CORRELATES OF IN-HOSPITAL MORTALITY IN PATIENTS WITH ACUTE CORONARY SYNDROME IN KOSOVO.

It has been demonstrated that pre-hospital emergency care reduces in-hospital mortality in patients admitted with acute coronary syndrome (ACS). The aim of this study was to analyze the relationship between pre-hospital emergency care and in-hospital mortality in ACS patients treated at the University Clinical Centre of Kosovo Emergency Department (UCCK ED). This observational clinical study included 1498 ACS patients treated at UCCK ED and followed-up by phone call for one year after discharge from the hospital. According to multivariate Cox regression analysis, age (HR=2.37, 95% CI 1.67-3.52), pre-hospital emergency care (HR=3.92, 95% CI 2.35-6.54), STEMI (HR=6.17, 95% CI 3.22-15.31), diabetes mellitus (HR=3.01, 95% CI 1.98-3.78), left ventricular ejection fraction <40% (HR=17.63, 95% CI 11.2-30.54) and ex-smoking (HR=2.34, 95% CI 1.57-3.85) were significant predictors of mortality in ACS patients. In-hospital mortality of patients admitted with ACS remains high in Kosovo as compared with developed countries. A better strategy for pre-hospital emergency care in Kosovo is recommended to save lives in these high-risk patients.

Fluvastatin Reduces Glucose Tolerance in Healthy Young Individuals Independently of Cold Induced BAT Activity.

Background: Statins are commonly prescribed for primary and secondary prevention of atherosclerotic disease. They reduce cholesterol biosynthesis by inhibiting hydroxymethylglutaryl-coenzyme A-reductase (HMG-CoA-reductase) and therefore mevalonate synthesis. Several studies reported a small, but significant increase in the diagnosis of diabetes mellitus with statin treatment. The molecular mechanisms behind this adverse effect are not yet fully understood. Brown adipose tissue (BAT), which plays a role in thermogenesis, has been associated with a reduced risk of insulin resistance. Statins inhibit adipose tissue browning and have been negatively linked to the presence of BAT in humans. We therefore speculated that inhibition of BAT by statins contributes to increased insulin resistance in humans. Methods: A prospective study was conducted in 17 young, healthy men. After screening whether significant cold-induced thermogenesis (CIT) was present, participants underwent glucose tolerance testing (oGTT) and assessment of BAT activity by FDG-PET/MRI after cold-exposure and treatment with a ß3-agonist. Fluvastatin 2x40mg per day was then administered for two weeks and oGTT and FDG-PET/MRI were repeated. Results: Two weeks of fluvastatin treatment led to a significant increase in glucose area under the curve (AUC) during oGTT (p=0.02), reduction in total cholesterol and LDL cholesterol (both p<0.0001). Insulin AUC (p=0.26), resting energy expenditure (REE) (p=0.44) and diet induced thermogenesis (DIT) (p=0.27) did not change significantly. The Matsuda index, as an indicator of insulin sensitivity, was lower after fluvastatin intake, but the difference was not statistically significant (p=0.09). As parameters of BAT activity, mean standard uptake value (SUVmean) (p=0.12), volume (p=0.49) and total glycolysis (p=0.74) did not change significantly during the intervention. Matsuda index, was inversely related to SUVmean and the respiratory exchange ratio (RER) (both R2 = 0.44, p=0.005) at baseline, but not after administration of fluvastatin (R2 = 0.08, p=0.29, and R2 = 0.14, p=0.16, respectively). Conclusions: Treatment with fluvastatin for two weeks reduced serum lipid levels but increased glucose AUC in young, healthy men, indicating reduced glucose tolerance. This was not associated with changes in cold-induced BAT activity.

Relation of diet-induced thermogenesis to brown adipose tissue activity in healthy men.

Human brown adipose tissue (BAT) is a thermogenic tissue activated by the sympathetic nervous system in response to cold exposure. It contributes to energy expenditure (EE) and takes up glucose and lipids from the circulation. Studies in rodents suggest that BAT contributes to the transient rise in EE after food intake, so-called diet-induced thermogenesis (DIT). We investigated the relationship between human BAT activity and DIT in response to glucose intake in 17 healthy volunteers. We assessed DIT, cold-induced thermogenesis (CIT), and maximum BAT activity at three separate study visits within 2 wk. DIT was measured by indirect calorimetry during an oral glucose tolerance test. CIT was assessed as the difference in EE after cold exposure of 2-h duration as compared with warm conditions. Maximal activity of BAT was assessed by 18-F-fluoro-deoxyglucose (18F-FDG) 18F-FDG-PET/MRI after cold exposure and concomitant pharmacological stimulation with mirabegron. Seventeen healthy men (mean age = 23.4 yr, mean body mass index = 23.2 kg/m2) participated in the study. EE increased from 1,908 (±181) kcal/24 h to 2,128 (±277) kcal/24 h (P < 0.0001, +11.5%) after mild cold exposure. An oral glucose load increased EE from 1,911 (±165) kcal/24 h to 2,096 (±167) kcal/24 h at 60 min (P < 0.0001, +9.7%). The increase in EE in response to cold was significantly associated with BAT activity (R2 = 0.43, P = 0.004). However, DIT was not associated with BAT activity (R2 = 0.015, P = 0.64). DIT after an oral glucose load was not associated with stimulated 18F-FDG uptake into BAT, suggesting that DIT is independent from BAT activity in humans (Clinicaltrials.gov Registration No. NCT03189511).NEW & NOTEWORTHY Cold-induced thermogenesis (CIT) was related to BAT activity as determined by FDG-PET/MRI after stimulation of BAT. Diet-induced thermogenesis (DIT) was not related to stimulated BAT activity. Supraclavicular skin temperature was related to CIT but not to DIT. DIT in humans is probably not a function of BAT.

Low-dose 18F-FDG TOF-PET/MR for accurate quantification of brown adipose tissue in healthy volunteers.

BACKGROUND: Positron emission tomography (PET) is increasingly applied for in vivo brown adipose tissue (BAT) research in healthy volunteers. To limit the radiation exposure, the injected 18F-FDG tracer dose should be as low as possible. With simultaneous PET/MR imaging, the radiation exposure due to computed tomography (CT) can be avoided, but more importantly, the PET acquisition time can often be increased to match the more extensive magnetic resonance (MR) imaging protocol. The potential gain in detected coincidence counts, due to the longer acquisition time, can then be applied to decrease the injected tracer dose. The aim of this study was to investigate the minimal 18F-FDG dose for a 10-min time-of-flight (TOF) PET/MR acquisition that would still allow accurate quantification of supraclavicular BAT volume and activity. METHODS: Twenty datasets from 13 volunteers were retrospectively included from a prospective clinical study. PET emission datasets were modified to simulate step-wise reductions of the original 75 MBq injected dose. The resulting PET images were visually and quantitatively assessed and compared to a 4-min reference scan. For the visual assessment, the image quality and artifacts were scored using a 5-point and a 3-point Likert scale. For the quantitative analysis, image noise and artifacts, BAT metabolic activity, BAT metabolic volume (BMV), and total BAT glycolysis (TBG) were investigated. RESULTS: The visual assessment showed still good image quality for the 35%, 30%, and 25% activity reconstructions with no artifacts. Quantitatively, the background noise was similar to the reference for the 35% and 30% activity reconstructions and the artifacts started to increase significantly in the 25% and lower activity reconstructions. There was no significant difference in supraclavicular BAT metabolic activity, BMV, and TBG between the reference and the 35% to 20% activity reconstructions. CONCLUSIONS: This study indicates that when the PET acquisition time is matched to the 10-min MRI protocol, the injected 18F-FDG tracer dose can be reduced to approximately 19 MBq (25%) while maintaining image quality and accurate supraclavicular BAT quantification. This could decrease the effective dose from 1.4 mSv to 0.36 mSv.

MRI characteristics of supraclavicular brown adipose tissue in relation to cold-induced thermogenesis in healthy human adults.

BACKGROUND: Brown adipose tissue (BAT) has been proposed as a target to treat obesity and metabolic disease. Currently, 18 F-Fluordeoxyglucose positron emission tomography (FDG-PET) is the standard for BAT-imaging. MRI might be a promising alternative, as it is not associated with ionizing radiation, offers a high resolution, and allows to discriminate different types of soft tissue. PURPOSE: We sought to evaluate whether supraclavicular BAT (scBAT) volume, fat-fraction (FF), and relaxation rate (R2*) determined by MRI can predict its metabolic activity, which was assessed by measurement of cold-induced thermogenesis (CIT). STUDY TYPE: Prospective cohort study. SUBJECTS: Twenty healthy volunteers (9 female, 11 male), aged 18-47 years, with a body mass index (BMI) of 18-30 kg/m2 . FIELD STRENGTH/SEQUENCE: Multiecho gradient MRI for water-fat separation was used on a 3T device to measure the FF and T2 * of BAT. ASSESSMENT: Prior to imaging, CIT was determined by measuring the difference in energy expenditure (EE) during warm conditions and after cold exposure. Volume, FF, and R2* of scBAT was assessed and compared with CIT. In 11 participants, two MRI sessions with and without cold exposure were performed and the dynamic changes in FF and R2* assessed. STATISTICAL TESTS: Linear regression was used to evaluate the relation of MRI measurements and CIT. P-values below 0.05 were considered significant; data are given as mean ± SD. RESULTS: R2* correlated positively with CIT (r = 0.64, R2 = 0.41 P = 0.0041). Volume and FF did not correlate significantly with CIT. After mild cold exposure EE increased significantly (P = 0.0002), with a mean CIT of 147 kcal/day. The mean volume of scBAT was 72.4 ± 38.4 ml, mean FF was 74.3 ± 5.8%, and the mean R2* (1/T2 *) was 33.5 ± 12.7 s-1 . DATA CONCLUSION: R2* of human scBAT can be used to estimate CIT. FF of scBAT was not associated with CIT. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1160-1168.

Resolution of Hypothyroidism Restores Cold-Induced Thermogenesis in Humans.

BACKGROUND: Hypothyroidism is a frequent endocrine disorder with common symptoms of increased cold sensitivity and unintended weight gain, indicating changes in energy expenditure (EE) and response to cold exposure. Thyroid hormones (TH) play an important role for proper function of brown adipose tissue (BAT) and cold-induced thermogenesis (CIT) in rodents, but the role of hypothyroidism on CIT in humans is uncertain. METHODS: This was a prospective observational study. Forty-two patients presenting with subclinical or overt hypothyroidism in whom TH replacement was planned were recruited. Thirty-three patients completed the study. Thermogenesis was measured by indirect calorimetry during warm conditions and after a mild cold stimulus of 90 minutes, both during the hypothyroid state and after at least three months of sufficient TH replacement. CIT was determined as the difference between EE during mildly cold and warm conditions. The primary endpoint was the change of CIT between the hypothyroid and euthyroid state. RESULTS: EE during warm conditions increased from a median of 1330 (interquartile range [IQR] 1251-1433) kcal/24 hours in the hypothyroid state to a median of 1442 (IQR 1294-1579) kcal/24 hours in the euthyroid state (+8.5%; p = 0.0002). EE during mild cold exposure increased from 1399 (IQR 1346-1571) kcal/24 hours to 1610 (IQR 1455-1674) kcal/24 hours (+15%; p < 0.0001). The median CIT was 55 (IQR 1-128) kcal/24 hours at the baseline visit, after restoration of euthyroidism CIT increased by 102% to a median of 111 (IQR 15.5-200) kcal/24 hours (p = 0.011). Serum levels of free thyroxine at the respective visit and mean outdoor temperature during the preceeding 30 days were significantly associated with CIT (p = 0.021 and p = 0.001, respectively). CONCLUSION: Restoring euthyroidism significantly increases CIT in hypothyroid humans.

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation.

Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.

Outdoor Temperature Influences Cold Induced Thermogenesis in Humans.

Objective: Energy expenditure (EE) increases in response to cold exposure, which is called cold induced thermogenesis (CIT). Brown adipose tissue (BAT) has been shown to contribute significantly to CIT in human adults. BAT activity and CIT are acutely influenced by ambient temperature. In the present study, we investigated the long-term effect of seasonal temperature variation on human CIT. Materials and Methods: We measured CIT in 56 healthy volunteers by indirect calorimetry. CIT was determined as difference between EE during warm conditions (EEwarm) and after a defined cold stimulus (EEcold). We recorded skin temperatures at eleven anatomically predefined locations, including the supraclavicular region, which is adjacent to the main human BAT depot. We analyzed the relation of EE, CIT and skin temperatures to the daily minimum, maximum and mean outdoor temperature averaged over 7 or 30 days, respectively, prior to the corresponding study visit by linear regression. Results: We observed a significant inverse correlation between outdoor temperatures and EEcold and CIT, respectively, while EEwarm was not influenced. The daily maximum temperature averaged over 7 days correlated best with EEcold (R2 = 0.123, p = 0.008) and CIT (R2 = 0.200, p = 0.0005). The mean skin temperatures before and after cold exposure were not related to outdoor temperatures. However, the difference between supraclavicular and parasternal skin temperature after cold exposure was inversely related to the average maximum temperature during the preceding 7 days (R2 = 0.07575, p = 0.0221). Conclusion: CIT is significantly related to outdoor temperatures indicating dynamic adaption of thermogenesis and BAT activity to environmental stimuli in adult humans. Clinical Trial Registration: www.ClinicalTrials.gov, Identifier NCT02682706.

Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the "Co-MED study".

BACKGROUND: Hypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C-terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia. METHODS: In this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured. RESULTS: The most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P < 0.01). Patients with CDI had lower copeptin levels than patients with DH or SO (both P < 0.01) or those with NDI. Copeptin identified CDI with an AUC of 0.99 (95% CI 0.97-1.00), and a cut-off value ≤ 4.4pmol/L showed a sensitivity of 100% and a specificity of 99% to predict CDI. Similarly, urea values were lower in CDI than in DH or SO (P < 0.05 and P < 0.01, respectively) or NDI. The AUC for diagnosing CDI was 0.98 (95% CI 0.96-1.00), and a cut-off value < 5.05 mmol/L showed high specificity and sensitivity for the diagnosis of CDI (98% and 100%, respectively). Copeptin and urea could not differentiate hypernatraemia induced by DH from that induced by SO (P = 0.66 and P = 0.30, respectively). CONCLUSIONS: Copeptin and urea reliably identify patients with CDI and are therefore helpful tools for therapeutic management in patients with severe hypernatraemia. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01456533 . Registered on 20 October 2011.

Development of a New Device for Synovial Biopsies.

BACKGROUND: Synovial biopsy is a reliable procedure that permits the identification of specific pathologies. Currently available needles for blind synovial biopsy usually consist of 2 components. We designed a novel 1-piece device for blind and minimal invasive synovial biopsy of the knee joint. METHODS: A convex-shaped trocar with internal sharp plunger at the distal end and a fluid channel was engineered. Synovial biopsy of the suprapatellar recessus of the knee was performed in 8 different cadavers. The intra-articular position of the tip was confirmed by aspiration of prior injected saline fluid. The trocar was levered upward with the open notch of the device facing the anterior wall of the recessus. Then, the punch mechanism was closed and the device removed. Routine histology of the obtained tissue was performed. After the intervention, the joints were prepared for macroscopic inspection of the synovial tissue, including penetration and biopsy sites. RESULTS: Fifteen interventions were performed. In all cases, sufficient synovial tissue was obtained. Mean length of the biopsies was 2.4 mm (range 2.0-4.3 mm) and width was 2.0 mm (range 1.4-2.6 mm). Inside the suprapatellar recessus, the mean distance from the entry site of the device to the biopsy site was 3.8 cm (range 1.1-3.4 cm). Histological analysis confirmed synovial and capsule tissue in all cases. CONCLUSION: This new device is a potentially useful tool for quick synovial biopsy of the knee in the clinical setting.

The relief formed by the descent phenomenon in the north-east part of Kosova.

In the diverse relief of north-east part of Kosova a relatively wide range occupies the relief modelled by the descent phenomenon, which is conditioned by morph-structural and climatic factors quite suitable for their development. The morphogenesis activity of descent phenomenon is conditioned by the types of rocks, tectonic process of this region and climatic conditions. These factors condition horizontal and vertical relief fragmentation, slope, especially in Gollaku mountains and in SE part of Kopaonik mountain. Along the tectonic descents, the steepness is detaching and the detaching lines consisting of magmatic rocks show overthrows, demolitions and stony torrents, but the Teri gene composition formations are modelled by sliding and muddy torrents, depending upon the presence of clayey and alevrolite belts on these Teri gene ones. The impact of factors and conditions on the relief of this part, the phenomena like demolitions, overthrows, sliding, muddy torrents, stony torrents, etc, operate here, which play an important morphological role in the modelling of relief.