Role of fibroblast growth factor-23 as an early marker of metabolic bone disease of prematurity.

PURPOSE: Metabolic bone disease of prematurity (MBDP) remains a significant cause of morbidity in extremely premature newborns. In high-risk patients, suspected diagnosis and subsequent treatment modifications, with limitations in terms of sensitivity and specificity, rely on low phosphorus levels and/or high levels of alkaline phosphatase (ALP). We investigated the potential of fibroblast growth factor-23 (FGF23) as an early marker for MBDP when measured at 3-4 weeks of life in at-risk patients. METHODS: A single-center prospective observational non-interventional study including preterm newborns of both sexes, with a gestational age of less than 32 weeks and/or a birth weight of less than 1500 g. In the standard biochemical screening for MBDP performed between 3 and 4 weeks of life within a nutritional profile, the determination of FGF23 was included along with other clinical and metabolic studies. The study was conducted at Marqués de Valdecilla University Hospital in Santander, Spain, from April 2020 to March 2021. Participants provided informed consent. Biochemical analyses were conducted using various platforms, and follow-up evaluations were performed at the discretion of neonatologists. Patients at high risk for MBDP received modifications in treatment accordingly. The sample was descriptively analyzed, presenting measures of central tendency and dispersion for continuous variables, and absolute numbers/percentages for categorical ones. Tests used included t-tests, Mann‒Whitney U tests, chi-square tests, logistic regressions, Pearson correlation, and ROC curve analysis (IBM SPSS Statistics version 19). Significance level: P < 0.05. RESULTS: In the study involving 25 at-risk premature newborns, it was found that 20% (n = 5) were diagnosed with MBDP. Three of these patients (60%) were identified as high-risk based on standard biochemical evaluation at 3-4 weeks of age, while the other two patients (40%) were diagnosed in subsequent weeks. However, in all 5 patients, measurement of FGF23 levels would allow for early identification and optimization of treatment before other markers become altered. Low levels of FGF23 at 3-4 weeks, even with normal phosphorus and ALP levels, indicate the need for modifications in nutritional supplementation. CONCLUSIONS: MBDP remains a significant concern in extremely premature newborns. Current diagnostic methods rely on limited biochemical markers. Early detection of low FGF23 levels enables timely interventions, potentially averting demineralization.

A new integrative approach to assess aortic stenosis burden and predict objective functional improvement after TAVR.

Background: A non-negligible rate of patients undergoing transcatheter aortic valve replacement (TAVR) do not report symptomatic improvement or even die in the short-midterm. We sought to assess the degree of objective functional recovery after TAVR and its prognostic implications and to develop a predictive model. Methods: In a cohort of patients undergoing TAVR, a prospective evaluation of clinical, anatomical, and physiological parameters was conducted before and after the procedure. These parameters were derived from echocardiography, non-invasive analysis of arterial pulse waves, and cardiac tomography. Objective functional improvement 6 months after TAVR was assessed using a 6-min walk test and nitro-terminal pro-brain natriuretic peptide (NT-proBNP) levels. The derived predictive model was prospectively validated in a different cohort. A clinical follow-up was conducted at 2 years. Results: Among the 212 patients included, objective functional improvement was observed in 169 patients (80%) and subjective improvement in 187 (88%). Patients with objective functional improvement showed a much lower death rate at 2 years (9% vs. 31% p = 0.0002). Independent predictors of improvement were as follows: mean aortic gradient of ≥40 mmHg, augmentation index75 of ≥45%, the posterior wall thickness of ≤12 mm, and absence of atrial fibrillation. A simple integer-based point score was developed (GAPA score), which showed an area under the curve of 0.81 for the overall cohort and 0.78 for the low-gradient subgroup. In a validation cohort of 216 patients, these values were 0.75 and 0.76, respectively. Conclusion: A total of 80% of patients experienced objective functional improvement after TAVR, showing a significantly lower 2-year mortality rate. A predictive score was built that showed a good discriminative performance in overall and low-gradient populations.

Modified Serum ALP Values and Timing of Apparition of Knee Epiphyseal Ossification Centers in Preterm Infants with Cholestasis and Risk of Concomitant Metabolic Bone Disease of Prematurity.

The usefulness of serum alkaline phosphatase (ALP) and phosphorous in screening and monitoring of metabolic bone disease of prematurity (MBDP) still has some limitations, especially in preterm infants with concomitant conditions such as cholestasis. We aimed to assess a modification of serum ALP (M-ALP) as a biomarker for MBDP in preterm infants, and the use of ultrasound monitoring for the apparition of knee ossification centers as marker of bone mineralization. Biochemical and clinical registers were taken from 94 preterm newborns <32 weeks. A significant correlation existed between serum ALP and direct bilirubin (DB), expressed by the regression equation: M-ALP (IU/L) = 302.1 + 96.9 (DB (mg/dL)). The ratio ALP/M-ALP > 1 was demonstrated to be more specific (87.5%) in the diagnosis of MBDP than the cut-off value of serum ALP > 500 IU/L (62.5%). ALP/M-ALP > 1 showed 100% sensitivity and specificity for the diagnosis of MBDP, and a good correlation with specific bone ALP (B-ALP). Patients with the knee nucleus by post-menstrual week 37 had lower B-ALP compared to patients with no nucleus, and no patients with MBDP presented the nucleus by the 40th week. In the absence of reliable specific B-ALP, reinterpreting serum ALP values by M-ALP plus monitoring of knee ossification centers contribute to better management of MBDP in preterm infants with cholestasis.

Vitamin D nutritional status and vitamin D regulated antimicrobial peptides in serum and pleural fluid of patients with infectious and noninfectious pleural effusions.

BACKGROUND: Vitamin D and vitamin D dependent antimicrobial peptides such as Cathelicidin (LL-37) and ß-defensin 2 have an important role in innate and adaptative immunity, but their role in pleural effusions has not been studied before. METHODS: Serum and pleural fluid samples from 152 patients with pleural effusion were collected, corresponding to 45 transudates and 107 exudates, 51 infectious effusions (14 complicated and 37 non-complicated), 44 congestive heart failure effusions and 38 malignant effusions. The levels of 25 OH-vitamin D, 1,25-(OH)2-vitamin D, Vitamin D Binding Protein (VDBP), LL-37 and ß-defensin 2, both in serum and pleural fluid were evaluated in this prospective study. Differences between groups were analysed using unpaired t tests or Mann-Whitney tests. Correlations between data sets were examined using Pearson correlation coefficient or Spearman rank correlation coefficient. Diagnostic accuracy was estimated using ROC curve analysis. RESULTS: Low serum 25 OH vitamin D levels were found in all groups. Infectious effusions (IE) had higher serum and pleural fluid LL-37 levels compared to congestive heart failure or malignant effusions. Among IE, complicated had higher serum and pleural fluid LL-37 levels, and lower serum ß-defensin-2 levels. Positive correlations were found between serum 25 OH-vitamin D levels and serum or pleural 1,25-(OH)2-vitamin D levels, and between 1,25-(OH)2-vitamin D and LL-37 serum. Diagnostic accuracy of the different molecules was moderate at best. CONCLUSIONS: Hypovitaminosis D is highly prevalent in pleural effusions. LL-37 is produced intrapleurally in IE. This production is higher in complicated IE. No evidence of pleural production of ß-defensin 2 was found in any of the groups. Diagnostic accuracy of the different molecules is at the best moderate for discriminating different types of effusions.

Lack of association between carotid intima-media wall thickness and carotid plaques and markers of endothelial cell activation in rheumatoid arthritis patients undergoing anti-TNF therapy.

INTRODUCTION: To determine the relationship between biomarkers of endothelial cell activation, and carotid artery intima-media wall thickness (IMT) and plaques, two surrogate markers of atherosclerosis, in a series of rheumatoid arthritis (RA) patients undergoing anti-TNF therapy. METHODS: 29 consecutive Spanish patients who fulfilled the 1987 American College of Rheumatology classification criteria for RA, had no history of cardiovascular (CV) disease, and had at least one year of follow-up after disease diagnosis were selected. All patients were undergoing anti-TNF-infliximab therapy because of severe disease refractory to conventional disease modifying antirheumatic drugs. Carotid ultrasonography was performed to determine IMT and carotid plaques. Levels of sICAM-3, sICAM-1, sVCAM-1, sPselectin and sE-selectin were assessed by ELISA immediately before an infusion of infliximab. RESULTS: The median disease duration was 14 years. Despite infliximab, no patient experienced a disease remission (DAS28: median 4.17). Only a marginally significant correlation between sVCAM-1 and carotid IMT was observed when both total correlation using Spearman correlation coefficient (p= 0.08) or partial correlation adjusting for sex, age at the time of study, disease duration, rheumatoid factor, and classic CV risk factors was performed (p= 0.09). Also, no association between presence of carotid plaques and levels of biomarkers of endothelial cell activation was observed. CONCLUSION: In long-standing RA patients without CV disease undergoing anti-TNF therapy no association between levels of soluble markers of endothelial cell activation and carotid ultrasonography abnormalities was observed. Further studies are needed to establish the best tools to be used in the assessment of CV risk of RA.

"Single nucleotide polymorphisms of the OPG/RANKL system genes in primary hyperparathyroidism and their relationship with bone mineral density".

BACKGROUND: Primary hyperparathyroidism (PHPT) affects mainly cortical bone. It is thought that parathyroid hormone (PTH) indirectly regulates the activity of osteoclasts by means of the osteoprotegerin/ligand of the receptor activator of nuclear factor-κß (OPG/RANKL) system. Several studies have confirmed that OPG (osteoprotegerin) and RANKL (ligand of the receptor activator of nuclear factor-κß) loci are determinants of bone mineral density (BMD) in the general population. The aim of this study is to analyze the relationship between fractures and BMD and the rs3102735 (163 A/G), rs3134070 (245 T/G) and rs2073618 (1181 G/C) SNPs of the OPG and the rs2277438 SNP of the RANKL, in patients with sporadic PHPT. METHODS: We enrolled 298 Caucasian patients with PHPT and 328 healthy volunteers in a cross-sectional study. We analyzed anthropometric data, history of fractures or renal lithiasis, biochemical determinants including markers for bone remodelling, BMD measurements in the lumbar spine, total hip, femoral neck and distal radius, and genotyping for the SNPs to be studied. RESULTS: Regarding the age of diagnosis, BMI, menopause status, frequency of fractures or renal lithiasis, we found no differences between genotypes in any of the SNPs studied in the PHPT group. Significant lower BMD in the distal radius with similar PTH levels was found in the minor allele homozygotes (GG) compared to heterozygotes and major allele homozygotes in both OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs in those with PHPT compared to control subjects. We found no differences between genotypes of the OPG rs2073618 (1181 G/C) SNP with regard to BMD in the PHPT subjects. In the evaluation of rs2277438 SNP of the RANKL in PHPT patients, we found a non significant trend towards lower BMD in the 1/3 distal radius and at total hip in the minor allele homocygotes (GG) genotype group versus heterocygotes and major allele homocygotes (AA). CONCLUSIONS: Our study provides the first evaluation of the relationship between SNPs of the OPG/RANK system and sporadic PHPT. Subjects with PHPT and minor homocygote genotype (GG) for the OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs have lower BMD in the distal radius, and this association does not appear to be mediated by differences in PTH serum levels.

Markers of inflammation before and during peritoneal dialysis.

In this study, we compared changes in inflammatory markers-C-reactive protein (CRP), pentraxin 3 (PTX3), serum component of amyloid A (SAA), and procalcitonin (PCT)-in 182 subjects: 69 from the general population (GP), 47 with CKD, 19 with an implanted intra-abdominal catheter for peritoneal dialysis ("prePD"), and 47 on peritoneal dialysis (PD). These were the results [median (95% confidence interval)] for the GP CKD, prePD, and PD groups respectively: CRP: 1.40 mg/L (1.15-2.10 mg/L), 5.30 mg/L (3.04-8.06 mg/L), 3.33 mg/L (2.15-12.58 mg/L), 7.25 mg/L (4.43-15.16 mg/L). SAA: 3.10 mg/L (2.90-3.53 mg/L), 7.77 mg/L (4.17-15.83 mg/L), 7.30 mg/L (4.81-10.96 mg/L), 9.14 mg/L (5.31-23.54 mg/L). PCT: 0.028 ng/mL (0.022-0.032 ng/mL), 0.121 ng/mL (0.094-0.166 ng/mL), 0.160 ng/mL (0.090-0.277 ng/mL), 0.363 ng/mL (0.222-0.481 ng/mL). PTX3: 0.54 ng/mL (0.33-0.62 ng/mL), 0.71 ng/ mL (0.32-1.50 ng/mL), 0.56 ng/mL (0.44-1.00 ng/ mL), 1.04 ng/mL (0.65-1.56 ng/mL). After catheter insertion, CRP showed a nonsignificant declining trend that disappeared throughout PD. The behavior of SAA was similar to that of CRP and was not modified by the changes induced by the start of PD. An increase in PTX3 was observed only with PD, which may be related to a local proinflammatory state caused by PD solution. We can conclude that catheter insertion for PD does not account for most of the local inflammatory changes observed in PD patients.

Inflammation markers, chronic kidney disease, and renal replacement therapy.

Chronic kidney disease (CKD) is associated with a proinflammatory state and an excess of cardiovascular risk. In this work, we describe changes in inflammatory markers-C-reactive protein (CRP), pentraxin 3 (PTX3), serum component of amyloid A (SAA), and procalcitonin (PCT)--in CKD patients compared with a control group of subjects with a normal estimated glomerular filtration rate (eGFR). Blood samples were obtained from 69 healthy individuals (GP) and 70 end-stage CKD patients--25 not yet on dialysis, 22 on peritoneal dialysis (PD), and 23 on hemodialysis (HD). These were the results [median (95% confidence interval)] for the GP CKD, PD, and HD groups respectively: CRP: 1.40 mg/L (1.19-2.11 mg/L), 6.50 mg/L (3.57-8.32mg/L), 7.60 mg/L (2.19-22.10mg/L), 9.60 mg/L (6.62-16.38 mg/L). SAA: 3.10 mg/L (2.90-3.53 mg/L), 7.11 mg/L (3.81-15.40mg/L), 9.69 mg/L (5.07-29.47mg/L), 15.90 mg/L (6.80-37.48 mg/L). PCT: 0.03 ng/mL (0.02-0.03 ng/mL), 0.12 ng/mL (0.09-0.16 ng/mL), 0.32 ng/mL (0.20-0.46 ng/ mL), 0.79 ng/mL (0.45-0.99 ng/mL). PTX3: 0.54 ng/mL (0.33-0.62 ng/mL), 0.71 ng/ mL (0.32-1.50 ng/mL), 1.52 ng/mL (0.65-2.13 ng/mL), 1.67 ng/mL (1.05-2.27 ng/mL). Compared with levels in the GP group, levels of SAA and CRP (systemic response) were significantly higher in CKD patients on and not on dialysis. Levels of PTX3 were higher only in dialyzed patients, significantly so in those on HD (greatly different from the CRP levels). These differing levels might be related to a local reaction caused by an invasive intervention (PD or HD). As eGFR declines and with the start of renal replacement therapy, PCT increases. Levels of PCT could potentially cause confusion when these patients are being evaluated for the presence of infection, and may also demonstrate some microvascular implications of dialysis therapy.

Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naïve population.

OBJECTIVE: This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment. METHODS: A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol). RESULTS: 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated. CONCLUSIONS: Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Genetic polymorphisms are associated with serum levels of sex hormone binding globulin in postmenopausal women.

BACKGROUND: Estrogen activity plays a critical role in bone homeostasis. The serum levels of sex hormone binding globulin (SHBG) influence free estrogen levels and activity on target tissues. The objective of this study was to analyze the influence of common polymorphisms of the SHBG gene on serum SHBG, bone mineral density (BMD), and osteoporotic fractures. METHODS: Four biallelic polymorphisms of the SHBG gene were studied by means of Taqman assays in 753 postmenopausal women. BMD was measured by DXA and serum SHBG was measured by ELISA. RESULTS: Age, body weight, and two polymorphisms of the SHBG gene (rs6257 and rs1799941 [A/G]) were significantly associated with serum SHBG in unadjusted and age- and weight-adjusted models. Alleles at the rs1799941 locus showed the strongest association with serum SHBG (p=0.0004). The difference in SHBG levels between women with AA and GG genotypes at the rs1799941 locus was 39%. There were no significant differences in BMD across SHBG genotypes. The genotypes showed similar frequency distributions in control women and women with vertebral or hip fractures. CONCLUSION: Some common genetic variants of the SHBG gene, and particularly an A/G polymorphism situated in the 5' region, influence serum SHBG levels. However, a significant association with BMD or osteoporotic fractures has not been demonstrated.

Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: findings of a randomized clinical trial in a drug-naïve population.

BACKGROUND: There is little information about weight gain induced by antipsychotics at long-term. OBJECTIVE: To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and risperidone) in a cohort of drug-naïve subjects after 1 year of treatment. METHODS: This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at 3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted. RESULTS: A total of 164 drug-naïve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (+/-4.1) for haloperidol, 5.9 kg (+/-5.1) for risperidone and 8.4 kg (+/-5.0) for olanzapine (F=7.045; p=0.002). After 1 year the difference in weight gain had disappeared: 9.7 kg (+/-5.7) for haloperidol, 8.9 kg (+/-8.8) for risperidone and 10.9 kg (+/-7.2) for olanzapine (F=0.817; p=0.445). CONCLUSIONS: Drug-naïve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain.

Hypothalamic-pituitary-adrenocortical axis function in patients with polymyalgia rheumatica and giant cell arteritis.

BACKGROUND: Giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are 2 closely related syndromes affecting elderly people. One of the most striking features of these conditions is the development of the disease in an almost exclusive manner in people older than 50 years. Despite this close association with age, the pathogenic mechanisms that could explain this age-related predisposition are unknown. Aging is accompanied by a number of quantitative and qualitative changes in the endocrine system that may predispose to several pathologic conditions that occur in the elderly. OBJECTIVE: To explore the hypothalamic-pituitary-adrenal axis in PMR and GCA. METHODS: Basal levels of adrenal hormones as well as the response to low-dose adrenocorticotropin hormone (ACTH) were investigated in 20 patients with active untreated disease and compared with levels in 16 healthy age-matched controls. RESULTS: Male patients with active disease had low basal levels of androstenedione compared to the controls. After low-dose ACTH challenge, cortisol and dehydroepiandrosterone reached higher levels in patients than in healthy subjects, indicating that the adrenal gland function was not suppressed. Furthermore, the authors did not find a clear relationship between the levels of acute phase reactants and adrenal hormones in the patient population. CONCLUSIONS: The authors' findings are probably more compatible with the hypothesis that the abnormalities found in the patient group are the consequences of chronic illness rather than a crucial factor contributing to the pathogenesis of the disease.

[Reproducibility of C-reactive protein analyses]. / Reproducibilidad de los análisis de proteína C reactiva.

The aim of this study was to measure the reliability of different nephelometric techniques for measuring C-reactive protein (CRP). One hundred and twenty samples were obtained from 40 patients. All 120 samples were divided in three parts to measure CRP using three different methods. Reliability was determined by the kappa index and intraclass correlation coefficient. The intraclass correlation coefficient ranged from 0.78 to 0.94. When CRP values were categorized in four groups, the kappa index reached 75-86% and percentage of agreement varied from 95% to 97%. When CRP values were divided into two groups, the kappa index was 73% to 78% and the percentage of agreement was 86% to 89%. We found that CRP determinations with different nephelometric methods were highly reproducible, even when different analysts were involved. Ultrasensitive techniques are needed only if the clinical objective is to obtain a CRP measurement under 0.3 mg/dl.