Carefully designed animal models of genetic risk factors are likely to aid our understanding of the pathogenesis of schizophrenia. Here, we study a mouse strain with a truncating lesion in the ...endogenous Disc1 ortholog designed to model the effects of a schizophrenia-predisposing mutation and offer a detailed account of the consequences that this mutation has on the development and function of a hippocampal circuit. We uncover widespread and cumulative cytoarchitectural alterations in the dentate gyrus during neonatal and adult neurogenesis, which include errors in axonal targeting and are accompanied by changes in short-term plasticity at the mossy fiber/CA3 circuit. We also provide evidence that cAMP levels are elevated as a result of the Disc1 mutation, leading to altered axonal targeting and dendritic growth. The identified structural alterations are, for the most part, not consistent with the growth-promoting and premature maturation effects inferred from previous RNAi-based Disc1 knockdown. Our results provide support to the notion that modest disturbances of neuronal connectivity and accompanying deficits in short-term synaptic dynamics is a general feature of schizophrenia-predisposing mutations.
Spatial cues can facilitate segregation of target speech from maskers. However, in clinical practice, masked speech understanding is most often evaluated using co-located speech and maskers (i.e., ...without spatial cues). Many hearing aid centers in France are equipped with five-loudspeaker arrays, allowing masked speech understanding to be measured with spatial cues. It is unclear how hearing status may affect utilization of spatial cues to segregate speech and noise. In this study, speech reception thresholds (SRTs) for target speech in “diffuse noise” (target speech from 1 speaker, noise from the remaining 4 speakers) in 297 adult listeners across 9 Audilab hearing centers. Participants were categorized according to pure-tone-average (PTA) thresholds: typically-hearing (TH; ≤ 20 dB HL), mild hearing loss (Mild; >20 ≤ 40 dB HL), moderate hearing loss 1 (Mod-1; >40 ≤ 55 dB HL), and moderate hearing loss 2 (Mod-2; >55 ≤ 65 dB HL). All participants were tested without aided hearing. SRTs in diffuse noise were significantly correlated with PTA thresholds, age at testing, as well as word and phoneme recognition scores in quiet. Stepwise linear regression analysis showed that SRTs in diffuse noise were significantly predicted by a combination of PTA threshold and word recognition scores in quiet. SRTs were also measured in co-located and diffuse noise in 65 additional participants. SRTs were significantly lower in diffuse noise than in co-located noise only for the TH and Mild groups; masking release with diffuse noise (relative to co-located noise) was significant only for the TH group. The results are consistent with previous studies that found that hard of hearing listeners have greater difficulty using spatial cues to segregate competing speech. The data suggest that speech understanding in diffuse noise provides additional insight into difficulties that hard of hearing individuals experience in complex listening environments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Study question Does once-daily linzagolix taken up to 12 months maintain pain reduction observed at 6 months in women with endometriosis? Summary answer Linzagolix alone or in combination ...with combined add-back therapy (ABT) for 12 months maintains improvements of endometriosis-associated pain (EAP) observed at 6 months. What is known already Linzagolix is an oral GnRH antagonist under development for EAP. In the EDELWEISS 3 study, the 200mg+ABT dose met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) and secondary endpoints such as DYS, NMPP, overall pelvic pain and dyschezia as well as interference of pain with daily activities at 6 months. Linzagolix 75mg significantly reduced dysmenorrhea but not NMPP at 3 months. Both doses of linzagolix were well tolerated over 6 months of treatment. Study design, size, duration EDELWEISS 6 was the extension study of EDELWEISS 3, a placebo-controlled Phase 3 study, investigating linzagolix 75mg and 200mg+ABT for up to 6 months in women with moderate to severe EAP. Subjects who completed EDELWEISS3 were invited to enter the extension study for an additional 6-month treatment on the same linzagolix dose; placebo subjects were randomized to either active dose. After end of treatment, subjects entered a drug-free post-treatment period of 6 months. Participants/materials, setting, methods Women participating to EDELWEISS 6 received linzagolix for up to 12 months consecutively. Key efficacy assessments included dysmenorrhea and non-menstrual pelvic pain (NMPP), dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain) at Month 12. We report the results for dysmenorrhea and NMPP. Main results and the role of chance Of 484 participants in EDELWEISS 3, 353 (72.9%) entered EDELWEISS 6 and were evaluated for efficacy. Demographics were similar to EDELWEISS 3 with a mean age of 35 years, a BMI of 24kg/m2 and 99% of subjects being White. Mean (SD) monthly baseline dysmenorrhea and NMPP pain scores on the VRS were 2.28 (0.41) and 1.76 (0.45), respectively. The threshold for a meaningful pain reduction was established at Month 3, being -1.10 and -0.80 for dysmenorrhea and NMPP, respectively. At Month 3, the proportion of subjects with a reduction of dysmenorrhea of 1.10 or greater, and stable or decreased use of analgesics was 45.2% for the 75mg group and 75.4% for the 200mg+ABT group, which increased to 49.6% and 84.7%, respectively, at Month 6, the end of EDELWEISS 3. At Month 12, the end of EDELWEISS 6 treatment, the proportion of subjects was further increased to 55.9% and 91.0%, respectively. For NMPP, the proportion of subjects with a reduction of 0.80 or greater and stable or decreased use of analgesics at Month 3 was 36.5% for 75 mg and 51.7% for 200mg+ABT, increased to 54% and 61% at Month 6, and increased to 59.5% and 67.6%, respectively, until Month 12. Limitations, reasons for caution Edelweiss 6 is the extension of the previously reported double blind, placebo controlled Edelweiss 3 study. The results confirm efficacy of 200mg + ABT at 12 months. Longer term data is required to further understand efficacy of GnRH antagonists in women with endometriosis associated pain. Wider implications of the findings The linzagolix 200mg+ABT group provided substantial and sustained improvement in EAP symptoms. The 75mg which did not meet the primary endpoint in EDELWEISS 3 still demonstrated marked improvements. There exists a substantial need for different treatment regimens in women suffering from endometriosis. Trial registration number NCT04335591
The SMARCA2 gene, which encodes BRM in the SWI/SNF chromatin-remodeling complex, was recently identified as being associated with schizophrenia (SZ) in a genome-wide approach. Polymorphisms in ...SMARCA2, associated with the disease, produce changes in the expression of the gene and/or in the encoded amino acid sequence. We show here that an SWI/SNF-centered network including the Smarca2 gene is modified by the down-regulation of REST/NRSF in a mouse neuronal cell line. REST/NRSF down-regulation also modifies the levels of Smarce1, Smarcd3 and SWI/SNF interactors (Hdac1, RcoR1 and Mecp2). Smarca2 down-regulation generates an abnormal dendritic spine morphology that is an intermediate phenotype of SZ. We further found that 8 (CSF2RA, HIST1H2BJ, NOTCH4, NRGN, SHOX, SMARCA2, TCF4 and ZNF804A) out of 10 genome-wide supported SZ-associated genes are part of an interacting network (including SMARCA2), 5 members of which encode transcription regulators. The expression of 3 (TCF4, SMARCA2 and CSF2RA) of the 10 genome-wide supported SZ-associated genes is modified when the REST/NRSF-SWI/SNF chromatin-remodeling complex is experimentally manipulated in mouse cell lines and in transgenic mouse models. The REST/NRSF-SWI/SNF deregulation also results in the differential expression of genes that are clustered in chromosomes suggesting the induction of genome-wide epigenetic changes. Finally, we found that SMARCA2 interactors and the genome-wide supported SZ-associated genes are considerably enriched in genes displaying positive selection in primates and in the human lineage which suggests the occurrence of novel protein interactions in primates. Altogether, these data identify the SWI/SNF chromatin-remodeling complex as a key component of the genetic architecture of SZ.
Hybrid lipid oligonucleotide conjugates are finding more and more biotechnological applications. This short critical review highlights their synthesis, supramolecular organization as well as their ...applications in the field of biotechnology (111 references).
Microelectrode arrays serve as an indispensable tool in electro-physiological research to study the electrical activity of neural cells, enabling measurements of single cell as well as network ...communication analysis. Recent experimental studies have reported that the neuronal geometry has an influence on electrical signaling and extracellular recordings. However, the corresponding mechanisms are not yet fully understood and require further investigation. Allowing systematic parameter studies, computational modeling provides the opportunity to examine the underlying effects that influence extracellular potentials. In this letter, we present an in silico single cell model to analyze the effect of geometrical variability on the extracellular electric potentials. We describe finite element models of a single neuron with varying geometric complexity in three-dimensional space. The electric potential generation of the neuron is modeled using Hodgkin-Huxley equations. The signal propagation is described with electro-quasi-static equations, and results are compared with corresponding cable equation descriptions. Our results show that both the geometric dimensions and the distribution of ion channels of a neuron are critical factors that significantly influence both the amplitude and shape of extracellular potentials.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Novel molecular genetic approaches, at genome-scale in different species allowed characterizing genes that have undergone recent selection. The interest in this research field is not limited to the ...natural curiosity about our evolutionary past, but it is also to identify novel susceptibility genes for neuropsychiatic disorders by pointing specific human traits, such as behavioral and cognitive abilities. Hypotheses have been proposed to relate specific psychiatric disorders to the origin of modern humans, as evidenced by the theory of Crow about schizophrenia. In the present review, we will focus on genes that underwent positive selection in humans or displayed a human specific evolutionary pattern and which were reported as associated with psychiatric disorders. This will include the (1) DRD4 gene associated with attentiondeficit/ hyperactivity disorder, located in a locus that underwent a positive selection; the (2) GABRB2 gene, a gene associated with schizophrenia and recently reported as the target of a positive selection; (3) MARK1, a candidate gene for autism that was reported as displaying a signature of adaptative evolution in the human lineage, and (4) the ADH and ALDH2 genes which are associated with alcoholism, and for which evidence of positive selection was identified in the human lineage since the divergence between humans and chimpanzees. Identification of novel candidate genes based on recent evolution selection, coupled to genome-wide strategies designed to detect rare structural variants, could lead to a better knowledge of the molecular mechanisms of neurodevelopmental disorders and might therefore help to develop new medical chemistry.
Abstract
Study question
Does once-daily linzagolix for up to 6 months reduce the pain symptoms in women with endometriosis?
Summary answer
Once-daily oral use of the GnRH agonist linzagolix alone or ...in combination with combined hormonal add-back therapy (ABT) for 24 weeks improved endometriosis-associated pain symptoms.
What is known already
Linzagolix is an oral GnRH antagonist under development to treat endometriosis-associated pain (EAP). In the EDELWEISS 3 study linzagolix 200mg+ABT met its co-primary endpoints at 3 months by reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP) in a clinically meaningful fashion along with a stable or decreased use of analgesics. Linzagolix 75mg significantly reduced DYS but not NMPP. Secondary endpoints were DYS, NMPP, overall pelvic pain, dyschezia, and dyspareunia at 6 months assessed with a numeric and/or verbal rating scale (NRS and/or VRS), and interference of pain with daily activities assessed with the Endometriosis-Health-Profile-30 (EHP-30) pain domain.
Study design, size, duration
EDELWEISS 3 was a randomized, double-blind, placebo-controlled Phase 3 study, investigating efficacy and safety of linzagolix 75mg and linzagolix 200mg with ABT (1mg estradiol/0.5mg norethindrone acetate) for up to 24 weeks in women with moderate to severe EAP. To qualify, subject had to demonstrate over 2 menstrual cycles at least moderate DYS and NMPP for ≥2 days each and at least moderate overall pelvic pain for ≥5 days.
Participants/materials, setting, methods
Eligible women with moderate to severe EAP were equally randomized to once daily oral: placebo, linzagolix 75mg or linzagolix 200mg+ABT. Efficacy assessments included DYS, NMPP, dyspareunia (assessed with a 4-point VRS), overall pelvic pain and dyschezia (assessed with an 11-point NRS), and interference of pain with daily activities (assessed with the EHP-30 pain domain). The co-primary endpoint was a responder analysis at Month 3. We present secondary endpoints at Month 6.
Main results and the role of chance
Participants (n = 484) had a mean age of 35 years, a BMI of 24kg/m2 with 99% of subjects being White.
At Month 6, compared to placebo significant improvements in DYS and NMPP (VRS) were observed in the 200mg+ABT group, with an estimated mean change from baseline (CfB) of -1.83 (95%CI: 1.96, 1.70; difference with placebo p < 0.001) and 0.92 (95%CI: 1.03, 0.82; p = 0.002), respectively. For the 75mg group, the mean CfB was 1.10 (95%CI: 1.23; 0.97; p < 0.001) and 0.84 (95%CI: 0.95; 0.73; p = 0.048), respectively.
For overall pelvic pain (NRS), marked improvements were observed with an estimated mean CfB of 3.39 (95%CI: 3.74, 3.03; p < 0.001) for 200mg+ABT and 2.84 (95%CI: 3.20, 2.48; p = 0.024) for 75mg.
Similarly, dyschezia (NRS) was significantly improved for both groups with a mean CfB of 1.99 (95%CI: 2.29, 1.70; p = 0.012) for 200mg+ABT and -1.98 (95%CI: 2.28, 1.69; p = 0.015) for 75mg.
Both doses offered a marked, statistically significant improvement in the interference of pain with daily activities as measured on the EHP-30 Pain Dimension, with an estimated mean CfB of 35.60 (95%CI: 38.73, 32.48; p < 0.001) and -27.37 (95%CI: 30.50, 24.25; p = 0.001) for the 200mg+ABT and 75mg group, respectively.
Both doses did not provide significant improvements in dyspareunia.
Limitations, reasons for caution
We report data of the EDELWEISS 3 study for up to Month 6. An extension study of this trial will provide more information on the sustained effect and potential symptom recurrence after stopping treatment.
Wider implications of the findings
The linzagolix 200mg+ABT group provided substantial improvement in endometriosis-associated pain symptoms. The 75mg dose was less effective but demonstrated still marked improvements. There exists an substantial need for different treatment regimens in women suffering from endometriosis.
Trial registration number
NCT03992846
Addressing a topic of extreme complexity and topicality, domestic and family violence permeates a historical context that highlights its relevance. This problem has been constantly highlighted in the ...media, highlighting a phenomenon that, although it has gained greater visibility in recent years, has always existed, but was often covered up by social taboos. Notably, women were the primary victims of this type of violence and were often silenced due to entrenched social conventions. The impacts of domestic and family violence are devastating, affecting countless lives. According to the Atlas of Violence (2023), between 2011 and 2021, the number of murders of women reached an average of 1.2 per 100 thousand women in the country. This alarming data illustrates the seriousness and urgency of tackling this problem effectively. Through data analysis, doctrine and interviews, the objective is to analyze the effectiveness and importance of the Maria da Penha Patrol of the Military Police of the State of Paraná as a crucial tool in the affirmation of women's rights, analyzing the theoretical foundation and the practical implementation of this type of patrol, which, although it acts in an ostensive and uniformed way, Its scope is the optimization of care and greater reception for victims of domestic violence, aiming at the reduction of service rates and the minimization of the number of fatal victims. In this context, the Maria da Penha Patrol in the PMPR emerges as a tool to help meet the established national goals, along with the actions provided for in the internal guidelines of the military organization, playing a fundamental role in the prevention, monitoring and protection of victims.
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