Neurolymphomatosis as primary presentation of extra-nodal NK/T-cell lymphoma, nasal type.

Neurolymphomatosis (NL) describes an infiltration of cranial and peripheral nerves by lymphoma cells, most frequently in non-Hodgkin B-cell lymphoma. This clinical entity is rare and poses a challenging diagnosis. We describe a case of a 64-year-old female patient with NL associated with extra-nodal NK/T-cell lymphoma (ENKTL), nasal type, presenting as a painful progressive mononeuropathy multiplex with an oral cavity lesion. ENKTL is usually associated with Epstein-Barr virus (EBV) infection and rarely affects the central and peripheral nervous system. Lumbar puncture, magnetic resonance imaging (MRI), nerve biopsy, and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) help to establish the diagnosis. Thereby, NL should be considered in the differential diagnosis of painful progressive multiple neuropathies, even in patients without previous history of cancer.

Changes in Bone Mineral Density in Patients With Non-dialysis-Dependent Chronic Kidney Disease Are Associated With Body Composition.

OBJECTIVE: Chronic kidney disease (CKD) and low bone mineral density (BMD) are highly prevalent and can co-exist. Parameters of mineral metabolism are associated with BMD in CKD, but other contributing factors may contribute. The aim of this study was to assess changes in BMD and its determinants in patients with nondialysis-dependent CKD (NDD-CKD). METHODS: Body composition and biochemical profiles were assessed in a retrospective hospital-based cohort study of patients with NDD-CKD. BMD, lean soft tissue (LST), appendicular LST (ALST), and percentage fat mass were assessed by dual-energy X-ray absorptiometry. The ALST index (ALSTI, ALST/height2) and load-capacity index (LCI, fat mass/LST) were calculated. Low BMD was defined as T-score ≤ -1.0. RESULTS: The mean time between assessments was 2.8 ± 1.3 years; 46 patients were included. A reduction in renal function was observed. Changes in body composition included reductions in ALST (P = .031), ALSTI (P = .021), a trend for BMD (P = .053), and an increase in percentage fat mass (P = .044) and LCI (P = .032). Females had a reduction in BMD (P = .034), ALST (P = .026), and ALSTI (P = .037). Patients with low BMD at baseline had lower LST (P = .013), ALST (P = .023), and percentage fat mass (P = .037) than those with normal BMD. Additionally, reductions in LST (P = .041), ALST (P = .006), and ALSTI (P = .008) were observed in patients who had low BMD at baseline, while no significant changes in body composition were observed in those with normal BMD at baseline. The following body composition parameters at baseline were determinants of BMD status at follow-up: LST (odds ratio [OR]: 0.899, 95% confidence interval [CI]: 0.829-0.976, P = .010), ALST (OR: 0.825, 95% CI: 0.704-0.967, P = .017), and ALSTI (OR: 0.586, 95% CI: 0.354-0.968, P = .037), independent of fat mass and LCI. CONCLUSIONS: Detrimental body composition changes were observed without changes in body weight; these were more significant in females. Moreover, this is the first longitudinal study showing a protective effect of LST against BMD loss in patients with NDD-CKD.

Soaking to Reduce Potassium and Phosphorus Content of Foods.

OBJECTIVES: To achieve and maintain normal serum potassium and phosphorus levels reducing potassium and phosphorus intake is frequently recommended for adults living with chronic kidney disease. Exploring food preparation methods to reduce potassium and phosphorus content appears warranted. The study aim is to determine the impact of soaking foods in hot water on potassium and phosphorus content in a variety of plant- and animal-based foods. METHODS: Twenty foods were selected that are common staples in Brazilian diet patterns. Food was soaked for 5-10 minutes in deionized water that had been brought to a boil and then removed from heat using a 5-part water to 1-part sample ratio. The potassium content was determined by flame photometry. The phosphorus content was determined by visible ultraviolet spectrophotometry. RESULTS: Soaking foods resulted in a reduction in potassium and phosphorus. Potassium reduction in beef, green leafy vegetables, and grains was 40-49%; in chicken, fish, and nonleafy vegetables 30-39%; and tubers 10-20%. Phosphorus reduction in grains and beans was 30-39%; in nonleafy vegetables 20-29%; and beef, chicken, and fish 10-20%. CONCLUSIONS: Soaking foods in hot water for 5-10 minutes reduces potassium and phosphorus content. Using this technique to prepare foods may be a more acceptable alternative to longer demineralization periods making it easier for adults living with chronic kidney disease to follow diet recommendations.

Sarcopenia and sarcopenic obesity in chronic kidney disease: update on prevalence, outcomes, risk factors and nutrition treatment.

PURPOSE OF REVIEW: This review summarizes literature from the last 18 months reporting on sarcopenia (or its components) in chronic kidney disease (CKD). RECENT FINDINGS: The prevalence of sarcopenia in CKD is reported to be 5-62.5%, with higher rates observed later in the disease. Sarcopenic obesity rates are reported to be 2-23%. Sarcopenia in CKD is associated with increased risk of mortality, cardiovascular disease and vascular calcification. Risk factors include kidney disease itself and the impacts of CKD on lifestyle (reduced physical activity, diet changes). In earlier stages of CKD, if the risks from sarcopenia outweigh the risk of reaching end-stage renal disease, ensuring adequate energy intake combined with modest protein liberalization and physical activity may be indicated. Protein intakes above 1.3 g/kg of body weight per day should be avoided. For dialysis patients, interventions that provide a combination of carbohydrate, protein and fat appear more effective than those that provide protein alone, though it may take as long as 48 weeks for detectable changes in muscle mass. SUMMARY: Sarcopenia is prevalent in CKD as kidney disease significantly impacts muscle mass and function. Nutrition interventions can improve components of sarcopenia, with an emphasis on adequate energy and protein.

Birth weight and body composition in 6-to-8 years old Maya children.

OBJECTIVE: To test the hypothesis that fetal growth, indexed by birth weight (BW), induce metabolic adjustments in the fetus that will be reflected in differences in body composition in a sample of 6-to 8-years old urban Maya children from Yucatan, Mexico. METHODS: We measured height (cm), weight (kg) and triceps skinfold (mm) in 260 children (boys: 132, girls: 128), and height (cm) and weight (kg) in their mothers. Body composition was estimated in children through bioelectrical impedance analysis. Outcome variables were fat free-mass index (FFMI = fat-free mass [kg]/height [m]2 ) and fat mass index (FMI = fat mass [kg]/height [m]2 ). The main independent variable was BW z-scores. Multiple linear regression models were used to analyze the association between BW z-scores and outcome variables measured during childhood. Separate analyses were done for boys and girls. Complementary models were run using outcomes as z-scores. Models were adjusted for location, children's and mothers' age, mother's body mass index and household overcrowding index. RESULTS: BW in boys was positively associated with FFMI and FMI. FFMI increase 0.34 kg/m2 per 1-SD increase in BW and FMI increase 0.40 kg/m2 per 1-SD increase in BW. When outcomes were used as z-scores, FFMI increase 0.24 SD and FMI increase 0.18 SD per 1-SD increase in BW, respectively. CONCLUSION: Our results are in contrast with previous findings that birth weight is more consistently associated with subsequent lean mass than with fat mass. Associations, detected only in boys, may be explained by sex differences in sensitivity to early life environments.

The timing of adrenarche in Maya girls, Merida, Mexico.

BACKGROUND: Adrenarche involves maturation of the hypothalamic-pituitary-adrenal axis and increased production of dehydroepiandrosterone and its sulfate ester, dehydroepiandrosterone-sulfate (DHEA-S). It occurs at ages 6 to 8 in industrialized populations, marking the transition from childhood to juvenility and cognitive development at middle childhood. Studies in subsistence level populations indicate a later age (8-9) for adrenarche, but only two such studies currently exist for comparison. AIMS: To investigate adrenarcheal age among Maya girls and its association with body composition and dietary variables. We hypothesized adrenarche would occur earlier given the current dual burden of nutrition in Mexico. MATERIALS AND METHODS: 25 Maya girls aged 7 to 9 from Merida, Mexico using ELISAs to measure salivary DHEA-S, standard anthropometry for height, weight, and skinfolds, bioelectrical impedance for body composition variables, as well as a food frequency questionnaire for dietary information. RESULTS: Our hypothesis was rejected-adrenarche occurred close to 9 years. While no measures of body composition were significantly associated with adrenarcheal status, girls eating meat and dairy products more frequently had significantly higher DHEA-S levels. DISCUSSION: Like other populations living in ecologically challenging environments, adrenarche occurred relatively late among Maya girls. Adrenarche has been linked to measures of body composition, particularly, the adiposity or body mass index rebound, but no relevant anthropometric measures were associated, possibly because of the small sample. CONCLUSION: Further studies are required to illuminate how adrenarcheal variation relates to developmental plasticity, body composition, pubertal progression, and animal product consumption in other transitional populations.

Synergistic Effect of Inflammatory Cytokines and Body Adiposity on Insulin Resistance and Endothelial Markers in Patients With Stages 3-5 Chronic Kidney Disease.

BACKGROUND: High body adiposity, inflammatory cytokines, insulin resistance (IR), and the endothelial markers-soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1)-are among cardiovascular risk factors observed in chronic kidney disease (CKD). Synergistic interaction of inflammatory cytokines with adiposity on IR, sICAM-1, and sVCAM-1 has not been reported in nondialysis-dependent CKD (NDD-CKD) patients. Thus the study aim was to evaluate the interaction of inflammatory cytokines on the association of body adiposity with the cardiometabolic risk factors-IR, sICAM-1, and sVCAM-1-in NDD-CKD patients. Cytokines association with estimated glomerular filtration rate (eGFR) and body adiposity was also examined. DESIGN AND METHODS: A cross-sectional study was conducted in an interdisciplinary outpatient Nephrology Clinic. SUBJECTS AND MEASUREMENTS: NDD-CKD adults with eGFR ≤60 mL/minute/1.73 m2 under regular treatment. Inflammatory cytokines, homeostasis model assessment of insulin resistance (HOMA-IR), sICAM-1, sVCAM-1, eGFR (by CKD-Epidemiology collaboration equation)-EPI equation, and body composition assessed by dual-energy X-ray absorptiometry and anthropometry were evaluated. Synergistic effects of inflammatory markers with body adiposity on studied cardiometabolic risk factors were assessed by interaction and mediation analysis. RESULTS: The study cohort comprised 241 NDD-CKD patients (54.8% men; eGFR = 29.4 ± 12.9 mL/minute/1.73 m2). Variables evaluated: Inflammatory cytokines were not associated with eGFR and not different among CKD stages. Percentage of total body adiposity (%TBA) was independently associated with tumor necrosis factor-alpha (TNFα) and HOMA-IR. Waist-to-height ratio was independently associated with TNFα, interleukin-8, monocyte chemoattractant protein-1 (MCP1), and HOMA-IR. Interaction analysis showed TNFα, interleukin-8, and MCP1 as independent mediators of the effects of high percentage of total body adiposity and waist-to-height ratio on HOMA-IR (P < .0001). Body adiposity did not associate with sICAM-1 and sVCAM-1. TNFα (ß = 0.40) and MCP1 (ß = 0.31) were independently associated with sVCAM-1 (P < .01). CONCLUSIONS: In NDD-CKD patients, inflammatory cytokines synergistically mediated the effects of body adiposity, enhancing the cardiometabolic risk. Inflammation was associated with sVCAM-1, but not with eGFR.

High abdominal adiposity and low phase angle in overweight renal transplant recipients.

Obesity is associated with increased risk of cardiovascular disease (CVD). Body mass index (BMI) is the most used parameter for obesity screening. However, the evaluation of CVD risk in overweight individuals should include the assessment of body fat distribution and body composition. Renal transplant recipients (RTR) have a high CVD risk and frequently present weight gain and loss of lean mass. The aim of this study was to evaluate body fat distribution and body composition in overweight RTR. This cross-sectional study was conducted with 86 RTR and 86 hypertensive individuals (comparison group, CG) presenting BMI 25-35 Kg/m2 and 45-70 years. Anthropometric evaluation included BMI, waist circumference, waist-to-height ratio, and a body shape index. Body composition was evaluated with bioelectrical impedance analysis (BIA). Glomerular filtration rate was estimated (eGFR) by CKD-EPI equation. RTR group (RTRG) and CG presented similar age and BMI. RTRG when compared to CG presented lower percentage of women and eGFR; higher central adiposity; and lower values of reactance, intracellular water, body cell mass and phase angle, more consistently observed in women. This study suggests that overweight RTR present higher abdominal adiposity and impairment in BIA parameters that are sensitive indicators of impaired membrane integrity, water distribution, and body cell mass.

Sarcopenia and its components in adult renal transplant recipients: prevalence and association with body adiposity.

Sarcopenia is a progressive and generalised skeletal muscle disorder associated with adverse outcomes. Ageing causes primary sarcopenia, while secondary causes include chronic kidney disease (CKD), long-term use of glucocorticoids and obesity. The aim of the present study was to evaluate the prevalence of sarcopenia using guidelines recommended by the European Working Group on Sarcopenia in Older People (EWGSOP, 2010; EWGSOP2, 2018) and the Foundation of the National Institutes of Health (FNIH) and analyse the relationship between sarcopenia and body adiposity in adult renal transplant recipients (RTR). This was a cross-sectional study of adult RTR (BMI ≥ 18·5 kg/m2). Body composition was evaluated by dual-energy X-ray absorptiometry (DXA) and anthropometry. Glomerular filtration rate was estimated (eGFR) by CKD-Epidemiology Collaboration equation. The prevalence of sarcopenia in adult RTR (n 185; 57 % men, 50 (se 0·82) years and eGFR 55·80 (se 1·52) ml/min) was 7 % (FNIH), 11 % (EWGSOP2) and 17 % (EWGSOP). Low muscle mass, muscle function and physical performance affected, respectively, up to 28, 46 and 10 % of the participants. According to EWGSOP and EWGSOP2, body adiposity evaluated by anthropometry and DXA (percentage trunk fat) was lower in participants with sarcopenia. Conversely, according to the FNIH criteria, RTR with sarcopenia presented higher waist:height ratio. The present study suggests that adult RTR sarcopenia prevalence varies according to the diagnostic criteria; low muscle mass, low muscle function and low physical performance are common conditions; the association of body adiposity and sarcopenia depends on the criteria used to define this syndrome; and the FNIH criteria detected higher adiposity in individuals with sarcopenia.

Vitamin B12 status in kidney transplant recipients: association with dietary intake, body adiposity and immunosuppression.

The aim of the present study was to evaluate the prevalence of vitamin B12 (B12) deficiency in kidney transplant recipients (KTR) and its possible association with B12 dietary intake, body adiposity and immunosuppressive drugs. In this cross-sectional study, we included 225 KTR, aged 47·50 (sd 12·11) years, and 125 (56 %) were men. Serum levels of B12 were determined by chemiluminescent microparticle intrinsic factor assay and the cut-off of 200 pg/ml was used to stratify KTR into B12-sufficient or B12-deficient group. B12 dietary intake was evaluated by three 24 h dietary recalls and was considered adequate when ≥2·4 µg/d. Body adiposity was estimated after taking anthropometric measures and using the dual-energy X-ray absorptiometry (DXA) method. B12 deficiency was seen in 14 % of the individuals. B12-deficient group, compared with the B12-sufficient group, exhibited lower intake of B12 (median 2·42 (interquartile range (IQR) 1·41-3·23) v. 3·16 (IQR 1·94-4·55) µg/d, P = 0·04) and higher values of waist circumference (median 96·0 (IQR 88·0-102·5) v. 90·0 (IQR 82·0-100·0) cm, P = 0·04). When the analysis included only women, B12 deficiency was associated with higher total and central body adiposity measurements obtained with anthropometry (BMI, body adiposity index, waist and neck circumferences) and DXA (total and trunk body fat). Among individuals with adequate intake of B12, the deficiency of this vitamin was more frequently seen in those using mycophenolate mofetil (MMF) (17 %) v. azathioprine (2 %), P = 0·01. In conclusion, the prevalence of B12 deficiency in KTR was estimated as 14 % and was associated with reduced intake of B12 as well as higher adiposity, especially in women, and with the use of MMF.

Caesarean birth and adiposity parameters in 6- to 8-year-old urban Maya children from two cities of Yucatan, Mexico.

OBJECTIVES: The purpose of this study was to analyze the association between birth mode and fat mass index (FMI = fat mass [kg]/height [m]2 ), and z-score values of waist circumference (WCZ) and sum of triceps and subscapular skinfolds (SumSkfZ) in a sample of 256 6- to 8-year-old urban Maya children from the cities of Merida and Motul in Yucatan, Mexico. METHODS: From September 2011 to January 2014, we measured height, weight, waist circumference and skinfolds in children, and height and weight in their mothers. Body composition was estimated in both generations through bioelectrical impedance analysis. Data on children's birth mode and birth weight were obtained from birth certificates. A pre-validated questionnaire for mothers was used regarding household living conditions. Multiple regression models were used to analyze the association between birth mode and adiposity parameters, adjusting for the effect of place of residence, household crowding index, children's birth weight, and maternal fat mass. Separate regression models were run for boys and girls. RESULTS: Caesarean-born children comprised 43% of the entire sample. Caesarean section (CS) was found to be associated with higher values of body adiposity in girls, but not in boys. Specifically, our models predicted that girls born by CS had an increased value of 0.817 kg/m2 in FMI and showed higher SDs values for WCZ and SumskfZ (0.29 and 0.32 SD, respectively) than girls who were delivered vaginally. DISCUSSION: Our results support the hypothesis that CS is associated with increased levels of adiposity in childhood, but only in girls.

Body proportionality and adiposity are not related in 6- to 8-year-old Yucatec Maya children.

OBJECTIVE: The aim of this study was to analyze the association between relative leg length (RLL) (leg length × 100/height) and adiposity in a sample of 6- to 8-year-old children of Maya ancestry from Motul and Merida, Mexico. METHODS: This cross-sectional study included 260 children (128 girls) measured between 2011 and 2015. The RLL was used as a measure of body proportionality. Linear regression models were performed to examine the association between RLL (predictor) and three adiposity indicators (outcome variables): fat mass index (kg/m2 ), waist circumference (z-score), and sum of triceps and subscapular skinfolds (z-score). RESULTS: The prevalence of stunting was 12%, and a higher prevalence (19%) of short RLL (leg stunting) was found. The prevalence of overweight and obesity were 16% and 20%, respectively, but the highest prevalence was found for abdominal obesity (40%). None of the adiposity indicators were related to RLL (P > .05), even after adjusting for the influence of children's sex and age. CONCLUSIONS: Our results suggest that the coexistence of short RLL and high body adiposity is not observed in all populations. Our findings do not discount the possibility that a negative association between RLL and adiposity is expressed at older ages.

Living conditions and change in age of menarche in adult Maya mothers and daughters from Yucatan, Mexico.

OBJECTIVES: To analyze whether living conditions, experienced by mothers and adult daughters during their childhood, are associated with age at menarche (AAM) in daughters. METHODS: From September, 2011, to January, 2014, AAM and childhood living conditions were collected from a sample of 246 dyads of Maya mothers (mean age = 59.60 years, SD = 8.64) and their adult daughters (mean age = 33.03 years, SD = 5.57) from the cities of Merida and Motul in Yucatan, Mexico. Indicators of childhood living conditions were number of siblings and quality of house construction materials in both generations, and father's absence among daughters in their pre-menarcheal years. Multiple regression models were used to assess the association between childhood conditions in mother-daughter dyads and daughter's AAM. RESULTS: The recalled mean AAM of adult Maya daughters was 12.05 years (SD = 1.53). After adjusting for the influence of mothers' AAM, number of siblings in both the mothers' and daughters' families directly predicted daughters' AAM (more siblings was associated with a later AAM); and a higher (better) index of household conditions in mothers' childhood was associated with earlier AAM in daughters. The household conditions index during the childhood of daughters and father's absence were not associated with their AAM. CONCLUSIONS: Our results suggest that better living conditions experienced by the mothers and daughters during their childhood may lower mean AAM in daughters in the context of populations that show important intergenerational changes in their social and economic conditions.

Vitamin D status in renal transplant recipients living in a low-latitude city: association with body fat, cardiovascular risk factors, estimated glomerular filtration rate and proteinuria.

Recent evidence suggests that vitamin D deficiency is associated with CVD, impaired kidney function and proteinuria. To date, no study has evaluated these associations in renal transplant recipients (RTR) adjusting for body adiposity assessed by a 'gold standard' method. This study aimed to evaluate the vitamin D status and its association with body adiposity, CVD risk factors, estimated glomerular filtration rate (eGFR) and proteinuria in RTR, living in Rio de Janeiro, Brazil (a low-latitude city (22°54'10"S)), taking into account body adiposity evaluated by dual-energy X-ray absorptiometry (DXA). This cross-sectional study included 195 RTR (114 men) aged 47·6 (sd 11·2) years. Nutritional evaluation included anthropometry and DXA. Risk factors for CVD were hypertension, diabetes mellitus, dyslipidaemia and the metabolic syndrome. eGFR was evaluated using the Chronic Kidney Disease Epidemiology Collaboration equation. Serum 25-hydroxyvitamin D (25(OH)D) concentration was used to define vitamin D status as follows: 10 % (n 19) had vitamin D deficiency (30 ng/ml). Percentage of body fat (DXA) was significantly associated with vitamin D deficiency independently of age, sex and eGFR. Lower 25(OH)D was associated with higher odds of the metabolic syndrome and dyslipidaemia after adjustment for age, sex and eGFR, but not after additional adjustment for body fat. Hypertension and diabetes were not related to 25(OH)D. Lower serum 25(OH)D was associated with increasing proteinuria and decreasing eGFR even after adjustments for age, sex and percentage of body fat. This study suggests that in RTR of a low-latitude city hypovitaminosis D is common, and is associated with excessive body fat, decreased eGFR and increased proteinuria.

Intergenerational changes in knee height among Maya mothers and their adult daughters from Merida, Mexico.

OBJECTIVES: To analyze differences in knee height (KH) between adult Maya mothers and daughters in Merida City, Mexico, and determine if these differences are associated with their childhood socioeconomic conditions. METHODS: From September 2011 to January 2014, we measured KH and collected data on childhood conditions (place of birth, type of drinking water, family size, and fathers' occupation) from a sample of 180 Maya mother-daughter dyads. Mean KH intergenerational difference was calculated and compared for each category of socioeconomic variables and a multiple regression model was used to assess the association between childhood conditions and KH difference. RESULTS: A relative increase of 1.05 cm (SD = 2.3 cm) or 0.45 standard deviations (effect size of difference) was observed in KH between generations. Place of birth was significantly associated with KH. With three other variables statistically adjusted for, the intergenerational KH difference was 1.5 cm greater when mothers were born outside Merida but daughters were born in the city. Piped water consumption by mother-daughter dyads was associated with 1.5 cm of increase in KH difference compared with dyads who consumed well water (P = 0.058). CONCLUSIONS: The relative increase in KH between mothers and daughters represents a portion of the expected change in growth in a group that has experienced few substantial improvements in their living conditions. Some improvements in childhood living conditions resulting from the intergenerational transition from rural to urban environments seem to be linked to a modest, but statistically significant intergenerational increase in KH among Maya women in Merida.

Intergenerational influences on the growth of Maya children: The effect of living conditions experienced by mothers and maternal grandmothers during their childhood.

OBJECTIVES: To test the hypothesis that living conditions experienced by maternal grandmothers (F1 generation) and mothers (F2 generation) during their childhood are related to height and leg length (LL: height - sitting height) of their 6-to-8 year old children (F3 generation). METHODS: From September 2011 to June 2012 we obtained height and LL, and calculated z-score values of these measurements for 109 triads (F1 , F2 , F3 ) who are Maya living in Merida, Yucatan, Mexico. Multiple regression models were adjusted to examine the relation of anthropometric and intergenerational socioeconomic parameters of F1 (house index and family size during childhood) and F2 (paternal job loss during childhood) with the z-score values of height and LL of F3 . RESULTS: Children's height and LL were positively associated with maternal height and LL. This association was relatively stronger in LL. Better categories of grand-maternal house index were significantly associated with higher values of height and LL in grandchildren. Grand-maternal family size was positively related with LL, but not with height. CONCLUSIONS: Our findings partially support the hypothesis that living conditions experienced by recent maternal ancestors (F1 and F2 ) during their growth period influence the growth of descendants (F3 ). Results suggest that LL is more sensitive to intergenerational influences than is total height and that the transition from a traditional rural lifestyle to urban conditions results in new exposures for risk in human physical growth.

Sex differences in systemic inflammation and immune function in diet-induced obesity rodent models: A systematic review.

Understanding sex differences in immunological responses in the context of obesity is important to improve health outcomes. This systematic review aimed to investigate sex differences in systemic inflammation, immune cell phenotype, and function in diet-induced obesity (DIO) animal models. A systematic search in Medline, Embase, and CINAHL from inception to April 2023 was conducted, using a combination of the following concepts: sex, obesity, cytokines, and immune cell phenotypes/function. Forty-one publications reporting on systemic inflammation (61%), cell phenotype (44%), and/or function (7%) were included. Females had lower systemic inflammation compared with males in response to DIO intervention and a higher proportion of macrophage (M)2-like cells compared with males that had a higher proportion of M1-like in adipose tissue. Although there were no clear sex differences in immune function, high-fat DIO intervention remains an important factor in the development of immune dysfunction in both males and females, including disturbances in cytokine production, proliferation, and migration of immune cells. Yet, the mechanistic links between diet and obesity on such immune dysfunction remain unclear. Future studies should investigate the role of diet and obesity in the functionality of immune cells and employ adequate methods for a high-quality investigation of sex differences in this context.

Application of the iPLUS non-coding sequence in improving biopharmaceuticals production.

The biotechnological landscape has witnessed significant growth in biological therapeutics particularly in the field of recombinant protein production. Here we investigate the function of 3'UTR cis-regulatory elements in increasing mRNA and protein levels in different biological therapeutics and model systems, spanning from monoclonal antibodies to mRNA vaccines. We explore the regulatory function of iPLUS - a universal sequence capable of consistently augmenting recombinant protein levels. By incorporating iPLUS in a vector to express a monoclonal antibody used in immunotherapy, in a mammalian cell line used by the industry (ExpiCHO), trastuzumab production increases by 2-fold. As yeast Pichia pastoris is widely used in the manufacture of industrial enzymes and pharmaceuticals, we then used iPLUS in tandem (3x) and iPLUSv2 (a variant of iPLUS) to provide proof-of-concept data that it increases the production of a reporter protein more than 100-fold. As iPLUS functions by also increasing mRNA levels, we hypothesize that these sequences could be used as an asset in the mRNA vaccine industry. In fact, by including iPLUSv2 downstream of Spike we were able to double its production. Moreover, the same effect was observed when we introduced iPLUSv2 downstream of MAGEC2, a tumor-specific antigen tested for cancer mRNA vaccines. Taken together, our study provides data (TLR4) showing that iPLUS may be used as a valuable asset in a variety of systems used by the biotech and biopharmaceutical industry. Our results underscore the critical role of non-coding sequences in controlling gene expression, offering a promising avenue to accelerate, enhance, and cost-effectively optimize biopharmaceutical production processes.

A novel simulated media system for in vitro evaluation of bioequivalent intestinal drug solubility.

Orally administered solid drug must dissolve in the gastrointestinal tract before absorption to provide a systemic response. Intestinal solubility is therefore crucial but difficult to measure since human intestinal fluid (HIF) is challenging to obtain, varies between fasted (Fa) and fed (Fe) states and exhibits inter and intra subject variability. A single simulated intestinal fluid (SIF) cannot reflect HIF variability, therefore current approaches are not optimal. In this study we have compared literature Fa/FeHIF drug solubilities to values measured in a novel in vitro simulated nine media system for either the fasted (Fa9SIF) or fed (Fe9SIF) state. The manuscript contains 129 literature sampled human intestinal fluid equilibrium solubility values and 387 simulated intestinal fluid equilibrium solubility values. Statistical comparison does not detect a difference (Fa/Fe9SIF vs Fa/FeHIF), a novel solubility correlation window enclosed 95% of an additional literature Fa/FeHIF data set and solubility behaviour is consistent with previous physicochemical studies. The Fa/Fe9SIF system therefore represents a novel in vitro methodology for bioequivalent intestinal solubility determination. Combined with intestinal permeability this provides an improved, population based, biopharmaceutical assessment that guides formulation development and indicates the presence of food based solubility effects. This transforms predictive ability during drug discovery and development and may represent a methodology applicable to other multicomponent fluids where no single component is responsible for performance.