bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-stage biochemical selection: cloning of prototype class IIS/IIC/IIG restriction endonuclease-methyltransferase TsoI from the thermophile Thermus scotoductus
Authors: Skowron Piotr M , Vitkute Jolanta , Ramanauskaite Danute , Mitkaite Goda , Jezewska-Frackowiak Joanna , Zebrowska Joanna , Zylicz-Stachula Agnieszka , Lubys Arvydas
Published: August 2013

Background

In continuing our research into the new family of bifunctional restriction endonucleases (REases), we describe the cloning of the tsoIRM gene. Currently, the family includes six thermostable enzymes: TaqII, Tth111II, TthHB27I, TspGWI, TspDTI, TsoI, isolated from various Thermus sp. and two thermolabile enzymes: RpaI and CchII, isolated from mesophilic bacteria Rhodopseudomonas palustris and Chlorobium chlorochromatii, respectively. The enzymes have several properties in common. They are large proteins (molecular size app. 120 kDa), coded by fused genes, with the REase and methyltransferase (MTase) in a single polypeptide, where both activities are affected by S-adenosylmethionine (SAM). They recognize similar asymmetric cognate sites and cleave at a distance of 11/9 nt from the recognition site. Thus far, we have cloned and characterised TaqII, Tth111II, TthHB27I, TspGWI and TspDTI.

Results

TsoI REase, which originate from thermophilic Thermus scotoductus RFL4 (T. scotoductus), was cloned in Escherichia coli (E. coli) using two rounds of biochemical selection of the T. scotoductus genomic library for the TsoI methylation phenotype. DNA sequencing of restriction-resistant clones revealed the common open reading frame (ORF) of 3348 bp, coding for a large polypeptide of 1116 aminoacid (aa) residues, which exhibited a high level of similarity to Tth111II (50% identity, 60% similarity). The ORF was PCR-amplified, subcloned into a pET21 derivative under the control of a T7 promoter and was subjected to the third round of biochemical selection in order to isolate error-free clones. Induction experiments resulted in synthesis of an app. 125 kDa protein, exhibiting TsoI-specific DNA cleavage. Also, the wild-type (wt) protein was purified and reaction optima were determined.

Conclusions

Previously we identified and cloned the Thermus family RM genes using a specially developed method based on partial proteolysis of thermostable REases. In the case of TsoI the classic biochemical selection method was successful, probably because of the substantially lower optimal reaction temperature of TsoI (app. 10-15°C). That allowed for sufficient MTase activity in vivo in recombinant E. coli. Interestingly, TsoI originates from bacteria with a high optimum growth temperature of 67°C, which indicates that not all bacterial enzymes match an organism’s thermophilic nature, and yet remain functional cell components. Besides basic research advances, the cloning and characterisation of the new prototype REase from the Thermus sp. family enzymes is also of practical importance in gene manipulation technology, as it extends the range of available DNA cleavage specificities.
Common rs7138803 variant of FAIM2 and obesity in Han Chinese
Authors: Li Cong , Qiu Xueping , Yang Na , Gao Jiajia , Rong Yuan , Xiong Chenling , Zheng Fang
Published: August 2013

Background

Obesity causes severe healthcare problem worldwide leading to numerous diseases, such as cardiovascular diseases and diabetes mellitus. Previous Genome-Wide Association Study (GWAS) identified an association between a single nucleotide polymorphism (SNP) rs7138803, on chromosome 12q13 and obesity in European Caucasians. Since the genetic architecture governing the obesity may vary among different populations, we investigate the variant rs7138803 in Chinese population to find out whether it is associated with obesity.

Methods

A population-based cohort association study was carried out using the High Resolution Melt (HRM) method with 1851 participants. The association between rs7138803 genotypes and body mass index (BMI) was modeled with a general linear model, and a case–control study for the association between rs7138803 genotypes and obesity was performed using Pearson’s χ2 test. There was no indication of a deviation from Hardy-Weinberg equilibrium (HWE p value = 0.51) in our sample.

Results

No association was detected between SNP rs7138803 and BMI in our Chinese Han population with a P value of 0.51. SNP rs7138803 was found to be not associated with common forms of obesity after adjusting for age and sex in the Chinese population. SNP rs7138803 was not associated with other obesity related traits, including T2DM, hypertension, lipid profiles, and ischemic stroke.

Conclusion

Our data suggest that the rs7138803 exerts no significant effect on obesity in Chinese Han population. Larger cohorts may be more appropriate to detect an effect of this SNP on common obesity.
Screening for phenotype selective activity in multidrug resistant cells identifies a novel tubulin active agent insensitive to common forms of cancer drug resistance
Authors: Fryknäs Mårten , Gullbo Joachim , Wang Xin , Rickardson Linda , Jarvius Malin , Wickström Malin , Hassan Saadia , Andersson Claes , Gustafsson Mats , Westman Gunnar , Nygren Peter , Linder Stig , Larsson Rolf
Published: August 2013

Background

Drug resistance is a common cause of treatment failure in cancer patients and encompasses a multitude of different mechanisms. The aim of the present study was to identify drugs effective on multidrug resistant cells.

Methods

The RPMI 8226 myeloma cell line and its multidrug resistant subline 8226/Dox40 was screened for cytotoxicity in response to 3,000 chemically diverse compounds using a fluorometric cytotoxicity assay (FMCA). Follow-up profiling was subsequently performed using various cellular and biochemical assays.

Results

One compound, designated VLX40, demonstrated a higher activity against 8226/Dox40 cells compared to its parental counterpart. VLX40 induced delayed cell death with apoptotic features. Mechanistic exploration was performed using gene expression analysis of drug exposed tumor cells to generate a drug-specific signature. Strong connections to tubulin inhibitors and microtubule cytoskeleton were retrieved. The mechanistic hypothesis of VLX40 acting as a tubulin inhibitor was confirmed by direct measurements of interaction with tubulin polymerization using a biochemical assay and supported by demonstration of G2/M cell cycle arrest. When tested against a broad panel of primary cultures of patient tumor cells (PCPTC) representing different forms of leukemia and solid tumors, VLX40 displayed high activity against both myeloid and lymphoid leukemias in contrast to the reference compound vincristine to which myeloid blast cells are often insensitive. Significantin vivoactivity was confirmed in myeloid U-937 cells implanted subcutaneously in mice using the hollow fiber model.

Conclusions

The results indicate that VLX40 may be a useful prototype for development of novel tubulin active agents that are insensitive to common mechanisms of cancer drug resistance.
Local therapies for inflammatory eye disease in translation: past, present and future
Authors: Tempest-Roe Shenzhen , Joshi Lavnish , Dick Andrew D , Taylor Simon RJ
Published: August 2013

Despite their side-effects and the advent of systemic immunosuppressives and biologics, the use of corticosteroids remains in the management of patients with uveitis, particularly when inflammation is associated with systemic disease or when bilateral ocular disease is present. The use of topical corticosteroids as local therapy for anterior uveitis is well-established, but periocular injections of corticosteroid can also be used to control mild or moderate intraocular inflammation. More recently, intraocular corticosteroids such as triamcinolone and steroid-loaded vitreal inserts and implants have been found to be effective, including in refractory cases. Additional benefits are noted when ocular inflammation is unilateral or asymmetric, when local therapy may preclude the need to increase the systemic medication.

Implants in particular have gained prominence with evidence of efficacy including both dexamethasone and fluocinolone loaded devices. However, an appealing avenue of research lies in the development of non-corticosteroid drugs in order to avoid the side-effects that limit the appeal of injected corticosteroids. Several existing drugs are being assessed, including anti-VEGF compounds such as ranibizumab and bevacizumab, anti-tumour necrosis factor alpha antibodies such as infliximab, as well as older cytotoxic medications such as methotrexate and cyclosporine, with varying degrees of success. Intravitreal sirolimus is currently undergoing phase 3 trials in uveitis and other inflammatory pathways have also been proposed as suitable therapeutic targets. Furthermore, the advent of biotechnology is seeing advances in generation of new therapeutic molecules such as high affinity binding peptides or modified high affinity or bivalent single chain Fab fragments, offering higher specificity and possibility of topical delivery.
Triangulating perspectives on functional neuroimaging for disorders of mental health
Authors: Anderson James A , Mizgalewicz Ania , Illes Judy
Published: August 2013

Background

Functional neuroimaging is being used in clinical psychiatry today despite the vigorous objections of many in the research community over issues of readiness. To date, a systematic examination of the perspectives of key stakeholders involved in this debate has not yet been attempted. To this fill this gap, we interviewed investigators who conduct functional neuroimaging studies involving adults with mood disorders, schizophrenia, obsessive compulsive disorder, and/or attention deficit hyperactivity disorder, providers who offer clinical neuroimaging services in the open marketplace, and consumers of these services, in order to understand perspectives underlying different views and practices.

Methods

Semi-structured interviews were conducted over the telephone. Verbal consent was obtained and all interviews were audio recorded. Interviews of investigators and service providers followed the same interview guide. A separate set of questions was developed for consumers. All interviews were transcribed and made software ready. We applied the qualitative methodology of constant comparison to analyze the data, whereby two researchers independently analyzed the results into textual themes. Coding discrepancies were discussed until consensus was achieved.

Results

Investigators, service providers, and consumers held many common perspectives about the potential or actual risks and benefits of functional neuroimaging for mental illness. However, we also found striking divergences. Service providers focused on the challenges posed by the persistence of symptoms based diagnostic categories, whereas the limitations of the science in this area was the challenge noted most frequently by investigators. The majority of consumers stated that their expectations were met.

Conclusion

Our findings point toward a fundamental tension between academic investigators on the one hand, and commercial service providers and their customers on the other. This scenario poses dangers to the communities directly involved, and to public trust in science and medicine more generally. We conclude with recommendations for work that needs to be done to minimize tensions and maximize the potential of neurotechnology through concerted efforts to respect its limitations while leveraging the strengths, investments, and hopes of each stakeholder group.
L1 Norm based common spatial patterns decomposition for scalp EEG BCI
Authors: Li Peiyang , Xu Peng , Zhang Rui , Guo Lanjin , Yao Dezhong
Published: August 2013

Background

Brain computer interfaces (BCI) is one of the most popular branches in biomedical engineering. It aims at constructing a communication between the disabled persons and the auxiliary equipments in order to improve the patients’ life. In motor imagery (MI) based BCI, one of the popular feature extraction strategies is Common Spatial Patterns (CSP). In practical BCI situation, scalp EEG inevitably has the outlier and artifacts introduced by ocular, head motion or the loose contact of electrodes in scalp EEG recordings. Because outlier and artifacts are usually observed with large amplitude, when CSP is solved in view of L2 norm, the effect of outlier and artifacts will be exaggerated due to the imposing of square to outliers, which will finally influence the MI based BCI performance. While, L1 norm will lower the outlier effects as proved in other application fields like EEG inverse problem, face recognition, etc.

Methods

In this paper, we present a new CSP implementation using the L1 norm technique, instead of the L2 norm, to solve the eigen problem for spatial filter estimation with aim to improve the robustness of CSP to outliers. To evaluate the performance of our method, we applied our method as well as the standard CSP and the regularized CSP with Tikhonov regularization (TR-CSP), on both the peer BCI dataset with simulated outliers and the dataset from the MI BCI system developed in our group. The McNemar test is used to investigate whether the difference among the three CSPs is of statistical significance.

Results

The results of both the simulation and real BCI datasets consistently reveal that the proposed method has much higher classification accuracies than the conventional CSP and the TR-CSP.

Conclusions

By combining L1 norm based Eigen decomposition into Common Spatial Patterns, the proposed approach can effectively improve the robustness of BCI system to EEG outliers and thus be potential for the actual MI BCI application, where outliers are inevitably introduced into EEG recordings.
Enhancing performance of a miniaturized surface plasmon resonance sensor in the reflectance detection mode using a waveguide-coupled bimetallic chip
Authors: Lee Yeon Kyung , Jang Dae Ho , Lee Kyeong-Seok , Kim Won Mok , Sohn Young-Soo
Published: August 2013

The characteristics of a waveguide-coupled bimetallic (WcBiM) chip in a miniaturized surface plasmon resonance (SPR) sensor and its detection capability for a low molecular weight biomolecule were investigated. The configuration of the WcBiM chip was gold (Au)/waveguide (ZnS-SiO2)/silver (Ag). In the intensity measurement mode, the sensitivity could be improved by reducing the full width at half maximum (FWHM) of the reflectance curve. The FWHM of the WcBiM chip is narrower than that of the Au chip, which suggests that the slope of the reflectance curve for the WcBiM chip is steeper. In order to generate enhanced resolution, the reflectance should be monitored at the specific angle where the slope is the steepest in the reflectance curve. For the detection of biotin that is a low molecular weight biomolecule, streptavidin was formed on the SPR sensor chip surface. The response of the SPR to biotin at various concentrations was then acquired. The sensitivities of the WcBiM chip and the Au chip were 0.0052%/(ng/ml) and 0.0021%/(ng/ml), respectively. The limit of detection of the biotin concentration for both the WcBiM and Au chips was calculated. The values were 2.87 ng/ml for the WcBiM chip and 16.63 ng/ml for the Au chip. Enhancement of the sensitivity in the intensity detection mode was achieved using the WcBiM chip compared with the Au chip. Therefore, sufficient sensitivity for the detection of a disease-related biomarker is attainable with the WcBiM chip in the intensity measurement mode using a miniaturized SPR sensor.
The iterative methods for solving nonlinear matrix equation "Equation missing"
Authors: Vaezzadeh Sarah , Vaezpour Seyyed Mansour , Saadati Reza , Park Choonkil
Published: August 2013

In this paper, we study the matrix equationX+A⋆X−1A+B⋆X−1B=Q, whereAandBare square matrices, andQis a positive definite matrix, and propose the iterative methods for finding positive definite solutions of the matrix equation. Also, general convergence results for the basic fixed point iteration for these equations are given. Some numerical examples are presented to show the usefulness of the iterations.

MSC:65F10, 65F30, 65H10, 15A24.
Mitochondria-targeted antioxidant MitoQ ameliorates experimental mouse colitis by suppressing NLRP3 inflammasome-mediated inflammatory cytokines
Authors: Dashdorj Amarjargal , KR Jyothi , Lim Sangbin , Jo Ara , Nguyen Minh Nam , Ha Joohun , Yoon Kyung-Sik , Kim Hyo Jong , Park Jae-Hoon , Murphy Michael P , Kim Sung Soo
Published: August 2013

Background

MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.

Methods

Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.

Results

Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.

Conclusion

Taken together, our results suggest that MitoQ may have potential as a novel therapeutic agent for the treatment of acute phases of inflammatory bowel disease.
The distinct expression patterns of claudin-2, -6, and −11 between human gastric neoplasms and adjacent non-neoplastic tissues
Authors: Lin Zhe , Zhang Xiaowei , Liu Zhijing , Liu Qihui , Wang Liping , Lu Yan , Liu Yuanyuan , Wang Min , Yang Minlan , Jin Xiangshu , Quan Chengshi
Published: August 2013

Background

Cancers have a multifactorial etiology a part of which is genetic. Recent data indicate that expression of the tight junction claudin proteins is involved in the etiology and progression of cancer.

Methods

To explore the correlations of the tight junction proteins claudin-2,-6, and −11 in the pathogenesis and clinical behavior of gastric cancer, 40 gastric cancer tissues and 28 samples of non-neoplastic tissues adjacent to the tumors were examined for expression of claudin-2,-6, and −11 by streptavidin-perosidase immunohistochemical staining method.

Results

The positive expression rates of claudin-2 in gastric cancer tissues and adjacent tissues were 25% and 68% respectively (P < 0.001). The positive expression rates of claudin-6 in gastric cancer tissues and adjacent tissues were 55% and 79% respectively (P = 0.045 < 0.05). In contrast, the positive expression rates of claudin-11 in gastric cancer tissues and gastric cancer adjacent tissues were 80% and 46% (P = 0.004 < 0.01). Thus in our study, the expression of claudin-2, and claudin-6 was down regulated in gastric cancer tissue while the expression of claudin-11 was up regulated. Correlations between claudin expression and clinical behavior were not observed.

Conclusion

Our study provides the first evidence that claudin-2,-6, and −11 protein expression varies between human gastric cancers and adjacent non-neoplastic tissues.

Virtual slides

The virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/5470513569630744
Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro
Authors: Sun Ting , Zhang Zizhu , Li Bin , Chen Guilin , Xie Xueshun , Wei Yongxin , Wu Jie , Zhou Youxin , Du Ziwei
Published: August 2013

Background

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells.

Methods

The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression.

Results

The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins.

Conclusions

Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.
Fibrosis: a key feature of Fabry disease with potential therapeutic implications
Authors: Weidemann Frank , Sanchez-Niño Maria D , Politei Juan , Oliveira João-Paulo , Wanner Christoph , Warnock David G , Ortiz Alberto
Published: August 2013

Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.
Monomeric Ti(IV) homopiperazine complexes and their exploitation for the ring opening polymerisation of rac-lactide
Authors: Hancock Stuart L , Mahon Mary F , Jones Matthew D
Published: August 2013

Background

The area of biodegradable/sustainable polymers is one of increasing importance in the 21st Century due to their positive environmental characteristics. Lewis acidic metal centres are currently one of the most popular choices for the initiator for the polymerisation. Thus, in this paper we report the synthesis and characterisation of a series of monometallic homopiperazine Ti(IV) complexes where we have systematically varied the sterics of the phenol moieties.

Results

When the ortho substituent of the ligand is either a Me, tBu or amyl then the β-cis isomer is isolated exclusively in the solid-state. Nevertheless, in solution multiple isomers are clearly observed from analysis of the NMR spectra. However, when the ortho substituent is an H-atom then the trans-isomer is formed in the solid-state and solely in solution. The complexes have been screened for the polymerisation of rac-lactide in solution and under the industrially preferred melt conditions. Narrow molecular weight material (PDI 1.07 – 1.23) is formed under melt conditions with controlled molecular weights.

Conclusions

Six new Ti(IV) complexes are presented which are highly active for the polymerisation. In all cases atactic polymer is prepared with predictable molecular weight control. This shows the potential applicability of Ti(IV) to initiate the polymerisations.
Sero-prevalence and factors associated with Toxoplasma gondii infection among pregnant women attending antenatal care in Mwanza, Tanzania
Authors: Mwambe Berno , Mshana Stephen E , Kidenya Benson R , Massinde Anthony N , Mazigo Humphrey D , Michael Denna , Majinge Charles , Groß Uwe
Published: August 2013

Background

Serological screening of pregnant women for Toxoplasma gondii-specific antibodies is not practiced as an antenatal care in Tanzania; and there is a limited data about sero-prevalence of T. gondii infection in developing countries. We therefore conducted this study to determine the sero-prevalence and factors associated with T. gondii infection among pregnant women attending antenatal care clinics in Mwanza, Tanzania.

Methods

Between 1st November 2012 and 31st May 2013 a total of 350 pregnant women attending antenatal care clinics in Mwanza were enrolled and screened for IgG and IgM antibodies against T. gondii using the ELISA technique.

Results

Of 350 pregnant women, 108 (30.9%) were sero-positive for T. gondii-specific antibodies. The risk of contracting T. gondii infection increases by 7% with each yearly increase in a woman’s age (OR=1.07, 95% CI: 1.02 - 1.11, p=0.002). The sero-positivity rate of T. gondii- specific antibodies was higher among pregnant women from the urban than those from rural communities (41.5% versus 22.0%); [OR=2.2, 95% CI; 1.4 - 3.7, p=0.001]. Likewise employed/business women were more likely to get T. gondii infection than peasants (40.0% versus 25.9%) [OR=1.9, 95% CI: 1.2 - 3.0, p=0.006].

Conclusions

Sero-prevalence of T. gondii- specific antibodies is high among pregnant women in Mwanza with a significant proportion of women at risk of contracting primary T. gondii infections. Screening of T. gondii infections during antenatal care should be considered in Tanzania as the main strategy to minimize congenital toxoplasmosis.
Analysis of the genetic diversity of the nematode parasite Baylisascaris schroederi from wild giant pandas in different mountain ranges in China
Authors: Zhou Xuan , Xie Yue , Zhang Zhi-he , Wang Cheng-dong , Sun Yun , Gu Xiao-bin , Wang Shu-xian , Peng Xue-rong , Yang Guang-you
Published: August 2013

Background

Baylisascaris schroederi is one of the most common nematodes of the giant panda, and can cause severe baylisascarosis in both wild and captive giant pandas. Previous studies of the giant pandas indicated that this population is genetically distinct, implying the presence of a new subspecies. Based on the co-evolution between the parasite and the host, the aim of this study was to investigate the genetic differentiation in the B. schroederi population collected from giant pandas inhabiting different mountain ranges, and further to identify whether the evolution of this parasite correlates with the evolution of giant pandas.

Methods

In this study, 48 B. schroederi were collected from 28 wild giant pandas inhabiting the Qinling, Minshan and Qionglai mountain ranges in China. The complete sequence of the mitochondrial cytochrome b (mtCytb) gene was amplified by PCR, and the corresponding population genetic diversity of the three mountain populations was determined. In addition, we discussed the evolutionary relationship between B. schroederi and its host giant panda.

Results

For the DNA dataset, insignificant Fst values and a significant, high level of gene flow were detected among the three mountain populations of B. schroederi, and high genetic variation within populations and a low genetic distance were observed. Both phylogenetic analyses and network mapping of the 16 haplotypes revealed a dispersed pattern and an absence of branches strictly corresponding to the three mountain range sampling sites. Neutrality tests and mismatch analysis indicated that B. schroederi experienced a population expansion in the past.

Conclusions

Taken together, the dispersed haplotype map, extremely high gene flow among the three populations of B. schroederi, low genetic structure and rapid evolutionary rate suggest that the B. schroederi populations did not follow a pattern of isolation by distance, indicating the existence of physical connections before these populations became geographically separated.
Dose and type of crystalloid fluid therapy in adult hospitalized patients
Authors: Smorenberg Annemieke , Ince Can , Groeneveld AB Johan
Published: August 2013

Objective

In this narrative review, an overview is given of the pros and cons of various crystalloid fluids used for infusion during initial resuscitation or maintenance phases in adult hospitalized patients. Special emphasis is given on dose, composition of fluids, presence of buffers (in balanced solutions) and electrolytes, according to recent literature. We also review the use of hypertonic solutions.

Methods

We extracted relevant clinical literature in English specifically examining patient-oriented outcomes related to fluid volume and type.

Results

A restrictive fluid therapy prevents complications seen with liberal, large-volume therapy, even though restrictive fluid loading with crystalloids may not demonstrate large hemodynamic effects in surgical or septic patients. Hypertonic solutions may serve the purpose of small volume resuscitation but carry the disadvantage of hypernatremia. Hypotonic solutions are contraindicated in (impending) cerebral edema, whereas hypertonic solutions are probably more helpful in ameliorating than in preventing this condition and improving outcome. Balanced solutions offer a better approach for plasma composition than unbalanced ones, and the evidence for benefits in patient morbidity and mortality is increasing, particularly by helping to prevent acute kidney injury.

Conclusions

Isotonic and hypertonic crystalloid fluids are the fluids of choice for resuscitation from hypovolemia and shock. The evidence that balanced solutions are superior to unbalanced ones is increasing. Hypertonic saline is effective in mannitol-refractory intracranial hypertension, whereas hypotonic solutions are contraindicated in this condition.
Impulsivity, anxiety, and alcohol misuse in bipolar disorder comorbid with eating disorders
Authors: Jen Andrew , Saunders Erika FH , Ornstein Rollyn M , Kamali Masoud , McInnis Melvin G
Published: August 2013

Background

Eating disorders (ED) are noted to occur with bipolar disorder (BD), but relationships between additional comorbidities, clinical correlates, and personality factors common to both remain largely unknown.

Methods

Using data from the Prechter Longitudinal Study of Bipolar Disorder, we measured the prevalence and demographic factors of comorbid ED with BD, presence of additional comorbidity of anxiety and substance use disorders, psychosis, suicide attempts, mixed symptoms, childhood abuse, impact of NEO-Personality Inventory (NEO-PI) personality factors, and mood outcome in 354 patients with BD. We analyzed the prevalence of ED using both broad and narrow criteria.

Results and discussion

ED was more common in the Prechter BD sample than the general population, with the majority of those with ED being female. Anxiety disorders, alcohol abuse/dependence, and NEO-PI N5 impulsiveness were independently associated with ED in a multivariable linear regression analysis. BD age at onset was earlier in the ED group than that in the non-ED group and was earlier than the average onset of ED. Anxiety occurred before ED and alcohol use disorders after both BD and ED. Childhood trauma was associated with ED. Impulsivity and anxiety associated with BD may fuel ED and put patients at risk for other impulsivity-related disorders such as alcohol use disorders. ED was associated with more severe and variable moods and more frequent depression. Patients with BD should be regularly screened for ED, anxiety disorders, and alcohol use disorders, and comorbidity should be promptly addressed.
IFN-γ-rich environment programs dendritic cells toward silencing of cytotoxic immune responses
Authors: Švajger Urban , Obermajer Nataša , Jeras Matjaž
Published: August 2013

Lately, there is increasing evidence that emphasizes the regulatory functions of IFN-γ, which serve as negative-feedback mechanisms after, e.g., pathogen clearance, to prevent unnecessary tissue destruction. Inflammatory processes involving Th1 and cytotoxic responses are characterized by high, local IFN-γ concentrations, followed by resolution and immune silencing. Although this is a well-known course of events, extensive attempts to address potential differential effects of IFN-γ in the manner of its availability (quantitatively) in the environment do not exist. We demonstrate that high doses of IFN-γ do not induce DC maturation and activation but instead, induce specific regulatory characteristics in DCs. Considering their phenotype, high doses of IFN-γ extensively induce the expression of ILT-4 and HLA-G inhibitory molecules. Interestingly, the well-known priming effect of IFN-γ for IL-12p70 production is lost at these conditions, and the DC cytokine profile is switched toward an increased IL-10/IL-12p70 ratio upon subsequent stimulation with CD40L. Furthermore, such DCs are capable of silencing cellular immune responses and activation of cytotoxic CD8+ T lymphocytes, resulting in reduced cell proliferation and down-regulation of granzyme B expression. Additionally, we find that in this manner, immune regulation mediated by IFN-γ is not mainly a result of increased enzymatic activity of IDO in DCs but rather, a result of HLA-G signaling, which can be reversed by blocking mAb. Altogether, our results identify a novel mechanism by which a Th1-like environment programs the functional status of DCs to silence ongoing cytotoxic responses to prevent unwanted tissue destruction and inflammation.
DNA Methylation Signatures for Prediction of Biochemical Recurrence After Radical Prostatectomy of Clinically Localized Prostate Cancer
Authors: Haldrup Christa , Mundbjerg Kamilla , Vestergaard Else Marie , Lamy Philippe , Wild Peter , Schulz Wolfgang A. , Arsov Christian , Visakorpi Tapio , Borre Michael , Høyer Søren , Ørntoft Torben F. , Sørensen Karina D.
Published: August 2013

Purpose

Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential.

Methods

Microarray-based screening and bisulfite sequencing of 20 nonmalignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 nonmalignant prostate tissue samples, 293 radical prostatectomy (RP) samples (cohort 1, training), and 114 malignant RP samples (cohort 2, validation) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC were evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed using log-rank tests and univariate and multivariate Cox regression analyses.

Results

Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer specific (area under the curve, 0.89 to 0.98). Furthermore, high C1orf114 methylation was significantly (P < .05) associated with biochemical recurrence in multivariate analysis in cohort 1 (hazard ratio [HR], 3.10; 95% CI, 1.89 to 5.09) and was successfully validated in cohort 2 (HR, 3.27; 95% CI, 1.17 to 9.12). Moreover, a significant (P < .05) three-gene prognostic methylation signature (AOX1/C1orf114/HAPLN3), classifying patients into low- and high-methylation subgroups, was trained in cohort 1 (HR, 1.91; 95% CI, 1.26 to 2.90) and validated in cohort 2 (HR, 2.33; 95% CI, 1.31 to 4.13).

Conclusion

We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.
Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers
Authors: Phillips Kelly-Anne , Milne Roger L. , Rookus Matti A. , Daly Mary B. , Antoniou Antonis C. , Peock Susan , Frost Debra , Easton Douglas F. , Ellis Steve , Friedlander Michael L. , Buys Saundra S. , Andrieu Nadine , Noguès Catherine , Stoppa-Lyonnet Dominique , Bonadona Valérie , Pujol Pascal , McLachlan Sue Anne , John Esther M. , Hooning Maartje J. , Seynaeve Caroline , Tollenaar Rob A.E.M. , Goldgar David E. , Terry Mary Beth , Caldes Trinidad , Weideman Prue C. , Andrulis Irene L. , Singer Christian F. , Birch Kate , Simard Jacques , Southey Melissa C. , Olsson Håkan L. , Jakubowska Anna , Olah Edith , Gerdes Anne-Marie , Foretova Lenka , Hopper John L.
Published: August 2013

Purpose

To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.

Methods

Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.

Results

Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).

Conclusion

This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.
Apatinib for Chemotherapy-Refractory Advanced Metastatic Gastric Cancer: Results From a Randomized, Placebo-Controlled, Parallel-Arm, Phase II Trial
Authors: Li Jin , Qin Shukui , Xu Jianming , Guo Weijian , Xiong Jianping , Bai Yuxian , Sun Guoping , Yang Yan , Wang Liwei , Xu Nong , Cheng Ying , Wang Zhehai , Zheng Leizhen , Tao Min , Zhu Xiaodong , Ji Dongmei , Liu Xin , Yu Hao
Published: August 2013

Purpose

Patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy have no treatment options that clearly confer a survival benefit. This trial investigated the safety and efficacy of apatinib, an inhibitor of vascular endothelial growth factor receptor, as a treatment option for heavily pretreated patients with mGC.

Patients and Methods

Patients who experienced treatment failure with at least two chemotherapeutic regimens were randomly assigned to receive placebo (group A), apatinib 850 mg once daily (group B), or apatinib 425 mg twice daily (group C).

Results

We enrolled 144 patients onto this study. In groups A, B, and C, the median overall survival (OS) times were 2.50 months (95% CI, 1.87 to 3.70 months), 4.83 months (95% CI, 4.03 to 5.97 months), and 4.27 months (95% CI, 3.83 to 4.77 months), respectively, and the median progression-free survival (PFS) times were 1.40 months (95% CI, 1.20 to 1.83 months), 3.67 months (95% CI, 2.17 to 6.80 months), and 3.20 months (95% CI, 2.37 to 4.53 months), respectively. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017). Nine patients had a partial response (three patients in group B and six patients in group C). Toxicities were tolerable or could be clinically managed. The most common grade 3 to 4 adverse events were hand-foot syndrome and hypertension. Hematologic toxicities were moderate, and grade 3 to 4 hematologic toxicities were rare.

Conclusion

Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens.
Adiposity and Insulin Resistance in Humans: The Role of the Different Tissue and Cellular Lipid Depots
Authors: Hocking Samantha , Samocha-Bonet Dorit , Milner Kerry-Lee , Greenfield Jerry R. , Chisholm Donald J.
Published: August 2013

Human adiposity has long been associated with insulin resistance and increased cardiovascular risk, and abdominal adiposity is considered particularly adverse. Intra-abdominal fat is associated with insulin resistance, possibly mediated by greater lipolytic activity, lower adiponectin levels, resistance to leptin, and increased inflammatory cytokines, although the latter contribution is less clear. Liver lipid is also closely associated with, and likely to be an important contributor to, insulin resistance, but it may also be in part the consequence of the lipogenic pathway of insulin action being up-regulated by hyperinsulinemia and unimpaired signaling. Again, intramyocellular triglyceride is associated with muscle insulin resistance, but anomalies include higher intramyocellular triglyceride in insulin-sensitive athletes and women (vs men). Such issues could be explained if the “culprits” were active lipid moieties such as diacylglycerol and ceramide species, dependent more on lipid metabolism and partitioning than triglyceride amount.

Subcutaneous fat, especially gluteofemoral, appears metabolically protective, illustrated by insulin resistance and dyslipidemia in patients with lipodystrophy. However, some studies suggest that deep sc abdominal fat may have adverse properties.

Pericardial and perivascular fat relate to atheromatous disease, but not clearly to insulin resistance.

There has been recent interest in recognizable brown adipose tissue in adult humans and its possible augmentation by a hormone, irisin, from exercising muscle. Brown adipose tissue is metabolically active, oxidizes fatty acids, and generates heat but, because of its small and variable quantities, its metabolic importance in humans under usual living conditions is still unclear.

Further understanding of specific roles of different lipid depots may help new approaches to control obesity and its metabolic sequelae.
Optimal Vitamin D Status: A Critical Analysis on the Basis of Evidence-Based Medicine
Authors: Bouillon Roger , Van Schoor Natasja M. , Gielen Evelien , Boonen Steven , Mathieu Chantal , Vanderschueren Dirk , Lips Paul
Published: August 2013

Context:

Public health authorities around the world recommend widely variable supplementation strategies for adults, whereas several professional organizations, including The Endocrine Society, recommend higher supplementation.

Methods:

We analyzed published randomized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health.

Conclusions:

The extraskeletal effects of vitamin D are plausible as based on preclinical data and observational studies. However, apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly, causality remains yet unproven in randomized controlled trials (RCTs). The greatest risk for cancer, infections, cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D (25OHD) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis, estimated from serum 1,25-dihydroxyvitamin D and PTH, calcium absorption, or bone mass, can be normalized by 25OHD levels above 20 ng/mL. Moreover, vitamin D supplementation (800 IU/d) in combination with calcium can reduce fracture incidence by about 20%. Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women. Based on calculations of the metabolic clearance of 25OHD, a daily intake of 500–700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore, the recommendations for a daily intake of 1500–2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects, as suggested by The Endocrine Society Task Force, are premature. Fortunately, ongoing RCTs will help to guide us to solve this important public health question.
Surgical Outcomes of Trigeminal Neuralgia in Patients With Multiple Sclerosis
Authors: Mohammad-Mohammadi Alireza , Recinos Pablo F. , Lee Joung H. , Elson Paul , Barnett Gene H.
Published: August 2013

BACKGROUND:

Trigeminal neuralgia (TN) is relatively frequent in multiple sclerosis (MS) patients and can be extremely disabling. Surgical interventions are less effective for the treatment of MS-related TN compared with classic TN, and higher recurrence rates are observed.

OBJECTIVE:

To evaluate initial pain-free response (IPFR), duration of pain-free intervals (PFIs), and factors predictive of outcome in different surgical modalities used to treat MS-related TN.

METHODS:

A total of 96 MS patients underwent 277 procedures (range, 1–11 procedures per patient) to treat TN at our institution from 1995 to 2011. Of these, 89 percutaneous retrogasserian glycerol rhizotomies, 82 balloon compressions, 52 stereotactic radiosurgeries, 28 peripheral neurectomies, 15 percutaneous radiofrequency rhizotomies, and 10 microvascular decompressions were performed as upfront or repeat treatments.

RESULTS:

Bilateral pain was observed in 10% of patients during the course of disease. During the follow-up period (median, 5.7 years), recurrence of symptoms was seen in 66% of patients, and 181 procedures were performed for symptom recurrence. As an initial procedure, balloon compression had the highest IPFR (95%; P = .006) and median PFI (28 months; P = .05), followed by percutaneous retrogasserian glycerol rhizotomy (IPFR, 74%, P = .04; median PFI, 9 months; P = .05). In general, repeat procedures had lower effectiveness compared with initial procedures, with no statistically significant difference seen across the various treatment modalities.

CONCLUSION:

Treatment failure occurs in most of the MS-related TN patients independently of the type of treatment. However, balloon compression had the highest rate of IPFR and PFI compared with other modalities in the initial treatment of MS-related TN.