Abstract Recent work identified novel progestin signaling molecules, including progesterone receptor membrane component 1 (Pgrmc1), Pgrmc2, serpine mRNA binding protein 1 (Serbp1), progestin and ...adiponectin receptors 7 (Paqr7) and Paqr8. These molecules mediate rapid progesterone (P4 ) effects in non-neural tissue and we recently mapped their expression in the brain. Many rapid effects of P4 require 17β-estradiol (E2 ) and P4 priming; therefore, we examined the effects of ovarian hormones on the expression of these non-classical progestin signaling molecules. We focused specifically on the anteroventral periventricular nucleus (AVPV), the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the ventrolateral portion of the ventromedial nucleus (VMNvl). These brain nuclei are important for female reproduction. Ovariectomized adult female rats were implanted with capsules containing sesame oil or E2 , and injected 48 h later with sesame oil or P4 . Brains were collected 8 h later and RNA was isolated from the AVPV, SDN-POA and VMNvl. We assessed the effects of ovarian hormones on mRNA levels using quantitative polymerase chain reaction (QPCR). In the AVPV, Serbp1 mRNA levels were increased by P4 in the presence of E2 , and Paqr8 was downregulated by P4 alone. In the SDN-POA, combined E2 and P4 increased Pgrmc1 and Serbp1 mRNA levels, and E2 alone increased Paqr8 mRNA levels. Finally, in the VMNvl, P4 increased mRNA levels encoding Pgrmc1, Pgrmc2 and Serbp1, and the combination of E2 and P4 increased Pgrmc1 and Serbp1 mRNA levels. Paqr7 was not regulated by E2 or P4 in any brain region examined. In summary, we showed that ovarian hormones regulate novel progestin signaling molecules in brain regions important for the neuroendocrine control of reproduction.
The efficacy of marine protected areas (MPAs) depends on their governance and management. We review their history in South Africa and recognise four periods. Period 1 (1964-1994) provided initial ...protection but was based on exclusionary, preservationist policies, was ad hoc in the absence of a national plan, and neglected social considerations. Period 2 (1994-2010) began introducing people-oriented policies, focused on ecosystems rather than species, and was strengthened by the formation of a national coordinating body. Period 3 (2010-2019) heralded improvements in design, ecosystem representation and stakeholder engagement, yet fractured governance hindered coordination and management. Period 4 (Since 2019) added challenges in managing new offshore MPAs. Progress in achieving effective MPA governance and management was assessed over these periods for 17 components of governance and management, representing key issues for which changes could be identified throughout. Fifteen components indicated overall improvements-most notably legislation and policies, MPA establishment, planning and design, and staff training and skills-whereas progress for most of the other components was weaker. Zero net gains were recorded for enforcement and compliance, and for the staff complement. Our recommendations flow principally from components assessed as faring poorly. We conclude with eight critical needs: (1) specify detailed objectives for every MPA; (2) fast-track management plans for new MPAs; (3) improve law enforcement and compliance; (4) enhance participation of adjacent communities and other stakeholders; (5) address MPA-related social impacts and injustices, and improve benefit sharing; (6) ensure financial sustainability; (7) strengthen evaluations of management effectiveness; and (8) improve cooperation between government authorities responsible for MPAs and fisheries.
Adeno-associated virus (AAV) vector-based gene therapy is a promising treatment strategy for delivery of neurotrophic transgenes to retinal ganglion cells (RGCs) in glaucoma patients. Retinal ...distribution of transgene expression following intravitreal injection (IVT) of AAV is variable in animal models and the vitreous humor may represent a barrier to initial vector penetration. The primary goal of our study was to investigate the effect of prior core vitrectomy with posterior hyaloid membrane peeling on pattern and efficiency of transduction of a capsid amino acid substituted AAV2 vector, carrying the green fluorescent protein (GFP) reporter transgene following IVT in dogs. When progressive intraocular inflammation developed starting 4 weeks post IVT, the study plan was modified to allow detailed characterization of the etiology as a secondary goal. Unexpectedly, surgical vitrectomy was found to significantly limit transduction, whereas in non-vitrectomized eyes transduction efficiency reached upwards to 37.3% of RGC layer cells. The developing retinitis was characterized by mononuclear cell infiltrates resulting from a delayed-type hypersensitivity reaction, which we suspect was directed at the GFP transgene. Our results, in a canine large animal model, support caution when considering surgical vitrectomy before IVT for retinal gene therapy in patients, as prior vitrectomy appears to significantly reduce transduction efficiency and may predispose the patient to development of vector-induced immune reactions.
It is generally assumed that the inhibitory neurotransmitter GABA and the stimulatory neurotransmitter glutamate are released from different neurons in adults. However, this tenet has made it ...difficult to explain how the same afferent signals can cause opposite changes in GABA and glutamate release. Such reciprocal release is a central mechanism in the neural control of many physiological processes including activation of gonadotropin-releasing hormone (GnRH) neurons, the neural signal for ovulation. Activation of GnRH neurons requires simultaneous suppression of GABA and stimulation of glutamate release, each of which occurs in response to a daily photoperiodic signal, but only in the presence of estradiol (E2). In rodents, E2 and photoperiodic signals converge in the anteroventral periventricular nucleus (AVPV), but it is unclear how these signals differentially regulate GABA and glutamate secretion. We now report that nearly all neurons in the AVPV of female rats express both vesicular glutamate transporter 2 (VGLUT2), a marker of hypothalamic glutamatergic neurons, as well as glutamic acid decarboxylase and vesicular GABA transporter (VGAT), markers of GABAergic neurons. These dual-phenotype neurons are the main targets of E2 in the region and are more than twice as numerous in females as in males. Moreover, dual-phenotype synaptic terminals contact GnRH neurons, and at the time of the surge, VGAT-containing vesicles decrease and VGLUT2-containing vesicles increase in these terminals. Thus, we propose a new model for ovulation that includes dual-phenotype GABA/glutamate neurons as central transducers of hormonal and neural signals to GnRH neurons.
To investigate whether clinical and radiographic disease control can be achieved and maintained in patients with early, active rheumatoid arthritis (RA) during the second year of aggressive treatment ...with conventional disease-modifying antirheumatic drugs (DMARDs) and intra-articular corticosteroid. This paper presents the results of the second year of the randomised, controlled double-blind CIMESTRA (Ciclosporine, Methotrexate, Steroid in RA) study.
160 patients with early RA (duration <6 months) were randomised to receive intra-articular betamethasone in any swollen joint in combination with step-up treatment with either methotrexate and placebo-ciclosporine (monotherapy) or methotrexate plus ciclosporine (combination therapy) during the first 76 weeks. At week 68 hydroxychlorochine 200 mg daily was added. From week 76-104 ciclosporine/placebo-ciclosporine was tapered to zero.
American College of Rheumatology 20% improvement (ACR20), ACR50 and ACR70 levels were achieved in 88%, 79% and 59% of patients in the combination vs 72%, 62% and 54% in the monotherapy group (p = 0.03, 0.02 and 0.6 between groups). The patients globally declined from 50 to 12 vs 52 to 9, with 51% and 50% in Disease Activity Score (DAS) remission, respectively. Mean (SD) progressions in total Sharp-van der Heijde scores were 1.42 (3.52) and 2.03 (5.86) in combination and monotherapy groups, respectively (not significant). Serum creatinine levels increased by 7% in the combination group (4% in monotherapy), but hypertension was not more prevalent.
Continuous methotrexate and intra-articular corticosteroid treatment resulted in excellent clinical response and disease control at 2 years, and the radiographic erosive progression was minimal. Addition of ciclosporine during the first 76 weeks resulted in significantly better ACR20 and ACR50 responses, but did not have any additional effect on remission rate and radiographic outcome.
We used a prototype GPS logger to track the movements of breeding African Penguins (Spheniscus demersus). The loggers also recorded temperature and water depth, which allowed us to reconstruct ...foraging tracks in three dimensions, although GPS signals are interrupted when the birds dive. Here we report the loggers performance in the field and assess the effects of GPS error, resolution and sampling rate on estimates of foraging track length and speed. There is a trade-off between sampling rate and battery lifespan. We tested loggers at sampling intervals of 1 s, 10 s, 1 min, 2 min and 10 min. Sampling less frequently increases the chance of tracking an entire foraging trip, but it slows uplink times, slightly decreases the accuracy of positional fixes, and significantly reduces the ability to measure fine-scale aspects of foraging behaviour. Compared with radio or satellite tracking, GPS loggers offer unprecedented detail about animal movements. The results of our analysis suggest that techniques that sample relatively infrequently, such as satellite tracking, underestimate actual track lengths by up to 50%. However, caution is needed when interpreting fine-scale sampling for relatively slow-moving organisms. Re-sampling 1-s tracks suggests that c. 35% of apparent movements at this scale are due to measurement error and, more importantly, the limited spatial resolution of GPS (1.85x1.54 m at the study area). We recommend that researchers use a 1-s sampling rate for fine-scale studies, but resample at less frequent intervals to remove spurious noise for slow-moving animals. At current levels of resolution, animals should move at least 4 m per sampling interval. We provide empirical correction factors to compare inferred track length sampled at different rates, but caution that these are idiosyncratic and strongly dependent on the animals behaviour. Overall, GPS loggers offer a significant advance for studies of fine-scale animal movement patterns. PUBLICATION ABSTRACT
The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during ...1 year of a treat-to-target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)).
A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score ≤0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp-van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients.
The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged -2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients (-1.8% and -2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0-19), non-alendronate: 0 (0-18)).
In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression.
Validation studies have not been able to confirm the stage-specific understanding as operationalised in the readiness for return to work (RRTW) questionnaire.
To explore retrospectively how working ...female cancer survivors experienced the process of becoming ready to RTW during and beyond participation in an occupational rehabilitation intervention and thereby expand the understanding of the RRTW construct.
A qualitative research design was employed. Thirteen female cancer survivors were included for semi-structured interviews one to two years after they had completed active treatment and returned to work. The RRTW construct guided data generation and analysis. Content analysis was performed in four analytical steps that combined a concept-driven and a data-driven analytic strategy.
Three themes were identified; "To have and then lose the safety net", "Realise a changed life situation", "Strive to balance work and everyday life". In a time span of approximately one to two years (from receiving treatment, being enrolled in an intervention and to gradually returning to work); the identified themes were interdependent of each other as one theme gradually evolved to the next theme in the process of engaging in sustained work participation.
The present study points towards continuous development of the RRTW construct and whether the addition of a preparedness dimension would improve validity.
Introduction
Research in development of new migraine therapeutics is hindered by the lack of suitable, predictive animal models. Cilostazol provokes headache in healthy humans and migraineurs by ...increasing intracellular cAMP levels. We aimed to investigate whether cilostazol could provoke headache-like behaviours and c-fos expression in rats. In order to evaluate the predictive validity of the model, we examined the response to the migraine specific drug sumatriptan.
Methods
The effect of cilostazol (125 mg/kg p.o.) in female Sprague Dawley rats was evaluated on a range of spontaneous behavioural parameters, light sensitivity and mechanical sensitivity thresholds. We also measured c-fos expression in the trigeminal nucleus caudalis.
Results
Cilostazol increased light sensitivity and grooming behaviour. These manifestations were not inhibited by sumatriptan. Cilostazol also induced c-fos expression in the trigeminal nucleus caudalis. Furthermore, trigeminal – but not hind paw hyperalgesia was observed.
Conclusion
The altered behaviours are suggestive of cilostazol induced headache with migraine-like features, but not specific. The presence of head specific hyperalgesia and the c-fos response in the trigeminal nucleus caudalis imply that the model involves trigeminal nociception. The model will be useful for studying mechanisms related to the cAMP pathway in headache, but its predictive properties appear to be more limited due to the lack of response to sumatriptan.
Weight trajectories might reflect individual health status. In this study, we aimed to examine the clinical and genetic associations of adult weight trajectories using electronic health records ...(EHRs) in the BioMe Biobank.
We constructed four weight trajectories based on a-priori definitions of weight changes (5% or 10%) using annual weight in EHRs (stable weight, weight gain, weight loss, and weight cycle); the final weight dataset included 21 487 participants with 162 783 annual weight measures. To confirm accurate assignment of weight trajectories, we manually reviewed weight trajectory plots for 100 random individuals. We then did a hypothesis-free phenome-wide association study (PheWAS) to identify diseases associated with each weight trajectory. Next, we estimated the single-nucleotide polymorphism-based heritability (h
) of weight trajectories using GCTA-GREML, and we did a hypothesis-driven analysis of anorexia nervosa and depression polygenic risk scores (PRS) on these weight trajectories, given both diseases are associated with weight changes. We extended our analyses to the UK Biobank to replicate findings from a patient population to a generally healthy population.
We found high concordance between manually assigned weight trajectories and those assigned by the algorithm (accuracy ≥98%). Stable weight was consistently associated with lower disease risks among those passing Bonferroni-corrected p value in our PheWAS (p≤4·4 × 10
). Additionally, we identified an association between depression and weight cycle (odds ratio OR 1·42, 95% CI 1·31-1·55, p≤7·7 × 10
). The adult weight trajectories were heritable (using 5% weight change as the cutoff: h
of 2·1%, 95% CI 0·9-3·3, for stable weight; 4·1%, 1·4-6·8, for weight gain; 5·5%, 2·8-8·2, for weight loss; and 4·7%, 2·3-7·1%, for weight cycle). Anorexia nervosa PRS was positively associated with weight loss trajectory among individuals without eating disorder diagnoses (OR
1·16, 95% CI 1·07-1·26, per 1 SD higher PRS, p=0·011), and the association was not attenuated by obesity PRS. No association was found between depression PRS and weight trajectories after permutation tests. All main findings were replicated in the UK Biobank (p<0·05).
Our findings suggest the importance of considering weight from a longitudinal aspect for its association with health and highlight a crucial role of weight management during disease development and progression.
Klarman Family Foundation, US National Institute of Mental Health (NIMH).
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