bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolfenamic acid inhibits ROS-generating oxidase Nox1-regulated p53 activity in intrastriatal injection of malonic acid rats
Authors: Yang Xin , Zhang Heling , Qu Tong , Wang Yi , Zhong Yongxian , Yan Yuchen , Ji Xuefei , Chi Tiayan , Liu Peng , Zou Libo
Published: July 2022

It has been reported that wild-type p53-induced gene 1 (Wig1), which is downstream of p53, regulates the expression of mutant huntingtin protein (mHtt) in Huntington’s disease (HD) patients and transgenic mouse brains. Intrastriatal injection of malonic acid in rats is often used as a model to study the pathological changes of Huntington’s disease, and this model has the advantages of a fast preparation and low cost. Therefore, in this study, we used intrastriatal injections of 6 μM malonic acid in rats to evaluate the effect of tolfenamic acid on motor and cognitive deficits and the effect of 6 mg/kg and 32 mg/kg tolfenamic acid on p53 and its downstream targets, such as Wig1. The results showed that 32 mg/kg tolfenamic acid attenuated motor and spatial memory dysfunction, prevented Nox1-mediated reactive oxygen species (ROS) production, and downregulated the activity of p53 by increasing the phosphorylation level at the Ser378 site and decreasing the acetylation level at the Lys382 site. Tolfenamic acid reduced mouse double minute 2 (Mdm2), phosphatase and tensin homologue (Pten), P53-upregulated modulator of apoptosis (Puma) and Bcl2-associated X (Bax) at the mRNA level to inhibit apoptosis and downregulated sestrin 2 (Sesn2) and hypoxia inducible factor 1, alpha subunit (Hif-1α) mRNA levels to exert antioxidative stress effects. In addition, 32 mg/kg tolfenamic acid played a role in neuroprotection by decreasing the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL)-positive cell numbers. However, there was no difference in the Wig mRNA level among all groups, and tolfenamic acid could not decrease the protein level of Wig1. In conclusion, tolfenamic acid inhibited the ROS-generating oxidase Nox1-regulated p53 activity and attenuated motor and spatial memory deficits in malonic acid-injected rats.
Management of Fournier’s gangrene during the Covid-19 pandemic era: make a virtue out of necessity
Authors: Paladini Alessio , Cochetti Giovanni , Tancredi Angelica , Mearini Matteo , Vitale Andrea , Pastore Francesca , Mangione Paolo , Mearini Ettore
Published: July 2022

Background

Fournier’s gangrene (FG) is a necrotizing fasciitis caused by aerobic and anaerobic bacterial infection that involves genitalia and perineum. Males, in their 60 s, are more affected with 1.6 new cases/100.000/year. Main risk factors are diabetes, malignancy, inflammatory bowel disease. FG is a potentially lethal disease with a rapid and progressive involvement of subcutaneous and fascial plane. A multimodal approach with surgical debridement, antibiotic therapy, intensive support care, and hyperbaric oxygen therapy (HBOT) is often needed.

We present the inpatient management of an FG case during the Covid-19 pandemic period. A narrative review of the Literature searching “Fournier’s gangrene”, “necrotizing fasciitis” on PubMed and Scopus was performed.

Case presentation

A 60 years old man affected by diabetes mellitus, with ileostomy after colectomy for ulcerative colitis, was admitted to our Emergency Department with fever and acute pain, edema, dyschromia of right hemiscrotum, penis, and perineal region. Computed tomography revealed air-gas content and fluid-edematous thickening of these regions. Fournier’s Gangrene Severity Index was 9. A prompt broad-spectrum antibiotic therapy with Piperacillin/Tazobactam, Imipenem and Daptomycin, surgical debridement of genitalia and perineal region with vital tissue exposure, were performed. Bedside daily surgical wound medications with fibrine debridement, normal saline and povidone-iodine solutions irrigation, iodoform and fatty gauze application, were performed until discharge on the 40thpostoperative day. Every 3 days office-based medication with silver dressing, after normal saline and povidone-iodine irrigation and fibrinous tissue debridement, was performed until complete re-epithelialization of the scrotum on the 60thpostoperative day.

Conclusions

FG is burdened by a high mortality rate, up to 30%. In the literature, HBOT could improve wound restoration and disease-specific survival. Unfortunately, in our center, we do not have HBOT. Moreover, one of the pandemic period problems was the patient’s displacement and outpatient hospital management. For all these reasons we decided for a conservative inpatient management. Daily cleaning of the surgical wound allowed to obtain its complete restoration avoiding surgical graft and hyperbaric oxygen chamber therapy, without foregoing optimal outcomes.
The association between blood albumin level and cardiovascular complications and mortality risk in ICU patients with CKD
Authors: Huang Fengming , Fan Jinmao , Wan Xin , Liu Huogen , Shi Yundi , Shu Hailin , Liu Ying , Lu Tongan , Gong Zhenbin , Gu Ling
Published: July 2022

Background

Studies involving the association of blood albumin with prognosis in patients with chronic kidney disease (CKD) during intensive care unit (ICU) were scarce.

Aim

We investigated whether reduced blood albumin level independently associated with an increased risk of cardiovascular (CV) complications and 1-year mortality risk in ICU patients with CKD.

Methods

The Medical Information Mart for Intensive Care III (MIMIC-III) database was used. Disease diagnosis and death information among a number of 925 ICU patients with CKD, who have been measured for blood biochemistry, were recorded. Here, multivariable logistic regression Models were structured to evaluate the associations between blood albumin levels (first value on admission, maximum and minimum value during ICU) and risks for CV complications and 1-year mortality among these CKD patients.

Results

In 925 CKD patients, the number of CV complication with heart failure (HF), myocardial infarction (MI) or stroke was 470 (50.8%). 406 (43.9%) patients were dead during the follow-up of 1 year after patients were discharged. Our smooth curve results suggested a curvilinear relation on association between blood albumin level and risk of CV complications. The “inflection point” of blood albumin level that patients were at highest risk of CV complications was 3.4 g/dL. The almost linear relationship with a downward trend was observed on the association between blood albumin level and 1-year mortality risk. We found that reduced blood albumin level contributed to lower risk for CV complications and higher risk for 1-year mortality respectively when blood albumin levels in CKD patients were below 3.4 g/dL. Additionally, albumin therapy had an obvious modifying effect on the independent association, suggesting a possible improved effect of albumin therapy on risk of CV complications and 1-year mortality risk in these CKD patients.

Conclusions

Our study reported that reduced blood albumin levels in CKD patients during ICU were related to lower risk for CV complications and increased risk of 1-year mortality.
The prevalence of Post-Ebola Syndrome hearing loss, Sierra Leone
Authors: Ficenec Samuel C. , Grant Donald S. , Sumah Ibrahim , Alhasan Foday , Yillah Mohamed S. , Brima Jenneh , Konuwa Edwin , Gbakie Michael A. , Kamara Fatima K. , Bond Nell G. , Engel Emily J. , Shaffer Jeffrey G. , Fischer William A. , Wohl David A. , Emmett Susan D. , Schieffelin John S.
Published: July 2022

Background

Globally, hearing loss is the second leading cause of disability, affecting approximately 18.7% of the world’s population. However, the burden of hearing loss is unequally distributed, with the majority of affected individuals located in Asia or Sub-Saharan Africa. Following the 2014 West African Ebola Outbreak, disease survivors began to describe hearing loss as part of the constellation of symptoms known as Post-Ebola Syndrome. The goal of this study was to more fully characterize hearing loss among Ebola Virus Disease (EVD) survivors.

Methodology and principal findings

EVD survivors and their household contacts were recruited (n = 1,12) from Eastern Sierra Leone. Each individual completed a symptom questionnaire, physical exam, and a two-step audiometry process measuring both air and bone conduction thresholds. In comparison to contacts, EVD survivors were more likely to have complaints or abnormal findings affecting every organ system. A significantly greater percentage of EVD survivors were found to have hearing loss in comparison to contacts (23% vs. 9%, p < 0.001). Additionally, survivors were more likely to have bilateral hearing loss of a mixed etiology. Logistic regression revealed that the presence of any symptoms of middle or inner ear (p < 0.001), eye (p = 0.005), psychiatric (p = 0.019), and nervous system (p = 0.037) increased the odds of developing hearing loss.

Conclusions and significance

This study is the first to use an objective and standardized measurement to report hearing loss among EVD survivors in a clinically meaningful manner. In this study it was found that greater than 1/5th of EVD survivors develop hearing loss. The association between hearing impairment and symptoms affecting the eye and nervous system may indicate a similar mechanism of pathogenesis, which should be investigated further. Due to the quality of life and socioeconomic detriments associated with untreated hearing loss, a greater emphasis must be placed on understanding and mitigating hearing loss following survival to aid in economic recovery following infectious disease epidemics.
A qualitative process analysis of daily contact testing as an alternative to self-isolation following close contact with a confirmed carrier of SARS-CoV-2
Authors: Denford Sarah , Martin Alex F. , Towler Lauren , Mowbray Fiona , Essery Rosie , Bloomer Rachael , Ready Derren , Love Nicola , Amlôt Richard , Oliver Isabel , Rubin G James , Yardley Lucy
Published: July 2022

Background

In July 2021, a randomised controlled trial was conducted to compare the effect on SARS-CoV-2 transmission of seven days of Daily Contact Testing (DCT) using Lateral Flow Test (LFT) and two Polymerase Chain Reaction (PCR) tests as an alternative to 10 days of standard self-isolation with one PCR, following close contact with a SARS-CoV-2 carrier. In this qualitative study, we used a nested process evaluation to aid interpretation of the trial and provide insight into factors influencing use of tests, understanding of test results, and how tests were used to inform behavioural decisions.

Methods

Interviews were conducted with 60 participants (42 randomised to DCT and 18 randomised to self-isolation) who had been in close contact with a confirmed SARS-CoV-2 carrier and had consented to take part in the trial.

Results

Data were organised into three overarching themes: (1) assessing the risks and benefits of DCT (2) use of testing during the study period and (3) future use of testing. Attitudes toward DCT as an alternative to self-isolation and behaviour during the testing period appeared to be informed by an assessment of the associated risks and benefits. Participants reported how important it was for them to avoid isolation, how necessary self-isolation was considered to be, and the ability of LFTs to detect infection. Behaviour during the testing period was modified to reduce risks and harms as much as possible. Testing was considered a potential compromise, reducing both risk of transmission and the negative impact of self-isolation, and was regarded as a way to return to normal.

Conclusion

Participants in this study viewed DCT as a sensible, feasible, and welcome means of avoiding unnecessary self-isolation. Although negative LFTs provided reassurance, most people still restricted their activity as recommended. DCT was also highly valued by those in vulnerable households as a means of providing reassurance of the absence of infection and as an important means of detecting infection and prompting self-isolation when necessary.
Cervical musculoskeletal, physical and psychological factors associated with ongoing dizziness in patients with whiplash associated disorder, 12 months after undertaking a neck specific or general exercise intervention
Authors: Treleaven Julia , Peterson Gunnel , Ludvigsson Maria Landén , Peolsson Anneli
Published: July 2022

Background

Exercise in the management of persistent whiplash often doesn’t specifically address dizziness. This study aimed to determine cervical musculoskeletal and sensorimotor measures, quality of life and psychological factors associated with the presence of dizziness in individuals with persistent whiplash 12 months post exercise intervention commencement.

Methods

A retrospective cross sectional review of questionnaires on dizziness, physical and psychological disability, quality of life and physical measures prospectively collected from 172 individuals during a randomised controlled trial. Associations between dizziness at 12 months post intervention and possible predictors was analysed with simple and multiple logistic regression models.

Results

Sixty-three % reported dizziness with a mean University of California Los Angeles dizziness score of 9 (SD 5) and dizziness intensity during activity of 26 mm (SD 24). They had poorer performance on sharpened Rhomberg, Neck muscle endurance (NME), and range of motion, elevated scores on pain, Neck disability index (NDI) and psychological and quality of life measures compared to those without dizziness. Less improvement in NDI and NME flexion from baseline to 12 months post exercise commencement, along with some baseline covariates were related to persistent dizziness and explained 50% of the variance.

Conclusion

Dizziness following exercise at 12 months post follow-up was associated with lack of improvement in NDI and NME flexion suggesting a cervicogenic role. Alternatively, the presence of dizziness may inhibit exercise response. Additional causes or contributing factors of dizziness should be investigated in those with persistent whiplash to improve quality of life.
Clinicopathologic, treatment and prognosis study of 46 Xp11.2 translocation/TFE3 gene fusion renal cell carcinomas
Authors: Zhou Jiale , Zhao Ling , Yang Zhaolin , Chen Yonghui , Wu Xiaorong , Xue Wei
Published: July 2022

Purpose

To report the clinicopathological features and mid- to long-term oncologic results of Xp11.2 translocation/transcription factor E3 (TFE3) gene fusion renal cell carcinomas (Xp11.2 translocation RCCs) in a single large-volume centrecentre.

Methods

Clinical and follow-up data of 46 patients who were diagnosed with Xp11.2 translocation RCC and underwentunderwent surgical intervention were retrospectively reviewed.

Result

Forty-six Xp11.2 translocation RCC patients were identified from 4218 renal tumour patients who were underwentunderwent surgery in our centrecentre from Jan. 2014 to Apr. 2020. The incidence of Xp11.2 translocation RCCs in our centre was 1.09%. During a median follow-up period of 30.5 months, 4 patients died of the disease. The total median overall survival and cancer specific survival were 30.0 months and 24.0 months, respectively. The 1-year, 3-year and 5-year OS rates were 97.4%, 88.8%, and 88.8%, respectively. In multivariable analysis, displaying symptoms when diagnosed (p = 0.019), lymph node metastasis (p = 0.002) and distal metastasis (p = 0.020) were identified as risk factors for poor prognosis.

Conclusion

Xp11.2 translocation RCC is a type of renal cell carcinoma with a relatively low incidence and various prognoses. Early-stage Xp11.2 translocation RCCs have a similar prognosis to most typical RCCs, but late-stage Xp11.2 translocation RCCs can lead to poor oncological outcomes.
Cross-cultural differences in men on active surveillance’ anxiety: a longitudinal comparison between Italian and Dutch patients from the Prostate cancer Research International Active Surveillance study
Authors: Dordoni Paola , Remmers Sebastiaan , Valdagni Riccardo , Bellardita Lara , De Luca Letizia , Badenchini Fabio , Marenghi Cristina , Roobol Monique J. , Venderbos Lionne D. F.
Published: July 2022

Background

Men diagnosed with localized prostate cancer (PCa) on active surveillance (AS) have shown to cope with anxiety caused by living with an ‘untreated cancer’ and different factors can influence the tolerance level for anxiety in these patients. The present study analyzes Italian (Milan) and Dutch (Rotterdam) men prospectively included in the Prostate cancer International Active Surveillance (PRIAS) trial, aiming to explore whether socio-demographic factors (i.e. age, relationship status, education, nationality) may be relevant factors in conditioning the level of anxiety at AS entry and over time.

Methods

Italian and Dutch men participating in the IRB-approved PRIAS study, after signing an informed consent, filled in the Memorial Anxiety Scale for PCa (MAX-PC) at multiple time points after diagnosis. A linear mixed model was used to assess the relationship between the level of patient’s anxiety and time spent on AS, country of origin, the interaction between country and time on AS, patients’ relationship status and education, on PCa anxiety during AS.

Results

823 MAX-PC questionnaires were available for Italian and 307 for Dutch men, respectively. Median age at diagnosis was 64 years (IQR 60–70 years) and did not differ between countries. On average, Dutch men had a higher total MAX-PC score than Italian men. However, the level of their anxiety decreased over time. Dutch men on average had a higher score on the PCa anxiety sub-domain, which did not decrease over time. Minimal differences were observed in the sub-domains PSA anxiety and fear of recurrence.

Conclusion

Significant differences in PCa anxiety between the Italian and Dutch cohorts were observed, the latter group of men showing higher overall levels of anxiety. These differences were not related to the socio-demographic factors we studied. Although both PRIAS-centers are dedicated AS-centers, differences in PCa-care organization (e.g. having a multidisciplinary team) may have contributed to the observed different level of anxiety at the start and during AS.

Trial registration This study is registered in the Dutch Trial Registry (www.trialregister.nl) under NL1622 (registration date 11-03-2009), ‘PRIAS: Prostate cancer Research International: Active Surveillance—guideline and study for the expectant management of localized prostate cancer with curative intent’.
Pericardial malignant infiltration as the cause of sudden death of a patient with metastatic urothelial carcinoma treated with atezolizumab
Authors: Palacka Patrik , Janega Pavol , Polakova Hana , Slopovsky Jan , De Angelis Valentina , Mego Michal
Published: July 2022

Background

Muscle-infiltrating urothelial carcinoma of the bladder is the most common genitourinary cancer. Immunotherapeutic agents targeting protein-1 programmed death or protein-1 programmed death ligand are currently considered the standard treatment in patients with either inoperable locally advanced or metastatic urothelial carcinoma (MUC) after platinum-based chemotherapy failure.

Case presentation

Here we report the case of a Caucasian male patient with metastatic urothelial carcinoma treated with second-line atezolizumab within a trial who achieved complete response by computed tomography (CT), but suddenly died due to cardiac tamponade resulting from malignant pericardial infiltration. Histopathology confirmed this as the only site of disease progression.

Conclusions

Cardiovascular toxicity of atezolizumab was considered within differential diagnoses, however histopathological examination revealed progression of malignancy in the pericardium as the cause of the sudden death. This is the first published case report of a patient treated with second-line atezolizumab in whom the rare disease progression of pericardial infiltration was confirmed. Despite its rarity, the clinicians should always consider the possibility of pericardial metastases.
Sleep and work functioning in nurses undertaking inpatient shifts in a blue-depleted light environment
Authors: Kjørstad Kaia , Faaland Patrick M. , Sivertsen Børge , Kallestad Håvard , Langsrud Knut , Vethe Daniel , Vestergaard Cecilie L. , Harris Anette , Pallesen Ståle , Scott Jan , Vedaa Øystein
Published: July 2022

Background

Blue-depleted light environments (BDLEs) may result in beneficial health outcomes for hospital inpatients in some cases. However, less is known about the effects on hospital staff working shifts. This study aimed to explore the effects of a BDLE compared with a standard hospital light environment (STLE) in a naturalistic setting on nurses’ functioning during shifts and sleep patterns between shifts.

Methods

Twenty-five nurses recruited from St. Olavs Hospital in Trondheim, Norway, completed 14 days of actigraphy recordings and self-reported assessments of sleep (e.g., total sleep time/sleep efficiency) and functioning while working shifts (e.g., mood, stress levels/caffeine use) in two different light environments. Additionally, participants were asked to complete several scales and questionnaires to assess the symptoms of medical conditions and mental health conditions and the side effects associated with each light environment.

Results

A multilevel fixed-effects regression model showed a within-subject increase in subjective sleepiness (by 17%) during evening shifts in the BDLE compared with the STLE (p = .034; Cohen’sd = 0.49) and an 0.2 increase in number of caffeinated beverages during nightshifts in the STLE compared with the BDLE (p = .027; Cohen’sd = 0.37). There were no significant differences on any sleep measures (either based on sleep diary data or actigraphy recordings) nor on self-reported levels of stress or mood across the two conditions. Exploratory between-group analyses of questionnaire data showed that there were no significant differences except that nurses working in the BDLE reported perceiving the lighting as warmer (p = .009) and more relaxing (p = .023) than nurses working in the STLE.

Conclusions

Overall, there was little evidence that the change in the light environment had any negative impact on nurses’ sleep and function, despite some indication of increased evening sleepiness in the BDLE. We recommend further investigations on this topic before BDLEs are implemented as standard solutions in healthcare institutions and propose specific suggestions for designing future large-scale trials and cohort studies.

Trial registration

The study was registered before data collection was completed on the ISRCTN website (ISRCTN21603406).
Circulating metabolites and molecular lipid species are associated with future cardiovascular morbidity and mortality in type 1 diabetes
Authors: Ferreira-Divino Luis F. , Suvitaival Tommi , Rotbain Curovic Viktor , Tofte Nete , Trošt Kajetan , Mattila Ismo M. , Theilade Simone , Winther Signe A. , Hansen Tine W. , Frimodt-Møller Marie , Legido-Quigley Cristina , Rossing Peter
Published: July 2022

Background

Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes.

Methods

The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use.

Results

Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01–1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67–0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70–0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59–0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58–0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04–1.68], p = 0.02), was associated with an increased risk.

Conclusions

Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes.
Slc2a6 regulates myoblast differentiation by targeting LDHB
Authors: Jiang Xuan , Feng Ninghan , Zhou Yizhou , Ye Xianlong , Wang Rong , Zhang Jingwei , Cui Siyuan , Ji Siyu , Chen Yongquan , Zhu Shenglong
Published: July 2022

Background

Type 2 diabetes mellitus is a global health problem. It often leads to a decline in the differentiation capacity of myoblasts and progressive loss of muscle mass, which in turn results in deterioration of skeletal muscle function. However, effective therapies against skeletal muscle diseases are unavailable.

Methods

Skeletal muscle mass and differentiation ability were determined in db/+ and db/db mice. Transcriptomics and metabolomics approaches were used to explore the genetic mechanism regulating myoblast differentiation in C2C12 myoblasts.

Results

In this study, the relatively uncharacterized solute carrier family gene Slc2a6 was found significantly up-regulated during myogenic differentiation and down-regulated during diabetes-induced muscle atrophy. Moreover, RNAi of Slc2a6 impaired the differentiation and myotube formation of C2C12 myoblasts. Both metabolomics and RNA-seq analyses showed that the significantly differentially expressed genes (e.g., LDHB) and metabolites (e.g., Lactate) during the myogenic differentiation of C2C12 myoblasts post-Slc2a6-RNAi were enriched in the glycolysis pathway. Furthermore, we show that Slc2a6 regulates the myogenic differentiation of C2C12 myoblasts partly through the glycolysis pathway by targeting LDHB, which affects lactic acid accumulation.

Conclusion

Our study broadens the understanding of myogenic differentiation and offers the Slc2a6-LDHB axis as a potential therapeutic target for the treatment of diabetes-associated muscle atrophy.
Combinatorial targeting of a chromatin complex comprising Dot1L, menin and the tyrosine kinase BAZ1B reveals a new therapeutic vulnerability of endocrine therapy-resistant breast cancer
Authors: Salvati Annamaria , Melone Viola , Sellitto Assunta , Rizzo Francesca , Tarallo Roberta , Nyman Tuula A. , Giurato Giorgio , Nassa Giovanni , Weisz Alessandro
Published: July 2022

Background

Targeting vulnerabilities of cancer cells by inhibiting key regulators of cell proliferation or survival represents a promising way to overcome resistance to current therapies. In breast cancer (BC), resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor alpha (ERα) signaling to the genome. Targeting components of the ERα pathway in these tumors represents, therefore, a rational way toward effective new treatments. Interaction proteomics identified several proteins associated with ERα in BC cells, including epigenetic complexes controlling gene transcription comprising the scaffold protein menin and the histone methyltransferase Dot1L.

Methods

We combined chromatin immunoprecipitation, transcriptome sequencing, siRNA-mediated gene knockdown (kd), pharmacological inhibition coupled to cellular and functional assays and interaction proteomics in antiestrogen (AE)-sensitive and AE-resistant human BC cell models to: map menin and Dot1L chromatin localization, search for their common and specific target genes, measure the effects of single or combinatorial knockdown or pharmacological inhibition of these proteins on cell proliferation and survival, and characterize their nuclear interactomes.

Results

Dot1L and menin associate in MCF-7 cells chromatin, where they co-localize in a significant fraction of sites, resulting in co-regulation of genes involved, among others, in estrogen, p53, HIF1α and death receptor signaling, regulation of cell cycle and epithelial-to-mesenchymal transition. Specific inhibitors of the two factors synergize with each other for inhibition of cell proliferation of AE (tamoxifen or fulvestrant)-sensitive and AE-resistant BC cells. Menin and Dot1L interactomes share a sizeable fraction of their nuclear partners, the majority being known BC fitness genes. Interestingly, these include B-WICH and WINAC complexes that share BAZ1B, a bromodomain protein comprising a tyrosine–protein kinase domain playing a central role in chromatin remodeling and transcriptional regulation. BAZ1B kd caused significant inhibition of ERα expression, proliferation and transcriptome changes resulting in inhibition of estrogen, myc, mTOR, PI3K and AKT signaling and metabolic pathways in AE-sensitive and AE-resistant BC cells.

Conclusions

Identification of a functional interplay between ERα, Dot1L, menin and BAZ1B and the significant effects of their co-inhibition on cell proliferation and survival in cell models of endocrine therapy-resistant BC reveal a new therapeutic vulnerability of these aggressive diseases.
Effect of menopausal hormone therapy on methylation levels in early and late postmenopausal women
Authors: Hilser James R. , Hartiala Jaana A. , Sriprasert Intira , Kono Naoko , Cai Zhiheng , Karim Roksana , DeYoung Joseph , Mack Wendy J. , Hodis Howard N. , Allayee Hooman
Published: July 2022

Background

Cardiovascular disease (CVD) remains the leading cause of death among postmenopausal women but standard primary prevention strategies in women are not as effective as in men. By comparison, the Early versus Late Intervention Trial with Estradiol (ELITE) study demonstrated that hormone therapy (HT) was associated with significant reduction in atherosclerosis progression in women who were within six years of menopause compared to those who were 10 or more years from menopause. These findings are consistent with other studies showing significant reductions in all-cause mortality and CVD with HT, particularly when initiated in women younger than 60 years of age or within 10 years since menopause. To explore the biological mechanisms underlying the age-related atheroprotective effects of HT, we investigated changes in methylation of blood cells of postmenopausal women who participated in ELITE.

Results

We first validated the epigenetic data generated from blood leukocytes of ELITE participants by replicating previously known associations between smoking and methylation levels at previously identified CpG sites, such as cg05575921 at theAHRRlocus. An epigenome-wide association study (EWAS) evaluating changes in methylation through interactions with time-since-menopause and HT revealed two significantly associated CpG sites on chromosomes 12 (cg19552895;p = 1.1 × 10–9) and 19 (cg18515510;p = 2.4 × 10–8). Specifically, HT resulted in modest, but significant, increases in methylation levels at both CpGs but only in women who were 10 or more years since menopause and randomized to HT. Changes in carotid artery intima-media thickness (CIMT) from baseline to 36 months after HT were not significantly correlated with changes in methylation levels at either cg19552895 or cg18515510. Evaluation of other previously identified CpG sites at which methylation levels in either blood or vascular tissue were associated with atherosclerosis also did not reveal any differences in methylation as a function of HT and time-since-menopause or with changes in CIMT.

Conclusions

We identified specific methylation differences in blood in response to HT among women who were 10 or more years since menopause. The functional consequence of these change with respect to atherosclerosis progression and protective effects of HT remains to be determined and will require additional studies.
Imbalance of flight–freeze responses and their cellular correlates in the Nlgn3−/y rat model of autism
Authors: Anstey Natasha J. , Kapgal Vijayakumar , Tiwari Shashank , Watson Thomas C. , Toft Anna K. H. , Dando Owen R. , Inkpen Felicity H. , Baxter Paul S. , Kozić Zrinko , Jackson Adam D. , He Xin , Nawaz Mohammad Sarfaraz , Kayenaat Aiman , Bhattacharya Aditi , Wyllie David J. A. , Chattarji Sumantra , Wood Emma R. , Hardt Oliver , Kind Peter C.
Published: July 2022

Background

Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lackingNlgn3.

Methods

This study uses a range of behavioural tests to understand differences in fear response behaviour inNlgn3−/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype andNlgn3−/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM).

Results

We observed that, unlike the wildtype,Nlgn3−/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices fromNlgn3−/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour inNlgn3−/y than wildtype rats, indicating the functional impact of the increased cellular excitability.

Limitations

Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated withNLGN3mutations appears during the first few years of life.

Conclusions

We describe altered fear responses inNlgn3−/yrats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD.
Coats disease in adolescence and adulthood with preserved vision after laser photocoagulation monotherapy: two case reports
Authors: Adriono Gitalisa Andayani , Nadhira Andi Marsa , Mahfudz Sausan Rasyid
Published: July 2022

Background

This case report describes two rare cases of Coats disease in nonjuvenile patients with preserved vision.

Case presentation

Two otherwise healthy Asian males aged 15 and 29 years old presented with unilateral gradual blurred vision and scotoma, respectively. Visual acuity was 6/6 (0 logMAR) with no other abnormalities observed in the anterior segment of the eyes. Both posterior segment examinations and fluorescein angiography revealed retinal telangiectatic vessels, exudation, and hemorrhage. Additionally, optical coherence tomography of the first patient showed subfoveal fluid. Both patients were diagnosed with stage 2 Coats disease. Laser photocoagulation was performed on both patients. The first patient showed initial good response to therapy with resolution of the subfoveal fluid; however, he developed cataract and underwent cataract surgery after 3 years. In the second case, although the exudates and hemorrhage still persisted, the macula was spared and the patient did not have visual complaints. No adverse events were reported, and final visual acuity of both patients remained 6/6.

Conclusions

Coats disease in adolescence and adulthood may present with good vision. In mild and moderate cases of Coats disease, laser photocoagulation monotherapy may help preserve vision. Nevertheless, as recurrences and complications may still occur later in life, lifelong monitoring is recommended.
Smoking and drinking behavior, knowledge, and attitudes among urban and rural public-school students in Efate Island, Vanuatu: a comparative study
Authors: Nakaseko Emi , Kotera Sayaka , Nakazawa Minato
Published: July 2022

Background

Underage smoking and drinking are public health issues in Vanuatu. This study aims to describe the behavior, knowledge, attitudes, and perceptions of parents, siblings, and peers regarding smoking and drinking among urban and rural public-school students in Vanuatu.

Methods

This cross-sectional study included 358 students (urban, 217; rural, 141; aged 12–14 years) from the public schools in Efate Island, Vanuatu. Data were collected using self-administered questionnaires. Chi-square and Mann–Whitney U tests were used to determine the rural–urban differences.

Results

Urban students showed a higher prevalence of ever smoking (13.5%), ever drinking (16.9%), intention to smoke (11.1%), and intention to drink (14.0%) compared to rural students (10.3%, 8.3%, 5.8%, and 9.5%, respectively); although a significant difference was only observed in the prevalence of ever drinking. Urban students were more likely to be aware of the health hazards of substance use and showed higher self-efficacy to refuse tobacco and alcohol compared to rural students. Parents in rural areas were less likely to talk about the health hazards of substance use with their children and were more likely to offer tobacco or alcohol to them compared to parents in urban areas.

Conclusions

The results provide evidence of rural–urban differences in the behavior, attitude, knowledge, and perceptions of parental behavior regarding smoking and drinking. The findings suggest that issues related to underage smoking and drinking differ between urban and rural students. Future intervention programs for reducing underage smoking and drinking should be adapted in recognition of urban and rural differences.
Compressive Behavior of Concrete Containing Glass Fibers and Confined with Glass FRP Composites
Authors: Yahiaoui Djarir , Saadi Mohamed , Bouzid Tayeb
Published: July 2022

In this paper, numerous experimental tests were carried out to study the behavior of concrete containing glass fibers and confined with glass fiber-reinforced polymer (GFRP). Concrete specimens containing different fiber percentages ( 0.3 wt.%, 0.6 wt.%, 0.9 wt.% or 1.2 wt.%) and with different strengths of concrete (8.5 MPa, 16 MPa and 25 MPa) and different confinement levels (two, four and six layers of GFRP) were used as research parameters. The samples were tested to failure under pure axial compression. The results imply that the confinement effect with GFRP is relatively higher for concrete samples containing glass fiber (GFCC) with a percentage equal to 0.6 wt.%. The theoretical of stress ratios (fcc/fco) estimated by using existing ultimate strength models are found to be close to the experimental results for high strength of GFCC, but not close to the experimental results for low strength of GFCC.
Changes in obsessive–compulsive symptoms during inpatient treatment of anorexia nervosa
Authors: Meule Adrian , Voderholzer Ulrich
Published: July 2022

Background

Obsessive–compulsive disorder (OCD) is one of the most prevalent comorbidities in anorexia nervosa (AN). As AN is a severe, life-threatening condition, reducing obsessive–compulsive symptomatology is not the primary objective during treatment of AN and, thus, these symptoms may remain unchanged or may even increase in terms of a “symptom shift”.

Methods

In this retrospective analysis, we examined clinical records of 149 adolescents (n = 96, 64%) and adults (n = 53, 36%) with AN (6 males, 4%) who received inpatient treatment and completed the Obsessive–Compulsive Inventory–Revised at admission and discharge.

Results

Obsessive–compulsive symptoms decreased from admission to discharge, irrespective of whether patients had comorbid OCD or not. Within-person decreases in obsessive–compulsive symptoms weakly correlated with increases in body weight.

Conclusions

These results indicate that obsessive–compulsive symptoms decrease during inpatient treatment of AN although they are not primarily targeted during treatment. Furthermore, these improvements seem to be associated with general improvements in AN symptomatology, suggesting the absence of a “symptom shift”. Yet, effect sizes were small and obsessive–compulsive symptoms were still clinically elevated in patients with comorbid OCD at discharge, suggesting that these patients need OCD-specific, psychotherapeutic aftercare.
Construct validity and factor structure of the Kessler-10 in South Africa
Authors: Hoffman Jacob , Cossie Qhama , Ametaj Amantia A. , Kim Hannah H. , James Roxanne , Stroud Rocky E. , Stevenson Anne , Zingela Zukiswa , Stein Dan J. , Gelaye Bizu
Published: July 2022

Background

The Kessler Psychological Distress Scale (K-10) is a short screening tool developed to identify, with good sensitivity, non-specific psychological distress in the general population. Sensitivity and specificity of the K-10 have been examined in various clinical populations in South Africa; however, other psychometric properties, such as construct validity and factor structure, have not been evaluated. We present evidence of the prevalence and severity of psychological distress in an outpatient setting in South Africa and evaluate the internal reliability, construct validity, and factor structure of the K-10 in this population.

Methods

We explored prevalence estimates of psychological distress using previously established cutoffs and assessed the reliability (consistency) of the K-10 by calculating Cronbach’s alpha, item-total correlations and omega total and hierarchical coefficients. Construct validity and factor structure of the K-10 were examined through split-sample exploratory factor analysis (EFA) followed by confirmatory factor analysis (CFA), comparing several theoretical models and the EFA.

Results

Overall, there was low prevalence of psychological distress in our sample of 2591 adults, the majority of whom were between the ages of 18–44 (77.7%). The K-10 showed good construct validity and reliability, with a Cronbach’s alpha of 0.84 and omega total of 0.88. EFA yielded a four-factor solution with likely measurement artifacts. CFA showed that the four-factor model from EFA displayed the best comparative fit indices, but was likely overfitted. The unidimensional model with correlated errors was deemed the best fitting model based on fit indices, prior theory, and previous studies.

Conclusion

The K-10 displays adequate psychometric properties, good internal reliability, and good fit with a unidimensional-factor structure with correlated errors. Further work is required to determine appropriate cutoff values in different populations and clinical subgroups within South Africa to aid in determining the K-10’s clinical utility.
Macromolecules in polysorbate 80 for injection: an important cause of anaphylactoid reactions
Authors: Li Yue , Duan Jinlian , Xia Heng , Li Yongkun , Shu Bin , Duan Weigang
Published: July 2022

Polysorbate 80 for injection (TW80) is a common excipient used for injection whose macromolecular impurities, including those that cause anaphylactoid reactions, are frequently ignored. The main aim of this study was to prove that the macromolecular impurities in the excipient are an important cause of anaphylactoid reactions. Component A (containing macromolecules > 100 kDa), Component B (containing macromolecules from 10 to 100 kDa), and Component C (containing substances < 10 kDa) were prepaired from the original TW80 using ultrafilters. The original TW80 contained numerous substances with molecular weights > 10kD. The original TW80 and Components A and B caused strong anaphylactoid reactions in both guinea pigs and rabbits by intravenous administration. Moreover, the original TW80 and Components A and B even caused strong passive cutaneous anaphylactoid (PCA) reactions and pulmonary capillary permeability. The PCA reaction and increased permeability were partly prevented by cromolyn sodium. Additionally, the original TW80 and Components A and B caused vasodilation and severe hemolysis in vitro. The anaphylactoid reactions were associated with histamine release but not with mast cell degranulation. Nevertheless, Component C almost caused no anaphylactoid reactions or hemolysis and was weaker in the few reactions that ocurred. Taken together, these results suggest that macromolecular substances are one of the main risk factors responsible for anaphylactoid reactions and hemolysis caused by TW80.
Novel method of ancient pottery analysis based on radioactive isotope ratios: a pilot study
Authors: Długosz-Lisiecka Magdalena , Sikora Jerzy , Krystek Marcin , Płaza Dominik , Kittel Piotr
Published: July 2022

The proposed method has been applied to a multi-phased settlement complex and pottery manufacturing centre in Ostrowite in northern Poland. In this study the radioactive isotope ratios method has been applied to a set of ceramic pottery specimens from the same multi-layered archaeological site and probably produced from local raw material. The pilot radiometric research was based on: 24 Neolithic (5200–5000 BCE), 21 Early Iron Age (800–600 BCE), 4 Roman Period (100–400 CE), and 13 Middle Ages (1030–1320 CE) pottery fragments, and also 8 samples of local clay (glacial till) and 3 burned clay samples. The method shows the similarities within the ceramic material used to manufacture the pottery. The variations in the quantitative and qualitative compositions of the basic products (clay, silt, loam, sand, ash and organic admixtures) used in the preparation of the ceramic paste change the isotopic composition and activity ratios. Pottery from each ceramic manufacturing centre, based on the specific composition of the raw materials, have characteristic isotope ratios. Radioactive isotope ratios as fingerprints of ancient ceramic manufacturing centres have not yet been applied as an archaeometric method. In this study two isotope ratios have been selected and applied: 40K/228Ac and 226Ra/208Tl. All analysis have been done using gamma spectrometry system, with quality and quantity analysis of the spectrums. Low-background passive shield was used for obtain improvement of results quality. The pilot study confirms the grouping of isotope ratio results for each sample type, even in terms of similarities with the base clay material collected in this region.