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Objective: To study the relationship between consumption of milk and milk products, calcium, lactose and vitamin D and occurrence of colorectal cancers. Design: Prospective cohort study. Subjects: A total of 9959 men and women aged 15 y or older without history of cancer at baseline. During a 24 y follow-up, 72 new cancers of the large bowel (38 in the colon and 34 in the rectum) were detected. Results: Consumption of milk and total milk products was suggested to be inversely related to colon cancer incidence, whereas no similar association was seen for rectal cancer. The relative risk between the highest and lowest quartiles of intake adjusted for potential confounding factors was 0.46 (95% confidence interval 0.14–1.46, P for trend 0.09) for milk and 0.37 (95% CI=0.12–1.39, P for trend 0.06) for total milk products. Lactose intake showed a similar inverse relationship with colon cancer: the relative risk was 0.31 (95% CI=0.08–1.15, P for trend 0.03). Intake of vitamin D or total dietary calcium was not significantly related to colorectal cancer risk, whereas calcium provided by fermented milk products was associated with increased colorectal cancer incidence; in the highest quartile the multivariate adjusted relative risk for colorectal cancer was 2.07 (95% CI=1.00–4.28). Conclusions: Our results indicate that individuals showing high consumption of milk have a potentially reduced risk of colon cancer; however, the association does not appear to be due to intake of calcium, vitamin D, or to specific effects of fermented milk. Sponsorship: This study was supported by a grant from the Swedish Cancer Foundation. European Journal of Clinical Nutrition (2001) 55, 1000–1007

• Infants born with ambiguous genitalia or nonpalpable testes need to be evaluated for congenital adrenal hyperplasia as it can be life threatening. • Adrenal steroid levels vary with gestational age. • Adrenal insufficiency should be treated with hydrocortisone to avoid adrenal crisis. High doses of hydrocortisone contain mineralocorticoid activity.

A 42-year-old man who had suffered from severe fatigue for 5 years was diagnosed as having chronic fatigue syndrome (CFS) and fibromyalgia. Endocrinological workup using combined anterior pituitary function tests showed that the patient had adrenocorticotropin hormone (ACTH) deficiency, with a normal pituitary MRI. Treatment with a physiologic dose of oral hydrocortisone replacement physically ameliorated his general fatigue. A secondary workup using a growth hormone-releasing peptide-2 test revealed that he also had growth hormone (GH) deficiency, and GH replacement therapy was started. His muscle pain and depression were improved by the therapy. Here, we present a rare case of combined deficiency of ACTH and GH in a middle-aged man with severe general fatigue. This case report aims to raise awareness of combined deficiency of ACTH and GH as a differential diagnosis of CFS and its mimics.

Findley first proposed the presence of age-related dysfunction of the hypothalamic-neurohypophyseal-renal axis more than 60 years ago. More sophisticated studies have since corroborated his findings. As a result, it is now clear that multiple abnormalities in water homeostasis occur commonly with aging, and that the elderly are uniquely susceptible to disorders of body volume and osmolality. This article summarizes the distinct points along the hypothalamic-neurohypophyseal-renal axis where these changes have been characterized, as well as the clinical significance of these changes, with special attention to effects on cognition, gait instability, osteoporosis, fractures, and morbidity and mortality.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disease caused by activating mutations in the arginine vasopressin (AVP) receptor-2 (AVPR2) gene. Affected patients excrete concentrated urine despite very low levels of AVP, and consequently develop euvolemic hyponatremia. Due to its low frequency, patients may be misdiagnosed and treated incorrectly. We report two related male infants with NSIAD that was initially confused with hyporeninemic hypoaldosteronism (HH). First, a 2-month-old male presented with hyponatremia, low plasma osmolality, relatively high urine osmolality, and low plasma renin-aldosterone levels. These clinical and laboratory findings were compatible with syndrome of inappropriate antidiuretic hormone secretion without apparent cause. Consequently,fludrocortisone was initiated with a presumptive diagnosis of HH While correction of hyponatremia, fludrocortisone treatment led to hypertension and discontinued in a short time. The second patient at age of 1 year was admitted with a history of oligohydramnios, four times hospitalizations due to hyponatremia since birth, and a diagnosis of epilepsy. Similarly, the second infant had clinical and laboratory findings compatible with syndrome of inappropriate antidiuretic hormone secretion with no apparent cause. Fluid restriction normalized his serum sodium despite plasma AVP level was undetectable. In both infants, AVPR2 gene analysis revealed a known mutation (c.409C>T; p.R137C) and confirmed the diagnosis of NSIAD. In conclusion, NSIAD should be considered in all patients with unexplained euvolemic hyponatremia despite high urine osmolality. In case of unawareness from NSIAD, plasma renin-aldosterone profile can be confused with HH, especially in the infants. 34645113

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. In this situation; while obesity cannot be controlled with diet and exercise, it was shown that Glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in short term. In this paper, we present our experience with Liraglutide treatment in an adolescent patient carrying MC4R gene variant. A female patient had admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had a marked excess of appetite since infancy. In the physical examination of the pubertal female patient with a body mass index (BMI) of 36.1kg/m2 (3.48 SDS), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss couldn't be achieved with lifestyle changes, metformin and orlistat treatments In genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant (reported previously) was found in the MC4R gene. GLP-1 RA Liraglutide treatment was initiated and a loss of 19.2% reduction was achieved in the patient's body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months after treatment was stopped. In our case carrying a pathogenic variant in the MC4R gene, decrease of appetite and weight loss were achieved with Liraglutide treatment, but this situation could not be maintained. In such cases, there is a need for effective and tolerable treatment options.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and a whole gene deletion in the other) with early growth impairment in infancy. Growth hormone deficiency was confirmed at 20 months of life. Recombinant growth hormone treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Lysosomal acid lipase (LAL) deficiency is a rare, autosomal recessive disease caused by mutations in the LIPA gene, which produces cholesteryl ester and triglyceride accumulation predominantly in hepatocytes, adrenal glands, and gastrointestinal tract. We describe two new cases occurring in siblings, aged 5 and 7 years, who presented with hepatomegaly, dyslipidemia, and abnormal liver function. Percutaneous liver biopsy revealed portal inflammation, hypertrophic Kupffer cells with a foamy appearance and microvesicular steatosis with fibrosis. Immunostaining for lysosomal markers, cathepsin D and LAMP1 reflected the lysosomal nature of the lipid vacuoles. After enzymatic confirmation, enzyme replacement therapy was initiated for both siblings. Follow-up transaminase levels and lipid profiles showed a notable decrease in AST and ALT and a slight increase in HDL cholesterol. It is crucial to increase awareness of this rare condition among clinicians and pathologists. The expression of lysosomal markers around the lipid vacuoles might help diagnose LAL deficiency in pediatric patients.

Abstract: In this study, children with vitamin B12 deficiency anemia (V-B12DA) and control subjects were evaluated for erythrocyte glutathione peroxidase, catalase and superoxide dismutase enzyme activities, glutathione, malondialdehyde, serum total sialic acid, total antioxidant status, cobalt, chromium, copper, selenium, vanadium, zinc, iron, lead, magnesium, calcium, sodium, potassium, chloride, phosphorus levels, and the associations of these variables were assessed. The study included 50 children with V-B12DA and 50 control subjects. It was found that the V-B12DA group was significantly lower than the control group, with regard to the mean±the standard error of the mean levels of cobalt (0.089±0.009; 0.058±0.0063 μmol/L, p12 (427.20±21.45; 157.08±3.96 pg/mL, p12DA, significantly linear correlations were observed between cobalt – vitamin B12 (r=0.334; p=0.025), vanadium – MCV (r=0.315; p=0.017), vitamin B12 – MCV (r=−0.297; p=0.026). The findings of the study indicated that the levels of cobalt, vanadium significantly associated with traditional vitamin B12-deficiency parameters. Vitamin B12 and MCV should be measured together with cobalt, vanadium for monitoring the vitamin B12 deficiency anemia.

Abstract: Lipoprotein(a)(Lp[a]) is a low-density lipoprotein-cholesterol (LDL-C)-like particle with potent pro-atherothrombotic properties. The association of Lp(a) with several circulating factors, including vitamins, remains unresolved. We performed an observational analysis using the National Health and Nutrition Examination Survey III cohort, a cohort used to monitor the nutrition status of US-citizens. We used multivariable linear regression to test associations of Lp(a) and LDL-C with levels of serum vitamins and minerals and whole-blood lead. Analyses controlled for factors known to associate with Lp(a) (age, sex, race/ethnicity, statin use, hemoglobin A1c, body mass index, hypertension, diabetes, glomerular filtration rate, alcohol intake, and saturated fat intake). LDL-C was corrected for Lp(a) mass. Multiple sensitivity tests were performed, including considering factors as categorical variables (deficient, normal, elevated). Among 7,662 subjects, Lp(a) correlated (β-coefficient) positively (change per 1 conventional unit increase) with carotenoids (lycopene (0.17(0.06,0.28), p=0.005), lutein (0.19(0.07,0.30), p=0.002), β-cryptoxanthin (0.21(0.05,0.37), p=0.01), β-carotene (0.05(0.02,0.09), p=0.003), and α-carotene (0.15(0.01,0.30), p=0.04)) and lead (0.54(0.03,1.05), p=0.04) levels when tested as continuous variables. LDL-C had similar associations. Lp(a) did not associate with vitamins A, B12, C, or E retinyl esters, folate, RBC-folate, selenium, ferritin, transferrin saturation, or calcium. With factors as categorical variables, Lp(a) but not LDL-C negatively associated with elevated vitamin B12 (−5.41(−9.50, −1.53), p=0.01) and folate (−2.86(−5.09, −0.63), p=0.01). In conclusion, Lp(a) associated similarly to LDL-C when vitamins, minerals, and lead were tested as continuous variables, while only Lp(a) correlated with vitamin B12 and folate when tested as categorical variables. These observations are hypotheses generating and require further studies to determine causality.

Objectives This study aimed to compare the effects of N-acetylcysteine and benfotiamine in protection of ovarian tissue from ischemia caused by slow neovascularization injury due to intraperitoneal ovarian autotransplant in rats. Materials and methods Twenty-eight female rats were divided into 4 groups, each containing 7 rats. Group 1 only had the abdomen opened and closed, group 2 was the transplant-only group, group 3 received benfotiamine for 3 weeks starting 1 day before the transplant procedure, and group 4 received N-acetylcysteine for 3 weeks starting 1 day before the transplant procedure. At the end of the experimental period, malondialdehyde levels in ovarian tissues together with the apoptosis and fibrosis, proliferating cell nuclear antigen and vascular endothelial growth factor immunoreactivity, and ovarian reserves were investigated. Results Apoptosis was significantly increased in group 2 animals. Primordial follicle count was higher in groups 3 and 4 than in group 2. Vascular endothelial growth factor immunoreactivity was decreased in groups 3 and 4 compared with group 2. Proliferating cell nuclear antigen immunoreactivity was reduced in the secondary follicles in all transplant groups. Conclusions In autologous intraperitoneal ovarian transplant, both benfotiamine and N-acetylcysteine are equal and effective agents in protection of ovarian tissue against ischemic injury.

Coexistence of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and Turner Syndrome (TS) is rare. We report a 6-year-old Portuguese girl with mosaic TS [45,XO(39)/47,XXX(21)] presented with premature pubarche at the age of 5 years. Laboratory findings showed elevated 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione and total testosterone, and sex-determining region Y (SRY) was negative. CYP21A2 gene analysis revealed two mutations (c.[844G>T]; [CYP21A2del]), consistent with the non-classical form of CAH. Complete deletion of CYP21A2 allele occurred de novo. At 6 years and 4 months, she presented accelerated growth velocity and hydrocortisone at the dose of 5 mg/m2/day was initiated. This case highlights the need to perform global examinations looking for virilization signs in TS patients follow-up. It also supports the reported genetic combination of TS and CAH. Therefore, CAH should be kept in mind in TS patients with SRY negative and virilization signs, even in the absence of short stature.

Objective Genetically engineered pigs are thought to be an alternative organ source for patients in end-stage heart failure unable to receive a timely allograft. However, cardiac xenografts exhibit growth and diastolic heart failure within 1 month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload-reducing agents to reduce this growth. In this study we investigated the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation. Methods Genetically engineered pig hearts were transplanted orthotopically into weight-matched baboons between 15 and 30 kg, using continuous perfusion preservation before implantation (n = 5). Xenografts included knockout of carbohydrate antigens and knockin of human transgenes for thromboregulation, complement regulation, and inflammation reduction (grafts with intact growth hormone, n = 2). Three grafts contained the additional knockout of GHR (GHR knockout grafts; n = 3). Transthoracic echocardiograms were obtained twice monthly and comprehensively analyzed by a blinded cardiologist. Hemodynamics were measured longitudinally after transplantation. Results All xenografts demonstrated life-supporting function after transplantation. There was no difference in intrinsic growth, measured using septal and posterior wall thickness and left ventricular mass, on transthoracic echocardiogram out to 1 month in either GHR knockout or GHR intact grafts. However, hypertrophy of the septal and posterior wall was markedly elevated by 2 months post transplantation. There was minimal hypertrophy out to 6 months in GHR knockout grafts. Physiologic mismatch was present in all grafts after transplantation, which is largely independent of growth. Conclusions Xenografts with GHR knockout show reduced post-transplantation xenograft growth using echocardiography >6 months after transplantation, without the need for other adjuncts.

Background The rs1344706 single nucleotide polymorphism in the ZNF804A gene has been associated with risk for psychosis in multiple genome-wide association studies, yet mechanisms underlying this association are not known. Given preclinical work suggesting an impact of ZNF804A on dopamine receptor gene transcription and clinical studies establishing dopaminergic dysfunction in patients with schizophrenia, we hypothesized that the ZNF804A risk single nucleotide polymorphism would be associated with variation in dopamine receptor availability in the human brain. Methods In this study, 72 healthy individuals genotyped for rs1344706 completed both [18F]fallypride and [11C]NNC-112 positron emission tomography scans to measure D2/D3 and D1 receptor availability, respectively. Genetic effects on estimates of binding potential for each ligand were tested first with canonical subject-specific striatal regions of interest analyses, followed by exploratory whole-brain voxelwise analyses to test for more localized striatal signals and for extrastriatal effects. Results Region of interest analyses revealed significantly less D2/D3 receptor availability in risk-allele homozygotes (TT) compared with non-risk allele carriers (G-allele carrier group: TG and GG) in the associative striatum and sensorimotor striatum, but no significant differences in striatal D1 receptor availability. Conclusions These data suggest that ZNF804A genotype may be meaningfully linked to dopaminergic function in the human brain. The results also may provide information to guide future studies of ZNF804A-related mechanisms of schizophrenia risk.

Vitamin D (Vit D) insufficiency is caused basically by inadequately sunlight-induced vitamin D in the skin. It is connected to a variety of ongoing illness, especially diabetes type II. Tests have indicated that Vit D is crucial for glucose-induced insulin production and increased insulin impacts. It diminishes insulin resistance and has anti-inflammatory properties. A few reports showed that the destitute eat less, indicating a negative effect on their wellbeing. Insulin resistance is connected to more Vit D levels. Many RCTs in subjects with type II diabetes recognized slight impacts of Vit D on glycemic and insulin resistance. At the same time, these call for more in-depth investigation and the current study is an excellent avenue to start. There is no reason to prescribe Vit D supplementation to avoid or cure type II diabetes mellitus.

A major consequence of diabetes (type 2) is diabetic nephropathy and its leading cause of chronic kidney disease. This study was amid to determination of insulin like growth factor −1 in diabetic nephropathy patients and its relation with other biochemistry. This study was carried out at the National Diabetes Center/ Mustansiriyah University during the period from 1/11/2020 to 30/3/2021. A highly significant increase of serum fasting blood sugar, total cholesterol, triglyceride, low density lipoprotein, and insulin like growth factor −1 in Nephropathy with Diabetes Mellitus when compared with Nephropathy without Diabetes Mellitus and highly significant decrease of glomerular filtration rate in Nephropathy with Diabetes Mellitus when compared with Nephropathy without Diabetes Mellitus. as Higher serum levels of fasting blood sugar, hypertension, and disturbances in lipid profile and kidney function are found in nephropathy with diabetes mellitus patients. Lower serum insulin like growth factor −1 levels were found to be positively linked with diabetic nephropathy. We propose that serum insulin like growth factor −1 levels be included in routine nephropathy studies in diabetic individuals.

Carbamazepine (CBZ) is a medication used commonly in epilepsy. Decreases in free T4 levels simulating central hypothyroidism have been reported, although the clinical significance is still unclear. We present a 24-year-old man with Bardet-Biedl syndrome (BBS) who was found to have isolated biochemical central hypothyroidism. BBS is a ciliopathy occasionally associated with anterior pituitary dysfunction. While taking CBZ for epilepsy, his TSH was 1.73 mIU/L (reference range: 0.20–4.00 mIU/L) with a low free T4 of 6.6 pmol/L (reference range: 10.0–26.0 pmol/L). Pituitary MRI was normal. Although treated with levothyroxine initially, his apparent biochemical central hypothyroidism was later recognised as secondary to CBZ drug effect. This was confirmed with a normal free T4 of 12.2 pmol/L while he was off CBZ and levothyroxine. Despite the association between CBZ and biochemical central hypothyroidism, nearly all patients remain clinically euthyroid. This effect is reversible and recognition could lead to reductions in unnecessary thyroid replacement therapy if CBZ is discontinued.

The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy-regulating hormone, is associated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, the hepatic expression of FNDC5/Irisin is still unknown. The gene expression of FNDC5/Irisin, associated to key regulators of DNL, inflammation and cancer progression was evaluated in liver tissue of 18 patients with HCC undergoing liver transplantation and of 18 deceased donors. Hepatic mRNA expression of FNDC5/Irisin and stearoyl-CoA desaturase (SCD-1), main enzymatic regulator of DNL, were significantly higher in HCC patients than in donors (p, This pre-print version may be used for non-commercial purposes in accordance with CC BY-NC-ND license terms and conditions.

Aim: of this paper is to review the recent literature on the relationship between ectopic fat accumulation and cardiovascular disease. Data synthesis: Ectopic fat is an important predictor of metabolic (in particular insulin resistance) and cardiovascular disease, carrying more risk than general fat accumulation. Recent studies have shown a link between ectopic fat accumulation, as cardiac (epicardial or intra-myocardial fat) and/or visceral and/or hepatic fat, and development of atherosclerosis, coronary heart disease and hypertension. Conclusions: Ectopic fat accumulation is not only a marker of cardiometabolic disease, since through the release of adipocitokines, lipotoxic and glucotoxic agents, participates in the crosstalk with insulin-sensitive organs leading to metabolic, cardiac and vascular dysfunctions., This article version may be used for non-commercial purposes in accordance with CC BY-NC-ND license terms and conditions.

Twelve years following gastric bypass surgery, a cachectic 69-year-old woman presented with both fasting and postprandial hypoglycaemia. Postprandial symptoms were relieved by dietary modification and acarbose, as is common in such cases. During a supervised fast, symptomatic hypoglycaemia occurred. Concurrent laboratory testing showed suppression of plasma insulin, c-peptide, proinsulin and insulin-like growth factor II. However, beta-hydroxybutyrate was also low, surprising given insulin deficiency. Elevated plasma free fatty acid (FFA) concentrations suggested that lipolysis was not impaired, making cachexia/malnutrition a less likely cause of hypoglycaemia. The apparent diagnosis was failure to counter-regulate—subsequent plasma carnitine measurements showed carnitine deficiency which presumably prevented FFA transport across mitochondrial membranes for ketogenesis. Repletion with high-dose oral carnitine supplements effected resolution of fasting hypoglycaemia.

A 47-year-old man was commenced on levothyroxine following a diagnosis of subclinical hypothyroidism with nonspecific symptoms. Despite increasing doses of levothyroxine, his thyroid-stimulating hormone (TSH) remained elevated and he was referred for further assessment as he was unable to tolerate further titration. On assessment, his thyroid function demonstrated an elevated TSH and elevated free-T4. The initial impression was of iatrogenic thyrotoxicosis, with possible underlying thyroid hormone resistance, TSHoma or assay interference. After discontinuation of levothyroxine, free-T4 normalised but TSH remained elevated. There was a normal response to thyrotropin-releasing hormone (TRH) testing. T3 suppression testing demonstrated free-T4 reduction but persistently high TSH. THRβ sequencing was normal. TSH measurement by alternative assays revealed discrepant results. Gel filtration chromatography revealed the presence of high-molecular weight TSH variant alongside normal TSH. Macro-TSH is a rare phenomenon with spuriously elevated TSH and which may mimic subclinical hypothyroidism. Recognition of macro-TSH avoids misdiagnosis and prevents inappropriate treatment.

Pseudohypoparathyroidism type 1A (PHP1A) is a disorder of multiple hormone resistance, mainly parathyroid hormone. It is associated with Albright hereditary osteodystrophy phenotypes. Patients with PHP1A may initially present with hypothyroidism during infancy and later develop typical PHP1A characteristics during their childhood. Central precocious puberty (CPP) is extremely rare among PHP1A patients in whom gonadotropin resistance is more usual. This study reported a 9.5-year-old boy with congenital hypothyroidism who developed hypocalcemia secondary to pseudohypoparathyroidism. He had relatively short stature with height standard deviation score of -0.9. Obesity had been noted since the age of 2 years. At the presentation of pseudohypoparathyroidism, pubertal-sized testes of 10 mL were observed, and CPP was documented with serum testosterone concentration of 298 ng/dL (normal for Tanner stage III, 100-320), luteinizing hormone of 3.9 IU/L (normal, 0.2-5.0), and follicle-stimulating hormone of 4.8 IU/L (normal, 1.2-5.8). Pituitary magnetic resonance imaging was unremarkable. Genetic analysis confirmed the diagnosis of PHP1A with a novel heterozygous missense variant of GNAS gene in the exon 13, c.1103A>G (p.Asp368Gly). Awareness of PHP1A diagnosis in patients with congenital hypothyroidism and early childhood-onset obesity is crucial for early diagnosis. Apart from multiple hormone resistance, CPP could be manifested in patients with PHP1A.

Intestinal electrical stimulation (IES) has been proposed for treating diabetes; however, its parameters need to be further systematically optimized. This study aimed to optimize the parameters of IES and investigate its possible mechanisms involving glucagon-like peptide-1 (GLP-1) in diabetic rats.Thirty-six high-fat diet-induced diabetic rats were chronically implanted with a pair of bipolar electrodes at the duodenum for IES. The oral glucose tolerance test (OGTT) was performed in a number of sessions with IES using different parameters and biphasic charge-balanced waveforms to derive the best values for train on-time, pulse frequency, and pulse width. Incretin hormones such as GLP-1 were assessed and the GLP-1 antagonist Exendin 9-39 was used to assess the role of GLP-1 in the ameliorating effect of IES on hyperglycemia.The most effective IES parameters in reducing blood glucose (BG) during the OGTT were derived: 1.2 sec on, 0.3 sec off, 80 Hz, 3 msec. IES with these parameters reduced BG level by at least 29% from 15 min to 180 min (p 0.05 for all points, N = 10). IES with these stimulation parameters increased plasma GLP-1 level at 30 min, 60 min, 90 min and gastric inhibitory peptide (GIP) level at 30 min (N = 8). Exendin 9-39 blocked the inhibitory effect of IES on BG (p 0.05, IES + Exendin 9-39 vs sham-IES, N = 8).IES with the most effective parameters derived in this study improves hyperglycemia in diabetic rats. The ameliorating effect of IES on hyperglycemia is attributed to the enhanced release of GLP-1. IES has great potential for treating diabetes.

BACKGROUND: Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. METHODS: Using hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. RESULTS: In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, including Ackr2 and Cxcl11. CONCLUSIONS: We demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

Osteoarthritis is a degenerative, painful and irreversible disease that affects millions of people worldwide. The causes and mechanisms of osteoarthritis have not been fully understood. Vitamin D is an essential factor in bone metabolism. Its actions are mediated by the vitamin D receptor, a transcription factor that controls gene expression, thus maintaining calcium and phosphate homeostasis. Vitamin D has been hypothesized to play essential role in a number of musculoskeletal diseases including osteoarthritis, and its deficiency is prevalent among osteoarthritis patients. A large number of studies have been done regarding the effects of vitamin D in pathogenesis and progression of osteoarthritis, as well as its use a therapeutic agent. Up to date, studies have provided controversial results, and no consensus concerning this matter was achieved. With this review, we aim to explore current data on the possible role of vitamin D and its receptor in pathogenesis of osteoarthritis and assess the efficiency of vitamin D supplementation as a therapeutic strategy.

Introduction Widespread white matter abnormalities and alterations in glutamate levels have been reported in patients with schizophrenia. We hypothesized that alterations in white matter integrity and glutamate levels in individuals at clinical high risk (CHR) for psychosis are associated with the subsequent development of psychosis. Methods Participants included 33 antipsychotic naive CHR (Female 7/Male 26, Age 19.55 (4.14) years) and 38 healthy controls (Female 10/Male 28, Age 20.92 (3.37) years). Whole brain diffusion tensor imaging for fractional anisotropy (FA) and right frontal white matter proton magnetic resonance spectroscopy for glutamate levels were acquired. CHR participants were clinically followed for 2 years to determine conversion to psychosis. Results CHR participants that transitioned to psychosis (N = 7, 21%) were characterized by significantly lower FA values in the posterior thalamic radiation compared to those who did not transition and healthy controls. In the CHR group that transitioned to psychosis only, positive exploratory correlations between glutamate levels and FA values of the posterior thalamic radiation and the retrolenticular part of the internal capsule and a negative correlation between glutamate levels and the cingulum FA values were found. Conclusion The results of the present study highlight that alterations in white matter structure and glutamate are related with the conversion to psychosis.

Background: Vitamins are the micronutrients required for boosting the immune system and managing any future infection. Vitamins are involved in neurogenesis, a defense mechanism working in neurons, metabolic reactions, neuronal survival, and neuronal transmission. Their deficiency leads to abnormal functions in the brain like oxidative stress, mitochondrial dysfunction, accumulation of proteins (synuclein, Aβ plaques), neurodegeneration, and excitotoxicity. Methods: In this review, we have compiled various reports collected from PubMed, Scholar Google, Research gate, and Science direct. The findings were evaluated, compiled, and represented in this manuscript. Conclusion: The deficiency of vitamins in the body causes various neurological disorders like Alzheimer’s disease, Parkinson’s disease, Huntington's disease, and depression. We have discussed the role of vitamins in neurological disorders and the normal human body. Depression is linked to a deficiency of vitamin-C and vitamin B. In the case of Alzheimer’s disease, there is a lack of vitamin- B1, B12, and vitamin-A, which results in Aβ-plaques. Similarly, in Parkinson’s disease, vitamin- D deficiency leads to a decrease in the level of dopamine, and imbalance in vitamin D leads to accumulation of synuclein. In MS, vitamin-C and vitamin-D deficiency causes demyelination of neurons. In Huntington's disease, vitamin- C deficiency decreases the antioxidant level, enhances oxidative stress, and disrupts the glucose cycle. vitamin B5 deficiency in Huntington's disease disrupts the synthesis of acetylcholine and hormones in the brain.

INTRODUCTION AND OBJECTIVES Advanced lipoprotein phenotyping is a better predictor of atherosclerotic cardiovascular risk than cholesterol concentration alone. Lipoprotein profiling in heart failure (HF) is incompletely characterized. We aimed to describe the lipoprotein profile in patients with chronic HF compared with a matched control population. METHODS This cross-sectional study was performed from May 2006 to April 2014 and included ambulatory patients with chronic HF. Lipid concentrations and the size of main lipoprotein fractions (high-density lipoprotein [HDL], low-density lipoprotein [LDL], and very low-density lipoprotein) and the particle concentration of their 3 subfractions (large, medium and small) were assessed using 1H magnetic resonance spectroscopy. RESULTS The 429 included patients with chronic HF were compared with 428 matched controls. Patients with chronic HF had lower total cholesterol and lower mean LDL (1115 vs 1352 nmol/L; P

Laboratory studies identified changes in the metabolism of halogens in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease, which indicates the presence of «accelerated self-halogenation» of CSF and/or an increase in haloperoxidases, specifically serum thyroperoxidase and CSF lactoperoxidase. Furthermore, an excess of some halogenated derivatives, such as advanced oxygenation protein products (AOPP), has been detected in the CSF and serum. «Accelerated self-halogenation» and increased levels of haloperoxidases and AOPP proteins indicate that halogenative stress is present in Parkinson's disease. In addition, 3-iodo-L-tyrosine, a halogenated derivative, shows «parkinsonian» toxicity in experimental models, since it has been observed to induce α-synuclein aggregation and damage to dopaminergic neurons in the mouse brain and intestine. The hypothesis is that patients with Parkinson's disease display halogenative stress related to a haloenzymatic alteration of the synthesis or degradation of oxyacid of halogens and their halogenated derivatives. This halogenative stress would be related to nervous system damage.

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS) remain two of the most commonly encountered metabolic emergencies. They are both potentially life threatening when not managed correctly. DKA occurs most frequently (but not exclusively) in people with type 1 diabetes who are absolutely insulin deficient. HHS (formerly known as HONK – hyperosmolar non-ketotic state) occurs most frequently (but not exclusively) in more elderly people with type 2 diabetes, who have insufficient insulin concentration to lower blood glucose but enough to prevent ketone production. Diabetes may present for the first time as DKA or HHS, but these conditions occur more frequently in people known to have diabetes. The treatment of DKA and HHS differs because the conditions are biochemically different. In DKA the emphasis of treatment has changed; with increasing access to bedside plasma ketone monitors, β-hydroxybutyrate concentration rather than blood glucose is often used to guide therapy. In HHS, glucose lowering should be achieved predominantly using fluid rehydration, with insulin being introduced only when the rate of glucose lowering has stabilized.

Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating renal neoplastic disorder with limited treatment options. It is characterized by the formation of large fluid-filled cysts that develop from kidney tubules through abnormal cell proliferation and cyst-filling fluid secretion driven by cAMP-dependent Cl−secretion. We have examined the effectiveness of the indazole carboxylic acid, H2-gamendazole (H2-GMZ), a derivative of lonidamine, to inhibit these processes and cyst formation usingin vitroandin vivomodels of ADPKD. H2-GMZ was effective in rapidly blocking forskolin-induced, Cl−-mediated short-circuit currents in human ADPKD cells at 1 μM and it significantly inhibited both cAMP- and EGF-induced proliferation of ADPKD cells with an IC50of 5-10 μM. Western blot analysis of H2-GMZ-treated ADPKD cells showed decreased phosphorylated ERK and hyperphosphorylated Rb levels. H2-GMZ treatment also decreased ErbB2, Akt, and Cdk4, consistent with inhibition of the chaperone Hsp90, and reduced the levels of the CFTR Cl−channel. H2-GMZ-treated ADPKD cultures contained a higher proportion of smaller cells with fewer and smaller lamellipodia and decreased cytoplasmic actin staining, and they were unable to accomplish wound closure even at low H2-GMZ concentrations, consistent with an alteration in the actin cytoskeleton and decreased cell motility. Studies using mouse metanephric organ cultures showed that H2-GMZ inhibited cAMP-stimulated cyst growth and enlargement.In vivo, H2-GMZ (20mg/kg) was effective in slowing postnatal cyst formation and kidney enlargement in thePkd1flox/flox:Pkhd1-Cremouse model. Thus, H2-GMZ treatment decreases Cl−secretion, cell proliferation, cell motility, and cyst growth. These properties, along with its reported low toxicity, suggest that H2-GMZ might be an attractive candidate for treatment of ADPKD.

Diabet. Med. 29, 893–904 (2012) Abstract Background Diabetes risk assessment has been proposed as part of the National Health Service Health Checks programme, and HbA1c has recently been recommended as a diagnostic test for diabetes at a threshold of 48 mmol/mol (6.5%). We estimated the potential population impact of different stepwise screening strategies to identify individuals at high risk who might be offered preventive interventions. Methods Using data from 5910 participants in the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with HbA1c measurements, we modelled different stepwise screening strategies for identifying and treating individuals at high risk of Type 2 diabetes using different HbA1c cut-off points with and without a stage of prestratification. For each strategy, we estimated the number needed to have a diagnostic test, the number needed to treat to prevent one new case of Type 2 diabetes, and the number of new cases that could be prevented in the population over 3 years. Relative risk reductions for estimated effects of intensive lifestyle intervention were derived from the US Diabetes Prevention Program. Results Compared with inviting all individuals in an average primary care trust for a diagnostic test, a stepwise screening approach using simple routine data such as age and anthropometric indices could prevent a slightly lower number (lower-upper estimates) of new cases of Type 2 diabetes over 3 years (224 [130–359] and 193 [109–315] cases respectively) but would only require half the population to be invited for a diagnostic blood test. A total of 162 (88–274) cases could be prevented by inviting individuals with a Cambridge risk score of ≥ 0.15, with only 40% of the total population requiring diagnostic blood tests. Using a participant completed questionnaire for risk assessment (FINDRISC) was less effective, mainly relating to the questionnaire response rate. Providing preventive interventions to those with a lower HbA1c of 37–

In the USA, as many as 20 % of recruits sustain stress fractures during basic training. In addition, approximately one-third of female recruits develop Fe deficiency upon completion of training. Fe is a cofactor in bone collagen formation and vitamin D activation, thus we hypothesised Fe deficiency may be contributing to altered bone microarchitecture and mechanics during 12-weeks of increased mechanical loading. Three-week old female Sprague Dawley rats were assigned to one of four groups: Fe-adequate sedentary, Fe-deficient sedentary, Fe-adequate exercise and Fe-deficient exercise. Exercise consisted of high-intensity treadmill running (54 min 3×/week). After 12-weeks, serum bone turnover markers, femoral geometry and microarchitecture, mechanical properties and fracture toughness and tibiae mineral composition and morphometry were measured. Fe deficiency increased the bone resorption markers C-terminal telopeptide type I collagen and tartate-resistant acid phosphatase 5b (TRAcP 5b). In exercised rats, Fe deficiency further increased bone TRAcP 5b, while in Fe-adequate rats, exercise increased the bone formation marker procollagen type I N-terminal propeptide. In the femur, exercise increased cortical thickness and maximum load. In the tibia, Fe deficiency increased the rate of bone formation, mineral apposition and Zn content. These data show that the femur and tibia structure and mechanical properties are not negatively impacted by Fe deficiency despite a decrease in tibiae Fe content and increase in serum bone resorption markers during 12-weeks of high-intensity running in young growing female rats.

Objective: The purpose of this study was to examine the lived experiences of university students with type 1 diabetes mellitus. Methods: University students participated in a 2-part focus group. Transcripts were analyzed thematically using an open-coding approach. Data analysis was guided by a framework analysis method and emergent themes were triangulated between study authors for validity. Results: Three major themes identified in this study were food issues within the university environment, lack of diabetes awareness on campus and internal struggles related to the participants' relationships with their diabetes. Conclusions: Results illustrate some of the unique challenges that interfere with diabetes self-management, academic performance and quality of life among this sample of university students. Findings can provide insight for diabetes educators and other healthcare practitioners regarding the issues that may interfere with optimal diabetes self-care in this population. Findings also can be used to inform university administrators how to make the university environment more diabetes friendly for its students.

ObjectivesTo investigate the role of endogenous TSG-6 in human osteoarthritis (OA) and assess the disease-modifying potential of a TSG-6-based biological treatment in cell, explant and animal models of OA.MethodsKnee articular cartilages from OA patients were analysed for TSG-6 protein and mRNA expression using immunohistochemistry and RNAscope, respectively. The inhibitory activities of TSG-6 and its isolated Link module domain (Link_TSG6) on cytokine-induced glycosaminoglycan loss in OA cartilage explants were compared. Mesenchymal stem/stromal cell (MSC)-derived chondrocyte pellet cultures were used to determine the effects of Link_TSG6 and full-length TSG-6 on IL-1α-, IL-1β- or TNF-stimulated ADAMTS4, ADAMTS5 and MMP13 mRNA expression. Link_TSG6 was administered i.a. to the rat ACLTpMMx model and cartilage damage and tactile allodynia were assayed.ResultsTSG-6 is predominantly associated with chondrocytes in regions of cartilage damage and its expression is negatively correlated with MMP13, the major collagenase implicated in OA progression. Link_TSG6 is more potent than full-length TSG-6 at dose-dependently inhibiting cytokine-mediated matrix breakdown in human OA cartilage explants; about 50% of donor cartilages, from 59 tested, were responsive to Link_TSG6 treatment. Similarly, Link_TSG6 displayed more potent effects in 3D pellet cultures, suppressing aggrecanase and collagenase gene expression. Link_TSG6 treatment reduced touch-evoked pain and dose-dependently inhibited cartilage damage in a rodent model of surgically-induced OA.ConclusionsNative TSG-6 is associated with a low catabolic chondrocyte phenotype in OA cartilage. Link_TSG6, which has enhanced chondroprotective activity compared to the full-length TSG-6 protein, demonstrates potential as a disease modifying OA drug (DMOAD) and warrants further investigation and development.KEY MESSAGESWhat is already known about this subject?TSG-6, a protein with anti-inflammatory and protective effects in other tissues, is expressed in joints affected by osteoarthritis – a condition for which there are no disease-modifying drugs.What does this study add?A novel protective mechanism has been identified, whereby TSG-6 inhibits inflammatory cytokine-induced catabolic pathways in cartilage.The Link module of TSG-6 (Link_TSG6) has been shown to have greater potency than TSG-6 as an inhibitor of cartilage damage and is efficacious in a rat model of osteoarthritis.Data from cartilage explants indicate that OA patients can be stratified for Link_TSG6 responsiveness.How might this impact on clinical practice or future developments?Link_TSG6 has been identified as potential disease-modifying OA drug that mimics an intrinsic protective process.

BACKGROUND: L-DOPA, the predominant therapy for Parkinson’s disease (PD) is associated with motor deficits after prolonged use. The nigrostriatal tract, a primary target of neurodegeneration in PD, contains abundant Vitamin-D receptors, suggesting a potential role for VD in the disease. Therefore, we tested the impact of Vitamin D(3) (V(3)) in a mouse model of PD. METHODS: PD was induced in adult male C57BL6 mice by a single intrastriatal injection of 6-hydroxydopamine. Two weeks post lesion, these mice received injections of a vehicle, VD(3), L-DOPA, or a combination of VD(3)/L-DOPA and compared with sham controls. Treatment lasted three weeks, during which motor-cognitive neurobehaviour was assessed. Five weeks post lesion, brains were collected and striatal levels of the following proteins assessed: tyrosine hydroxylase (TH), dopamine decarboxylase (DDC), monoamine oxidase (MAO-B), Catechol-O-methyl transferase (COMT), dopamine transporter (DAT), brain-derived neurotrophic factor (BDNF), microglia marker (CD11b), inflammation (IL-1β), apoptotic signaling (BAX) and oxidative stress (p47phox). RESULTS: Treatment with VD(3) attenuated behavioural deficits induced by 6-OHDA, protein associated with dopamine metabolism and biomarkers of oxidative stress. VD(3) significantly increased contralateral wall touches, exploratory motor and cognitive activities. VD(3) significantly enhanced the expression of TH, DAT, BDNF, while significantly reducing expression of MAO-B, CD11b, IL-I β and p47phox. CONCLUSION: VD(3) reversed some of the 6-OHDA induced changes in proteins involved in modulating the dopamine system, behavioural deficits and oxidative stress biomarkers. The data suggests that VD(3) might be beneficial in reducing L-DOPA dosage, thereby reducing problems associated with dosage and prolonged use of L-DOPA in PD management.

Objective: Pediatric obesity predisposes children and adolescents to early onset insulin resistance and dysglycemia. In the last 20 years this has led to a rise in the prevalence of prediabetes, diabetes and fatty liver in youngsters, due to the high degree of insulin resistance experienced by these patients and the consequent high availability of glucose. As glucose accesses the liver, it is partly metabolized through glycolysis, whose main product is pyruvate that is then converted into Acetyl CoA and lactate. Therefore, lactate production rate (LPR) represents the best proxy for the assessment of glycolysis. Since to date there are not methods to estimate postprandial LPR, here we proposed a novel oral glucose-lactate model to estimate LPR during an oral glucose tolerance test and tested it in 24 youth with and without obesity. Methods: The model is based on the oral glucose minimal model and assumes that LPR is a fraction (fr) of glucose disposal rate, proportional to glucose concentration and controlled by insulin action. Results: The model well fitted the glucose and lactate data, and provided both precise parameter estimates (e.g. fr=22.5 [12.6-54.1]%, median [IQR]), CV=18 [13-25]%) and LPR time course. Conclusions: The proposed model is a valid tool to assess LPR, and thus glycolysis, during OGTT in nondiabetic subjects. Significance: The proposed methodology will allow to assess postprandial LPR in simple and cost-effective way.

Purpose This study aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppressive therapy on bone mineral density (BMD) and bone turnover markers (BTMs) in differentiated thyroid cancer (DTC) patients after postoperative 1-2 years in Northeast China. Methods Five male, sixteen premenopausal, and eight postmenopausal female DTC patients receiving TSH suppressive therapy after thyroidectomy were enrolled. Patients were matched with healthy controls in a ratio of 1:2. All participants completed postoperative 1-year follow-up, and postmenopausal women completed 2-year follow-up. We measured BMD of the lumbar spine (LS), femoral neck (FN), and total hip (TH) using dual-energy X-ray absorptiometry (DXA). Bone formation marker P1NP and bone resorption marker β-CTX were also evaluated. Fracture risks were assessed by FRAX. Results There was no difference in BMD and BTMs between DTC patients and controls in the male group at 1-year follow-up. In the premenopausal women, the LS-BMD, FN-BMD, and TH-BMD in DTC patients were all higher than those in controls, but only FN-BMD showed a significant difference. The change rate of P1NP showed a significant difference between DTC patients and controls, while no difference was found in the β-CTX level. In the postmenopausal women, no difference in BMD and BTMs were observed between DTC patients and controls at the 1-year and 2-year follow-up. Conclusion Our study indicated that postoperative 1-year TSH suppressive therapy did not show detrimental effects on BMD and BTMs in men, premenopausal, and postmenopausal DTC patients. The 2-year postoperative TSH suppressive therapy did not lead to additional loss of bone mass in postmenopausal DTC patients.

Aim Dyslipidemia and altered iron metabolism are typical features of non-alcoholic fatty liver disease (NAFLD). Proprotein convertase subtilisin/kexin type 7 (PCSK7), a transmembrane-anchored endonuclease, is associated with triglycerides level and processing of transferrin receptor 1. However, the significance of circulating PCSK7 has not been fully addressed, though prosegment PCSK7 is secreted from cells. We investigated the associations of plasma PCSK7 level with several parameters. Methods Plasma PCSK7 concentration was measured in 282 subjects (male/female: 126/156) without medication of the Tanno-Sobetsu Study, a population-based cohort study. Results There was no significant sex difference in PCSK7 level. Current smoking habit, but not alcohol drinking habit, was associated with increased PCSK7 level. PCSK7 concentration was negatively correlated with age and blood urea nitrogen and was positively correlated with body mass index (BMI) and levels of γ-glutamyl transpeptidase (γGTP), triglycerides and fatty liver index (FLI), which is calculated by BMI, waist circumference and levels of γGTP and triglycerides, as a noninvasive and simple predictor of NAFLD. There were no significant correlations of PCSK7 level with levels of iron and plasma PCSK9, a secreted PCSK family member and a regulator of low-density lipoprotein cholesterol level. Multivariable regression analyses after adjustment of age, sex and current smoking habit showed that PCSK7 concentration was independently associated with BMI (β=0.130, P=0.035), triglycerides (β=0.141, P=0.027) or FLI (β=0.139, P=0.030). Conclusions Plasma PCSK7 concentration is independently associated with chronic liver disease including obesity and elevated triglycerides level in a general population of individuals who had not regularly taken any medications.

The primary objective of this study was to examine if people with protein C deficiency, which is a natural anticoagulant and also an endogenous acyl ghrelin peptidase, have elevated circulating levels of acyl ghrelin. The clinical trial was conducted in a university hospital setting. People with protein C deficiency were identified and invited to participate by a specialized coagulation outpatient clinic. People with protein C deficiency were examined and compared to age, sex, and body mass index matched healthy controls with regards to acyl ghrelin, unacylated ghrelin, growth hormone (GH) and insulin-like growth-factor I (IGF-I) in a cross-sectional case-control study. Systemic levels of acyl ghrelin, desacyl ghrelin, acyl-to-desacyl ghrelin ratio, GH and IGF-I were similar in people with protein C deficiency and healthy controls. Despite a significant reduction of protein C in people with protein C deficiency, there was no difference in acyl ghrelin or the secondary end points unacylated ghrelin, GH, or IGF-I in people with protein C deficiency.

Sotos syndrome is characterized by overgrowth, distinctive facial appearance, and learning disability. It is caused by heterozygous mutations, including deletions of NSD1 located at chromosome 5q35. While advanced bone age can occur in some cases, precocious puberty (PP) is reported only in three cases until now. Here, we reported a case of Sotos syndrome diagnosed at the infancy period with central precocious puberty. The discovery of potential factors that trigger puberty is one of the central mysteries of pubertal biology. Depot gonadotropin-releasing hormone (GnRH) analogs constitute the first-line therapy in central precocious puberty (CPP), which has proven to be both effective and safe. In our cases, leuprolide acetate in maximum dose could not be successful for the control of pubertal progression, and cyproterone acetate (CPA) was added to therapy. Then, pubertal progression was controlled. In some specific syndromes with precocious puberty, such as Sotos syndrome, treatment can be challenging. Cyproterone acetate would be an asset for the benefit of treatment.

Background: Generalized lymphatic anomalies (GLA) are complex vessel malformations that can impair lymphatic function. Potential GLA complications include lipid-rich lymph in the thoracic space or peritoneal cavity, respectively chylothorax and chylous ascites. To reduce the potential for chyle accumulation, GLA patients limit dietary fats. We hypothesized that dietary fatty acid composition impacts the potential for lymphatic dysfunction and chyle accumulation in GLA. Methods and Results: Adipose-specific overexpression of lymphatic growth factors has demonstrated lethal chylothorax in mice. Here, we utilized mice with inducible adipocyte overexpression of vascular endothelial growth factor-D (VD mice) to mimic lymphatic proliferation in GLA and assessed the incidence of chyle accumulation on a mixed high fat diet (HFD), high saturated fat diet (HSFD), or high unsaturated fat diet (HUSFD). Lipid transport was assessed by uptake rates of bolus oral triglyceride load and mesenteric fat analysis. Lymphatic expansion and inflammation were determined by whole mount immunofluorescence and gene expression. Body composition was assessed by MRI. HSFD 2-month wildtype groups resulted in an increase in TNF-α, IL-6, and IL-10 expression compared with chow-fed controls. The chyle accumulation incidence was highest in HFD-fed mice compared with either HSFD or HUSFD. Strikingly, increased mortality was observed irrespective of which high fat diet was consumed after administration of a bolus lipid load. Conclusion: Chronic HFD increases risk of chyle accumulation, however increased mortality was driven particularly by a bolus lipid load in VD mice. These findings suggest that although chronic HFD increases chyle accumulation risk, a single large meal feeding may increase risk of lethal chylothorax instances for GLA patients.

Aims To determine the first manifestation of cardiovascular or kidney disease (CVKD) and associated resource use in type 2 diabetes mellitus (T2DM) patients during seven years of follow-up. Methods Observational-retrospective secondary data study using medical records of patients aged ≥18 years with T2DM and without prior CVKD between 2013 and 2019. The index date was 01/01/2013 (fixed date). The manifestation of CVKD was defined by the first diagnosis of heart-failure (HF), chronic-kidney disease (CKD), myocardial-infarction (MI), stroke or peripheral-artery disease (PAD). The main variables were baseline characteristics, manifestation of CVKD, mortality, resource use and costs. Descriptive analyses and Cox model were applied to the data. Results 26,542 patients were selected (mean age: 66.6 years, women: 47.8%, mean duration of T2DM: 17.1 years). 18.7% (N = 4974) developed a first CVKD manifestation during the seven years [distribution: HF (22.4%), CKD (36.6%), MI (14.5%), stroke (15.3%) and PAD (11.3%)]. Overall mortality was 8.3% (N = 2214). The mortality risk of the group that developed HF or CKD as the first manifestation compared to the CVKD-free cohort was higher [HR: 2.5 (95% CI: 1.8–3.4) and 1.8 (95% CI: 1.4–2.3)], respectively. The cumulative costs per patient of HF (€50,942.80) and CKD (€48,979.20) were higher than MI (€47,343.20) and stroke (€47,070.30) and similar to PAD (€51,240.00) vs. €13,098.90 in patients who did not develop CVKD, p Conclusions In T2DM patients, HF and CKD were the first most common manifestations and had higher mortality and re-hospitalisation rates. HF and CKD were associated with the highest resource use and costs for the Spanish National-Health-System.

Background: VitD3 may contribute to a successful pregnancy through modulation of immune responses. Therefore, VitD3 deficiency may have a role in the immunopathogenesis of unexplained recurrent spontaneous abortion (URSA). However, the mechanisms of immunomodulatory actions of VitD3 in decreasing the risk of recurrent spontaneous abortion have not been understood well. Objective: The purpose of this research was to investigate the influence of 1,25VitD3 on regulatory T cells /Th17 axis, the gene expressions and concentrations of related cytokines including, TGF-β, IL-10, IL-6, IL-23, and IL-17A in peripheral blood mononuclear cells (PBMCs) of healthy women as a control group and women with URSA. Method: Isolation of PBMCs was performed from peripheral blood of the subjects of the studied groups (20 women with URSA as a case group, and 20 control women). The effects of 1,25VitD3 (50 nM, for 24 hours) on the studied parameters were evaluated and were compared to the positive and negative controls in vitro. Flow cytometry analysis was used to determine the percentages of regulatory T cells and Th17 cells. For gene expression measurement and cytokines assay, Realtime PCR and ELISA were carried out. Results: The proportion of regulatory T cells was markedly lower, while the proportion of Th17 cells in women with URSA was considerably higher than in the control group (P=0.01, P=0.01). The ratio of the frequency of Tregs to the baseline (1,25VitD3/Untreated) increased, while the ratio of the frequency of Th17 cells to the baseline decreased in women with URSA relative to the controls (P= 0.01, P=0.04). 1,25VitD3 increased IL-10 expressions at both the protein and mRNA levels in PBMCs in women with URSA relative to the control group (P=0.0001, P=0.04). TGF-β levels in the cultured supernatants decreased significantly in the case group in the presence of 1,25Vit- D3 relative to the controls (P=0.03). 1,25VitD3 treatment also significantly decreased gene expressions of IL-6, IL-17A, and IL-23 in PBMCs of women with URSA (P=0.01, P=0.001, P=0.0005), as well as the levels of those cytokines in cell culture supernatants (P=0.03, P=0.02, P=0.01, respectively) in women with URSA relative to the controls. Conclusion: According to the findings of this research, modulation of immune responses by 1,25VitD3 is accomplished by strengthening Tregs function and inhibiting inflammatory responses of Th17 cells, which may have a positive impact on pregnancy outcome. Thus, as an immunomodulating agent, VitD3 may be effective in reducing the risk of URSA.

Aims To assess lipid trajectories throughout pregnancy in relation to early postpartum glucose intolerance in women with gestational diabetes mellitus (GDM). Methods This prospective cohort study included 221 Chinese women with GDM who completed plasma lipid test in each trimester of pregnancy and oral glucose tolerance test at 6–9 weeks postdelivery between January 1, 2018 and January 8, 2020. Using the group-based trajectory modeling, total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol(HDL-c) were identified separately as three trajectories: low, moderate, and high trajectory. The associations between lipid trajectories and early postpartum glucose intolerance were all evaluated. Results Seventy-three participants developed postpartum glucose intolerance. For patients in low, moderate and high trajectory, the incidence of postpartum glucose intolerance was 38.4%, 34.9%, and 17.9%, respectively. GDM women with lower LDL-c trajectories presented a higher risk of postpartum glucose intolerance. The adjusted odds ratio (95% CI) for glucose intolerance was 3.14 (1.17–8.39) in low LDL-c trajectory and 2.68 (1.05–6.85) in moderate trajectory when compared with the high one. However, TC trajectory was not associated with the risk of postpartum glucose intolerance, nor were TG trajectory and HDL-c trajectory. Moreover, a significant difference of insulin sensitivity was observed in participants with different LDL-c trajectories; participants in high LDL-c trajectory had the highest insulin sensitivity, whereas the women in low LDL-c trajectory had the lowest insulin sensitivity (P = 0.02). Conclusions The high trajectory of LDL-c during pregnancy may play a protective role on postpartum glucose intolerance in women with GDM. Further studies are warranted to explore the underlying mechanism. Trial registration The study was reviewed and approved by the Institutional Review Board of The First Affiliated Hospital of Sun Yat-sen University (reference number: [2014]No. 93). All participants provided written informed consent forms, and the ethics committee approved this consent procedure.