bluuebunny/crossref_metadata_2025 huggingface dataset:
Review article: the endocannabinoid system in liver disease, a potential therapeutic target
Authors: Basu P. P. , Aloysius M. M. , Shah N. J. , Brown Jr R. S.
Published: February 2014

Background

Endocannabinoids are a family of potent lipid‐soluble molecules, acting on the cannabinoid (CB) receptors that mediate the effects of marijuana. The CB receptors, endocannabinoids and the enzymes involved in their synthesis and degradation are located in the brain and peripheral tissues, including the liver.

Aims

To review the current understanding of the role of the endocannabinoid system in liver disease‐associated pathophysiological conditions, and drugs targeting the endocannabinoid system as therapy for liver disease.

Methods

Original articles and reviews were used to summarise the relevant pre‐clinical and clinical research findings relating to this topic.

Results

The endocannabinoid system as a whole plays an important role in liver diseases (i.e. non‐alcoholic liver disease, alcoholic liver disease, hepatic encephalopathy and autoimmune hepatitis) and related pathophysiological conditions (i.e. altered hepatic haemodynamics, cirrhotic cardiomyopathy, metabolic syndrome and ischaemia/reperfusion disease). Pharmacological targeting of the endocannabinoid system has had success as treatment for patients with liver disease, but adverse events led to withdrawal of marketing approval. However, there is optimism over novel therapeutics targeting the endocannabinoid system currently in the pre‐clinical stage of development.

Conclusions

The endocannabinoid system plays an important role in the pathophysiology of liver disease and its associated conditions. While some drugs targeting the endocannabinoid system have deleterious neurological adverse events, there is promise for a newer generation of therapies that do not cross the blood–brain barrier.
The Volterran Urns: Etruscan Painting and Travertine Supply
Authors: Gliozzo E. , Spangenberg J. E. , Sorge E. , Memmi I.
Published: February 2014

The artistic evolution of the Volterran cinerary urns is a good representation of Etruscan painting from the fourth to the first century bc. The interest generated by this type of object directed our research towards the study of the Volterran artefacts, including the analysis of the pigments as well as that of the rocks used for the coffers. The entire colour range shown by the painted urns has been sampled and investigated through Raman microscopy and scanning electron microscopy. Rock samples were taken both from the urns and from outcrops in ancient carbonate rock quarries near Volterra, from where they may potentially have been sourced. A set of 30 samples was collected and submitted to stable carbon and oxygen isotope analyses. The results obtained showed that the pigments used for the decoration of the Volterran urns were basically constituted by red ochre, Egyptian blue, carbon black and gypsum. The identification of lead‐based pigments and barium sulphates further informed us about old restorations undergone by several urns. As far as the provenance issue is concerned, the isotopic data indicate that the rocks used for the four urns were favourably comparable to those outcropping at Pignano, while two other urns were more similar to those sampled along the Elsa River at Colle Val d'Elsa.
Suitability and limitations of native species for seed mixtures to re‐vegetate degraded areas
Authors: Oliveira Graça , Clemente Adelaide , Nunes Alice , Correia Otília
Published: February 2014

Questions

How do native species perform when included in seed mixtures to re‐vegetate degraded areas? Is their germination and establishment affected by seeding density?

Location

Limestone quarry spoil, SW Portugal.

Methods

A glasshouse experiment simulating usual hydroseeding procedures (substrate, time of the year, slurry composition, seed mixture) was performed to evaluate the suitability of six native species (Origanum vulgare, Piptatherum miliaceum, Phagnalon saxatile, Sedum album, S. sediforme, Thymus mastichina) to re‐vegetate a Mediterranean quarry. Other native species were added to create the seed mixtures. Three treatments were assayed for each target species sown: (1) alone (T), (2) in a low‐density seed mixture (ca. 15 g·m−2), and (3) in a high‐density seed mixture (ca. 30 g·m−2). Plants were monitored for 8 months.

Results

The target species were able to germinate, establish and grow when sown alone, but their performance was drastically impaired when included in seed mixtures. This was related to plant morphologies, as some co‐seeded species rapidly developed large leaves, which presumably reduced resource availability for the small‐leaved seedlings of most target species. Almost no seedlings of the latter survived in the mixture treatments. Low‐ and high‐seeding densities yielded similar plant covers and heights.

Conclusions

Even when apparently suitable to restore a given site, candidate native species cannot simply be included in current re‐vegetation ‘recipes’, because their success largely depends on the density and seedling characteristics of the co‐seeded species (even if these are also native). The early performance and morphology of the latter must be taken into account in the design of seed mixtures used in restoration actions.
Application of High‐Content Analysis in Clinical Cytology for Translational Safety Biomarkers of Drug‐Induced Toxicity for Lymphoma Chemotherapy
Authors: Domingos Margarida Canelas , Davies Anthony M. , O'Brien Peter J.
Published: February 2014

Drug cytotoxicity detected by high‐content analysis (HCA) of live, cultured, human hepatocytes concurs with human toxic potential. We assessed HCA effectiveness in vivo using human, lymphoma line (HuT‐78) and blood cells from healthy dogs and lymphomatous dogs treated with anticancer drugs: cytarabine, arsenic trioxide (AT), doxorubicin and mitoxantrone. DNA was stained with Hoechst‐33342, calcium with fluo‐4, mitochondria with TMRM and cell permeability with toto‐3. HuT‐78 and canine blood lymphocytes were treated 24 hr with 10 times increasing drug concentrations to determine concentration–response relationships to test agents. These showed hormesis (biphasic response) for TMRM and nuclear area. Fluorescence intensity was decreased with AT and mitoantrone but increased with cytarabine for TMRM, decreased from cell injury or anthracycline interaction for Hoechst‐33342 and decreased with AT and interfered with by doxorubicin for fluo‐4. Nuclear area increased with anthracyclines and AT. Mitochondria, calcium and nuclear area were affected in peripheral blood lymphocytes of lymphomatous dogs receiving chemotherapy: mitochondria were inhibited by acute treatment, but increased 2 weeks after treatment, as were ionized calcium, nuclear area and DNA. We conclude (i) concentration–response relationships are determinable in vitro for human and canine lymphocytes by HCA, (ii) cytotoxicity is detectable in vivo during and after anticancer drug treatment using canine blood lymphocytes: mitochondria are most affected, with smaller changes in calcium and nuclei and (iii) blood cell viability may be a biomarker for anticancer drug toxicity.
Semi‐Mechanistic Modelling and Simulation of Inhibition of Platelet Aggregation by Antiplatelet Agents
Authors: Yun Hwi‐yeol , Kang Wonku , Lee Byung‐yo , Park Sunkyung , Yoon Young‐Ran , Yeul Ma Jin , Kwon Kwang‐il
Published: February 2014

Antiplatelet agents are a class of pharmaceuticals that decrease platelet aggregation and thus inhibit thrombus formation. We examined the relationships between plasma concentrations of antiplatelet agents (triflusal, clopidogrel and cilostazol) and the platelet aggregation inhibitory effect after dosing. We used triflusal, cilostazol and clopidogrel for the development of a semi‐mechanistic PK/PD model. The drugs chosen are used widely and reflect various mechanisms of antiplatelet agents. Time courses of plasma concentrations of the antiplatelet agents and their platelet aggregation effects were analysed using ADPAT V. Pharmacokinetic profiles were fitted to an extended parent–metabolite pharmacokinetic model, based on a two‐compartment model, and the pharmacodynamic effects of the agents were fitted to a platelet aggregation effect model that consisted of the following parameters: Ks, the active‐form platelet synthesis rate constant; K, the apparent reaction rate constant of the agent and active‐form platelets; Kel‐PRP, the apparent rate constant of platelets; and ε, an intrinsic activity parameter. This semi‐mechanistic PK/PD model described well the relationship between plasma concentrations of antiplatelet agents and platelet aggregation effects. In addition, the estimated parameters were suitable for the explanation of the agents and also have a good correlation with platelet characteristics, such as platelet half‐life and platelet aggregation baseline effects. Specifically, we discovered the strong correlations between estimated K parameter and in vitro drug activity. We conclude that this semi‐mechanistic PK/PD model explained drug PK/PD characteristics well and will be useful for accurate predictions of antiplatelet effect in the clinical situations.
Bayesian hidden Markov models to identify RNA–protein interaction sites in PAR‐CLIP
Authors: Yun Jonghyun , Wang Tao , Xiao Guanghua
Published: February 2014

The photoactivatable ribonucleoside enhanced cross‐linking immunoprecipitation (PAR‐CLIP) has been increasingly used for the global mapping of RNA–protein interaction sites. There are two key features of the PAR‐CLIP experiments: The sequence read tags are likely to form an enriched peak around each RNA–protein interaction site; and the cross‐linking procedure is likely to introduce a specific mutation in each sequence read tag at the interaction site. Several ad hoc methods have been developed to identify the RNA–protein interaction sites using either sequence read counts or mutation counts alone; however, rigorous statistical methods for analyzing PAR‐CLIP are still lacking. In this article, we propose an integrative model to establish a joint distribution of observed read and mutation counts. To pinpoint the interaction sites at single base‐pair resolution, we developed a novel modeling approach that adopts non‐homogeneous hidden Markov models to incorporate the nucleotide sequence at each genomic location. Both simulation studies and data application showed that our method outperforms the ad hoc methods, and provides reliable inferences for the RNA–protein binding sites from PAR‐CLIP data.
Test the reliability of doubly robust estimation with missing response data
Authors: Chen Baojiang , Qin Jing
Published: February 2014

In statistical inference, one has to make sure that the underlying regression model is correctly specified otherwise the resulting estimation may be biased. Model checking is an important method to detect any departure of the regression model from the true one. Missing data are a ubiquitous problem in social and medical studies. If the underlying regression model is correctly specified, recent researches show great popularity of the doubly robust (DR) estimates method for handling missing data because of its robustness to the misspecification of either the missing data model or the conditional mean model, that is, the model for the conditional expectation of true regression model conditioning on the observed quantities. However, little work has been devoted to the goodness of fit test for DR estimates method. In this article, we propose a testing method to assess the reliability of the estimator derived from the DR estimating equation with possibly missing response and always observed auxiliary variables. Numerical studies demonstrate that the proposed test can control type I errors well. Furthermore the proposed method can detect departures from model assumptions in the marginal mean model of interest powerfully. A real dementia data set is used to illustrate the method for the diagnosis of model misspecification in the problem of missing response with an always observed auxiliary variable for cross‐sectional data.
A Bayesian localized conditional autoregressive model for estimating the health effects of air pollution
Authors: Lee Duncan , Rushworth Alastair , Sahu Sujit K.
Published: February 2014

Estimation of the long‐term health effects of air pollution is a challenging task, especially when modeling spatial small‐area disease incidence data in an ecological study design. The challenge comes from the unobserved underlying spatial autocorrelation structure in these data, which is accounted for using random effects modeled by a globally smooth conditional autoregressive model. These smooth random effects confound the effects of air pollution, which are also globally smooth. To avoid this collinearity a Bayesian localized conditional autoregressive model is developed for the random effects. This localized model is flexible spatially, in the sense that it is not only able to model areas of spatial smoothness, but also it is able to capture step changes in the random effects surface. This methodological development allows us to improve the estimation performance of the covariate effects, compared to using traditional conditional auto‐regressive models. These results are established using a simulation study, and are then illustrated with our motivating study on air pollution and respiratory ill health in Greater Glasgow, Scotland in 2011. The model shows substantial health effects of particulate matter air pollution and nitrogen dioxide, whose effects have been consistently attenuated by the currently available globally smooth models.
Relapse kinetics in acute myeloid leukaemias with MLL translocations or partial tandem duplications within the MLL gene
Authors: Ommen Hans B. , Hokland Peter , Haferlach Torsten , Abildgaard Lotte , Alpermann Tamara , Haferlach Claudia , Kern Wolfgang , Schnittger Susanne
Published: February 2014

Correct action upon re‐emergence of minimal residual disease in acute myeloid leukaemia (AML) patients has not yet been established. The applicability of demethylating agents and use of allogeneic stem cell transplantation will be dependent on pre‐relapse AML growth rates. We here delineate molecular growth kinetics of AML harbouring MLL partial tandem duplication (MLL‐PTD; 37 cases) compared to those harbouring MLL translocations (43 cases). The kinetics of MLL‐PTD relapses was both significantly slower than those of MLL translocation positive ones (median doubling time: MLL‐PTD: 24 d, MLL‐translocations: 12 d, P = 0·015, Wilcoxon rank sum test), and displayed greater variation depending on additional mutations. Thus, MLL‐PTD+ cases with additional RUNX1 mutations or FLT3‐internal tandem duplication relapsed significantly faster than cases without one of those two mutations (Wilcoxon rank sum test, P = 0·042). As rapid relapses occurred in all MLL subgroups, frequent sampling are necessary to obtain acceptable relapse detection rates and times from molecular relapse to haematological relapse (blood sampling every second month: MLL‐PTD: 75%/50 d; MLL translocations: 85%/25 d). In conclusion, in this cohort relapse kinetics is heavily dependent on AML subtype as well as additional genetic aberrations, with possibly great consequences for the rational choice of pre‐emptive therapies.
Effect of partial bladder outlet obstruction and reversal on rabbit bladder physiology and biochemistry: duration of recovery period and severity of function
Authors: Jock Marley , Leggett Robert E. , Schuler Catherine , Callaghan Connor , Levin Robert M.
Published: February 2014

Objectives

To use a rabbit model of partial bladder outlet obstruction (BOO) to investigate the point at which obstructive bladder dysfunction becomes irreversible.

Methods

Partial BOO was induced in New Zealand White rabbits. It was then reversed and the rabbits were allowed to recover for 4, 8 or 12 weeks. Both at the time of reversal and at the end of the study, the rabbits were grouped according to bladder decompensation level (mild, intermediate or severe) based on bladder mass (weight).

Results

A strong correlation was observed between the production and distribution of collagen and the reduction of smooth muscle contractile function. We found that only in the bladders that were severely decompensated at the time of reversal did collagen levels not decrease.

Conclusion

The data show that recovery of function after reversal of partial BOO is directly related primarily to collagen levels at the time of reversal.
Novel method of full‐thickness bladder closure with an endoscopic suturing machine: a survival study in a porcine model
Authors: Oliveira Carlos , Autorino Riccardo , Ferreira Carlos , Cicione Antonio , Damiano Rocco , De Sio Marco , Correia‐Pinto Jorge , Lima Estevao
Published: February 2014

Objective

To assess the feasibility of a pure endoscopic closure method for vesical perforations using fully absorbable material.

Materials and Methods

A pilot experimental study was performed in eight anaesthetized female pigs. Four 10‐mm and four 20‐mm endoscopic full thickness cystotomies were created. An endoscopic suturing machine (RD‐180®; LSI Solutions, Victor, NY, USA) was deployed through the working channel of a cystoscope and used to close the incisions with absorbable sutures. Immediate assessment of the quality of the closure was obtained by distending the bladder with saline solution stained with methylene blue under laparoscopic control. After 3 weeks of follow‐up, a necropsy examination was performed to check for signs of peritonitis and wound dehiscence and to assess the quality of healing.

Results

The experiment was completed in all eight pigs without complications. The median procedure time was 10 ± 4.3 min. The immediate bladder distention test did not show any methylene blue leakage. The postoperative period was uneventful. The post mortem examination after 3 weeks revealed complete healing of the bladder wall incisions with no signs of infection, wound dehiscence or adhesions in the peritoneal cavity of any of the pigs.

Conclusion

This study describes a successful novel method for endoscopic closure of bladder perforations. The technique was easy, reproducible and safe. Nevertheless, further experimental investigation should be carried out before clinical application of this method.
Is radical nephrectomy a legitimate therapeutic option in patients with renal masses amenable to nephron‐sparing surgery?
Authors: Tomaszewski Jeffrey J. , Smaldone Marc C. , Uzzo Robert G. , Kutikov Alexander
Published: February 2014

The decision to perform a radical nephrectomy (RN) or a partial nephrectomy (PN), not unlike most decisions in clinical practice, ultimately hinges on the balance of risk. Do the higher risks of a more complex surgery (PN) justify the theoretical benefits of kidney tissue preservation? Data suggest that for patients with an anatomically complex renal mass and a normal contralateral kidney, for whom additional surgical intensity may be risky, such as the elderly and comorbid, RN presents a robust treatment option. Nevertheless, PN, especially for small and anatomically simple renal masses in young patients without comorbidities should remain the surgical reference standard, as preservation of renal tissue can serve as an ‘insurance policy’ not only against future renal functional decline, but also against the possibility of tumour development in the contralateral kidney. In the present review, we outline the ongoing debate between the role of RN and PN in treatment of the enhancing renal mass.
Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non‐peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats
Authors: Hicks C , Ramos L , Reekie T , Misagh G H , Narlawar R , Kassiou M , McGregor I S
Published: February 2014

Background and Purpose

There is current interest in oxytocin (OT) as a possible therapeutic in psychiatric disorders. However, the usefulness of OT may be constrained by peripheral autonomic effects, which may involve an action at both OT and vasopressin V1A receptors. Here, we characterized the cardiovascular and thermoregulatory effects of OT, vasopressin (AVP) and the non‐peptide OT receptor agonist WAY 267,464 in rats, and assessed the relative involvement of the OT and V1A receptors in these effects.

Experimental Approach

Biotelemetry in freely moving male Wistar rats was used to examine body temperature and heart rate after OT (0.01 – 1 mg kg−1; i.p.), AVP (0.001 – 0.1 mg kg−1; i.p.) or WAY 267,464 (10 and 100 mg kg−1; i.p.). The actions of the OT receptor antagonist Compound 25 (C25, 5 and 10 mg kg−1) and V1A receptor antagonist SR49059 (1 and 10 mg kg−1) were studied, as well as possible V1A receptor antagonist effects of WAY 267,464.

Key Results

OT and AVP dose‐dependently reduced body temperature and heart rate. WAY 267,464 had similar, but more modest, effects. SR49059, but not C25, prevented the hypothermia and bradycardia induced by OT and AVP. WAY 267,464 (100 mg·kg−1) prevented the effects of OT, and to some extent AVP.

Conclusions and Implications

Peripherally administered OT and AVP have profound cardiovascular and thermoregulatory effects that appear to principally involve the V1A receptor rather than the OT receptor. Additionally, WAY 267,464 is not a simple OT receptor agonist, as it has functionally relevant V1A antagonist actions.
Amitriptyline up‐regulates connexin43‐gap junction in rat cultured cortical astrocytes via activation of the p38 and c‐Fos/AP‐1 signalling pathway
Authors: Morioka N , Suekama K , Zhang F F , Kajitani N , Hisaoka‐Nakashima K , Takebayashi M , Nakata Y
Published: February 2014

Background and Purpose

Intercellular communication via gap junctions, comprised of connexin (Cx) proteins, allow for communication between astrocytes, which in turn is crucial for maintaining CNS homeostasis. The expression of Cx43 is decreased in post‐mortem brains from patients with major depression. A potentially novel mechanism of tricyclic antidepressants is to increase the expression and functioning of gap junctions in astrocytes.

Experimental Approach

The effect of amitriptyline on the expression of Cx43 and gap junction intercellular communication (GJIC) in rat primary cultured cortical astrocytes was investigated. We also investigated the role of p38 MAPK intracellular signalling pathway in the amitriptyline‐induced expression of Cx43 and GJIC.

Key Results

Treatment with amitriptyline for 48 h significantly up‐regulated Cx43 mRNA, protein and GJIC. The up‐regulation of Cx43 was not monoamine‐related since noradrenaline, 5‐HT and dopamine did not induce Cx43 expression and pretreatment with α‐ and β‐adrenoceptor antagonists had no effect. Intracellular signalling involved p38 MAPK, as amitriptyline significantly increased p38 MAPK phosphorylation and Cx43 expression and GJIC were significantly blocked by the p38 inhibitor SB 202190. Furthermore, amitriptyline‐induced Cx43 expression and GJIC were markedly reduced by transcription factor AP‐1 inhibitors (curcumin and tanshinone IIA). The translocation of c‐Fos from the cytosol and the nucleus of cortical astrocytes was increased by amitriptyline, and this response was dependent on p38 activity.

Conclusion and Implication

These findings indicate a novel mechanism of action of amitriptyline through cortical astrocytes, and further suggest that targeting this mechanism could lead to the development of a new class of antidepressants.
Major issues in the origins of ray‐finned fish (Actinopterygii) biodiversity
Authors: Sallan Lauren C.
Published: February 2014

Ray‐finned fishes (Actinopterygii) dominate modern aquatic ecosystems and are represented by over 32000 extant species. The vast majority of living actinopterygians are teleosts; their success is often attributed to a genome duplication event or morphological novelties. The remainder are ‘living fossils’ belonging to a few depauperate lineages with long‐retained ecomorphologies:Polypteriformes (bichirs),Holostei (bowfin and gar) andChondrostei (paddlefish and sturgeon). Despite over a century of systematic work, the circumstances surrounding the origins of these clades, as well as their basic interrelationships and diagnoses, have been largely mired in uncertainty. Here,Ireview the systematics and characteristics of these major ray‐finned fish clades, and the early fossil record ofActinopterygii, in order to gauge the sources of doubt. Recent relaxed molecular clock studies have pushed the origins of actinopterygian crown clades to the mid‐latePalaeozoic [Silurian–Carboniferous; 420 to 298 million years ago (Ma)], despite a diagnostic body fossil record extending only to the laterMesozoic (251 to 66Ma). This disjunct, recently termed the ‘TeleostGap’ (although it affects all crown lineages), is based partly on calibrations from potentialPalaeozoic stem‐taxa and thus has been attributed to poor fossil sampling. Actinopterygian fossils of appropriate ages are usually abundant and well preserved, yet long‐term neglect of this record in both taxonomic and systematic studies has exacerbated the gaps and obscured potential synapomorphies. At the moment, it is possible that laterPalaeozoic‐age teleost, holostean, chondrostean and/or polypteriform crown taxa sit unrecognized in museum drawers. However, it is equally likely that the ‘TeleostGap’ is an artifact of incorrect attributions to extant lineages, overwriting both a post‐Palaeozoic crown actinopterygian radiation and the ecomorphological diversity of stem‐taxa.
GATA4 immunolocalization in breast carcinoma as a potent prognostic predictor
Authors: Takagi Kiyoshi , Moriguchi Takashi , Miki Yasuhiro , Nakamura Yasuhiro , Watanabe Mika , Ishida Takanori , Yamamoto Masayuki , Sasano Hironobu , Suzuki Takashi
Published: February 2014

Transcriptional GATA factors are known lineage selector genes and regulate a variety of biological processes including specification and differentiation of tissues. In the present study, we examined expression profiles of six GATA factor genes in invasive ductal carcinomas (IDC) of the breast using microarray analysis (n = 20) and found that GATA4 expression was closely correlated with recurrence in patients. Because the significance of GATA4 has remained largely unknown in breast carcinoma, we further immunolocalized GATA4 in ductal carcinoma in situ (DCIS) of the breast (n = 48) and IDC (n = 163). GATA4 immunoreactivity was detected in the nuclei of carcinoma cells and was positive in 27% of DCIS and 31% of IDC cases. GATA4 status was significantly associated with nuclear grade and van Nuys classification in DCIS and was positively associated with distant metastasis, histological grade and HER2 status, but negatively correlated with progesterone receptor labeling index in IDC. Subsequent multivariate analysis demonstrated that GATA4 status was an independent prognostic factor for both disease‐free and breast cancer‐specific survival of IDC patients. All of these results indicate that GATA4 plays important roles in the progression of breast carcinoma from an early stage and that immunohistochemical GATA4 status is considered a potent prognostic factor in human breast cancer patients.
Modeling the Met Form of Human Tyrosinase: A Refined and Hydrated Pocket for Antagonist Design
Authors: Favre Elisabeth , Daina Antoine , Carrupt Pierre‐Alain , Nurisso Alessandra
Published: February 2014

Tyrosinases are type 3 copper proteins involved in melanin biosynthesis, responsible for skin and hair color in mammals. To steer tyrosinase inhibitor discovery for therapeutic and cosmetic purposes, structural information about human tyrosinase is necessary. As this protein has never been crystallized so far, we derived a robust homology model built using structural information from Streptomyces castaneoglobisporus and Ipomea batata catecholoxidase enzymes. The active site containing two copper atoms in co‐ordination with six histidine residues was refined through an optimization protocol based on molecular mechanics parameters for copper co‐ordination and charges calculated by quantum mechanics methods. Five structural water molecules and a hydroxyl ion were found to be essential for optimization. The superimposition of the human homology model on crystallographic structures of tyrosinases from other species revealed similar overall backbone topologies, active site conformations, and conserved water molecules. Phenylthiourea (PTU), the tyrosinase inhibitor of reference, was then docked into the solvated human active pocket. A binding mode consistent with crystallographic information was obtained. Taken together, these findings demonstrated that the human tyrosinase model, deposited in the Protein Model Database, is a reliable structure for future rational inhibitor design projects.
Spatial Ability Mediates the Gender Difference in Middle School Students' Science Performance
Authors: Ganley Colleen M. , Vasilyeva Marina , Dulaney Alana
Published: February 2014

Prior research has demonstrated a male advantage in spatial skills and science achievement. The present research integrated these findings by testing the potential role of spatial skills in gender differences in the science performance of eighth‐grade students (13–15 years old). In (N = 113), the findings showed that mental rotation ability mediated gender differences in physical science and technology/engineering test scores. In (N = 73,245), science performance was examined in a state population of eighth‐grade students. As in , the results revealed larger gender differences on items that showed higher correlations with mental rotation. These findings underscore the importance of considering spatial training interventions aimed at reducing gender differences in the science performance of school‐aged children.
Time With Peers From Middle Childhood to Late Adolescence: Developmental Course and Adjustment Correlates
Authors: Lam Chun Bun , McHale Susan M. , Crouter Ann C.
Published: February 2014

This study examined the developmental course and adjustment correlates of time with peers from age 8 to 18. On seven occasions over 8 years, the two eldest siblings from 201 European American, working‐ and middle‐class families provided questionnaire and/or phone diary data. Multilevel models revealed that girls' time with mixed‐/opposite‐sex peers increased beginning in middle childhood, but boys' time increased beginning in early adolescence. For both girls and boys, time with same‐sex peers peaked in middle adolescence. At the within‐person level, unsupervised time with mixed‐/opposite‐sex peers longitudinally predicted problem behaviors and depressive symptoms, and supervised time with mixed‐/opposite‐sex peers longitudinally predicted better school performance. Findings highlight the importance of social context in understanding peer involvement and its implications for youth development.
Assessment of quality of life during gonadotrophin treatment for male hypogonadotrophic hypogonadism
Authors: Shiraishi Koji , Oka Shintaro , Matsuyama Hideyasu
Published: February 2014

Objective

The management of male hypogonadotrophic hypogonadism (MHH) with gonadotrophins is effective in promoting genital development and spermatogenesis. We investigated the changes in SF‐36 subscales, including physical, social and psychological QOL, during gonadotrophin or testosterone treatment and analysed the factors that are involved in the outcomes of health‐related quality of life (HRQOL) in MHH patients.

Patients and Design

Thirty‐seven MHH patients (mean age: 26·1 years old) who underwent gonadotrophin (n = 31) or testosterone treatment (n = 6), excluding infertility cases, were asked to respond to a SF‐36 questionnaire before and every 6 months during the 2‐year treatment period. The changes in SF‐36 domains and the associations between improvements and patient factors were examined.

Results

The scores in all of the SF‐36 domains were lower than in the normal Japanese population. In all eight domains, except for bodily pain and social functioning, the mean scores for physical function (PF), role‐physical (RP), general health (GH), vitality (VT), role‐emotional (RE) and mental health (MH) significantly increased over the course of treatment in patients with gonadotrophin. These changes were particularly noticeable in the psychological domains; GH, VT, RE and MH exhibited large increases 18 months after treatment. Testosterone treatment increased only PF and RP domains. In patients with sperm in their ejaculate, the improvements in GH, VT, RE and MH were significantly greater than those who did not exhibit sperm.

Conclusion

Gonadotrophin treatment for MHH was associated with significant improvements in SF‐36 domains. Gonadotrophin treatment could prevent negative physical and psychological sequelae in the management of MHH.
Metabolic, cardiovascular and anthropometric differences between prepubertal girls and boys
Authors: Ayyavoo Ahila , Derraik José G. B. , Hofman Paul L. , Biggs Janene , Cutfield Wayne S.
Published: February 2014

Objective

We aimed to assess possible differences in insulin sensitivity and other metabolic, anthropometric and cardiovascular parameters between boys and girls prior to puberty.

Methods

We studied 85 healthy prepubertal children (33 girls and 52 boys) aged 8·7 ± 1·9 years (range 4·0–11·9 years), born 38–40 weeks gestation, and of birth weight appropriate‐for‐gestational‐age. Insulin sensitivity was measured using frequently sampled intravenous glucose tests and Bergman's minimal model. Other clinical assessments included anthropometric measures, fasting lipid and hormonal profiles, body composition from whole‐body dual‐energy X‐ray absorptiometry and 24‐h ambulatory blood pressure monitoring.

Results

Prepubertal girls and boys were of similar parent‐adjusted height SDS (P = 0·26), but girls had considerably more body fat (P < 0·0001), less fat‐free mass (P = 0·0002) and greater abdominal adiposity (P < 0·0001). These differences in body composition were independent of adrenal androgens. Insulin sensitivity was 18% lower in girls (11·0 vs 13·4 × 10−4/min (mU/l);P = 0·028), but this difference disappeared with adjustment for adiposity and DHEAS concentrations. There were, however, some apparent sex differences in cardiovascular parameters, with girls displaying increased heart rate and reduced blood pressure dipping. Girls also had higher triglyceride concentrations (+23%;P = 0·036).

Conclusion

There are a number of anthropometric, metabolic and cardiovascular differences between sexes prior to the appearance of external signs of puberty. Although differences in insulin sensitivity were eliminated when adiposity andDHEASconcentrations were accounted for, there were independent differences in body composition and cardiovascular parameters. Thus, gender, adrenarche and adiposity should be accounted for in studies examining metabolic and cardiovascular outcomes prior to puberty.
Antepartum determinants of rapid early‐life weight gain in term infants born to women with and without gestational diabetes
Authors: Kramer Caroline K. , Hamilton Jill K. , Ye Chang , Hanley Anthony J. , Connelly Philip W. , Sermer Mathew , Zinman Bernard , Retnakaran Ravi
Published: February 2014

Objective

Rapid weight gain in the first 3 months of life has been associated with an unfavourable cardio‐metabolic phenotype in adulthood. However, little is known about the antepartum determinants of this rapid weight gain, which may reflect key developmental exposures that program metabolic pathways. Thus, we sought to characterize the antepartum determinants of rapid weight gain in the first 3 months of life in infants exposed to gestational diabetes mellitus (GDM), a patient population at risk for early cardio‐metabolic disease.

Design

Prospective observational cohort study.

Patients

Pregnant women with (n = 90) and without GDM (n = 250) underwent detailed antepartum metabolic characterization, followed by assessment of their term offspring at age 3 months.

Measurements

Rapid infant weight gain in the first 3 months was defined as weight gain ≥ 0·5 SD.

Results

No features of maternal metabolic function in pregnancy (including insulin sensitivity, lipid profile, adiponectin, leptin and C‐reactive protein) were associated with infant weight gain in either the GDM or non‐GDM group. Interestingly, although all infants were born at term (≥37 weeks), length of gestation was inversely associated with weight gain at 3 months in the infants of women with GDM (β = −148·5, P = 0·01). In these infants, length of gestation <39 weeks was an independent predictor of rapid weight gain (OR = 7·9, 95%CI 1·7–38, P = 0·009) in the fully adjusted model. These associations were not observed in infants of women without GDM.

Conclusions

Delivery before 39 weeks is independently associated with rapid weight gain in the first 3 months of life in term infants of women with GDM and hence may be an antepartum marker of future cardio‐metabolic risk.
Association of aromatase (TTTA)n repeat polymorphisms with central precocious puberty in girls
Authors: Lee Hae Sang , Kim Kyung Hee , Hwang Jin Soon
Published: February 2014

Objective

Precocious puberty is characterized by early activation of the pituitary‐gonadal axis. Oestrogen is the final key factor to start the onset of puberty. The cytochrome P450 19A1 (CYP19A1) gene encodes an aromatase that is responsible for the conversion of androgens to oestrogen, which is a key step in oestrogen biosynthesis. The aim of this study was to identify CYP19A1 gene mutations or polymorphisms in girls with central precocious puberty (CPP).

Methods

We evaluated the frequency of allelic variants of the CYP19A1 exons and the tetranucleotide tandem repeat (TTTA)n in intron 4 in 203 idiopathic central precocious puberty (CPP) girls and 101 normal healthy women.

Results

The genotype analysis of the CYP19A1 (TTTA)n polymorphism revealed six different alleles ranging from seven to 13 repeats. Among the six different repeat alleles detected in this study, the (TTTA)13 repeat allele was only detected in the patient group and carriers of the (TTTA)13 allele were significantly associated with an increased risk of CPP (OR = 1·509, 95% CI = 1·425–1·598, P = 0·033). Carriers of the (TTTA)13 repeat allele were significantly younger at pubertal onset and had higher levels of oestrogen than noncarriers of the (TTTA)13 repeat allele. Although nine polymorphisms were detected in exons of the CYP19A1 gene, no clinical significance was observed.

Conclusion

In this study, carriers of a higher repeat (TTTA)13 polymorphism in intron 4 of the CYP19A1 gene had higher levels of oestrogen. Those carrying the (TTTA)13 repeat allele may have a higher risk of developing CPP.
Escape and lipodystrophy in acromegaly during pegvisomant therapy, a retrospective multicentre Spanish study
Authors: Sesmilo Gemma , Resmini Eugenia , Bernabeu Ignacio , Aller Javier , Soto Alfonso , Mora Mireia , Picó Antonio , Fajardo Carmen , Torres Elena , Álvarez‐Escolá Cristina , García Rogelio , Blanco Concepción , Cámara Rosa , Gaztambide Sonia , Salinas Isabel , Pozo Carlos Del , Castells Ignasi , Villabona Carles , Biagetti Betina , Webb Susan M.
Published: February 2014

Background

Pegvisomant is an effective treatment for acromegaly.

Objective

To investigate escape (loss of biochemical control in patients previously controlled) and lipodystrophy in acromegalic patients treated with pegvisomant and to evaluate possible associations with clinical features.

Patients and methods

Multicentre retrospective study involving 19 Spanish centres.

Results

Ninety‐seven patients were included (59% women, mean age at diagnosis 42 ± 13 years, 80% macroadenomas); mean follow‐up on pegvisomant was 5 ± 2·5 years, and 89 (92%) achieved normal IGF‐1. Escape was reported in 30/89 (34%) of responders, after a mean treatment duration of 25 ± 21 months. The mean initial dose of pegvisomant was 11 ± 5 mg/day, and mean dose at escape was 14 ± 7 mg/day. Most patients (26/30, 87%) achieved control with dose increase (57%), additional medical treatment (3%) or both (27%). Mean new dose that controlled IGF‐1 after escape was 20 ± 7 mg/day. Treatments associated were somatostatin analogues (SSA in 47%), cabergoline (CAB in 47%) and both (6%).

Lipodystrophy was observed in 15 patients (13 females), mild in six, moderate in six, severe in three and persistent in four. Among patients with lipodystrophy, three escaped and three were nonresponders to pegvisomant. Four patients discontinued the drug, and four had dose reductions because of lipodystrophy. It tended to be more frequent in females (P = 0·06) and in patients treated with triple association SSA+CAB+PEG (P = 0·018).

No relationship between escape and clinical variables was found, except prior CAB (P = 0·04) and metformin treatment (0·02) and grade of lipodystrophy (P = 0·02).

Conclusions

A significant proportion of patients treated with pegvisomant escaped (34%); however, the majority (87%) was easily controlled with either dose increase, further medical treatment or both. Lipodystrophy developed in 15%, mostly females, and influenced the response to treatment.
Evaluation of Guided Bone Regeneration around Oral Implants over Different Healing Times Using Two Different Bovine Bone Materials: A Randomized, Controlled Clinical and Histological Investigation
Authors: Kohal Ralf Joachim , Straub Lisa Marie , Wolkewitz Martin , Bächle Maria , Patzelt Sebastian Berthold Maximilian
Published: February 2014

Purpose

To evaluate the potential of two bone substitute materials and the influence of different healing periods in guided bone regeneration therapy of osseous defects around implants.

Materials and Methods

Twenty‐four edentulous patients received implants in the region of the lost lower incisors. Around two standardized osseous defects were created, treated either with a 50:50 mixture of PepGen P‐15® and OsteoGraf®/N‐700 (test group) or with BioOss® (control group), and covered with titanium membranes. After healing periods of 2, 4, 6, or 9 months, the implants were removed together with the surrounding bone and subsequently prepared for histological evaluations.

Results

Defect depths in both groups showed a clinical reduction after intervention. The histologically measured distance from the implant shoulder to the first point of bone‐implant contact (BIC) after treatment did not differ between the two groups. The healing time influenced the level of the first point of BIC, with a longer healing period producing a more coronal first point of BIC. A greater percentage BIC and a higher fraction of mineralized bone were found in the pristine bone area compared with the augmented defect area.

Conclusion

It can be concluded that in the treatment of osseous defects around oral implants, both materials were equally effective bone substitute materials when used in combination with guided bone regeneration.
Effect of Platform Shift/Switch and Concave Abutments on Crestal Bone Levels and Mucosal Profile following Flap and Flapless Implant Surgery
Authors: Gamborena Inãki , Lee Jaebum , Fiorini Tiago , Wenzel Brent A. , Schüpbach Peter , Wikesjö Ulf M.E. , Susin Cristiano
Published: February 2014

Background

Crestal remodeling/bone loss appears to be a common sequel to dental implant placement. Several hypotheses/clinical strategies have been proposed to explain/avert crestal remodeling; however, causative mechanisms remain unclear and the efficacy of these clinical approaches uncertain.

Objective

The objective of the present study was to provide a histological account of crestal bone levels and mucosal profile at platform shift/switch and concave abutments following flapless and conventional flap surgery and subcrestal implant placement using a dog model.

Methods

Four dental implants each were placed in the left/right mandibular posterior jaw quadrants in five adult male Hound/Labrador mongrel dogs using flap surgery with a 1 × 5 mm gap defect or using a flapless approach, both involving placement 2 mm subcrestally and platform shift/switch versus concave abutments. Block biopsies for histological/histometric analysis were collected at 8 weeks.

Results

No significant differences were observed regarding crestal bone levels, with all groups showing mean bone levels above the implant platform. Similarly, crestal bone‐implant contact was not significantly different among groups. Moreover, peri‐implant mucosal profiles were not statistically different among groups for buccal sites; average mucosal height reached 4.1 to 4.9 mm above the implant platform. Comparison between buccal and lingual sites showed a nonsignificant tendency toward greater crestal resorption at buccal sites, adjusting for other factors. Mean crestal bone‐implant contact level approximated the implant platform for lingual sites while consistently remaining below the platform at the buccal sites. Peri‐implant mucosal height was significantly higher at buccal than at lingual sites, with the epithelial attachment located a significant distance away from the implant platform at buccal sites.

Conclusions

The surgical approaches (subcrestal implant placement by flap surgery or a flapless approach) and abutment designs (platform shift/switch or concave) used in this study seem to have a limited impact on crestal remodeling, associated bone loss, and mucosal profile. Bioclinical strategies should be developed to circumvent the limitations of current clinical protocol.
Soft and Hard Tissue Changes around Tissue‐Oriented Tulip‐Design Implant Abutments: A 1‐Year Randomized Prospective Clinical Trial
Authors: Gutmacher Zvi , Levi Guy , Blumenfeld Israel , Machtei Eli E.
Published: February 2014

Background

The advantages of platform switching using narrower abutments remain controversial. Many researchers suggest that platform switching can yield enhanced clinical results, while others remain skeptical. We hypothesize that the effectiveness of platform switching might be associated with the degree of reduction in size of the abutment.

Purpose

To radiographically and clinically examine a new abutment design created to move the implant‐abutment interface farther medially.

Materials and Methods

This was a prospective, randomized controlled clinical trial that included 27 patients (41 MIS Lance Plus® implants; MIS Implant Technologies, Karmiel, Israel). The patients' age ranged from 39 to 75 years. At the second stage of the surgery, the implants were randomly assigned to either the new platform switch Tulip abutment (TA) design or to the standard platform abutment (SA). Implant probing depth (IPD) and bleeding on probing (BOP) were recorded at baseline and after 12 months. Standardized periapical radiographs were taken (at baseline and at 12 months) and the marginal bone height measured.

Results

All implants were successfully integrated. The mean IPD at 1 year post‐op was 2.91 mm for the SA group and 2.69 mm for the TA group (p > .05). Similarly, the BOP at 1 year was almost identical in both groups. The mean values of bone resorption at baseline were 0.98 ± 0.37 mm and 0.69 ± 0.20 for the TA and SA groups, respectively (p > .05). Bone loss (baseline to 12 months) was significantly greater in the SA group compared with the TA group.

Conclusions

Use of the new TA, with its significantly downsized diameter, resulted in reduced bone loss at 1 year. Further research will be required to assess the long‐term effect of this abutment on peri‐implant health.