Elevated Serum Concentrations Research Articles

B-314 Utility of he4 in differential diagnosis of pleural effusions

Abstract Background The usefulness of tumor markers in the differential diagnosis of cancer in patients with pleural effusions (PE) remains controversial. Few studies have reported the measurement of human epididymal protein 4 (HE4) in pleural fluid. HE4 is a tumor marker associated with different types of cancer. An elevated serum concentration has been observed in ovarian and lung cancers. Other benign pathologies can increase HE4 levels, which can be detect with different laboratory tests identified with adenosine deaminase (ADA), C-reactive protein (CRP), % polynuclear cell count (%PMN) and glomerular filtration rate (GFR) can be used in order to detect possible false positives. The objective of this study was to assess the diagnostic usefulness of HE4 in malignant pleural effusions by comparing HE4 concentrations between benign and malignant samples, while considering the causes of HE4 false positives. Methods HE4, ADA, differential leukocyte count, CRP and GFR concentrations were determined in 238 pleural effusion samples. Diagnostic efficacy analysis using receiver operating curves (ROC) identified the ability of HE4 to detect malignancy, searching for cut-off points with 100% specificity. Results HE4 concentrations showed significant differences (P<0.01) between malignant (median 1065pmol/L) and benign (median 699pmol/L) pleural effusions. Significant differences (P<0.01) were found in HE4 concentrations for gynecological and lung cancer origin (median 7397 pmol/L and 5150 pmol/L respectively) and other malignant pleural effusions (median 1065 pmol/L). Patients with benign diseases with renal failure showed a higher HE4 concentration (median 964pmol/L) than in patients without these pathologies (median 696pmol/L) identified with GFR<30 mL/min. No differences were demonstrated in HE4 concentration levels using ADA, differential leukocyte count or CRP, so only glomerular filtration rate was considered cause of false positives. A sensitivity of 23% was obtained for HE4, with a cut-off point of 3050pmol/L and a specificity of 100% for the whole group. In the potential false positive group, the sensitivity of HE4 was 28% with a cutoff point of 3050 pmol/L with a specificity of 100%. In the group without potential false positives, we obtained a sensitivity of 30% with a specificity of 100% for a cutoff point of 1992pmol/L. When we used a specific cut-off point for each group, we obtained a sensitivity of 38% with a specificity of 100%. Conclusions HE4 levels are higher in malignant pleural effusions compared to other pathologies. HE4 levels allow the identification of malignant pleural effusions with moderate sensitivity and maximum specificity. HE4 levels can differentiate between tumors of gynecological or lung origin and others. Glomerular filtration rate (GFR<30 mL/min) was considered the main cause of false positives. If we identify possible false positives, we can use specific cut-offs and improve sensitivity up to 38% with maximum specificity compared to using a single cut-off for all effusions.

Rewired glutamate metabolism diminishes cytostatic action of L-asparaginase

Tumor cells often adapt to amino acid deprivation through metabolic rewiring, compensating for the loss with alternative amino acids/substrates. We have described such a scenario in leukemic cells treated with L-asparaginase (ASNase). Clinical effect of ASNase is based on nutrient stress achieved by its dual enzymatic action which leads to depletion of asparagine and glutamine and is accompanied with elevated aspartate and glutamate concentrations in serum of acute lymphoblastic leukemia patients. We showed that in these limited conditions glutamate uptake compensates for the loss of glutamine availability. Extracellular glutamate flux detection confirms its integration into the TCA cycle and its participation in nucleotide and glutathione synthesis. Importantly, it is glutamate-driven de novo synthesis of glutathione which is the essential metabolic pathway necessary for glutamate's pro-survival effect. In vivo findings support this effect by showing that inhibition of glutamate transporters enhances the therapeutic effect of ASNase. In summary, ASNase induces elevated extracellular glutamate levels under nutrient stress, which leads to a rewiring of intracellular glutamate metabolism and has a negative impact on ASNase treatment.

Attempted Self-Harm with Elemental Thallium Purchased Online: Case Report with Analytical Confirmation

IntroductionThallium is a highly toxic metal, with most publications demonstrating poisoning from thallium salts. We report on a patient with elevated serum and urine thallium concentrations from an intentional ingestion of elemental thallium purchased from the internet for self-harm.Case ReportThe regional poison center was contacted about an 18-year-old man who ingested a fragment from a 100-gram bar reported to be elemental thallium. Serial serum and urine thallium concentrations were obtained. Prussian blue was started on hospital day (HD) 2. A metal fragment was seen on abdominal x-ray and removed via colonoscopy on HD3. The ingested fragment was analyzed via inductively coupled plasma mass spectrometry (ICP-MS) and found to be 87.0% elemental thallium. The initial serum thallium concentration obtained on HD1 was 423.5 mcg/L (reference range < 5.1 mcg/L), which subsequently decreased to 4.5 mcg/L, 29 days after the ingestion. An initial random urine thallium concentration obtained on HD 3 was 1850.5 mcg/g creatinine (reference range < 0.4 mcg/g creatinine). The patient remained hospitalized for 23 days and, when seen in follow-up, had not developed any signs or symptoms of thallium toxicity.DiscussionElemental thallium ingestion is a rare toxicologic exposure, with limited published clinical and analytical experience to guide management. This case report describes a patient with ingestion of elemental thallium who developed elevated serum and urine thallium concentrations and was treated with Prussian blue. Despite having elevated serum and urine thallium concentrations consistent with previous fatal exposures, more evidence is needed to understand the differences between elemental thallium and thallium salts.

Experimental study on H2O2 activation of HSC-T6 and hepatic fibrosis in cholestatic mice by "Yajieshaba"

Ethnopharmacological relevanceYajieshaba (YJSB), approved by the Yunnan Provincial Food and Drug Administration in 2008, are known for their anti-inflammatory, antiviral, and pro-apoptotic properties, effectively treating Hepatic fibrosis (HF). However, its mechanism of action remains unclear. Aim of the studyThe objective of this investigation is to explore how YJSB influences the TGF-β1/Smad signaling pathway as a strategy for reducing HF. MethodsThe establishment of a HF model in mice involved ligation of the common bile duct, followed by administration of YJSB. Body and liver weights were measured, and the liver index calculated. Serum levels of ALT, AST, ALP, TBA, and TBIL were assessed using colorimetric methods. Additionally, liver homogenates were analyzed for PIIINP, Col-IV, LN, HA, and Hyp, as well as TGF-β1 activity, using ELISA. Histological analyses of liver sections, stained with H&E, Ag, and Masson's trichrome, were performed to examine inflammation and the accumulation of collagen and reticular fibers. These studies aimed to elucidate the pharmacodynamic effects of YJSB on HF in mice with bile duct obstruction. The target pathways of YJSB were preliminarily identified through immunofluorescence detection of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, P-Smad3C, and Smad4 proteins. In vitro experiments included the induction of hepatic stellate cell (HSC-T6) activation by H2O2. A cell injury model was established for HSC-T6, and the CCK-8 assay was used to determine the optimal YJSB concentration and treatment duration. After pirfenidone (PFD) administration, which inhibits the TGF-β1/Smad pathway, the effects of YJSB on HSC-T6 cell proliferation were observed. ELISA assays quantified Col-III, α-SMA, and Col-I in cell lysates to assess YJSB's impact on collagen synthesis in HSC-T6 cells. Western blot analysis was performed to assess the protein levels within the TGF-β1/Smad signaling cascade. ResultsIn the HF mouse model, administration of YJSB notably augmented the body weight and reduced the liver index. Concurrently, there was an elevation in serum concentrations of ALP, AST, ALT, TBA, and TBIL. Similarly, in the liver homogenates of HF mice, increases were observed in the levels of HA, PIIINP, Col-IV, LN, Hyp, and TGF-β1. Histological assessments using H&E, Ag, and Masson stains indicated a substantial diminution in liver tissue damage. Through immunofluorescence analysis, it was discerned that YJSB modulated the expression of TGF-β1, P-Smad2L, P-Smad2C, and P-Smad3L downwards, while elevating P-Smad3C and Smad4 protein expressions. Additional investigations revealed a significant reduction in α-SMA, Col-I, and Col-III levels in cell culture fluids, suggesting a decrease in collagen synthesis and a protective role against cellular damage. Western blot analyses demonstrated that the TGF-β1/Smad pathway inhibitor, PFD, acted in synergy with YJSB, enhancing its regulatory effects on this pathway, decreasing levels of TGF-β1, P-Smad2L, P-Smad2C, P-Smad3L, and promoting the expression of P-Smad3C. ConclusionsYJSB demonstrates a pharmacodynamic effect against HF, enhancing liver functionality and effectively mitigating the damage associated with bile duct obstruction. The proposed action mechanism of YJSB involves modulation of the TGF-β1/Smad signaling pathway. Research indicates that YJSB might play a role in suppressing the movement, programmed cell death, and activation of HSC-T6, potentially decelerating the advancement of hepatic fibrosis.

Pharmacological Study of Guben Yifei-Tang on a Rat Model of Pneumoconiosis

Background Diffuse pulmonary fibrosis is a progressively worsening lung disease that poses a serious threat to human health. Current treatment options are limited and generally ineffective. Objectives This study aimed to investigate the therapeutic effects of GubenYifei-Tang (GB) in a rat model of pneumoconiosis. Materials and Methods We established a chronic pneumoconiosis model in rats through intratracheal injection of silica dust. Subsequently, the rats were randomly assigned to various groups, including the model group (NC group), Hanfangji Masu tablet group (TET group), high-dose GB group (GB-H group), low-dose GB group (GB-L group), and a blank control group comprising 12 normal rats (NC group). We assessed blood biochemical, vascular endothelial function, immunoinflammatory factors, and oxidative stress indices in four rats from each group at the 1st, 3rd, and 6th months of administration. Results Throughout the 6-month administration period, rats in the GB-L and GB-H groups displayed no significant abnormalities in their general condition or body weight. Both high and low doses of GB significantly reduced the respiratory rate and increased the respiratory amplitude of the pneumoconiosis model rats ( p &lt; 0.05). Additionally, they significantly decreased the mean pulmonary arterial pressure of these rats ( p &lt; 0.05). Moreover, we observed noteworthy improvements in blood gas indices and hypoxemia symptoms, including increased pH, decreased arterial partial pressure of carbon dioxide, increased arterial oxygen partial pressure, and arterial oxygen saturation. Compared to the NC group, the model group rats exhibited significantly elevated concentrations of serum transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and interleukin-1 ( p &lt; 0.01). High-dose GB significantly reduced serum levels of TGF-β, TNF-α, and interleukin-10 in rats, while low-dose GB partially improved serum inflammatory factor levels. Additionally, the lung mass index, malondialdehyde (MDA) levels, and hydroxyproline levels were significantly increased in the model group rats compared to the NC group ( p &lt; 0.01), accompanied by decreased superoxide dismutase (SOD) levels. Both high and low doses of GB demonstrated substantial improvements in lung mass index, MDA, SOD, and hydroxyproline levels in rats ( p &lt; 0.05). Conclusion In the rat model of pneumoconiosis, GB exerts a positive therapeutic impact on lung tissue lesions and respiratory function, with its effectiveness being both time- and dose-dependent.

Impact of dietary arginine supplementation on immune responses and growth performance in Newcastle disease virus-infected broiler chicks.

Newcastle disease (ND) poses significant challenges within the poultry industry, leading to increased mortality rates, compromised growth, weakened immunity and elevated levels of inflammation. This study explores the potential of dietary arginine supplementation to ameliorate these adverse effects of ND, leveraging arginine's well-documented benefits in enhancing growth and immune responses. A total of 480 one-day-old male broiler chicks were meticulously categorised into eight groups, encompassing both infected and noninfected cohorts. These chicks received diets with arginine levels at 85%, 100%, 125% and 150% of recommended standards. The study entailed a comprehensive examination of clinical manifestations, growth performance metrics, haemagglutination inhibition (HI) test results, and serum concentrations of proinflammatory cytokines, adrenocorticotropic hormone (ACTH), and cortisol (CORT). The infection significantly curtailed feed consumption (p = 0.0001) and weight gain (p = 0.0001) while concurrently depressing HI titres. Additionally, infected chicks experienced an exacerbated feed conversion ratio (p = 0.0001), escalated mortality rates (p = 0.0001), and elevated serum concentrations of proinflammatory cytokines (p = 0.0001), ACTH (p = 0.0001), and CORT (p = 0.0001). Remarkably, dietary arginine supplementation effectively mitigated the adverse impacts of ND infection on growth, immune responses and proinflammatory cytokine levels. In the context of ND infection, mortality rates and inflammation surge, while growth and immunity are significantly compromised. The strategic inclusion of arginine in the diet emerges as a potent strategy to counteract the deleterious effects of ND. Supplementation with arginine at levels exceeding the conventional dietary recommendations is recommended to alleviate the detrimental consequences of ND effectively.

Chronic infusion of the tryptophan metabolite kynurenine increases mean arterial pressure in male Sprague-Dawley rats.

Chronic kidney disease is the loss of renal function that can occur from aging or through a myriad of other disease states. Rising serum concentrations of kynurenine, a tryptophan metabolite, have been shown to correlate with increasing severity of chronic kidney disease. This study used chronic intravenous infusion in conscious male Sprague-Dawley rats to test the hypothesis that kynurenine can induce renal damage and promote alterations in blood pressure, heart rate, and decreased renal function. We found that kynurenine infusion increased mean arterial pressure, increased the maximum and minimum range of heart rate, decreased glomerular filtration rate, and induced kidney damage in a dose-dependent manner. This study shows that kynurenine infusion can promote kidney disease in healthy, young rats, implying that the increase in kynurenine levels associated with chronic kidney disease may establish a feed-forward mechanism that exacerbates the loss of renal function.NEW & NOTEWORTHY In humans, an elevated serum concentration of kynurenine has long been associated with negative outcomes in various disease states as well as in aging. However, it has been unknown whether these increased kynurenine levels are mediating the disorders or simply associated with them. This study shows that chronically infusing kynurenine can contribute to the development of hypertension and kidney impairment. The mechanism of this action remains to be determined in future studies.

The Role of ACE2 Receptor and Its Polymorphisms in COVID-19 Infection and Severity and Its Association with Lipid Profile, Thrombin, and D-Dimer Levels in Iraqi Patients: A Cross-Sectional Study.

COVID-19 patients experience a complex interplay involving ACE2, thrombin, D-dimer, and lipid profile, yet its full understanding remains elusive. ACE2, a pivotal regulator of the renin-angiotensin system and the primary receptor for SARS-CoV-2 undergoes downregulation upon viral binding, potentially leading to severe cases with acute respiratory distress syndrome (ARDS). A specific ACE2 gene polymorphism (rs2285666) may be associated with COVID-19 susceptibility, with the A allele potentially increasing infection risk. COVID-19 disease progression is linked to coagulation abnormalities, but the exact connection with thrombin and D-dimer remains uncertain. A study examining coagulation parameters in COVID-19 patients admitted to Al-Diwania Educational Hospital from February to May 2022 found that thrombin and D-dimer levels were directly related to disease severity. Severe cases exhibited significantly altered coagulation function compared to mild and recovered cases, with notably higher D-dimer levels and elevated thrombin serum concentrations. Moreover, dyslipidemia, particularly low HDL cholesterol, is a prevalent comorbidity in COVID-19 patients and may be linked to worse outcomes. In conclusion, COVID-19 is associated with a prothrombotic state and dysregulation of the renin-angiotensin system due to ACE2 downregulation following viral binding. The intricate interplay between ACE2, thrombin, D-dimer, and lipid profile necessitates further investigation. The multifaceted nature of the disease demands continued research to unravel its pathogenesis and identify potential therapeutic targets.

Dihydromyricetin improves growth performance, immunity, and intestinal functions in weaned pigs challenged by enterotoxigenic Escherichia coli.

Enteric infection is a major cause of enteric disorder in neonatal pigs during the weaning transition. Dihydromyricetin (DMY) is a natural flavanonol compound extracted from Ampelopsis grossedentata with numerous biological activities such as antioxidative and immunomodulatory functions. The objective of this study was to investigate the effects of dietary dihydromyricetin supplementation on growth performance, immunity, and intestinal functions in weaned pigs challenged by enterotoxigenic Escherichia coli (ETEC). In total, 24 weaned DLY (Duroc × Landrace × Yorkshire) pigs were allotted to 3 treatments. Pigs fed with basal diet or basal diet containing 300 mg/kg DMY were orally infused with sterilized culture or ETEC (2.5 × 1011 colony-forming units). Dietary DMY supplementation significantly elevated the final weight and average daily gain (ADG) but reduced diarrhea incidence in the weaned pigs of the EDMY group compared to the pigs of the ECON group (p < 0.05). Compared to the ECON group, DMY also improved the digestibility of dry matter (DM), ether extract (EE), gross energy (GE), and ash of the EDMY group (p < 0.05). Moreover, DMY not only significantly decreased the ratio of albumin/globulin but also elevated serum concentrations of immunoglobulins (e.g., IgA and IgG) in the weaned pigs of the EDMY group compared to the pigs of the ECON group (p < 0.05). Interestingly, the villus height, the ratio of villus height to crypt depth (V:C), and the activities of mucosal alkaline phosphatase, sucrase, and maltase in the duodenum and jejunum of the EDMY group were higher than those in the ECON group (p < 0.05). Importantly, DMY significantly elevated the expression levels of jejunal zonula occludens-1 (ZO-1), claudin-1, cationic amino acid transporter-1 (CAT-1), and fatty acid transport protein-1 (FATP-1) in the weaned pigs of the EDMY group compared to the pigs of the ECON group (p < 0.05). Additionally, compared to the ECON group, DMY increased the concentrations of microbial SCFA metabolites (e.g., acetic acid and propanoic acid), but reduced the abundance of Escherichia coli in the cecum of the EDMY group (p < 0.05). Dietary DMY supplementation can attenuate the ETEC-induced growth retardation and intestinal injury, which was attributed to the amelioration of intestinal nutrient digestion and transport functions as well as the improved microbiota.

Periostin Predicts All-Cause Mortality in Male but Not Female End-Stage Renal Disease Patients on Hemodialysis.

Periostin is a matricellular protein. Elevated serum concentrations of periostin have been reported in patients with various cardiovascular diseases, including heart failure. Patients with end-stage renal disease have a substantially increased risk for cardiovascular diseases. However, there is a lack of clinical studies to clarify the prognostic significance of systemic periostin on all-cause mortality in patients with end-stage renal disease on hemodialysis. 313 stable end-stage renal disease patients were recruited and followed for 5 years concerning all-cause mortality. At baseline, we collected blood samples and clinical data. Serum periostin concentrations were measured using a certified ELISA. The optimal cut-off value for serum periostin regarding all-cause mortality, calculated through receiver operating characteristic analysis, was 777.5 pmol/L. Kaplan-Meier survival analysis using this cut-off value demonstrated that higher periostin concentrations are linked to higher all-cause mortality (log-rank test: p = 0.002). Subgroup analysis revealed that serum periostin concentrations only affected all-cause mortality in male but not in female patients (p = 0.002 in male patients and p = 0.474 in female patients). Multivariate Cox regression analyses, adjusted for confounding factors, likewise showed that elevated serum periostin concentrations were positively associated with all-cause mortality in male (p = 0.028) but not in female patients on hemodialysis (p = 0.313). Baseline serum periostin is an independent risk factor for all-cause mortality in male patients with chronic renal disease on hemodialysis.

Unraveling the Potential of Saccharum officinarum and Chlorella vulgaris towards 5-Fluorouracil-Induced Nephrotoxicity in Rats.

5-Fluorouracil (5-FU) is often used as a chemotherapeutic agent in treating tumors and is said to have adverse effects, including nephrotoxicity. Therefore, the present study aimed to evaluate the protective effects of Chlorella vulgaris (VL) and Saccharum officinarum L. (SOL) against 5-FU-induced nephrotoxicity in rats through the measurement of renal histology, kidney damage indicators, and antioxidant measures. A total of forty-eight male rats were allotted into six groups: group 1 acted as a control negative group (control), group 2 received 5-FU and worked as a control positive group (FU), group 3 received SOL 15 mL/kg (SOL), group 4 received VL 400 mg/kg (VL), group 5 received 5-FU+SOL (5-FU+SOL), and group 6 received 5-FU+VL (5-FU+VL). After fifteen days, blood and renal tissue specimens were collected for hematological, biochemical, molecular, and histopathological examinations. Findings of the current investigation showed that 5-FU leads to hematological alterations and kidney injury evinced by elevated serum concentrations of uric acid, creatinine, and urea (p < 0.01), and a marked increase in kidney MDA and NO levels with a reduction in kidney CAT, SOD and GSH activities (p < 0.05). Alterations of the histopathological structure of kidney tissue in the FU group were noticed compared to the other groups. 5-FU administration elevated expression levels of TNF-α, lipocalin 2, and KIM1 (p < 0.01) compared to the control ones. 5-FU-induced nephrotoxicity was ameliorated after treatment with SOL and VL via their free radical scavenging, potent antioxidant, and anti-inflammatory effects. In conclusion, our findings demonstrate that the treatment with SOL and VL significantly improved nephrotoxicity induced by 5-FU in rats.

Bioanalytical HPLC method with fluorescence detector for determination of Entresto™ when co-administered with ibuprofen and fexofenadine: a pharmacokinetic study.

Entresto™ (LCZ696) has been approved globally for heart failure management. However, its lifelong use alongside over-the-counter (OTC) drugs like ibuprofen (IBU) and fexofenadine (FEX) necessitates an in-depth investigation of potential pharmacokinetic interactions, as they share the same metabolic and elimination pathways. This study aimed to develop a bioanalytical HPLC method with a fluorescence detector (FLD) to quantify LCZ696 analytes (valsartan, VAL; sacubitril, SAC; and sacubitril active metabolite, LBQ657) in rat plasma. Additionally, an in vivo study was performed to investigate the pharmacokinetic interactions of LCZ696 with IBU and FEX. Utilizing HPLC with a gradient-mode mobile phase of acetonitrile and 0.025 M phosphate buffer (pH 3), the study demonstrated a significant increase in the bioavailability of LCZ696 analytes (VAL and LBQ657) when co-administered with IBU (C max 0.23 ± 0.07 and 0.53 ± 0.21 μg mL-1, respectively) compared to the control (0.17 ± 0.03 and 0.33 ± 0.14 μg mL-1). A more significant increase in C max was noticed with FEX (0.38 ± 0.01 and 0.77 ± 0.18 μg mL-1, respectively). Moreover, a decrease in the clearance (Cl/F) of VAL and LBQ657 was observed (18.05 ± 1.94 and 12.42 ± 2.97 L h-1 kg, respectively) with a more pronounced effect in the case of FEX (30.87 ± 4.29 and 33.14 ± 9.57 L h-1 kg, respectively) compared to the control (49.99 ± 7.31 and 51.19 ± 9.12 L h-1 kg, respectively). In conclusion, our study underscores the importance of cautious administration and appropriate dose spacing of IBU and FEX in patients treated with LCZ696 to prevent elevated serum concentrations and potential toxicity. The novelty of this work lies in its dual contribution: developing a highly sensitive HPLC-FLD method and comprehensively elucidating significant pharmacokinetic interactions between LCZ696 and common OTC drugs.

Marginal Zinc Deficiency Promotes Pancreatic Islet Enlargement While Zinc Supplementation Improves the Pancreatic Insulin Response in Zucker Diabetic Fatty Rats.

Zinc deficiency has been associated with the worsening of diabetes while zinc supplementation has been proposed to ameliorate diabetes. This study examined the effects of marginal zinc deficiency (MZD) and zinc supplementation (ZS) on obesity, glycemic control, pancreatic islets, hepatic steatosis and renal function of Zucker diabetic fatty (ZDF) rats. Male ZDF rats were fed an MZD, zinc control (ZC) or ZS diet (4, 30 and 300 mg Zn/kg diet, respectively), and lean Zucker rats were fed a ZC diet for 8 weeks. MZD and ZS did not alter body weight or whole-body composition in ZDF rats. MZD ZDF rats had reduced zinc concentrations in the femur and pancreas, a greater number of enlarged pancreatic islets and a diminished response to an oral glucose load based on a 1.8-fold greater incremental area-under-the-curve (AUC) for glucose compared to ZC ZDF. ZS ZDF rats had elevated serum, femur and pancreatic zinc concentrations, unchanged pancreatic parameters and a 50% reduction in the AUC for insulin compared to ZC ZDF rats, suggesting greater insulin sensitivity. Dietary zinc intake did not alter hepatic steatosis, creatinine clearance, or levels of proteins that contribute to insulin signaling, inflammation or zinc transport in epididymal fat. Potential adverse effects of ZS were suggested by reduced hepatic copper concentrations and elevated serum urea compared to ZC ZDF rats. In summary, ZS improved the pancreatic insulin response but not the glucose handling. In contrast, reduced zinc status in ZDF rats led to impaired glucose tolerance and a compensatory increase in the number and size of pancreatic islets which could lead to β-cell exhaustion.

Phenylbutyrate Treatment in a Boy with MCT8 Deficiency: Improvement of Thyroid Function Tests and Possible Livertoxicity.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G > T (p.V235L). During a treatment period of 13 months, PB led to a significant decrease of elevated TSH and T3 serum concentrations, while fT4 increased. Weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate (PAA) in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies towards body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.

Dietary Selenium Insufficiency Induces Cardiac Inflammatory Injury in Chicks

BackgroundLaying hens undergo intensive metabolism and are vulnerable to cardiac insults. Previous research demonstrated overt heart disorders of broiler chickens induced by dietary Se deficiency. ObjectivesThis study aimed to reveal effects and mechanism of dietary Se insufficiency on cardiac injuries of egg-type chicks in their early life. MethodsWhite Leghorn chicks (0-d-old, female) were fed a corn-soy, Se-insufficient basal diet (BD, 0.05 mg Se/kg; n = 11) or the BD supplemented with 0.3 mg Se/kg (as sodium selenite; n = 8) for 35 d. Cardiac tissues were collected at the end of study for histology and to determine its relationship with heart Se contents, selenoprotein expression profiles, antioxidant and inflammatory status, and the Toll-like receptor 4/extracellular signal-regulated kinases/p38 map kinase/c-Jun N-terminal kinase (TLR4/ERK/P38/JNK) pathway. ResultsCompared with those fed 0.35 mg Se/kg, chicks fed BD had significantly lower body weights and average daily gain, and 28% lower heart Se, and developed cardiac mononuclear inflammatory cell infiltration, along with elevated (P < 0.05) serum concentrations of creatine kinase, aldolase, and interleukin-1 (IL-1). The BD decreased (P < 0.05) body weight and heart glutathione contents and expression of selenoproteins but increased (P < 0.05) heart concentrations of malondialdehyde and reactive oxygen species. These changes were associated with increased (P < 0.05) mRNA and/or protein concentrations of cyclooxygenases, lipoxygenase-12, cytokines (IL-1β), nuclear factor (NF) κB subunit, chemokines, and receptors (CCL20, CXCR1, and CXCLI2) and increased (P < 0.1) TLR4/ERK /P38/JNK in the heart of Se-insufficient chicks. ConclusionsDietary Se insufficiency induces infiltration of mononuclear inflammatory cells in the heart of egg-type chicks. This cardiac injury was mediated by decreased functional expressions of selenoproteins, which resulted in apparent elevated oxidative stress and subsequent activations of the TLR4 pathway and NF κB.

Magnetic resonance imaging characteristics of Graves orbitopathy with elevated IgG4 serum concentration

Magnetic resonance imaging characteristics of Graves orbitopathy with elevated IgG4 serum concentration

Association Between Fluoroquinolones and Major Adverse Cardiovascular Events: A Systematic Review.

Fluoroquinolones (FQs) are routinely administered antibiotics that have demonstrated an increased propensity to cause major adverse cardiovascular events (MACE). We conducted a systematic review aimed to investigate the association between FQ usage and the risk of MACE. A comprehensive literature search was conducted using PubMed, Scopus, and the Cochrane Library from inception to September 2023 to retrieve studies comparing FQ administration with placebo and reporting the occurrence of MACE. Relevant studies that explored the occurrence of MACE, defined as "acute myocardial infarction, stroke, cardiovascular mortality, arrhythmia, or heart failure" with FQ usage were eligible for inclusion. Four studies with a total of 42,808 patients were included. Levofloxacin, moxifloxacin, and gatifloxacin were observed to have an increased propensity to cause MACE, particularly arrhythmias, whereas ciprofloxacin was associated with the lowest risk of causing MACE. Despite the methodological diversity in the included studies, this systematic review uncovered a consistent trend of heightened likelihood of MACE with FQ administration across studies, suggesting that elevated serum concentrations of some FQs may correlate with higher risks of MACE development. This systematic review emphasizes the need for cautious administration of FQs, particularly in patients with a preexisting cardiovascular condition. Routine cardiac monitoring using electrocardiograms is warranted for patients on high doses of FQs to preemptively detect the development of MACE, particularly arrhythmias.

C-reactive protein, cardiovascular issues of an acute-phase protein: an update for theclinician

Inflammation is an important pathogenic factor for the development of atherosclerotic cardiovascular disease. Currently, the most frequently used biomarker reflecting systemic inflammation is C-reactive protein (CRP), an acute-phase protein produced primarily by hepatocytes under the influence of interleukin-6, interleukin-1 beta, and tumor necrosis factor. Growing evidence from epidemiological studies has shown a robust association between elevated serum or plasma CRP concentrations and the incidence of a first cardiovascular adverse event (including acute myocardial infarction, ischemic stroke, and sudden cardiac death) in the general population, as well as recurrence of major adverse cardiovascular events among patients with established disease. The additive value that CRP measurement gives to traditional risk factors is reflected in novel cardiovascular risk calculators and in current intervention regimens, which already consider CRP as a target therapeutic. However, the variations in CRP levels, that depend on sex, ethnicity, hormonal status, and some peculiarities of the measurement assays, must be taken into consideration when deciding to implement CRP as a useful biomarker in the study and treatment of atherosclerotic cardiovascular disease. This review aims to offer an updated vision of the importance of measuring CRP levels as a biomarker of cardiovascular risk beyond the traditional factors that estimate the risk of atherosclerotic disease.

The Effect of Maternal Overweight/Obesity on Serum and Breastmilk Leptin, and Its Associations with Body Composition, Cardiometabolic Health Indices, and Maternal Diet: The BLOOM Study.

In overweight and obese patients, elevated serum and breastmilk leptin concentrations are observed, with serum leptin also being likely affected by the diet. We analyzed serum and breastmilk leptin in normal weight (NW) and overweight/obese (OW/OB) mothers, and evaluated its associations with (1) maternal anthropometric parameters; (2) markers of cardiometabolic health; and (3) the maternal diet. The BLOOM (Breastmilk and the Link to Overweight/Obesity and Maternal diet) study was conducted among 40 women (n = 20 OW/OB; n = 20, NW) who were exclusively or predominantly breastfeeding for 15.5 ± 1.2 (OW/OB group (0.99)) weeks. We collected 24 h breastmilk and fasting blood samples for leptin analysis by ELISA. Maternal dietary habits were evaluated using a 3-day dietary record and food frequency questionnaire, which were used to calculate the Polish-adapted Mediterranean Diet score. Maternal anthropometric measurements and DEXA scans were performed, and anthropometric and cardiometabolic indices were calculated. The OW mothers had 1.4 times higher serum levels, while OB mothers had 4.5 and 6.2 higher serum and breastmilk leptin levels, respectively, in comparison to the NW mothers. The FM% was correlated with serum and breastmilk leptin levels (r = 0.878, r = 0.638). Serum leptin was associated with markers of cardiometabolic health such as AIP, CMI, and VAI in the NW mothers, and with LAP in the OW/OB mothers. Higher energy, fructose intake and adherence to the Mediterranean diet were associated with serum leptin in the NW mothers (β = 0.323, 0.039-0.608; β = 0.318, 0.065-0.572; β = 0.279, 0.031-0.528); meanwhile, higher adherence to the Mediterranean diet could protect against elevated breastmilk leptin concentrations in OW/OB mothers (β = -0.444, -0.839--0.050), even after adjustment for FM%. Our results suggest a potential association between maternal serum leptin concentrations and cardiometabolic health. In addition, we confirm the importance of healthy dietary patterns in the improvement of breastmilk composition.

Identification of Serum Interleukin-22 as Novel Biomarker in Pulmonary Hypertension: A Translational Study.

Growing evidence suggests the crucial involvement of inflammation in the pathogenesis of pulmonary hypertension (PH). The current study analyzed the expression of interleukin (IL)-17a and IL-22 as potential biomarkers for PH in a preclinical rat model of PH as well as the serum levels in a PH patient collective. PH was induced by monocrotalin (60 mg/kg body weight s.c.) in 10 Sprague Dawley rats (PH) and compared to 6 sham-treated controls (CON) as well as 10 monocrotalin-induced, macitentan-treated rats (PH_MAC). Lung and cardiac tissues were subjected to histological and immunohistochemical analysis for the ILs, and their serum levels were quantified using ELISA. Serum IL levels were also measured in a PH patient cohort. IL-22 expression was significantly increased in the lungs of the PH and PH_MAC groups (p = 0.002), whereas increased IL17a expression was demonstrated only in the lungs and RV of the PH (p < 0.05) but not the PH_MAC group (p = n.s.). The PH group showed elevated serum concentrations for IL-22 (p = 0.04) and IL-17a (p = 0.008). Compared to the PH group, the PH_MAC group demonstrated a decrease in IL-22 (p = 0.021) but not IL17a (p = n.s.). In the PH patient collective (n = 92), increased serum levels of IL-22 but not IL-17a could be shown (p < 0.0001). This elevation remained significant across the different etiological groups (p < 0.05). Correlation analysis revealed multiple significant relations between IL-22 and various clinical, laboratory, functional and hemodynamic parameters. IL-22 could serve as a promising inflammatory biomarker of PH with potential value for initial diagnosis, functional classification or even prognosis estimation. Its validation in larger patients' cohorts regarding outcome and survival data, as well as the probability of promising therapeutic target structures, remains the object of further studies.