bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between continuity of care and type 2 diabetes development among patients with thyroid disorder
Authors: Lee Sang Ah , Choi Dong-Woo , Kwon Junhyun , Lee Doo Woong , Park Eun-Cheol
Published: December 2019

Thyroid disorders are associated with blood glucose abnormalities. For rendering the patients euthyroid, routine screening and care are essential. Therefore, the aim of this study was to investigate the association between continuity of care (COC) and type 2 diabetes onset among patients with thyroid disorders.

We used the national claim data. Our study population was 4099 patients with hyperthyroidism or hypothyroidism. For calculating COC, the Most Frequent Provider Continuity Index (MFPCI), Modified Modified Continuity Index (MMCI), and COC Index (COCI) were used. The dependent variable was type 2 diabetes onset. The Cox proportional hazard regression model was used.

Among 4099 patients with thyroid disorders, 25.3% experienced onset of type 2 diabetes. Thyroid patients who had MFPCI and COCI below the median were more likely to experience onset of type 2 diabetes than who had these indices above the median (MFPCI: hazard ratio [HR] = 1.26, 95% confidence interval [CI] = 1.09–1.46; COCI: HR = 1.22, 95% CI = 1.06–1.41). Our subgroup analysis showed that female patients and those 20 to 34 years of age showed a significant association between COC and onset of type 2 diabetes.

Patients with thyroid disorders with low COC showed an increased risk of developing type 2 diabetes. Therefore, efforts to enhance COC among patients with thyroid disorders needs to be encouraged.
The effectiveness of catgut implantation at acupoints for allergic rhinitis
Authors: Zhong Juan , Shen Yifeng , Liu Shuqin , Dai Menglin , Yang Yepeng , Zhang Dazheng , Liu Min , Zhang Lijuan , Zhang Qinxiu
Published: December 2019

Background:

Catgut implantation at acupoint (CIAA) is increasing used in allergic rhinitis therapy, and many studies have published that it is effective in the treatment of allergic rhinitis. However, it is controversy if CIAA can provide an evidence-based clinical benefit in the allergic rhinitis population.

Methods:

We will go through 8 databases, and conduct a systematic review of CIAA and health-related outcomes in allergic rhinitis patients according to the Preferred Reporting Items for Systematic Reviews. The primary objective is to assess the impact of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines on clinical outcomes relevant to allergic rhinitis patients, such as effective rate, life-quality evaluation, and adverse events. Cochrane Risk Assessment Tool will be used to assess the quality of eligible studies according to the Cochrane handbook.

Results:

The results of this systematic review will provide a synthesis of current evidence of CIAA and we have a specific opportunity to determine the efficacy and safety of it.

Conclusion:

This study will explore whether or not CIAA can be used as one of the nondrug therapies to prevent or treat allergic rhinitis.

PROSPERO registration number: CRD42018095074 (https://www.crd.york.ac.uk/PROSPERO/#recordDetails)
Prevalence difference of Helicobacter pylori infection between Tibetan and Han ethnics
Authors: Bai Dan , Wang An-Mo , Liu Kai , Duan Si-Yu , Zhang Wei-Han , Hu Jian-Kun , Chen Xin-Zu
Published: December 2019

Objectives:

Helicobacter pylori (Hp) is an identified carcinogenic pathogen of human gastric cancer. China is not only one of the countries with high incidence and mortality of gastric cancer, but also a high infection area of Hp. As a multi-ethnic country, China may have a diverse prevalence of Hp infection among ethnics. This meta-analysis tends to compare the prevalence of Hp infection between Tibetan and Han ethnics, the results may provide evidence for targeted screening and eradication of Hp in China.

Methods:

The following databases will be searched: PubMed, Web of Science, Technology Periodical Database (VIP), China National Knowledge infrastructure (CNKI), and WanFang databases. Studies which reported the prevalence of Hp infection between Tibetans and Hans in China are eligible. Two reviewers will independently screen studies, extract data and assess the risk of bias of included studies. The prevalence of Hp infection between Tibetan and Han ethnics will be compared by meta-analysis. Heterogeneity tests and meta-analyses will be conducted using RevMan 5.3 and Stata 12.0 softwares. Meanwhile, subgroup analysis, publication bias and sensitivity analysis evaluation will be performed where applicable.

Results:

This study will be reported in compliance with the PRISMA statement.

This systematic review will not be submitted for any ethical approval since no privacy health information will be included. The findings will be published through peer-reviewed publications or conference presentations.

Prospero Registration Number:

CRD42019121192.

Conclusions:

Our study will provide us evidence for tailored strategy and robustness of Hp screening and eradication among Tibetans.
Chromosome 1q21 translocation and spermatogenesis failure
Authors: Li Ranwei , Wang Xiuyang , Feng Shuqiang , Yang Xiao , Zhang Qiushuang , Zhan Peng
Published: December 2019

Rationale:

For the carriers of chromosome reciprocal translocation, the reason why some are fertile and others are infertile remains unclear. Here, we describe 2 patients who are carriers of chromosome 1q21 translocation with azoospermia.

Patient concerns:

A 29-year-old male and a 33-year-old male presented at the clinic with a diagnosis of infertility.

Diagnosis:

Both patients with azoospermia were diagnosed with Routine semen analysis, cytogenetic diagnosis and detection of serum reproductive hormones. The karyotype results of 2 patients were 46,XY,t(1;17)(q21;q23) and 46,XY,t(1;10)(q21;p12), respectively.

Interventions:

After genetic counseling and informed consent, 1 patient (Case 2) chose microsopic testicular sperm extraction (micro-TESE).

Outcomes:

After micro-TESE, no sperm was found for the patient. Finally, both patients chose clinical treatment through artificial insemination with donor sperm.

Lessons:

These outcomes suggest that breakpoint at 1q21 should be paid attention by physician in genetic counseling, may harbor some genes associated with spermatogenesis, and deserves further be studied on the function of related genes.
Consumer Use of Provider Quality Report Cards
Authors: Bhandari Neeraj , Scanlon Dennis P. , Shi Yunfeng , Smith Rachel A.
Published: December 2019

Objective:

The objective of this study was to measure the dissemination of comparative provider quality information (CPQI) and evaluate its impact on consumers’ awareness and use of CPQI.

Data Sources:

Two-period, random-digit-dial panel survey of chronically ill consumers residing in 14 regions of the United States; summaries of CPQI dissemination activities of regional multistakeholder alliances; and the LexisNexis Academic and Access World News databases.

Study Design/Methods:

Fixed effects regression to isolate the effect of CPQI producers’ dissemination activities and the print media’s CPQI coverage on chronically ill consumers’ self-reported awareness and use of CPQI.

Principal Findings:

Direct CPQI dissemination had no overall effect on either awareness or use of CPQI. One unit increase in the media coverage of an Aligning Forces for Quality (AF4Q) multistakeholder alliance report increased consumer awareness and use of CPQI by 1.4 percentage points (P=0.049) and 1.1 percentage points (P=0.009), respectively. Similar increases for the Centers for Medicare and Medicaid Services (CMS) CPQI and for the nonalliance, non-CMS CPQI improved CPQI use by 1.6 percentage points (P<0.001) and 0.2 percentage points (P=0.041), respectively.

Conclusion:

Even though CPQI producers’ direct dissemination efforts had little impact, the small but significant consumer impacts of CPQI’s limited press coverage suggests that limited use of media in the dissemination of report cards may be a significant factor behind low consumer awareness and use.
Activities of Intellectual Disability Clinical Nurse Specialists in Ireland
Authors: Doody Owen , Slevin Eamonn , Taggart Laurence
Published: December 2019

Purpose/Aim:

The aim of this study was to identify the contribution of Irish intellectual disability clinical nurse specialists (ID CNSs) to service delivery.

Design:

A nonexperimental descriptive design was selected to survey ID CNSs presently working in Ireland. The questionnaire was developed based on focus group interviews, available literature, and expert panel views.

Methods:

Ethical approval and access were granted to all ID CNSs in Ireland. Thirty-two responded (33.68% response rate) from all work areas (voluntary organizations or health service executive) practicing within residential, community, or school services. Respondents were surveyed across a range of areas (demographic details and support to client, staff, family, organization, community, other agencies, and professional development).

Results:

Findings identify that ID CNSs are active in all aspects of their roles as clinical specialist, educator, communicator, researcher, change agent, and leader, thus supporting person-centered care and improving service delivery.

Conclusions:

To meet changing healthcare demands, promote person-centered care, and improve service delivery, the CNS role in ID should be developed and supported. The findings merit a further study on ID CNS role activity, possible variables influencing role activity, and team members' views.
Development and Pilot Implementation of a Search Protocol to Improve Patient Safety on a Psychiatric Inpatient Unit
Authors: Abela-Dimech Frances , Johnston Kim , Strudwick Gillian
Published: December 2019

Purpose/Objective:

A mental health organization in Ontario, Canada, noted an increase in unsafe items entering locked inpatient units. The purpose of this project was to develop and implement a search protocol to improve patient, staff, and visitor safety by preventing unsafe items from entering a locked inpatient unit.

Description of the Project:

Under the guidance of a clinical nurse specialist, an interprofessional team used the Failure Mode and Effects Analysis framework to identify what items were considered unsafe, how these unsafe items were entering the unit, and what strategies could be used to prevent these items from entering the unit. A standardized search protocol was identified as a strategy to prevent items from entering the unit.

Outcome:

The standardized search protocol was developed and piloted on 1 unit. To support the search protocol, an interprofessional team created a poster using a mnemonic aid to educate patients, staff, and visitors about which items could not be brought onto the unit. Educational sessions on the search protocol were provided for staff. The difference between the number of incidents before and after the implementation of the search protocol was statistically significant.

Conclusions:

Safety on an inpatient unit was increased as incidents of unsafe items entering the unit decreased.
Age does not affect sex effect of conditioned pain modulation of pressure and thermal pain across 2 conditioning stimuli
Authors: Riley Joseph L. , Cruz-Almeida Yenisel , Staud Roland , Fillingim Roger B.
Published: December 2019

Introduction:

Conditioned pain modulation (CPM) is a laboratory test resulting in pain inhibition through activation of descending inhibitory mechanisms. Older adults consistently demonstrate reduced CPM compared with younger samples; however, studies of sex differences in younger cohorts have shown mixed results.

Objectives:

This study tested for sex differences in CPM within samples of younger and older adults.

Methods:

Participants were 67 younger adults (mean age = 25.4 years) and 50 older adults (66.4 years). Study conditioning paradigms were the cold-pressor test and contact heat pain administered in separate sessions. Pressure pain threshold and ramping suprathreshold heat were the test stimuli across three time points after presentation of the conditioning stimuli (CS).

Results:

Significant inhibition was observed during both testing sessions. The hypothesis for sex differences across both age cohorts was supported only for ∆PPTh. However, sex differences did not reach significance for either paradigm using ascending suprathreshold heat as the test stimuli. The overall trend was that younger males experienced the strongest CPM and older females the weakest. From a methodological perspective, duration differences were seen in CPM, with inhibition decaying more quickly for PPTh than for suprathreshold heat pain. Furthermore, there were no differences in inhibition induced by cold-pressor test and contact heat pain as CS.

Conclusion:

Sex differences were similar across both age cohorts with males experiencing greater inhibition than females. Cross-sectional associations were also demonstrated between CPM inhibition and measures of recent pain, further supporting CPM as an experimental model with clinical utility.
Mouth Corner Lift with Botulinum Toxin Type A and Hyaluronic Acid Filler
Authors: Jeong Tae-Kwang
Published: December 2019

An upturned mouth corner is associated with brightness, optimism, and friendliness, whereas a downturned mouth corner not only conveys negative feelings such as sadness, depression, and tiredness, but also makes a person appear years older than they are. Surgical approaches to the correction of a downturned mouth corner can result in predictable and long-lasting results. However, because of their fear of postsurgical scars and long downtimes, many patients are reluctant to undergo surgery involving the mouth corner. As a consequence, minimally invasive procedures have become increasingly popular in recent years. Among these, botulinum toxin type A and injectable fillers play a significant role. The author uses botulinum toxin type A and hyaluronic acid filler injections as complementary procedures for lifting flat or downturned mouth corners in young patients. This method has produced reliable and consistent outcomes without severe complications such as necrosis or infection in over 100 patients, as reflected in high patient satisfaction. The combination of botulinum toxin type A and hyaluronic acid filler provides excellent results in young patients who desire an uplifted mouth corner and are reluctant to undergo surgery.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, V.
Comparison of the Wide-Awake Approach and Conventional Approach in Extensor Indicis Proprius–to–Extensor Pollicis Longus Tendon Transfer for Chronic Extensor Pollicis Longus Rupture
Authors: Hong JungJun , Kang Ho-Jung , Whang Jong-ick , Sung Seung-Yong , Kim Sung-Hoon , Shin Sung-Chul , Kim Si-Nae , Kim Ji-Sup
Published: December 2019

Background:

The wide-awake approach enables surgeons to perform optimal tensioning of a transferred tendon intraoperatively. The authors hypothesized that the extensor indicis proprius–to–extensor pollicis longus tendon transfer using the wide-awake approach would yield better results than conventional surgery.

Methods:

A retrospective analysis was performed of the prospectively collected data of 29 consecutive patients who underwent extensor indicis proprius–to–extensor pollicis longus tendon transfer. Patients were treated with the wide-awake approach (group A, n = 11) and conventional surgery under general anesthesia (group B, n = 18). The groups were compared retrospectively for thumb interphalangeal and metacarpophalangeal joint motion, grip and pinch strength, specific extensor indicis proprius–to–extensor pollicis longus evaluation method (SEEM), and Disabilities of the Arm, Shoulder and Hand questionnaire score at 6 weeks and 2, 4, 6, and 12 months postoperatively.

Results:

Group A showed significantly better interphalangeal joint flexion and total arc of motion at 6 weeks and 2, 4, and 6 months, and significantly better metacarpophalangeal joint flexion and total arc of motion at all time points. Interphalangeal and metacarpophalangeal joint extension showed no difference at all time points. Group A showed significantly better specific extensor indicis proprius–to–extensor pollicis longus evaluation method scores at 2 and 4 months, and Disabilities of the Arm, Shoulder and Hand questionnaire scores at 4, 6, and 12 months. Grip and pinch strength showed no difference at all time points. The complication rate and duration until return to work were not different between groups.

Conclusion:

Compared with the conventional approach, the wide-awake approach showed significantly better results in the thumb’s range of motion and functional outcomes, especially in the early postoperative periods.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Effect of Long-Term Retention of Gadolinium on Metabolism of Deep Cerebellar Nuclei After Repeated Injections of Gadodiamide in Rats
Authors: El Hamrani Dounia , Vives Véronique , Buchholz Rebecca , Même William , Factor Cecile , Fingerhut Stefanie , Sperling Michael , Karst Uwe , Robert Philippe , Même Sandra
Published: December 2019

Objectives

The aim of this study was to determine potential metabolism and histological modifications due to gadolinium retention within deep cerebellar nuclei (DCN) after linear gadolinium-based contrast agent injection (gadodiamide) in rats at 1 year after the last injection.

Materials and Methods

Twenty female rats received 20 doses of gadodiamide (0.6 mmol of gadolinium per kilogram each) over 5 weeks. They were followed at 1 week (M0), 6 weeks (M1), and 54 to 55 weeks (M13) postinjections to evaluate hypersignal on unenhanced T1-weighted magnetic resonance imaging and metabolic alterations by 1H magnetic resonance spectroscopy (1H-MRS). At 1 year postinjections, brains were sampled to determine the localization of gadolinium within cerebellum by laser ablation inductively coupled mass spectroscopy and to evaluate morphological changes by semiquantitative immunofluorescence analysis.

Results

There is a significant increase of the ratio DCN/brainstem for the gadodiamide group at M0 (+7.2% vs control group = 0.989 ± 0.01), M1 (+7.6% vs control group = 1.002 ± 0.018), and it lasted up to M13 (+4.7% vs control group = 0.9862 ± 0.008). No variation among metabolic markers (cellular homeostasis [creatine, choline, taurine], excitatory neurotransmitter [glutamate], and metabolites specific to a cellular compartment [N-acetyl aspartate for neurons and myo-inositol for glial cells]) were detected by 1H-MRS between gadodiamide and saline groups at M0, M1, and M13. At M13, laser ablation inductively coupled mass spectroscopy demonstrated that long-term gadolinium retention occurred preferentially in DCN. No histological abnormalities (including analysis of astrocytes, neurons, and microglial cells) were found in the rostral part of DCN.

Conclusions

Repeated administration of gadodiamide lead to a retention of gadolinium preferentially within DCN at 1 year postinjections. This retention did not lead to any detectable changes of the measured metabolic biomarkers nor histological alterations.
Randomized and Comparative Clinical Trial of Bovine Mesh Versus Polypropylene Mesh in the Repair of Inguinal Hernias
Authors: Sun Li , Chen Jie , Li Juan , Shen Yingmo
Published: December 2019

Background:

The type of mesh (synthetic vs. biological) play integral roles in the recovery and long-term outcomes of patients undergoing hernia repair. The aim of this study was to determine whether a biological mesh from bovine pericardium is equivalent to a standard polypropylene mesh in an open inguinal hernia repair using the Lichtenstein technique.

Materials and Methods:

A prospective, randomized, double-blinded, single-center trial was conducted to evaluate the safety and efficacy of a biological mesh compared with a commonly used polypropylene mesh using Lichtenstein’s inguinal hernia repair in a 6-month study. Patients were evaluated for recurrence and complications by a blinded surgeon at 1 day, 1 week, 1 month, 3 months, and 6 months after surgery.

Results:

A total of 132 patients were randomized into experimental group receiving the bovine mesh (n=66) and control group receiving the standard polypropylene mesh (n=66). No recurrences were diagnosed in both arms within 6-month follow-up. Patients in the experimental group reported markedly less groin pain during the 3-month postoperative assessment period compared with the control group. There were no statistically significant differences in other complications, such as incision inflammation, physical limitation, testicular problems, and foreign body sensation, between the 2 groups.

Conclusions:

Biological mesh is safe and effective in repairing inguinal hernia, with comparable intraoperative and early postoperative morbidity to the synthetic mesh.
Role of Endoanal Ultrasonography in Grading Anal Sphincter Integrity in Rectal Prolapse and in Predicting Improvement in the Continence State After Surgical Treatment
Authors: Emile Sameh H. , Youssef Mohamed , Thabet Waleed , Omar Waleed , Khafagy Wael , Farid Mohamed , Abdelnaby Mahmoud
Published: December 2019

Background:

Rectal prolapse can be associated with fecal incontinence (FI) that may not completely resolve after surgical treatment. We aimed to examine the utility of endoanal ultrasonography (EAUS) in identifying the pattern of anal sphincter injury in rectal prolapse and in predicting the improvement in continence state after surgical treatment.

Methods:

Records of patients of rectal prolapse who underwent surgical treatment and were evaluated with EAUS before surgery were screened. According to the degree of anal sphincter injury preoperative EAUS, 4 grades of anal sphincter injury were recognized (0 to III). The preoperative patient characteristics and outcome of surgery in each group were compared.

Results:

Fifty-nine patients (33 male), mean age 36.2 years, were included in the study. Forty-four (74.5%) patients complained of FI preoperatively. There were 12 (20.3%) patients with grade 0 injury, 29 (49.1%) with grade I, 7 (11.8%) with grade II, and 11 (18.6%) with grade III. Patients with grade III presented more with external rectal prolapse had a significantly longer duration of symptoms and had undergone previous surgery for rectal prolapse significantly more than the patients of the other 3 grades. Patients with grade II and grade III anal sphincter injury had significantly higher incontinence scores and lower anal pressures than grade 0 and grade I patients.

Conclusion:

Preoperative EAUS is a useful tool for the assessment of anal sphincter injury in patients with rectal prolapse and for predicting improvement in FI after surgical treatment as higher grades of sphincter injury were associated with less improvement in continence than lower grades.
Experience of Using Adrenocorticotropic Hormone in the Treatment of Patients With Acute Neuromyelitis Optica Who Failed Systemic Steroids: A Case Series
Authors: Berkovich Regina
Published: December 2019

Objectives

Neuromyelitis optica (NMO) has a complex pathology. Clinical symptoms, derived from damage to optic nerves and spinal cord, cause optic neuritis and/or longitudinally extensive myelitis. Treatment options are limited. We assessed adrenocorticotropic hormone (ACTH) use in patients developing exacerbations on systemic steroid treatment and declining other treatments.

Methods

Patients with NMO who initiated intravenous methylprednisolone (IVMP) for exacerbations and experienced a subsequent exacerbation on monthly IVMP or had inadequate response to IVMP received ACTH 80 U/d intramuscularly for 7 days (for acute relapse), followed by 80 U every 2 weeks (for long taper down/maintenance). Every 1 to 3 months, relapse, Expanded Disability Status Scale, laboratory, and adverse event assessments were performed.

Results

Six patients (mean age: 48.6 years; NMO-suggestive clinical/imaging presentations; cerebral spinal fluid revealing no oligoclonal bands; aquaporin-4 positive [n = 5]) were identified: 5 experiencing subsequent exacerbations with monthly IVMP and 1 with inadequate response to IVMP. No relapses occurred during ACTH treatment or taper-down period, laboratory values indicated no safety concerns, and annual follow-up magnetic resonance imagings were stable. Adverse events were generally characterized as improved or unchanged versus with IVMP, although 1 patient reported transient edema (lower extremities) only during ACTH treatment. Potential treatment-related AEs included edema, acne, urinary tract infection, and insomnia and were reportedly less severe with ACTH treatment than IVMP.

Conclusions

Adrenocorticotropic hormone treatment for acute NMO was associated with clinical improvement, suggesting that ACTH could have a role in treating acute NMO patients failing IVMP and declining other treatments. Fewer/less severe AEs were observed with ACTH versus IVMP. Larger, controlled clinical studies are needed.
miR-16-5p and miR-19b-3p prevent amyloid β-induced injury by targeting BACE1 in SH-SY5Y cells
Authors: Zhang Nan , Li Wei-Wei , Lv Chun-Mei , Gao Yi-Wen , Liu Xiao-Liang , Zhao Li
Published: December 2019

Purpose:

Alzheimer’s disease is the most common neurodegenerative disease, characterized by accumulation of amyloid β peptides. MicroRNAs have been identified as significant regulators and therapeutic targets of Alzheimer’s disease. However, the roles of miR-16-5p and miR-19b-3p and their mechanisms in Alzheimer’s disease progression remain largely unknown.

Materials and methods:

Amyloid β-treated SH-SY5Y cells were used to study Alzheimer’s disease progression in vitro. Transfection was conducted into SH-SY5Y cells using Lipofectamine 2000. The expression levels of miR-16-5p, miR-19b-3p and beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) were measured by quantitative real-time PCR or western blot, respectively. Cell viability and apoptosis were detected in amyloid β-treated SH-SY5Y cells by MTT or flow cytometry, respectively. The interaction between BACE1 and miR-16-5p or miR-19b-3p was explored by luciferase reporter and RNA immunoprecipitation analyses.

Results:

The expression levels of miR-16-5p and miR-19b-3p were reduced but BACE1 protein expression was enhanced in SH-SY5Y cells after treatment of amyloid β. Overexpression of miR-16-5p or miR-19b-3p attenuated amyloid β-induced viability inhibition and apoptosis promotion in SH-SY5Y cells, while their knockdown exacerbated amyloid β-induced injury. BACE1 was confirmed as a target of miR-16-5p and miR-19b-3p and its overexpression aggravated amyloid β-induced loss of viability and production of apoptosis, while its depletion caused an opposite effect. Moreover, upregulation of BACE1 alleviated the regulatory effects of miR-16-5p and miR-19b-3p on amyloid β-induced injury.

Conclusion:

MiR-16-5p and miR-19b-3p relieved amyloid β-induced injury by targeting BACE1 in SH-SY5Y cells, indicating miR-16-5p and miR-19b-3p as protective agents for treatment of Alzheimer’s disease.
Possible interaction between the ventral hippocampal cannabinoid CB2 and muscarinic acetylcholine receptors on the modulation of memory consolidation in mice
Authors: Nasehi Mohammad , Forouzanmehr Ensiyeh , Khakpai Fatemeh , Zarrindast Mohammad-Reza
Published: December 2019

To clarify possible interaction between the ventral hippocampal cannabinoid CB2 receptors and the cholinergic system in control of the memory process, the effects of cannabinoid and acetylcholine receptor agents on memory consolidation have been investigated in mice. Animals implanted with bilateral cannulas at the CA3 region of the ventral hippocampus and microinjected with scopolamine and cannabinergic agents. These animals were tested using a one-trial step-down inhibitory avoidance task. The results indicated impairment of memory consolidation by posttraining intra-CA3 microinjection of scopolamine (1 and 2 µg/mouse). Nevertheless, coinjection of various doses of scopolamine (0.01, 1 and 2 µg/mouse) with an ineffective dose of AM630 (1 µg/mouse) or GP1a (1 µg/mouse) did not show any significant effect on deficiency of memory consolidation produced by scopolamine. Posttraining application of cannabinoid CB2 receptor antagonist, AM630 (1, 10 and 100 µg/mouse; intra-CA3) alone had no significant influence on memory performance, but its coinjection with significant dose of scopolamine (1 µg/mouse) decreased memory consolidation. Moreover, posttraining injection of GP1a, cannabinoid CB2 receptor agonist, (10 and 100 µg/mouse; intra-CA3) decreased memory consolidation. Posttraining coadministration of diverse doses of GP1a (1, 10 and 100 µg/mouse; intra-CA3) with an effective dose of scopolamine (1 µg/mouse) meaningfully increased deficiency of memory consolidation produced by GP1a (100 µg/mouse). In addition, all drugs had no significant effect on locomotion. Consequently, these results propose that a probable interaction between the CA3 cannabinoid CB2 receptors and muscarinic acetylcholine receptors (mAChR) modulates memory consolidation process in mice.
Expression of sirtuin type 3 in locus ceruleus is associated with long-term intermittent hypoxia-induced neurocognitive impairment in mice
Authors: Zhang Jing , Zhu Ying , Lai Chunliu , Du Hongchun , Tang Kejing
Published: December 2019

Recent studies revealed that increased oxidative stress is one of the major mechanisms underlying the cognitive dysfunction induced by long-term intermittent hypoxia (LTIH). Locus ceruleus (LC) neurons, which fire at high rate across wakefulness, are essential for optimal cognitive function. The aim of this study was to investigate whether sirtuin type 3 (SirT3), a redox responses coordinator, plays a role in LTIH-induced neurocognitive impairment. Mice were subjected to LTIH or room air [normal control (NC)] for 10 weeks (10 h/day). Morris water maze test was used to detect spatial learning and memory ability. The oxidative stress was evaluated through the level of superoxide dismutase 2 (SOD2) and dihydroethidium and ethidium (DHE). Then the correlation between the number of platform crossing and SirT3 content measured by western blot was analyzed. Results showed that performance on the Morris water maze test was significantly worse for LTIH mice than for NC mice. LTIH exposure downregulated SirT3 and SOD2 in LC neurons, increasing DHE immunodensity. In addition, the SirT3 protein levels in LC neurons were positively related to the number of platform crossing. These observations suggest that SirT3-SOD2-intracellular superoxide is a key component associated with the cognitive dysfunction induced by LTIH. Moreover, they lend support to a rational basis for targeting upregulation of SirT3 in LC as a disease modifying strategy.

Video abstract:
http://links.lww.com/WNR/A577
Selenium nanoparticles reduce glucose metabolism and promote apoptosis of glioma cells through reactive oxygen species-dependent manner
Authors: Xu Binchu , Zhang Qingping , Luo Xinlin , Ning Xinjie , Luo Juncheng , Guo Jian , Liu Qingchang , Ling Gengqiang , Zhou Nan
Published: December 2019

Gliomas are the most common, malignant, and lethal tumors in adults. Furthermore, gliomas are highly resistant to current chemotherapeutic drugs. Thus, new effective anticancer drugs for glioma are urgently needed. Selenium nanoparticles have been reported to have potent anti-tumor activity, although the specific mechanism is not fully understood. This study aimed to test the anti-tumor effect of selenium nanoparticles and its mechanism. We used selenium nanoparticles to treat commercial glioma cell lines, and patient-derived glioma cells, and then used the MTT assay to determine selenium nanoparticles effect against these. Apoptotic cell death was determined by annexin V-Fluos staining kit. Glucose uptake, lactate, and adenosine triphosphate production, together with hexokinase 2 and pyruvate kinase activities were measured to determine the glucose metabolism level. Reactive oxygen species production was tested using 2′,7′-dichlorodihydrofluorescein diacetate. Our results showed that selenium nanoparticles had a potent cytotoxic effect in glioma cells, regardless of whether they were drug-resistant or not, whereas it showed less toxic effect in normal healthy cells. Further tests showed that selenium nanoparticles treatment leads to apoptotic cell death enhancement and glucose metabolism reduction, and this process was in a reactive oxygen species pathway-dependent manner. These results may provide a novel direction for glioma therapy in the future.
Cholinergic circuit genes in the healthy brain are differentially expressed in regions that exhibit gray matter loss in Parkinson’s disease
Authors: Keo Arlin , Dzyubachyk Oleh , van der Grond Jeroen , Hafkemeijer Anne , van de Berg Wilma D.J. , van Hilten Jacobus J. , Reinders Marcel J. T. , Mahfouz Ahmed
Published: December 2019

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance. In Parkinson’s disease, the posterior cingulate network and anterior cingulate network showed decreased gray matter and therefore we examined the underlying molecular processes of these anatomical networks in the healthy brain. Whole brain transcriptomics from post-mortem samples from healthy adults, revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS signaling pathways in these PD-related regions. Our results also suggest involvement of the cholinergic circuit, in which genesNPPA, SOSTDC1, andTYRP1may play a protective role. Furthermore, both networks were associated with memory and neuropsychiatric disorders that overlap with Parkinson’s disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinson’s disease.
Membrane metalloendopeptidase suppresses prostate carcinogenesis by attenuating effects of gastrin-releasing peptide on stem/progenitor cells
Authors: Cheng Chieh-Yang , Zhou Zongxiang , Stone Meredith , Lu Bao , Flesken-Nikitin Andrea , Nanus David M. , Nikitin Alexander Yu.
Published: December 2019

Aberrant neuroendocrine signaling is frequent yet poorly understood feature of prostate cancers. Membrane metalloendopeptidase (MME) is responsible for the catalytic inactivation of neuropeptide substrates, and is downregulated in nearly 50% of prostate cancers. However its role in prostate carcinogenesis, including formation of castration-resistant prostate carcinomas, remains uncertain. Here we report that MME cooperates with PTEN in suppression of carcinogenesis by controlling activities of prostate stem/progenitor cells. Lack of MME and PTEN results in development of adenocarcinomas characterized by propensity for vascular invasion and formation of proliferative neuroendocrine clusters after castration. Effects of MME on prostate stem/progenitor cells depend on its catalytic activity and can be recapitulated by addition of the MME substrate, gastrin-releasing peptide (GRP). Knockdown or inhibition of GRP receptor (GRPR) abrogate effects of MME deficiency, and delay growth of human prostate cancer xenografts by reducing the number of cancer propagating cells. In sum, our study provides a definitive proof of tumor suppressive role of MME, links GRP/GRPR signaling to the control of prostate stem/progenitor cells, and shows how dysregulation of such signaling may promote formation of castration-resistant prostate carcinomas. It also identifies GRPR as a valuable target for therapies aimed at eradication of cancer propagating cells in prostate cancers with MME downregulation.
Design to Data for mutants of β-glucosidase B fromPaenibacillus polymyxa: Q22T, W123R, F155G, Y169M, W438D, V401A
Authors: Hou Chengrui , Smith Paul , Huang Joyce , Fell Jason , Huang Peishan , Vater Ashley , Siegel Justin B.
Published: December 2019

A key goal of protein engineering is to accurately model the stability and catalytic activity of enzymes. However, the limitations of functional predictive abilities pose a major challenge for modeling algorithm design, and can be attributed to the lack of large data sets quantifying the functional properties of enzymes. Here, the thermal stability (TM) and Michaelis-Menten constants (kcat, KM, andkcat/KM) of six new variants of the β-glucosidase B (BglB) protein are quantitatively characterized. Molecular stability of the enzyme variants were hypothesized using the Foldit software and BglB was synthesized inE. colicells. Testing was done through a colorimetric kinetic assay and thermal stability fluorescence-based protein unfolding assay. Results from the assays suggest that all mutations, with the exception of variant Y169M, all experienced reduced catalytic efficiency compared to the wildtype. Assay results indicate that variant W123R is more thermally stable compared to the wildtype, while the differences in thermal stability between the other variants, and the wildtype are negligible. The collected thermal stability and catalytic efficiency data has been added to a data set with the aim of improving Rosetta algorithms for modeling and predicting the functional interactions between biomolecules through a machine learning algorithm and facilitate the precise engineering of protein catalysts.
Prostatic osteopontin expression is associated with symptomatic benign prostatic hyperplasia
Authors: Popovics Petra , Awadallah Wisam N. , Kohrt Sarah , Case Thomas C. , Miller Nicole L. , Ricke Emily , Huang Wei , Ramirez-Solano Marisol , Liu Qi , Vezina Chad M. , Matusik Robert J. , Ricke William A. , Grabowska Magdalena M.
Published: December 2019

Background

Male lower urinary tract symptoms (LUTS) occur in more than half of men above 50 years of age. LUTS were traditionally attributed to benign prostatic hyperplasia (BPH) and therefore the clinical terminology often use LUTS and BPH interchangeably. More recently, LUTS were also linked to fibrogenic and inflammatory processes. We tested whether osteopontin (OPN), a pro-inflammatory and pro-fibrotic molecule, is increased in symptomatic BPH. We also tested whether prostate epithelial and stromal cells secrete OPN in response to pro-inflammatory stimuli and identified downstream targets of OPN in prostate stromal cells.

Methods

Immunohistochemistry was performed on prostate sections obtained from the transition zone (TZ) of patients who underwent surgery (Holmium laser enucleation of the prostate) to relieve LUTS i.e. surgical BPH (S-BPH) or patients who underwent radical prostatectomy to remove low-grade prostate cancer (incidental BPH, I-BPH). Images of stained tissue sections were captured with a Nuance Multispectral Imaging system and histoscore, as a measure of OPN staining intensity, was determined with inForm software. OPN protein abundance was determined by Western blot. The ability of prostate cells to secrete osteopontin in response to IL-1β and TGF-β1 was determined in stromal (BHPrS-1) and epithelial (NHPrE-1 and BHPrE-1) cells by ELISA. qPCR was used to measure gene expression changes in these cells in response to OPN.

Results

OPN immunostaining (p=0.0107) and protein levels were more abundant in S-BPH than I-BPH. Staining was distributed across all cell types with highest levels in epithelial cells. Multiple OPN protein variants were identified in immortalized prostate stromal and epithelial cells. TGF-β1 stimulated OPN secretion by NHPrE-1 cells and both IL-1β and TGF-β1 stimulated OPN secretion by BHPrS-1 cells. Interestingly, recombinant OPN increased the mRNA expression ofCXCL1,CXCL2,CXCL8,PTGS2andIL6in BHPrS-1, but not in epithelial cell lines.

Conclusions

OPN is more abundant in prostates of men with S-BPH compared to men with I-BPH. OPN secretion is stimulated by pro-inflammatory cytokines, and OPN acts directly on stromal cells to drive the synthesis of pro-inflammatory mRNAs. Pharmacological manipulation of prostatic OPN may have the potential to reduce LUTS by inhibiting both inflammatory and fibrotic pathways.
Overcoming the design, build, test (DBT) bottleneck for synthesis of nonrepetitive protein-RNA binding cassettes for RNA applications
Authors: Katz Noa , Tripto Eitamar , Goldberg Sarah , Atar Orna , Yakhini Zohar , Orenstein Yaron , Amit Roee
Published: December 2019

The design-build-test (DBT) cycle in synthetic biology is considered to be a major bottleneck for progress in the field. The emergence of high-throughput experimental techniques, such as oligo libraries (OLs), combined with machine learning (ML) algorithms, provide the ingredients for a potential “big-data” solution that can generate a sufficient predictive capability to overcome the DBT bottleneck. In this work, we apply the OL-ML approach to the design of RNA cassettes used in gene editing and RNA tracking systems. RNA cassettes are typically made of repetitive hairpins, therefore hindering their retention, synthesis, and functionality. Here, we carried out a high-throughput OL-based experiment to generate thousands of new binding sites for the phage coat proteins of bacteriophages MS2 (MCP), PP7 (PCP), and Qβ (QCP). We then applied a neural network to vastly expand this space of binding sites to millions of additional predicted sites, which allowed us to identify the structural and sequence features that are critical for the binding of each RBP. To verify our approach, we designed new non-repetitive binding site cassettes and tested their functionality in U2OS mammalian cells. We found that all our cassettes exhibited multiple trackable puncta. Additionally, we designed and verified two additional cassettes, the first containing sites that can bind both PCP and QCP, and the second with sites that can bind either MCP or QCP, allowing for an additional orthogonal channel. Consequently, we provide the scientific community with a novel resource for rapidly creating functional non-repetitive binding site cassettes using one or more of three phage coat proteins with a variety of binding affinities for any application spanning bacteria to mammalian cells.
Cortical neuron response selectivity derives from strength in numbers of synapses
Authors: Scholl Benjamin , Thomas Connon I. , Ryan Melissa A. , Kamasawa Naomi , Fitzpatrick David
Published: December 2019

Single neocortical neurons are driven by populations of excitatory inputs, forming the basis of neural selectivity to features of sensory input. Excitatory connections are thought to mature during development through activity-dependent Hebbian plasticity1, whereby similarity between presynaptic and postsynaptic activity selectively strengthens some synapses and weakens others2. Evidence in support of this process ranges from measurements of synaptic ultrastructure to slice andin vivophysiology and imaging studies3,4,5,6,7,8. These corroborating lines of evidence lead to the prediction that a small number of strong synaptic inputs drive neural selectivity, while weak synaptic inputs are less correlated with the functional properties of somatic output and act to modulate activity overall6,7. Supporting evidence from cortical circuits, however, has been limited to measurements of neighboring, connected cell pairs, raising the question of whether this prediction holds for the full profile of synapses converging onto cortical neurons. Here we measure the strengths of functionally characterized excitatory inputs contacting single pyramidal neurons in ferret primary visual cortex (V1) by combiningin vivotwo-photon synaptic imaging andpost hocelectron microscopy (EM). Using EM reconstruction of individual synapses as a metric of strength, we find no evidence that strong synapses play a predominant role in the selectivity of cortical neuron responses to visual stimuli. Instead, selectivity appears to arise from the total number of synapses activated by different stimuli. Moreover, spatial clustering of co-active inputs, thought to amplify synaptic drive, appears reserved for weaker synapses, further enhancing the contribution of the large number of weak synapses to somatic response. Our results challenge the role of Hebbian mechanisms in shaping neuronal selectivity in cortical circuits, and suggest that selectivity reflects the co-activation of large populations of presynaptic neurons with similar properties and a mixture of strengths.
Transposon mutagenesis identifies cooperating genetic drivers during keratinocyte transformation and cutaneous squamous cell carcinoma progression
Authors: Aiderus Aziz , Newberg Justin Y. , Guzman-Rojas Liliana , Contreras-Sandoval Ana M. , Meshey Amanda L. , Jones Devin J. , Amaya-Manzanares Felipe , Rangel Roberto , Ward Jerrold M. , Lee Song-Choon , Ban Kenneth Hon-Kim , Rogers Keith , Rogers Susan M. , Selvanesan Luxmanan , McNoe Leslie A. , Copeland Neal G. , Jenkins Nancy A. , Tsai Kenneth Y. , Black Michael A. , Mann Karen M. , Mann Michael B.
Published: December 2019

The systematic identification of genetic events driving cellular transformation and tumor progression in the absence of a highly recurrent oncogenic driver mutation is a challenge in cutaneous oncology. In cutaneous squamous cell carcinoma (cuSCC), the high UV-induced mutational burden poses a hurdle to achieve a complete molecular landscape of this disease. Here, we utilized theSleeping Beautytransposon mutagenesis system to statistically define drivers of keratinocyte transformation and cuSCC progressionin vivoin the absence of UV-IR, and identified both known tumor suppressor genes and novel oncogenic drivers of cuSCC. Functional analysis confirms an oncogenic role for theZMIZgenes, and tumor suppressive roles forKMT2C, CREBBPandNCOA2, in the initiation or progression of human cuSCC. Taken together, ourin vivoscreen demonstrates an extremely heterogeneous genetic landscape of cuSCC initiation and progression, which can be harnessed to better understand skin oncogenic etiology and prioritize therapeutic candidates.
HIV-1 Vpr induces cell cycle arrest and enhances viral gene expression by depleting CCDC137
Authors: Zhang Fengwen , Bieniasz Paul D.
Published: December 2019

The HIV-1 Vpr accessory protein induces ubiquitin/proteasome-dependent degradation of many cellular proteins by recruiting them to a cullin4A-DDB1-DCAF1 complex. In so doing, Vpr enhances HIV-1 gene expression and induces (G2/M) cell cycle arrest. However, the identities of Vpr target proteins through which these biological effects are exerted are unknown. We show that a chromosome periphery protein, CCDC137/cPERP-B, is targeted for depletion by HIV-1 Vpr, in a cullin4A-DDB1-DCAF1 dependent manner. CCDC137 depletion caused G2/M cell-cycle arrest, while Vpr-resistant CCDC137 mutants conferred resistance to Vpr-induced G2/M arrest. CCDC137 depletion also recapitulated the ability of Vpr to enhance HIV-1 gene expression, particularly in macrophages. Our findings indicate that Vpr promotes cell-cycle arrest and HIV-1 gene expression through depletion of CCDC137.
The String Decomposition Problem and its Applications to Centromere Assembly
Authors: Dvorkina Tatiana , Bzikadze Andrey V. , Pevzner Pavel A.
Published: December 2019

Recent attempts to assemble long tandem repeats (such as multi-megabase long centromeres) faced the challenge of accurate translation of long error-prone reads from the nucleotide alphabet into the alphabet of repeatunits. Centromeres represent a particularly complex type ofnested tandem repeats, where each unit is itself a repeat formed by chromosome-specificmonomers(a repeat within repeat). Given a set of monomers forming a specific centromere, translation of a read into monomers is modeled as the String Decomposition Problem, finding a concatenate of monomers with the highest-scoring sequence alignment to a given read. We developed a StringDecomposer algorithm for solving this problem, benchmarked it on the set of reads generated by the Telomere-to-Telomere consortium, and identified a novel (rare) monomer that extends the set of twelve X-chromosome specific monomers identified more than three decades ago. The accurate translation of each read into a monomer alphabet turns centromere assembly into a more tractable problem than the notoriously difficult problem of assembling centromeres in the nucleotide alphabet. Our identification of a novel monomer emphasizes the importance of careful identification of all (even rare) monomers for follow-up centromere assembly efforts.