Alterations in circulating mitochondrial signals at hospital admission for COPD exacerbation.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) exacerbation (ECOPD) alters the natural course of the disease. To date, only C-reactive protein has been used as a biomarker in ECOPD, but it has important limitations. The mitochondria release peptides (Humanin (HN), FGF-21, GDF-15, MOTS-c and Romo1) under certain metabolic conditions. Here, we aimed to evaluate the pathophysiologic, diagnostic and prognostic value of measuring serum mitochondrial peptides at hospital admission in patients with ECOPD. METHODS: A total of 51 consecutive patients admitted to our hospital for ECOPD were included and followed for 1 year; in addition, 160 participants with stable COPD from our out-patient clinic were recruited as controls. RESULTS: Serum FGF-21 (p < .001), MOTS-c (p < .001) and Romo1 (p = .002) levels were lower, and GDF-15 (p < .001) levels were higher, in patients with ECOPD than stable COPD, but no differences were found in HN. In receiver operating characteristic analysis, MOTS-c (AUC 0.744, 95% CI 0.679-0.802, p < .001) and GDF-15 (AUC 0.735, 95% CI 0.670-0.793, p < .001) had the best diagnostic power for ECOPD, with a diagnostic accuracy similar to that of C-RP (AUC 0.796 95% IC 0.735-0.848, p < .001). FGF-21 (AUC 0.700, 95% CI 0.633-0.761, p < .001) and Romo1 (AUC 0.645 95% CI 0.573-0.712, p = .001) had lower diagnostic accuracy. HN levels did not differentiate patients with ECOPD versus stable COPD (p = .557). In Cox regression analysis, HN (HR 2.661, CI95% 1.009-7.016, p = .048) and MOTS-c (HR 3.441, CI95% 1.252-9.297, p = .016) levels exceeding mean levels were independent risk factors for re-admission. CONCLUSIONS: Most mitochondrial peptides are altered in ECOPD, as compared with stable COPD. MOTS-c and GDF15 levels have a diagnostic accuracy similar to C-RP for ECOPD. HN and MOTS-c independently predict future re-hospitalization.

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.

Genetic DNA profile in urine and hair follicles from patients who have undergone allogeneic hematopoietic stem cell transplantation.

Biological samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) constitute a challenge for individual identification. In this study we analyzed the genetic profiles (by the amplification of 15 autosomic STRs) of HSCT patients found in different types of samples (blood, hair and urine) that may be the source of DNA in civil or criminal forensic cases. Our results show that while in hair follicles the donor component was not detected in any patient, thus being a reliable source of biological material for forensic identification, mixed chimerism was detected in urine samples from all patient, and no correlation was found between the time elapsed from the transplant and the percentage of chimerism. These results certainly have practical implications if the urine is being considered as a source of DNA for identification purposes in HSTC patients. Moreover, taking into consideration that chimerism was found not only in patients with leukocyturia (given the hematopoietic origin of leukocytes, this was expected), but also in those without observable leukocytes in the sediment, we conclude that an alternative source or sources of donor DNA must be implicated.

Circulating levels of mitochondrial oxidative stress-related peptides MOTS-c and Romo1 in stable COPD: A cross-sectional study.

Background: MOTS-c and Romo1 are mitochondrial peptides that are modulated by oxidative stress. No previous studies have explored circulating levels of MOTS-c in patients with chronic obstructive pulmonary disease (COPD). Methods: We enrolled 142 patients with stable COPD and 47 smokers with normal lung function in an observational cross-sectional study. We assessed serum levels of both MOTS-c and Romo1 and associated these findings with clinical characteristics of COPD. Results: Compared with smokers with normal lung function, patients with COPD had lower levels of MOTS-c (p = 0.02) and higher levels of Romo1 (p = 0.01). A multivariate logistic regression analysis revealed that above-median MOTS-c levels were positively associated with Romo1 levels (OR 1.075, 95% CI 1.005-1.150, p = 0.036), but no association was found with other COPD characteristics. Below-median levels of circulating MOTS-c were associated with oxygen desaturation (OR 3.25 95% CI 1.456-8.522, p = 0.005) and walking <350 meters (OR 3.246 95% CI 1.229-8.577, p = 0.018) in six-minute walk test. Above-median levels of Romo1 were positively associated with current smoking (OR 2.756, 95% CI 1.133-6.704, p = 0.025) and negatively associated with baseline oxygen saturation (OR 0.776 95% CI 0.641-0.939, p = 0.009). Conclusions: Reduced levels of circulating MOTS-c and increased levels of Romo1 were detected in patients diagnosed with COPD. Low levels of MOTS-c were associated with oxygen desaturation and poorer exercise capacity using 6 min walk test. Romo1 was associated with current smoking and baseline oxygen saturation. Trial registration: www.clinicaltrials.gov; No.: NCT04449419; URL: www.clinicaltrials.gov. Date of registration: June 26, 2020.

Associations between serum mitokine levels and outcomes in stable COPD: an observational prospective study.

Mitokines (Humanin (HN), GDF15 and FGF21) are produced as a result of mitochondrial dysfunction and may have major roles in chronic inflammation, malnutrition and exercise capacity in people with COPD. Except for GDF15, studies on this subject are lacking. A total of 165 patients with stable COPD and 49 smokers without COPD were enrolled. We assessed their serum mitokine levels and clinical characteristics at baseline. We recorded moderate and severe exacerbation for the next 12 months. Baseline serum HN (p = 0.037) and GDF-15 (p = 0.013) levels were higher in the COPD group. High HN levels were independently associated with a high risk of exacerbation (HRE) (OR 2.798, 95% CI 1.266-6.187, p = 0.011), malnutrition (OR 6.645, 95% CI 1.859-23.749, p = 0.004), and 6MWD (OR 0.995, 95% CI 0.991-0.999, p = 0.008), and future moderate (HR 1.826, 95% CI 1.181-2.822, p = 0.007) and severe exacerbations (HR 3.445, 95% CI 1.357-8.740, p = 0.009). High GDF15 levels were associated with HRE (OR 3.028, 95% CI 1.134-8.083, p = 0.027), 6MWD (OR 0.995, 95% CI 0.990-0.999, p = 0.017) and predicted desaturation in 6MWT (OR 3.999, 95% CI 1.487-10.757, p = 0.006). High FGF21 levels were associated with HRE (OR 2.144, 95% CI 1.000-4.600, p = 0.05), and predicted future severe exacerbation (HR 4.217, 95% CI 1.459-12.193, p = 0.008). The mitokine levels were higher in patients with COPD than smokers without COPD, and were associated with important clinical outcomes such as exercise capacity and COPD exacerbation. Among the mitokines, HN showed the strongest association with COPD and may serve as a future risk biomarker in this disease.Trial registation NCT04449419.

High parathyroid hormone predicts exacerbations in COPD patients with hypovitaminosis D.

BACKGROUND: Hypovitaminosis D has been linked to deterioration in clinical parameters and lung function in COPD. As a response to low levels of vitamin D serum Parathyroid Hormone (iPTH) is increased in some, but not all, patients. The aim of this study was to determine whether COPD patients with elevated PTH levels are at higher risk of COPD exacerbations and hospitalizations. METHODS: 166 COPD outpatients were randomly preselected. Clinical and analytical characteristics were assessed at baseline. After excluding patients with other conditions known to disturb calcium metabolism 141 patients were identified. Except one, all patients were prospectively followed for 12 months after obtaining the blood samples. Hypovitaminosis D was considered when serum 25(OH)D < 30 ng/mL. Secondary hyperparathyroidism was considered when serum iPTH was higher than normal (50 pg/mL) in patients with hypovitaminosis D. COPD exacerbations and hospital admissions were recorded during the follow-up. RESULTS: Prevalence of hypovitaminosis D in COPD patients was 89.3%, prevalence of secondary hyperparathyroidism associated with hypovitaminosis D was 22,9%. Cox proportional risk analysis showed that patients belonging to the high iPTH-low 25(OH)D group were at a higher risk of moderate COPD exacerbations (HR 1.81 (CI95% 1.043-3.127), p = 0.035) and hospital admissions (HR 5.45 (CI95% 2.018-14.720), p = 0.002) as compared with those with normal iPTH-low 25(OH)D levels. CONCLUSIONS: COPD patients with hypovitaminosis D and elevated iPTH have higher risk of moderate exacerbations and hospitalizations than those with hypovitaminosis D and normal iPTH.

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection.

BACKGROUND: The role of vitamin D status in COVID-19 patients is a matter of debate. OBJECTIVES: To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity. METHODS: Retrospective case-control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. The association of serum 25OHD levels with COVID-19 severity (admission to the intensive care unit, requirements for mechanical ventilation, or mortality) was also evaluated. RESULTS: Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean ±â€…standard deviation 25OHD levels were 13.8 ±â€…7.2 ng/mL, compared with 20.9 ±â€…7.4 ng/mL in controls (P < .0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001). 25OHD inversely correlates with serum ferritin (P = .013) and D-dimer levels (P = .027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/mL. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components. CONCLUSIONS: 25OHD levels are lower in hospitalized COVID-19 patients than in population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection.

BACKGROUND: The role of vitamin D status in COVID-19 patients is a matter of debate. OBJECTIVES: To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity. METHODS: Retrospective case-control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. The association of serum 25OHD levels with COVID-19 severity (admission to the intensive care unit, requirements for mechanical ventilation, or mortality) was also evaluated. RESULTS: Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean ±â€…standard deviation 25OHD levels were 13.8 ±â€…7.2 ng/mL, compared with 20.9 ±â€…7.4 ng/mL in controls (P < .0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001). 25OHD inversely correlates with serum ferritin (P = .013) and D-dimer levels (P = .027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/mL. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components. CONCLUSIONS: 25OHD levels are lower in hospitalized COVID-19 patients than in population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.

Vitamin D and antiphospholipid syndrome: A retrospective cohort study and meta-analysis.

OBJECTIVES: (a) To determine serum 25-OH vitamin D (vitD) levels in primary antiphospholipid syndrome (APS) and to compare them with patients with positive antiphospholipid serology who do not meet clinical criteria for APS, and with healthy controls. (b) To analyze the association of vitD levels with both the clinical manifestations and the immunological profile of patients with primary APS. (c) To perform a meta-analysis evaluating potential differences in serum vitD levels between APS and controls as well as the frequency of vitD deficiency in APS patients. METHODS: Retrospective study including 74 patients with primary APS, 54 with positive antiphospholipid (aPL) serology not meeting clinical criteria for APS, and 215 healthy controls. We considered 30 and 10ng/ml as the thresholds for vitD insufficiency and deficiency, respectively. Meta-analysis included four case-control studies (325 primary APS patients and 507 controls) and was conducted by fitting random effects models and checked for heterogeneity. RESULTS: Median serum vitD levels were similar in the three groups: 21ng/ml in primary APS, 25ng/ml in the aPL-positive group, and 21ng/ml in controls (p = 0.115). However, we found differences in the PTH levels, being 40.4 ± 24.9pg/ml in APS, 34.1 ± 18.2pg/ml in aPL serology, and 23.4 ±12.6pg/ml in healthy controls (p < 0.001). Regarding vitD deficiency, we found significant differences across the groups: 16.2% in APS, 11.1% in patients with positive serology, and 3.7% in controls (p = 0.001). There was a trend for the presence of thrombotic events in patients with vitD deficiency (38.9% vs 19.1%, p = 0.071). The meta-analysis confirmed that the combined mean difference in serum vitD levels between APS and controls was -3.605 (p < 0.001) and that APS patients had an increased frequency of vitD deficiency, with an OR = 3.06 (95% CI: 2.12-4.43, p < 0.001). CONCLUSIONS: APS patients show higher frequency of vitD deficiency than the healthy individuals. The meta-analysis study, including three cohorts and ours, suggests that APS patients have significantly lower serum vitD levels and higher frequency of vitD deficiency than controls.

Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults.

BACKGROUND: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. METHODS: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20-77yr) with unexplained low ALP levels. RESULTS: Nine had mild hyperphosphatemia and three had mild hypercalcemia. ALP levels were inversely correlated with serum calcium (r=-0.38, p=0.012), pyridoxal phosphate (PLP; r=-0.51, p=0.001) and urine phosphoethanolamine (PEA; r=-0.49, p=0.001). Although many subjects experienced minor complaints, such as mild musculoskeletal pain, none had major health problems. Mutations in ALPL were found in 21 subjects (50%), including six novel mutations. All but one, were heterozygous mutations. Missense mutations were the most common (present in 18 subjects; 86%) and the majority were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss (48% versus 12%; p=0.04), slightly lower levels of serum ALP (p=0.002), higher levels of PLP (p<0.0001) and PEA (p<0.0001), as well as mildly increased serum phosphate (p=0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele. CONCLUSION: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the associated clinical manifestations are usually mild, in approximately 50% of the cases, enzyme activity is low enough to cause substrate accumulation and may predispose to defects in calcified tissues.

A common polymorphism in the 5'-untranslated region of the aromatase gene influences bone mass and fracture risk.

OBJECTIVE: The aromatization of androgenic precursors in peripheral tissues, including bone, is the main source of estrogens after the menopause. CYP19, the gene encoding aromatase, has a long 5'-untranslated region with several variants of exon I and specific promoters. The aim of this study was to investigate the possible relationship between a common biallelic (C/G) polymorphism located on exon I.2 and bone mineral density (BMD). DESIGN: This was designed to be an association study between CYP19 polymorphism and BMD and the risk of vertebral fractures in women. METHODS: DNA was extracted from the peripheral blood of 299 women (116 premenopausal and 183 postmenopausal). CYP19 alleles were identified by a method based on the exonuclease activity of Taq-polymerase. BMD was determined by dual-energy absorptiometry. RESULTS: In premenopausal women there were no genotype-related differences in BMD. However, postmenopausal women with the CC genotype had lower spine and hip BMD than those with the GG genotype. The association between CYP19 genotypes and BMD was independent of other variables, such as age, height, body weight, calcium intake or years since menopause. The CC genotype was also associated with an increased risk of osteoporotic vertebral fractures (odds ratio 2.0; P=0.03). Serum levels of estrone and estradiol were similar in women with CC and GG alleles. CONCLUSIONS: A common biallelic polymorphism in the 5'-untranslated region of the CYP19-aromatase gene was associated with significant differences in bone mass and the risk of vertebral fractures in postmenopausal women. Given the frequency of allelic variants, genotype-related differences appear to be important from the perspective of the individual as well as the general population. Further studies are needed to elucidate underlying mechanisms that may be dependent on differences in estrogen bioactivity at the bone tissue level.

Bone disease in long-term adult kidney transplant patients with normal renal function.

BACKGROUND: In successful renal transplantation, the degree of renal function recovery is usually incomplete and information is scarce about the abnormalities of mineral metabolism in long-term adult renal recipients with normal renal function. This study was designed to investigate bone mineral metabolism in patients with a long-term normal functioning kidney. METHODS: Twenty-nine adult asymptomatic renal transplant (RT) recipients with stable graft function for more than 10 years and serum creatinine <2 mg/dL were studied. They were classified into two groups according to glomerular filtration rate: Group A (N = 12; nine men, three women)>70 mL/min (x: 126 +/- 55 mL/min) and Group B (N = 17; nine men, eight women) <70 mL/min (x: 56 +/- 11 mL/min). Circulating biochemical markers of bone remodelling, bone histomorphometry, and densitometry (lumbar spine and hip) were obtained to investigate bone disease in these patients. RESULTS: Serum PTH was slightly elevated in 10 patients (83%) in group A. Serum PTH levels were positively related to serum calcium, osteocalcin, BAP, telopeptide, OH-proline, and creatinine. There was no histologic data to support overactivity on bone in this group of patients, with only one showing high bone turnover. Mineralization was prolonged in 34% of patients. Twenty-two patients (75%) exhibited normal bone turnover. In the group with GFR>70 mL/min the prevalence of mineralization defect in the presence of normal serum levels of calcitriol suggested vitamin D resistance. Lumbar and femoral neck osteoporosis was present in 25% and 33% of patients in group A, and 23% and 53% in group B, respectively. T-score at lumbar spine was negatively correlated with months since transplantation. Patients under treatment with cyclosporine (CsA) showed increased concentrations of osteocalcin and D-pyr and higher lumbar bone mineral density (BMD), but bone histomorphometry was not influenced by CsA. CONCLUSION: Patients with long-term renal transplantation with normal renal function frequently present with slight increases in PTH, but without an effect on bone histology. CsA did not induce changes in bone histology and delayed mineralization was frequently observed.