Hypercholesterolemia promotes early renal dysfunction in apolipoprotein E-deficient mice

<p>Abstract</p> <p>Background</p> <p>Aging and dyslipidemia are processes which can lead to deleterious consequences to renal function. Therefore, the aim of this study was to determine the effects of both hypercholesterolemia and aging on renal function in mice.</p> <p>Methods</p> <p>Male hypercholesterolemic apolipoprotein E-deficient mice (ApoE, n = 13) and age-matched C57BL/6 control mice (C57, n = 15) were studied at 2 (young) and 8 (adult) month-old. At each time point, animals were placed in metabolic cages for 24 hours to urine volume and urinary creatinine quantification. Blood samples were collected for serum cholesterol, urea and creatinine measurements. Glomerular filtration rate (GFR) was estimated through creatinine clearance determination. Mesangial expansion was evaluated by Periodic Acid Schiff staining, renal fibrosis was determined through Masson's trichrome staining and neuronal nitric oxide synthase (nNOS) expression in the kidney was performed by Western Blotting. To statistical analysis two-way ANOVA followed by Fisher's <it>post hoc </it>test was used.</p> <p>Results</p> <p>Total plasma cholesterol was increased about 5-fold in ApoE mice at both time points compared to C57 animals. At 2-month-old, GFR was already markedly reduced in ApoE compared to C57 mice (187 ± 28 vs 358 ± 92 μL/min, p < 0.05). Adult C57 (-77%) and ApoE (-50%) mice also presented a significant reduction of GFR. In addition, serum urea was significantly increased in young ApoE animals compared to C57 mice (11 ± 1.3 vs 7 ± 0.9 mmol/L, p < 0.01). A significant mesangial expansion was observed at 2-month old ApoE mice compared to C57 mice (35 ± 0.6 vs 30 ± 0.9%, respectively, p < 0.05), which was aggravated at 8-month old animals (40 ± 3 and 35 ± 3%, respectively). Tubulointersticial fibrosis was augmented at both young (17 ± 2%, p < 0.05) and adult (20 ± 1%, p < 0.05) ApoE mice compared to respective C57 age controls (8 ± 1 and 12 ± 2%, respectively). The expression of nNOS was markedly reduced in a time-dependent manner in both strains.</p> <p>Conclusions</p> <p>These data show that both hypercholesterolemia and aging contribute to the loss of renal function in mice.</p

Molecular Characterization and Patient Outcome of Melanoma Nodal Metastases and an Unknown Primary Site

Background Melanoma of unknown primary site (MUP) is not a completely understood entity with nodal metastases as the most common first clinical manifestation. The aim of this multicentric study was to assess frequency and type of oncogenic BRAF/NRAS/KIT mutations in MUP with clinically detected nodal metastases in relation to clinicopathologic features and outcome. Materials and Methods We analyzed series of 103 MUP patients (period: 1992-2010) after therapeutic lymphadenectomy (LND): 40 axillary, 47 groin, 16 cervical, none treated with BRAF inhibitors. We performed molecular characterization of BRAF/NRAS/KIT mutational status in nodal metastases using direct sequencing of respective coding sequences. Median follow-up time was 53 months. Results BRAF mutations were detected in 55 cases (53 %) (51 V600E, 93 %; 4 others, 7 %), and mutually exclusive NRAS mutations were found in 14 cases (14 %) (7 p.Q61R, 4 p.Q61K, 2 p.Q61H, 1 p.Q13R). We have not detected any mutations in KIT. The 5-year overall survival (OS) was 34 %; median was 24 months. We have not found significant correlation between mutational status (BRAF/NRAS) and OS; however, for BRAF or NRAS mutated melanomas we observed significantly shorter disease-free survival (DFS) when compared with wild-type melanoma patients (p = .04; 5-year DFS, 18 vs 19 vs 31 %, respectively). The most important factor influencing OS was number of metastatic lymph nodes >1 (p = .03). Conclusions Our large study on molecular characterization of MUP with nodal metastases showed that MUPs had molecular features similar to sporadic non-chronic-sun-damaged melanomas. BRAF/NRAS mutational status had negative impact on DFS in this group of patients. These observations might have potential implication for molecular-targeted therapy in MUPs

Mental health experiences of mothers in Jos, Nigeria: an interpretative phenomenological analysis

Objectives: There is an increasing mental health disease burden in mothers with infants and young children, especially in low- and middle-income countries such as Nigeria. Children of distressed mothers suffer early-life exposure from the effects of maternal distress which contributes to the risk of physical and mental health problems in their childhood and beyond. This study explored mental health lived experiences of mothers in Jos, Nigeria. Methods: Purposive and Snowball sampling techniques were adopted, and a total of 40 mothers participated with 8 to 11 participants in one of the four focus group discussions. Participants were between the ages of 18 and 43 years, self-identified as mothers with each having a child between the ages of 3 and 48months. Each focus group lasted approximately 60min and was audio-recorded. Interviews were transcribed verbatim and analysed using interpretative phenomenological analysis. Results: Three overarching themes emerged from the data set such as (1) experience of persisting psychological distress from the time of labour/birth; (2) cultural practices that influence feelings; and (3) anxiety due to limited knowledge about childcare, access to support and healthy food. Conclusion: Maternal mental health in Nigeria is under-researched and distressed mothers have limited knowledge about evidence-based early child development. The study recommends developing and testing culturally appropriate parenting interventions in Jos, Nigeria. This is likely to be beneficial for the mother and may also improve child outcomes

Culturally adapted psychological intervention for treating maternal depression in British mothers of African and Caribbean origin: a randomized controlled feasibility trial

Background: Women are likely to suffer from maternal depression due to childbirth difficulties and parenting responsibilities, leading to long-term negative consequences on their children and families. British mothers of African/Caribbean origin uptake of mental healthcare is low due to the lack of access to culturally appropriate care. Methods: A mixed-methods randomized controlled feasibility trial was adopted to test the appropriateness and acceptability of Learning Through Play plus Culturally adapted Cognitive Behaviour Therapy (LTP+CaCBT) for treating maternal depression compared with Psychoeducation (PE). Mothers (N = 26) aged 20–55 were screened for depression using the Patient Health Questionnaire (PHQ-9). Those who scored >5 on PHQ-9 were further interviewed using the Revised Clinical Interview Schedule to confirm the diagnosis and randomized into LTP+CaCBT (n = 13) or PE (n = 13) groups. Assessments were taken at baseline, end of the intervention at 3- and 6-months post-randomization. N = 2 focus groups (LTP+CaCBT, n = 12; PE, n = 7) and N = 8 individual interviews were conducted (LTP+CaCBT, n = 4; PE, n = 4). Results: The LTP+CaCBT group showed higher acceptability, feasibility and satisfaction levels than the PE group. Participants experienced the intervention as beneficial to their parenting skills with reduced depression and anxiety in the LTP+CaCBT compared to the PE group. Conclusions: This is the first feasibility trial of an integrated online parenting intervention for British African and Caribbean mothers. The results indicated that culturally adapted LTP+CaCBT is acceptable and feasible. There is a need to study the clinical and cost-effectiveness of LTP+CaCBT in an appropriately powered randomized control trial and include the child's outcomes

Psychological interventions for maternal depression among women of African and Caribbean origin: a systematic review

Background Maternal depression is a leading cause of disease burden for women worldwide; however, there are ethnic inequalities in access to psychological interventions in high-income countries (HICs). Culturally appropriate interventions might prove beneficial for African and Caribbean women living in HICs as ethnic minorities. Method The review strategy was formulated using PICo (Population, phenomenon of Interest, and Context) framework with Boolean operators (AND/OR/NOT) to ensure rigour in the use of search terms (“postpartum depression”, “maternal depression”, “postnatal depression”, “perinatal depression” “mental health”, “psychotherapy” “intervention”, “treatment”, “black Caribbean”, “black African”, “mothers” and “women”). Five databases, including Scopus, PsycINFO, Applied Social Science Index and Abstracts (ASSIA), ProQuest Central and Web of Science, were searched for published articles between 2000 and July 2020. 13 studies met the inclusion criteria and the relevant data extracted were synthesised and thematically analysed. Results Data synthesis and analysis of included studies produced four themes including (i) enhance parenting confidence and self-care; (ii) effective mother-child interpersonal relationship; (iii) culturally appropriate maternal care; and (iv) internet-mediated care for maternal depression. Conclusion In the quest to address maternal mental health disparities among mothers of African and Caribbean origin in HICs, the authors recommend culturally adapted psychological interventions to be tested in randomised control trials

Targeting Wnt signaling for improved glioma immunotherapy

IntroductionDespite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)–including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes.MethodsUsing multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated in vitro cytostatic effects and a switch from proliferation to differentiation after treatment with ICG-001.ResultsIn these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene Survivin/BIRC5–a hallmark of Wnt/CBP/β-catenin inhibition. We found that in a syngeneic mouse model of glioma (K-luc), ICG-001 treatment enhanced tumor infiltration by CD3+ and CD8+ cells with increased expression of the vascular endothelial marker CD31 (PECAM-1). We also observed differential gene expression and induced immune cell infiltration in tumors pretreated with ICG-001 and then treated with CAR T cells as compared with single treatment groups or when ICG-001 treatment was administered after CAR T cell therapy.DiscussionWe conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients