Circulating osteopontin: a dual marker of bone destruction and angiogenesis in patients with multiple myeloma

The matrix protein osteopontin has been shown to be a marker of osteoclastic activity in multiple myeloma patients, as well as a regulator of angiogenesis. We measured serum levels of osteopontin in 50 untreated multiple myeloma patients (in 25, also after treatment) and examined the relation to markers of osteolytic and angiogenic activity. The median (range) of serum osteopontin was 85 (5-232) in the patient group vs. 36 (2-190) ng/ml in the control group. Serum osteopontin levels were significantly higher in patients with advanced stage or grade of myeloma disease. All patients with serum osteopontin levels >100 ng/ml had advanced stage (II or III) or high grade bone disease, whereas stage I or low grade patients had serum osteopontin levels <100ng/ml. Serum osteopontin levels significantly decreased after treatment. There was a positive correlation of osteopontin with the bone turnover marker N-terminal propeptide of procollagen type I (NTx) and the angiogenic markers vascular endothelial growth factor (VEGF) and bone marrow microvessel density (r: 0.35, 0.47 and 0.30 respectively, p < 0.05). These results support osteopontin as a dual marker of bone destruction and angiogenic activity in myeloma patients. Osteopontin represents a useful biomarker for monitoring myeloma disease activity

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Familial hypercholesterolemia and its manifestations: Practical considerations for general practitioners

Familial hypercholesterolemia (FH) is the most common genetic disorder of lipid metabolism, affecting almost 1 in 250 individuals worldwide. It is usually inherited via the autosomal dominant way and is characterized by aberrantly high total and low-density lipoprotein cholesterol (LDL-C) concentrations from early childhood, predisposing to increased risk of premature atherosclerotic cardiovascular disease (ASCVD), mostly coronary heart disease (CHD). Despite its high prevalence in the general population and the high ASCVD risk, FH is often underdiagnosed and undertreated. Genetic diagnosis is not always necessary since specific criteria, taking into account the patient’s individual and family history, clinical signs, and untreated LDL-C concentrations, may be used for prompt diagnosis. Except for CHD, which may be already evident at diagnosis, leading to increased mortality, other non-CHD morbidities, such as stroke, peripheral artery disease, carotid artery stenosis, and aortic valve calcification may be also present, substantiating the need for prompt intervention. Statins constitute the mainstay of treatment both in adults and children &gt;8 years old. In cases of statin intolerance or not achieving the LDL-C target despite maximally tolerated statin dose, ezetimibe and/or proprotein convertase subtilisin-kexin type 9 inhibitors may be used. The advent of recently approved medications, such as inclisiran and bempedoic acid, either as monotherapy or as add-on therapy to statins, has further enhanced the therapeutic armamentarium that can be used in FH patients. The purpose of this narrative review is to provide practical considerations regarding the diagnostic and therapeutic approach to FH patients

Could Lowering Phytosterol Absorption as Part of Lipid-Lowering Therapy Have a Beneficial Effect on Residual Risk?

Plant sterols are molecules that are structurally similar to cholesterol and provided only as dietary sources (e.g., vegetables, fruits, nuts, cereals) since they cannot be synthesized by humans. Sterol-enriched diets (≥2 g/day) may decrease total and low-density lipoprotein cholesterol concentrations by 5–10%, either alone or when added to statins, since they antagonize dietary cholesterol absorption in the intestine. On the other hand, increased serum phytosterol concentrations, (including when associated with sitosterolemia, a rare genetic defect) may contribute to atherosclerotic risk, although a threshold for such a role has not been established. Medications such as ezetimibe may effectively reduce cholesterol and phytosterol absorption. Whether the therapeutic approach associated with the reduction of phytosterol absorption is also translated into a reduction in a patient’s residual cardiovascular risk needs to be established

Insulin Metabolism and Assessment of Hepatic Insulin Extraction During Liver Regeneration. A Study in a Rat Model

Background: Liver regeneration is a complex procedure in which insulin metabolism has been implicated. The aim of this experimental study was to evaluate the role of insulin in rat hepatic regeneration following major hepatectomy (70%), employing an isolated perfused rat liver (IPRL) model to assess the extraction of insulin from the regenerating liver. Methods: Eighty-six male rats were randomized in 9 groups. A group of rats was studied at postoperative day (POD) 1 having a sham operation while control rats had no operation. All other animals were subjected to 70% hepatectomy. In phase B, at POD 1, 2, 3, 5, 7, and 14, the IPRL was applied. The regenerating liver was perfused with insulin (450 mu/ml) at a flow of 1.4 ml/gr liver/min for 20 min. Animal weight, liver weight, glucose, lactate, aspartate transferase (AST), alanine transferase (ALT), total bilirubin, albumin, prothrombin time (PT), insulin clearance, and tissue proliferating cell nuclear antigen (PCNA) expression were recorded. Results: We observed reduction of the liver's biochemical activities resulting in increase of AST (684%), ALT (532%), PT (27.7%), international normalized ratio (72%), and total bilirubin (82.8%) at first POD, while a normalization of the essential liver's functions occurs at fifth POD. Endogenous insulin concentration increased, while insulin extraction by the liver was reduced at the first POD in animals who underwent hepatectomy (13.94 ± 0.8 vs 7.97 ± 1.80 u/ml, p = 0.0005 and 71 ± 9.9 vs 165.88 µU/gr liver/min, respectively, p = 0.0005). Conclusions: Insulin seems to take part in hepatic regeneration, as the pancreas increases insulin production and the liver absorbs less despite the reduced hepatic mass and function

Effects of Moxonidine Administration on Serum Neuropeptide Y Levels in Hypertensive Individuals: A Prospective Observational Study

Moxonidine is a centrally acting, anti-hypertensive medication that exerts additional metabolic properties. It is unknown whether its effects are mediated by neurotransmitters or sympathetic tone regulators, including Neuropeptide Y (NPY). In this study, we evaluated the effects of moxonidine administration on serum NPY in humans. Methods: Ninety individuals with mild or moderate arterial hypertension that required monotherapy were categorized in three age and gender-matched groups according to their Body Mass Index (BMI) as normal weight (n = 30), overweight (n = 30), and obese (n = 30). Moxonidine was administered in therapeutic doses of up to 0.6 mg daily for 12 weeks, and clinical, biochemical and hormonal parameters were recorded. Results: In all three groups, a decrease in systolic and diastolic blood pressure and heart rate was shown. After treatment, BMI, 24 h urine catecholamines and catecholamines’ metabolites, and serum total cholesterol were also reduced. Most importantly, we found a decrease in serum NPY levels in all study groups, with the largest mean decrease in the group of obese and overweight participants compared to normal weight. Conclusions: Moxonidine administration results in improvement in cardio-metabolic parameters, as well as a decrease in serum NPY levels, which therefore represents it being a potent agent against obesity-associated hypertension. Its involvement in energy balance regulation warrants further investigation

Effects of Moxonidine Administration on Serum Neuropeptide Y Levels in Hypertensive Individuals: A Prospective Observational Study

Moxonidine is a centrally acting, anti-hypertensive medication that exerts additional metabolic properties. It is unknown whether its effects are mediated by neurotransmitters or sympathetic tone regulators, including Neuropeptide Y (NPY). In this study, we evaluated the effects of moxonidine administration on serum NPY in humans. Methods: Ninety individuals with mild or moderate arterial hypertension that required monotherapy were categorized in three age and gender-matched groups according to their Body Mass Index (BMI) as normal weight (n = 30), overweight (n = 30), and obese (n = 30). Moxonidine was administered in therapeutic doses of up to 0.6 mg daily for 12 weeks, and clinical, biochemical and hormonal parameters were recorded. Results: In all three groups, a decrease in systolic and diastolic blood pressure and heart rate was shown. After treatment, BMI, 24 h urine catecholamines and catecholamines&rsquo; metabolites, and serum total cholesterol were also reduced. Most importantly, we found a decrease in serum NPY levels in all study groups, with the largest mean decrease in the group of obese and overweight participants compared to normal weight. Conclusions: Moxonidine administration results in improvement in cardio-metabolic parameters, as well as a decrease in serum NPY levels, which therefore represents it being a potent agent against obesity-associated hypertension. Its involvement in energy balance regulation warrants further investigation

Clinical presentation and diagnostic evaluation of pheochromocytoma: case series and literature review

Background Pheochromocytoma is a rare tumor frequently overlooked mainly due to the wide range of its clinical presentation, which may vary from entirely untypical signs and symptoms to life-threatening complications. Methods The present study aims to present a case series recently treated in our center, with emphasis placed on patients’ specific characteristics, clinical presentation and diagnostic evaluation. Relevant literature and current guidelines are being briefly reviewed to summarize screening for pheochromocytoma and appropriate diagnostic procedures. Results While the classic symptoms include headache, palpitations and sweating with permanent or paroxysmal hypertension, a wide range of clinical manifestations may be attributed to pheochromocytoma. The initial screening test is measurement of plasma or 24-hour urine metanephrine levels. Abdominal computerized tomography with intravenous contrast infusion is suggested as the imaging examination of choice, whereas magnetic resonance imaging should be preferred over CT in exceptional cases. 123I-metaiodobenzylguanidine scintigraphy is particularly useful for establishing the diagnosis of pheochromocytoma and should be further applied to detect or exclude possible metastatic lesions. Conclusion Early diagnosis of pheochromocytoma is of great significance not only because it represents a curable form of secondary hypertension, but also because it is often related to familial syndromes, malignancy or metastatic disease. Physicians need to be familiar with relevant clinical manifestations and diagnostic steps to raise clinical suspiction of pheochromocytoma and establish a timely diagnosis