Effective reduction in seizure severity and prevention of a fatty liver by a novel low ratio ketogenic diet composition in the rapid kindling rat model of epileptogenesis.

Drug-resistant epilepsy patients may benefit from non-pharmacological therapies, such as the ketogenic diet (KD). However, its high fat content poses compliance challenges and metabolic risks. To mitigate this, we developed a novel KD composition with less fat and additional nutrients (citrate, nicotinamide riboside, and omega-3 fatty acids) for ketone-independent neuroprotection. The efficacy, metabolic and neuropathological effects of the novel KD and a classic KD were compared to a control diet in the rapid kindling model of temporal lobe epilepsy. Both KD groups entered ketosis before kindling onset, with higher ketone levels in the classic KD group. Remarkably, rats on the novel KD had slower progression of behavioral seizures as compared to rats on a control diet, while this was not the case for rats on a classic KD. Both KDs reduced electrographic after-discharge duration, preserved neurons in the dorsal hippocampus, and normalized activity in open field tests. The novel KD, despite lower fat and ketone levels, demonstrated effective reduction of behavioral seizure severity while the classic KD did not, suggesting alternative mode(s) of action are involved. Additionally, the novel KD significantly mitigated liver triglyceride and plasma fatty acid levels compared to the classic KD, indicating a reduced risk of long-term liver steatosis. Our findings highlight the potential of the novel KD to enhance therapeutic efficacy and compliance in epilepsy patients.

A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy.

The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the ß-hydroxybutyrate (ßHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-ßHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the ßHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the ßHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.

Muscle Protein Synthesis with a Hybrid Dairy and Plant-Based Protein Blend (P4) Is Equal to Whey Protein in a Murine Ageing Model after Fasting.

P4, a specific combination of dairy proteins (whey and casein) and plant-based protein isolates (pea and soy), has been shown to provide a more balanced amino acid (AA) profile than its single constituent proteins; however, less is known about how this translates to muscle protein synthesis (MPS). The aim of this study was to investigate the effect of P4 compared to whey or casein against fasted control on MPS. C57BL/6J mice, aged 25 months, were fasted overnight, followed by oral gavage of either whey, P4, casein, or water as a fasted control. Thirty minutes after ingestion, puromycin (0.04 µmol∙g-1 bodyweight) was subcutaneously injected; 30-min thereafter, mice were sacrificed. MPS was measured by the SUnSET method, and signalling proteins were determined in the left-tibialis anterior (TA) muscle by the WES technique. AA composition was determined in plasma and right-TA muscle. Dried blood spots (DBS) were analysed for postprandial AA dynamics at 10, 20, 45, 60 min. MPS was 1.6-fold increased with whey (p = 0.006) and 1.5-fold with P4 compared to fasted (p = 0.008), while no change was seen with casein. This was confirmed by a significant increase of phosphorylated/total ratio of 4E-BP1 for both whey (p = 0.012) and P4 (p = 0.001). No changes were observed in p70S6K and mTOR phosphorylation/total ratio with whey or P4. Intramuscular leucine levels were lower for P4 (0.71 µmol∙g dry weight-1) compared to whey (0.97 µmol∙g dry weight-1) (p = 0.0007). Ten minutes postprandial, DBS showed significantly increased blood AA levels of BCAAs, histidine, lysine, threonine, arginine, and tyrosine for P4 versus fasted. In conclusion, a hybrid mix of dairy and plant-based proteins (P4) resulted in a MPS response that was similar to whey protein in aged mice after fasting. This suggests that other anabolic triggers beyond leucine or the well-balanced amino acid profile and bioavailability of the blend benefit stimulation of MPS.

A novel orthotopic mouse model replicates human lung cancer cachexia.

INTRODUCTION: Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia. METHODS: Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D ; p53R172HΔG ) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis. RESULTS: Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (-13.7 ± 5.7%; P < 0.01), muscle mass (-13.8 ± 8.1%; P < 0.01) and muscle strength (-25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia. CONCLUSIONS: We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.

The Modulatory Effects of Fatty Acids on Cancer Progression.

Cancer is the second leading cause of death worldwide and the global cancer burden rises rapidly. The risk factors for cancer development can often be attributed to lifestyle factors, of which an unhealthy diet is a major contributor. Dietary fat is an important macronutrient and therefore a crucial part of a well-balanced and healthy diet, but it is still unclear which specific fatty acids contribute to a healthy and well-balanced diet in the context of cancer risk and prognosis. In this review, we describe epidemiological evidence on the associations between the intake of different classes of fatty acids and the risk of developing cancer, and we provide preclinical evidence on how specific fatty acids can act on tumor cells, thereby modulating tumor progression and metastasis. Moreover, the pro- and anti-inflammatory effects of each of the different groups of fatty acids will be discussed specifically in the context of inflammation-induced cancer progression and we will highlight challenges as well as opportunities for successful application of fatty acid tailored nutritional interventions in the clinic.

Effects of a nutritional intervention on impaired behavior and cognitive function in an emphysematous murine model of COPD with endotoxin-induced lung inflammation.

One cluster of the extrapulmonary manifestations in chronic obstructive pulmonary disease (COPD) is related to the brain, which includes anxiety, depression and cognitive impairment. Brain-related comorbidities are related to worsening of symptoms and increased mortality in COPD patients. In this study, a murine model of COPD was used to examine the effects of emphysema and repetitive pulmonary inflammatory events on systemic inflammatory outcomes and brain function. In addition, the effect of a dietary intervention on brain-related parameters was assessed. Adult male C57Bl/6J mice were exposed to elastase or vehicle intratracheally (i.t.) once a week on three consecutive weeks. Two weeks after the final administration, mice were i.t. exposed to lipopolysaccharide (LPS) or vehicle for three times with a 10 day interval. A dietary intervention enriched with omega-3 PUFAs, prebiotic fibers, tryptophan and vitamin D was administered from the first LPS exposure onward. Behavior and cognitive function, the degree of emphysema and both pulmonary and systemic inflammation as well as blood-brain barrier (BBB) integrity and neuroinflammation in the brain were assessed. A lower score in the cognitive test was observed in elastase-exposed mice. Mice exposed to elastase plus LPS showed less locomotion in the behavior test. The enriched diet seemed to reduce anxiety-like behavior over time and cognitive impairments associated with the presented COPD model, without affecting locomotion. In addition, the enriched diet restored the disbalance in splenic T-helper 1 (Th1) and Th2 cells. There was a trend toward recovering elastase plus LPS-induced decreased expression of occludin in brain microvessels, a measure of BBB integrity, as well as improving expression levels of kynurenine pathway markers in the brain by the enriched diet. The findings of this study demonstrate brain-associated comorbidities - including cognitive and behavioral impairments - in this murine model for COPD. Although no changes in lung parameters were observed, exposure to the specific enriched diet in this model appeared to improve systemic immune disbalance, BBB integrity and derailed kynurenine pathway which may lead to reduction of anxiety-like behavior and improved cognition.

Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1ß, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

Fatty Acids as a Tool to Boost Cancer Immunotherapy Efficacy.

Although immunotherapy represents one of the most potent therapeutic anti-cancer approaches, only a limited number of patients shows clinical benefit. Recent evidence suggests that patients' nutritional status plays a major role in immunotherapy outcome. Fatty acids are essential in a balanced diet and well-known to influence the immune response. Moreover, short-chain fatty acids (SCFAs) show beneficial effects in metabolic disorders as well as in cancer and polyunsaturated fatty acids (PUFAs) contribute to body weight and fat free mass preservation in cancer patients. In line with these data, several studies imply a role for SCFAs and PUFAs in boosting the outcome of immunotherapy. In this review, we specifically focus on mechanistic data showing that SCFAs modulate the immunogenicity of tumor cells and we discuss the direct effects of SCFAs and PUFAs on the immune system in the context of cancer. We provide preclinical and clinical evidence indicating that SCFAs and PUFAs may have the potential to boost immunotherapy efficacy. Finally, we describe the challenges and address opportunities for successful application of nutritional interventions focusing on SCFAs and PUFAs to increase the therapeutic potential of immunotherapeutic approaches for cancer.

Changes in intestinal homeostasis and immunity in a cigarette smoke- and LPS-induced murine model for COPD: the lung-gut axis.

Chronic obstructive pulmonary disease (COPD) is often associated with intestinal comorbidities. In this study, changes in intestinal homeostasis and immunity in a cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD model were investigated. Mice were exposed to cigarette smoke or air for 72 days, except days 42, 52, and 62 on which the mice were treated with saline or LPS via intratracheal instillation. Cigarette smoke exposure increased the airway inflammatory cell numbers, mucus production, and different inflammatory mediators, including C-reactive protein (CRP) and keratinocyte-derived chemokine (KC), in bronchoalveolar lavage (BAL) fluid and serum. LPS did not further impact airway inflammatory cell numbers or mucus production but decreased inflammatory mediator levels in BAL fluid. T helper (Th) 1 cells were enhanced in the spleen after cigarette smoke exposure; however, in combination with LPS, cigarette exposure caused an increase in Th1 and Th2 cells. Histomorphological changes were observed in the proximal small intestine after cigarette smoke exposure, and addition of LPS had no effect. Cigarette smoke activated the intestinal immune network for IgA production in the distal small intestine that was associated with increased fecal sIgA levels and enlargement of Peyer's patches. Cigarette smoke plus LPS decreased fecal sIgA levels and the size of Peyer's patches. In conclusion, cigarette smoke with or without LPS affects intestinal health as observed by changes in intestinal histomorphology and immune network for IgA production. Elevated systemic mediators might play a role in the lung-gut cross talk. These findings contribute to a better understanding of intestinal disorders related to COPD.

Increased exploration and hyperlocomotion in a cigarette smoke and LPS-induced murine model of COPD: linking pulmonary and systemic inflammation with the brain.

Brain-related comorbidities are frequently observed in chronic obstructive pulmonary disease (COPD) and are related to increased disease progression and mortality. To date, it is unclear which mechanisms are involved in the development of brain-related problems in COPD. In this study, a cigarette smoke and lipopolysaccharide (LPS) exposure murine model was used to induce COPD-like features and assess the impact on brain and behavior. Mice were daily exposed to cigarette smoke for 72 days, except for days 42, 52, and 62, on which mice were intratracheally exposed to the bacterial trigger LPS. Emphysema and pulmonary inflammation as well as behavior and brain pathology were assessed. Cigarette smoke-exposed mice showed increased alveolar enlargement and numbers of macrophages and neutrophils in bronchoalveolar lavage. Cigarette smoke exposure resulted in lower body weight, which was accompanied by lower serum leptin levels, more time spent in the inner zone of the open field, and decreased claudin-5 and occludin protein expression levels in brain microvessels. Combined cigarette smoke and LPS exposure resulted in increased locomotion and elevated microglial activation in the hippocampus of the brain. These novel findings show that systemic inflammation observed after combined cigarette smoke and LPS exposure in this COPD model is associated with increased exploratory behavior. Findings suggest that neuroinflammation is present in the brain area involved in cognitive functioning and that blood-brain barrier integrity is compromised. These findings can contribute to our knowledge about possible processes involved in brain-related comorbidities in COPD, which is valuable for optimizing and developing therapy strategies.

Effect of targeted nutrient supplementation on physical activity and health-related quality of life in COPD: study protocol for the randomised controlled NUTRECOVER trial.

INTRODUCTION: Physical and mental health are often affected in chronic obstructive pulmonary disease (COPD) adversely affecting disease course and quality of life. Abnormalities in whole body and cellular energy metabolism, dietary and plasma nutrient status and intestinal permeability have been well established in these patients as systemic determinants of functional decline and underexplored treatable traits. The aim of this study is to investigate the efficacy of 1 year targeted nutrient supplementation on physical activity level and health-related quality of life in patients with COPD. METHODS AND ANALYSIS: This study is a single-centre randomised, placebo-controlled, double-blind trial in 166 patients with COPD recruited from multiple hospitals in the Netherlands. The intervention group will receive a multinutrient supplement, including vitamin D, tryptophan, long-chain polyunsaturated fatty acids and prebiotic dietary fibres as main components (94 kCal per daily dose). The control group will receive an isocaloric isonitrogenous placebo. Both groups will ingest one portion per day for at least 12 months and will additionally receive counselling on healthy lifestyle and medical adherence over the course of the study. Coprimary outcomes are physical activity assessed by triaxial accelerometry and health-related quality of life measured by the EuroQol-5 dimensions questionnaire. Secondary outcomes are cognitive function, psychological well-being, physical performance, patient-reported outcomes and the metabolic profile assessed by body composition, systemic inflammation, plasma nutrient levels, intestinal integrity and microbiome composition. Outcomes will be measured at baseline and after 12 months of supplementation. In case patients are hospitalised for a COPD exacerbation, a subset outcome panel will be measured during a 4-week recovery period after hospitalisation. ETHICS AND DISSEMINATION: This study was approved by the local Ethics Committee of Maastricht University. Subjects will be included after written informed consent is provided. Study outcomes will be disseminated through presentations at (inter)national conferences and through peer-reviewed journals. TRIAL REGISTRATION: NCT03807310.

Intratracheal administration of solutions in mice; development and validation of an optimized method with improved efficacy, reproducibility and accuracy.

Animal models are still vital in the field of respiratory disease research. To improve the accuracy and consistency of the dose of specific compounds administered specifically in the respiratory tract, it is important to optimize and to compare the technique to currently available techniques. In this study, an optimized intubation-mediated intratracheal administration (IMIT) technique is described and compared to oropharyngeal aspiration (OA). Adult female Balb/c mice were treated with Evans Blue using IMIT or OA and sacrificed after a short recovery to observe the distribution of solutions throughout the lungs. Additionally, mice were treated with increasing doses of lipopolysaccharide (LPS) or saline to compare efficacy of both techniques. Inflammatory cell numbers in bronchoalveolar lavage were quantified 24 h post-administration. Evans Blue staining revealed a more homogeneous distribution and less variability among animals treated using IMIT as compared to OA. Higher inflammatory cell numbers were observed in IMIT mice compared to OA mice after exposure to vehicle or the lowest LPS concentration. This study shows that the optimized IMIT is superior to OA with regards to efficacy, reproducibility and accuracy. This IMIT method can be deployed to refine 3R animal welfare aspects of the experimental design and improve the reproducibility of respiratory disease mouse models.

Nutrition in the prevention and management of sarcopenia - A special focus on Asian Indians.

Sarcopenia, characterized by loss of muscle mass and strength, is common in advanced old age but can be accelerated by chronic disease, malnutrition and physical inactivity. Early initiation of intervention to achieve and maintain a higher peak muscle mass and strength may allow for prevention or delay of sarcopenia and facilitate independent living even in old age. In this context, malnutrition, a significant contributor to sarcopenia, is often overlooked among the Indian population. Maintenance of an optimal energy and protein balance with adequate physical activity level is essential to preserve physical function in the aging population. However, research on the role of micronutrients in muscle maintenance, is still in its infancy. This narrative review, therefore, aims to explore the current status of International and Indian research on the role of nutrition in sarcopenia mitigation and the way forward.

Gut microbiota and short-chain fatty acid alterations in cachectic cancer patients.

BACKGROUND: Cancer cachexia is characterized by a negative energy balance, muscle and adipose tissue wasting, insulin resistance, and systemic inflammation. Because of its strong negative impact on prognosis and its multifactorial nature that is still not fully understood, cachexia remains an important challenge in the field of cancer treatment. Recent animal studies indicate that the gut microbiota is involved in the pathogenesis and manifestation of cancer cachexia, but human data are lacking. The present study investigates gut microbiota composition, short-chain fatty acids (SCFA), and inflammatory parameters in human cancer cachexia. METHODS: Faecal samples were prospectively collected in patients (N = 107) with pancreatic cancer, lung cancer, breast cancer, or ovarian cancer. Household partners (N = 76) of the patients were included as healthy controls with similar diet and environmental conditions. Patients were classified as cachectic if they lost >5% body weight in the last 6 months. Gut microbiota composition was analysed by sequencing of the 16S rRNA V4 gene region. Faecal SCFA levels were quantified by gas chromatography. Faecal calprotectin was assessed with enzyme-linked immunosorbent assay. Serum C-reactive protein and leucocyte counts were retrieved from medical records. RESULTS: Cachexia prevalence was highest in pancreatic cancer (66.7%), followed by ovarian cancer (25%), lung cancer (20.8%), and breast cancer (17.3%). Microbial α-diversity was not significantly different between cachectic cancer patients (N = 33), non-cachectic cancer patients (N = 74), or healthy controls (N = 76) (species richness P = 0.31; Shannon effective index P = 0.46). Community structure (ß-diversity) tended to differ between these groups (P = 0.053), although overall differences were subtle and no clear clustering of samples was observed. Proteobacteria (P < 0.001), an unknown genus from the Enterobacteriaceae family (P < 0.01), and Veillonella (P < 0.001) were more abundant among cachectic cancer patients. Megamonas (P < 0.05) and Peptococcus (P < 0.001) also showed differential abundance. Faecal levels of all SCFA tended to be lower in cachectic cancer patients, but only acetate concentrations were significantly reduced (P < 0.05). Faecal calprotectin levels were positively correlated with the abundance of Peptococcus, unknown Enterobacteriaceae, and Veillonella. We also identified several correlations and interactions between clinical and microbial parameters. CONCLUSIONS: This clinical study provided the first insights into the alterations of gut microbiota composition and SCFA levels that occur in cachectic cancer patients and how they are related to inflammatory parameters. These results pave the way for further research examining the role of the gut microbiota in cancer cachexia and its potential use as therapeutic target.

Deep Learning Based Automated Orthotopic Lung Tumor Segmentation in Whole-Body Mouse CT-Scans.

Lung cancer is the leading cause of cancer related deaths worldwide. The development of orthotopic mouse models of lung cancer, which recapitulates the disease more realistically compared to the widely used subcutaneous tumor models, is expected to critically aid the development of novel therapies to battle lung cancer or related comorbidities such as cachexia. However, follow-up of tumor take, tumor growth and detection of therapeutic effects is difficult, time consuming and requires a vast number of animals in orthotopic models. Here, we describe a solution for the fully automatic segmentation and quantification of orthotopic lung tumor volume and mass in whole-body mouse computed tomography (CT) scans. The goal is to drastically enhance the efficiency of the research process by replacing time-consuming manual procedures with fast, automated ones. A deep learning algorithm was trained on 60 unique manually delineated lung tumors and evaluated by four-fold cross validation. Quantitative performance metrics demonstrated high accuracy and robustness of the deep learning algorithm for automated tumor volume analyses (mean dice similarity coefficient of 0.80), and superior processing time (69 times faster) compared to manual segmentation. Moreover, manual delineations of the tumor volume by three independent annotators was sensitive to bias in human interpretation while the algorithm was less vulnerable to bias. In addition, we showed that besides longitudinal quantification of tumor development, the deep learning algorithm can also be used in parallel with the previously published method for muscle mass quantification and to optimize the experimental design reducing the number of animals needed in preclinical studies. In conclusion, we implemented a method for fast and highly accurate tumor quantification with minimal operator involvement in data analysis. This deep learning algorithm provides a helpful tool for the noninvasive detection and analysis of tumor take, tumor growth and therapeutic effects in mouse orthotopic lung cancer models.

Phosphorus bioaccessibility measured in four amino acid-based formulas using in-vitro batch digestion translates well into phosphorus bioavailability in mice.

OBJECTIVE: The aim of this study was to quantify the bioaccessibility of phosphorus from amino acid-based formulas (AAFs) under different digestive conditions. METHODS: We developed in-vitro batch digestion models with stomach digestion at different pH mimicking the normal digestive condition and conditions representing use of acid-suppressive medication. To validate bioaccessibility findings, we devised a low phosphorus murine model to test phosphorus bioavailability under compromised digestive conditions using proton pump inhibitors (PPIs) to neutralize stomach pH. RESULTS: In vitro phosphorus bioaccessibility of AAFs Neocate® Infant and Neocate Junior ranged between 57% and 65% under normal digestive conditions for infants (stomach pH 3.5) and between 38% and 46% under conditions that simulated bypass of stomach acidification, which is comparable to control diet and two EleCare® AAFs. In vivo bioavailability analysis showed that both Neocate formulas were able to normalize plasma phosphorus levels when administered to low phosphorus mice along with PPIs (control diet + PPI 8 ± 0.4; Neocate Infant 10.1 ± 0.9; Neocate Junior 9.2 ± 0.6; EleCare Infant 8.6 ± 0.4; EleCare Junior 8.7 ± 0.5; n = 8-10; P < 0.0001 versus baseline 3.4 ± 0.2 mg/dL). In comparison, plasma phosphorus levels remained lower on the low phosphorus diet (5.7 ± 0.2 mg/dL). Furthermore, urinary phosphorus/creatinine and intact fibroblast growth factor 23 were significantly lowered by low phosphorus diet. In contrast, intact parathyroid hormone and 1,25-dihydroxy vitamin D decreased and increased, respectively, and these parameters likewise normalized in mice administered AAFs. CONCLUSION: The present findings indicated that phosphorus bioaccessibility in the in-vitro batch digestion model translates well into phosphorus bioavailability in mice even under compromised digestive conditions that bypass gastric acidification.

Different elemental infant formulas show equivalent phosphorus and calcium bioavailability in healthy volunteers.

Retrospective chart reviews have reported hypophosphatemia associated with elemental formula use in infants and children with systemic disease involving multiple diagnoses. The present study aims to evaluate the bioavailability of phosphorus from 2 commercial elemental formulas and to test our hypothesis of bioequivalence of the 2 products in healthy volunteers receiving gastric acid-suppressive medication. A single-center, double-blind, randomized, cross-over study was conducted in healthy volunteers with esomeprazole-induced hypochlorhydria. After a standardized low phosphorus meal followed by overnight fasting, subjects consumed 1 gram of phosphorus in a single oral dose of 1217 kcal of Product A (Neocate) or Product B (Elecare). The alternate product was given following a 1-week washout period. Blood and urine were collected at baseline and different time-points for up to 6 hours after product consumption. Area-under-the-curve (AUC) and peak values (Cpeak) for serum phosphate and calcium and urinary creatinine-corrected phosphate and calcium were assessed for bioequivalence of Products A and B. Results show that the geometric mean ratio (GMR) and 90% CI for serum phosphate were 1.041 (0.998-1.086) and 1.020 (0.963-1.080) for AUC0-360 and Cpeak, respectively, meeting the predetermined criteria for bioequivalence. Urinary creatinine-corrected phosphate followed a similar pattern after intake of Product A and B, but did not reach bioequivalence criteria (GMR: AUC70-370 = 1.105 (0.918-1.330); Cpeak = 1.182 (1.040-1.343)). Serum calcium concentrations (GMR: AUC0-360 = 1.002 (0.996-1.009); Cpeak = 0.991 (0.983-0.999)) and urinary creatinine-corrected calcium excretion (GMR: AUC70-370 = 1.117 (1.023-1.219); Cpeak = 1.157 (1.073-1.247)) demonstrated bioequivalence of the products. In conclusion, both elemental infant formulas showed equivalent serum phosphorus and calcium bioavailability in healthy volunteers even if combined with treatment with acid-suppressive medication.

Impaired Nutritional Condition After Stroke From the Hyperacute to the Chronic Phase: A Systematic Review and Meta-Analysis.

BACKGROUND: Malnutrition is common after stroke and can affect rehabilitation and healthcare costs. A comprehensive overview of stroke patients' nutritional condition from the hyperacute to the chronic phase is lacking. This systematic review aimed to investigate the prevalence of impaired nutritional condition (INC) across the continuum of care in specific phases after stroke. METHODS: CAB ABSTRACTS, Embase, MEDLINE, were used to collect studies published between 01-01-1999 and 26-08-2020. Primary and secondary outcomes were prevalence of INC and prevalence of malnutrition, respectively. Exploratory outcomes were prevalence of INC at follow-up, nutritional examination methods, prevalence of dysphagia, stroke severity, adverse events, and continent-specific prevalence of INC. A random-effects meta-analysis model was used to estimate the phase-specific pooled prevalence of INC and malnutrition. RESULTS: The dataset consisted of 78 study groups selected over a total of 1,244 identified records. The pooled prevalence of INC and malnutrition were 19% (95%CI:7-31) (N = 4) and 19% (95%CI:9-29) (N = 3), 34% (95%CI:25-43) (N = 34) and 26% (95%CI:18-35) (N = 29), 52% (95%CI:43-61) (N = 34) and 37% (95%CI:28-45) (N = 31), 21% (95%CI:12-31) (N = 3) and 11% (95%CI:0-24) (N = 3) and 72% (95%CI:41-100) (N = 3) and 30% (95%CI:0-76) (N = 2) in the hyperacute, acute, early subacute, late subacute, and chronic phase, respectively. CONCLUSION: INC and malnutrition are highly prevalent in all stages of stroke care. Since malnutrition has been shown to negatively affect clinical outcomes, mortality, and overall healthcare expenditure in stroke survivors, it is essential to examine and monitor the nutritional status of stroke patients throughout their care journey to guide and plan, timely nutritional support and dietary modification.

Design of the DYNAMO study: a multi-center randomized controlled trial to investigate the effect of pre-thickened oral nutritional supplements in nursing home residents with dysphagia and malnutrition (risk).

BACKGROUND: Oropharyngeal Dysphagia (OD) and malnutrition are frequently reported conditions in nursing home residents, and are often interrelated. Best care for dysphagic residents with, or at risk of, malnutrition should target adequate nutritional intake and the safety and efficacy of swallowing. The effect of oral nutritional supplements (ONS) suitable for nursing home residents with concurrent OD and malnutrition (risk) on nutritional status has not been investigated before. The current study aims to investigate the effect of daily use of a range of pre-thickened ONS on the body weight of nursing home residents with OD and malnutrition (risk) compared to standard OD and nutritional care. METHODS / DESIGN: The DYNAMO study is a randomized, controlled, multi-center, open label trial with two parallel groups. Study participants will be recruited in nursing homes of several care organizations in the south of the Netherlands. Study duration is 12 weeks. Residents in the control group will receive standard OD and nutritional care, and residents in the test group will receive standard OD and nutritional care with extra daily supplementation of pre-thickened ONS. The main outcome parameter is the difference in body weight change between the control and test groups. An a priori estimation of the required sample size per group (control / test) totals 78. Other outcome parameters are differences in: nutritional intake, health-related quality of life, OD-specific quality of life, activities of daily living, vital signs, and blood nutrient and metabolite levels. DISCUSSION: Regular ONS could address the nutritional needs of nursing home residents with malnutrition (risk), but might be too thin and unsafe for residents with OD. Pre-thickened ONS is suitable for residents with OD. It offers the advantage of being a ready-to-use amylase-resistant product available in several consistencies which are able to increase swallowing efficacy and safety. The DYNAMO study is the first to investigate the effects of pre-thickened ONS on nutritional status in nursing home residents with concurrent OD and malnutrition (risk). TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR NL7898. Registered 24 July 2019, https://www.trialregister.nl/trial/7898.

Nutritional Interventions in Cancer Cachexia: Evidence and Perspectives From Experimental Models.

Cancer cachexia is a complex metabolic syndrome characterized by involuntary skeletal muscle loss and is associated with poor clinical outcome, decreased survival and negatively influences cancer therapy. No curative treatments are available for cancer cachexia, but nutritional intervention is recommended as a cornerstone of multimodal therapy. Optimal nutritional care is pivotal in the treatment of cancer cachexia, and the effects of nutrients may extend beyond provision of adequate energy uptake, targeting different mechanisms or metabolic pathways that are affected or deregulated by cachexia. The evidence to support this notion derived from nutritional intervention studies in experimental models of cancer cachexia is systematically discussed in this review. Moreover, experimental variables and readout parameters to determine skeletal muscle wasting and cachexia are methodologically evaluated to allow critical comparison of similar studies. Single- and multinutrient intervention studies including qualitative modulation of dietary protein, dietary fat, and supplementation with specific nutrients, such as carnitine and creatine, were reviewed for their efficacy to counteract muscle mass loss and its underlying mechanisms in experimental cancer cachexia. Numerous studies showed favorable effects on impaired protein turnover and related metabolic abnormalities of nutritional supplementation in parallel with a beneficial impact on cancer-induced muscle wasting. The combination of high quality nutrients in a multitargeted, multinutrient approach appears specifically promising, preferentially as a multimodal intervention, although more studies investigating the optimal quantity and combination of nutrients are needed. During the review process, a wide variation in timing, duration, dosing, and route of supplementation, as well as a wide variation in animal models were observed. Better standardization in dietary design, and the development of experimental models that better recapitulate the etiology of human cachexia, will further facilitate successful translation of experimentally-based multinutrient, multimodal interventions into clinical practice.