Low Density Lipoproteins as Circulating Fast Temperature Sensors

Background: The potential physiological significance of the nanophase transition of neutral lipids in the core of low density lipoprotein (LDL) particles is dependent on whether the rate is fast enough to integrate small (62uC) temperature changes in the blood circulation. Methodology/Principal Findings: Using sub-second, time-resolved small-angle X-ray scattering technology with synchrotron radiation, we have monitored the dynamics of structural changes within LDL, which were triggered by temperature-jumps and-drops, respectively. Our findings reveal that the melting transition is complete within less than 10 milliseconds. The freezing transition proceeds slowly with a half-time of approximately two seconds. Thus, the time period over which LDL particles reside in cooler regions of the body readily facilitates structural reorientation of the apolar core lipids. Conclusions/Significance: Low density lipoproteins, the biological nanoparticles responsible for the transport of cholesterol in blood, are shown to act as intrinsic nano-thermometers, which can follow the periodic temperature changes during blood circulation. Our results demonstrate that the lipid core in LDL changes from a liquid crystalline to an oily state within fractions of seconds. This may, through the coupling to the protein structure of LDL, have important repercussions o

Metabolic Disturbances Associated with Systemic Lupus Erythematosus

The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment

An increase of cereal intake as an approach to weight reduction in children is effective only when accompanied by nutrition education: a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>The main emphasis of dietary advice for control of obesity has been on reducing dietary fat. Increasing ready to eat cereal (RTEC) consumption could be a strategy to reduce fat intake and increase carbohydrate intake resulting in a diet with lower energy density.</p> <p>Objectives</p> <p>1. To determine if an increase in RTEC intake is an effective strategy to reduce excess body weight and blood lipids in overweight or at risk of overweight children. 2. To determine if a nutrition education program would make a difference on the response to an increase in cereal intake. 3) To determine if increase in RTEC intake alone or with a nutrition education program has an effect on plasma lipid profile.</p> <p>Experimental design</p> <p>One hundred and forty seven overweight or at risk of overweight children (6–12 y of age) were assigned to one of four different treatments: a. One serving of 33 ± 7 g of RTEC for breakfast; b. one serving of 33 ± 7 g of RTEC for breakfast and another one for dinner; c. one serving of 33 ± 7 g of RTEC for breakfast and a nutrition education program. d. Non intervention, control group. Anthropometry, body composition, physical activity and blood lipids were measured at baseline, before treatments, and 12 weeks after treatments.</p> <p>Results</p> <p>After 12 weeks of intervention only the children that received 33 ± 7 g of RTEC and nutrition education had significantly lower body weight [-1.01 (-1.69, -0.34) ], p < 0.01], lower BMI [-0.95 (-1.71, -0.20), p < 0.01] and lower total body fat [-0.71 (-1.71, 0.28), p < 0.05] compared with the control group [1.19 (0.39, 1.98), 0.01 (-0.38, 0.41), 0.44 (-0.46, 1.35) respectively]. Plasma triglycerides and VLDL were significantly reduced [-20.74 (-36.44, -5.05), -3.78 (-6.91, -0.64) respectively, p < 0.05] and HDL increased significantly [6.61 (2.15, 11.08), p < 0.01] only in this treatment group. The groups that received 1 or 2 doses of RTEC alone were not significantly different to the control group.</p> <p>Conclusion</p> <p>A strategy to increase RTEC consumption, as a source of carbohydrate, to reduce obesity is effective only when accompanied by nutrition education. The need for education could be extrapolated to other strategies intended for treatment of obesity.</p> <p>Trial Registration</p> <p>Australian New Zealand Clincial Trial Registry. Request no: ACTRN12608000025336</p

Assessment of Clinical Outcomes Among Children and Adolescents Hospitalized With COVID-19 in 6 Sub-Saharan African Countries

Importance: Little is known about COVID-19 outcomes among children and adolescents in sub-Saharan Africa, where preexisting comorbidities are prevalent. / Objective: To assess the clinical outcomes and factors associated with outcomes among children and adolescents hospitalized with COVID-19 in 6 countries in sub-Saharan Africa. / Design, Setting, and Participants: This cohort study was a retrospective record review of data from 25 hospitals in the Democratic Republic of the Congo, Ghana, Kenya, Nigeria, South Africa, and Uganda from March 1 to December 31, 2020, and included 469 hospitalized patients aged 0 to 19 years with SARS-CoV-2 infection. / Exposures: Age, sex, preexisting comorbidities, and region of residence. / Main Outcomes and Measures: An ordinal primary outcome scale was used comprising 5 categories: (1) hospitalization without oxygen supplementation, (2) hospitalization with oxygen supplementation, (3) ICU admission, (4) invasive mechanical ventilation, and (5) death. The secondary outcome was length of hospital stay. / Results: Among 469 hospitalized children and adolescents, the median age was 5.9 years (IQR, 1.6-11.1 years); 245 patients (52.4%) were male, and 115 (24.5%) had comorbidities. A total of 39 patients (8.3%) were from central Africa, 172 (36.7%) from eastern Africa, 208 (44.3%) from southern Africa, and 50 (10.7%) from western Africa. Eighteen patients had suspected (n = 6) or confirmed (n = 12) multisystem inflammatory syndrome in children. Thirty-nine patients (8.3%) died, including 22 of 69 patients (31.9%) who required intensive care unit admission and 4 of 18 patients (22.2%) with suspected or confirmed multisystem inflammatory syndrome in children. Among 468 patients, 418 (89.3%) were discharged, and 16 (3.4%) remained hospitalized. The likelihood of outcomes with higher vs lower severity among children younger than 1 year expressed as adjusted odds ratio (aOR) was 4.89 (95% CI, 1.44-16.61) times higher than that of adolescents aged 15 to 19 years. The presence of hypertension (aOR, 5.91; 95% CI, 1.89-18.50), chronic lung disease (aOR, 2.97; 95% CI, 1.65-5.37), or a hematological disorder (aOR, 3.10; 95% CI, 1.04-9.24) was associated with severe outcomes. Age younger than 1 year (adjusted subdistribution hazard ratio [asHR], 0.48; 95% CI, 0.27-0.87), the presence of 1 comorbidity (asHR, 0.54; 95% CI, 0.40-0.72), and the presence of 2 or more comorbidities (asHR, 0.26; 95% CI, 0.18-0.38) were associated with reduced rates of hospital discharge. / Conclusions and Relevance: In this cohort study of children and adolescents hospitalized with COVID-19 in sub-Saharan Africa, high rates of morbidity and mortality were observed among infants and patients with noncommunicable disease comorbidities, suggesting that COVID-19 vaccination and therapeutic interventions are needed for young populations in this region

The Critical Need for Pooled Data on Coronavirus Disease 2019 in African Children: An AFREhealth Call for Action Through Multicountry Research Collaboration

Globally, there are prevailing knowledge gaps in the epidemiology, clinical manifestations, and outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among children and adolescents; and these gaps are especially wide in African countries. The availability of robust age-disaggregated data is a critical first step in improving knowledge on disease burden and manifestations of coronavirus disease 2019 (COVID-19) among children. Furthermore, it is essential to improve understanding of SARS-CoV-2 interactions with comorbidities and coinfections such as human immunodeficiency virus (HIV), tuberculosis, malaria, sickle cell disease, and malnutrition, which are highly prevalent among children in sub-Saharan Africa. The African Forum for Research and Education in Health (AFREhealth) COVID-19 Research Collaboration on Children and Adolescents is conducting studies across Western, Central, Eastern, and Southern Africa to address existing knowledge gaps. This consortium is expected to generate key evidence to inform clinical practice and public health policy-making for COVID-19 while concurrently addressing other major diseases affecting children in African countries

Serum Metabolomics Reveals Higher Levels of Polyunsaturated Fatty Acids in Lepromatous Leprosy: Potential Markers for Susceptibility and Pathogenesis

Leprosy is an infectious disease caused by the obligate intracellular bacterium Mycobacterium leprae. M. leprae infects the skin and nerves, leading to disfigurement and nerve damage, with the severity of the disease varying widely. We believe there are multiple factors (genetic, bacterial, nutritional and environmental), which may explain the differences in clinical manifestations of the disease. We studied the metabolites in the serum of infected patients to search for specific molecules that may contribute to variations in the severity of disease seen in leprosy. We found that there were variations in levels of certain lipids in the patients with different bacterial loads. In particular, we found that three polyunsaturated fatty acids (PUFAs) involved in the inhibition of inflammation were more abundant in the serum of patients with higher bacterial loads. However, we do not know whether these PUFAs originated from the host or the bacteria. The variations in the metabolite profile that we observed provide a foundation for future research into the explanations of how leprosy causes disease

Gene Therapy in a Humanized Mouse Model of Familial Hypercholesterolemia Leads to Marked Regression of Atherosclerosis

Familial hypercholesterolemia (FH) is an autosomal codominant disorder caused by mutations in the low-density lipoprotein receptor (LDLR) gene. Homozygous FH patients (hoFH) have severe hypercholesterolemia leading to life threatening atherosclerosis in childhood and adolescence. Mice with germ line interruptions in the Ldlr and Apobec1 genes (Ldlr(-/-)Apobec1(-/-)) simulate metabolic and clinical aspects of hoFH, including atherogenesis on a chow diet.In this study, vectors based on adeno-associated virus 8 (AAV8) were used to deliver the gene for mouse Ldlr (mLDLR) to the livers of Ldlr(-/-)Apobec1(-/-) mice. A single intravenous injection of AAV8.mLDLR was found to significantly reduce plasma cholesterol and non-HDL cholesterol levels in chow-fed animals at doses as low as 3×10(9) genome copies/mouse. Whereas Ldlr(-/-)Apobec1(-/-) mice fed a western-type diet and injected with a control AAV8.null vector experienced a further 65% progression in atherosclerosis over 2 months compared with baseline mice, Ldlr(-/-)Apobec1(-/-) mice treated with AAV8.mLDLR realized an 87% regression of atherosclerotic lesions after 3 months compared to baseline mice. Immunohistochemical analyses revealed a substantial remodeling of atherosclerotic lesions.Collectively, the results presented herein suggest that AAV8-based gene therapy for FH may be feasible and support further development of this approach. The pre-clinical data from these studies will enable for the effective translation of gene therapy into the clinic for treatment of FH

A school-based intervention to reduce overweight and inactivity in children aged 6–12 years: study design of a randomized controlled trial

Background Effective interventions to prevent overweight and obesity in children are urgently needed especially in inner-city neighbourhoods where prevalence of overweight and inactivity among primary school children is high. A school based intervention was developed aiming at the reduction of overweight and inactivity in these children by addressing both behavioural and environmental determinants. Methods/design The main components of the intervention (Lekker Fit!) are the re-establishment of a professional physical education teacher; three (instead of two) PE classes per week; additional sport and play activities outside school hours; fitness testing; classroom education on healthy nutrition, active living and healthy lifestyle choices; and the involvement of parents. The effectiveness of the intervention is evaluated through a cluster randomized controlled trial in 20 primary schools among grades 3 through 8 (6–12 year olds). Primary outcome measures are BMI, waist circumference and fitness. Secondary outcome measures are assessed in a subgroup of grade 6–8 pupils (9–12 year olds) through classroom questionnaires and constitute of nutrition and physical activity behaviours and behavioural determinants. Multilevel regression analyses are used to study differences in outcomes between children in the intervention schools and in control schools, taking clustering of children within schools into account. Discussion Hypotheses are that the intervention results in a lower prevalence of children being overweight and an improved mean fitness score, in comparison with a control group where the intervention is not implemented. The results of our study will contribute to the discussion on the role of physical education and physical activity in the school curriculum. Trial registration [ISRCTN84383524

Lifestyle modification and metformin as long-term treatment options for obese adolescents: study protocol

<p>Abstract</p> <p>Background</p> <p>Childhood obesity is a serious health concern affecting over 155 million children in developed countries worldwide. Childhood obesity is associated with significantly increased risk for development of type 2 diabetes, cardiovascular disease and psychosocial functioning problems (i.e., depression and decreased quality of life). The two major strategies for management of obesity and associated metabolic abnormalities are lifestyle modification and pharmacologic therapy. This paper will provide the background rationale and methods of the REACH childhood obesity treatment program.</p> <p>Methods/design</p> <p>The REACH study is a 2-year multidisciplinary, family-based, childhood obesity treatment program. Seventy-two obese adolescents (aged 10-16 years) and their parents are being recruited to participate in this randomized placebo controlled trial. Participants are randomized to receive either metformin or placebo, and are then randomized to a moderate or a vigorous intensity supervised exercise program for the first 12-weeks. After the 12-week exercise program, participants engage in weekly exercise sessions with an exercise facilitator at a local community center. Participants engage in treatment sessions with a dietitian and social worker monthly for the first year, and then every three months for the second year. The primary outcome measure is change in body mass index and the secondary outcome measures are changes in body composition, risk factors for type 2 diabetes and cardiovascular disease, changes in diet, physical activity, and psychosocial well-being (e.g., quality of life). It is hypothesized that participants who take metformin and engage in vigorous intensity exercise will show the greatest improvements in body mass index. In addition, it is hypothesized that participants who adhere to the REACH program will show improvements in body composition, physical activity, diet, psychosocial functioning and risk factor profiles for type 2 diabetes and cardiovascular disease. These improvements are expected to be maintained over the 2-year program.</p> <p>Discussion</p> <p>The findings from this study will advance the knowledge regarding the long-term efficacy and sustainability of interventions for childhood obesity.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov number NCT00934570</p