The impact of psychological stressors on the progression of motor and non-motor disturbances observed in Parkinson's disease (PD) has received little attention. Given that PD likely results from many ...different environmental “hits”, we were interested in whether a chronic unpredictable stressor regimen would act additively or possibly even synergistically to augment the impact of the toxicant, paraquat, which has previously been linked to PD. Our findings support the contention that paraquat itself acted as a systemic stressor, with the pesticide increasing plasma corticosterone, as well as altering glucocorticoid receptor (GR) expression in the hippocampus. Furthermore, stressed mice that also received paraquat displayed synergistic motor coordination impairment on a rotarod test and augmented signs of anhedonia (sucrose preference test). The individual stressor and paraquat treatments also caused a range of non-motor (e.g. open field, Y and plus mazes) deficits, but there were no signs of an interaction (neither additive nor synergistic) between the insults. Similarly, paraquat caused the expected loss of substantia nigra dopamine neurons and microglial activation, but this effect was not further influenced by the chronic stressor. Taken together, these results indicate that paraquat has many effects comparable to that of a more traditional stressor and that at least some behavioral measures (i.e. sucrose preference and rotarod) are augmented by the combined pesticide and stress treatments. Thus, although psychological stressors might not necessarily increase the neurodegenerative effects of the toxicant exposure, they may promote co-morbid behaviors pathology.
•Paraquat induced behavioral and neurochemical alterations similar to those induced by a chronic unpredictable stressor.•Chronic unpredictable stress did not influence the degeneration of midbrain dopamine neurons or microglia activation.•The paraquat and chronic stressor exposure resulted in augmented motor impairment and anhedonic-like behavior.
Long-term survivors of childhood, adolescent and young adult (AYA) malignancies with past exposure to potentially cardiotoxic treatments are at risk of peripartum cardiac dysfunction. Incidence and ...risk factors for peripartum cardiac dysfunction and maternal cardiac outcomes in this population were investigated. Eligible long-term survivors were aged <30 years at cancer diagnosis, with ≥1 pregnancy occurring ≥5 years after diagnosis. "Peripartum" cardiac events were defined as occurring within pregnancy or ≤5months after delivery. Cardiac events were classified "symptomatic" or "subclinical". "Peripartum cardiomyopathy" (PPCM) was defined as symptomatic dysfunction without prior cardiac dysfunction. Of 64 eligible women, 5 (7.8%) had peripartum cardiac events: 3 symptomatic, 2 subclinical. Of 110 live births, 2 (1.8%, 95% CI 0.2-6.4) were defined as PPCM: Significantly greater than the published general population incidence of 1:3000 (
< 0.001), representing a 55-fold (95% CI 6.6-192.0) increased risk. Risk factor analyses were hypothesis-generating, revealing younger age at cancer diagnosis and higher anthracycline dose. Postpartum, cardiac function of 4 women (80%) failed to return to baseline. In conclusion, peripartum cardiac dysfunction is an uncommon but potentially serious complication in long-term survivors of paediatric and AYA malignancies previously treated with cardiotoxic therapies. Peripartum cardiac assessment is strongly recommended for at-risk patients.
DNA damage in the brain is influenced by endogenous processes and metabolism along with exogenous exposures. Accumulation of DNA damage in the brain can contribute to various neurological disorders, ...including neurodegenerative diseases and neuropsychiatric disorders. Traditional methods for assessing DNA damage in the brain, such as immunohistochemistry and mass spectrometry, have provided valuable insights but are limited by their inability to map specific DNA adducts and regional distributions within the brain or genome. Recent advancements in DNA damage detection methods offer new opportunities to address these limitations and further our understanding of DNA damage and repair in the brain. Here, we review emerging techniques offering more precise and sensitive ways to detect and quantify DNA lesions in the brain or neural cells. We highlight the advancements and applications of these techniques and discuss their potential for determining the role of DNA damage in neurological disease.
Universal frameworks for zoo animal welfare have been suggested. However, there is little evidence of a cross-cultural understanding of zoo animal welfare. This paper reports themes emerging from a ...qualitative study of international (European and Chinese) zoo professionals on zoo animal welfare issues. Structured telephone interviews were conducted with eight Chinese and eight European zoo staff, covering aspects of zoological animal welfare, conservation and zoological husbandry practices. These qualitative data were thematically analysed, and key themes generated. This paper describes three themes relating to ‘What is animal welfare’ ‘Animal welfare frameworks’ and ‘The human element in animal welfare’. This analysis indicates that the concept of animal welfare has cultural equivalence across Europe and between Europe and China, and that zoo staff are familiar with welfare frameworks. In China, a need for senior leadership and motivating staff to improve animal welfare emerged.
Norovirus is estimated to cause 677 million annual cases of gastroenteritis worldwide, resulting in 210,000 deaths. As viral gastroenteritis is generally self-limiting, clinical samples for ...epidemiological studies only partially represent circulating noroviruses in the population and is biased towards severe symptomatic cases. As infected individuals from both symptomatic and asymptomatic cases shed viruses into the sewerage system at a high concentration, waste water samples are useful for the molecular epidemiological analysis of norovirus genotypes at a population level. Using Illumina MiSeq and Sanger sequencing, we surveyed circulating norovirus within Australia and New Zealand, from July 2014 to December 2016. Importantly, norovirus genomic diversity during 2016 was compared between clinical and waste water samples to identify potential pandemic variants, novel recombinant viruses and the timing of their emergence. Although the GII.4 Sydney 2012 variant was prominent in 2014 and 2015, its prevalence significantly decreased in both clinical and waste water samples over 2016. This was concomitant with the emergence of multiple norovirus strains, including twoGII.4 Sydney 2012 recombinant viruses, GII.P4 New Orleans 2009/GII.4 Sydney 2012 and GII.P16/GII.4 Sydney 2012, along with three other emerging strains GII.17, GII.P12/GII.3 and GII.P16/GII.2. This is unusual, as a single GII.4 pandemic variant is generally responsible for 65-80% of all human norovirus infections at any one time and predominates until it is replaced by a new pandemic variant. In sumary, this study demonstrates the combined use of clinical and wastewater samples provides a more complete picture of norovirus circulating within the population.
Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess ...whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD.
We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18–80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926).
Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated: 50 (50%) to receive cyclophosphamide and 51 (50%) to receive rituximab. 48 (96%) participants in the cyclophosphamide group and 49 (96%) in the rituximab group received at least one dose of treatment and were included in analyses; 43 (86%) participants in the cyclophosphamide group and 42 (82%) participants in the rituximab group completed 24 weeks of treatment and follow-up. At 24 weeks, FVC was improved from baseline in both the cyclophosphamide group (unadjusted mean increase 99 mL SD 329) and the rituximab group (97 mL 234); in the adjusted mixed-effects model, the difference in the primary endpoint at 24 weeks was –40 mL (95% CI –153 to 74; p=0·49) between the rituximab group and the cyclophosphamide group. KBILD quality-of-life scores were improved at 24 weeks by a mean 9·4 points (SD 20·8) in the cyclophosphamide group and 8·8 points (17·0) in the rituximab group. No significant differences in secondary endpoints were identified between the treatment groups, with the exception of change in GDA score at week 48, which favoured cyclophosphamide (difference 0·90 95% CI 0·11 to 1·68). Improvements in lung function and respiratory-related quality-of-life measures were observed in both treatment groups. Lower corticosteroid exposure over 48 weeks of follow-up was recorded in the rituximab group. Two (4%) of 48 participants who received cyclophosphamide and three (6%) of 49 who received rituximab died during the study, all due to complications of CTD or ILD. Overall survival, progression-free survival, and time to treatment failure did not significantly differ between the two groups. All participants reported at least one adverse event during the study. Numerically fewer adverse events were reported by participants receiving rituximab (445 events) than those receiving cyclophosphamide (646 events). Gastrointestinal and respiratory disorders were the most commonly reported adverse events in both groups. There were 62 serious adverse events of which 33 occurred in the cyclophosphamide group and 29 in the rituximab group.
Rituximab was not superior to cyclophosphamide to treat patients with CTD-ILD, although participants in both treatment groups had increased FVC at 24 weeks, in addition to clinically important improvements in patient-reported quality of life. Rituximab was associated with fewer adverse events. Rituximab should be considered as a therapeutic alternative to cyclophosphamide in individuals with CTD-ILD requiring intravenous therapy.
Efficacy and Mechanism Evaluation Programme (Medical Research Council and National Institute for Health Research, UK).
Characterising the people that work in zoos is a key element of understanding how zoos might better contribute to conservation activities. The purpose of this study was to investigate demographics, ...early life experiences and perceptions of zoo staff to the role of the modern zoo. This paper reports the key characteristics and qualitative themes emerging from study of international (European and Chinese) zoo professionals. Semi-structured telephone interviews were conducted with eight Chinese and eight European zoo staff about aspects of zoological animal welfare, conservation and zoological practices. These qualitative data were thematically analysed, and themes generated. This paper describes interviewee demographics and two themes relating to ‘early life influences’ and ‘the role of the modern zoo’. This analysis indicates that demographic data and early life influences of zoo professionals were broadly similar between two culturally diverse regions, but that their views on the role of the modern zoo differed, particularly in terms of their perceptions of conservation activities, with European interviewees focussing on biodiversity conservation, and Chinese interviewees focussing on animal protection.
Spontaneous thelarche and isolated menses occur in female GnRH deficiency; sequence variants in FRFR1, GNRHR, PROKR2, and KAL1 are the most commonly associated genetic abnormalities.
Context:
GnRH ...deficiency is a rare genetic disorder of absent or partial pubertal development. The clinical and genetic characteristics of GnRH-deficient women have not been well-described.
Objective:
To determine the phenotypic and genotypic spectrum of a large series of GnRH-deficient women.
Design, Setting, and Subjects:
Retrospective study of 248 females with GnRH deficiency evaluated at an academic medical center between 1980 and 2010.
Main Outcome Measures:
Clinical presentation, baseline endogenous GnRH secretory activity, and DNA sequence variants in 11 genes associated with GnRH deficiency.
Results:
Eighty-eight percent had undergone pubarche, 51% had spontaneous thelarche, and 10% had 1–2 menses. Women with spontaneous thelarche were more likely to demonstrate normal pubarche (P = 0.04). In 27% of women, neuroendocrine studies demonstrated evidence of some endogenous GnRH secretory activity. Thirty-six percent (a large excess relative to controls) harbored a rare sequence variant in a gene associated with GnRH deficiency (87% heterozygous and 13% biallelic), with variants in FGFR1 (15%), GNRHR (6.6%), and PROKR2 (6.6%) being most prevalent. One woman had a biallelic variant in the X-linked gene, KAL1, and nine women had heterozygous variants.
Conclusions:
The clinical presentation of female GnRH deficiency varies from primary amenorrhea and absence of any secondary sexual characteristics to spontaneous breast development and occasional menses. In this cohort, rare sequence variants were present in all of the known genes associated with GnRH deficiency, including the novel identification of GnRH-deficient women with KAL1 variants. The pathogenic mechanism through which KAL1 variants disrupt female reproductive development requires further investigation.
Religious activity, particularly as associated with what might be called everyday organized religion, has been unconsidered in recent discussions of the geographies and policies relating to ...creativity, and has been almost absent in the discipline of Geography’s recent ‘creative turn’. We argue both that religion has been given little or no attention in academic discussions of vernacular creativity, while arts policy as it developed in the United Kingdom in the post-war period has had a strongly secular focus. This continues in more recent policies and initiatives that have sought to promote the amateur and voluntary arts sectors. We explore the reasons for these absences, before turning to examples of strongly creative practice in a range of case studies, focused in a small area of suburban West London. These show a remarkable diversity of creativity including the design, construction and transformation of buildings and spaces for religious worship, but also in ritual, performance and the everyday practices of making sacred space. Our case studies include examination of performance and material culture in a Tamil-speaking Hindu temple, and in Roman Catholic, Anglican and Pentecostal churches. These include changes to architectural form, stained glass artwork, community craft projects, and musical performance and composition. We suggest that religious creativity has a hidden significance that has become more important in the United Kingdom’s increasingly diverse cities and suburbs, and that significant population groups are marginalized in creativity debates and policies that focus on the secular arts. We also suggest that there are distinctive characteristics to what we describe as ‘devotional creativity’, particularly in different understandings of space, practice and experience.
Sustained nitric oxide (NO) generation positively correlates with lung cancer development and progression. Herein, we genetically confirmed this role of iNOS and evaluated the chemopreventive ...efficacy of silibinin in carcinogen-treated B6/129 wild-type (WT) and iNOS(-/-) mice.
Male B6/129-Nos2(tm1Lau) (iNOS(-/-)) and B6/129PF2 WT mice were injected i.p. with 1 mg/g body weight urethane once weekly for 7 consecutive weeks, followed by silibinin gavage (742 mg/kg body weight) for 5 d/wk for 18 weeks.
Quantification of micro-CT data in real-time showed that silibinin significantly decreases urethane-induced tumor number and size in WT mice, consistent with measurements made ex vivo at study termination. Genetic ablation of iNOS decreased urethane-induced tumor multiplicity by 87% (P < 0.001) compared to WT mice. Silibinin decreased tumor multiplicity by 71% (P < 0.01) in WT mice, but did not show any such considerable effect in iNOS(-/-) mice. Tumors from WT mice expressed more iNOS (P < 0.01) but almost similar eNOS and nNOS than those in silibinin-treated mice. In these tumors, silibinin moderately (P < 0.01) inhibited cell proliferation but strongly (P < 0.01) reduced the number of newly formed nestin-positive microvessels. Silibinin decreased VEGFR2 level, and STAT3 and NF-κB activation in tumors.
The lack of effect of silibinin in iNOS(-/-) mice suggests that silibinin exerts most of its chemopreventive and angiopreventive effects through its inhibition of iNOS expression in lung tumors. Our results support iNOS as a potential target for controlling lung cancer, and demonstrate the value of real-time noninvasive micro-CT imaging modality for evaluating the efficacy of lung cancer chemopreventive agents.
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