bluuebunny/crossref_metadata_2025 huggingface dataset:
Tianzhi granule improves cognition and BPSD of vascular dementia: a randomized controlled trial
Authors: Shi Jing , Wei Mingqing , Ni Jingnian , Sun Feng , Sun Li , Wang Junfu , Yu Tao , Wang Kai , Lv Peiyuan , Wang Yunfu , Zhang Yulian , Gao Xuguang , Gao Xuanzhao , Luo Benyan , Mao Shanping , Zhang Baorong , Ren Xiangyang , Yu Fengchun , Hu Wenli , Yin Ping , Wu Nanjin , Liu Xianfeng , Bi Qi , Wang Yongyan , Tian Jinzhou ,   The CHASE Study Group
Published: February 2020

Background and purpose

Tianzhi granule (TZ) is usually used for patients with vascular dementia (VaD) in China. The aim was to assess the effect of TZ by a randomized clinical trial (RCT).

Methods

A 24-week RCT was conducted in 16 centres. Participants were grouped into TZ, donepezil or placebo. The co-primary outcomes were the Vascular Dementia Assessment Scale-cognitive subscale (VADAS-cog) and Clinician’s Interview-based Impression of Change-plus caregiver information (CIBIC-plus).

Results

A total of 543 patients with mild to moderate VaD were enrolled, of whom 242 took TZ granules, 241 took donepezil, and 60 took placebo. The least-squares mean changes from baseline and 95% CI were 6.20 (5.31, 7.09) (TZ group), 6.53 (5.63, 7.42) (donepezil group) and 3.47 (1.76, 5.19) (placebo group), both TZ and donepezil showed small but significantly improvement compared with placebo group. The percent of improvement on the global impression which was measured by CIBIC-plus was 73.71% in TZ and 58.18% in placebo, there was significant different between TZ and placebo group (P = 0.004). No significant differences were observed between TZ and donepezil. No significant differences of adverse events were found.

Conclusions

TZ and donepezil could bring symptomatic benefit for mild to moderate VaD.

Trial registration The protocol had retrospectively registered at clinical trial.gov, Unique identifier: NCT02453932, date of registration: May 27, 2015; https://www.clinicaltrials.gov/ct2/show/NCT02453932?term=NCT02453932&rank=1
Quantification of total apolipoprotein E and its isoforms in cerebrospinal fluid from patients with neurodegenerative diseases
Authors: Minta K. , Brinkmalm G. , Janelidze S. , Sjödin S. , Portelius E. , Stomrud E. , Zetterberg H. , Blennow K. , Hansson O. , Andreasson U.
Published: February 2020

Background

The human APOE gene, which codes for apolipoprotein E (apoE), has three major polymorphic alleles: ε2, ε3, and ε4 that give rise to amino acid substitutions. APOE-ε4 is a strong risk factor of sporadic Alzheimer’s disease (AD) but the reason why is still unknown despite intense research for more than 20 years. The aim of the study was to investigate if the concentrations of total apoE and the specific apoE isoforms in cerebrospinal fluid (CSF) differ between various neurodegenerative diseases and control individuals, as well as among the APOE genotypes.

Methods

Quantification of total apoE and specific apoE isoforms (E2, E3, and E4) in CSF was performed using high-resolution parallel reaction monitoring mass spectrometry. In total, 1820 individuals were involved in the study including clinically diagnosed AD patients (n = 228), cognitively unimpaired (CU) patients (n = 896), and patients with other neurodegenerative disorders (n = 696). Follow-up data was available for 100 individuals, assessed at two time points. Subjects were dichotomized based on an Aβ42/40 CSF concentration ratio cut-off into Aβ positive (Aβ+, < 0.091) and Aβ negative (Aβ−, > 0.091) groups.

Results

Even though there was a significant increase of total apoE in the amyloid β-positive (Aβ+) group compared with amyloid β-negative (Aβ−) individuals (p < 0.001), the magnitude of the effect was very small (AUC = 0.55). Moreover, CSF total apoE concentrations did not differ between Aβ− CU controls and clinically diagnosed AD patients. There was a difference in concentration between isoforms in heterozygous individuals in an isoform-dependent manner (E2 < E3 < E4) (p < 0.001, AUC = 0.64–0.69), and these associations remained when dichotomizing the samples into Aβ+ and Aβ− groups (p < 0.01, AUC = 0.63–0.74). In the cohort with follow-up samples, neither total apoE nor isoform-specific apoE concentrations differed between the two time points (p > 0.05).

Conclusions

The results indicate that neither the concentrations of total apoE nor the different apoE isoforms in CSF are associated with APOE-ε4 carrier status, Aβ status, or clinical dementia diagnoses.
Multipotency of mouse trophoblast stem cells
Authors: Hou Minmin , Han Junwen , Li Gu , Kwon Min-Young , Jiang Jiani , Emani Sirisha , Taglauer Elizabeth S. , Park Jin-Ah , Choi Eun-Bee , Vodnala Munender , Fong Yick W. , Emani Sitaram M. , Rosas Ivan O. , Perrella Mark A. , Liu Xiaoli
Published: February 2020

Background

In a number of disease processes, the body is unable to repair injured tissue, promoting the need to develop strategies for tissue repair and regeneration, including the use of cellular therapeutics. Trophoblast stem cells (TSCs) are considered putative stem cells as they differentiate into other subtypes of trophoblast cells. To identify cells for future therapeutic strategies, we investigated whether TSCs have properties of stem/progenitor cells including self-renewal and the capacity to differentiate into parenchymal cells of fetal organs, in vitro and in vivo.

Methods

TSCs were isolated using anti-CD117 micro-beads, from embryonic day 18.5 placentas. In vitro, CD117+TSCs were cultured, at a limiting dilution in growth medium for the development of multicellular clones and in specialized medium for differentiation into lung epithelial cells, cardiomyocytes, and retinal photoreceptor cells. CD117+TSCs were also injected in utero into lung, heart, and the sub-retinal space of embryonic day 13.5 fetuses, and the organs were harvested for histological assessment after a natural delivery.

Results

We first identified CD117+cells within the labyrinth zone and chorionic basal plate of murine placentas in late pregnancy, embryonic day 18.5. CD117+TSCs formed multicellular clones that remained positive for CD117 in vitro, consistent with self-renewal properties. The clonal cells demonstrated multipotency, capable of differentiating into lung epithelial cells (endoderm), cardiomyocytes (mesoderm), and retinal photoreceptor cells (ectoderm). Finally, injection of CD117+TSCs in utero into lungs, hearts, and the sub-retinal spaces of fetuses resulted in their engraftment on day 1 after birth, and the CD117+TSCs differentiated into lung alveolar epithelial cells, heart cardiomyocytes, and retina photoreceptor cells, corresponding with the organs in which they were injected.

Conclusions

Our findings demonstrate that CD117+TSCs have the properties of stem cells including clonogenicity, self-renewal, and multipotency. In utero administration of CD117+TSCs engraft and differentiate into resident cells of the lung, heart, and retina during mouse development.
Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells
Authors: Vallés Gema , Bensiamar Fátima , Maestro-Paramio Leila , García-Rey Eduardo , Vilaboa Nuria , Saldaña Laura
Published: February 2020

Background

The mechanisms by which macrophage phenotype contributes to mesenchymal stem cells (MSC)-mediated bone repair remain unclear. In this work, we investigated the influence of factors released by human macrophages polarized to a pro-inflammatory or an anti-inflammatory phenotype on the ability of human MSC to attach, migrate, and differentiate toward the osteoblastic lineage. We focused on the role of TNF-α and IL-10, key pro-inflammatory and anti-inflammatory cytokines, respectively, in regulating MSC functions.

Methods

MSC were treated with media conditioned by pro-inflammatory or anti-inflammatory macrophages to study their influence in cell attachment, migration, and osteogenic differentiation. The involvement of TNF-α and IL-10 in the regulation of MSC functions was investigated using neutralizing antibodies and recombinant cytokines.

Results

Treatment of MSC with media conditioned by pro-inflammatory or anti-inflammatory macrophages promoted cell elongation and enhanced MSC ability to attach and migrate. These effects were more noticeable when MSC were treated with media from pro-inflammatory macrophages. Interestingly, MSC osteogenic activity was enhanced by factors released by anti-inflammatory macrophages, but not by pro-inflammatory macrophages. Significant IL-10 levels originated from anti-inflammatory macrophages enhanced MSC osteogenesis by increasing ALP activity and mineralization in MSC layers cultured under osteogenic conditions. Moreover, macrophage-derived IL-10 regulated the expression of the osteogenic markersRUNX2,COL1A1, andALPL. Notably, low TNF-α levels secreted by anti-inflammatory macrophages increased ALP activity in differentiating MSC whereas high TNF-α levels produced by pro-inflammatory macrophages had no effects on osteogenesis. Experiments in which MSC were treated with cytokines revealed that IL-10 was more effective in promoting matrix maturation and mineralization than TNF-α.

Conclusions

Factors secreted by pro-inflammatory macrophages substantially increased MSC attachment and migration whereas those released by anti-inflammatory macrophages enhanced MSC osteogenic activity as well as cell migration. IL-10 was identified as an important cytokine secreted by anti-inflammatory macrophages that potentiates MSC osteogenesis. Our findings provide novel insights into how environments provided by macrophages regulate MSC osteogenesis, which may be helpful to develop strategies to enhance bone regeneration.
Differences in virulence between the two more prevalent Staphylococcus aureus clonal complexes in rabbitries (CC121 and CC96) using an experimental model of mammary gland infection
Authors: Penadés Mariola , Viana David , García-Quirós Ana , Muñoz-Silvestre Asunción , Moreno-Grua Elena , Pérez-Fuentes Sara , Pascual Juan José , Corpa Juan M. , Selva Laura
Published: February 2020

Staphylococcal mastitis is a major health problem in humans and livestock that leads to economic loss running in millions. This process is currently one of the main reasons for culling adult rabbit does. Surprisingly, the two most prevalent S. aureus lineages isolated from non-differentiable natural clinical mastitis in rabbits (ST121 and ST96) generate different immune responses. This study aimed to genetically compare both types of strains to search for possible dissimilarities to explain differences in immune response, and to check whether they showed similar virulence in in vitro tests as in experimental intramammary in vivo infection. The main differences were observed in the enterotoxin gene cluster (egc) and the immune-evasion-cluster (IEC) genes. While isolate ST121 harboured all six egc cluster members (seg, sei, selm, seln, selo, selu), isolate ST96 lacked the egc cluster. Strain ST96 carried a phage integrase Sa3 (Sa3int), compatible with a phage integrated into the hlb gene (β-haemolysin-converting bacteriophages) with IEC type F, while isolate ST121 lacked IEC genes and the hlb gene was intact. Moreover, the in vitro tests confirmed a different virulence capacity between strains as ST121 showed greater cytotoxicity for erythrocytes, polymorphonuclear leukocytes and macrophages than strain ST96. Differences were also found 7 days after experimental intramammary infection with 100 colony-forming units. The animals inoculated with strain ST121 developed more severe gross and histological mastitis, higher counts of macrophages in tissue and of all the cell populations in peripheral blood, and a significantly larger total number of bacteria than those infected by strain ST96.
Random field-aided tracking of autonomous kinetically passive wireless agents
Authors: Schlupkothen Stephan , Heidenblut Tim , Ascheid Gerd
Published: February 2020

Continuous miniaturization of circuitry has open the door for various novel application scenarios of millimeter-sized wireless agents such as for the exploration of difficult-to-access fluid environments. In this context, agents are envisioned to be employed, e.g., for pipeline inspection or groundwater analysis. In either case, the demand for miniature sensors is incompatible with propulsion capabilities. Consequently, the agents are condemned to be kinetically passive and are, thus, subject to the fluid dynamics present in the environment. In these situations, the localization is complicated by the fact that unknown external forces (e.g., from the fluid) govern the motion of the agents. In this work, a comprehensive framework is presented that targets the simultaneous estimation of the external forces stemming from the fluid and the agents’ positions which are traversing the environment. More precisely, a Bayesian hierarchical model is proposed that models’ relevant characteristics of the fluid via a spatial random field and incorporates this as control input into the motion model. The random field model facilitates the consideration of spatial correlation among the agents’ trajectories and, thereby, improves the localization significantly. Additionally, this is combined with multiple particle filtering to account for the fact that within such underground fluid environments, only a localization based on distance and/or bearing measurements is feasible. In the results provided in this work, which are based on realistic computational fluid dynamics simulations, it is shown that—via the proposed spatial model—significant improvements in terms of localization accuracy can be achieved.
Long-term effects of alcohol consumption on cognitive function: a systematic review and dose-response analysis of evidence published between 2007 and 2018
Authors: Brennan Sue E. , McDonald Steve , Page Matthew J. , Reid Jane , Ward Stephanie , Forbes Andrew B. , McKenzie Joanne E.
Published: February 2020

Background

Understanding the long-term health effects of low to moderate alcohol consumption is important for establishing thresholds for minimising the lifetime risk of harm. Recent research has elucidated the dose-response relationship between alcohol and cardiovascular outcomes, showing an increased risk of harm at levels of intake previously thought to be protective. The primary objective of this review was to examine (1) whether there is a dose-response relationship between levels of alcohol consumption and long-term cognitive effects, and (2) what the effects are of different levels of consumption.

Methods

The review was conducted according to a pre-specified protocol. Eligible studies were those published 2007 onwards that compared cognitive function among people with different levels of alcohol consumption (measured ≥ 6 months prior to first follow-up of cognition). Major cognitive impairment was excluded. Searches were limited to MEDLINE, Embase and PsycINFO (January 2007 to April 2018). Screening, data extraction, and risk of bias assessment (ROBINS-I) were piloted by three authors, then completed by a single author and checked by a second. Analyses were undertaken to identify and characterise dose-response relationships between levels of alcohol consumption and cognition. Certainty of evidence was assessed using GRADE.

Results

We included 27 cohort studies (from 4786 citations). Eighteen studies examined the effects of alcohol consumption at different levels (risk of bias 16 serious, 2 critical). Ten studies provided data for dose-response analysis. The pooled dose-response relationship showed a maximum standardised mean difference (SMD) indicating slightly better cognition among women with moderate alcohol consumption compared to current non-drinkers (SMD 0.18, 95%CI 0.02 to 0.34, at 14.4 grams/day; 5 studies, very low certainty evidence), and a trivial difference for men (SMD 0.05, 95% CI 0.00 to 0.10, at 19.4 grams/day; 6 studies, very low certainty evidence).

Conclusions

Major limitations in the design and reporting of included studies made it impossible to discern if the effects of ‘lower’ levels of alcohol intake are due to bias. Further review of the evidence is unlikely to resolve this issue without meta-analysis of individual patient data from cohort studies that address biases in the selection of participants and classification of alcohol consumption.
The mir-767-105 cluster: a crucial factor related to the poor prognosis of hepatocellular carcinoma
Authors: Rui Tao , Xu Siyi , Feng Shi , Zhang Xueyou , Huang Haitao , Ling Qi
Published: February 2020

MiRNAs have been widely reported as the therapeutic target for hepatocellular carcinoma (HCC). However, mirna clusters, as the more impressive tumor regulatory factors, have received little attention. By deeply digging the Cancer Genome Atlas (TCGA) database, we aimed to explore the vital mirna cluster that regulated the poor prognosis of HCC. The results showed that the upregulation of mirna cluster-767-105 in HCC was the most significant, compared with the non-tumor tissues. Besides, high expression of all three members of the cluster was positively correlated with poor prognosis of HCC and the resistance of sorafenib. Cox analysis proved that all the three mirnas were independent prognostic factors, while the mir-767 was the most compelling (HR value 8.388, 95%CI 2.524–27.897). The higher expression of the three-mirna signature also significantly indicated the worse prognosis. Through bioinformatics analysis, we screened their common potential target genes, which were highly correlated with tumor regulation. These results supported that the mirna cluster-767-105 promoted the poor outcome of HCC and could be a robust target for the therapy of HCC patients.
Simultaneous removals of cadmium(II) ions and reactive yellow 4 dye from aqueous solution by bone meal-derived apatite: kinetics, equilibrium and thermodynamic evaluations
Authors: Ofudje Edwin A. , Adeogun Idowu A. , Idowu Mopelola A. , Kareem Sarafadeen O. , Ndukwe Nelly A.
Published: February 2020

The simultaneous removal of Cadmium ions and reactive yellow 4 dye (RY4 dye) by bone meal-derived apatite (BMDA) were investigated in a batch process. The structural elucidation of the prepared BMDA was done using TEM, XRD, FT-IR and EDX to evaluate the structures of the adsorbent. Different experimental features such as the agitation time, BMDA dosage, temperature, initial adsorbate concentration and pH of the solution were examined on the uptake pattern of the pollutants. The mechanism of adsorption was examined with Elovich, pseudo-first-order, intraparticle diffusion and pseudo-second-order kinetic models, while Langmuir, Dubinin-Radushkevich (D-R), Freundlich and Tempkin isotherms were exploited in order to describe the behaviour of the equilibrium process. Analysis from XRD revealed peaks corresponding to single phase apatite powder, while the various forces responsible for the interactions between the BMDA surface and the pollutants were obtained to CO32−, OH− and PO43− as observed by FT-IR analysis. SEM and TEM investigations confirmed a round-like morphology which agglomerated together upon the adsorption of pollutants.

The kinetic modelling of the adsorption data were well illustrated with the pseudo-first-order model with correlation coefficient (R2) values ranging from 0.997 to 0.999. Isotherms studies revealed that best fit was achieved with Langmuir isotherm with adsorption capacities of 94.85 and 116.16 mg/g for RY4 dye and Cd(II) ions respectively. Thermodynamic study signified the uptake of the pollutants to be spontaneous, feasible and endothermic in nature. The values of entropy change (ΔS) for the sorption processes calculated are 86.57 and 60.16 J/mol/K for Cd(II) and RY4 dye, respectively.
Detection of plastic strain using GNSS data of pre- and post-seismic deformation of the 2011 Tohoku-oki earthquake
Authors: Fukahata Yukitoshi , Meneses-Gutierrez Angela , Sagiya Takeshi
Published: February 2020

In general, there are three mechanisms causing crustal deformation: elastic, viscous, and plastic deformation. The separation of observed crustal deformation to each component has been a challenging problem. In this study, we succeed in separating plastic deformation as well as viscous deformation in the northern Niigata–Kobe Tectonic Zone (NKTZ), central Japan, using GNSS data before and after the 2011 Tohoku-oki earthquake, under the assumptions that elastic deformation is principally caused by the plate coupling along the Japan trench and that plastic deformation ceased after the Tohoku-oki earthquake due to the stress drop caused by the earthquake. The cessation of plastic deformation can be understood with the concept of stress shadow used in the field of seismic activity. The separated strain rates are about 30 nanostrain/year both for the plastic deformation in the preseismic period and for the viscous deformation in both the pre- and post-seismic periods, which means that the inelastic strain rate in the northern NKTZ is about 60 and 30 nanostrain/year in the pre- and post-seismic periods, respectively. This result requires the revision of the strain-rate paradox in Japan. The strain rate was exceptionally faster before the Tohoku-oki earthquake due to the effect of plastic strain, and the discrepancy between the geodetic and geologic strain rates is much smaller in usual time, when the plastic strain is off. In order to estimate the onset timing of plastic deformation, the information on stress history is essentially important.
CtpB is a plasma membrane copper (I) transporting P-type ATPase of Mycobacterium tuberculosis
Authors: León-Torres Andrés , Arango Epifania , Castillo Eliana , Soto Carlos Y.
Published: February 2020

Background

The intracellular concentration of heavy-metal cations, such as copper, nickel, and zinc is pivotal for the mycobacterial response to the hostile environment inside macrophages. To date, copper transport mediated by P-type ATPases across the mycobacterial plasma membrane has not been sufficiently explored.

Results

In this work, the ATPase activity of the putative Mycobacterium tuberculosis P1B-type ATPase CtpB was associated with copper (I) transport from mycobacterial cells. Although CtpB heterologously expressed in M. smegmatis induced tolerance to toxic concentrations of Cu2+ and a metal preference for Cu+, the disruption of ctpB in M. tuberculosis cells did not promote impaired cell growth or heavy-metal accumulation in whole mutant cells in cultures under high doses of copper. In addition, the Cu+ ATPase activity of CtpB embedded in the plasma membrane showed features of high affinity/slow turnover ATPases, with enzymatic parameters KM 0.19 ± 0.04 µM and Vmax 2.29 ± 0.10 nmol/mg min. In contrast, the ctpB gene transcription was activated in cells under culture conditions that mimicked the hostile intraphagosomal environment, such as hypoxia, nitrosative and oxidative stress, but not under high doses of copper.

Conclusions

The overall results suggest that M. tuberculosis CtpB is associated with Cu+ transport from mycobacterial cells possibly playing a role different from copper detoxification.
The Adverse Effects of Androgen Deprivation Therapy in Prostate Cancer and the Benefits and Potential Anti-oncogenic Mechanisms of Progressive Resistance Training
Authors: Lam Teresa , Birzniece Vita , McLean Mark , Gurney Howard , Hayden Amy , Cheema Birinder S.
Published: February 2020

Prostate cancer has the second highest incidence of all cancers amongst men worldwide. Androgen deprivation therapy (ADT) remains a common form of treatment. However, in reducing serum testosterone to castrate levels and rendering men hypogonadal, ADT contributes to a myriad of adverse effects which can affect prostate cancer prognosis. Physical activity is currently recommended as synergistic medicine in prostate cancer patients to alleviate the adverse effects of treatment. Progressive resistance training (PRT) is an anabolic exercise modality which may be of benefit in prostate cancer patients given its potency in maintaining and positively adapting skeletal muscle. However, currently, there is a scarcity of RCTs which have evaluated the use of isolated PRT in counteracting the adverse effects of prostate cancer treatment. Moreover, although physical activity in general has been found to reduce relapse rates and improve survival in prostate cancer, the precise anti-oncogenic effects of specific exercise modalities, including PRT, have not been fully established. Thus, the overall objective of this article is to provide a rationale for the in-depth investigation of PRT and its biological effects in men with prostate cancer on ADT. This will be achieved by (1) summarising the metabolic effects of ADT in patients with prostate cancer and its effect on prostate cancer progression and prognosis, (2) reviewing the existing evidence regarding the metabolic benefits of PRT in this cohort, (3) exploring the possible oncological pathways by which PRT can affect prostate cancer prognosis and progression and (4) outlining avenues for future research.
Impact of bariatric surgery on cerebral vascular reactivity and cognitive function: a non-randomized pilot study
Authors: Tucker Wesley J. , Thomas Binu P. , Puzziferri Nancy , Samuel T. Jake , Zaha Vlad G. , Lingvay Ildiko , Almandoz Jaime , Wang Jing , Gonzales Edward A. , Brothers R. Matthew , Nelson Michael D.
Published: February 2020

Background

Bariatric surgery is an effective long-term weight loss strategy yielding improvements in neurocognitive function; however, the mechanism(s) responsible for these improvements remains unclear. Here, we assessed the feasibility of using magnetic resonance imaging (MRI) to evaluate whether cerebral vascular reactivity (CVR) is impaired in severely obese bariatric surgery candidates compared with normal weight healthy controls and whether CVR improves following bariatric surgery. We also investigated whether changes in CVR were associated with changes in cognitive function.

Methods

Bariatric surgery candidates (n = 6) were compared with normal weight healthy controls of a similar age (n = 10) at baseline, and then reassessed 2 weeks and 14 weeks following sleeve gastrectomy bariatric surgery. Young reference controls (n = 7) were also studied at baseline to establish the range of normal for each outcome measure. Microvascular and macrovascular CVR to hypercapnia (5% CO2) were assessed using blood-oxygen-level-dependent (BOLD) MRI, and changes in the middle cerebral artery (MCA) cross-sectional area, respectively. Cognitive function was assessed using a validated neurocognitive software.

Results

Compliance with the CVR protocol was high. Both macro- and micro-cerebrovascular function were highest in the young reference controls. Cognitive function was lower in obese bariatric surgery candidates compared with normal weight controls, and improved by 17% at 2 weeks and 21% by 14 weeks following bariatric surgery. To our surprise, whole-brain CVR BOLD did not differ between obese bariatric surgery candidates and normal weight controls of similar age (0.184 ± 0.101 vs. 0.192 ± 0.034 %BOLD/mmHgCO2), and did not change after bariatric surgery. In contrast, we observed vasoconstriction of the MCA during hypercapnia in 60% of the obese patients prior to surgery, which appeared to be abolished following bariatric surgery. Improvements in cognitive function were not associated with improvements in either CVR BOLD or MCA vasodilation after bariatric surgery.

Conclusions

Assessing CVR responses to a hypercapnic challenge with MRI was feasible in severely obese bariatric patients. However, no changes in whole-brain BOLD CVR were observed following bariatric surgery despite improvements in cognitive function. We recommend that future large trials assess CVR responses to cognitive tasks (rather than hypercapnia) to better define the mechanisms responsible for cognitive function improvements following bariatric surgery.
Once-weekly Somapacitan is Effective and Well Tolerated in Adults with GH Deficiency: A Randomized Phase 3 Trial
Authors: Johannsson Gudmundur , Gordon Murray B , Højby Rasmussen Michael , Håkonsson Ida Holme , Karges Wolfram , Sværke Claus , Tahara Shigeyuki , Takano Koji , Biller Beverly M K
Published: February 2020

Context

Growth hormone (GH) replacement requires daily GH injections, which is burdensome for some adult patients with GH deficiency (AGHD).

Objective

To demonstrate efficacy and safety of somapacitan, a once-weekly reversible albumin-binding GH derivative, versus placebo in AGHD.

Design

Randomized, parallel-group, placebo-controlled (double-blind) and active-controlled (open-label) phase 3 trial, REAL 1 (NCT02229851).

Setting

Clinics in 17 countries.

Patients

Treatment-naïve patients with AGHD (n = 301 main study period, 272 extension period); 257 patients completed the trial.

Interventions

Patients were randomized 2:2:1 to once-weekly somapacitan, daily GH, or once-weekly placebo for 34 weeks (main period). During the 52-week extension period, patients continued treatment with somapacitan or daily GH.

Main outcome measures

Body composition measured using dual-energy x-ray absorptiometry (DXA). The primary endpoint was change in truncal fat percentage to week 34. Insulin-like growth factor 1 (IGF-I) standard deviation score (SDS) values were used to dose titrate.

Results

At 34 weeks, somapacitan significantly reduced truncal fat percentage (estimated difference: −1.53% [−2.68; −0.38]; P = 0.0090), demonstrating superiority compared with placebo, and it improved other body composition parameters (including visceral fat and lean body mass) and IGF-I SDS. At 86 weeks, improvements were maintained with both somapacitan and daily GH. Somapacitan was well tolerated, with similar adverse events (including injection-site reactions) compared with daily GH.

Conclusions

In AGHD patients, somapacitan administered once weekly demonstrated superiority over placebo, and the overall treatment effects and safety of somapacitan were in accordance with known effects and safety of GH replacement for up to 86 weeks of treatment. Somapacitan may provide an effective alternative to daily GH in AGHD. A short visual summary of our work is available (1).
Reduced Insulin Clearance and Insulin-Degrading Enzyme Activity Contribute to Hyperinsulinemia in African Americans
Authors: Fosam Andin , Sikder Shanaz , Abel Brent S , Tella Sri Harsha , Walter Mary F , Mari Andrea , Muniyappa Ranganath
Published: February 2020

Background

African Americans (AAs) are at a higher risk for developing type 2 diabetes compared with non-Hispanic whites (NHWs). The causal role of β-cell glucose sensitivity (β-GS) and insulin clearance in hyperinsulinemia in AA adults is unclear.

Objective

Using a cross-sectional study design, we compared β-cell function and insulin clearance in nondiabetic AAs (n = 36) and NHWs (n = 47) after a mixed meal test (MMT).

Methods

Insulin secretion rate, glucose sensitivity, rate sensitivity, and insulin sensitivity during MMT were derived from a mathematical model. Levels of insulin-degrading enzyme (IDE) and carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), key players in insulin clearance, were measured (by enzyme-linked immunosorbent assay) in hepatic cytosolic fractions from age-, sex-, and body mass index–matched AA and NHW cadaveric donors (n = 10).

Results

Fasting and mean postprandial plasma glucose levels were similar in both ethnic groups. AAs had significantly higher fasting and mean postprandial plasma insulin levels. However, fasting ISR, total insulin output, and insulin sensitivity during MMT were not different between the groups. β-GS and rate sensitivity were higher in AAs. Fasting and meal plasma insulin clearance were lower in AAs. Hepatic levels of IDE and CEACAM-1 were similar in AAs and NHWs. Hepatic IDE activity was significantly lower in AAs.

Conclusions

In this study, lower insulin clearance contributes to higher plasma insulin levels in AAs. Reduced insulin clearance may be explained by lower IDE activity levels in AAs. Further confirmatory studies are needed to investigate diminished insulin clearance in AAs as a result of lower IDE activity levels.
Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men
Authors: Izzi-Engbeaya Chioma , Jones Sophie , Crustna Yoshibye , Machenahalli Pratibha C , Papadopoulou Deborah , Modi Manish , Panayi Christos , Starikova Jessica , Eng Pei Chia , Phylactou Maria , Mills Edouard , Yang Lisa , Ratnasabapathy Risheka , Sykes Mark , Plumptre Isabella , Coumbe Ben , Wing Victoria C , Pacuszka Ewa , Bech Paul , Minnion James , Tharakan George , Tan Tricia , Veldhuis Johannes , Abbara Ali , Comninos Alexander N , Dhillo Waljit S
Published: February 2020

Context

Glucagon-like peptide-1 (GLP-1) potently reduces food intake and augments glucose-stimulated insulin secretion. Recent animal data suggest that GLP-1 may also influence reproduction. As GLP-1 receptor agonists are currently widely used in clinical practice to treat obesity/type 2 diabetes, it is necessary to determine the effects of GLP-1 on the reproductive system in humans.

Objective

To investigate the effects of GLP-1 administration on the reproductive axis in humans.

Design

Single-blind, randomized, placebo-controlled crossover study.

Setting

Clinical Research Facility, Imperial College Healthcare NHS Trust.

Participants

Eighteen healthy men (mean age 24.7 ± 0.1years, mean BMI 22.1 ± 0.4kg/m2).

Intervention

Eight-hour intravenous infusion of 0.8 pmol/kg/min GLP-1 or rate-matched vehicle infusion.

Main Outcome Measures

Number of luteinizing hormone (LH) pulses, LH, follicle-stimulating hormone (FSH), and testosterone levels.

Results

The number of LH pulses (number of LH pulses/500 min: vehicle 4.2 ± 0.4, GLP-1 4.5 ± 0.3, P = 0.46), LH area under the curve (AUC) (vehicle 1518 ± 88min.IU/L, GLP-1 1524 ± 101min.IU/L, P = 0.95), follicle-stimulating hormone AUC (vehicle 1210 ± 112 min IU/L, GLP-1 1216 ± 112 min IU/L, P = 0.86), and testosterone AUC (vehicle 10893 ± 615 min nmol/L, GLP-1 11088 ± 792 min nmol/L, P = 0.77) did not significantly differ during vehicle and GLP-1 administration. Glucagon-like peptide-1 significantly reduced food intake (vehicle 15.7 ± 1.3 kcal/kg, GLP-1 13.4 ± 1.3 kcal/kg, P = 0.01).

Conclusions

In contrast to the animal literature, our data demonstrate that acute GLP-1 administration does not affect reproductive hormone secretion in healthy men.
Underlying Breast Cancer Risk and Menopausal Hormone Therapy
Authors: Santen Richard J , Heitjan Daniel F , Gompel Anne , Lumsden Mary Ann , Pinkerton JoAnn V , Davis Susan R , Stuenkel Cynthia A
Published: February 2020

The recent Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) publication calculated the attributable risk of breast cancer from use of estrogen alone and estrogen plus a synthetic progestogen for less than 5 to 15 or more years of use. This CGHFB report calculated attributable risk based on their findings of relative risk from pooled data from 58 studies. Notably, neither the CGHFBC nor other previous studies have examined the effect of underlying risk of breast cancer on attributable risk. This omission prompted us to determine the magnitude of the effect of underlying risk on attributable risk in this perspective. Meaningful communication of the potential risk of menopausal hormonal therapy requires providing women with the estimated risk above their existing underlying risk (ie, attributable risk). Therefore, we have estimated attributable risks from the data published by the CGHFBC, taking into account varying degrees of underlying risk. Based on the Endocrine Society Guideline on Menopausal Hormone Therapy (MHT), we divided groups into 3 categories of risk: low (1.5%), intermediate (3.0%), and high (6.0%) underlying risk of breast cancer over 5 years. In women taking estrogen plus a synthetic progestogen for 5 to 9 years, the attributable risks of MHT increased from 12, to 42, to 85 additional women per 1000 in the low-, intermediate-, and high-risk groups, respectively. The attributable risks for estrogen alone were lower but also increased based on underlying risk. Notably, the attributable risks were amplified with duration of MHT use, which increased both relative risk and breast cancer incidence.
Ontogenesis of evolved changes in respiratory physiology in deer mice native to high altitude
Authors: Ivy Catherine M. , Greaves Mary A. , Sangster Elizabeth D. , Robertson Cayleih E. , Natarajan Chandrasekhar , Storz Jay F. , McClelland Grant B. , Scott Graham R.
Published: February 2020

High-altitude environments are cold and hypoxic, and many high-altitude natives have evolved changes in respiratory physiology that improve O2 uptake in hypoxia as adults. Altricial mammals undergo a dramatic metabolic transition from ectothermy to endothermy in early post-natal life, which may influence the ontogenetic development of respiratory traits at high altitude. We examined the developmental changes in respiratory and haematological traits in deer mice (Peromyscus maniculatus) native to high altitude, comparing the respiratory responses to progressive hypoxia between highland and lowland deer mice. Among adults, highlanders exhibited higher total ventilation and a more effective breathing pattern (relatively deeper tidal volumes), for mice that were caught and tested at their native altitudes and those lab-raised in normoxia. Lab-raised progeny of each population were also tested at post-natal day (P)7, 14, 21 and 30. Highlanders developed an enhanced hypoxic ventilatory response by P21, concurrent with the full maturation of the carotid bodies, and their more effective breathing pattern arose by P14; these ages correspond to critical benchmarks in the full development of homeothermy in highlanders. However, highlanders exhibited developmental delays in ventilatory sensitivity to hypoxia, hyperplasia of type I cells in the carotid body and increases in blood haemoglobin content compared with lowland mice. Nevertheless, highlanders maintained consistently higher arterial O2 saturation in hypoxia across development, in association with increases in blood–O2 affinity that were apparent from birth. We conclude that evolved changes in respiratory physiology in high-altitude deer mice become expressed in association with the post-natal development of endothermy.
Divergent neurogenomic responses shape social learning of both personality and mate preference
Authors: Delclos Pablo J. , Forero Santiago A. , Rosenthal Gil G.
Published: February 2020

Behavior plays a fundamental role in shaping the origin and fate of species. Mating decisions can act to promote or restrict gene flow, as can personality traits that influence dispersal and niche use. Mate choice and personality are often both learned and therefore influenced by an individual's social environment throughout development. Likewise, the molecular pathways that shape these behaviors may also be co-expressed. In this study on swordtail fish (Xiphophorus birchmanni), we show that female mating preferences for species-typical pheromone cues are entirely dependent on social experience with adult males. Experience with adults also shapes development along the shy-bold personality axis, with shy behaviors arising from exposure to risk-averse heterospecifics as a potential stress-coping strategy. In maturing females, conspecific exposure results in a strong upregulation of olfaction and vision genes compared to heterospecific exposure, as well as immune response genes previously linked to anxiety, learning and memory. Conversely, heterospecific exposure involves an increased expression of genes important for neurogenesis, synaptic plasticity and social decision-making. We identify subsets of genes within the social decision-making network and with known stress-coping roles that may be directly coupled to the olfactory processes females rely on for social communication. Based on these results, we conclude that the social environment affects the neurogenomic trajectory through which socially-sensitive behaviors are learned, resulting in adult phenotypes adapted for specific social groupings.
Study on the evaluation of rheumatoid arthritis via doppler ultrasonography and anti-cyclic citrullinated peptide antibody analysis
Authors: Shang Li-na , Di Gui-xin , Wei Feng-ju , Zhang Zheng
Published: February 2020

Objective: This study aims to discuss the value of ultrasonic analysis and anti-cyclic citrullinated peptide (CCP) antibody analysis in evaluating the state of rheumatoid arthritis (RA).

Methods: This study was conducted during March 2016 to December 2016. Total 82 patients with RA who sought treatment in the Affiliated Hospital of Hebei University were included in this study. Data on ultrasonic and anti-CCP antibody, ESR, and RF were collected and compared. The RA patients were divided into two groups of mild disease activity (DAS28 ≤ 3.2) and moderate-severe disease activity (DAS28 > 3.2) to compare the changes in synovial thickness of joints. The changes of joint ultrasonography were also compared between positive and negative anti-CCP antibodies group.

Results: It is found that the number of patients suffering from joint involvement in the negative anti-CCP antibody group was larger than that of the anti-CCP positive antibody group (P <0.05); the thickness of the synovium of joints of patients in the group with moderate-severe disease activity evaluated via ultrasonography was significantly larger than that of the group with mild disease activity (P <0.05).

Conclusion: It is possible to observe the degree of disease activity dynamically by combining ultrasonography with anti-CCP antibody and make a better assessment of patients to facilitate treatment.

doi: https://doi.org/10.12669/pjms.36.3.1492

How to cite this:Shang L, Di G, Wei F, Zhang Z. Study on the evaluation of rheumatoid arthritis via doppler ultrasonography and anti-cyclic citrullinated peptide antibody analysis. Pak J Med Sci. 2020;36(3):569-573. doi: https://doi.org/10.12669/pjms.36.3.1492

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Herbal pharmacovigilance in Nepal: challenges and recommendations
Authors: Shrestha Sunil , Danekhu Krisha , Sapkota Binaya , Jha Nisha , KC Bhuvan
Published: February 2020

Traditional herbal medicine is widely used globally. Despite its extensive use, there are no proper regulations on standardization and use of herbal medicinal products. Nepal has a rich biodiversity and demography comprising of different socio-ethnic groups. Herbal medicines are utilized prominently in Nepalese communities. These herbal products may cause side effects and adverse effects, such as nephrotoxicity, neurotoxicity with the heavy metal toxicity associated with their powdered dosage forms. The side effects of using herbal products have been documented, such as bleeding with use of Ginkgo biloba and increase in blood pressure with use of Ephedra. Regulation of herbal products is essential to promote their optimal and rational use. Standard tools are available for assessing adverse effects of herbal products from health authorities, like the World Health Organization. In Nepal, self-medication practice using traditional herbal medicines is common and includes the concomitant use of allopathic. There is no focal point to address the regulatory issues on herbal products currently in Nepal. The Department of Drug Administration in Nepal is nominated as a national pharmacovigilance center and there are no reports on adverse events from the use of herbal medicines so far. However, not having any reports does not ensure the absolute safety and effectiveness of herbal products, so vigilance is warranted. Herbal pharmacovigilance is needed for Nepal to ensure safe and effective use of herbal medicines as the current pharmacovigilance ecosystem does not capture those cases. In the Nepalese context, the absence of reporting mechanisms may have underreported adverse cases of herbal products. The present opinion article aims to discuss the use of herbal products in Nepal, the challenges associated with the adverse reaction due to herbal medicines, and recommendations to overcome these challenges
Effects of vitamin D deficiency on neurobehavioural outcomes in children: a systematic review
Authors: Mutua Agnes M. , Mogire Reagan M. , Elliott Alison M. , Williams Thomas N. , Webb Emily L. , Abubakar Amina , Atkinson Sarah H.
Published: February 2020

Introduction: Vitamin D plays an important role in brain development in experimental studies; however, the effect of vitamin D deficiency on child development remains inadequately characterized. We aimed to estimate the effects of vitamin D deficiency on neurobehavioural outcomes in children up to 18 years of age.

Methods: We searched PubMed, EMBASE, PsycINFO, Scopus, Cochrane Library, Web of Science and Open Grey for published studies up to 10th January 2020. We included all studies that assessed the effects of maternal or child vitamin D status or vitamin D supplementation on neurobehavioural outcomes in children. Study findings were synthesized qualitatively as the high level of heterogeneity in study populations and methodologies precluded a quantitative meta-analysis.

Results: Our search identified 5,633 studies, of which 32 studies with 31,445 participants from 18 countries were included in the systematic review. Of the studies identified, two were randomized controlled trials (RCTs) of vitamin D supplementation in children, while 30 were observational. One RCT (n=55) reported a beneficial effect of supplementation with lower doses compared to higher doses of vitamin D on motor development while the other RCT (n=70) found no beneficial effect of vitamin D supplementation on cognition in extremely preterm infants. Twelve mother-child studies (n=17,136) and five studies in children (n=1,091) reported an association between low maternal or child 25-hydroxyvitamin D levels and impaired neurobehavioural outcomes in children, while 15 mother-child studies (n=20,778) and eight studies in children (n=7,496) reported no association.

Conclusions: Although animal studies point to an effect of vitamin D deficiency on brain development, there are few studies on the effects of vitamin D deficiency on neurobehavioural outcomes in children and their findings are inconsistent. There is a need for well-conducted, adequately powered studies to further determine these effects in children.

Registration: PROSPERO ID CRD42018087619; registered on 15 February 2018.
Multiculturalism, biosemiotics, and cross-cultural friendship: An essay review of Olteanu’s multimodal semiotics of culture
Authors: Emmeche Claus
Published: February 2020

Review of Multiculturalism as Multimodal Communication: A Semiotic Perspective [Series Numanities – Arts and Humanities in Progress 9; Dario Martinelli, series ed.] by Alin Olteanu. Cham: Springer, 2019, xviii+140 pp.
Möbius semioticity: Six takes on Peeter Torop’s semiotics-of-culture model of textuality
Authors: Robinson Douglas
Published: February 2020

Möbius semioticity: Six takes on Peeter Torop’s semiotics-of-culture model of textuality
Psychological type
Authors: Poroikov Sergey
Published: February 2020

A systematic description of psychological types is given based on the generally accepted classifications of K. G. Jung, N. McWilliams, K. Leongard, A. E. Lichko, and P. B. gannushkin. It is shown that the known types of neurotic and accentuated personalities are varieties of seven basic psychological types. This typology finds its correspondence in well-known systematizations of needs, emotions, mental States, and defenses.
The book is addressed to psychologists, psychotherapists, psychiatrists, teachers and students of psychological and medical universities, as well as those interested in personality psychology.