bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut microenvironmental changes as a potential trigger in Parkinson’s disease through the gut–brain axis
Authors: Chen Szu-Ju , Lin Chin-Hsien
Published: July 2022

Parkinson’s disease (PD) is the second most common neurodegenerative disease attributed to the synergistic effects of genetic risk and environmental stimuli. Although PD is characterized by motor dysfunction resulting from intraneuronal alpha-synuclein accumulations, termed Lewy bodies, and dopaminergic neuronal degeneration in the substantia nigra, multiple systems are involved in the disease process, resulting in heterogenous clinical presentation and progression. Genetic predisposition to PD regarding aberrant immune responses, abnormal protein aggregation, autophagolysosomal impairment, and mitochondrial dysfunction leads to vulnerable neurons that are sensitive to environmental triggers and, together, result in neuronal degeneration. Neuropathology studies have shown that, at least in some patients, Lewy bodies start from the enteric nervous system and then spread to the central dopaminergic neurons through the gut–brain axis, suggesting the contribution of an altered gut microenvironment in the pathogenesis of PD. A plethora of evidence has revealed different gut microbiomes and gut metabolites in patients with PD compared to unaffected controls. Chronic gut inflammation and impaired intestinal barrier integrity have been observed in human PD patients and mouse models of PD. These observations led to the hypothesis that an altered gut microenvironment is a potential trigger of the PD process in a genetically susceptible host. In this review, we will discuss the complex interplay between genetic factors and gut microenvironmental changes contributing to PD pathogenesis.
Oncogenic roles of the lncRNA LINC00460 in human cancers
Authors: Su Min , Tang Jinming , Yang Desong , Wu Zhining , Liao Qianjin , Wang Hui , Xiao Yuhang , Wang Wenxiang
Published: July 2022

Long noncoding RNAs (lncRNAs) represent an important group of endogenous RNAs with limit protein-encoding capability, with a length of more than 200 nucleotides. Emerging evidence have demonstrated that lncRNAs are greatly involved in multiple cancers by playing critical roles in tumor initiation and progression. Long intergenic non-protein coding RNA 460 (LINC00460), a novel cancer-related lncRNA, exhibits abnormal expression and oncogenic function in multiple cancers, and positively correlates with poor clinical characteristics of cancer patients. LINC00460 has also been shown to be a promising biomarker for diagnosis as well as prognostic evaluation in cancer patients. In this review, we briefly summarized recent knowledge on the expression, functional roles, molecular mechanisms, and diagnostic and prognostic values of LINC00460 in human malignancies.
Experiences of living with type 2 diabetes in Pakistan: the role of culture and family in physical activity
Authors: Tariq Omama , Rosten Claire , Huber Jörg
Published: July 2022

Background

Diabetes-related guidelines recommend lifestyle changes for people living with type 2 diabetes (PLwD). In South Asian (SA) families, cultural and contextual expectations often influence people’s decisions. However, broad explanations provided in the existing literature and theories concerning family involvement can increase the chance of health professionals overlooking the complexities of family roles within SA communities. Previous literature has identified the need to examine the perspectives of PLwD and their family members in Pakistan to shed light on factors perceived to support and hinder recommended physical activity (PA) to manage type 2 diabetes. This study explored (1) the enablers of and barriers to PA in the context of PLwD in Pakistan and (2) family involvement regarding PLwD’s engagement with PA.

Methods

Semi-structured interviews were conducted with 30 PLwD and 17 family members of PLwD who were recruited in metropolitan Lahore (Pakistan) and primarily used state health services available to relatively disadvantaged populations. Interviews were transcribed and analysed using thematic analysis.

Results

Three themes were identified: (1) Going for a walk as a feasible PA; (2) the role of family members in influencing PA; and (3) gender differences and cultural acceptability of an activity. PA enablers for PLwD consist of gender-specific opportunities for activity facilitated by peers and family members. Culturally acceptable opportunities for PA in Pakistan for specific genders and age groups within the socio-cultural context constituted an essential factor. In this study, all women with diabetes described walking as the only acceptable form of PA, whereas some men mentioned other activities such as running, playing cricket, and cycling.

Conclusions

Medical guidelines must consider patients’ daily routines, account for cultural and familial expectations of different genders and age groups, and address social and physical barriers encountered by these different groups to encourage PA among PLwD in SA cultures.
Neuropsychology and MRI correlates of neurodegeneration in SPG11 hereditary spastic paraplegia
Authors: Utz Kathrin S. , Kohl Zacharias , Marterstock Dominique Cornelius , Doerfler Arnd , Winkler Jürgen , Schmidt Manuel , Regensburger Martin
Published: July 2022

Background

SPG11-linked hereditary spastic paraplegia is characterized by multisystem neurodegeneration leading to a complex clinical and yet incurable phenotype of progressive spasticity and weakness. Severe cognitive symptoms are present in the majority of SPG11 patients, but a systematic and multidimensional analysis of the neuropsychological phenotype in a larger cohort is lacking. While thinning of the corpus callosum is a well-known structural hallmark observed in SPG11 patients, the neuroanatomical pattern of cortical degeneration is less understood. We here aimed to integrate neuropsychological and brain morphometric measures in SPG11.

Methods

We examined the neuropsychological profile in 16 SPG11 patients using a defined neuropsychological testing battery. Long-term follow up testing was performed in 7 patients. Cortical and subcortical degeneration was analyzed using an approved, artificial intelligence based magnetic resonance imaging brain morphometry, comparing patients to established reference values and to matched controls.

Results

In SPG11 patients, verbal fluency and memory as well as frontal-executive functions were severely impaired. Later disease stages were associated with a global pattern of impairments. Interestingly, reaction times correlated significantly with disease progression. Brain morphometry showed a significant reduction of cortical and subcortical parenchymal volume following a rostro-caudal gradient in SPG11. Whereas performance in memory tasks correlated with white matter damage, verbal fluency measures showed strong associations with frontal and parietal cortical volumes.

Conclusions

The present data will help define neuropsychological and imaging read out parameters in early as well as in advanced clinical stages for future interventional trials in SPG11.
Natural history of Type 1 spinal muscular atrophy: a retrospective, global, multicenter study
Authors: Cances Claude , Vlodavets Dmitry , Comi Giacomo Pietro , Masson Riccardo , Mazurkiewicz-Bełdzińska Maria , Saito Kayoko , Zanoteli Edmar , Dodman Angela , El-Khairi Muna , Gorni Ksenija , Gravestock Isaac , Hoffart Janine , Scalco Renata S. , Darras Basil T. ,   the ANCHOVY Working Group, Alberti Katia , Baranello Giovanni , Barisic Nina , Brolatti Noemi , Bruno Claudio , Cances Claude , Comi Giacomo Pietro , Darras Basil T. , Deconinck Nicolas , Vos Elke , De Waele Liesbeth , Dodman Angela , Dosi Claudia , El-Khairi Muna , Engelbrekt Amanda , Goemans Nathalie , Gorni Ksenija , Govoni Alessandra , Gravestock Isaac , Haginoya Kazuhiro , Hoffart Janine , Kotulska-Jozwiak Katarzyna , Goff Laure Le , Levine Alexis , Manel Saidi , Masson Riccardo , Mastella Chiara , Mauri Eleonora , Mazurkiewicz-Bełdzińska Maria , Meneri Megi , Moroni Isabella , Pierzchlewicz Katarzyna , Portefaix Aurelie , Prufer Alexandra , Rauso Myriam , Saito Kayoko , Scalco Renata S. , Schembri Veronica , Sicolo Mariangela , Tahon Valentine , Tomas Josipa , Vincent-Genod Dominique , Vlodavets Dmitry , Vuillerot Carole , Yotsumata Kazuyuki , Zanoteli Edmar
Published: July 2022

Background

ANCHOVY was a global, multicenter, chart-review study that aimed to describe the natural history of Type 1 spinal muscular atrophy (SMA) from a broad geographical area and provide further contextualization of results from the FIREFISH (NCT02913482) interventional study of risdiplam treatment in Type 1 SMA.

Methods

Data were extracted from medical records of patients with first symptoms attributable to Type 1 SMA between 28 days and 3 months of age, genetic confirmation of SMA, and confirmed survival of motor neuron 2 copy number of two or unknown. The study period started on 1 January 2008 for all sites; study end dates were site-specific due to local treatment availabilities. Primary endpoints were time to death and/or permanent ventilation and proportion of patients achieving motor milestones. Secondary endpoints included time to initiation of respiratory and feeding support.

Results

Data for 60 patients from nine countries across Asia, Europe and North and South America were analyzed. The median age (interquartile range [IQR]) for reaching death or permanent ventilation was ~ 7.3 (5.9–10.5) months. The median age (IQR) at permanent ventilation was ~ 12.7 (6.9–16.4) months and at death was ~ 41.2 (7.3–not applicable) months. No patients were able to sit without support or achieved any level of crawling, standing or walking.

Interpretation

Findings from ANCHOVY were consistent with published natural history data on Type 1 SMA demonstrating the disease’s devastating course, which markedly differed from risdiplam-treated infants (FIREFISH Part 2). The results provide meaningful additions to the literature, including a broader geographical representation.
DNA methylation and transcriptomic features are preserved throughout disease recurrence and chemoresistance in high grade serous ovarian cancers
Authors: Gull Nicole , Jones Michelle R. , Peng Pei-Chen , Coetzee Simon G. , Silva Tiago C. , Plummer Jasmine T. , Reyes Alberto Luiz P. , Davis Brian D. , Chen Stephanie S. , Lawrenson Kate , Lester Jenny , Walsh Christine , Rimel Bobbie J. , Li Andrew J. , Cass Ilana , Berg Yonatan , Govindavari John-Paul B. , Rutgers Joanna K. L. , Berman Benjamin P. , Karlan Beth Y. , Gayther Simon A.
Published: July 2022

Background

Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC).

Methods

We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations.

Results

Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P = 0.006) in these BRCA1/2 carriers.

Conclusion

These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even after extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.
EIF2B2 gene mutation causing early onset vanishing white matter disease: a case report
Authors: Filareto Ilaria , Cinelli Giulia , Scalabrini Ilaria , Caramaschi Elisa , Bergonzini Patrizia , Spezia Elisabetta , Todeschini Alessandra , Iughetti Lorenzo
Published: July 2022

Background

Leukoencephalopathy with vanishing white matter (VWM) is an autosomal recessive neurological disease. The physiopathology of disease is still little understood, but it seems to involve impairment in maturation of astrocytes; as a consequence white matter is more prone to cellular stress. Disease is caused by mutations in five genes encoding subunits of the translation initiation factor eIF2B. We know five different types of VWM syndrome classified based different ages of onset (prenatal, infantile, childhood, juvenile and adult onset).

Case presentation

We report the case of a 4-month-old boy with early seizure onset, recurrent hypoglycemia and post mortem diagnosis of vanishing white matter disease (VMD). At the admission he presented suspected critical episodes, resolved after intravenous administration of benzodiazepines. The brain MRI showed total absence of myelination that suggested hypomyelination leukoencephalopathy. The whole exome sequencing (WES) revealed a variant of EIF2B2 gene (p. Val308Met) present in homozygosity. In this case report we also describe the clinical evolution of seizures, in fact the epileptic seizures had a polymorphic aspect, from several complex partial seizures secondarily generalized to status epilepticus.

Conclusion

Infantile and early childhood onset forms are associated with chronic progressive neurological signs, with episodes of rapid neurological worsening, and poor prognosis, with death in few months or years. Clinical presentation of epilepsy is poorly documented and do not include detailed information about the type, time of onset and severity of seizures. No therapeutic strategies for VWM disease have been reported.
Ketamine for acute pain after trauma: the KAPT randomized controlled trial
Authors: Puzio Thaddeus J. , Klugh James , Wandling Michael W. , Green Charles , Balogh Julius , Prater Samuel J. , Stephens Christopher T. , Sergot Paulina B. , Wade Charles E. , Kao Lillian S. , Harvin John A.
Published: July 2022

Background

Evidence for effective pain management and opioid minimization of intravenous ketamine in elective surgery has been extrapolated to acutely injured patients, despite limited supporting evidence in this population. This trial seeks to determine the effectiveness of the addition of sub-dissociative ketamine to a pill-based, opioid-minimizing multi-modal pain regimen (MMPR) for post traumatic pain.

Methods

This is a single-center, parallel-group, randomized, controlled comparative effectiveness trial comparing a MMPR to a MMPR plus a sub-dissociative ketamine infusion. All trauma patients 16 years and older admitted following a trauma which require intermediate (IMU) or intensive care unit (ICU) level of care are eligible. Prisoners, patients who are pregnant, patients not expected to survive, and those with contraindications to ketamine are excluded from this study. The primary outcome is opioid use, measured by morphine milligram equivalents (MME) per patient per day (MME/patient/day). The secondary outcomes include total MME, pain scores, morbidity, lengths of stay, opioid prescriptions at discharge, and patient centered outcomes at discharge and 6 months.

Discussion

This trial will determine the effectiveness of sub-dissociative ketamine infusion as part of a MMPR in reducing in-hospital opioid exposure in adult trauma patients. Furthermore, it will inform decisions regarding acute pain strategies on patient centered outcomes.

Trial registration

The Ketamine for Acute Pain Management After Trauma (KAPT) with registration # NCT04129086 was registered on October 16, 2019.
Underrepresentation of ethnic minorities in hypertension research—a survey of enablers and barriers among South Asian and African communities in Glasgow
Authors: Lip Stefanie , Dempster Georgia , Jain Sahil , Brooksbank Katriona , Ghouri Nazim , McCallum Linsay , Padmanabhan Sandosh
Published: July 2022

Background

Hypertension is the biggest contributor to the global cardiovascular burden with evidence for ethnic differences in treatment response and outcomes. Under-representation of ethnic minorities in clinical research is well known, and despite wide-ranging public engagement events by the Glasgow Blood Pressure Clinic team, there was a lack of participation of ethnic minorities in both engagement activities and clinical trials conducted by them. This study aims to explore the awareness and knowledge of hypertension and the facilitators and barriers to participation in hypertension clinical research among South Asian (SA) and African (AFR) communities in Glasgow.

Methods

A survey questionnaire was co-developed with representatives from South Asian (SA) and African (AFR) patients and community members in Glasgow to understand awareness and knowledge of hypertension and enablers and barriers to participation in clinical research. The survey was distributed to adults (aged > 18) years of SA or AFR ancestry at public engagement events at venues that were frequently visited by these two communities in Glasgow.

Results

The survey response rate was 337 (67.4%) consisting of 242 (71.8%) South Asian (SA) and 56 (16.9%) African (AFR) respondents. Thirty-nine questionnaires were excluded because of incompletion. Most of the respondents were not born in the UK and were in the 35–53-year group (AFR 29 (51%), SA 113 (47%)). The proportion living in the most deprived (SIMD 1) and least deprived (SIMD 5) was respectively 26 (12.4%) and 34 (16.2%) for SA and 20 (42.6%) and 2 (4.3%) for AFR. There was a considerable recognition that treatment needs to be ethnicity-specific (SA/AFR = 107 (48%)/23 (45.1%)) and that current cardiovascular disease treatment guidelines were not tailored for different ethnicities 84 (38.5%)/23 (45.1%). The key enablers encouraging research participation are enhanced health information, conducting aspects of their clinical research visits/appointments at a location they frequently visited and allowing a family member to accompany them. Barriers included concerns about the use of personal information and side effects of the new treatment.

Conclusion

Our survey confirmed enablers and barriers to ethnic minority participation in research. We find improving and evolving awareness and beliefs among the ethnic minority population including community leaders. Thus, continual review of researchers’ beliefs and attitudes is also essential to ensure engagement activities keep up with these changing perceptions.
Efficacy and safety of progressively reducing biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis in persistent remission: a study protocol for a non-inferiority randomized, controlled, single-blind trial
Authors: Lei Shangwen , Li Zijia , Zhang Xiaoli , Zhou Shuhong
Published: July 2022

Background

To compare the effects of two biologic disease-modifying antirheumatic drug (bDMARD) administration strategies on the maintenance effect and safety of patients with rheumatoid arthritis (RA) in remission, to analyze the effects of gradual drug reduction and dose maintenance treatment on clinical outcomes in patients who have achieved remission with different types of bDMARDs, to search and screen out people who may benefit from drug reduction strategies, and to provide references for drug reduction strategies and treatment options for patients with RA in remission, so as to help improve the safety of the treatment and reduce the economic burden.

Methods

The study will be a 24-month non-inferiority randomized, controlled, single-blind trial and is planned to be launched in our hospital from September 2021 to August 2023. Patients will be randomized in a ratio of 2:1 to two groups: maintenance or injection spacing by 50%/gradual reduction of dosage every 3 months up to complete stop. When the patient relapses, return to the last effective dose. If the remission can be maintained, the medication of bDMARDs can be stopped 9 months after enrollment. The primary outcome will be the persistent flare rate.

Discussion

Our study may provide a reference for the selection of drug reduction strategies and treatment options for patients with RA in remission, so as to help improve the safety of the treatment and reduce the economic burden.

Trial registration

Chinese Clinical Trial Registry ChiCTR2100044751. Registered on 26 March 2021
Effectiveness of a training intervention to improve the management of vertigo in primary care: a multicentre cluster-randomised trial, VERTAP
Authors: Patiño Jenniffer Elizabeth Pérez , Moreno José Lluís Ballvé , Matos Yolanda Rando , Ortega Jesús Almeda , Puértolas Oriol Cunillera , Muñoz Ricard Carrillo , Balboa Iván Villar , Compta Xavier González , Agudelo Olga Lucía Arias , Muñoz Sebastiá Calero , Rodríguez Vanessa Monforte , Cortes Anna Navarro , Rodríguez Eva Peguero
Published: July 2022

Background

Benign paroxysmal positional vertigo (BPPV) is the most common type of vertigo. While BPPV is best treated with canalicular repositioning manoeuvres, they are not routinely performed in primary care (PC).

Methods

To evaluate the effectiveness of blended training (online and face-to-face) on the diagnosis and management of vertigo to improve adherence of family doctors to clinical practice guidelines, we designed a community multicentre cluster-randomised open-label trial with an intervention (IG) and a control (GC) group of 10 primary care teams (PCT) each. Outcome variables will be ICD-10 diagnostic codes (proportion of nonspecific diagnoses such as dizziness and vertigo versus specific diagnoses such as BPPV, vestibular neuritis, and Menière’s disease); number of referrals to ENT or neurology specialists; prescription of antivertigo agents; and duration of sick leave due to vertigo. The baseline comparability of the two study groups will be analysed to ensure homogeneity. A description of all baseline variables will be performed. Student’s t-test will be used to evaluate the differences between the groups. Logistic regression multivariate analysis will be performed to study the relationship between baseline variables of professionals and centres with outcome variables.

Discussion

With the improvement of the diagnosis and management of vertigo by family doctors after this training, we expect an increase in the proportion of specific diagnoses, a decrease in the prescription of antivertigo agents, a decrease in referrals to ENT or neurology specialists and a reduction in the duration of sick leave due to temporary disability. The blended training will be easily expanded within primary care services, since it is mainly delivered online, with a single face-to-face session to ensure that the manoeuvres have been adequately learned.

Trial registration

ClinicalTrials.govNCT04929444. Registered June 18, 2021. This protocol has been approved by the Ethics Committee of the Institut Universitari d’Investigació en Atenció Primària Jordi Gol (IDIAP Jordi Gol) with the code 20/004-P. All patient data will be anonymised in agreement with the 2016/679 European Regulation.
Comparing the effect of a lactation-specific relaxation and visualisation intervention versus standard care on lactation and mental health outcomes in mothers of very premature infants (the EXPRESS trial): study protocol for a multi-centre, unmasked, randomised, parallel-group trial
Authors: Levene Ilana , Bell Jennifer L. , Cole Christina , Stanbury Kayleigh , O’Brien Frances , Fewtrell Mary , Quigley Maria A.
Published: July 2022

Background

Premature birth is the leading cause of neonatal death and can cause major morbidity. Maximising the amount of maternal breastmilk given to very premature infants is important to improve outcomes, but this can be challenging for parents. Parents of infants receiving neonatal care also have high rates of anxiety and distress. There is growing evidence for the impact of maternal relaxation interventions on lactation, as well as mental health. The trial will assess whether a brief self-directed relaxation and visualisation intervention, recommended for use several times a day during expression of milk, improves lactation and mental health outcomes for mothers of very premature infants.

Methods

Multi-centre, randomised, controlled, unmasked, parallel-group trial with planned 132 participants who have experienced premature birth between 23 weeks and 31 weeks and 6 days of gestation and plan to express milk for at least 14 days. The primary outcome is the highest 24-h expressed milk yield recorded on any of day 4, day 14 or day 21 after birth. Secondary outcomes include exclusive breastmilk feeding at 36 weeks post-menstrual age and at 4 months after the estimated date of delivery, Spielberger State Trait Anxiety Index at day 21 and Post-traumatic stress Check List (for DSM 5) at day 21.

Discussion

Breastmilk feeding for premature infants is an important research priority, but there are few randomised controlled trials assessing interventions to help parents reach lactation goals in this challenging context. This trial will assess whether a no cost, easily scalable relaxation tool has a role in this setting. Given the lack of harm and potential for immediate dissemination, even a small benefit could have an important global impact.

Trial registration

ISRCTN16356650. Date assigned: 19/04/2021.
Population genetics and genetic variation of Ctenocephalides felis and Pulex irritans in China by analysis of nuclear and mitochondrial genes
Authors: Zhang Yu , Nie Yu , Li Le-Yan , Chen Shu-Yu , Liu Guo-Hua , Liu Wei
Published: July 2022

Background

Fleas are the most economically significant blood-feeding ectoparasites worldwide. Ctenocephalides felis and Pulex irritans can parasitize various animals closely related to humans and are of high veterinary significance.

Methods

In this study, 82 samples were collected from 7 provinces of China. Through studying the nuclear genes ITS1 and EF-1α and two different mitochondrial genes cox1 and cox2, the population genetics and genetic variation of C. felis and P. irritans in China were further investigated.

Results

The intraspecies differences between C. felis and P. irritans ranged from 0 to 3.9%. The interspecific variance in the EF-1α, cox1, and cox2 sequences was 8.2–18.3%, while the ITS1 sequence was 50.1–52.2%. High genetic diversity was observed in both C. felis and P. irritans, and the nucleotide diversity of cox1 was higher than that of cox2. Moderate gene flow was detected in the C. felis and P. irritans populations. Both species possessed many haplotypes, but the haplotype distribution was uneven. Fu's Fs and Tajima's D tests showed that C. felis and P. irritans experienced a bottleneck effect in Guangxi Zhuang Autonomous Region and Henan province. Evolutionary analysis suggested that C. felis may have two geographical lineages in China, while no multiple lineages of P.irritans were found.

Conclusions

Using sequence comparison and the construction of phylogenetic trees, we found a moderate amount of gene flow in the C. felis and P. irritans populations. Both species possessed many haplotypes, but the distribution of haplotypes varied among the provinces. Fu’s Fs and Tajima’s D tests indicated that both species had experienced a bottleneck effect in Guangxi and Henan provinces. Evolutionary analysis suggested that C. felis may have two geographical lineages in China, while no multiple lineages of P.irritans were found. This study will help better understand fleas' population genetics and evolutionary biology.

Graphical Abstract
Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways
Authors: Ibanez Kristen R. , McFarland Karen N. , Phillips Jennifer , Allen Mariet , Lessard Christian B. , Zobel Lillian , De La Cruz Elsa Gonzalez , Shah Shivani , Vo Quan , Wang Xue , Quicksall Zachary , Ryu Daniel , Funk Cory , Ertekin-Taner Nilüfer , Prokop Stefan , Golde Todd E. , Chakrabarty Paramita
Published: July 2022

Background

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimer’s disease (AD), but little is known about its function in relation to AD pathogenesis.

Methods

Here, we use a mouse model that is deficient in Abi3 locus to study how the loss of function of Abi3 impacts two cardinal neuropathological hallmarks of AD—amyloid β plaques and tau pathology. Our study employs extensive neuropathological and transcriptomic characterization using transgenic mouse models and adeno-associated virus-mediated gene targeting strategies.

Results

Analysis of bulk RNAseq data confirmed age-progressive increase in Abi3 levels in rodent models of AD-type amyloidosis and upregulation in AD patients relative to healthy controls. Using RNAscope in situ hybridization, we localized the cellular distribution of Abi3 in mouse and human brains, finding that Abi3 is expressed in both microglial and non-microglial cells. Next, we evaluated Abi3−/− mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Using multiple transcriptomic datasets, we show that expression of Abi3 and Gngt2 are tightly correlated in rodent models of AD and human brains, suggesting a tight co-expression relationship. RNAseq of the Abi3-Gngt2−/− mice revealed upregulation of Trem2, Plcg2, and Tyrobp, concomitant with induction of an AD-associated neurodegenerative signature, even in the absence of AD-typical neuropathology. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in Aβ deposition. Additionally, in Abi3-Gngt2−/− mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, using in vitro culture assays, we show that the AD-associated S209F mutation alters the extent of ABI3 phosphorylation.

Conclusions

These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function and early inflammatory gliosis in AD. Our studies also demonstrate that inflammatory gliosis could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting immune pathways in AD.
Aggressive angiomyxoma as a rare cause of scrotum enlargement in a 10-month-old boy: a case report
Authors: Nyandwi Léonidas , Idrissa Salahoudine , Moustapha Hellé , Ada Mahamoud Omid Ali , Boubacar Efared , Boubacar Idrissa , Abdelfatteh Zakhama , Amine Ksia , Habibou Abarchi
Published: July 2022

Background

Aggressive angiomyxoma (AAM) is a locally infiltrative mesenchymal tumour that most commonly affects the pelvis and/or perineum in adult women. AAM is very rare in males, especially in infancy.

Case presentation

A 10-month-old fulani (African) male infant was referred to our department for a large painless mass in the right testicule. The mass was detected during the neonatal period and gradually increased in size. Ultrasound examination revealed a large heterogeneous lesion; computed tomography results led to the conclusion that the mass was a mesenteric hernia. An inguinal and scrotal surgical approach was adopted. Exploratory surgery found a normal right testicle displaced upwardly and a large scrotal mass. Radical excision of the mass and orchidopexy were performed. Subsequent histology and immunohistochemstry studies indicated that the mass was a scrotal angiomyxoma. The postoperative course was uneventful. No recurrence occurred during the 6-month follow-up.

Conclusion

To the best of our knowledge, this is the youngest patient with AAM reported to date. Angiomyxoma should be included in the differential diagnosis of scrotal masses, for which radical excision is justifiable to prevent recurrence.
Oxidative stress-induced premature senescence and aggravated denervated skeletal muscular atrophy by regulating progerin–p53 interaction
Authors: Xiang Yaoxian , You Zongqi , Huang Xinying , Dai Junxi , Zhang Junpeng , Nie Shuqi , Xu Lei , Jiang Junjian , Xu Jianguang
Published: July 2022

Background

Progerin elevates atrophic gene expression and helps modify the nuclear membrane to cause severe muscle pathology, which is similar to muscle weakness in the elderly, to alter the development and function of the skeletal muscles. Stress-induced premature senescence (SIPS), a state of cell growth arrest owing to such stimuli as oxidation, can be caused by progerin. However, evidence for whether SIPS-induced progerin accumulation is connected to denervation-induced muscle atrophy is not sufficient.

Methods

Flow cytometry and a reactive oxygen species (ROS) as well as inducible nitric oxide synthase (iNOS) inhibitors were used to assess the effect of oxidation on protein (p53), progerin, and nuclear progerin–p53 interaction in the denervated muscles of models of mice suffering from sciatic injury. Loss-of-function approach with the targeted deletion of p53 was used to assess connection among SIPS, denervated muscle atrophy, and fibrogenesis.

Results

The augmentation of ROS and iNOS-derived NO in the denervated muscles of models of mice suffering from sciatic injury upregulates p53 and progerin. The abnormal accumulation of progerin in the nuclear membrane as well as the activation of nuclear progerin–p53 interaction triggered premature senescence in the denervated muscle cells of mice. The p53-dependent SIPS in denervated muscles contributes to their atrophy and fibrogenesis.

Conclusion

Oxidative stress-triggered premature senescence via nuclear progerin–p53 interaction that promotes denervated skeletal muscular atrophy and fibrogenesis.
Effects of furosemide and tracer selection on urinary activity and peri-bladder artefacts in PSMA PET/CT: a single-centre retrospective study
Authors: Donswijk Maarten L. , Wondergem Maurits , de Wit - van der Veen Linda , Bruin Natascha M. , van Leeuwen Pim J. , van der Poel Henk G. , Stokkel Marcel P. M. , Vogel Wouter V.
Published: July 2022

Background

High urinary activity in urinary bladder and ureters may hamper interpretation of prostate cancer and regional nodal metastases in prostate-specific membrane antigen (PSMA) PET/CT. The goal of this study was to assess effects of furosemide and choice of tracer on urinary activity in the bladder and ureters, as well as on occurrence of peri-bladder artefacts in PET/CT.

Methods

Four cohorts with a total of 202 men staged with PSMA PET/CT for prostate cancer received either 68Ga-PSMA-11 as tracer, with (cohort G+) or without 10mg intravenous furosemide (G−) concurrent with tracer, or 18F-DCFPyL with (F+) or without furosemide (F−). SUVmax of bladder and ureters, presence, type, and severity of peri-bladder artefacts were compared between cohorts. The influence of furosemide and choice of tracer was determined while taking differences in biodistribution time into account.

Results

Median SUVmax bladder was 43,5; 14,8; 61,7 and 22,8 in cohorts G−, G+, F− and F+, respectively, resulting in significant overall (p < 0.001) and between cohort differences (p adjusted < 0.001 to 0.003) except between G− and F+. Median SUVmax ureter was 6.4; 4.5; 8.1 and 6.0 in cohorts G−, G+, F− and F+, respectively, resulting in significant overall (p < 0.001) and between cohort differences for G+ : F− and F− : F+ (p < 0.001, respectively, 0.019). Significant effects of furosemide and choice of tracer on SUVmax bladder (p < 0.001 resp. p = 0.001) and of furosemide on SUVmax ureter (p < 0.001) were found, whereas differences in biodistribution time had not impacted these results significantly. Peri-bladder artefacts were present in 42/202 (21%) patients and were significantly more frequent in the F− cohort, respectively, less frequent in the G+ cohort (p = 0.001 resp. p < 0.001). Peri-bladder artefacts had a direct positive correlation with SUVmax bladder (p = 0.033).

Conclusions

Increased urinary activity and higher incidence of peri-bladder artefacts were found in 18F-DCFPyL compared to 68Ga-PSMA-11 PET/CT. Effective reduction of urinary activity may be reached through forced diuresis using 10mg intravenous furosemide, which is especially advantageous in 18F-DCFPyL PET/CT.
[18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer’s disease pathology in APP/PS1 mice
Authors: Hsieh Chia-Ju , Hou Catherine , Zhu Yi , Lee Ji Youn , Kohli Neha , Gallagher Evan , Xu Kuiying , Lee Hsiaoju , Li Shihong , McManus Meagan J. , Mach Robert H.
Published: July 2022

Background

Oxidative stress is implicated in the pathogenesis of the most common neurodegenerative diseases, such as Alzheimer’s disease (AD). However, tracking oxidative stress in the brain has proven difficult and impeded its use as a biomarker. Herein, we investigate the utility of a novel positron emission tomography (PET) tracer, [18F]ROStrace, as a biomarker of oxidative stress throughout the course of AD in the well-established APP/PS1 double-mutant mouse model. PET imaging studies were conducted in wild-type (WT) and APP/PS1 mice at 3 different time points, representing early (5 mo.), middle (10 mo.), and advanced (16 mo.) life (n = 6–12, per sex). Semi-quantitation SUVRs of the plateau phase (40–60 min post-injection; SUVR40–60) of ten brain subregions were designated by the Mirrione atlas and analyzed by Pmod. Statistical parametric mapping (SPM) was used to distinguish brain regions with elevated ROS in APP/PS1 relative to WT in both sexes. The PET studies were validated by ex vivo autoradiography and immunofluorescence with the parent compound, dihydroethidium.

Results

[18F]ROStrace retention was increased in the APP/PS1 brain compared to age-matched controls by 10 mo. of age (p < 0.0001) and preceded the accumulation of oxidative damage in APP/PS1 neurons at 16 mo. (p < 0.005). [18F]ROStrace retention and oxidative damages were higher and occurred earlier in female APP/PS1 mice as measured by PET (p < 0.001), autoradiography, and immunohistochemistry (p < 0.05). [18F]ROStrace differences emerged midlife, temporally and spatially correlating with increased Aβ burden (r2 = 0.30; p = 0.0016), which was also greatest in the female brain (p < 0.001).

Conclusions

[18F]ROStrace identifies increased oxidative stress and neuroinflammation in APP/PS1 female mice, concurrent with increased amyloid burden midlife. Differences in oxidative stress during this crucial time may partially explain the sexual dimorphism in AD. [18F]ROStrace may provide a long-awaited tool to stratify at-risk patients who may benefit from antioxidant therapy prior to irreparable neurodegeneration.
What lies on macroalgal surface: diversity of polysaccharide degraders in culturable epiphytic bacteria
Authors: Barbato Marta , Vacchini Violetta , Engelen Aschwin H. , Patania Giovanni , Mapelli Francesca , Borin Sara , Crotti Elena
Published: July 2022

Macroalgal surface constitutes a peculiar ecological niche and an advantageous substratum for microorganisms able to degrade the wide diversity of algal glycans. The degrading enzymatic activities of macroalgal epiphytes are of paramount interest for the industrial by-product sector and biomass resource applications. We characterized the polysaccharide hydrolytic profile of bacterial isolates obtained from three macroalgal species: the red macroalgae Asparagopsis taxiformis and Sphaerococcus coronopifolius (Rhodophyceae) and the brown Halopteris scoparia (Phaeophyceae), sampled in South Portugal. Bacterial enrichment cultures supplemented with chlorinated aliphatic compounds, typically released by marine algae, were established using as inoculum the decaying biomass of the three macroalgae, obtaining a collection of 634 bacterial strains. Although collected from the same site and exposed to the same seawater seeding microbiota, macroalgal cultivable bacterial communities in terms of functional and phylogenetic diversity showed host specificity. Isolates were tested for the hydrolysis of starch, pectin, alginate and agar, exhibiting a different hydrolytic potential according to their host: A. taxiformis showed the highest percentage of active isolates (91%), followed by S. coronopifolius (54%) and H. scoparia (46%). Only 30% of the isolates were able to degrade starch, while the other polymers were degraded by 55–58% of the isolates. Interestingly, several isolates showed promiscuous capacities to hydrolyze more than one polysaccharide. The isolate functional fingerprint was statistically correlated to bacterial phylogeny, host species and enrichment medium. In conclusion, this work depicts macroalgae as holobionts with an associated microbiota of interest for blue biotechnologies, suggesting isolation strategies and bacterial targets for polysaccharidases’ discovery.
Post-tuberculosis tracheobronchial stenosis: long-term follow-up after self-expandable metallic stents placement and development of a prediction score—the Restenosis Score
Authors: Li Fuqi , Tian Sen , Huang Haidong , Zhang Wei , Huang Yi , Wu Ning , Wang Qin , Wang Xiangqi , Dong Yuchao , Bai Chong
Published: July 2022

Background

The insertion of self-expandable metallic stents (SEMS) for post-tuberculosis tracheobronchial stenosis (PTTS) was controversial. This study aimed to evaluate the efficacy and safety of SEMS for treating PTTS, and developed a scoring system for predicting the occurrence of restenosis after stenting in PTTS patients.

Methods

We conducted a retrospective review of 87 patients who were diagnosed with PTTS and experienced SEMS insertion between January 2000 and December 2017. All procedures were performed via flexible bronchoscopy under conscious sedation and local anesthesia.

Results

A total of 85 SEMS were successfully placed in 77 patients. Comparing with pre-stenting, there were significant improvements in the lumen diameters of the stenotic segment, mMRC scale and lung function after short-term SEMS placement. During the long-term (average 163.32 months) follow-up, 48 patients (62.3%) did not develop restenosis after stenting; the other 29 patients (37.7%) developed and eventually, 12 remained under interventional therapies and 11 had bronchial atresia. Multivariate Cox regression analysis revealed that the difference value between SEMS length and the stenosis-segment length, stenosis type, and the number of pre-stenting thermal ablation were independently related to restenosis occurrence and were subsequently used to establish the Restenosis Score. The model’s development group (0.83, 95% CI 0.74–0.92) and external validation set (0.94, 95% CI 0.77–1.00) showed excellent discrimination.

Conclusion

SEMS placement could serve as a safe and effective treatment option for most patients with PTTS. Further, we built a prediction model depending on the independent predictors of restenosis occurrence, the Restenosis Score. This validated tool might provide a decision support and a better management for PTTS patients who underwent SEMS implantation.
Facilitators and barriers for harm reduction after first use of novel nicotine delivery devices: a qualitative investigation of cigarette smokers
Authors: Kinchen Gill , Cox Sharon , Kale Dimitra , Shahab Lion
Published: July 2022

Background

Novel nicotine delivery devices (NNDDs) are a safer alternative to combustible tobacco smoking. Understanding what factors can facilitate people who smoke to use NNDDs can inform intervention design and public health messaging. This study aims to explore the facilitators and barriers to NNDD use from the perspective of smokers without prior use, after trialling two NNDDs.

Method

UK adults who smoke combustible cigarettes (n = 11) were recruited from a larger quantitative study after trialling two NNDDs, an electronic cigarette and a heated tobacco product (order randomly allocated). Semi-structured interviews were conducted, transcribed and thematically analysed, using the COM-B model of behaviour and NVivo12 pro software.

Results

Five main themes were identified: health knowledge, availability of and accessibility to NNDD products, cost, social acceptance, and NNDD use experience. There was curiosity and interest in the uptake and use of NNDDs, but the absence of centralised product information was identified as a barrier. Other themes were related to the design and functionality of the NNDD products. For example, the e-cigarette with its low maintenance was seen as easier to use than the heated tobacco product, which offered too short a single use duration and was described as ‘cumbersome’. Throat discomfort and high anticipated cost were among additional barriers identified for both product types.

Conclusion

This study highlights the need for reliable objective information on the health effects of NNDDs compared with combustible cigarettes, which could facilitate their regular use. Product adjustment such as single use duration alignment with combustible cigarette smoking duration may encourage uptake. Interventions offering opportunity for experience of NNDD use and knowledge dissemination of NNDDs could increase motivation to adopt harm reducing behaviours as demonstrated in this study.
Mind full of kindness: self-awareness, self-regulation, and self-transcendence as vehicles for compassion
Authors: Miller Jacob T. , Verhaeghen Paul
Published: July 2022

Background

We investigated the relationship between mindfulness and compassion in a broader way than is typically done by (a) using a recent, comprehensive conceptualization of mindfulness as a manifold of self-awareness, self-regulation, and self-transcendence, and (b) by casting a wide net of compassion measures [i.e., the Compassionate Love for Humanity Scale (Sprecher and Fehr in J Soc Pers Relatsh 22(5):629–651, 2005); Compassion Scale (Martins et al. in J Health Care Poor Underserved 24:1235–1246, 2013); Compassion Scale (Pommier in Assessment 27:21–39, 2020); Relational Compassion Scale (Hacker in The relational compassion scale: Development and validation of a new self-rated scale for the assessment of self-other compassion, University of Glasgow, 2008); and the SOCS-O scale (Gu et al. in Clin Psychol Rev 37:1–12, 2020)]. Additionally, we examined the interplay between mindfulness, compassion, and ethical sensitivities by assessing the influence of the moral foundations (individualizing and binding) on compassion, and the influence of mindfulness, the moral foundations, and compassion on awareness of privilege.

Methods

We surveyed 407 undergraduate students. Factor analysis was used to examine the dimensionality of the compassion measures; path analysis to examine the relationships between all variables.

Results

Factor analysis revealed distinct affective (empathy, indifference), cognitive (common humanity, recognizing suffering), and motivational (willingness to act) aspects of compassion. Mindfulness, under its aspects of reflective awareness, self-compassion, and self-transcendence, was associated with compassion, with reflective awareness predicting multiple aspects of compassion over and beyond the normal mechanisms of the mindfulness manifold and the moral foundations. Individualizing was associated with all aspects of compassion; binding was only connected to recognizing suffering and a willingness to act. Awareness of privilege was positively connected to mindfulness through individualizing and the recognition of common humanity; it was also directly negatively related to the moral foundation of binding.

Conclusions

Mindfulness and compassion have synergistic and distinct positive effects on ethical sensitivities. Given that both compassion and ethical sensitivities have roots in mindfulness, mindfulness interventions might be one possible venue to enhance these positive aspects of individuals’ psychology.