bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and mechanistic basis of the high catalytic activity of monooxygenase Tet(X4) on tigecycline
Authors: Cheng Qipeng , Cheung Yanchu , Liu Chenyu , Xiao Qingjie , Sun Bo , Zhou Jiahai , Chan Edward Wai Chi , Zhang Rong , Chen Sheng
Published: December 2021

Background

Tigecycline is a tetracycline derivative that constitutes one of the last-resort antibiotics used clinically to treat infections caused by both multiple drug-resistant (MDR) Gram-negative and Gram-positive bacteria. Resistance to this drug is often caused by chromosome-encoding mechanisms including over-expression of efflux pumps and ribosome protection. However, a number of variants of the flavin adenine dinucleotide (FAD)-dependent monooxygenase TetX, such as Tet(X4), emerged in recent years as conferring resistance to tigecycline in strains of Enterobacteriaceae, Acinetobacter sp., Pseudomonas sp., and Empedobacter sp. To date, mechanistic details underlying the improvement of catalytic activities of new TetX enzymes are not available.

Results

In this study, we found that Tet(X4) exhibited higher affinity and catalytic efficiency toward tigecycline when compared to Tet(X2), resulting in the expression of phenotypic tigecycline resistance in E. coli strains bearing the tet(X4) gene. Comparison between the structures of Tet(X4) and Tet(X4)-tigecycline complex and those of Tet(X2) showed that they shared an identical FAD-binding site and that the FAD and tigecycline adopted similar conformation in the catalytic pocket. Although the amino acid changes in Tet(X4) are not pivotal residues for FAD binding and substrate recognition, such substitutions caused the refolding of several alpha helixes and beta sheets in the secondary structure of the substrate-binding domain of Tet(X4), resulting in the formation of a larger number of loops in the structure. These changes in turn render the substrate-binding domain of Tet(X4) more flexible and efficient in capturing substrate molecules, thereby improving catalytic efficiency.

Conclusions

Our works provide a better understanding of the molecular recognition of tigecycline by the TetX enzymes; these findings can help guide the rational design of the next-generation tetracycline antibiotics that can resist inactivation of the TetX variants.
Application of a complete blood count to screening lethargic and anorectic cats for pancreatitis
Authors: Krasztel Magdalena Maria , Czopowicz Michał , Szaluś-Jordanow Olga , Moroz Agata , Mickiewicz Marcin , Kaba Jarosław
Published: December 2021

Background

Feline pancreatitis (FP) is an important health problem of cats. Its diagnostics is based on the combination of quantification of serum pancreatic lipase immunoreactivity (fPLI) and abdominal ultrasonography (AUS). These modalities allow for establishing highly specific diagnosis, however they are relatively expensive and time-consuming. On the other hand, a screening test of high sensitivity which would allow to rule out FP on the first visit without a considerable increase of costs would be clinically useful. To evaluate accuracy of nonspecific inflammatory biomarkers based on complete blood count (CBC) in diagnosing FP 73 client-owned cats with signs of lethargy and reduced appetite lasting for at least 2 days before presentation were enrolled in the cross-sectional study. They were examined with fPLI assay and AUS and classified as cats with very low risk of FP when fPLI ≤3.5 μg/L and AUS negative for FP, or as cats with increased risk of FP in the case of any other combination of results. Then, 7 various CBC measurements were measured in each cat and linked to the risk of FP using the multivariable logistic regression.

Results

Five CBC measurements turned out to be significantly associated with the risk of FP – total leukocyte count (WBC; crude odds ratio(ORcrude) = 12.2; CI 95%: 1.52, 98.5), total neutrophil count (ORcrude = 5.84; CI 95%: 1.22, 27.9), band neutrophil count (BNC; ORcrude = 6.67; CI 95%: 1.98, 22.4), neutrophil-to-lymphocyte ratio (ORcrude = 3.68; CI 95%: 1.25, 10.9), and eosinophil count (EC; ORcrude = 0.34; CI 95%: 0.12, 0.96). The model based on WBC, BNC, and EC proved to have at least fair diagnostic potential (area under ROC curve 82.7%; CI 95%: 72.8%, 92.5%). When WBC <  18 G/L, BNC <  0.27 G/L, and EC >  0.3 G/L was considered as a negative result, and any other combination as the positive result, the CBC model had high sensitivity (91.8%; CI 95%: 80.8%, 96.8%) at a relatively low specificity (58.3%; CI 95%: 38.8%, 75.5%).

Conclusion

The combination of three CBC measurements is an immediately available and fairly accurate screening method for identification of lethargic and anorectic cats with increased risk of FP.
Long-term safety and exploratory efficacy of fevipiprant in patients with inadequately controlled asthma: the SPIRIT randomised clinical trial
Authors: Maspero Jorge , Agache Ioana Octavia , Kamei Tadashi , Yoshida Makoto , Boone Bryan , Felser James M. , Kawakami Fernando , Knorr Barbara , Lawrence David , Lehmann Thomas , Wang Wei , Pedinoff Andrew J.
Published: December 2021

Background

The prostaglandin D2 (PGD2) receptor 2 (DP2 receptor) pathway is an important regulator of the inflammatory cascade in asthma, which can be stimulated by allergic or non-allergic triggers. Fevipiprant is an oral, non-steroidal, highly selective, reversible antagonist of the DP2 receptor that inhibits the binding of PGD2 and its metabolites.

Methods

SPIRIT, a 2-treatment period (52-week, double-blind and optional 104-week single-blind), randomised, placebo-controlled, multicentre, parallel-group study, assessed the long-term safety of fevipiprant (150 mg and 450 mg o.d.) added to standard of care in patients ≥ 12 years with uncontrolled asthma. Stratified block randomisation was used. Patients were randomised in an approximate ratio of 3:3:1 (fevipiprant 150 mg, fevipiprant 450 mg or placebo). Patients were either newly enrolled or had participated in a previous fevipiprant Phase 3 trial. Primary endpoints were: time-to-first treatment emergent adverse event (AE); serious AE; and AE leading to discontinuation from study treatment. Data from both treatment periods were combined for analyses. Data were collected during study site visits.

Results

In total, 1093 patients were randomised to receive fevipiprant 150 mg, 1085 to fevipiprant 450 mg, and 360 to placebo. Overall, 1184 patients had ≥ 52 weeks’ treatment, while 163 received ≥ 104 weeks’ treatment. Both doses were well tolerated, with a safety profile similar to placebo both in new patients and in those enrolled from previous studies.

In exploratory analyses, reduced rates of moderate-to-severe asthma exacerbations, increased time-to-first moderate-to-severe asthma exacerbation and improved FEV1 were observed for both doses of fevipiprant versus placebo; these were without multiplicity adjustment and should be interpreted with caution. SPIRIT was terminated early, on 16 December 2019, by the Sponsor.

Conclusions

In patients with uncontrolled asthma, the addition of fevipiprant had a favourable long-term safety profile.

Trial registration

Clinicaltrials.gov, NCT03052517, prospectively registered 23 January 2017, https://clinicaltrials.gov/ct2/show/NCT03052517.
Crosstalk between autophagy and microbiota in cancer progression
Authors: Wang Yu , Du Jiang , Wu Xuemei , Abdelrehem Ahmed , Ren Yu , Liu Chao , Zhou Xuan , Wang Sinan
Published: December 2021

Autophagy is a highly conserved catabolic process seen in eukaryotes and is essentially a lysosome-dependent protein degradation pathway. The dysregulation of autophagy is often associated with the pathogenesis of numerous types of cancers, and can not only promote the survival of cancer but also trigger the tumor cell death. During cancer development, the microbial community might predispose cells to tumorigenesis by promoting mucosal inflammation, causing systemic disorders, and may also regulate the immune response to cancer. The complex relationship between autophagy and microorganisms can protect the body by activating the immune system. In addition, autophagy and microorganisms can crosstalk with each other in multifaceted ways to influence various physiological and pathological responses involved in cancer progression. Various molecular mechanisms, correlating the microbiota disorders and autophagy activation, control the outcomes of protumor or antitumor responses, which depend on the cancer type, tumor microenvironment and disease stage. In this review, we mainly emphasize the leading role of autophagy during the interaction between pathogenic microorganisms and human cancers and investigate the various molecular mechanisms by which autophagy modulates such complicated biological processes. Moreover, we also highlight the possibility of curing cancers with multiple molecular agents targeting the microbiota/autophagy axis. Finally, we summarize the emerging clinical trials investigating the therapeutic potential of targeting either autophagy or microbiota as anticancer strategies, although the crosstalk between them has not been explored thoroughly.
A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy
Authors: Li Jiali , Li Shichao , Li Yang , Yuan Guanjie , Shen Yaqi , Peng Yang , Kong Li , Yang Conglian , Zhang Zhiping , Li Zhen
Published: December 2021

Background

Immunochemotherapy is a potent anti-tumor strategy, however, how to select therapeutic drugs to enhance the combined therapeutic effect still needs to be explored.

Methods and results

Herein, a magnetic resonance nanoprobe (MnP@Lip) with STING (Stimulator of INterferon Genes) activation character was synthesized and co-administered with platinum-based chemotherapeutics for enhanced immunochemotherapy. MnP@Lip nanoparticles was prepared by simple fabrication process with good reproducibility, pH-sensitive drug release behavior and biocompatibility. In vitro experiments elucidated that Mn2+ can promote the polarization of M0 and/or M2 macrophages to M1 phenotype, and promote the maturation of BMDC cells. Upon Mn2+ treatment, the STING pathway was activated in tumor cells, mouse lung epithelial cells, and immune cells. More importantly, anti-tumor experiments in vivo proved that MnP@Lip combined with platinum-based chemotherapeutics increased T cells infiltration in the tumor microenvironment, and inhibited tumor growth in the orthotopic therapeutic and postoperative tumor models.

Conclusions

This kind of therapeutic strategy that combined MnP@Lip nanoparticles with platinum-based chemotherapeutics may provide a novel insight for immunochemotherapy.

Graphical Abstract
Sex-related differences of early cardiac functional and proteomic alterations in a rat model of myocardial ischemia
Authors: Barta Bálint András , Ruppert Mihály , Fröhlich Klemens Erwin , Cosenza-Contreras Miguel , Oláh Attila , Sayour Alex Ali , Kovács Krisztián , Karvaly Gellért Balázs , Biniossek Martin , Merkely Béla , Schilling Oliver , Radovits Tamás
Published: December 2021

Background

Reduced cardiovascular risk in premenopausal women has been the focus of research in recent decades. Previous hypothesis-driven experiments have highlighted the role of sex hormones on distinct inflammatory responses, mitochondrial proteins, extracellular remodeling and estrogen-mediated cardioprotective signaling pathways related to post-ischemic recovery, which were associated with better cardiac functional outcomes in females. We aimed to investigate the early, sex-specific functional and proteomic changes following myocardial ischemia in an unbiased approach.

Methods

Ischemia was induced in male (M-Isch) and female (F-Isch) rats with sc. injection of isoproterenol (85 mg/kg) daily for 2 days, while controls (M-Co, F-Co) received sc. saline solution. At 48 h after the first injection pressure–volume analysis was carried out to assess left ventricular function. FFPE tissue slides were scanned and analyzed digitally, while myocardial proteins were quantified by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using isobaric labeling. Concentrations of circulating steroid hormones were measured with LC–MS/MS. Feature selection (PLS and PLS-DA) was used to examine associations among functional, proteomic and hormonal datasets.

Results

Induction of ischemia resulted in 38% vs 17% mortality in M-Isch and F-Isch respectively. The extent of ischemic damage to surviving rats was comparable between the sexes. Systolic dysfunction was more pronounced in males, while females developed a more severe impairment of diastolic function. 2224 proteins were quantified, with 520 showing sex-specific differential regulation. Our analysis identified transcriptional, cytoskeletal, contractile, and mitochondrial proteins, molecular chaperones and the extracellular matrix as sources of disparity between the sexes. Bioinformatics highlighted possible associations of estrogens and their metabolites with early functional and proteomic alterations.

Conclusions

Our study has highlighted sex-specific alterations in systolic and diastolic function shortly after ischemia, and provided a comprehensive look at the underlying proteomic changes and the influence of estrogens and their metabolites. According to our bioinformatic analysis, inflammatory, mitochondrial, chaperone, cytoskeletal, extracellular and matricellular proteins are major sources of intersex disparity, and may be promising targets for early sex-specific pharmacologic interventions.

Graphical Abstract
Would you offer contraception to a 14-year-old girl? Perspectives of health students and professionals in Dar es Salaam, Tanzania
Authors: Mwakawanga Dorkasi L. , Mkonyi Ever , Mushy Stella E. , Trent Maria , Bonilla Zobeida , Massae Agnes F. , Lukumay Gift G. , Mgopa Lucy R. , Mohammed Inari , Wadley James , Ross Michael W. , Leshabari Sebalda , Rosser B. R. Simon
Published: December 2021

Background

Rates of unplanned adolescent pregnancy and unsafe induced abortions are very high in Sub-Saharan African countries including Tanzania. Despite their availability and accessibility, modern family planning methods are reported to be critically underutilized by adolescents. This study is part of a broader study that aims to develop a curriculum that will be used in training health professionals by investigating the sexual health training needs of health providers and students in Tanzania.

Aim

This study describes the perceptions of health professionals and students on the provision of contraceptives to adolescents.

Methods

Qualitative formative assessment type of research was conducted using 18 focus groups stratified among health professionals and students (midwives, nurses, and medical doctors). Study participants were presented with the theoretical scenario of a 14-year-old girl who sought contraceptive services at a family planning clinic. This theoretical scenario was used to determine how health professionals and students would handle the case. Thematic analysis guided the examination and determination of data results.

Results

Three main themes emerged from the data, including (1) knowledge about the provision of contraceptives to adolescents, (2) perception of the adolescents’ right to contraceptive use, and (3) barriers to the provision of contraceptives to adolescents. Participants stated that having a baseline knowledge of contraceptive services for adolescents and their rights to contraceptives would trigger their decision on offering the contraceptive. On the other hand, being unaware of the reproductive health rights for adolescents, judgmental behavior of providers, as well as religious and cultural dynamics were all found to be major barriers for providers to offer contraceptive services to the 14-year-old adolescent girl in the theoretical scenario.

Conclusion

These findings support the need for comprehensive sexual health education in Tanzanian health professional training programs.
HIV/AIDS late presentation and its associated factors in China from 2010 to 2020: a systematic review and meta-analysis
Authors: Sun Chengqing , Li Jianjun , Liu Xiaoyan , Zhang Zhi , Qiu Tao , Hu Haiyang , Wang You , Fu Gengfeng
Published: December 2021

Background

Late presentation to HIV/AIDS care presents serious health concerns, like increased transmission and high healthcare costs, increased mortality, early development of opportunistic infection, increased risk of antiretroviral therapy drug resistance. Despite the effort to contain the HIV/AIDS epidemic, LP has remained an impediment to individual immune reconstitution and public health.

Objective

This review aimed to estimate the prevalence and determine the factors associated with late presentation to HIV/AIDS care.

Methods

We searched PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Wanfang, and Weipu database for articles published from 2010 to 2020. We utilized I2 statistics and Q-test to estimate heterogeneity between studies. Random-effects meta-analysis models were used to calculate the aggregate odds ratio of late presentation to HIV/AIDS care.

Results

Of 9563 titles and abstracts retrieved, 189 were identified as potentially eligible and 39 fulfilled the inclusion criteria. The pooled prevalence of late presentation to HIV/AIDS care was 43.26%. The major risk factors were patients ≥ 50 years old (OR = 2.19, 95% CI: 1.85–2.58; I2 = 97.44%), married (OR = 1.50, 95% CI: 1.35–1.68; I2 = 96.58%), with heterosexual contact as risk factor for infection (OR = 1.91, 95% CI: 1.73–2.11; I2 = 90.74%) and diagnosed in medical institutions (OR = 2.35,95% CI: 2.11–2.62; I2 = 96.05%). In middle or low HIV prevalence areas, patients ≥ 50 years old (P = 0.01), married (P < 0.01) and diagnosed in medical institutions (P = 0.01) were more likely to be presented late than in high prevalence areas. From 2016–2020, the OR of patients who were married and diagnosed in medical facilities were significantly lower than before (P < 0.01).

Conclusion

Patients ≥ 50 years old, married, with heterosexual contact as risk factor for infection, and diagnosed in medical institutions were risk factors of LP. Gender had no significant relationship with LP. In middle or low prevalence areas, patients who were ≥ 50 years old, married, and diagnosed in medical institutions were more likely to be presented late than in other areas. Married patients and those diagnosed in medical institutions after 2015 have a lower risk of LP than before.
Success and complication rate of miniscrew assisted non-surgical palatal expansion in adults - a consecutive study using a novel force-controlled polycyclic activation protocol
Authors: Winsauer Heinz , Walter Andre , Katsaros Christos , Ploder Oliver
Published: December 2021

Introduction

Bone-borne miniscrew assisted palatal expansion (MAPE) is a common technique to improve maxillary transverse deficiency in young adolescents. Adult patients usually present a challenge, as they often require additional surgical assisted maxillary expansion (SARPE). There is still no clear statement about non-surgical expansion in adult patients using this technique. The aim of this study was to evaluate the success and complication rate of non-surgical palatal expansion in adults utilizing MAPE with a novel force-controlled polycyclic expansion protocol (FCPC).

Methods

This consecutive study consisted of 33 adult patients with an average age of 29.1 ± 10.2 years (min. 18 years, max. 58 years), including one dropout patient. First, four miniscrews were inserted and after 12-weeks latency, the expander was placed and the FCPC protocol was applied (MAPE group). In case of missing expansion, a SARPE was performed (SARPE group). After maximum expansion, a cone beam CT was made and widening of the midpalatal suture was measured. The outcome variables were successful non-surgical expansion and, with sample size power above 80%, the odds of failed non-surgical expansion and associated complications were evaluated. The primary predictor variable was age. Statistical analysis was performed using R (Version 3.1) to calculate power, to construct various models for measuring the odds of requiring surgical intervention/complications, and others.

Results

Successful non-surgical expansion was achieved in 27 patients (84.4%), ranging from 18 to 49 years. Mean age differed significantly between both groups (26.8 ± 8.2 years vs. 41.3 ± 9.9 years; p < 0.001). Mean expansion at the anterior and posterior palate for the MAPE group was 5.4 ± 1.5 mm and 2.5 ± 1.1 mm, respectively. Among these subjects’ complications were observed in 18.5%. Age significantly increased the odds of complications (p = 0.019).

Conclusions

1. The success rate of MAPE among individuals aged 18 to 49 years was 84.4%.

2. A V-shaped expansion pattern in the antero-posterior dimension was mostly observed.

3. Complications were significantly associated with age.

4. A careful expansion protocol seems to be beneficial to prevent unfavorable results in adult patients.

Trial registration

Consecutive cohort study, Review Board No. EK-2-2014/0016.
Discrimination of MSA-P and MSA-C by RT-QuIC analysis of olfactory mucosa: the first assessment of assay reproducibility between two specialized laboratories
Authors: Bargar Connor , De Luca Chiara Maria Giulia , Devigili Grazia , Elia Antonio Emanuele , Cilia Roberto , Portaleone Sara Maria , Wang Wen , Tramacere Irene , Bistaffa Edoardo , Cazzaniga Federico Angelo , Felisati Giovanni , Legname Giuseppe , Di Fonzo Alessio , Xu Rong , Gunzler Steven Alexander , Giaccone Giorgio , Eleopra Roberto , Chen Shu Guang , Moda Fabio
Published: December 2021

Background

Detection of the pathological and disease-associated alpha-synuclein (αSynD) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson’s disease (PD). We recently showed that αSynD can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn_RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes.

Methods

OM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn_RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn_RT-QuIC analytical procedures. Results were correlated with demographic and clinical data.

Results

The αSyn_RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83–1.00). In particular, αSyn_RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn_RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn_RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability.

Conclusions

Our study provides evidence that OM-αSynD may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn_RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials.
The effectiveness of a model-based health education program on genital warts preventive behaviors: a quasi-experimental study
Authors: Hosseini Zahra , Seyrafi Niloofar , Aghamolaei Teamur , Mohseni Shokrollah , Alavi Azin , Dadipoor Sakineh
Published: December 2021

Background

Genital warts (GWs) are highly prevalent among Iranian women. GWs are not only highly infectious but are also followed by severe adverse effects, including the development of cervical cancer. Therefore, the present study aimed to explore the effect of an educational intervention based on the health belief model (HBM) on the adoption of GWs preventive behaviors by married women in Bandar Abbas, a city in the south of Iran.

Methods

A quasi-experimental intervention was conducted between 2019 and 2020 among 150 women participants (75 as the intervention and 75 as the control group). The sampling method was multi-stage clustering. The required data was collected using a reliable and valid tripartite questionnaire which explored demographic information, awareness, and HBM constructs. A total number of 15 educational sessions were held, each 90 min long. The control group received only one 90-min session. The final follow-up was completed three months after the intervention in November 2020.

Results

The two research groups had no statistically significant differences in terms of awareness, perceived susceptibility, severity, benefits, barriers, and self-efficacy before the intervention (in the pre-test) (p > .05). After the educational intervention, the two groups showed statistically significant differences in all constructs except for the perceived benefits (p < .001). In the intervention group, in the pretest (before the intervention), the behavior score was 2.77 ± 2.59, which was increased to 3.73 ± .52 after the intervention (p < .001). In the control group, however, the difference was not statistically significant (p = 0.227).

Conclusion

The present findings showed that the educational intervention based on the HBM can improve the prevalence of GWs preventive behaviors in women. This education should be provided by experts at regular intervals in all healthcare centers.
Enhanced synchronization between prelimbic and infralimbic cortices during fear extinction learning
Authors: Watanabe Mayumi , Uematsu Akira , Johansen Joshua P.
Published: December 2021

The ability to extinguish aversive memories when they are no longer associated with danger is critical for balancing survival with competing adaptive demands. Previous studies demonstrated that the infralimbic cortex (IL) is essential for extinction of learned fear, while neural activity in the prelimbic cortex (PL) facilitates fear responding and is negatively correlated with the strength of extinction memories. Though these adjacent regions in the prefrontal cortex maintain mutual synaptic connectivity, it has been unclear whether PL and IL interact functionally with each other during fear extinction learning. Here we addressed this question by recording local field potentials (LFPs) simultaneously from PL and IL of awake behaving rats during extinction of auditory fear memories. We found that LFP power in the fast gamma frequency (100–200 Hz) in both PL and IL regions increased during extinction learning. In addition, coherency analysis showed that synchronization between PL and IL in the fast gamma frequency was enhanced over the course of extinction. These findings support the hypothesis that interregional interactions between PL and IL increase as animals extinguish aversive memories.
Polycystic ovary rat model exposure to 150 kHz intermediate frequency: hypothalamic-pituitary-ovarian axis at the receptor, cellular, tissue, and hormone levels
Authors: Mohammed Stephanie , Sundaram Venkatesan , Adidam Venkata Chalapathi R. , Zyuzikov Nikolay
Published: December 2021

Introduction

The hypothalamic-pituitary-ovarian (HPO) axis is the principal regulator of the reproductive system. The neurons in the arcuate nucleus of the hypothalamus signal the basophilic cells of the anterior pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH), which bind to the granulosa and theca cells of a follicle in the ovary to promote healthy follicular development. Disruption of this process at any time can lead to polycystic ovaries and, if left untreated, can lead to Polycystic Ovarian Syndrome (PCOS), one of the leading causes of infertility. A novel treatment option using 150 kHz Intermediate Frequency (IF) Electromagnetic Radiation (EMR) has been proposed to monitor the effect of this frequency during cystic development.

Methods

To prove this, an experiment was conducted to study the effect of whole-body exposure to 150 kHz EMR for 8 weeks at receptor, cellular, tissue and hormonal levels on the HPO axis of 25 young cyclic female rats.

Results

The results showed that 150 kHz EMR did not affect the histoarchitecture of neurons of arcuate nucleus of the hypothalamus of PCO-induced rats. It was also found that the number of basophilic cells of the pituitary gland was increased and the immunoreactivity of LH and FSH secretion increased. This EMR field also decreased the development of follicular cysts in the ovary and possibly increased the immunoreactivity of the LH and FSH receptors as well on the theca and granulosa cells of follicles in the ovary.

Conclusion

There are still many limitations to this study. If properly evaluated, the results of this experiment could help develop a new non-invasive treatment option for women with PCOS in the near future.
Early-life exposures and age at thelarche in the Sister Study cohort
Authors: Goldberg Mandy , D’Aloisio Aimee A. , O’Brien Katie M. , Zhao Shanshan , Sandler Dale P.
Published: December 2021

Background

Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974.

Methods

Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood.

Results

Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche.

Conclusions

Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.
The ELSA trial: single versus combinatory effects of non-prohibited beta-2 agonists on skeletal muscle metabolism, cardio-pulmonary function and endurance performance—study protocol for a randomized 4-way balanced cross-over trial
Authors: Zügel Martina , Bizjak Daniel A. , Nussbaumer Dorle , Winkert Kay , Takabayashi Kensuke , Kirsten Johannes , Washington Mickel , Treff Gunnar , Dreyhaupt Jens , Steeb Luise , Diel Patrick , Parr Maria Kristina , Steinacker Jürgen M. , Persch Hasema
Published: December 2021

Background

Asthma and/or airway hyper-responsiveness (AHR) are common in elite endurance athletes with a high prevalence rate of beta-2 adrenoreceptor (beta-2) agonists use. Nevertheless, there are data on dose-dependent ergogenic effects of beta-2 agonists suggesting increased muscle strength, endurance and neuromuscular performance. Therefore, most beta-2 agonists belong to the World Anti Doping Agency (WADA) list of prohibited substances and it is tempting to speculate that illegitimate use of beta-2 agonists might be a common practice to boost performance in competitive sports. It is currently unknown whether or not inhaled beta-2 agonists enhance performance by stimulatory effects in skeletal and cardiac muscle.

Methods

The ELSA trial is a double-blinded, placebo-controlled, randomized, balanced, four-way cross-over study. Study participants (n=24, 12 ♀, 12 ♂) complete four study arms (i.e. periods with treatment A, placebo; B, salbutamol; C, formoterol; D, formoterol + salbutamol) in random order after an initial preliminary testing session. Participants inhale the study medication 20 min before the 10-min time trial (TT; exercise performance test), where participants cycle 10 min at the highest possible workload. Cardiac output is measured continuously. A skeletal muscle biopsy is collected 3 h after the TT. Study endpoints include measures of skeletal muscle expression of nuclear receptors, hormones and cytokine levels, urinary and plasma concentrations of salbutamol and formoterol, circulating cardiac markers, cardiopulmonary function and exercise performance (average power and peak power during the TT). Blood and urine are collected and respiratory testing is performed 24 h post TT.

Summary/conclusions

This clinical trial evaluates the potential performance-enhancing effects of non-prohibited, not medically indicated inhaled short- and long-acting beta-2 agonists on skeletal muscle gene expression, endocrine regulation, cardiac biomarkers, cardiopulmonary function and acute endurance exercise performance. These data will be used by WADA to adapt the annually published list of prohibited substances (WADA 2021) and will be published in scientific journals.

Trial registration

The trial is registered at the European Clinical Trials Database (Eudra CT) with the number: 2015-005598-19 as well as at the German register for clinical studies (DRKS number 00010574).
TIMELAPSE study—efficacy of low-dose amitriptyline versus cognitive behavioral therapy for chronic insomnia in patients with medical comorbidity: study protocol of a randomized controlled multicenter non-inferiority trial
Authors: Rauwerda Nynke L. , Knoop Hans , Pot Irene , van Straten Annemieke , Rikkert Marian E. , Zondervan Anouk , Timmerhuis Thom P. J. , Braamse Annemarie M. J. , Boss H. Myrthe
Published: December 2021

Background

Insomnia is common in people with long-term medical conditions and is related to increased mortality and morbidity. Cognitive behavioral therapy for insomnia (CBT-I) is first choice treatment and effective for people with insomnia and comorbid long-term medical conditions. However, CBT-I has some limitations as it might not always be available or appeal to patients with medical conditions. Furthermore, a small proportion of patients do not respond to CBT-I. Preliminary evidence and clinical experience suggest that low-dose amitriptyline (AM) might be an effective alternative to treat insomnia in patients with medical comorbidity. In this randomized controlled trial, we will determine whether AM is non-inferior to the first choice treatment for insomnia, CBT-I.

Methods/design

This study will test if treatment with low-dose amitriptyline for insomnia in patients with medical comorbidity is non-inferior to CBT-I in a multicenter randomized controlled non-inferiority trial. Participants will be 190 adults with a long-term medical condition and insomnia. Participants will be randomly allocated to one of two intervention arms: 12 weeks AM (starting with 10 mg per day, and if ineffective at 3 weeks, doubling this dose) or 12 weeks of CBT-I consisting of 6 weekly sessions and a follow-up session 6 weeks later. The primary outcome is subjective insomnia severity, measured with the Insomnia Severity Index (ISI). The primary endpoint is at 12 weeks. Secondary outcomes include sleep quality (e.g., sleep efficiency), questionnaires on daytime functioning (physical functioning and impairment of functioning), and symptoms (e.g., fatigue, pain, anxiety) at 12 weeks and 12 months post treatment and relapse of insomnia until 12 months after treatment.

Discussion

Irrespective of the outcome, this study will be a much-needed contribution to evidence based clinical guidelines on the treatment of insomnia in patients with medical comorbidity.

Trial registration

Dutch Trial Register NTR NL7971. Registered on 18 August 2019
Evaluation of the Intensive Treatment and Rehabilitation Program for Residential Treatment and Rehabilitation Centers (INTREPRET) in the Philippines: a study protocol for a randomized controlled trial
Authors: Harada Takayuki , Baba Toshiaki , Shirasaka Tomohiro , Kanamori Shogo
Published: December 2021

Background

The Philippines has been severely affected by the methamphetamine crisis. The government has launched a policy war against drug use, although the severe sanctions imposed on drug users have been criticized internationally. To help implement a more effective and humane approach to drug use, this study aimed to introduce a comprehensive treatment program for methamphetamine users based on cognitive-behavioral therapy (CBT) whose effectiveness will be evaluated through a randomized controlled trial.

Methods

Methamphetamine users admitted into government-run rehabilitation facilities are recruited and randomly assigned to either a CBT-based treatment program or existing therapeutic community (TC)-based treatment. The CBT treatment program was developed based on the Matrix Model that considers cultural and social factors in the Philippines. After 6 months of treatment, there will be a three-month follow-up, when the participants’ drug use (tested through urine testing) and other psychological variables, including craving, coping skills, and well-being, will be compared. Potential participants are given a summary of the study and a consent form. The consent form is signed and dated by participants prior to their study participation. Ethical approval was obtained prior to the commencement of the study.

Discussion

This is the first randomized controlled trial to compare the residential CBT program and the TC model for methamphetamine users in the Philippines. The study aims to fill the current knowledge and capacity gaps by introducing a CBT-based treatment program to improve the psychosocial well-being of drug users in the Philippines. Moreover, if the effectiveness of the treatment program is demonstrated, anti-drug campaigns and severe sanctions against drug users may be reconsidered.

Trial registration

UMIN Clinical Trials Registry JPRN-UMIN000038597. Registered on 15 November 2019. Protocol version October 17, 2021 ver.2
Genetic diversity of Anopheles stephensi in Ethiopia provides insight into patterns of spread
Authors: Carter Tamar E. , Yared Solomon , Getachew Dejene , Spear Joseph , Choi Sae Hee , Samake Jeanne N. , Mumba Peter , Dengela Dereje , Yohannes Gedeon , Chibsa Sheleme , Murphy Matthew , Dissanayake Gunawardena , Flately Cecilia , Lopez Karen , Janies Daniel , Zohdy Sarah , Irish Seth R. , Balkew Meshesha
Published: December 2021

Background

The recent detection of the South Asian malaria vector Anopheles stephensi in the Horn of Africa (HOA) raises concerns about the impact of this mosquito on malaria transmission in the region. Analysis of An. stephensi genetic diversity and population structure can provide insight into the history of the mosquito in the HOA to improve predictions of future spread. We investigated the genetic diversity of An. stephensi in eastern Ethiopia, where detection suggests a range expansion into this region, in order to understand the history of this invasive population.

Methods

We sequenced the cytochrome oxidase subunit I (COI) and cytochrome B gene (CytB) in 187 An. stephensi collected from 10 sites in Ethiopia in 2018. Population genetic, phylogenetic, and minimum spanning network analyses were conducted for Ethiopian sequences. Molecular identification of blood meal sources was also performed using universal vertebrate CytB sequencing.

Results

Six An. stephensi COI-CytB haplotypes were observed, with the highest number of haplotypes in the northeastern sites (Semera, Bati, and Gewana towns) relative to the southeastern sites (Kebridehar, Godey, and Degehabur) in eastern Ethiopia. We observed population differentiation, with the highest differentiation between the northeastern sites compared to central sites (Erer Gota, Dire Dawa, and Awash Sebat Kilo) and the southeastern sites. Phylogenetic and network analysis revealed that the HOA An. stephensi are more genetically similar to An. stephensi from southern Asia than from the Arabian Peninsula. Finally, molecular blood meal analysis revealed evidence of feeding on cows, goats, dogs, and humans, as well as evidence of multiple (mixed) blood meals.

Conclusion

We show that An. stephensi is genetically diverse in Ethiopia and with evidence of geographical structure. Variation in the level of diversity supports the hypothesis for a more recent introduction of An. stephensi into southeastern Ethiopia relative to the northeastern region. We also find evidence that supports the hypothesis that HOA An. stephensi populations originate from South Asia rather than the Arabian Peninsula. The evidence of both zoophagic and anthropophagic feeding support the need for additional investigation into the potential for livestock movement to play a role in vector spread in this region.

Graphical Abstract
Drug targeting of aminoacyl-tRNA synthetases in Anopheles species and Aedes aegypti that cause malaria and dengue
Authors: Chakraborti Soumyananda , Chhibber-Goel Jyoti , Sharma Amit
Published: December 2021

Background

Mosquito-borne diseases have a devastating impact on human civilization. A few species of Anopheles mosquitoes are responsible for malaria transmission, and while there has been a reduction in malaria-related deaths worldwide, growing insecticide resistance is a cause for concern. Aedes mosquitoes are known vectors of viral infections, including dengue, yellow fever, chikungunya, and Zika. Aminoacyl-tRNA synthetases (aaRSs) are key players in protein synthesis and are potent anti-infective drug targets. The structure–function activity relationship of aaRSs in mosquitoes (in particular, Anopheles and Aedes spp.) remains unexplored.

Methods

We employed computational techniques to identify aaRSs from five different mosquito species (Anopheles culicifacies, Anopheles stephensi, Anopheles gambiae, Anopheles minimus, and Aedes aegypti). The VectorBase database (https://vectorbase.org/vectorbase/app) and web-based tools were utilized to predict the subcellular localizations (TargetP-2.0, UniProt, DeepLoc-1.0), physicochemical characteristics (ProtParam), and domain arrangements (PfAM, InterPro) of the aaRSs. Structural models for prolyl (PRS)-, and phenylalanyl (FRS)-tRNA synthetases—were generated using the I-TASSER and Phyre protein modeling servers.

Results

Among the vector species, a total of 37 (An. gambiae), 37 (An. culicifacies), 37 (An. stephensi), 37 (An. minimus), and 35 (Ae. aegypti) different aaRSs were characterized within their respective mosquito genomes. Sequence identity amongst the aaRSs from the four Anopheles spp. was > 80% and in Ae. aegypti was > 50%.

Conclusions

Structural analysis of two important aminoacyl-tRNA synthetases [prolyl (PRS) and phenylanalyl (FRS)] of Anopheles spp. suggests structural and sequence similarity with potential antimalarial inhibitor [halofuginone (HF) and bicyclic azetidine (BRD1369)] binding sites. This suggests the potential for repurposing of these inhibitors against the studied Anopheles spp. and Ae. aegypti.
Semi-field evaluation of novel chemical lures for Aedes aegypti, Culex quinquefasciatus, and Anopheles minimus (Diptera: Culicidae) in Thailand
Authors: Kim Dae-Yun , Leepasert Theerachart , Bangs Michael J. , Chareonviriyaphap Theeraphap
Published: December 2021

Background

Entomological surveillance is an important means of assessing the efficacy of insect vector management programs and estimating disease transmission thresholds. Among baited traps, Biogents’ BG-Sentinel (BGS) trap baited with BG-Lure is considered to have the most similar outcome to, and be a possible replacement for, human-landing catches for the epidemiologically relevant monitoring of adult Aedes aegypti and Culex quinquefasciatus. In contrast to the BGS trap, the Black Hole ultraviolet (UV) light trap, which is widely used to catch nocturnal flying insects, is not baited with synthetic human odor-mimicking lures.

Methods

We evaluated the l-lactic acid-based Kasetsart University (KU)-lures nos. 1–6 as novel candidate chemical lures for the diurnal species Ae. aegypti and the nocturnal species Cx. quinquefasciatus using two commercial traps (the BGS trap and the Black Hole UV light trap) in a semi-field screen (SFS) house. Firstly, we optimized the dose of each KU-lure in an SFS house (140 m3). Secondly, six different candidate KU-lures were screened by comparing their percent attraction using a single discriminating dose (0.5 g). Finally, we evaluated the synergism of the KU-lures selected in this way with commercially available traps.

Results

BGS traps baited with KU-lure no. 1 exhibited the greatest percent attraction for Ae. aegypti (29.5% ± 14.3%), whereas those baited with KU-lure no. 6 most strongly attracted Cx. quinquefasciatus (33.3% ± 10.7%). Interestingly, BGS traps treated with 10 g BG-Lure did not significantly attract more Ae. aegypti or Cx. quinquefasciatus than the untreated BGS traps. CO2 at a flow rate of 250 ml/min most strongly attracted both Ae. aegypti and Cx. quinquefasciatus (42.2% ± 14.2% and 75.1% ± 16.9%, respectively). BGS and Black Hole UV light traps with KU-lure no. 6 exhibited a stronger attraction for Cx. quinquefasciatus than untreated traps, and the percent attraction did not differ between the treated traps.

Conclusions

Synergistic effects of KU-lures nos. 1 and 6 with the mosquito traps were demonstrated for both the diurnal and nocturnal species in the SFS house assays. However, further studies are urgently needed for the development of species-specific lures to increase trap efficacy in the field for local vector mosquitoes in Thailand.

Graphical Abstract