Growth Hormone Therapy in Decompensated Cirrhosis: An Open-Label, Randomized Control Trial.

INTRODUCTION: Effect of long-term growth-hormone (GH) therapy in decompensated cirrhosis (DC) is unknown. We studied the safety and efficacy of GH therapy on malnutrition, nitrogen metabolism, and hormonal changes in patients with DC. METHODS: Patients with DC were randomized to standard medical therapy plus GH (group A; n = 38) or standard medical therapy alone (group B; n = 38). Body mass index, midarm muscle circumference (MAMC), hand grip strength (HGS), liver frailty index (LFI), skeletal muscle index (SMI), nitrogen balance, Child-Turcotte-Pugh, model for end-stage liver disease, quality of life (QOL), serum albumin, GH, insulin like growth factor-1, and acid labile subunit (ALS) were assessed at baseline and at 12 months. RESULTS: The mean difference between baseline and 12-months in SMI (-6.122 [-9.460 to -2.785] cm 2 /m 2 ), body mass index (-2.078 [-3.584 to -0.5718] kg/m 2 ), MAMC (-1.960 [-2.928 to -0.9908] cm), HGS (-5.595 [-7.159 to -4.031] kg), albumin (-0.3967 [-0.6876 to -0.1057] g/dL), LFI (0.3328 [0.07786-0.5878]), Child-Turcotte-Pugh (0.9624 [0.1435-1.781]), model for end-stage liver disease (1.401 [0.04698-2.75]), insulin-like growth factor-1 (-6.295 [-11.09 to -1.495] ng/dL), and ALS (-8.728 [-14.12 to -3.341] pg/mL) were statistically significantly better ( P < 0.05) in group A. There was no improvement in nutritional parameters, clinical scores, QOL scores, or nitrogen balance in group B. The mean difference between group A and B in SMI, HGS, MAMC, LFI, ALS, physical component summary, and mental component summary at 12 months was also statistically significant. Survival at 12 months was similar in both groups ( P = 0.35). No serious adverse events were observed. DISCUSSION: Long-term use of GH is safe in DC and leads to improvement in malnutrition and possibly QOL. However, there is no improvement in 12-month survival (NCT03420144).

Emerging drugs for the treatment of sarcopenia in cirrhosis of the liver.

INTRODUCTION: Malnutrition and sarcopenia are common and impact the prognosis in patients with liver cirrhosis. The etiology is multifactorial and includes periods of reduced caloric intake, increased catabolism and direct molecular mechanisms that inhibit muscle synthesis. Although these conditions are widely acknowledged, and there is a growing interest in their diagnosis, robust evidence regarding the treatment and reversibility of these conditions is still lacking. AREAS COVERED: We have explored the current evidence on the pharmacological treatment of sarcopenia in patients with cirrhosis. Additionally, we have searched for drugs already in use and ongoing trials for other chronic diseases. EXPERT OPINION: The current guidelines recommend the use of a protein-adequate diet and moderate physical activity for treating sarcopenia in patients with cirrhosis. Currently, robust evidence is derived only from the supplementation of Branched-Chain Amino Acids, capable of increasing muscle mass and function. There are many drugs targeting various pathways that contribute to sarcopenia. However, evidence is sporadic and insufficient to suggest their use in clinical practice.Novel drugs specifically designed to enhance muscle mass and function should be developed. Finally, gender significantly influences the type of muscle alteration and therapeutic mechanisms; therefore, future studies should be designed taking gender differences into consideration.

Enhancing Oral Mucosal Barrier, Mitigating Microinflammation, and Addressing Malnutrition in Dialysis Patients: The Impact of Tangerine Peel Lemon Glycerin.

Objective: This study investigates the efficacy of tangerine peel lemon glycerin extract oral spray in improving oral mucosal barrier, reducing microinflammation, and addressing malnutrition in maintenance dialysis (MHD) patients. Methods: Tangerine peel and dry lemon underwent glycerin extraction. From January 2021 to June 2022, 72 MHD patients with thirst were prospectively chosen at Sinopharm Gezhouba Central Hospital. Randomization divided them into an observation group (n=36) and a control group (n=36). Both received routine maintenance dialysis and chronic kidney disease management. Oral conditions were assessed using OHIP-14, a homemade visual thirst score scale, SFR, sAA, and saliva pH. Microinflammatory indexes (CRP, TNF-α, IL-6) and nutritional status indicators (Alb, PA, Hb) were measured. The observation group used 1ml of tangerine peel lemon glycerin extract with a pH value of 5.9~6.1 q6h, while the control group used 1ml of purified water q6h. Results: After 3 months, the observation group showed significant improvement in OHIP-14 and visual thirst score scale (P < .01). Saliva pH, CRP, TNF-α, and IL-6 levels decreased, and SAA activity, SFR, Alb, PA, and Hb levels increased significantly in the observation group compared to the control group (P < .01). Conclusions: Tangerine peel lemon glycerin spray demonstrates promise in improving the oral mucosal barrier, exhibiting antibacterial and anti-inflammatory properties that mitigate microinflammation and malnutrition. This finding suggests a connection between oral health, systemic pathology, psychological state, and social adaptability.

Classes of medications prescribed to malnourished children and their relationship with time to recovery.

OBJECTIVE: There is conflicting evidence around prescription practices in the management of malnutrition; the study objective was to explore medication classifications prescribed and their relationship between time-to-recovery and specific demographic characteristics among children with malnutrition in Guatemala. DESIGN: Descriptive correlational study of data obtained in a retrospective record review. SAMPLE: Children aged 0-5 years with malnutrition treated in a Guatemalan Nutrition Rehabilitation Center between 2019 and 2020 (N = 155). MEASURES: Variables assessed were medication classification of prescribed medications, age, gender, time-to-recovery, malnutrition severity, and COVID cohort. RESULTS: The most frequently used medication classifications were vitamins (95%), respiratory (75%), antipyretic (68%), antibiotic (61%), and gastrointestinal agents (54%). Antibiotic, respiratory, corticosteroid, antipyretic, and gastrointestinal agents were prescribed significantly more in cases with a time-to-recovery of 6 weeks or greater. CONCLUSIONS: Medication classifications prescribed most often were related to common comorbidities of malnutrition and illnesses affecting children in Guatemala, such as respiratory and diarrheal diseases. The medication used in cases with a time-to-recovery of ≥6 weeks suggest these cases may have had more comorbidities, which could explain the longer recovery times. Caution is suggested in routine prophylactic antibiotic use in public health settings, given the lack of association with improved recovery times, the potential for antibiotic drug resistance, and the negative effects on renal function among children.

Extended-Hours Hemodialysis without Dietary Restrictions Increases Body Mass Index and Normalizes Hypertension: A Case Report.

Dialysis technology has made remarkable progress. However, many patients still suffer from malnutrition and hypertension. They cause many complications and significantly impact patients' quality of life and prognosis. To solve these problems, we developed a new dialysis modality, extended-hours hemodialysis without dietary restrictions. Here we report a case of a man who has received this treatment for 18 years. He had been on conventional hemodialysis (three times a week for 4 hours) since his dialysis initiation. He suffered from hypertension and was on five antihypertensive drugs to control his blood pressure. In addition, dietary restrictions were strict, and the nutritional status was somewhat poor. After being transferred to our clinic, the dialysis time was gradually extended to 8 hours, and dietary restrictions were greatly relaxed. Interestingly, his body mass index (BMI) increased, and his hypertension was controlled. After 3 years, he stopped all antihypertensive drugs. This result suggests that improving nutritional status may control hypertension. However, salt intake was substantially increased. Serum phosphorus and serum potassium levels were at a slightly higher level but were controlled by medications. At the time of transfer, anemia was treated with erythropoiesis-stimulating agents and glycated iron oxide, but these drugs were gradually reduced and discontinued. However, he maintained high average erythrocyte counts and normal hemoglobin levels. Dialysis conditions were wholly slow dialysis, lower than conventional dialysis methods, but the dialysis efficiency was satisfactory. In conclusion, we speculate that extended-hours hemodialysis without dietary restrictions reduces the risk of malnutrition and hypertension.

Mechanisms by which sialylated milk oligosaccharides impact bone biology in a gnotobiotic mouse model of infant undernutrition.

Undernutrition in children is a pressing global health problem, manifested in part by impaired linear growth (stunting). Current nutritional interventions have been largely ineffective in overcoming stunting, emphasizing the need to obtain better understanding of its underlying causes. Treating Bangladeshi children with severe acute malnutrition with therapeutic foods reduced plasma levels of a biomarker of osteoclastic activity without affecting biomarkers of osteoblastic activity or improving their severe stunting. To characterize interactions among the gut microbiota, human milk oligosaccharides (HMOs), and osteoclast and osteoblast biology, young germ-free mice were colonized with cultured bacterial strains from a 6-mo-old stunted infant and fed a diet mimicking that consumed by the donor population. Adding purified bovine sialylated milk oligosaccharides (S-BMO) with structures similar to those in human milk to this diet increased femoral trabecular bone volume and cortical thickness, reduced osteoclasts and their bone marrow progenitors, and altered regulators of osteoclastogenesis and mediators of Th2 responses. Comparisons of germ-free and colonized mice revealed S-BMO-dependent and microbiota-dependent increases in cecal levels of succinate, increased numbers of small intestinal tuft cells, and evidence for activation of a succinate-induced tuft cell signaling pathway linked to Th2 immune responses. A prominent fucosylated HMO, 2'-fucosyllactose, failed to elicit these changes in bone biology, highlighting the structural specificity of the S-BMO effects. These results underscore the need to further characterize the balance between, and determinants of, osteoclastic and osteoblastic activity in stunted infants/children, and suggest that certain milk oligosaccharides may have therapeutic utility in this setting.

Zinc finger protein 5 (ZFP5) associates with ethylene signaling to regulate the phosphate and potassium deficiency-induced root hair development in Arabidopsis.

KEY MESSAGE: Zinc finger protein transcription factor ZFP5 positively regulates root hair elongation in response to Pi and potassium deficiency by mainly activating the expression of EIN2 in Arabidopsis. Phosphate (Pi) and potassium (K+) are major plant nutrients required for plant growth and development, and plants respond to low-nutrient conditions via metabolic and morphology changes. The C2H2 transcription factor ZFP5 is a key regulator of trichome and root hair development in Arabidopsis. However, its role in regulating root hair development under nutrient deprivations remains unknown. Here, we show that Pi and potassium deficiency could not restore the short root hair phenotype of zfp5 mutant and ZFP5 RNAi lines to wild type level. The deprivation of either of these nutrients also induced the expression of ZFP5 and the activity of an ethylene reporter, pEBS:GUS. The significant reduction of root hair length in ein2-1 and ein3-1 as compared to wild-type under Pi and potassium deficiency supports the involvement of ethylene in root hair elongation. Furthermore, the application of 1-aminocyclopropane-1-carboxylic acid (ACC) significantly enhanced the expression level of ZFP5 while the application of 2-aminoethoxyvinyl glycine (AVG) had the opposite effect when either Pi or potassium was deprived. Further experiments reveal that ZFP5 mainly regulates transcription of ETHYLENE INSENSITIVE 2 (EIN2) to control deficiency-mediated root hair development through ethylene signaling. Generally, these results suggest that ZFP5 regulates root hair elongation by interacting with ethylene signaling mainly through regulates the expression of EIN2 in response to Pi and potassium deficiency in Arabidopsis.

Moringa oleifera treatment increases Tbet expression in CD4+ T cells and remediates immune defects of malnutrition in Plasmodium chabaudi-infected mice.

BACKGROUND: Malaria is a worldwide problem that affects millions of people yearly. In rural areas where anti-malarial drugs are not easily accessible, many people use herbal treatments, such as Moringa oleifera, to treat a variety of diseases and ailments including malaria. While Moringa is reported to possess potent and curative anti-malarial properties, previous studies have mostly been restricted to assessment of parasitaemia. In this study, the effect of Moringa on malaria immunity in a murine model was investigated. METHODS: Using a high dose (60 mg/mouse) for a short time (7 days) or low dose Moringa (30 mg/mouse) for a longer time (3 weeks), cytokine production, and Tbet expression by effector CD4+ T cells (Teff) were determined. Mice were also treated with Moringa after infection (curatively) or before infection (prophylactically) to determine the effect of the plant extract on parasitaemia and immunity. Given that Moringa also possess many nutritional benefits, the contribution of Moringa on malnourished malaria infected mice was determined. Malnutrition was induced by limiting access to food to only 4 h a day for 4 weeks, while control mice had unlimited access to mouse laboratory chow. All data was collected by flow cytometry and analysed using one-Way ANOVA or two tailed Student's t test. RESULTS: Moringa-treated mice had increased numbers of effector CD4+ T cells accompanied by an increase in Tbet expression compared to control untreated mice. Mice that were treated with Moringa curatively also exhibited increased effector CD4+ T cell numbers, IFN-gamma and TNF secretion. Interestingly, the mice that were treated prophylactically had significantly higher Tbet expression. In the absence of adaptive immunity, high parasitaemia was observed in the RAG1 knockout mice. The food limited mice (malnourished) had reduced numbers of CD4+ T cells, TNF proportions, and significantly greater Tbet expression compared to the control group. Supplementation with Moringa in the limited group slightly restored CD4+ T cell activation, IL-2, and IL-10 production. CONCLUSIONS: Taken together, these data suggest that Moringa treatment leads to increased CD4+ T cell activation, Th1 differentiation and production of pro-inflammatory cytokines after malaria infection. Thus, Moringa may be immunologically useful in the treatment of malaria and malnutrition. Further investigations are required to identify the active components in Moringa.

Supplementation With Lactoferrin and Lysozyme Ameliorates Environmental Enteric Dysfunction: A Double-Blind, Randomized, Placebo-Controlled Trial.

INTRODUCTION: Environmental enteric dysfunction (EED) predisposes children throughout the developing world to high rates of systemic exposure to enteric pathogens and stunting. Effective interventions that treat or prevent EED may help children achieve their full physical and cognitive potential. The objective of this study is to test whether 2 components of breast milk would improve a biomarker of EED and linear growth during the second year of life. METHODS: A prospective, randomized, double-blind, placebo-controlled clinical trial among children aged 12-23 months was conducted in rural Malawi. The experimental group received a daily supplement of 1.5 g of lactoferrin and 0.2 g of lysozyme for 16 weeks. The primary outcome was an improvement in EED, as measured by the change in the percentage of ingested lactulose excreted into the urine (Δ%L). RESULTS: Among 214 children who completed the study, there was a significant difference in Δ%L between the control and experimental groups over 8 weeks (an increase of 0.23% vs 0.14%, respectively; P = 0.04). However, this relative improvement was not as strongly sustained over the full 16 weeks of the study (an increase of 0.16% vs 0.11%, respectively; P = 0.17). No difference in linear growth over this short period was observed. The experimental intervention group had significantly lower rates of hospitalization and the development of acute malnutrition during the course of the study (2.5% vs 10.3%, relative risk 0.25; P < 0.02). DISCUSSION: Supplementation with lactoferrin and lysozyme in a population of agrarian children during the second year of life has a beneficial effect on gut health. This intervention also protected against hospitalization and the development of acute malnutrition, a finding with a significant clinical and public health importance. This finding should be pursued in larger studies with longer follow-up and optimized dosing.

Malnutrition in Pancreatic Ductal Adenocarcinoma (PDA): Dietary Pancreatic Enzymes Improve Short-Term Health but Stimulate Tumor Growth.

Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that resists efforts to identify better chemotherapeutics. PDA is associated with chronic pancreatitis and acinar cell dedifferentiation. This reduces enzyme production by the exocrine pancreas, resulting in digestive insufficiencies. Malabsorption of partially digested food causes bloating, overfilled intestines, abdominal pain, excessive feces, steatorrhea, and malnutrition. These maladies affect quality of life and restrict treatment options for pancreatitis and PDA. Here, we characterize health benefits and risks of dietary pancreatic enzymes in three mouse models of PDA-KC, KCR8-16, and KIC. KC expresses oncogenic KrasG12D in pancreatic tissue whereas KCR8-16 also has deletions of the Rgs8 and Rgs16 genes. Rgs proteins inhibit the release of digestive enzymes evoked by G-protein-coupled-receptor agonists. KC and KCR8-16 mice developed dedifferentiated exocrine pancreata within 2 months of age and became malnourished, underweight, hypoglycemic, and hypothermic. KC mice adapted but KCR8-16 mice rapidly transitioned to starvation after mild metabolic challenges. Dietary pancreatic enzyme supplements reversed these symptoms in KC and KCR8-16 animals, and extended survival. Therefore, we tested the benefits of pancreatic enzymes in an aggressive mouse model of PDA (KIC). Median survival improved with dietary pancreatic enzyme supplements and was extended further when combined with warfarin and gemcitabine chemotherapy. However, dietary pancreatic enzymes stimulated tumor growth in the terminal stages of disease progression in KIC mice.

Fluoropyrimidine with or without platinum as first-line chemotherapy in patients with advanced gastric cancer and severe peritoneal metastasis: a multicenter retrospective study.

BACKGROUND: There is no standard first-line chemotherapy for advanced gastric cancer with severe peritoneal metastasis. Although fluoropyrimidine is often used, its efficacy is limited, and it remains unclear whether combination therapy with platinum improves clinical outcomes. METHODS: This retrospective study involved patients at six Japanese academic hospitals between 2010 and 2016. Patients with advanced gastric cancer and severe peritoneal metastasis were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support. We then compared the efficacy and safety of fluoropyrimidine monotherapy with those of fluoropyrimidine/platinum combination therapy. RESULTS: Compared with the combination therapy group (n = 64), the monotherapy group (n = 65) had worse general health (more patients with elderly age, performance status > 2, and having both massive ascites and inadequate oral intake). Both overall survival (9.0 vs 5.0 months, p < 0.01) and progression-free survival (4.3 vs 2.3 months, p < 0.01) were significantly longer in the combination group, and the significance remained after adjusting for prognostic variables (hazard ratios of 0.47 and 0.41, respectively; p < 0.01). Improvements in ascites and oral intake were also greater in the combination group. Although neutropenia (grade ≥ 3) occurred more frequently with combination therapy, both treatments in this study were tolerable. CONCLUSIONS: Combination therapy with fluoropyrimidine and platinum might be more effective than monotherapy with fluoropyrimidine and was tolerable for patients with advanced gastric cancer and severe peritoneal metastasis.

Effects of an Antioxidant-enriched Multivitamin in Cystic Fibrosis. A Randomized, Controlled, Multicenter Clinical Trial.

RATIONALE: Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant-antioxidant imbalance and oxidative stress. OBJECTIVES: Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. METHODS: In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. MEASUREMENTS AND MAIN RESULTS: Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (ß-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. CONCLUSIONS: Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Use of cyproheptadine to stimulate appetite and body weight gain: A systematic review.

OBJECTIVE: A systematic review identifying the use of cyproheptadine (CY) as an appetite stimulant was completed. METHOD: Studies of any design exploring the efficacy of CY as an appetite stimulant in all age groups and populations were included. Primary outcomes of studies included were weight gain, appetite stimulation, and/or caloric/nutritional intake increase. The review was completed in accordance with PRISMA standards. RESULTS: A total of 46 articles across 21 different treatment populations met criteria for the review, including 32 randomized controlled trials, 4 prospective cohort studies, 4 retrospective cohort studies, 4 case reports and 2 case series. Of these, 39 demonstrated that CY resulted in significant weight gain in the sample under study. Studies exploring the use of CY in those with malignant/progressive disease states, such as HIV and cancer, showed minimal to no benefit of the medication. Transient mild to moderate sedation was the most commonly reported side effect. Studies included were heterogeneous in terms of methods as well as study patient demographics, characteristics and concurrent medical conditions. Few studies provided objective measures of appetite change. DISCUSSION: CY appears to be a safe, generally well-tolerated medication that has utility in helping facilitate weight gain in patients drawn from a variety of underweight populations. Future prospective randomized controlled studies in low weight patients that include objective measures of appetite and intake are needed to better understand the mechanism by which CY augments weight gain.

Increased Plasmodium chabaudi malaria mortality in mice with nutritional iron deficiency can be reduced by short-term adjunctive iron supplementation.

BACKGROUND: Iron deficiency is the most widespread nutrient deficiency and an important cause of developmental impairment in children. However, some studies have indicated that iron deficiency can also protect against malaria, which is a leading cause of childhood morbidity and mortality in large parts of the world. This has rendered interventions against iron deficiency in malaria-endemic areas controversial. METHODS: The effect of nutritional iron deficiency on the clinical outcome of Plasmodium chabaudi AS infection in A/J mice and the impact of intravenous iron supplementation with ferric carboxymaltose were studied before and after parasite infection. Plasma levels of the iron status markers hepcidin and fibroblast growth factor 23 were measured in animals surviving and succumbing to malaria, and accompanying tissue pathology in the liver and the spleen was assessed. RESULTS: Nutritional iron deficiency was associated with increased mortality from P. chabaudi malaria. This increased mortality could be partially offset by carefully timed, short-duration adjunctive iron supplementation. Moribund animals were characterized by low levels of hepcidin and high levels of fibroblast growth factor 23. All infected mice had extramedullary splenic haematopoiesis, and iron-supplemented mice had visually detectable intracellular iron stores. CONCLUSIONS: Blood transfusions are the only currently available means to correct severe anaemia in children with malaria. The potential of carefully timed, short-duration adjunctive iron supplementation as a safe alternative should be considered.

Wernicke's encephalopathy following reduced food intake due to depressive disorders.

Wernicke's encephalopathy (WE) is an unexpected common neurological disorder caused by thiamine deficiency often due to alcohol abuse, but WE-not alcohol related is also frequent. A prolonged reduction of food intake can cause WE. This condition can arise in depression disorders, especially in the early stages of these psychiatric syndromes. WE is characterized by the triad of signs: ataxia, ocular dysfunctions and confusional state. However, they rarely appear together and this makes the diagnosis particularly difficult, especially when there is not a history of alcohol abuse. Electroencephalography, since in the early stage of the disease, can be helpful in detecting pattern of metabolic encephalopathy. We describe three cases of thiamine deficiency responsible of WE, caused by a decrease in appetite and food intake due to the onset of a depressive disorder. In our series, the most frequent symptom observed at the onset of the disease was the motor incoordination. We recommend to perform quickly thiamine infusion in all depressed patients with a history of reduced food intake, presenting to Emergency Department with recent onset of motor incoordination, with or without alterations in eyes' movements and confusional state, after exclusion of other neurological conditions.

Historical Perspective on the Rise and Fall and Rise of Antibiotics and Human Weight Gain.

In recent medical and popular literature, audiences have been asked to consider whether antibiotics have contributed to the rising obesity epidemic. Prominent magazines have stated that weight may be adversely affected by antibiotics that destroy existing microbiomes and replace them with less helpful ones. However, there is a long history of efforts to investigate the relationship between antibiotics and human weight gain. In the early 1950s, amid initial findings that low doses of antibiotics served as growth promoters in animal livestock, investigators explored the role of antibiotics as magic bullets for human malnutrition. Nevertheless, early enthusiasm was tempered by controlled studies showing that antibiotics did not serve as useful, nonspecific growth promoters for humans. In subsequent decades, against the backdrop of rising concern over antibiotic resistance, investigators studying the role of antibiotics in acute malnutrition have had to navigate a more complicated public health calculus. In a related historical stream, scientists since the 1910s have explored the role of the intestinal microflora in human health. By the 2000s, as increasing resources and more sophisticated tools were devoted to understanding the microbiome (a term coined in 2001), attention would turn to the role of antibiotics and the intestinal microflora in the rising obesity epidemic. Despite scientific and commercial enthusiasm, easy answers (whether about antibiotics or probiotics) have again given way to an appreciation for the complexity of human growth. History encourages caution about our hopes for simplistic answers for presumed "fat drugs" and slimming probiotics alike.

Gut microbiota and malnutrition.

Malnutrition is the leading cause of death worldwide in children under the age of five, and is the focus of the first World Health Organization (WHO) Millennium Development Goal. Breastfeeding, food and water security are major protective factors against malnutrition and critical factors in the maturation of healthy gut microbiota, characterized by a transient bifidobacterial bloom before a global rise in anaerobes. Early depletion in gut Bifidobacterium longum, a typical maternal probiotic, known to inhibit pathogens, represents the first step in gut microbiota alteration associated with severe acute malnutrition (SAM). Later, the absence of the Healthy Mature Anaerobic Gut Microbiota (HMAGM) leads to deficient energy harvest, vitamin biosynthesis and immune protection, and is associated with diarrhea, malabsorption and systemic invasion by microbial pathogens. A therapeutic diet and infection treatment may be unable to restore bifidobacteria and HMAGM. Besides refeeding and antibiotics, future trials including non-toxic missing microbes and nutrients necessary to restore bifidobacteria and HMAGM, including prebiotics and antioxidants, are warranted in children with severe or refractory disease.

Myocardial and haemodynamic responses to two fluid regimens in African children with severe malnutrition and hypovolaemic shock (AFRIM study).

BACKGROUND: Fluid therapy in severely malnourished children is hypothesized to be deleterious owing to compromised cardiac function. We evaluated World Health Organization (WHO) fluid resuscitation guidelines for hypovolaemic shock using myocardial and haemodynamic function and safety endpoints. METHODS: A prospective observational study of two sequential fluid management strategies was conducted at two East African hospitals. Eligible participants were severely malnourished children, aged 6-60 months, with hypovolaemic shock secondary to gastroenteritis. Group 1 received up to two boluses of 15 ml/kg/h of Ringer's lactate (RL) prior to rehydration as per WHO guidelines. Group 2 received rehydration only (10 ml/kg/h of RL) up to a maximum of 5 h. Comprehensive clinical, haemodynamic and echocardiographic data were collected from admission to day 28. RESULTS: Twenty children were enrolled (11 in group 1 and 9 in group 2), including 15 children (75%) with kwashiorkor, 8 (40%) with elevated brain natriuretic peptide >300 pg/ml, and 9 (45%) with markedly elevated median systemic vascular resistance index (SVRI) >1600 dscm-5/m2 indicative of severe hypovolaemia. Echocardiographic evidence of fluid-responsiveness (FR) was heterogeneous in group 1, with both increased and decreased stroke volume and myocardial fractional shortening. In group 2, these variables were more homogenous and typical of FR. Median SVRI marginally decreased post fluid administration (both groups) but remained high at 24 h. Mortality at 48 h and to day 28, respectively, was 36% (4 deaths) and 81.8% (9 deaths) in group 1 and 44% (4 deaths) and 55.6% (5 deaths) in group 2. We observed no pulmonary oedema or congestive cardiac failure on or during admission; most deaths were unrelated to fluid interventions or echocardiographic findings of response to fluids. CONCLUSION: Baseline and cardiac response to fluid resuscitation do not indicate an effect of compromised cardiac function on response to fluid loading or that fluid overload is common in severely malnourished children with hypovolaemic shock. Endocrine response to shock and persistently high SVRI post fluid-therapy resuscitation may indicate a need for further research investigating enhanced fluid volumes to adequately correct volume deficit. The adverse outcomes are concerning, but appear to be unrelated to immediate fluid management.

Correlates of whole-blood polyunsaturated fatty acids among young children with moderate acute malnutrition.

BACKGROUND: Severe acute malnutrition (SAM) has been associated with low polyunsaturated fatty acid (PUFA) status. However, investigations regarding PUFA status and correlates in children with moderate acute malnutrition (MAM) from low-income countries are scarce. The aim of this study was to describe whole-blood PUFA levels in children with moderate acute malnutrition (MAM) and to identify correlates of PUFAs. METHODS: We conducted a cross-sectional study using baseline data from a prospective nutritional intervention trial among 1609 children with MAM aged 6-23 months in Burkina Faso,West Africa. Whole-blood PUFAs were measured by gas chromatography and expressed as percent of total whole-blood fatty acids (FA%). Potential correlates of PUFAs including infection, inflammation, hemoglobin, anthropometry (difference between children diagnosed as having MAM based on low mid-upper-arm-circumference (MUAC) only, low MUAC and weight-for-height z-score (WHZ), or low WHZ only) and diet were assessed by linear regression adjusted for age and sex. RESULTS: Children with MAM had low concentrations of whole-blood PUFAs, particularly n-3 PUFAs. Moreover, children diagnosed with MAM based only on low MUAC had 0.32 (95% confidence interval (CI), 0.14; 0.50) and 0.40 (95% CI, 0.16; 0.63) FA% lower arachidonic acid (AA) than those recruited based on both low WHZ as well as low MUAC and those recruited with low WHZ only, respectively. Infection and inflammation were associated with low levels of all long-chain (LC)-PUFAs, while hemoglobin was positively associated with whole-blood LC-PUFAs. CONCLUSION: While PUFA deficiency was not a general problem, overall whole-blood PUFA concentrations, especially of n-3 PUFAs, were low. Infection, inflammation, hemoglobin, anthropometry and diet were correlates of PUFAs concentrations in children with MAM. TRIAL REGISTRATION: The trial is registered at http://www.isrctn.com ( ISRCTN42569496 ).

Supplementation with nutrients modulating insulin-like growth factor-1 negatively correlated with changes in the levels of pro-inflammatory cytokines in community-dwelling elderly people at risk of undernutrition.

BACKGROUND: Suboptimal nutrition accompanied by chronic low-grade increases in circulating cytokine levels is more common in elderly people. We explored the improvement in nutritional status, especially in the level of insulin-like growth factor-1 (IGF-1) and its relationship with changes in circulating cytokine levels, after providing extra protein and energy content to community-dwelling older adults at risk of undernutrition. METHODS: Sixty nondiabetic subjects, aged ≥65 years and living independently in a community for elderly people, with a serum pre-albumin level ≤30 mg dL-1 and a body mass index <25 kg m-2 , were recruited. The subjects were followed for a 2-week pre-intervention period, during which they maintained routine dietary habits. This was followed by an intervention period, during which they received oral nutritional supplementation for 2 weeks. RESULTS: Following 2 weeks of intervention, there were significant increases in total lymphocyte count (TLC) and insulin-like growth factor (IGF)-1, pre-albumin and transferrin compared to baseline. Body weight and mid-arm circumference significantly increased without alteration of tricep skinfold thickness at the end of the intervention. There was a significant reduction in interleukin (IL)-6 levels and a trend toward a decrease in the tumor necrosis factor (TNF)-α levels. At baseline, age was negatively correlated with IGF-1 levels and positively correlated with IL-6 and TNF-α levels. The change (▵, from baseline) in IGF-1 level was positively correlated with age and negatively correlated with ▵IL-6 and ▵TNF-α. CONCLUSIONS: A 2-week intervention with oral nutritional supplementation improved nutritional status and decreased circulating cytokine levels. Specifically, ▵IGF-1 was negatively correlated with changes in pro-inflammatory cytokine levels in community-dwelling elderly people at risk of undernutrition. (Clinicaltrials.gov: NCT02656186).