartrate-resistant acid phosphatase staining. Micro-computed tomography was performed to analyze bone biological parameters. Gene and protein expression were determined by real-time polymerase chain reaction and immunoblotting, respectively. Type 1 diabetic mice displayed osteopenia phenotype and captopril treatment showed no osteoprotective effects in diabetic mice as shown by the reduction of bone mineral density, trabecular thickness and bone volume/total volume. The mRNA expression of ACE and renin receptor, and the protein expression of renin and angiotensin II were markedly up-regulated in the bone of vehicle-treated diabetic mice compared to those of non-diabetic mice, and these molecular changes of skeletal RAS components were effectively inhibited by treatment with captopril. However, treatment with captopril significantly elevated serum tartrate-resistant acid phosphatase 5b levels, reduced the ratio of osteoprotegerin/receptor activator of nuclear factor-?B ligand expression, increased carbonic anhydrase II mRNA expression and the number of matured osteoclasts and decreased transforming growth factor-? and osteocalcin mRNA expression in the tibia compared to those of diabetic mice. The present study demonstrated that the use of the ACEI, captopril, has no beneficial effect on the skeletal biological properties of diabetic mice. However, this could be attributed, at least partially, to its suppression of osteogenesis and stimulation of osteoclastogenesis, even though it could effectively inhibit high activity of local RAS in the bone of diabetic mice.
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Bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/ raxibacumab-treated New Zealand white rabbits.
Toxins (Basel)
PUBLISHED: 01-25-2013
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Inhaled Bacillus anthracis spores germinate and the subsequent vegetative growth results in bacteremia and toxin production. Anthrax toxin is tripartite: the lethal factor and edema factor are enzymatic moieties, while the protective antigen (PA) binds to cell receptors and the enzymatic moieties. Antibiotics can control B. anthracis bacteremia, whereas raxibacumab binds PA and blocks lethal toxin effects. This study assessed plasma PA kinetics in rabbits following an inhaled B. anthracis spore challenge. Additionally, at 84 h post-challenge, 42% of challenged rabbits that had survived were treated with either levofloxacin/placebo or levofloxacin/raxibacumab. The profiles were modeled using a modified Gompertz/second exponential growth phase model in untreated rabbits, with added monoexponential PA elimination in treated rabbits. Shorter survival times were related to a higher plateau and a faster increase in PA levels. PA elimination half-lives were 10 and 19 h for the levofloxacin/placebo and levofloxacin/raxibacumab groups, respectively, with the difference attributable to persistent circulating PA-raxibacumab complex. PA kinetics were similar between untreated and treated rabbits, with one exception: treated rabbits had a plateau phase nearly twice as long as that for untreated rabbits. Treated rabbits that succumbed to disease had higher plateau PA levels and shorter plateau duration than surviving treated rabbits.
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Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor.
Arthritis Rheum.
PUBLISHED: 01-22-2013
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To determine the necessity for any individual BAFF receptor in the development of systemic lupus erythematosus (SLE).
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.