Cyclosporin A inhibits PDGF-BB induced hyaluronan synthesis in orbital fibroblasts.

Orbital connective tissue changes are contributors to the pathogenesis in thyroid eye disease (TED). Activated fibroblasts respond to immune stimuli with proliferation and increased hyaluronan (HA) production. Cyclosporin A (CsA) was reported to be beneficial in the treatment of TED. PDGF isoforms are increased in orbital tissue of TED patients and enhance HA production. We aimed to study the effect of CsA on HA production and hyaluronan synthase (HAS1, 2 and 3) and hyaluronidase (HYAL1 and 2) mRNA expressions in orbital fibroblasts (OFs). Measurements were performed in the presence or absence of CsA (10 µM) in unstimulated or PDGF-BB (10 ng/ml) stimulated OFs. The HA production of TED OFs (n = 7) and NON-TED OFs (n = 6) were measured by ELISA. The levels of mRNA expressions were examined using RT-PCR. The proliferation rate and metabolic activity were measured by BrdU incorporation and MTT assays, respectively. Treatment with CsA resulted in an average 42% decrease in HA production of OFs (p < 0.0001). CsA decreased the expression levels of HAS2, HAS3 and HYAL2 (p = 0.005, p = 0.005 and p = 0.002, respectively.) PDGF-BB increased HA production (p < 0.001) and HAS2 expression (p = 0.004). CsA could reduce the PDGF-BB-stimulated HA production (p < 0.001) and HAS2 expression (p = 0.005) below the untreated level. In addition, CsA treatment caused a decrease in proliferation potential (p = 0.002) and metabolic activity (p < 0.0001). These findings point to the fact that CsA affects HA metabolism via HAS2, HAS3 and HYAL2 inhibition in OFs. In addition to its well characterized immunosuppressant properties, CsA's beneficial effect in TED may be related to its direct inhibitory effect on basal and growth factor stimulated HA production.

Effects of 1-year tofacitinib therapy on angiogenic biomarkers in rheumatoid arthritis.

OBJECTIVES: Cardiovascular (CV) morbidity and mortality, and perpetuated synovial angiogenesis have been associated with RA. In our study we evaluated angiogenic factors in relation to vascular inflammation and function, and clinical markers in RA patients undergoing 1-year tofacitinib therapy. METHODS: Thirty RA patients treated with either 5 mg or 10 mg twice daily tofacitinib were included in a 12-month follow-up study. Eventually, 26 patients completed the study and were included in data analysis. Levels of various angiogenic cytokines (TNF-α, IL-6), growth factors [VEGF, basic fibroblast (bFGF), epidermal (EGF), placental (PlGF)], cathepsin K (CathK), CXC chemokine ligand 8 (CXCL8), galectin-3 (Gal-3) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) were determined at baseline, and at 6 and 12 months after initiating tofacitinib treatment. In order to assess flow-mediated vasodilation, common carotid intima-media thickness (ccIMT) and carotid-femoral pulse-wave velocity, ultrasonography was performed. Synovial and aortic inflammation was also assessed by 18F-fluorodeoxyglucose-PET/CT. RESULTS: One-year tofacitinib therapy significantly decreased IL-6, VEGF, bFGF, EGF, PlGF and CathK, while it increased Gal-3 production (P < 0.05). bFGF, PlGF and NT-proBNP levels were higher, while platelet-endothelial cell adhesion molecule 1 (PECAM-1) levels were lower in RF-seropositive patients (P < 0.05). TNF-α, bFGF and PlGF correlated with post-treatment synovial inflammation, while aortic inflammation was rather dependent on IL-6 and PECAM-1 as determined by PET/CT (P < 0.05). In the correlation analyses, NT-proBNP, CXCL8 and Cath variables correlated with ccIMT (P < 0.05). CONCLUSIONS: Decreasing production of bFGF, PlGF or IL-6 by 1-year tofacitinib therapy potentially inhibits synovial and aortic inflammation. Although NT-proBNP, CXCL8 and CathK were associated with ccIMT, their role in RA-associated atherosclerosis needs to be further evaluated.

Advanced glycation end products and their soluble receptor (sRAGE) in patients with Hashimoto's thyroiditis on levothyroxine substitution.

Background: Advanced glycation end products (AGEs) are heterogenous group of irreversible chemical moieties originated from non-enzymatic glycation and oxidation of proteins, nucleic acids, and lipids. The engagement of AGEs with their chief cellular receptor (RAGE) activates a myriad of signaling pathways contributing to the progression of chronic diseases like autoimmune thyroiditis, type 2 diabetes mellitus and its complications. Soluble RAGE (sRAGE) prevents AGE-RAGE interaction in a competitive manner. Objective: We investigated the association between serum AGE, sRAGE and thyroid function in 73 Hashimoto thyroiditis patients (HT) on levothyroxine substitution, and in 83 age, BMI and gender-matched healthy controls. Methods: The serum AGEs levels were determined by autofluorescence on a multi-mode microplate reader, and the serum sRAGE levels by ELISA method. Results: Mean AGE level was lower (10.71 vs 11.45 AU/µg protein; p=0.046), while mean sRAGE level was higher (923 vs 755 pg/mL; p<0.0005) in the serum of HT patients than the controls. AGE correlated with age, while sRAGE correlated negatively with BMI in both groups. We found negative correlation between AGE and fT3 levels (r=-0.32; p=0.006) and sRAGE and TSH levels (r=-0.27; p=0.022) in HT patients, while we failed to find association between AGE, sRAGE and parameters of thyroid function in the control group. Median AGE/sRAGE ratio was lower in HT patients than in controls (2.4, IQR 1.9 - 3.1 vs 3.3, IQR 2.3 - 4.1 AU/pg; p < 0.001). In HT patients, the AGE/sRAGE ratio correlated positively with BMI and correlated negatively with fT3. Conclusion: According to our results in HT patients lower TSH and higher fT3 levels within the reference range is accompanied by a favorable AGE/RAGE balance. Further investigations are needed to confirm these results.

One-year safety and efficacy results of insulin treatment simplification with IDegLira in type 2 diabetes.

INTRODUCTION: This study aimed to investigate the sustained safety and efficacy of insulin treatment simplification with IDegLira in patients with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) during a 12-month follow-up. METHODS: Seventy-two adults with type 2 diabetes and an HbA1c ≤ 7.5% (58 mmol/mol) treated with multiple daily insulin injections (MDI) participated in the trial (age 63.8 ± 9.5 years, HbA1c 6.4 ± 0.7%, [46 ± 8 mmol/mol] body weight 92.95 ± 18.83 kg, total daily insulin dose: 43.21 ± 10.80 units; mean ± SD). Previous insulins were stopped, and once daily IDegLira was started. IDegLira was titrated by the patients to achieve a self-measured prebreakfast plasma glucose concentration of ≥5 mmol/L to ≤6 mmol/L. RESULTS: After 12 months, good glycaemic control was maintained, while body weight decreased significantly. Mean HbA1c changed to 6.2 ± 0.8% (44 ± 9 mmol/mol) (p = .109) and body weight changed by -3.89 kg to 89.06 ± 18.61 kg (p < .0001). The simplified treatment was safe and well-tolerated. Percentage of patients experiencing at least one episode of hypoglycaemia was 49% during the month before simplification and 17% during the last 3 months of the follow-up. CONCLUSIONS: Insulin treatment simplification with IDegLira in selected patients with type 2 diabetes is safe, maintains adequate glycaemic control and is associated with weight loss over 12 months.

Alcohol consumption affects the late endocrine consequences of mild traumatic brain injury.

BACKGROUND: Currently there are no widely applied methods which could identify, at the time of head trauma, those mild traumatic brain injury (mTBI) patients who later develop pituitary dysfunction. The effect of alcohol consumption on post-TBI endocrine dysfunction is unclear. METHODS: Five hundred and eight TBI patients, 406 of them with mTBI, were studied. Sixty-one patients (46 males, 15 females) were available for follow-up. Admission serum samples were evaluated for S100B protein and markers of alcohol consumption: ethanol level for day-of-injury intake and carbohydrate deficient transferrin (CDT) level for regular alcohol consumption. Regular alcohol consumption was defined as CDT > 1.5%, including both social and heavy drinkers. Admission and one-year follow-up samples were evaluated for pituitary dysfunction. RESULTS: Newly developed pituitary hormone deficiency was found in 16% of mTBI patients. When cohorts developing and not developing late pituitary dysfunction were compared, 30% and 69% of patients were regular alcohol consumers, respectively (p = 0.02). Neither S100B level nor day-of-injury alcohol consumption was predictive of late pituitary dysfunction. CONCLUSION: The findings of this preliminary study suggest that regular alcohol consumption may protect against the late endocrine consequences of mTBI. Alcohol intake during the weeks preceding mTBI may identify patients at higher risk for late pituitary dysfunction.

Different Effects of Cigarette Smoke, Heated Tobacco Product and E-Cigarette Vapour on Orbital Fibroblasts in Graves' Orbitopathy; a Study by Real Time Cell Electronic Sensing.

Thyroid autoimmunity in Graves' disease (GD) is accompanied by Graves' orbitopathy (GO) in 40% of the cases. Orbital fibroblasts (OF) play a key role in the pathogenesis and cigarette smoking is a known deteriorating factor. Alongside conventional cigarettes (CC) new alternatives became available for smokers, including heated tobacco products (HTP) and E-cigarettes (ECIG). We aimed to study the cellular effects of smoke extracts (SE) in orbital fibroblasts. Primary OF cultures from GO and NON-GO orbits were exposed to different concentrations of SE (1%, 50%) and the changes were followed using Real Time Cell Electronic Sensing (RT-CES). Untreated GO and NON-GO cells had different maximum cell index (CI) values of 3.3 and 2.79 respectively (p < 0.0001). CC, HTP and ECIG treated NON-GO fibroblasts exhibited peak CIs of 2.62, 3.32 and 3.41 while treated GO cells' CIs were higher, 5.38, 6.25 and 6.33, respectively (p < 0.0001). The metabolic activity (MTT) decreased (p < 0.001) and hyaluronan production doubled (p < 0.02) after 50% of CC SE treatment in all cell cultures. GO fibroblasts were more sensitive to low concentration SE then NON-GO fibroblasts (p < 0.0001). The studied SEs exerted different effects. RT-CES is a sensitive technique to detect the effects of very low concentration of SE on fibroblasts.

Glucocorticoids Directly Affect Hyaluronan Production of Orbital Fibroblasts; A Potential Pleiotropic Effect in Graves' Orbitopathy.

Orbital connective tissue expansion is a hallmark of Graves' orbitopathy (GO). In moderate-to-severe active GO, glucocorticoids (GC) are the first line of treatment. Here we show that hydrocortisone (HC), prednisolone (P), methylprednisolone (MP), and dexamethasone (DEX) inhibit the hyaluronan (HA) production of orbital (OF) and dermal (DF) fibroblasts. HA production of GO OFs (n = 4), NON-GO OFs (n = 4) and DFs (n = 4) was measured by ELISA. mRNA expression of enzymes of HA metabolism and fibroblast proliferation was examined by RT-PCR and BrdU incorporation, respectively. After 24 h of GC treatment (1µM) HA production decreased by an average of 67.9 ± 3.11% (p < 0.0001) in all cell cultures. HAS2, HAS3 and HYAL1 expression in OFs also decreased (p = 0.009, p = 0.0005 and p = 0.015, respectively). Ten ng/mL PDGF-BB increased HA production and fibroblast proliferation in all cell lines (p < 0.0001); GC treatment remained effective and reduced HA production under PDGF-BB-stimulated conditions (p < 0.0001). MP and DEX reduced (p < 0.001, p = 0.002, respectively) PDGF-BB-induced HAS2 expression in OFs. MP and DEX treatment decreased PDGF-BB stimulated HAS3 expression (p = 0.035 and p = 0.029, respectively). None of the GCs tested reduced the PDGF-BB stimulated proliferation rate. Our results confirm that GCs directly reduce the HA production of OFs, which may contribute to the beneficial effect of GCs in GO.

Lower educational status interferes with maternal iodine intake during both pregnancy and lactation.

OBJECTIVE: To investigate factors affecting conscious iodine intake among pregnant and lactating women in a rural area in Hungary. METHODS: Pregnant women were studied and followed during lactation. Urinary and breast milk iodine concentration (UIC and MIC) were measured by inductively coupled plasma mass spectrometry. Potential interfering factors, including age, educational status and smoking were assessed. RESULTS: During pregnancy and lactation, mild iodine deficiency was observed; median UIC were 66 and 49 µg/L, respectively. Educational status was found to be a strong determinant of both iodine nutrition and smoking status during pregnancy (P < 0.01 and P < 0.001) and lactation (P < 0.001 and P < 0.01). While smoking and non-smoking lactating mothers had similar concentrations of urinary iodine (median UIC: 47 and 51 µg/L, P = 0.95), the breast milk of smoking mothers contained less iodine (median MIC: 150 and 203 µg/L, P = 0.03). CONCLUSIONS: Both low iodine intake and smoking contribute to the higher risk of iodine deficiency in women with lower educational status. In smokers, MIC is often low in spite of normal UIC, presumably due to the iodine transport blocking effect of the cigarette smoke towards breast milk; normal UIC may be misinterpreted as sufficient iodine supply towards the child. Antenatal health promotion strategies should focus on young women with lower educational status, even in regions where sufficient iodine intake has been achieved in non-pregnant adults.

The 4G/5G Polymorphism of Plasminogen Activator Inhibitor Type 1 is a Predictor of Moderate-to-Severe Thyroid Eye Disease.

INTRODUCTION: Thyroid eye disease (TED) is an autoimmune disease of the orbits. Once developed, complete cure is rare. Plasminogen activator inhibitor type 1 (PAI-1) contributes to remodeling of connective tissue and has a central role in the pathogenesis of TED. We aimed to test if the 4G/5G polymorphism of PAI-1 is a predictor of the development of moderate-to-severe TED. METHODS: A total of 185 patients with Graves' disease, 87 of them with TED, 98 without TED, as well as 201 healthy controls, were studied. Genomic DNA was isolated from peripheral blood samples. The 4G/5G polymorphism of the PAI-1 gene was analyzed by allele-specific PCR, and the distribution of genotypes was calculated in each group. Plasma PAI-1 and thyroid hormone levels were measured by ELISA and ECLIA, respectively. RESULTS: The 4G/4G genotype was associated with the development of moderate-to-severe TED (OR = 2.54; 95% CI: 1.26-5.14; p < 0.01). The 4G/5G polymorphism of PAI-1 was not a predictor of plasma PAI-1 levels. CONCLUSION: The 4G/4G genotype of PAI-1 is a risk factor for the development of moderate-to-severe TED. Patients with Graves' disease who harbor this genotype may be candidates for special attention towards the development of TED.

New Formulations of Levothyroxine in the Treatment of Hypothyroidism: Trick or Treat?

Background: Levothyroxine (LT4) as a medication is used by up to 5.3% of the adult population. For optimal efficacy, the traditional tablet formulation (LT4tab) requires that patients avoid concomitant ingestion with food, drinks, and certain medications, as well as excellent patient compliance. Some comorbidities influence bioavailability of LT4 and may mandate repeated dose adjustments. Summary: New LT4 formulations (soft gel [LT4soft] and liquid [LT4liq]) containing predissolved LT4 are claimed to improve bioavailability, presumably by facilitating absorption. Thus, these formulations may well be more suitable than LT4tab for patients whose daily requirements are subjected to variations in bioavailability. Here, we review the evidence and indications for use of new LT4 formulations and highlight areas of uncertainty that are worthy of further investigation. While bioequivalence is established for LT4soft and LT4liq administered to healthy volunteers compared with LT4tab in pharmacokinetic (PK) studies, therapeutic equivalence of the new formulations seems to be different in several clinical settings. Some evidence suggests that new formulations of LT4 may mitigate against the strict requirements relating to concomitant ingestion with food, drinks, and certain medications, which apply to traditional LT4 tablets. The principal indication is in selected patients with disease fluctuations and intermittent therapies with interfering medications, where the need for frequent dose adjustments and office visits may be diminished. Whether the use of LT4soft or LT4liq in patients with impaired gastric acid secretion results in better control of hypothyroidism than LT4tab remains unclear. Conclusions: The evidence in favor of using LT4soft and LT4liq in clinical practice over LT4tab is weak, and the underlying putative PK mechanisms unclear. Additional studies to investigate these potential benefits, define the cost-effectiveness, and understand the PK mechanisms involved with new LT4 formulations are needed.

Characteristics of Hyaluronan Synthesis Inhibition by 4-Methylumbelliferone in Orbital Fibroblasts.

Purpose: Hyaluronan (HA) overproduction by orbital fibroblasts (OFs) is a major factor in the pathogenesis of Graves' orbitopathy (GO). 4-methylumbelliferone (4-MU) is an inhibitor of HA synthesis in different cell types in vitro and has beneficial effects in animal models of autoimmune diseases. Methods: HA production and mRNA expression of HA synthases (HAS1, HAS2, and HAS3) and hyaluronidases (HYAL1 and HYAL2) were measured in the presence and absence of 4-MU in unstimulated and transforming growth factor-ß-stimulated fibroblasts from GO orbital (n = 4), non-GO orbital (n = 4), and dermal origin (n = 4). Results: The 4-MU treatment (1 mM) for 24 hours resulted in an average 87% reduction (P < 0.001) of HA synthesis, decreased the expression of the dominant HAS isoform (HAS2) by 80% (P < 0.0001), and increased the HYAL2 expression by 2.5-fold (P < 0.001) in control OFs, GO OFs, and dermal fibroblasts (DFs) regardless of the origin of the cells. The proliferation rate of all studied cell lines was reduced to an average 16% by 4-MU (P < 0.0001) without any effects on cell viability. HA production stimulated by transforming growth factor-ß was decreased by 4-MU via inhibition of stimulated HAS1 expression in addition to the observed effects of 4-MU in unstimulated cases. Characteristics of HA synthesis inhibition by 4-MU did not differ in OFs compared with DFs. Conclusions: 4-MU has been found to inhibit the HA synthesis and the proliferation rate in OFs in vitro, adding it to the list of putative therapeutic agents in a disease the cure of which is largely unresolved.

Simplifying Complex Insulin Regimens While Preserving Good Glycemic Control in Type 2 Diabetes.

INTRODUCTION: Type 2 diabetic patients suffering from severe hyperglycemia are often assigned a regimen involving multiple daily injections (MDI) of insulin. If the glucose toxicity resolves, the regimen can potentially be simplified, but there are no guidelines for this, and many patients are left on the MDI regimen. We aimed to prospectively examine the safety and efficacy of switching from MDI to once-daily IDegLira, a fixed-ratio combination of insulin degludec and liraglutide, in relatively well controlled (HbA1c ≤ 7.5%) subjects with type 2 diabetes on a low total daily insulin dose (TDD). METHODS: 62 adults with type 2 diabetes (baseline age 64.06 ± 10.24 years, HbA1c 6.42 ± 0.68%, BMI 33.53 ± 6.90 kg/m2, body weight 93.81 ± 19.26 kg, TDD 43.31 ± 10.99 IU/day, insulin requirement 0.47 ± 0.13 IU/kg, duration of diabetes 10.84 ± 7.50 years, mean ± SD) treated with MDI ± metformin were enrolled in our study. Previous insulins were stopped and once-daily IDegLira was started. IDegLira was titrated by the patients to achieve a self-measured pre-breakfast blood glucose concentration of < 6 mmol/L. RESULTS: After a mean follow-up period of 99.2 days, mean HbA1c had decreased by 0.30% to 6.12 ± 0.65% (p < 0.0001), body weight had decreased by 3.11 kg to 90.70 ± 19.12 kg (p < 0.0001), and BMI had reduced to 32.39 ± 6.71 kg/m2 (p < 0.0001). After 3 months of treatment, the mean dose of IDegLira was 20.76 ± 6.60 units and the mean insulin requirement had decreased to 0.23 ± 0.08 IU/kg. IDegLira ± metformin combination therapy was found to be safe and generally well tolerated. During the month before the baseline visit, 28 patients (45%) had at least one episode of documented or symptomatic hypoglycemia, while only 6 (9.67%) patients reported a total of 13 documented episodes during the follow-up. CONCLUSION: In everyday clinical practice, switching from low-dose MDI to IDegLira in patients with well-controlled type 2 diabetes is safe, may result in weight loss and similar or better glycemic control, and substantially reduces the insulin requirement. Simplifying complex treatment regimens decreases treatment burden and may improve adherence to therapy. CLINICAL TRIAL NUMBER: NCT04020445.

Early Stage Graves' Disease is Uniformly Accompanied by Orbital Immune Activity even in Patients who Fail to Develop Orbithopathy during Follow-up.

PURPOSE: Graves' orbitopathy (GO) is a complication of Graves' disease (GD), the development of which cannot be predicted at the time of diagnosis of GD. Our aims were (i) to test if orbital 99mTc-labelled diethylenetriamine pentaacetic acid single-photon emission computer tomography (DTPA SPECT) can predict development of GO later during the course of the disease and (ii) to study whether orbital immune activity can be detected in GD patients who do not develop GO during follow-up. METHODS: Fifty-four orbits of 27 patients with newly diagnosed GD were entered into the case-control study. Individuals showing signs of GO at enrolment were excluded. During the two-year follow-up, eye signs were recorded every 3 months. Orbital DTPA uptakes on SPECT images were measured when entering the study and at the end of the follow-up period, or when clinical signs of GO developed, whichever occurred first. RESULTS: During the follow-up, 6 patients (22%) were diagnosed with GO. There was no significant difference between the initial DTPA uptakes of the patients with or without later developing GO (10.45±1.72 MBq/cm3 vs. 9.18±1.18 MBq/cm3 respectively). However, the DTPA uptakes of both GD groups (ie. with and without GO) were higher than that of the control group (7.45±1.36 MBq/cm3, p<0.05). CONCLUSIONS: We have shown that GD is accompanied by moderate orbital immune activity in GD patients without GO, irrespective of later development of GO. Why this orbital autoimmunity remains subclinical in the majority of the cases, and progresses into clinically detectable GO in others, remains unclear.

Thyroglobulin level at week 16 of pregnancy is superior to urinary iodine concentration in revealing preconceptual and first trimester iodine supply.

Pregnant women are prone to iodine deficiency due to the increased need for iodine during gestation. Progress has recently occurred in establishing serum thyroglobulin (Tg) as an iodine status biomarker, but there is no accepted reference range for iodine sufficiency during pregnancy. An observational study was conducted in 164 pregnant women. At week 16 of gestation urinary iodine concentration (UIC), serum Tg, and thyroid functions were measured, and information on the type of iodine supplementation and smoking were recorded. The parameters of those who started iodine supplementation (≥150 µg/day) at least 4 weeks before pregnancy (n = 27), who started at the detection of pregnancy (n = 51), and who had no iodine supplementation (n = 74) were compared. Sufficient iodine supply was found in the studied population based on median UIC (162 µg/L). Iodine supplementation ≥150 µg/day resulted in higher median UIC regardless of its duration (nonusers: 130 µg/L vs. prepregnancy iodine starters: 240 µg/L, and pregnancy iodine starters: 205 µg/L, p < .001, and p = .023, respectively). Median Tg value of pregnancy starters was identical to that of nonusers (14.5 vs. 14.6 µg/L), whereas prepregnancy starters had lower median Tg (9.1 µg/L, p = .018). Serum Tg concentration at week 16 of pregnancy showed negative relationship (p = .010) with duration of iodine supplementation and positive relationship (p = .008) with smoking, a known interfering factor of iodine metabolism, by multiple regression analysis. Serum Tg at week 16 of pregnancy may be a promising biomarker of preconceptual and first trimester maternal iodine status, the critical early phase of foetal brain development.

Plasminogen Activator Inhibitor Type 1: A Possible Novel Biomarker of Late Pituitary Dysfunction after Mild Traumatic Brain Injury.

More than 80% of traumatic brain injury (TBI) patients suffer from mild TBI (mTBI). However, even mTBI carries the risk of late pituitary dysfunction. A predictive biomarker at the time of injury that could identify patients who subsequently may develop permanent pituitary dysfunction would help to direct patients toward endocrine care. We enrolled 508 TBI patients (406 with mTBI) into our study. Blood samples were collected for identification of predictive biomarkers of late pituitary dysfunction at the time of admission. Follow-up blood samples were collected between 6 and 12 months after the TBI and were evaluated for pituitary function. Of the 406 mTBI patients, 76 were available for follow-up. Pre-existing mild pituitary dysfunction was found for 15 patients based on hormone levels at the time of injury. Of the remaining 61 patients, 10 have shown deficiency in at least one pituitary hormone: 4 had growth hormone deficiency, 3 gonadotropin, 2 thyrotropin, and 1 patient combined gonadotropin and thyrotropin deficiency. Hence, newly developed pituitary hormone deficiency was found in 16% of mTBI patients. Neither the cause of mTBI nor its complications were predictive of late pituitary dysfunction. Of the hemostasis parameters studied, lower plasminogen activator inhibitor type 1 (PAI-1) level at the time of injury was found to be predictive for the development of late pituitary dysfunction; sensitivity, specificity, and positive and negative predictive values were 80%, 67%, 32%, and 94%, respectively. Even mTBI carries a substantial risk of endocrine consequences. Serum PAI-1 level at the time of TBI may serve as a predictive biomarker of late pituitary dysfunction in mTBI patients.

Paraoxonase-1 and myeloperoxidase correlate with vascular biomarkers in overweight patients with newly diagnosed untreated hyperlipidaemia.

BACKGROUND: In hyperlipidaemic state, increased levels of myeloperoxidase (MPO) and decreased paraoxonase-1 (PON1) activity have been reported; however, their relationships with other atherosclerotic biomarkers have not been completely clarified. PATIENTS AND METHODS: Serum concentrations of lipid and inflammatory parameters, MPO levels, and PON1 activities were investigated in 167 untreated hyperlipidaemic patients with and without vascular complications and in 32 healthy controls. Additionally, levels of CD40 ligand (sCD40L) and asymmetric dimethyl arginine (ADMA), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1, and oxidized LDL were determined. RESULTS: We found elevated C-reactive protein (CRP), ADMA, sCD40L, sICAM-1 concentrations, and higher MPO levels in patients with vascular complications compared to those without. The PON1 arylesterase activity correlated negatively with sCD40L, ADMA, and sICAM-1 levels, respectively. In contrast, MPO concentrations showed positive correlations with sCD40L, ADMA, and sICAM-1 levels, respectively. CONCLUSIONS: It can therefore be stated that PON1 activity and MPO level correlate strongly with the vascular biomarkers, highlighting the importance of the HDL-associated pro- and antioxidant enzymes in the development of endothelial dysfunction and atherogenesis.

Paraoxonase-1 arylesterase activity is an independent predictor of myeloperoxidase levels in overweight patients with or without cardiovascular complications.

OBJECTIVES: Myeloperoxidase (MPO), matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) were shown to contribute to atherogenesis, while human paraoxonase-1 (PON1) protects against oxidative stress. Although several studies investigated these biomarkers, their associations have not been completely clarified yet. We aimed to investigate these parameters in overweight hyperlipidemic, lipid-lowering therapy-naive patients (n=167) with and without vascular complications. DESIGN AND METHODS: MPO, MMP-9 and TIMP-1 levels were measured by ELISA. PON1 activities were detected spectrophotometrically. PON1 phenotype was calculated by using a dual substrate method. RESULTS: Patients with vascular complications (VC) had significantly higher MPO and TIMP-1 levels compared to those without (patients with no vascular complications; NVC) (728 (367.25-1177.90) mg/ml vs. 315.9 (176.05-687.40) mg/ml; p<0.001; and 172.7 (157.7-197.7) ng/ml vs. 152.6 (129.3-172.3) ng/ml; p<0.0001; respectively). MPO levels showed a significant negative correlation with PON1 arylesterase activity (whole patient group (W): r=0.42, p<0.0001; VC: r=0.44, p=0.01; NVC: r=0.39, p<0.0001) and positive correlations with MMP-9 (W: r=0.37, p<0.0001; VC: r=0.29, p=0.07; NVC: r=0.42, p<0.0001) and TIMP-1 (W: r=0.42, p<0.0001; VC: r=0.33, p<0.05; NVC: r=0.41, p<0.0001), respectively. PON1 arylesterase activity was found to be an independent predictor of MPO levels in the whole patient group (ß=-0.350, p<0.0001) or when studied separately in the subgroups with or without cardiovascular complications (VC: ß=-0.57, p<0.05; NVC: ß=-0.33, p<0.0001). CONCLUSIONS: Our results suggest that parallel investigation of MPO, MMP-9 and TIMP-1 levels and PON1 arylesterase activity may be a more accurate indicator of atherosclerosis, which may allow earlier treatment and therefore, improvement of treatment efficacy.

Cell density-dependent stimulation of PAI-1 and hyaluronan synthesis by TGF-ß in orbital fibroblasts.

During the course of Graves' orbitopathy (GO), orbital fibroblasts are exposed to factors that lead to proliferation and extracellular matrix (ECM) overproduction. Increased levels of tissue plasminogen activator inhibitor type 1 (PAI-1 (SERPINE1)) might promote the accumulation of ECM components. PAI-1 expression is regulated by cell density and various cytokines and growth factors including transforming growth factorß(TGF-ß). We examined the effects of increasing cell densities and TGF-ß on orbital fibroblasts obtained from GO patients and controls. Responses were evaluated by the measurement of proliferation, PAI-1 expression, and ECM production. There was an inverse correlation between cell density and the per cell production of PAI-1. GO orbital, normal orbital, and dermal fibroblasts behaved similarly in this respect. Proliferation rate also declined with increasing cell densities. Hyaluronan (HA) production was constant throughout the cell densities tested in all cell lines. In both GO and normal orbital fibroblasts, but not in dermal fibroblasts, TGF-ß stimulated PAI-1 production in a cell density-dependent manner, reaching up to a five-fold increase above baseline. This has been accompanied by increased HA secretion and pericellular HA levels at high cell densities. Increasing cell density is a negative regulator of proliferation and PAI-1 secretion both in normal and GO orbital fibroblasts; these negative regulatory effects are partially reversed in the presence of TGF-ß. Cell density-dependent regulation of PAI-1 expression in the orbit, together with the local cytokine environment, may have a regulatory role in the turnover of the orbital ECM and may contribute to the expansion of orbital soft tissue in GO.

[Novel treatment opportunities in Graves' orbitopathy]. / Új lehetoségek az endokrin orbitopathia kezelésében.

Graves' orbitopathy is the most common extrathyroidal manifestation of Graves' disease. Up to now, curative treatment modalities for the most severe sight-threatening cases have not been developed. Here the authors summarize the treatment protocol of Graves' orbitopathy and review novel therapeutic options. They review the literature on this topic and present their own clinical experience. The authors point out that anti-CD20 antibody could positively influence the clinical course of Graves' orbitopathy. Selenium is efficient in mild cases. Further prospective investigations are warranted.

[Laboratory diagnosis of a rare congenital neurodegenerative disease: cerebrotendinous xanthomatosis]. / Egy ritka, veleszületett neurodegeneratív betegség: a cerebrotendinosus xanthomatosis laboratóriumi diagnosztikája.

Cerebrotendinous xanthomatosis is a rare neurodegenerative disease characterized by the accumulation of cholesterol and cholestanol in the brain and the tendons caused by mutations of the gene encoding sterol 27-hydroxylase (CYP27A1), which is involved in bile acid synthesis. The diagnosis is often missed and delayed because of the variable clinical presentation of the disease. Blood testing for cerebrotendinous xanthomatosis is routinely performed using gas chromatography-mass spectrometry measurement of elevated cholestanol level, and the diagnosis is confirmed by molecular genetic analysis. Early recognition and initiation of chenodeoxycholic acid therapy with hydoxymethyl­glutaryl­Coenzyme-A reductase inhibitors is critical to prevent irreversible neurological damage and permanent disability. The authors summarize the current knowledge about the pathomechanism, laboratory diagnosis and therapeutic options of cerebrotendinous xanthomatosis.