Sclerostin: Intracellular mechanisms of action and its role in the pathogenesis of skeletal and vascular disorders.

Sclerostin is a glycoprotein involved in the regulation of bone metabolism, exclusively secreted by osteocytes. It affects the activity of bone morphogenetic proteins (BMPs) and is an inhibitor of the Wnt/ß-catenin metabolic pathway in bone cells. Osteocytes reduce the release of sclerostin in response to mechanical stimuli acting on bone, and thus promote the activation of osteogenic pathway Wnt/ß-catenin in osteoblasts. This signaling pathway plays a key role in osteogenesis and bone turnover. Loss of sclerostin gene function is related to 3 different craniotubular hyperostosis processes: sclerosteosis, craniodiaphyseal dysplasia, and van Buchem disease. Additionally, experimental and clinical studies suggest that sclerostin may promote vascular calcification. Antibodies directed against sclerostin stimulate bone formation and represent a new therapeutic option in the treatment of diseases with increased bone resorption, such as osteoporosis and inflammatory diseases where there is generalized bone loss, periarticular osteoporosis, and cartilage damage, such as rheumatoid arthritis (RA), ankylosing spondylitis (AS), and glucocorticoid-induced osteoporosis (GIO). Antibody use has the potential to offer new therapeutic approaches in the therapy of mineral and bone disorders resulting from chronic kidney disease (CKD-MBD) and vascular calcifications.

Factors limiting usefulness of serum and urinary NGAL as a marker of acute kidney injury in preterm newborns.

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is postulated to be a highly sensitive and specific marker of acute kidney injury (AKI). The aim of this study was to assess the factors affecting serum and urine total NGAL in preterm newborns, limiting the role of this new potential marker of AKI. METHODS: Serum and urinary total NGAL concentrations were determined in 57 preterm infants admitted to the Neonatal Intensive Care Unit in the following points of time: first week of life, between 8 and 14 days of life, and after the fourth week of life. Patients' clinical conditions were evaluated based on NTISS (Neonatal Therapeutic Intervention Scoring System). Two gestational age subgroups were distinguished: ≤29 and 30 to 35 weeks of gestation. We sought correlation between total NGAL values and gestational age, birth weight, Apgar score and severity of clinical condition, with particular interest in inflammatory status. RESULTS: Serum and urinary total NGAL concentration correlated with inflammatory markers, such as CRP and procalcitonin, as well as with NTISS values. Birth weight and gestational age influence urinary NGAL (uNGAL) values in the first two weeks of life. In AKI (N = 8) patients uNGAL values were significantly higher than in non-AKI newborns. CONCLUSIONS: We conclude that inflammatory status and prematurity limits the specificity of total NGAL measurement as a marker of AKI.

Ramipril/amlodipine single pill - effectiveness, tolerance and patient satisfaction with antihypertensive therapy in relation to nutritional status.

BACKGROUND: Overweight and obesity decrease the effectiveness of antihypertensive therapy despite the more frequent use of polytherapy. One method for improving therapy effectiveness is by decreasing non-compliance with the use of fixed-dose combinations (FDC). The aim of this study was to assess the effectiveness, tolerance, and satisfaction with ramipril/amlodipine FDC antihypertensive therapy in relation to nutritional status. METHODS: The survey enrolled 24,240 hypertensive patients recently switched to ramipril/amlodipine FDC (EGIRAMLON) at the same doses as previously prescribed separate pills. RESULTS: The effectiveness of antihypertensive therapy increased during follow-up from 32.9% to 76.5%. Overweight and obesity were associated with the increased risk of not attaining the recommended BP values [adjusted for age OR=0.74 (95% CI 0.67-0.83) and 0.70 (0.61-0.81) for overweight; 0.54 (0.47-0.60) and 0.49 (0.42-0.57) for obese, at the first and the second examination, respectively]. "Very good" or "good" the FDP tolerance was reported by 98.8%, 97.6% and 96.4%, respectively. Adverse events (AE) were reported in 0.35% of patients regardless of nutritional status. High levels of satisfaction with the FDC were reported by 57.0% of patients with normal weight, 54.5% of overweight, and 50.6% with obesity. Effectiveness and convenience were the most important for patients. CONCLUSIONS: The effectiveness of therapy with ramipril/amlodipine FDC in the study population was high, but slightly lower in overweigh and obese. This FDC was well tolerated and a significant number of patients satisfied with the therapy regardless of nutritional status. Although the perceived tolerance and satisfaction with treatment were lower in obese and overweight than in normal weight patients; the incidence of AE and perceived benefit from the use of a single-pill, compared to multiple tablets, were comparable irrespective of nutritional status.

Serum and urinary NGAL in septic newborns.

Neutrophil gelatinase-associated lipocalin (NGAL) is postulated to be a potentially new and highly specific/sensitive marker of acute kidney injury (AKI). The aim of this study was to assess the impact of inflammation on serum and urine NGAL in newborns that were treated due to infection. We determined serum and urine NGAL concentrations in 73 infants (51 with sepsis; 22 with severe sepsis) admitted to the Intensive Care Unit in the first month of life, for three consecutive days during the course of treatment for infection. 29 neonates without infection served as the control group. Septic patients, in particular, severe sepsis patients, had increased serum and urinary NGAL levels in the three subsequent days of observation. Five septic patients who developed AKI had elevated serum and urinary NGAL values to a similar extent as septic neonates without AKI. A strong correlation was found between the concentration of serum and urinary NGAL and inflammatory markers, such as CRP and procalcitonin. Serum and urinary NGAL levels were also significantly associated with NTISS (neonatal therapeutic intervention scoring system) values. We conclude that increased serum and urinary NGAL values are not solely a marker of AKI, and more accurately reflect the severity of inflammatory status.

Long-term inhibition of intestinal lipase by orlistat improves release of gut hormones increasing satiety in obese women.

BACKGROUND: Reduced postprandial secretion of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), cholecystokinin, and increased hunger was reported after a single dose of orlistat, an inhibitor of intestinal lipase. As yet, the influence of long-term therapy with orlistat on PYYand GLP-1 release has not been studied. Our study was aimed at assessing the influence of 8-week therapy with orlistat as a component of a weight loss program on pre-prandial circulating PYY and GLP-1 levels. METHODS: Forty obese women, without concomitant diseases, were randomly allocated to groups receiving orlistat or placebo during an 8-week weight management program. Body mass, body composition and plasma levels of PYY, GLP-1 and insulin (for QUICKI calculation) were determined prior to and at the end of therapy. RESULTS: Women treated with orlistat obtained significantly greater body and fat mass loss than those receiving placebo (9.0 ± 3.1 vs. 5.9 ± 3.2% and 21.9 ± 10.9 vs. 7.4 ± 15.6%, respectively). Only in those treated with orlistat a slight, but significant increase of the QUICKI was found (8.0 ± 16.5 vs. -0.1 ± 12.7 %, respectively). Weight loss was followed by a significant increase of plasma levels of PYY and GLP-1 in group treated with orlistat, and was about 2-times greater than receiving placebo. The increase was independent of body mass changes. CONCLUSION: The long-term inhibition of intestinal lipase by orlistat increases the pre-prandial levels of GLP-1 and PYY, independent of body mass changes. Therefore, it seems that long-term treatment with orlistat may exert hunger suppressing and insulin sensitizing incretin effect beyond weight reduction.

Do primary care physicians follow the current recommendations for hypertensive pharmacotherapy?

INTRODUCTION: In 2007, the joint recommendations of the European Society of Cardiology and the European Society of Hypertension (ESC/ESH) were announced. OBJECTIVES: The aim of this survey was to evaluate the implementation rate of the new ESC/ESH recommendations by primary care physicians and to assess the effectiveness of antihypertensive therapy. PATIENTS AND METHODS: Data concerning pharmacotherapy, blood pressure (BP) measurements, and compliance with the guidelines were collected in 10,880 hypertensive patients during 3 subsequent follow-up visits. RESULTS: Combined antihypertensive treatment (angiotensin converting enzyme inhibitors with ß-blocker, diuretic, or calcium-channel blocker) was used in 69.2% of the patients at baseline. A combination of ß-blocker with diuretic was prescribed in 7.4% of the patients. In 71% of these patients no history of cardiovascular events was reported (myocardial infarction, revascularization, or heart failure). Diuretics were not used in 20.7% of the patients receiving a 3-drug regimen and in 6.7% of those receiving a 4-drug regimen. BP target levels set by individual physicians were frequently lower than those recommended by the guidelines. The percentage of patients who reached the recommended BP target increased during the survey to 25.3%. CONCLUSIONS: A combination of ß-blocker and diuretic is still commonly used in the treatment of hypertension in patients without coronary artery disease and heart failure. Despite the use of combination treatment in about 90% of hypertensive patients and attempts at reaching lower target BP values than those recommended by the guidelines, treatment targets were achieved only in one-fourth of the patients.

Factors that favor the occurrence of cough in patients treated with ramipril--a pharmacoepidemiological study.

BACKGROUND: Dry cough is a common cause for the discontinuation of ramipril treatment. The aim of this pharmacoepidemiological study was to assess the incidence of ramipril-related cough among the Polish population and to characterize patients at risk of experiencing the adverse effect of cough during ramipril treatment. MATERIAL/METHODS: This was a prospective observational study involving 10,380 patients treated with ramipril for a period of no longer than 8 weeks, consisting of 3 visits: baseline, first follow-up (after 4-8 weeks) and second follow-up visit (after 4-8 weeks of cessation of ramipril, conducted only for evaluating coughing patients). RESULTS: The incidence of ramipril-related cough was 7.1%. Logistic regression analysis identified female sex (OR=1.35), cigarette smoking (OR=2.50), chronic obstructive pulmonary disease (OR=1.70), asthma (OR=1.60) and previous history of tuberculosis (OR=6.20) to be significantly and independently associated with the onset of ramipril-related cough. Coughing subsided within a period of 2-20 days after ramipril was discontinued. In all patients reporting the appearance of cough within the first 5 days after therapy initiation, the adverse effect subsided after therapy discontinuation. If cough appeared within 6-10 days, it subsided after discontinuation in 81.6% of subjects. Cough persisted in 30.4% of those reporting later onset. CONCLUSIONS: 1. Female sex, cigarette smoking, COPD, asthma, and previous history of tuberculosis increase the risk of ramipril-related cough. 2. The later the cough occurs during treatment, the less often the drug is the causative agent and the cough and also less likely to disappear after discontinuation of ramipril.

Effectiveness of lipid-lowering therapy with statins for secondary prevention of atherosclerosis--guidelines vs. reality.

BACKGROUND: The aim of the study was to analyze the effectiveness of lipid-lowering therapy and therapeutic decisions made by physicians for patients not achieving LDL targets. METHODS: 11,768 patients undergoing therapy with statins for secondary prevention of atherosclerosis participated in a two-visit survey. In subjects not achieving the LDL-target (< 100 mg/dl), further therapeutic decisions made by physicians were recorded. RESULTS: Initially the LDL-target was achieved by 7.8% of patients on simvastatin and by 18.0% on atorvastatin, of which 20.8% were treated with at least a 40 mg dose. The most common changes in therapy to improve effectiveness was substituting simvastatin for another statin (75.2%, usually atorvastatin), or increasing atorvastatin dosage (59.8%). Intensification of a low fat diet and weight reduction were more frequently recommended in treatment with atorvastatin than with simvastatin (59.8% vs. 55.9%, p < 0.001). After enhanced therapy, the LDL-target was achieved by 27.8% on simvastatin and by 35.0% on atorvastatin (p < 0.001). In those with LDL levels remaining above the target, substitution of simvastatin with atorvastatin (49.9%), or the increase of atorvastatin dose (41.4%) was recommended. As previously, life-style counseling was more frequent in patients on atorvastatin (66.1% vs. 45.7% p < 0.001). CONCLUSIONS: 1. The use of low dose statins and noncompliance with behavioral modification guidelines are responsible for the low levels of effectiveness found with lipid-lowering therapies. 2. Physicians prefer substitution of less effective statins over the increase of dose in patients not achieving LDL targets. 3. Life-style changes are under-prescribed by physicians and under-implemented by their patients.

Using NGAL as an early diagnostic test of acute kidney injury.

Neutrophil gelatinase-associated lipocalin (NGAL) has generated great interest as a novel biomarker for the timely detection of acute kidney injury (AKI). Despite the enthusiasm surrounding NGAL, the research so far details and attempts to minimize a host of limitations that substantially preclude its use as a valuable diagnostic biomarker to detect AKI and guide clinical treatment. In our review of the current research, obvious drawbacks such as variable sensitivity and specificity, even among similar patient populations were discovered. Furthermore, there are not well-defined cutoff values among various patient populations which would permit use of NGAL as a positive or negative diagnostic marker similar to troponin in cardiac injury. Moreover, due to the wide variation in baseline concentration of NGAL among patients, the added requirement of serial measurements, that may not even be accurate in at-risk or chronic kidney injury populations, further degrades the benefit of early detection.