Aware of the important benefits of human milk, most U.S. women initiate breastfeeding but difficulties with milk supply lead some to quit earlier than intended. Yet, the contribution of maternal ...physiology to lactation difficulties remains poorly understood. Human milk fat globules, by enveloping cell contents during their secretion into milk, are a rich source of mammary cell RNA. Here, we pair this non-invasive mRNA source with RNA-sequencing to probe the milk fat layer transcriptome during three stages of lactation: colostral, transitional, and mature milk production. The resulting transcriptomes paint an exquisite portrait of human lactation. The resulting transcriptional profiles cluster not by postpartum day, but by milk Na:K ratio, indicating that women sampled during similar postpartum time frames could be at markedly different stages of gene expression. Each stage of lactation is characterized by a dynamic range (10(5)-fold) in transcript abundances not previously observed with microarray technology. We discovered that transcripts for isoferritins and cathepsins are strikingly abundant during colostrum production, highlighting the potential importance of these proteins for neonatal health. Two transcripts, encoding β-casein (CSN2) and α-lactalbumin (LALBA), make up 45% of the total pool of mRNA in mature lactation. Genes significantly expressed across all stages of lactation are associated with making, modifying, transporting, and packaging milk proteins. Stage-specific transcripts are associated with immune defense during the colostral stage, up-regulation of the machinery needed for milk protein synthesis during the transitional stage, and the production of lipids during mature lactation. We observed strong modulation of key genes involved in lactose synthesis and insulin signaling. In particular, protein tyrosine phosphatase, receptor type, F (PTPRF) may serve as a biomarker linking insulin resistance with insufficient milk supply. This study provides the methodology and reference data set to enable future targeted research on the physiological contributors of sub-optimal lactation in humans.
Introduction: This service-learning, health promotion project used Leininger's Culture Care Theory to engage Baccalaureate Nursing students in a health promotion initiative specific to Hispanic ...community members. Methods: Thirty-seven students examined population health data, surveyed Hispanic community members to identify health priorities, and developed a population-specific intervention on diet and risk factors for diabetes. Students created a 5-min script focused on healthy eating plans with recognition of traditional foods associated with the Hispanic culture. Students delivered the script to community members attending an annual Hispanic Heritage Festival. Results: Seventy-six percent of the 488 community participants reported increased knowledge about diabetes risk factors and healthy eating habits. Each student completed a self-reflection on how the project impacted their transcultural skills and reported increased confidence related to engagement and communication with the Hispanic community. Discussion/Significance: Incorporating community-based service-learning into the undergraduate curricula is a powerful educational approach that can enhance students’ ability to provide culturally congruent nursing care.
Abstract
Objectives
To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin ...pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population.
Methods
A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children’s Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, ‘clinician-guided’, were compared with alternative ‘CDS-guided’ dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10–15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test.
Results
A total of n=144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P<0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P<0.0001).
Conclusions
In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children.
The mechanism of colistin-induced neurotoxicity is still unknown. Our recent study (L. Zhang, Y. H. Zhao, W. J. Ding, G. Z. Jiang, Z. Y. Lu, L. Li, J. L. Wang, J. Li, and J. C. Li, Antimicrob Agents ...Chemother 59:2189-2197, 2015, http://dx.doi.org/10.1128/AAC.04092-14; H. Jiang, J. C. Li, T. Zhou, C. H. Wang, H. Zhang, and H. Wang, Int J Mol Med 33:1298-1304, 2014, http://dx.doi.org/10.3892/ijmm.2014.1684) indicates that colistin induces autophagy and apoptosis in rat adrenal medulla PC-12 cells, and there is interplay between both cellular events. As an important cellular stress sensor, phosphoprotein p53 can trigger cell cycle arrest and apoptosis and regulate autophagy. The aim of the present study was to investigate the involvement of the p53 pathway in colistin-induced neurotoxicity in PC-12 cells. Specifically, cells were treated with colistin (125 μg/ml) in the absence and presence of a p53 inhibitor, pifithrin-α (PFT-α; 20 nM), for 12 h and 24 h, and the typical hallmarks of autophagy and apoptosis were examined by fluorescence/immunofluorescence microscopy and electron microscopy, real-time PCR, and Western blotting. The results indicate that colistin had a stimulatory effect on the expression levels of the target genes and proteins involved in autophagy and apoptosis, including LC3-II/I, p53, DRAM (damage-regulated autophagy modulator), PUMA (p53 upregulated modulator of apoptosis), Bax, p-AMPK (activated form of AMP-activated protein kinase), and caspase-3. In contrast, colistin appeared to have an inhibitory effect on the expression of p-mTOR (activated form of mammalian target of rapamycin), which is another target protein in autophagy. Importantly, analysis of the levels of p53 in the cells treated with colistin revealed an increase in nuclear p53 at 12 h and cytoplasmic p53 at 24 h. Pretreatment of colistin-treated cells with PFT-α inhibited autophagy and promoted colistin-induced apoptosis. This is the first study to demonstrate that colistin-induced autophagy and apoptosis are associated with the p53-mediated pathway.
Sunscreen use and dietary antioxidants are advocated as preventives of skin aging, but supporting evidence is lacking.
To determine whether regular use of sunscreen compared with discretionary use or ...β-carotene supplements compared with placebo retard skin aging, measured by degree of photoaging.
Randomized, controlled, community-based intervention. (Australian New Zealand Clinical Trials Registry: ACTRN12610000086066).
Nambour, Australia (latitude 26° S).
903 adults younger than 55 years out of 1621 adults randomly selected from a community register.
Random assignment into 4 groups: daily use of broad-spectrum sunscreen and 30 mg of β-carotene, daily use of sunscreen and placebo, discretionary use of sunscreen and 30 mg of β-carotene, and discretionary use of sunscreen and placebo.
Change in microtopography between 1992 and 1996 in the sunscreen and β-carotene groups compared with controls, graded by assessors blinded to treatment allocation.
The daily sunscreen group showed no detectable increase in skin aging after 4.5 years. Skin aging from baseline to the end of the trial was 24% less in the daily sunscreen group than in the discretionary sunscreen group (relative odds, 0.76 95% CI, 0.59 to 0.98). β-Carotene supplementation had no overall effect on skin aging, although contrasting associations were seen in subgroups with different severity of aging at baseline.
Some outcome data were missing, and power to detect moderate treatment effects was modest.
Regular sunscreen use retards skin aging in healthy, middle-aged men and women. No overall effect of β-carotene on skin aging was identified, and further study is required to definitively exclude potential benefit or potential harm.
National Health and Medical Research Council of Australia.
Both parametric and nonparametric methods have been proposed to support model-informed precision dosing (MIPD). However, which approach leads to better models remains uncertain. Using open-source ...software, these 2 statistical approaches for model development were compared using the pharmacokinetics of vancomycin in a challenging subpopulation of class 3 obesity.
Patients on vancomycin at the University of Vermont Medical Center from November 1, 2021, to February 14, 2023, were entered into the MIPD software. The inclusion criteria were body mass index (BMI) of at least 40 kg/m2 and 1 or more vancomycin levels. A parametric model was created using nlmixr2/NONMEM, and a nonparametric model was created using metrics. Then, a priori and a posteriori predictions were evaluated using the normalized root mean squared error (nRMSE) for precision and the mean percentage error (MPE) for bias. The parametric model was evaluated in a simulated MIPD context using an external validation dataset.
In total, 83 patients were included in the model development, with a median age of 56.6 years (range: 24-89 years), and a median BMI of 46.3 kg/m2 (range: 40-70.3 kg/m2). Both parametric and nonparametric models were 2-compartmental, with creatinine clearance and fat-free mass as covariates to c clearance and volume parameters, respectively. The a priori MPE and nRMSE for the parametric versus nonparametric models were -6.3% versus 2.69% and 27.2% versus 30.7%, respectively. The a posteriori MPE and RMSE were 0.16% and 0.84%, and 13.8% and 13.1%. The parametric model matched or outperformed previously published models on an external validation dataset (n = 576 patients).
Minimal differences were found in the model structure and predictive error between the parametric and nonparametric approaches for modeling vancomycin class 3 obesity. However, the parametric model outperformed several other models, suggesting that institution-specific models may improve pharmacokinetics management.
IMPORTANCE: With emerging new systemic treatments for metastatic melanoma, early detection of disease recurrence is increasingly important. OBJECTIVE: To investigate the risk of melanoma recurrence ...in patients with a localized melanoma at a high risk of metastasis. DESIGN, SETTING, AND PARTICIPANTS: A total of 1254 patients with newly diagnosed, histologically confirmed tumor category T1b to T4b melanoma in Queensland, Australia, were recruited prospectively between October 1, 2010, and October 1, 2014, for participation in a cohort study. Data analysis was conducted from February 8, 2018, to February 20, 2019. We used Cox proportional hazards regression analysis to examine associations between patient and tumor factors and melanoma recurrence. EXPOSURES: Disease-free survival (DFS) by melanoma tumor category defined by the 7th vs 8th editions of the AJCC Cancer Staging Manual (AJCC 7 vs AJCC 8). MAIN OUTCOMES AND MEASURES: Melanoma recurrences were self-reported through follow-up questionnaires administered every 6 months and confirmed by histologic or imaging findings. RESULTS: Of 1254 patients recruited, 825 individuals (65.8%) agreed to participate. Thirty-six were found to be ineligible after providing consent and a further 89 patients were excluded after reclassifying tumors using AJCC 8, leaving 700 participants with high-risk primary melanoma (mean SD age, 62.2 13.5 years; 410 58.6% men). Independent predictors of recurrence were head or neck site of primary tumor, ulceration, thickness, and mitotic rate greater than 3/mm2 (hazard ratio, 2.36; 95% CI, 1.19-4.71). Ninety-four patients (13.4%) developed a recurrence within 2 years of diagnosis: 66 tumors (70.2%) were locoregional, and 28 tumors (29.8%) developed at distant sites. After surgery for locoregional disease, 37 of 64 patients (57.8%) remained disease free at 2 years, 7 patients (10.9%) developed new locoregional recurrence, and 20 patients (31.3%), developed distant disease. Two-year DFS was similar when comparing AJCC 7 and AJCC 8, for T1b (AJCC 7, 253 93.3% DFS; AJCC 8, 242 93.0% DFS) and T4b (AJCC 7 and AJCC 8, 50 68.0% DFS category tumors in both editions. Patients with T2a to T4a tumors who did not have a sentinel lymph node biopsy (SLNB) at diagnosis had lower DFS than patients with the same tumor category and a negative SLNB (T2a: 136 91.1%; 95% CI, 86.4-95.9 vs 96 96.9%; 95 % CI, 93.4-100.0; T4a: 33 78.8%; 95% CI, 64.8-92.7 vs 6 83.3; 95% CI, 53.5-100.0). CONCLUSIONS AND RELEVANCE: These findings suggest that 13.4% of patients with a high-risk primary melanoma will experience disease recurrence within 2 years. Head or neck location of initial tumor, SLNB positivity, and signs of rapid tumor growth may be associated with primary melanoma recurrence.
Inflammation is implicated in chronic diseases including cancer and CVD, which are major causes of mortality. Diet can influence inflammation status. We therefore examined whether the inflammatory ...potential of a person's diet is associated with mortality.
The inflammatory potential of the usual diet was assessed by calculating Dietary Inflammatory Index (DII) scores from repeated FFQ data (collected in 1992, 1994 and 1996), placing each participant's diet on a continuum from anti- to pro-inflammatory. DII scores were analysed as a continuous variable and as categories by creating quartile groups. Death registry data were used to ascertain all-cause mortality and separately mortality from CVD, cancers and other causes between 1992 and 2022. Cox proportional hazard regression analysis was used to calculate adjusted hazard ratios (HR) with 95 % CI, comparing higher and lowest quartile groups, or HR change per one DII unit increase.
Nambour, Australia.
A community-based sample of 1440 adults aged 25-75 years.
During follow-up, 488 participants died, including 188 from CVD, 151 from cancer and 170 from other causes. Participants in the most pro-inflammatory diet group were at increased risk of all-cause mortality (HR
= 1·55; 95 % CI 1·19, 2·03;
< 0·001) and other-cause mortality (HR
= 1·69; 95 % CI 1·12, 2·54;
0·01). A one-unit increase in DII score was associated with a 36 % increased risk of CVD among those younger than 55 years of age (HR for a one-unit increase in DII score 1·36, 95 % CI 1·04, 1·78). The risk of cancer mortality was also increased for those with a more pro-inflammatory diet in age ≤ 55 years (HR for a one-unit increase in DII score 1·20, 95 % CI 1·02, 1·40) and age 56-65 years (HR for a one-unit increase in DII score 1·11, 95 % CI 1·00, 1·23).
A pro-inflammatory diet increases the risk of all-cause mortality. Our results support the promotion of anti-inflammatory diets to help promote longevity.
Nuclear hormone receptors (NHRs) regulate the expression of proteins that control aspects of reproduction, development and metabolism, and are major therapeutic targets. However, NHRs are ubiquitous ...and participate in multiple physiological processes. Drugs that act at NHRs are therefore commonly restricted by toxicity, often at nontarget organs. For endogenous NHR ligands, intracellular lipid-binding proteins, including the fatty acid-binding proteins (FABPs), can chaperone ligands to the nucleus and promote NHR activation. Drugs also bind FABPs, raising the possibility that FABPs similarly regulate drug activity at the NHRs. Here, we investigate the ability of FABP1 and FABP2 (intracellular lipid-binding proteins that are highly expressed in tissues involved in lipid metabolism, including the liver and intestine) to influence drug-mediated activation of the lipid regulator peroxisome proliferator-activated receptor (PPAR) α. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARα activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARα. Nuclear accumulation of FABP on drug binding is driven largely by reduced nuclear egress rather than an increased rate of nuclear entry. Importin binding assays indicate that nuclear access occurs via an importin-independent mechanism. Together, the data suggest that specific drug-FABP complexes can interact with PPARα to effect nuclear accumulation of FABP and NHR activation. Because FABPs are expressed in a regionally selective manner, this may provide a means to tailor the patterns of NHR drug activation in a tissue-specific manner.
Background: Fatty acid-binding proteins (FABPs) chaperone intracellular transport of lipophilic ligands.
Results: FABP1 and FABP2 differentially promote drug activation of peroxisome proliferator-activated receptor α (PPARα) via ligand-dependent protein-protein interactions.
Conclusion: Drug activation of PPARα is regulated by the presence of different FABPs.
Significance: FABPs may act in a tissue-specific manner to enhance the selectivity of PPARα agonists.
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