CBD supplementation reduces arterial blood pressure via modulation of the sympatho-chromaffin system: A substudy from the HYPER-H21-4 trial.

Data concerning the effects of cannabidiol (CBD) on blood pressure (BP) is controversial. HYPER-H21-4 was a randomized, placebo-controlled, crossover trial which sought to elucidate if 5-week administration of CBD will reduce BP in hypertensive patients. In the substudy of this trial, we aimed to establish the mechanistic background of CBD-induced BP reduction. Specifically, we explored the dynamic of catestatin, a sympathoinhibitory peptide implicated in the pathophysiology of hypertension. In the present analysis, 54 patients with Grade 1 hypertension were included. 5-week administration of CBD but not placebo reduced serum catestatin concentration in comparison to baseline (13.50 [10.85-19.05] vs. 9.65 [6.37-12.26] ng/mL, p < 0.001). Serum catestatin levels at the start of the treatment period demonstrated a negative correlation with the extent of reduction in mean arterial pressure (r = -0.474, p < 0.001). Moreover, the extent of change in catestatin serum levels showed a strong correlation with the extent of mean arterial pressure reduction (r = 0.712, p < 0.001). Overall, the results of the present study imply that the antihypertensive effects of CBD may be explained by its interaction with the sympatho-chromaffin system, although further research is warranted.

Emerging Biomarkers for Early Detection of Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major and serious global health problem that leads to kidney damage as well as multiple systemic diseases. Early diagnosis and treatment are two major measures to prevent further deterioration of kidney function and to delay adverse outcomes. However, the paucity of early, predictive and noninvasive biomarkers has undermined our ability to promptly detect and treat this common clinical condition which affects more than 10% of the population worldwide. Despite all limitations, kidney function is still measured by serum creatinine, cystatin C, and albuminuria, as well as estimating glomerular filtration rate using different equations. This review aims to provide comprehensive insight into diagnostic methods available for early detection of CKD. In the review, we discuss the following topics: (i) markers of glomerular injury; (ii) markers of tubulointerstitial injury; (iii) the role of omics; (iv) the role of microbiota; (v) and finally, the role of microRNA in the early detection of CKD. Despite all novel findings, none of these biomarkers have met the criteria of an ideal early marker. Since the central role in CKD progression is the proximal tubule (PT), most data from the literature have analyzed biomarkers of PT injury, such as KIM-1 (kidney injury molecule-1), NGAL (neutrophil gelatinase-associated lipocalin), and L-FABP (liver fatty acid-binding protein).

Knowledge, Attitudes, and Screening for Obstructive Sleep Apnea and Diabetes Mellitus among War Veterans Seeking Treatment of Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is one of the most common psychiatric disorders. However, we should not neglect the somatic aspects of PTSD. Associations with cardiovascular diseases (CVD) are particularly concerning because PTSD was associated with an even 53% higher risk for CVD. This study aimed to analyze the prevalence of several CVD risk factors, especially diabetes mellitus among PTSD patients divided into three groups according to obstructive sleep apnea (OSA) risk stratification (low, intermediate, and high). This cross-sectional study included one hundred male PTSD veterans. The mean age was 53 (40-67) years. The estimated OSA risk was 95% for the whole cohort, and 53% were in the high-risk group. Median HbA1c was 5.6 (4.6-10)%. The hemoglobin A1c (HbA1c) levels showed that 34 patients were in the prediabetes group, and 20 of them fulfilled the criteria for diabetes. However, only 13 of them were aware of their previous diagnosis of diabetes mellitus. In testing knowledge about diabetes, 62% and only 23% of patients knew the correct definition of HbA1c and level of fasting plasma glucose, respectively. Diabetic patients had insufficient knowledge about diabetic complications and treatment. A higher level of PTSD symptoms in veterans was associated with a higher prevalence of OSA. The results strongly support further research and education into early detection of CVD risk factors associated with PTSD.

Carbohydrate Antigen 125: A Biomarker at the Crossroads of Congestion and Inflammation in Heart Failure.

Because heart failure (HF) is more lethal than some of the common malignancies in the general population, such as prostate cancer in men and breast cancer in women, there is a need for a cost-effective prognostic biomarker in HF beyond natriuretic peptides, especially concerning congestion, the most common reason for the hospitalisation of patients with worsening of HF. Furthermore, despite diuretics being the mainstay of treatment for volume overload in HF patients, no randomised trials have shown the mortality benefits of diuretics in HF patients, and appropriate diuretic titration strategies in this population are unclear. Recently, carbohydrate antigen (CA) 125, a well-established marker of ovarian cancer, emerged as both a prognostic indicator and a guide in tailoring decongestion therapy for patients with HF. Hence, in this review the authors present the molecular background regarding the role of CA125 in HF and address valuable clinical aspects regarding the relationship of CA125 with both prognosis and therapeutic management in HF.

Association of Dephosphorylated-Uncarboxylated Matrix Gla Protein and Risk of Major Bleeding in Patients Presenting with Acute Myocardial Infarction.

The "Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines" (CRUSADE) score emerged as a predictor of major bleeding in patients presenting with the acute coronary syndrome. On the other hand, previous studies established the association of dephosphorylated-uncarboxylated Matrix Gla protein (dp-ucMGP) and vitamin K, as well as their subsequent impact on coagulation cascade and bleeding tendency. Therefore, in the present study, we explored if dp-ucMGP plasma levels were associated with CRUSADE bleeding score. In this cross-sectional study, physical examination and clinical data, including plasma dp-ucMGP levels, were obtained from 80 consecutive patients with acute myocardial infarction (AMI). A significant positive correlation was found between CRUSADE bleeding score and both dp-ucMGP plasma levels (r = 0.442, p < 0.001) and risk score of in-hospital mortality (r = 0.520, p < 0.001), respectively. In comparing the three risk groups of risk for in-hospital bleeding, the high/very high-risk group had significantly higher dp-ucMGP levels from both very low/low group (1277 vs. 794 pmol/L, p < 0.001) and the moderate group (1277 vs. 941 pmol/L, p = 0.047). Overall, since higher dp-ucMGP levels were associated with elevated CRUSADE score and prolonged hemostasis parameters, this may suggest that there is a biological link between dp-ucMGP plasma levels and the risk of bleeding in patients who present with AMI.

Serum Adropin Levels in Patients on Hemodialysis.

Adropin is a novel pleotropic peptide involved in energy homeostasis, with possible contribution to cardiovascular protection through production of nitric oxide and subsequent blood pressure regulation. Given that patients undergoing hemodialysis (HD) are related with high cardiovascular risk, hyperlipidemia, chronic low-grade inflammation, and malnutrition the aim of our study was to investigate serum adropin levels in HD patients to evaluate possible associations with nutritional status and other relevant clinical and laboratory parameters. The study included 70 patients on HD and 60 healthy controls. Serum adropin levels were determined by an enzyme-linked immunosorbent assay in a commercially available diagnostic kit. Serum adropin levels were significantly lower in the HD group compared to the control group (2.20 ± 0.72 vs. 4.05 ± 0.93 ng/mL, p < 0.001). Moreover, there was a significant negative correlation with malnutrition-inflammation score (r = -0.476, p < 0.001), dialysis malnutrition score (r = -0.350, p = 0.003), HD duration (r = -0.305, p = 0.010), and high sensitivity C-reactive protein (hsCRP) (r = -0.646, p < 0.001). Additionally, there was a significant negative correlation between adropin levels and pre-dialysis systolic (r = -0.301, p = 0.011) and diastolic blood pressure (r = -0.299, p = 0.011). These results are implying that adropin is potentially involved in the pathophysiological mechanisms of chronic kidney disease (CKD)/HD and its complications. However, future larger scale longitudinal studies need to further address it.

Clinical Implications of Uric Acid in Heart Failure: A Comprehensive Review.

Affecting more than 26 million people worldwide and with rising prevalence, heart failure (HF) represents a major global health problem. Hence, further research is needed in order to abate poor HF outcomes and mitigate significant expenses that burden health care systems. Based on available data, experts agree that there is an urgent need for a cost-effective prognostic biomarker in HF. Although a significant number of biomarkers have already been investigated in this setting, the clinical utility of adding biomarker evaluation to routine HF care still remains ambiguous. Specifically, in this review we focused on uric acid (UA), a purine metabolism detriment whose role as cardiovascular risk factor has been exhaustingly debated for decades. Multiple large population studies indicate that UA is an independent predictor of mortality in acute and chronic HF, making it a significant prognostic factor in both settings. High serum levels have been also associated with an increased incidence of HF, thus expanding the clinical utility of UA. Importantly, emerging data suggests that UA is also implicated in the pathogenesis of HF, which sheds light on UA as a feasible therapeutic target. Although to date clinical studies have not been able to prove the benefits of xanthine oxidase in HF patients, we discuss the putative role of UA and xanthine oxidase in the pathophysiology of HF as a therapeutic target.

The Role of Natural Killer (NK) Cells in Acute Coronary Syndrome: A Comprehensive Review.

With poor outcomes and an immense financial burden, acute coronary syndrome (ACS) and its ischemic repercussions still present a major global health problem. Unfavorable outcomes seem to be mainly due to adverse cardiac remodeling. Since the inflammatory response takes an important role in remodeling secondary to myocardial infarction (MI), and as inflammation in this manner has not been completely elucidated, we attempted to give rise to a further understanding of ACS pathophysiology. Hence, in this review, we integrated current knowledge of complex communication networks between natural killer (NK) cells and immune and resident heart cells in the context of ACS. Based on available data, the role of NK cells seems to be important in the infarcted myocardium, where it affects heart remodeling. On the other hand, in atherosclerotic plaque, NK cells seem to be mere passers-by, except in the case of chronic infections by atherogenic pathogens. In that case, NK cells seem to support proinflammatory milieu. NK cell research is challenging due to ethical reasons, convergent evolution, and phenotypic diversity among individuals. Therefore, we argue that further research of NK cells in ACS is valuable, given their therapeutic potential in improving postischemic heart remodeling.

Hypoglycemia and Glucagon Utilization in Insulin-Treated Diabetic Patients.

BACKGROUND: First choice of therapy for severe hypoglycemia outside hospital environment is glucagon injection, an undertaught and underused remedy. Aim of this study was to investigate knowledge about glucagon therapy, possession rate and usage rate in insulin-treated diabetic patients, with special emphasis on history of hypoglycemia and severe hypoglycemia episodes. METHODS: In this cross-sectional study, 300 insulin-treated diabetic patients (146 males and 154 females, mean age 61.1±16.4 years) were recruited from comprehensive Diabetes Center in Croatia. Specialized self-administered, 13-item questionnaire regarding glucagon therapy and history of hypoglycemia was obtained from each patient, as well as data collected from medical history documentation. RESULTS: Experience of hypoglycemic episode was reported by 233 (77.7%), and severe hypoglycemia by 73 (24.3%) patients. Participants with experience of hypoglycemia have significantly longer diabetes duration (17.2±11.2 vs. 11.9±8.5 years, P<0.001) and lower BMI values (26.38±3.97 vs. 31.11±7.17 kg/m2, P<0.001). Knowledge about glucagon therapy had 55.3% patients, 44.7% obtained it from the pharmacy, while glucagon was used in 35.6% cases of severe hypoglycemia. Glucagon knowledge was better in patients that attended at least one diabetes lecture (P=0.038), while educational level showed no statistical significance (P=0.286). Main significant positive predictor of glucagon knowledge was history of severe hypoglycemia (OR 4.71, 95% CI 1.38 - 16.02, P=0.013). CONCLUSIONS: Glucagon therapy was underused in treating severe hypoglycemia. It is highly important to emphasize value of quality education as one of the fundamentals of good diabetes management.

Adropin and Inflammation Biomarker Levels in Male Patients With Obstructive Sleep Apnea: A Link With Glucose Metabolism and Sleep Parameters.

STUDY OBJECTIVES: The main objectives of the study were to determine plasma adropin, systemic inflammation biomarker levels, and glucose metabolism parameters in patients with moderate and severe obstructive sleep apnea (OSA) compared to healthy controls. METHODS: In this study, we included 50 male patients with OSA (25 moderate and 25 severe) and 25 age- and sex-matched control subjects. All subjects underwent fasting sampling of peripheral blood for laboratory analyses. RESULTS: Adropin plasma levels were significantly lower in the severe OSA group in comparison with the moderate and control groups (4.50 ± 1.45 versus 6.55 ± 1.68 versus 8.15 ± 1.79 ng/mL, P < .001). Plasma biomarkers of systemic inflammation were significantly increased in patients with moderate OSA (interleukin [IL]-6 and tumor necrosis factor alpha [TNF-α]) and severe OSA (IL-6, TNF-α, high-sensitivity C-reactive protein) when compared with controls (P < .001). Adropin levels showed a significant negative correlation with IL-6 (r = -.419, P < .001), TNF-α (r = -.540, P < .001), fasting glucose (r = -.331, P = .004), hemoglobin A1c (r = -.438, P < .001), homeostatic model assessment insulin resistance index (r = -.213, P = .046), and polysomnographic parameters including apnea-hypopnea index (r = -.615, P < .001) and oxygen desaturation index (r = -.573, P < .001). A multivariate regression analysis showed that plasma adropin remained as a significant negative predictor of severe OSA status, when adjusted for age and body mass index and computed along with other inflammatory biomarkers in the regression model (odds ratio 0.069, 95% confidence interval 0.009-0.517, P = .009). CONCLUSIONS: Plasma adropin concentrations significantly correlate with indices of disease severity in patients with OSA, suggesting that adropin potentially plays an important role in the complex pathophysiology of the disease.

The effectiveness of lixisenatide as an add on therapy to basal insulin in diabetic type 2 patients previously treated with different insulin regimes: a multi-center observational study.

INTRODUCTION: This observational study aimed to assess the effectiveness of lixisenatide as add on therapy to basal insulin in diabetic type 2 patients previously treated with different insulin regimes. METHODS: Patients with diabetes type 2, prescribed with lixisenatide and basal insulin were divided in three groups (premixed insulin, basal bolus insulin and basal oral therapy (BOT). Difference in mean change in HbA1c, body mass index, total insulin doses, fasting blood glucose (FPG) and prandial blood glucose (PPG) were assessed after 3-6-months of follow-up. RESULTS: The primary outcomes were assessed in 111 patients. Lixisenatide added to basal insulin, reduced HbA1c and body weight significantly in all three groups of patients (p < 0.001 for all), with the most prominent reduction in the basal bolus group of patients which had the highest baseline HbA1c compared to premix and BOT treatment groups. Regarding a difference in total insulin dose the reduction was statistically significant in the basal bolus (p = 0.006) and premix group (p < 0.001). FPG and PPG were also significantly reduced over time in all three groups (p < 0.001 for all). A composite outcome (reduction of HbA1c below 7% (53 mmol/mol) with any weight loss) was achieved in 27% of total patients included in the study, reduction of HbA1c below 7% was observed in 30% of patients, while 90% of patients experienced weight reduction. CONCLUSION: These results indicate that lixisenatide add on basal insulin treatment (BIT) can improve glycemic control in a population with long-standing type 2 diabetes and previously uncontrolled on other insulin therapy.

[CROATIAN GUIDELINES FOR THE PHARMACOTHERAPY OF TYPE 2 DIABETES]. / HRVATSKE SMJERNICE ZA FARMAKOLOSKO LIJECENJE SECERNE BOLESTI TIPA 2.

INTRODUCTION: The Croatian Association for Diabetes and Metabolic Disorders of the Croatian Medical Association has issued in 2011 the first national guidelines for the nutrition, education, self-control, and pharmacotherapy of diabetes type 2. According to the increased number of available medicines and new evidence related to the effectiveness and safety of medicines already involved in the therapy there was a need for update of the existing guidelines for the pharmacotherapy of type 2 diabetes in the Republic of Croatia. PARTICIPANTS: as co-authors of the Guidelines there are listed all members of the Croatian Association for Diabetes and Metabolic Diseases, as well as other representatives of professional societies within the Croatian Medical Association, who have contributed with comments and suggestions to the development of the Guidelines. EVIDENCE: These guidelines are evidence-based, according to the GRADE system (eng. Grading of Recommendations, Assessment, Development and Evaluation), which describes the level of evidence and strength of recommendations. CONCLUSIONS: An individual patient approach based on physiological principles in blood glucose control is essential for diabetes' patients management. Glycemic targets and selection of the pharmacological agents should be tailored to the patient, taking into account the age, duration of disease, life expectancy, risk of hypoglyce- mia, comorbidities, developed vascular and other complications as well as other factors. Because of all this, is of national interest to have a practical, rational and applicable guidelines for the pharmacotherapy of type 2 diabetes.

Successful treatment of renal artery embolism even forty-eight hours after event.

Renal artery embolism is a disease that is easily missed due to its infrequent and nonspecific presentations. Although early diagnosis and optimal thrombolytic treatment can sometimes restore renal function, therapeutic guidelines have not yet been established. However, early anticoagulant therapy is beneficial and selective infusion of lytic agents into renal artery has been reported with increasing frequency and efficacy if used in the early stage. We report that intra-arterial thrombolytic therapy with low dose of 35 mg recombinant tissue plasminogen activator (t-PA) may be an effective and safe strategy for the treatment of renal artery embolism, despite the period of ischemia being longer than 48 hours.

Expression of calcium/calmodulin-dependent protein kinase II and pain-related behavior in rat models of type 1 and type 2 diabetes.

BACKGROUND: Abnormalities in peripheral nerves and dorsal root ganglia are noticed in the early stage of experimentally provoked diabetic neuropathy. Enzyme calcium/calmodulin-dependent protein kinase II (CaMKII) may have a modulating role in diabetic neuropathy because of its role in calcium homeostasis. METHODS: A model of type 1 diabetes mellitus (DM1) was induced with 55 mg/kg of the streptozotocin and for DM2 induction a combination of high-fat diet and low-dose streptozotocin (35 mg/kg) was used. Pain-related behavior was analyzed using thermal and mechanical stimuli. Two weeks and 2 months after induction of diabetes rats were euthanized, and the expression of CaMKII and its isoforms in the dorsal root ganglia were analyzed using immunofluorescence. RESULTS: Both types of diabetes were successfully induced, as confirmed by hyperglycemia. Increased pain-related behavior became evident in DM1 rats in 2 weeks after diabetes induction, but not in DM2 rats. The expression of total CaMKII and the phosphorylated α isoform of CaMKII increased in DM1 animals concurrently with pain-related behavior. Expression of α, ß, γ, and δ isoforms in DM1 animals and expression of total CaMKII and all of its analyzed isoforms in DM2 animals remained unchanged. CONCLUSIONS: Our findings may indicate involvement of CaMKII in transmission of nociceptive input early in DM1, but not in DM2. CaMKII may be a suitable pharmacological target for diabetic neuropathy.

[New insights in steroid diabetes]. / Nove spoznaje o steroidnom dijabetesu.

Glucocorticoids (GC) are the cornerstone in the treatment of numerous chronic autoimmune and inflammatory diseases. GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidemia and skeletal muscle atrophy. GCs are the most common cause of drug-induced diabetes mellitus. However, not everyone treated with glucocorticoids develops diabetes. Predictors of development of diabetes are age, weight, family history of diabetes mellitus, or personal history of gestational diabetes. There is evidence that patients with decreased insulin secretory reserve are much more likely to develop diabetes. Diabetes from topical steroid use is uncommon, but high-dose steroids have been associated with significant hyperglycemia, including development of hyperglycemic hyperosmolar syndrome and even diabetic ketoacidosis in patients with type 1 diabetes mellitus. Several mechanisms contribute to the development of hyperglycemia and steroid-induced diabetes, including decreased peripheral insulin sensitivity, increased hepatic glucose production, and inhibition of pancreatic insulin production and secretion. Physicians treating patients with GCs should be aware of the induction of metabolic disturbances and should not solely rely on fasting measurements. In addition, our review indicates that insulin therapy could be considered when treating patients on GC therapy.

Acute renal failure associated with rhabdomyolysis in acute Q Fever.

The clinical presentation of Q fever is polymorphic and non-specific, and it may be presented as an acute or chronic disease. Renal complications of acute Q fever such as acute glomerulonephritis are not uncommon. Acute renal failure induced by rhabdomyolysis in acute Q fever has until now never been reported in the literature. We presented a case of acute Q fever associated by extreme rhabdomyolysis and consecutive acute renal failure. A male patient was treated with doxycycline and continuous venovenous hemodiafiltration. After two weeks of treatment, the patient completely recovered kidney function, and there were no clinical abnormalities. Acute Q fever must be considered as a possible cause of rhabdomyolysis and acute renal failure. The continuous venovenous hemodiafiltration may be effective, and it seems to be the treatment of choice in severe rhabdomyolysis and consecutive acute renal failure.

Oxygenation alters ganglioside expression in rat liver following partial hepatectomy.

Gangliosides from livers of weanling rats were analyzed after 15% partial hepatectomy (PH) and different pre- and post-operative hyberbaric oxygenation (pre- and postHBO). Neu5Ac was the predominant ganglioside-derived sialic acid (>85%) compared to Neu5Gc. Almost identical low total sialic acid content (Neu5Ac+Neu5Gc) of the control and operated nonHBO animals opposed a 6.4- to 7.6-fold increase in pre- and postHBO animals (69.26 and 81.64pmol/mg wet weight, respectively). NanoESI-QTOF mass spectrometry combined with HPTLC immunostaining revealed GM3(Neu5Ac) and GM3(Neu5Gc) as major gangliosides, correlating with the respective sialic acid concentrations. Minor neolacto-series gangliosides were enhanced in preHBO and postHBO, but GM1-core gangliosides only in preHBO rats. GM2 and GalNAc-GM1b were clearly detectable in oxygenated rats compared to traces in the control and nonHBO animals. These results point at a functional role of gangliosides in liver growth regulation and reconstitution after PH combined with pre- and post-operative HBO treatment.