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Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease 1 – 6 . Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor 5 , 6 . Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system. Astrocytes can respond to diseases and injuries of the central nervous system by driving the death of neurons and mature oligodendrocytes through the delivery of long-chain saturated fatty acids contained in lipoparticles.

Poor penetration of anticancer drugs into tumors can be an important factor limiting their effícacy. We studied mouse tumor models to show that a previously characterized tumor-penetrating peptide, iRGD, increased vascular and tissue permeability in a tumor-specific and neuropilin-1–dependent manner, allowing coadministered drugs to penetrate into extravascular tumor tissue. Importantly, this effect did not require the drugs to be chemically conjugated to the peptide. Systemic injection with iRGD improved the therapeutic index of drugs of various compositions, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab). Thus, coadministration of iRGD may be a valuable way to enhance the effícacy of anticancer drugs while reducing their side effects, a primary goal of cancer therapy research.

Insufficient resources have been identified as a significant factor contributing to delayed development across all domains for children living with their incarcerated mothers. Often lacking extended family support, these children experience environments resembling confinement, devoid of essential cognitive, social, and emotional stimuli crucial for their development. This deprivation can result in substantial educational setbacks and hinder their social integration. This review aims to examine the impact of the prison environment on the development of children residing with their incarcerated mothers. Current research underscores a notable scarcity of comprehensive data on the developmental paths of these children. Some studies suggest that prison nurseries may cultivate positive intergenerational attachments, potentially mitigating the typically low resilience observed in cases of maternal separation. However, while lower-order cognitive functions may not exhibit significant delays, the development of higher-order thinking skills presents more considerable challenges. Addressing the developmental risks faced by children in prison settings is critical, given their heightened vulnerability to systemic neglect. Therefore, prioritizing optimal child development is essential to ensure these children achieve their milestones.

Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity. This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment. 411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI –4·2 to –1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, –1·7 letters [95% CI –4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI –332 to 1483). SRT can reduce ranibizumab treatment burden without compromising vision. Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.

AimsIndividuals with epilepsy are at risk of developing pre-ictal, ictal, postictal or interictal psychoses. Antipsychotic drugs (APDs) are the main class of drugs used to treat psychosis and schizophrenia. The efficacy and safety of APDs as a treatment for epileptic psychosis is not well understood. Hence, we aimed to conduct a systematic review assessing the effectiveness and adverse effects of antipsychotic drugs to treat psychosis in people with epilepsy.MethodsWe adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched MEDLINE, Embase, PsycInfo and AMED from database inception to 20/06/2023. We contacted experts in the field and performed citation searches to identify additional records. Title, abstract, full-text review, and data analysis were conducted in duplicate, with conflicts resolved by discussion among authors. Given the heterogeneity of study designs, meta-analysis was not deemed appropriate; instead, the results were tabulated in a narrative synthesis. The Joanna Briggs Institute Risk of Bias tool was used to assess study quality.ResultsWe identified 13 studies, with a total of 1,180 participants. In the 9 case series included, the psychotic symptoms of all but 3 out of 28 patients treated with APDs partially improved or fully resolved. 3 of the cohort studies reported an association between antipsychotic use and longer duration of psychotic episodes, 2 found similar results in both APD and non-APD groups, and 2 did not report control psychosis outcomes. When reported, seizure frequency was observed to remain unchanged or decrease following APD treatment.ConclusionAvailable evidence does not suggest that antipsychotics increase seizure risk in individuals with epilepsy. However, further data from randomised controlled trials and well-controlled cohort studies are urgently needed to draw more definitive conclusions.

Background. Secondary hospital-acquired fungal infections are common in critically-ill patients and mortality remains high despite antimicrobial therapy. Interleukin-7 (IL-7) is a potent immunotherapeutic agent that improves host immunity and has shown efficacy in bacterial and viral models of infection. This study examined the ability of IL-7, which is currently in multiple clinical trials (including hepatitis and human immunodeficiency virus), to improve survival in a clinically relevant 2-hit model of fungal sepsis. Methods. Mice underwent cecal ligation and puncture to induce peritonitis. Four days later, surviving mice had intravenous injection with Candida albicans. Following Candida infection, mice were treated with IL-7 or saline control. The effect of IL-7 on host immunity and survival was recorded. Results. IL-7 ameliorated the loss of immune effector cells and increased lymphocyte functions, including activation, proliferation, expression of adhesion molecules, and interferon-γ production. These beneficial effects of IL-7 were associated with an increase in global immunity as reflected by an enhanced delayed type hypersensitivity response and a 1.7-fold improvement in survival. Conclusions. The present findings showing that IL-7 improves survival in fungal sepsis, together with its previously reported efficacy in bacterial and viral infectious models, further supports its use as a novel immunotherapeutic in sepsis.

The objective of this experiment was to study and compare the effects of dietary supplementation of organic and inorganic zinc (Zn) on growth performance, nutrient utilisation and gene expression pattern of glucose transporter protein in peripheral blood mononuclear cells (PBMC) in Malabari kids. Fifteen, 3–4-month-old goat kids were divided into three groups uniformly by using completely randomised design (CRD). Group G1 was fed on basal diet as per NRC requirement, and G2 and G3 were fed on basal diet + 40 ppm Zn as inorganic zinc sulphate (ZnSO4) and 40 ppm Zn as organic Zn methionine, respectively, for a period of 91 days. Supplementation of inorganic and organic Zn had no significant effect on dry matter (DM) intake. The digestibility of crude protein (CP), ether extract (EE), neutral detergent fibre (NDF), hemicellulose and cellulose was significantly more in the organic Zn–supplemented group. The average daily gain and feed:gain ratio were significantly (p < 0.05) better in group G3 in comparison to G1 and G2, while the nitrogen retention was found to be (p < 0.01) higher in group G3 than in group G1. Zinc balance was found to be significantly (p < 0.01) increased in both supplemented groups with respect to unsupplemented group G1. The blood glucose level was (p < 0.01) lower in group G3 compared to group G1 suggesting the insulin-like activity of Zn. Serum Zn concentration was significantly (p < 0.01) increased in both Zn-supplemented groups. There was a significant (p < 0.05) rise in glucose transporter GLUT1 expression in groups G2 and G3 when compared to control group G1. Moreover, GLUT1 expression was found to be higher (p < 0.05) in group G3 as against the animals of group G2. Lowered blood glucose level might have stimulated more glucose transporter GLUT1 expression in PBMC. Organic Zn supplemented at 40 ppm level resulted in better growth performance, nutrient digestibility and nitrogen as well as Zn retention in goat kids. There was better absorption, and hence, less amount of Zn got excreted in the organic Zn–supplemented group.

Background/AimsProspective data on switching anti-vascular endothelial growth factors in patients with neovascular age-related macular degeneration (nAMD) who have previously shown no/partial response are limited. This prospective study assessed the effect of switching from aflibercept to ranibizumab on anatomical and functional outcomes in patients with persistent/recurrent disease activity.MethodsSAFARI (NCT02161575) was a 6-month, prospective, single-arm study conducted in the UK and Germany. Patients, meeting strict eligibility criteria for one of two subgroups (primary treatment failure or suboptimal treatment response), received 3 monthly intravitreal ranibizumab injections (0.5 mg). Thereafter, ranibizumab was administered pro re nata at monthly visits. The primary endpoint was change from baseline (CfB) to day 90 in central subfield retinal thickness (CSRT). Best-corrected visual acuity (BCVA) and retinal morphology parameters were assessed.ResultsOne hundred patients were enrolled (primary treatment failure, 1; suboptimal treatment response, 99). In the overall population, there was a significant CfB in median CSRT of −30.75 µm (95% CI −59.50,–20.50; p<0.0001) to day 90. Improvements were also observed in other quantitative and qualitative optical coherence tomography parameters. In Early Treatment Diabetic Retinopathy Study letters assessed by category, 55% and 59% of patients gained 0–≥15 letters versus baseline at day 90 and day 180, respectively. However, mean improvements in BCVA (CfB) to each time point were small (≤2 letters). No new safety signals were identified.ConclusionSwitching from aflibercept to ranibizumab led to a significant improvement in CSRT, with ~60% experiencing stabilised/improved BCVA. Therefore, patients with nAMD who have shown a suboptimal response to aflibercept may benefit from switching to ranibizumab.

Astrocytes respond to injury, infection, and inflammation in the central nervous system by acquiring reactive states in which they may become dysfunctional and contribute to disease pathology. A sub-state of reactive astrocytes induced by proinflammatory factors TNF, IL-1α, and C1q (“TIC”) has been implicated in many neurodegenerative diseases as a source of neurotoxicity. Here, we used an established human induced pluripotent stem cell (hiPSC) model to investigate the surface marker profile and proteome of TIC-induced reactive astrocytes. We propose VCAM1, BST2, ICOSL, HLA-E, PD-L1, and PDPN as putative, novel markers of this reactive sub-state. We found that several of these markers colocalize with GFAP + cells in post-mortem samples from people with Alzheimer’s disease. Moreover, our whole-cells proteomic analysis of TIC-induced reactive astrocytes identified proteins and related pathways primarily linked to potential engagement with peripheral immune cells. Taken together, our findings will serve as new tools to purify reactive astrocyte subtypes and to further explore their involvement in immune responses associated with injury and disease.

Background:Musa Balbisiana Colla (Plantain flower) comprising of significant nutrients likely vitamins, minerals and phytochemical substituents such as flavonoids. The nutrients present in the plantain flower possess numerous therapeutic beneficiaries. The phytoestrogens commonly known as flavonoids act against the deficiency of estrogen and aid in achieving the quality health status of women. Although there are surplus quantity of plantain flowers in India, it is not used by several people in the nation. Aim: The present research aims to develop and evaluate the nutritional composition and shelf life of Plantain Flower (Musa Balbisiana Colla) cookies. Methods: The plantain flower acquired from the farm has been processed as well as powdered. The cookies were prepared by utilizing plantain flower powder at the differential concentrations of 10%, 20%, and 30%. It is standardized by mixing with powdered sugar, jaggery, and butter. The sensory analysis of Plantain flower cookies was performed by 25 semi-trained panel members using a 9-point hedonic scale and the best-accepted product was nutritionally evaluated. Results:The plantain flower cookies with 20% variation proved to achieve excellent overall acceptability when compared to cookies with 10 and 30% variations. The high level of product acceptability has been achieved in 20% variation compared to 10% and 30% levels. The nutritional analysis of plantain flower cookies estimated the following nutrients per 100 g as energy: 373.99 kcal, carbohydrates: 66.53 g, Total fat: 7.95 g, protein: 9.07 g, dietary fiber: 9.69 g, sodium: 239 mg, potassium: 365 mg, calcium: 139 mg, magnesium: 131 mg, iron: 4.80 mg, total phenol content: 93.83 mg and flavonoids: 46.33 mg. Conclusion:The nutritionally enriched plantain flower possessing surplus health beneficiaries will be utilized by incorporating them in the diverse nutritional food preparations for perimenopausal women.