Levodopa alters resting-state functional connectivity more selectively in Parkinson's disease with freezing of gait.

Freezing of gait (FOG) is a debilitating motor symptom of Parkinson's disease (PD). Although PD dopaminergic medication (L-DOPA) seems to generally reduce FOG severity, its effect on neural mechanisms of FOG remains to be determined. The purpose of this study was to quantify the effect of L-DOPA on brain resting-state functional connectivity in individuals with FOG. Functional magnetic resonance imaging was acquired at rest in 30 individuals living with PD (15 freezers) in the ON- and OFF- medication state. A seed-to-voxel analysis was performed with seeds in the bilateral basal ganglia nuclei, the thalamus and the mesencephalic locomotor region. In freezers, medication-state contrasts revealed numerous changes in resting-state functional connectivity, not modulated by L-DOPA in non-freezers. In freezers, L-DOPA increased the functional connectivity between the seeds and regions including the posterior parietal, the posterior cingulate, the motor and the medial prefrontal cortices. Comparisons with non-freezers revealed that L-DOPA generally normalizes brain functional connectivity to non-freezers levels but can also increase functional connectivity, possibly compensating for dysfunctional networks in freezers. Our findings suggest that L-DOPA could contribute to a better sensorimotor, attentional, response inhibition and limbic processing to prevent FOG when triggers are encountered but could also contribute to FOG by interfering with the processing capacity of the striatum. This study shows that levodopa taken to control PD symptoms induces changes in functional connectivity at rest, in freezers only. Increases (green) in functional connectivity of GPe, GPi, putamen and thalamus with cognitive, sensorimotor and limbic cortical regions of the Interference model (blue) was observed. Our results suggest that levodopa can normalize connections similar to non-freezers or increases connectivity to compensate for dysfunctional networks.

How maternal age and environmental cues influence embryonic developmental pathways and diapause dynamics in a North American annual killifish.

BACKGROUND: Temporary pools are variable environments with seasonal drought/flood phases. Annual killifish have adapted to life in temporary pools by producing embryos that undergo diapause to traverse the dry phase. To fill existing knowledge gaps about embryo diapause regulation and evolution in annual killifishes, we test the effect of maternal age, incubation temperature, and incubation medium on diapause induction and length in Millerichthys robustus, the only North American fish species that has evolved an annual life history. RESULTS: All embryos at extreme temperatures follow a defined developmental pathway: skipping diapause at 30°C, and entering diapause at 18°C, both regardless of maternal age, and incubation medium. However, maternal age, and incubation medium influenced whether diapause is entered, and time arrested in diapause for embryos incubated at 25°C. At 25°C, five-week-old, and 52-week-old females produced more embryos that entered diapause than 26-week-old females. Also, embryos incubated in aqueous medium skipped diapause more frequently at this intermediate temperature. CONCLUSIONS: Millerichthys developmental dynamics associated with maternal age under intermediate range of temperatures are likely adapted to the particular patterns of flood/drought in North American temporary pools. Millerichthys also exhibits developmental patterns largely comparable with other annual fishes, probably due to common seasonal patterns in temporary pools.

Impacts of digital technologies on education and factors influencing schools' digital capacity and transformation: A literature review.

Digital technologies have brought changes to the nature and scope of education and led education systems worldwide to adopt strategies and policies for ICT integration. The latter brought about issues regarding the quality of teaching and learning with ICTs, especially concerning the understanding, adaptation, and design of the education systems in accordance with current technological trends. These issues were emphasized during the recent COVID-19 pandemic that accelerated the use of digital technologies in education, generating questions regarding digitalization in schools. Specifically, many schools demonstrated a lack of experience and low digital capacity, which resulted in widening gaps, inequalities, and learning losses. Such results have engendered the need for schools to learn and build upon the experience to enhance their digital capacity and preparedness, increase their digitalization levels, and achieve a successful digital transformation. Given that the integration of digital technologies is a complex and continuous process that impacts different actors within the school ecosystem, there is a need to show how these impacts are interconnected and identify the factors that can encourage an effective and efficient change in the school environments. For this purpose, we conducted a non-systematic literature review. The results of the literature review were organized thematically based on the evidence presented about the impact of digital technology on education and the factors that affect the schools' digital capacity and digital transformation. The findings suggest that ICT integration in schools impacts more than just students' performance; it affects several other school-related aspects and stakeholders, too. Furthermore, various factors affect the impact of digital technologies on education. These factors are interconnected and play a vital role in the digital transformation process. The study results shed light on how ICTs can positively contribute to the digital transformation of schools and which factors should be considered for schools to achieve effective and efficient change.

Use of community-based reference ranges to estimate the prevalence of polycystic ovary syndrome by the recognised diagnostic criteria, a cross-sectional study.

STUDY QUESTION: Does the application of reference ranges for sex steroids and the modified Ferriman-Gallwey (mFG) scale established in the community from which the study sample was drawn, combined with the most conservative polycystic ovary morphology (PCOM) criteria to the recognised diagnostic criteria for polycystic ovary syndrome (PCOS) improve the certainty of diagnosis of PCOS in non-healthcare-seeking women? SUMMARY ANSWER: Despite application of the stringent definitions of the elements used to diagnose PCOS in a non-healthcare seeking community-based sample, the risk of diagnostic uncertainty remains. WHAT IS KNOWN ALREADY: There is heterogeneity in prevalence estimates for PCOS due, in part, to lack of standardisation of the elements comprising the recognised National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AE-PCOS) diagnostic criteria. The AE-PCOS Society proposed refinements to the definitions of biochemical androgen excess and PCOM that can now be incorporated into these sets of diagnostic criteria to estimate PCOS prevalence. STUDY DESIGN, SIZE, DURATION: An Australian cross-sectional study of 168 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 168 included women were aged 18-39 years, euthyroid and normoprolactinemic, not recently pregnant, breast feeding or using systemic hormones. Each provided menstrual history and assessment of the mFG, had measurement of sex steroids by liquid chromatography, tandem mass spectrometry, and a pelvic ultrasound. The presence of PCOS was determined using modified (m) NIH, Rotterdam, and AE-PCOS criteria according to AE-PCOS Society recommendations. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 10.1% of the included participants met the mNIH PCOS criteria, which requires the presence of menstrual dysfunction, while 18.5% met the mRotterdam and 17.5% the AE-PCOS criteria, with the latter requiring hyperandrogenism. Eight of the 27 participants with menstrual dysfunction, 10 of 31 women with PCOM, and 39 of 68 women with hyperandrogenism had no other feature of PCOS. Of the 19 participants with hyperandrogenaemia, 10 met the mNIH criteria (52.5%) and 14 met both the mRotterdam and AE-PCOS criteria (78.9%). Women who had the combination of hyperandrogenism and PCOM explained the greatest discrepancy between the mNIH and the other criteria. LIMITATIONS, REASONS FOR CAUTION: Clinical androgenisation relied on participant self-assessment, which has been shown to be valid when compared with clinician assessment. The sample size was a function of both the strict inclusion criteria and the requirements of non-healthcare-seeking women having a blood draw and pelvic ultrasound which may have introduced a selection bias. WIDER IMPLICATIONS OF THE FINDINGS: Despite applying stringent cut-offs for serum androgens, the mFG scale and the ovarian follicle count, these criteria remain arbitrary. Accordingly, healthy women may be captured by these criteria, and misidentified as having PCOS, while women with the condition may be missed. Consequently, PCOS remains a diagnosis to be made with care. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Grollo-Ruzzene Foundation. Dr S.R.D. is an NHMRC Senior Principal Research Fellow (Grant no. 1135843). S.R.D. has been paid for developing and delivering educational presentations for Besins Healthcare, BioFemme and Pfizer Australia, has been on Advisory Boards for Theramex, Abbott Laboratories, Mayne Pharmaceuticals and Roche and a consultant to Lawley Pharmaceuticals and Que Oncology and has received has received institutional grant funding for Que Oncology research; there are no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

The plant hormone salicylic acid interacts with the mechanism of anti-herbivory conferred by fungal endophytes in grasses.

The plant hormone salicylic acid (SA) is recognized as an effective defence against biotrophic pathogens, but its role as regulator of beneficial plant symbionts has received little attention. We studied the relationship between the SA hormone and leaf fungal endophytes on herbivore defences in symbiotic grasses. We hypothesize that the SA exposure suppresses the endophyte reducing the fungal-produced alkaloids. Because of the role that alkaloids play in anti-herbivore defences, any reduction in their production should make host plants more susceptible to herbivores. Lolium multiflorum plants symbiotic and nonsymbiotic with the endophyte Epichloë occultans were exposed to SA followed by a challenge with the aphid Rhopalosiphum padi. We measured the level of plant resistance to aphids, and the defences conferred by endophytes and host plants. Symbiotic plants had lower concentrations of SA than did the nonsymbiotic counterparts. Consistent with our prediction, the hormonal treatment reduced the concentration of loline alkaloids (i.e., N-formyllolines and N-acetylnorlolines) and consequently decreased the endophyte-conferred resistance against aphids. Our study highlights the importance of the interaction between the plant immune system and endophytes for the stability of the defensive mutualism. Our results indicate that the SA plays a critical role in regulating the endophyte-conferred resistance against herbivores.

Cathepsin B-degradable, NIR-responsive nanoparticulate platform for target-specific cancer therapy.

Stimuli-responsive anticancer formulations can promote drug release and activation within the target tumour, facilitate cellular uptake, as well as improve the therapeutic efficacy of drugs and reduce off-target effects. In the present work, indocyanine green (ICG)-containing polyglutamate (PGA) nanoparticles were developed and characterized. Digestion of nanoparticles with cathepsin B, a matrix metalloproteinase overexpressed in the microenvironment of advanced tumours, decreased particle size and increased ICG cellular uptake. Incorporation of ICG in PGA nanoparticles provided the NIR-absorbing agent with time-dependent altered optical properties in the presence of cathepsin B. Having minimal dark toxicity, the formulation exhibited significant cytotoxicity upon NIR exposure. Combined use of the formulation with saporin, a ribosome-inactivating protein, resulted in synergistically enhanced cytotoxicity attributed to the photo-induced release of saporin from endo/lysosomes. The results suggest that this therapeutic approach can offer significant therapeutic benefit in the treatment of superficial malignancies, such as head and neck tumours.

LEP (G2548A-G19A) and ADIPOQ (T45G-G276T) gene polymorphisms are associated with markers for metabolic syndrome.

BACKGROUND AND AIMS: There is a link between genetics with metabolic balance and adiposity homeostasis on metabolic syndrome (MetS). Polymorphism in adipokine genes such as leptin and adiponectin may play an important role in its development. This study aimed to determine the association of the individual and general components of MetS with genetic alterations in LEP (rs7799039 and rs2167270) and ADIPOQ (rs1501299 and rs2241766) genes in the Mexican population. METHODS AND RESULTS: The polymorphisms of the LEP gene rs7799039 and rs2167270, together with rs1501299 and rs2241766 polymorphisms of the ADIPOQ gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) on 328 individuals (n = 131 MetS). The rs7799039 under the recessive inheritance model was found to be associated with increased risk of MetS (OR = 2.16, 95% CI = 1.06-4.37), dyslipidemia (OR = 7.97, 95% CI = 2.17-29.36), low HDL (OR = 7.01, 95% CI = 1.65-29.71) and hypertension (OR = 13.02, 95% CI = 1.76-96.44); the heterozygote demonstrate a protective effect on MetS (OR = 0.48, 95% CI = 0.28-0.88) and diabetes (OR = 0.09, 95% CI = 0.02-0.53) under the over the dominant model. Haplotype analysis showed linkage disequilibrium between the SNPs of ADIPOQ rs1501299/rs2241766, and their association as risk factors for low HDL and hypertension. CONCLUSION: The association of rs7799039 with the presence of MetS, suggests a risk factor for the development of dyslipidemia, as well as its heterozygous as a protective factor for DM. There is a linkage disequilibrium between the SNPs of ADIPOQ.

Differential expression of the androgen receptor gene is correlated with CAG polymorphic repeats in patients with prostate cancer.

Prostate cancer (PCa) is one of the most common types of cancer in men. The aetiology of the disease is not well established, but it has been related to one of the main pathways of regulation of prostate proliferation, mediated by androgens. The androgen receptor (AR) gene encodes the androgen-receptor protein, which functions as a transactivation factor for steroid hormones. It has been proposed that the AR gene transcription levels are mediated by short tandem repeats corresponding to the CAG sequence. However, there are conflicting results in this relationship. We evaluated the expression levels of the AR gene and identified the number of CAG repeats (CAGn) in the Mexican population, establishing the relationship between expression levels and increase in the number of CAG repeats. We evaluated the expression levels of AR in tissue samples of PCa and benign prostate disease, such as benign prostatic hyperplasia, or prostatitis, to determine the difference in their expression levels. Our results showed a statistically insignificant underexpression of 0.64-fold decrease in AR levels of PCa patients compared to benign prostate disease patients (P = 0.623) and suggest that the number of CAGn was correlated with the relative expression of the AR gene (P = 0.009) and this correlation was positive, moderate, and proportional (ρ = 0.467) and no correlation was found between CAGn with other clinical features.

Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: data from the nationwide registry RelevarEM.

INTRODUCTION: The discontinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS) is commonly seen in real-world settings due to several factors. AREA COVER: The aim of this study is to describe the frequency of disease activity after discontinuation of DMTs in MS patients included in the Argentinean MS and NMOSD registry. DISCUSION: Patients with relapsing remitting MS (RRMS) and active secondary progressive MS (SPMS) were included based on the following criteria: they discontinued treatment for more than 6 months, they had been treated with a DMT for ≥2 years, and they had at least 6 months of follow-up in the registry after discontinuation. Demographic and clinical data were collected. Disease activity during follow-up was defined as the presence of a clinical relapse or a new magnetic resonance (MRI) lesion (either new lesions on T2-weighted sequence and/or contrast enhancement). Bivariate analysis was applied to identify clinical and demographic factors related to disease activity. CONCLUSION: We included 377 patients (75.5% RRMS, 22.5% SPMS) who had discontinued DMTs. The mean (SD) follow-up after discontinuation was 15.7 (7.9) months. After discontinuation, the presence of relapse was detected in 18.8% and 3.5% in RRMS and SPMS, respectively; and new MRI activity in 22% and 3.5%, respectively. We found that higher risk of relapse and MRI activity was associated with younger age (p < 0.001), shorter disease duration (p < 0.001), and RRMS phenotype (p = 0.006). Males showed higher MRI activity (p 0.011). This study provides real-world data that can guide physicians when considering discontinuation of DMTs.

Adherence to French and ESGO Quality Indicators in Ovarian Cancer Surgery: An Ad-Hoc Analysis from the Prospective Multicentric CURSOC Study.

BACKGROUND: Quality Indicators for ovarian cancer (OC) have been developed by the European Society of Gynaecological Oncology (ESGO) and by the French National Cancer Institute (Institut National du Cancer, INCa). The aim of the study was to characterize OC care distribution in France by case-volume and to prospectively evaluate the adherence of high-volume institutions to INCa/ESGO quality indicators. METHODS: The cost-utility of radical surgery in ovarian cancer (CURSOC) trial is a prospective, multicenter, comparative and non-randomized study that includes patients with stage IIIC-IV epithelial OC treated in nine French health care tertiary institutions. Adherence to institutional quality indicators were anonymously assessed by an independent committee. OC care distribution in France were provided by the nationwide database of hospital procedures. RESULTS: More than half of patients are treated in low-volume institutions. Among the nine high-volume centers participating in the study, four (44.4%) met all institutional INCa/ESGO quality indicators. The other five (55.6%) did not fulfil one of the quality indicator criteria. CONCLUSIONS: Access to high-volume OC providers in France is restricted to a minority of patients, and yet half of the referral institutions included in this study failed to meet all recommended institutional quality indicators. It is mandatory that national authorities work both to improve OC centralization and to incorporate quality assurance programs into certified centers.

Pregnant Agencies: Movement and Participation in Maternal-Fetal Interactions.

Pregnancy presents some interesting challenges for the philosophy of embodied cognition. Mother and fetus are generally considered to be passive during pregnancy, both individually and in their relation. In this paper, we use the enactive operational concepts of autonomy, agency, individuation, and participation to examine the relation between mother and fetus in utero. Based on biological, physiological, and phenomenological research, we explore the emergence of agentive capacities in embryo and fetus, as well as how maternal agency changes as pregnancy advances. We show that qualitatively different kinds of agency have their beginnings already in utero, and to what extent fetal and maternal movement modulate affectivity and individuation in pregnancy. We thus propose that mother and fetus are both agents who participate in pregnancy. Pregnancy then emerges as a relational developmental organization that anchors and holds its developing participants. We end the paper with reflections on ethical implications of this proposal, and suggestions for future research.

Carboxylesterase 1 family knockout alters drug disposition and lipid metabolism

The mammalian carboxylesterase 1 (Ces1/CES1) family comprises several enzymes that hydrolyze many xenobiotic chemicals and endogenous lipids. To investigate the pharmacological and physiological roles of Ces1/CES1, we generated Ces1 cluster knockout (Ces1 -/- ) mice, and a hepatic human CES1 transgenic model in the Ces1 -/- background (TgCES1). Ces1 -/- mice displayed profoundly decreased conversion of the anticancer prodrug irinotecan to SN-38 in plasma and tissues. TgCES1 mice exhibited enhanced metabolism of irinotecan to SN-38 in liver and kidney. Ces1 and hCES1 activity increased irinotecan toxicity, likely by enhancing the formation of pharmacodynamically active SN-38. Ces1 -/- mice also showed markedly increased capecitabine plasma exposure, which was moderately decreased in TgCES1 mice. Ces1 -/- mice were overweight with increased adipose tissue, white adipose tissue inflammation (in males), a higher lipid load in brown adipose tissue, and impaired blood glucose tolerance (in males). These phenotypes were mostly reversed in TgCES1 mice. TgCES1 mice displayed increased triglyceride secretion from liver to plasma, together with higher triglyceride levels in the male liver. These results indicate that the carboxylesterase 1 family plays essential roles in drug and lipid metabolism and detoxification. Ces1 -/- and TgCES1 mice will provide excellent tools for further study of the in vivo functions of Ces1/CES1 enzymes.

Effect of tumor burden and radical surgery on survival difference between upfront, early interval or delayed cytoreductive surgery in ovarian cancer / 부인종양

Objective@#We sought to evaluate the impact on survival of tumor burden and surgical complexity in relation to the number of cycles of neoadjuvant chemotherapy (NACT) in patients with advanced ovarian cancer (OC) with minimal (CC-1) or no residual disease (CC-0). @*Methods@#This retrospective study included patients with International Federation of Gynaecology and Obstetrics IIIC–IV stage OC who underwent debulking surgery at 4 high-volume institutions between January 2008 and December 2015. We assessed the overall survival (OS) of primary debulking surgery (PDS group), early interval debulking surgery after 3–4 cycles of NACT (early IDS group) and delayed debulking surgery after 6 cycles (DDS group) with CC-0 or CC-1 according to peritoneal cancer index (PCI) and Aletti score. @*Results@#Five hundred forty-nine women were included: 175 (31.9%) had PDS, 224 (40.8%) early IDS and 150 (27.3%) DDS. Regardless of Aletti score, median OS after PDS was significantly higher than after early IDS or DDS, but the survival difference was higher in women with an Aletti score 10, there were no differences between PDS and early IDS, but DDS was associated with decreased OS. @*Conclusion@#The benefit of complete PDS compared with NACT was maximal in patients with a low complexity score. In patients with low tumor burden, there was a survival benefit of PDS over early IDS or DDS. In women with high tumor load, DDS impaired the oncological outcome.

Concordance between preoperative ESMO-ESGO-ESTRO risk classification and final histology in early-stage endometrial cancer / 부인종양

Objective@#To evaluate the concordance between preoperative European Society for Medical Oncology (ESMO)-European Society of Gynaecological Oncology (ESGO)-European SocieTy for Radiotherapy and Oncology (ESTRO) risk classification in early-stage endometrial cancer (EC) assessed by biopsy and magnetic resonance imaging (MRI) with this classification based on histology of surgical specimen. @*Methods@#This bicentric retrospective study included women diagnosed with early-stage EC (≤stage II) who had a complete preoperative assessment and underwent a surgical management from January 2011 to December 2018. Patients were preoperatively classified into 3 degrees of risk of lymph node (LN) involvement based on biopsy and MRI. Based on final histological report, patients were re-classified using the preoperative classification. Concordance between the preoperative assessment and definitive histology was calculated with weighted Cohen's kappa coefficient. @*Results@#A total of 333 women were included and kappa coefficient of preoperative risk classification was 0.49. The risk was underestimated and overestimated in 37% and 10% of cases, respectively. Twenty-nine percent of patients had an incomplete LN staging according to the degree of risk of re-classification. The observed discordance in the risk classification was attributed to MRI in 75% of cases, to biopsy in 18% and in 7% to both (p<0.001). Kappa coefficient for concordance was 0.25 for MRI and 0.73 for biopsy. @*Conclusion@#Concordance between preoperative ESMO-ESGO-ESTRO risk classification and final histology is weak. Given that the risk was underestimated in the majority of patients wrongly classified, sentinel LN procedure instead of no LN dissection could be an option offered to preoperative low-risk patients to decrease the indication of second surgery for re-staging and/or to avoid toxicity of adjuvant radiotherapy.