STABLE ISOTOPES IN OBESITY RESEARCH

Obesity is recognized as a major public health problem. Obesity is a multifactorial disease and is often associated with a wide range of comorbidities including hypertension, non-insulin dependent (Type II) diabetes mellitus, and cardiovascular disease, all of which contribute to morbidity and mortality. This review deals with stable isotope mass spectrometric methods and the application of stable isotopes to metabolic studies of obesity. Body composition and total energy expenditure (TEE) can be measured by mass spectrometry using stable isotope labeled water, and the metabolism of protein, lipid, and carbohydrate can be measured using appropriate labeled tracer molecules

Study of thyroid dysfunction and dyslipidemia in chronic kidney diseases

Background: Though there are many studies on thyroid dysfunction and dyslipidemia in Chronic Kidney Disease (CKD), no study is conclusive. Aim of this study was to correlate abnormalities in thyroid function and lipid profile with the severity of renal failure and also to observe the difference of these abnormalities between patients on conservative management verses hemodialysis.Methods: Hundred consecutive CKD cases admitted to Medicine Department were taken up for the study. They were divided into two groups as Group-A [on conservative management] and Group-B [on regular Hemodialysis (HD)]. Hundred healthy persons were taken as control in Group-C. After evaluation of thyroid function and lipid profile statistical analysis was done by students t-test, chi-square and regression analysis.Results: Hundred CKD cases with 74% male (n=74) and 26% female (n=26) in a M: F ratio of 2.9:1 were found to be in different stages CKD (0, 2, 20, 28 and 50 in stage-1 to stage-5 respectively). In 50 cases of stage-5 CKD, 30 were on HD and 20 on conservative management. Diabetes Mellitus (DM) (40%) was the commonest etiology of CKD followed by Hypertension (HTN), obstructive uropathy, chronic glomerulonephritis (CGN) and polycystic kidney disease (PKD). Thyromegaly was not found in a single case. In all CKD cases (Group-A+B) TT3 (TT3) was significantly low (P =0.0011) when compared with control (Group-C) and no difference was found between Group-A and Group-B. Fall in TT3 worsened with increasing severity of CKD. Lipid profile study revealed Decreased High-Density Lipoprotein Cholesterol (HDLc) and increased Triglyceride (TG), Total Cholesterol (TC), Low Density Lipoprotein Cholesterol (LDLc), TC/HDLc and LDLc/HDLc in Group-A than Group-B but only TG and TC increase was statistically significant. The levels of TG and TC and TC/HDLc increased as the stage of CKD progressed and was statistically significant (P= 0.035).Conclusions: There occurs a state of biochemical hypothyroidism without overt clinical hypothyroid state in CKD, the extent of which correlates with the severity of CKD. Increased cardiovascular complications occur due to accelerated atherosclerosis in CKD. This study confirmed that atherogenic lipid profile and thyroid dysfunction worsen with the progression of disease. Difference between patients on conservative management and HD was not found

Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: A randomized controlled trial in non-obese humans

Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-center, randomized clinical trial to determine CR's effect on inflammation and cell-mediated immunity, 218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75), and outcomes tested at baseline, 12, and 24 months of CR. CR induced a 10.4% weight loss over the 2-y period. Relative to AL group, CR reduced circulating inflammatory markers, including total WBC and lymphocyte counts, ICAM-1 and leptin. Serum CRP and TNF-α concentrations were about 40% and 50% lower in CR group, respectively. CR had no effect on the delayed-type hypersensitivity skin response or antibody response to vaccines, nor did it cause difference in clinically significant infections. In conclusion, long-term moderate CR without malnutrition induces a significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity. Given the established role of these pro-inflammatory molecules in the pathogenesis of multiple chronic diseases, these CR-induced adaptations suggest a shift toward a healthy phenotype

New fat free mass - fat mass model for use in physiological energy balance equations

<p>Abstract</p> <p>Background</p> <p>The Forbes equation relating fat-free mass (<it>FFM</it>) to fat mass (<it>FM</it>) has been used to predict longitudinal changes in <it>FFM </it>during weight change but has important limitations when paired with a one dimensional energy balance differential equation. Direct use of the Forbes model within a one dimensional energy balance differential equation requires calibration of a translate parameter for the specific population under study. Comparison of translates to a representative sample of the US population indicate that this parameter is a reflection of age, height, race and gender effects.</p> <p>Results</p> <p>We developed a class of fourth order polynomial equations relating <it>FFM </it>to <it>FM </it>that consider age, height, race and gender as covariates eliminating the need to calibrate a parameter to baseline subject data while providing meaningful individual estimates of <it>FFM</it>. Moreover, the intercepts of these polynomial equations are nonnegative and are consistent with observations of very low <it>FM </it>measured during a severe Somali famine. The models preserve the predictive power of the Forbes model for changes in body composition when compared to results from several longitudinal weight change studies.</p> <p>Conclusions</p> <p>The newly developed <it>FFM</it>-<it>FM </it>models provide new opportunities to compare individuals undergoing weight change to subjects in energy balance, analyze body composition for individual parameters, and predict body composition during weight change when pairing with energy balance differential equations.</p

A protein subunit vaccine elicits a balanced immune response that protects against Pseudomonas pulmonary infection

The opportunistic pathogen Pseudomonas aeruginosa (Pa) causes severe nosocomial infections, especially in immunocompromised individuals and the elderly. Increasing drug resistance, the absence of a licensed vaccine and increased hospitalizations due to SARS-CoV-2 have made Pa a major healthcare risk. To address this, we formulated a candidate subunit vaccine against Pa (L-PaF), by fusing the type III secretion system tip and translocator proteins with LTA1 in an oil-in-water emulsion (ME). This was mixed with the TLR4 agonist (BECC438b). Lung mRNA sequencing showed that the formulation activates genes from multiple immunological pathways eliciting a protective Th1-Th17 response following IN immunization. Following infection, however, the immunized mice showed an adaptive response while the PBS-vaccinated mice experienced rapid onset of an inflammatory response. The latter displayed a hypoxic lung environment with high bacterial burden. Finally, the importance of IL-17 and immunoglobulins were demonstrated using knockout mice. These findings suggest a need for a balanced humoral and cellular response to prevent the onset of Pa infection and that our formulation could elicit such a response

Development of a Broadly Protective, Self-Adjuvanting Subunit Vaccine to Prevent Infections by Pseudomonas aeruginosa

Infections caused by the opportunistic pathogen Pseudomonas aeruginosa can be difficult to treat due to innate and acquired antibiotic resistance and this is exacerbated by the emergence of multi-drug resistant strains. Unfortunately, no licensed vaccine yet exists to prevent Pseudomonas infections. Here we describe a novel subunit vaccine that targets the P. aeruginosa type III secretion system (T3SS). This vaccine is based on the novel antigen PaF (Pa Fusion), a fusion of the T3SS needle tip protein, PcrV, and the first of two translocator proteins, PopB. Additionally, PaF is made self-adjuvanting by the N-terminal fusion of the A1 subunit of the mucosal adjuvant double-mutant heat-labile enterotoxin (dmLT). Here we show that this triple fusion, designated L-PaF, can activate dendritic cells in vitro and elicits strong IgG and IgA titers in mice when administered intranasally. This self-adjuvanting vaccine expedites the clearance of P. aeruginosa from the lungs of challenged mice while stimulating host expression of IL-17A, which may be important for generating a protective immune response in humans. L-PaF’s protective capacity was recapitulated in a rat pneumonia model, further supporting the efficacy of this novel fusion vaccine

Application of microneedle arrays for enhancement of transdermal permeation of Insulin: in vitro experiments, scaling analyses and numerical simulations

The aim of this investigation is to study the effect of donor concentration and microneedle (MN) length on permeation of insulin and further evaluating the data using scaling analyses and numerical simulations. Histological evaluation of skin sections was carried to evaluate the skin disruption and depth of penetration by MNs. Scaling analyses was done using dimensionless parameters like concentration of drug (Ct/Cs), thickness (h/L) and surface area of the skin (Sa/L2). Simulation studies were carried out using MATLAB and COMSOL software to simulate the insulin permeation using histological sections of MN treated skin and experimental parameters like passive diffusion coefficient. A 1.6 fold increase in transdermal flux and 1.9 fold decrease in lag time values were observed with 1.5mm MN when compared with passive studies. Good correlation (R2>0.99) was observed between different parameters using scaling analyses. Also, the in vitro and simulated permeations profiles were found to be similar (f2≥50). Insulin permeation significantly increased with increase in donor concentration and MN length (p<0.05). The developed scaling correlations and numerical simulations were found to be accurate and would help researchers to predict the permeation of insulin with new dimensions of MN in optimizing insulin delivery. Overall, it can be inferred that the application of MNs can significantly enhance insulin permeation and may be an efficient alternative for injectable insulin therapy in humans

Effects of 2-year calorie restriction on circulating levels of IGF-1, IGF-binding proteins and cortisol in nonobese men and women: A randomized clinical trial

Young-onset calorie restriction (CR) in rodents decreases serum IGF-1 concentration and increases serum corticosterone levels, which have been hypothesized to play major roles in mediating its anticancer and anti-aging effects. However, little is known on the effects of CR on the IGF-1 system and cortisol in humans. To test the sustained effects of CR on these key hormonal adaptations, we performed a multicenter randomized trial of a 2-year 25% CR intervention in 218 nonobese (body mass index between 22 and 27.8 kg m(-2) ) young and middle-aged (20-50 years age range) men and women. Average CR during the first 6 months was 19.5 ± 0.8% and 9.1 ± 0.7% over the next 18 months of the study. Weight loss averaged 7.6 ± 0.3 kg over the 2-years period of which 71% was fat mass loss (P < 0.0001). Average CR during the CR caused a significant 21% increase in serum IGFBP-1 and a 42% reduction in IGF-1:IGFBP-1 ratio at 2 years (P < 0.008), but did not change IGF-1 and IGF-1:IGFBP-3 ratio levels. Serum cortisol concentrations were slightly but significantly increased by CR at 1 year only (P = 0.003). Calorie restriction had no effect on serum concentrations of PDGF-AB and TGFβ-1. We conclude, on the basis of the present and previous findings, that, in contrast to rodents, humans do not respond to CR with a decrease in serum IGF-1 concentration or with a sustained and biological relevant increase in serum cortisol. However, long-term CR in humans significantly and persistently increases serum IGFBP-1 concentration