Low vitamin C status and hypermobility-related disorders in patients with bleeding disorder of unknown cause.

INTRODUCTION: Bleeding disorder of unknown cause (BDUC) is a challenging diagnosis that predominantly affects women. Previous investigations into connective tissue disorders (CTD) and vitamin C have not been conducted. AIM: To examine the association between hypermobility-related disorders, vitamin C status and BDUC. METHODS: Patients were selected following laboratory and genetic screening that yielded negative results for known hemostasis disorders. Sixty patients with BDUC and an ISTH BAT score ≥ 10 underwent clinically examination for skin hyperextensibility and for hypermobility assessed by Beighton score. Vitamin C was analyzed by high-performance liquid chromatography. Genetic screening for causal variants in 42 CTD genes was performed. RESULTS: The majority of patients were female (56/60). Median ISTH BAT score was 13 (range 10-23). Beighton score was positive in 29/60 patients compared to 1/20 healthy controls (HC) (p < .001). Hyperextensive skin was observed in (18/60) patients, and none (0/20) of the HC (p = .0041). Ten patients met the clinical diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS), and one patient was diagnosed with Noonan syndrome. Genetic screening excluded various subtypes of EDS with known genetic backgrounds. Average vitamin C level was adequate, but lower than in HC (55.9 vs. 70.4 µmol/L; p = .001). Suboptimal, or low vitamin C were identified in 19/60 compared to 1/20 HC (p = .018). CONCLUSION: Our study demonstrates that BDUC is frequently associated with hypermobility disorders and low vitamin C status. Our results could pave the way for a randomized study of vitamin C supplementation in patients with BDUC.

Remote ischaemic preconditioning on gene expression and circulating proteins after subacute laparoscopic cholecystectomy: randomized clinical trial.

BACKGROUND: Surgical stress may lead to postsurgical hypercoagulability, endothelial dysfunction and systemic inflammation, which can impact on patient recovery. Remote ischaemic preconditioning is a procedure that activates the body's endogenous defences against ischaemia and reperfusion injury. Studies have suggested that remote ischaemic preconditioning has antithrombotic, antioxidative and anti-inflammatory effects. The hypothesis was that remote ischaemic preconditioning reduces surgery-induced systemic stress response. METHOD: During a 24-month period (2019-2021), adult patients undergoing subacute laparoscopic cholecystectomy due to acute cholecystitis were randomized to remote ischaemic preconditioning or control. Remote ischaemic preconditioning was performed less than 4 h before surgery on the upper arm. It consisted of four cycles of 5 min ischaemia and 5 min reperfusion. The gene expression of 750 genes involved in inflammatory processes, oxidative stress and endothelial function was investigated preoperatively and 2-4 h after surgery in both groups. In addition, changes in 20 inflammation- and vascular trauma-associated proteins were assessed preoperatively, 2-4 h after surgery and 24 h after surgery. RESULTS: A total of 60 patients were randomized. There were no statistically significant differences in gene expression 2-4 h after surgery between the groups (P > 0.05). Remote ischaemic preconditioning did not affect concentrations of circulating proteins up to 24 h after surgery (P > 0.05). CONCLUSION: The study did not demonstrate any effect of remote ischaemic preconditioning on expression levels of the chosen genes or in circulating immunological cytokines and vascular trauma-associated proteins up to 24 h after subacute laparoscopic cholecystectomy in patients with acute cholecystitis.

An increasing proportion of the population is not covered by the current RDA for vitamin C - interrogation of EPIC-Norfolk and NHANES 2017/2018 cohorts.

With the rising prevalence of obesity globally, increasing proportions of the population may not be covered by current recommended daily allowances (RDAs) that are supposed to provide 97.5% of the population with a sufficient nutrient status but are typically based on a healthy young 70 kg male reference person. Using the EPIC-Norfolk (UK) and the NHANES (US) cohorts, we estimated the effect of body weight on the dose-concentration relationship to derive weight-based requirements to achieve an 'adequate' plasma concentration of vitamin C estimated to be 50 µmol/L. Inverse correlations between body weight and vitamin C were observed in both cohorts (p < 0.0001). Moreover, only about 2/3 of the cohorts achieved an adequate plasma vitamin C status by consuming the RDA or above, while only 1/3 to 1/2 of the cohorts achieved adequacy by an intake of the local RDA ± 10%. Using vitamin C as an example, the present data demonstrate that a considerable and expectedly increasing proportion of the world population is unable to achieve an adequate target plasma concentration with the current recommended daily intakes of vitamin C. This needs to be considered in future public health recommendations.

In this paper, we highlight the inverse association between body weight and vitamin C status. Our study strongly suggests that a large proportion of the population is not covered by the current recommended intakes of vitamin C.

Hemostatic Effects of Exercise-related Hypoglycemia in Male Persons With Type 1 Diabetes.

CONTEXT: People with type 1 diabetes (T1D) are at increased risk of thrombosis compared to the general population; however, the underlying mechanisms remain unclear. Hypoglycemia induced at rest can induce coagulation activation, but little is known about the hemostatic effects of exercise-related hypoglycemia in people with T1D. OBJECTIVE: We compared hemostatic profiles of individuals with T1D with healthy controls and explored hemostatic effects of hypoglycemia, induced with or without exercise, in participants with T1D. METHODS: Thrombelastography was used for a baseline hemostatic comparison between fifteen men with T1D and matched healthy controls. In addition, the participants with T1D underwent two euglycemic-hypoglycemic clamp days in a randomized, crossover fashion. Hypoglycemia was induced with the participants at rest (Hypo-rest) or during exercise (Hypo-exercise). Thrombelastography provides data on the rate of coagulation activation (R-time), the rate of clot formation (K-time, α-Angle), the maximum clot amplitude (MA), the functional fibrinogen contribution to the clot strength (MA-FF) and the fibrinolysis (LY-30). RESULTS: The T1D group exhibited a faster rate of coagulation activation (shorter R-time) and a faster clot formation (greater α-Angle) compared with the controls. During the clamp experiments, Hypo-exercise induced an increased clot strength (MA) with a mean difference from baseline of 2.77 mm (95% CI, 2.04-3.51) accompanied with a decreased fibrinolysis (LY-30) of -0.45 percentage point (-0.60 to -0.29). Hypo-rest resulted in increased functional fibrinogen (MA-FF) of 0.74 mm (0.13-1.36) along with an increased fibrinolysis (LY-30) of 0.54 percentage point (0.11-0.98). CONCLUSION: Individuals with T1D exhibit a hypercoagulable hemostatic profile compared with healthy controls and exercise-related hypoglycemia may increase the susceptibility to thrombosis via both procoagulant and antifibrinolytic effects.

Validation of computed tomography as a diagnostic tool in guinea pigs with non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) and subsequent steatohepatitis (NASH) is the most common cause of liver disease and liver transplantation in humans. Affecting millions of patients worldwide, diagnosis relies on a biopsy, not without risk to the patient, and emphasises the need for improved diagnostic measures to determine and monitor disease progression. Despite intensive research, approved pharmacological treatment modalities are few, underlining that animal models with increased translational validity are important to advance preclinical drug development. This study validates the applicability of computed tomography (CT) as a non-invasive diagnostic tool for the assessment of liver steatosis in a guinea pig model of NAFLD/NASH. Guinea pigs with induced NAFLD or NASH were compared to healthy controls at two separate time points: week 16, serving as baseline measure, and week 25 to monitor disease progression over time. The animals were subsequently euthanised, and samples were collected to confirm disease stage. The data showed a strong negative correlation between liver triglycerides and Hounsfield unit (HU) values (R2 = 0.8157; p < 0.0001). A significant difference in histopathological scoring and HU values between grade 0 and more advanced stages of steatosis was recorded (p < 0.001), although the degree of liver fibrosis could not be accurately evaluated by differences in HU. In conclusion, the present study validates CT scanning for the determination of hepatic steatosis in guinea pigs, and it strongly supports the technique as a relevant non-invasive diagnostic tool in this species.

Ascorbate deficiency increases progression of shigellosis in guinea pigs and mice infection models.

Shigella spp. are the causative agents of bacterial dysentery and shigellosis, mainly in children living in developing countries. The study of Shigella entire life cycle in vivo and the evaluation of vaccine candidates' protective efficacy have been hampered by the lack of a suitable animal model of infection. None of the studies evaluated so far (rabbit, guinea pig, mouse) allowed the recapitulation of full shigellosis symptoms upon Shigella oral challenge. Historical reports have suggested that dysentery and scurvy are both metabolic diseases associated with ascorbate deficiency. Mammals, which are susceptible to Shigella infection (humans, non-human primates and guinea pigs) are among the few species unable to synthesize ascorbate. We optimized a low-ascorbate diet to induce moderate ascorbate deficiency, but not scurvy, in guinea pigs to investigate whether poor vitamin C status increases the progression of shigellosis. Moderate ascorbate deficiency increased shigellosis symptom severity during an extended period of time (up to 48 h) in all strains tested (Shigella sonnei, Shigella flexneri 5a, and 2a). At late time points, an important influx of neutrophils was observed both within the disrupted colonic mucosa and in the luminal compartment, although Shigella was able to disseminate deep into the organ to reach the sub-mucosal layer and the bloodstream. Moreover, we found that ascorbate deficiency also increased Shigella penetration into the colon epithelium layer in a Gulo-/- mouse infection model. The use of these new rodent models of shigellosis opens new doors for the study of both Shigella infection strategies and immune responses to Shigella infection.

Dietary Long-Chain Fatty Acids Accelerate Metabolic Dysfunction in Guinea Pigs with Non-Alcoholic Steatohepatitis.

The composition of dietary fatty acids may be important for the development and progression of metabolic syndrome and non-alcoholic steatohepatitis (NASH). This study investigated the effect of two high-fat diets based on coconut oil, containing predominantly medium-chain fatty acids (MCFA), or cocoa butter, containing mainly long-chain fatty acids (LCFA), on glucose homeostasis and NASH in guinea pigs following 16 and 32 weeks of diet. At week 16, glucose intolerance was increased in the LCFA animals compared to the MCFA animals (p < 0.001), with both groups differing from the controls by week 32 (p < 0.0001), supported by increased hemoglobin A1c (p < 0.05). NASH was present in both high-fat groups from week 16, with advancing fibrosis appearing more progressive in the LCFA animals at week 16. In agreement, gene expression showed overall increased expression of NASH target genes in the LCFA animals compared to the MCFA animals at weeks 16 and 32 (p < 0.05 and p < 0.0001, respectively). The LCFA animals also displayed increased plasma uric acid at both time points (p < 0.05), a phenomenon linked to NASH in humans. In conclusion, this study reports that a diet high in LCFA promotes metabolic imbalance and may accelerate NASH-associated hepatic fibrosis. This highlights the importance of a critical evaluation of fatty acid composition when investigating NASH-associated endpoints.

Effects of two- and twelve-weeks sodium-glucose cotransporter 2 inhibition on DNA and RNA oxidation: two randomized, placebo-controlled trials.

Animal studies have shown that SGLT2 inhibition decreases oxidative stress, which may explain the cardiovascular protective effects observed following SGLT2 inhibition treatment. Thus, we investigated the effects of two and twelve weeks SGLT2 inhibition on DNA and RNA oxidation. Individuals with type 2 diabetes (n = 31) were randomized to two weeks of treatment with the SGLT2 inhibitor empagliflozin treatment (25 mg once daily) or placebo. The primary outcome was changes in DNA and RNA oxidation measured as urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), respectively. In another trial, individuals with type 2 diabetes (n = 35) were randomized to twelve weeks of dapagliflozin treatment (10 mg once daily) or placebo in a crossover study. Changes in urinary excretion of 8-oxodG and 8-oxoGuo were investigated as a posthoc analysis. Compared with placebo treatment, two weeks of empagliflozin treatment did not change urinary excretion of 8-oxodG (between-group difference: 0.3 nmol/24-hour (95% CI: -4.2 to 4.8)) or 8-oxoGuo (1.3 nmol/24-hour (95% CI: -4.7 to 7.3)). From a mean baseline 8-oxodG/creatinine urinary excretion of 1.34 nmol/mmol, dapagliflozin-treated individuals changed 8-oxodG/creatinine by -0.17 nmol/mmol (95% CI: -0.29 to -0.04) following twelve weeks of treatment, whereas placebo-treated individuals did not change 8-oxodG/creatinine (within-group effect: 0.10 nmol/mmol (95% CI: -0.02 to 0.22)) resulting in a significant between-group difference (p = 0.01). Urinary excretion of 8-oxoGuo was unaffected by dapagliflozin treatment. In conclusion, two weeks of empagliflozin treatment did not change DNA or RNA oxidation. However, a posthoc analysis revealed that longer-term dapagliflozin treatment decreased DNA oxidation. Clinicaltrials.gov: NCT02890745 and NCT02914691.HighlightsPlasma ferritin correlated with DNA and RNA oxidation in individuals with T2D.Twelve weeks dapagliflozin treatment decreased DNA oxidation.Dapagliflozin and empagliflozin treatment did not change RNA oxidation.Lipid peroxidation was unaffected by two weeks empagliflozin treatment.

The dietary regulation of LEAP2 depends on meal composition in mice.

Ghrelin represents a key hormone regulating energy balance. Upon activation of the growth hormone secretagogue receptor (GHSR), ghrelin increases blood glucose levels, food intake, and promotes weight gain. The liver-expressed antimicrobial peptide 2 (LEAP2) acts as an endogenous antagonist of the GHSR. While the regulation of LEAP2 and its effect on the GHSR likely occur in an opposite pattern to that of ghrelin, the dietary regulation of LEAP2 remains to be described. We, therefore, examined the regulation of LEAP2 by different acute meal challenges (glucose, mixed meal, olive, lard, and fish oil) and diets (chow vs. high-fat) in C57BL/6 male mice. In addition, the effect of specific fatty acids (oleic, docosahexaenoic, and linoleic acid) on LEAP2 was assessed in murine intestinal organoids. While only mixed meal increased liver Leap2 expression, all meal challenges except fish oil increased jejunal Leap2 expression compared to water. Leap2 expression correlated with levels of hepatic glycogen and jejunal lipids. Lipid versus water dosing increased LEAP2 levels in the systemic circulation and portal vein where fish oil was associated with the smallest increase. In line with this, oleic acid, but not docosahexaenoic acid increased Leap2 expression in intestinal organoids. Feeding mice with high-fat versus chow diet not only increased plasma LEAP2 levels, but also the increment in plasma LEAP2 upon dosing with olive oil versus water. Taken together, these results show that LEAP2 is regulated by meal ingestion in both the small intestine and the liver according to the meal/diet of interest and local energy stores.

Factors Affecting the Vitamin C Dose-Concentration Relationship: Implications for Global Vitamin C Dietary Recommendations.

Vitamin C status is known to be associated with several demographic and lifestyle factors. These include gender, age, ethnicity, pregnancy/lactation, body weight, smoking status and dietary habits. In the present study, our aim was to investigate the National Health and Nutrition Examination Survey (NHANES) 2017-2018 datasets to assess the impact of these factors on vitamin C dose-concentration relationships to establish if there are higher requirements for vitamin C in certain subpopulations, and the possible extent of these additional requirements. The final cohort comprised 2828 non-supplementing adult males and females (aged 18-80+ years) with both vitamin C serum concentrations and dietary intake data available. The data were subsequently stratified by gender, age tertiles (≤36, 37-58, ≥59 years), ethnicity (non-Hispanic white, non-Hispanic black, and total Hispanic), socioeconomic tertiles (poverty income ratios: ≤1.35, 1.36-3.0, >3.0), weight tertiles (<72, 72-91, >91 kg), BMI tertiles (<26, 26-32, >32 kg/m2) and smoking status. Sigmoidal (four parameter logistic) curves with asymmetrical 95% confidence intervals were fitted to the dose-concentration data. We found that males required vitamin C intakes ~1.2-fold higher than females to reach 'adequate' serum vitamin C concentrations of 50 µmol/L. Males had both higher body weight and a higher prevalence of smoking than females. Smokers required vitamin C intakes ~2.0-fold higher than non-smokers to reach adequate vitamin C concentrations. Relative to adults in the lighter weight tertile, adults in the heavier weight tertile required ~2.0-fold higher dietary intakes of vitamin C to reach adequate serum concentrations. We did not observe any impact of ethnicity or socioeconomic status on the vitamin C dose-concentration relationship, and although no significant difference between younger and older adults was observed at vitamin C intakes > 75 mg/day, at intakes < 75 mg/day, older adults had an attenuated serum response to vitamin C intake. In conclusion, certain demographic and lifestyle factors, specifically gender, smoking and body weight, have a significant impact on vitamin C requirements. Overall, the data indicate that the general population should consume ~110 mg/day of vitamin C to attain adequate serum concentrations, smokers require ~165 mg/day relative to non-smokers, and heavier people (100+ kg) require ~155 mg/day to reach comparable vitamin C concentrations. These findings have important implications for global vitamin C dietary recommendations.

Effect of Remote Ischaemic Preconditioning on Perioperative Endothelial Dysfunction in Non-Cardiac Surgery: A Randomised Clinical Trial.

Endothelial dysfunction result from inflammation and excessive production of reactive oxygen species as part of the surgical stress response. Remote ischemic preconditioning (RIPC) potentially exerts anti-oxidative and anti-inflammatory properties, which might stabilise the endothelial function after non-cardiac surgery. This was a single centre randomised clinical trial including 60 patients undergoing sub-acute laparoscopic cholecystectomy due to acute cholecystitis. Patients were randomised to RIPC or control. The RIPC procedure consisted of four cycles of five minutes of ischaemia and reperfusion of one upper extremity. Endothelial function was assessed as the reactive hyperaemia index (RHI) and circulating biomarkers of nitric oxide (NO) bioavailability (L-arginine, asymmetric dimethylarginine (ADMA), L-arginine/ADMA ratio, tetra- and dihydrobiopterin (BH4 and BH2), and total plasma biopterin) preoperative, 2-4 h after surgery and 24 h after surgery. RHI did not differ between the groups (p = 0.07). Neither did levels of circulating biomarkers of NO bioavailability change in response to RIPC. L-arginine and L-arginine/ADMA ratio was suppressed preoperatively and increased 24 h after surgery (p < 0.001). The BH4/BH2-ratio had a high preoperative level, decreased 2-4 h after surgery and remained low 24 h after surgery (p = 0.01). RIPC did not influence endothelial function or markers of NO bioavailability until 24 h after sub-acute laparoscopic cholecystectomy. In response to surgery, markers of NO bioavailability increased, and oxidative stress decreased. These findings support that a minimally invasive removal of the inflamed gallbladder countereffects reduced markers of NO bioavailability and increased oxidative stress caused by acute cholecystitis.

Does Aging Affect Vitamin C Status Relative to Intake? Findings from NHANES 2017-2018.

The aging population is growing and fueling a global increase in chronic diseases and healthcare expenditure. In this study, we examine vitamin C dose-concentration relationships based on data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 to identify a possible age-dependent change in intake vs. concentration relationship among non-supplemented individuals (n = 2828). The vitamin C intake was similar between the younger (18-36 years), middle (37-58 years) and older (59-80+ years) age groups; however, circulating vitamin C concentrations were significantly lower in the middle and older age groups (p < 0.001). For intakes above 75 mg/day, no significant difference in the intake vs. serum concentration relationship was identified between younger and older individuals. However, for intakes below 75 mg/day, we found significantly lower serum concentrations relative to intake for the older compared to younger individuals, despite smoking being more prevalent in the younger compared to older adults (p < 0.001). This effect persisted among non-smokers and was further exacerbated by smoking in older people. Collectively, the present study suggests that healthy aging in non-institutionalized individuals does not increase requirements for vitamin C. In contrast, the lower serum concentrations relative to intake observed in older individuals at intakes < 75 mg/day may suggest that older individuals are more sensitive to a low vitamin C intake, perhaps due to the increased impact of long-term smoking and increased chronic disease prevalence in older adults. This finding may have implications for future intake guidelines in countries with low RDAs and for WHO/FAO, but requires further investigation.

Vitamin C - a scoping review for Nordic Nutrition Recommendations 2023.

Vitamin C has multiple metabolic functions in the body, but the available information on the exact relationship between these functions and the intake necessary to maintain them is very limited. However, most attempts to objectively measure adequacy of vitamin C status, including, for example, replacement of metabolic turnover, chronic disease prevention, urinary excretion, and saturation of immune cells and body compartment, currently point toward 50 µmol/L as a reasonable target plasma concentration. As a strong correlation between body weight and vitamin C status exists, recommended intakes (RIs) for other age groups may be extrapolated from the adult RI based on weight. However, as body weights above 70 kg are becoming increasingly common - also in the Nordic region - an RI of 140 mg/day for individuals weighing 100 kg or more should be considered to compensate for the larger volume of distribution. Finally, smoking continues to be a common contributor to poor vitamin C status; therefore, it is proposed that people who smoke increase their daily vitamin C intake by 40 mg/day to compensate for the increased metabolic turnover induced by smoking.

Comparison of the neuromuscular effects of two infusion rates of rocuronium in anesthetized pigs.

BACKGROUND: Neuromuscular blocking agents are frequently administered to pigs used for research. In humans, administration of the drugs is not without risk and may result in accidental awareness under general anaesthesia and postoperative residual neuromuscular blockade that can lead to serious respiratory complications. Despite the extensive administration, the pharmacodynamics of neuromuscular blocking agents are not thoroughly studied in pigs. Therefore, this study investigates the neuromuscular response of two infusion rates of rocuronium, a commonly used non-depolarizing neuromuscular blocking agent. A group of 14 female Danish Landrace-Yorkshire-Duroc pigs used for supervised surgical training, weighing 40.3 ± 2.1 kg (mean ± SD), were included in the study. They received a loading dose of 0.85 mg/kg rocuronium intravenously followed by infusion of either 2.5 mg/kg/hour (L, low dose) or 5 mg/kg/hour (H, high dose) rocuronium for 30 min. Neuromuscular monitoring was performed with acceleromyography using train-of-four (TOF) stimulation. Onset time, time to reappearance of T1, T4, TOF ratio 90% and 100% were recorded. RESULTS: All pigs in group H experienced loss of T1 throughout rocuronium infusion, whereas six out of seven pigs in group L had reappearance of T1 during rocuronium infusion, with additional reappearance of T4 in three of these pigs. The time to recovery of TOF ratio 90% was 14.0 ± 5.4 (L) and 21.7 ± 6.1 (H) minutes and recovery to TOF ratio 100% was 18.7 ± 6.5 (L) and 27.9 ± 9.2 min (H) (mean ± SD). Substantial inter-animal variation in neuromuscular recovery time was observed. CONCLUSION: The large inter-animal variation in pharmacodynamic profiles emphasizes that individual neuromuscular monitoring and titration to effect should be used routinely in research protocols that include rocuronium. In addition to other important measures, these actions are key in order to avoid overdosing and limit the risk of residual neuromuscular blockade.

Vitamin C Deficiency Exacerbates Dysfunction of Atherosclerotic Coronary Arteries in Guinea Pigs Fed a High-Fat Diet.

Vitamin C (vitC) deficiency has been associated with an increased risk of cardiovascular disease; while several putative mechanistic links have been proposed, functional evidence supporting a causal relationship is scarce. In this study, we investigated how vitC deficiency affects coronary artery vasomotor function and the development of coronary atherosclerotic plaques in guinea pigs subjected to chronic dyslipidemia by a high-fat diet regime. Female Hartley guinea pigs were fed either a control (low-fat diet and sufficient vitC) (N = 8) or a high-fat diet with either sufficient (N = 8) or deficient (N = 10) vitC for 32 weeks. Guinea pigs subjected to the high-fat diet developed significant atherosclerotic plaques in their coronary arteries, with no quantitative effect of vitC deficiency. In isolated coronary arteries, vasomotor responses to potassium, carbachol, nitric oxide, or bradykinin were studied in a wire myograph. Carbachol, bradykinin, and nitric oxide mediated relaxation in the coronary arteries of the control group. While vasorelaxation to carbachol and nitric oxide was preserved in the two high-fat diet groups, bradykinin-induced vasorelaxation was abolished. Interestingly, bradykinin induced a significant contraction in coronary arteries from vitC-deficient guinea pigs (p < 0.05). The bradykinin-induced contraction was unaffected by L-NAME but significantly inhibited by both indomethacin and vitC, suggesting that, during vitC deficiency, increased release of arachidonic acid metabolites and vascular oxidative stress are involved in the constrictor effects mediated by bradykinin. In conclusion, the present study shows supporting evidence that poor vitC status negatively affects coronary artery function.

Prolonged insulin-induced hypoglycaemia reduces ß-cell activity rather than number in pancreatic islets in non-diabetic rats.

Pancreatic ß-cells have an extraordinary ability to adapt to acute fluctuations in glucose levels by rapid changing insulin production to meet metabolic needs. Although acute changes have been characterised, effects of prolonged metabolic stress on ß-cell dynamics are still unclear. Here, the aim was to investigate pancreatic ß-cell dynamics and function during and after prolonged hypoglycaemia. Hypoglycaemia was induced in male and female rats by infusion of human insulin for 8 weeks, followed by a 4-week infusion-free recovery period. Animals were euthanized after 4 or 8 weeks of infusion, and either 2 days and 4 weeks after infusion-stop. Total volumes of pancreatic islets and ß-cell nuclei, islet insulin and glucagon content, and plasma c-peptide levels were quantified. Prolonged hypoglycaemia reduced c-peptide levels, islet volume and almost depleted islet insulin. Relative ß-cell nuclei: total pancreas volume decreased, while being unchanged relative to islet volume. Glucagon: total pancreas volume decreased during hypoglycaemia, whereas glucagon: islet volume increased. Within two days after infusion-stop, plasma glucose and c-peptide levels normalised and all remaining parameters were fully reversed after 4 weeks. In conclusion, our findings indicate that prolonged hypoglycaemia inactivates ß-cells, which can rapidly be reactivated when needed, demonstrating the high plasticity of ß-cells even following prolonged suppression.

Lower Vitamin C Levels Are Associated With Less Improvement in Negative Symptoms in Initially Antipsychotic-Naïve Patients With First-Episode Psychosis.

Low levels of vitamin C have been observed in patients with schizophrenia and psychosis, and vitamin C may affect the dopaminergic system. Likewise, antipsychotic medication modulates striatal dopamine D2 receptors. We measured vitamin C levels in 52 patients with first-episode psychoses (24 females, age 23.1 ± 5.2 years) and 57 matched HCs (20 females, age 22.7 ± 4.3 years) before and after 6 weeks where patients received aripiprazole monotherapy (mean dose 10.4 mg ± 4.8 mg). At baseline, patients displayed lower levels of vitamin C (57.4 ± 25.9 µM) than controls (72.7 ± 21.4 µM) (t = 3.4, P = .001). Baseline symptoms and vitamin C levels were not correlated. Higher baseline vitamin C levels were associated with more improvement in negative symptoms (n = 39, R2 = 0.20, F = 8.2, P = .007), but not with age, sex, or p-aripiprazole. Because negative symptoms are generally considered challenging to alleviate, a potential adjunctive effect of vitamin C on treatment response should be tested in future randomized clinical trials.