Search Results (23)

The complications observed in preterm infants are largely attributable to underdeveloped organ systems and inadequate nutritional stores at birth. Insufficient nutritional support can further exacerbate persistent sequelae, such as bronchopulmonary dysplasia (BPD), metabolic bone disease of prematurity (MBDP), and retinopathy of prematurity (ROP). As a result, clinicians have collaborated to develop optimal nutrition strategies for preterm neonates. However, these clinical nutrition plans may be hindered by several factors, including fluid restrictions due to patent ductus arteriosus (PDA) and delayed enteral nutrition following necrotizing enterocolitis (NEC). Modified strategies for specific conditions can help prevent further deterioration, but inadequate nutritional support may limit organ growth and contribute to additional complications. Achieving an optimal balance between nutritional support and managing specific medical conditions varies across institutions. In addition to fluid balance and energy intake, supplementary nutrition—such as vitamins and probiotics—plays a crucial role in disease prevention. Drawing on recent evidence and our clinical experiences with neonatal nutritional strategies, this review article summarizes the specialized nutritional management required for preterm neonates with conditions such as BPD, NEC, MBDP, PDA, and ROP. Full article

Background/Objectives: Metabolic bone disease of prematurity (MBDP) is a multifactorial disorder resulting from disrupted transplacental mineral transfer and postnatal nutritional deficits, particularly affecting preterm neonates born before 32 weeks of gestation or weighing under 1500 g. Although substantial research has focused on skeletal outcomes, few studies have explored the association between MBDP and neonatal neurological impairment. This narrative review is the first to integrate the pathophysiological mechanisms, diagnostic methods, and preventive strategies for MBDP, while simultaneously investigating its potential impact on neurodevelopment. Methods: A narrative review of recent peer-reviewed studies, systematic reviews, and clinical trials was performed focusing on biochemical markers (alkaline phosphatase, FGF23, calcium, and phosphorus), emerging tools such as bioelectrical impedance analysis (BIA), and the effects of early nutritional interventions on both skeletal and neurodevelopmental outcomes in preterm infants (n = seven included articles). Results: Early elevations in ALP, particularly when combined with low serum phosphorus and FGF23 levels, provide sensitive markers for identifying MBDP. Furthermore, insufficient vitamin D levels during gestation and in the neonatal period have been associated with increased risks of seizures, hypotonia, and developmental delays. Studies suggest that enhanced vitamin D supplementation in preterm infants (up to 800 IU/day) may improve mineral absorption and bone formation and confer neuroprotective benefits through anti-inflammatory and antioxidant mechanisms. Conclusions: This is the first review on the neurological implications of biochemical actors of MBDP. As a result, diagnostic and therapeutic strategies, including vitamin D supplementation, can improve bone and neurodevelopmental outcomes. Future prospective studies are required to standardize diagnostic criteria and optimize therapeutic regimens for enhanced long-term benefits. Full article

Background/Objectives: Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder that cause premature aging due to LMNA mutations and progerin accumulation. Although lonafarnib, an FDA-approved farnesyltransferase inhibitor, offers modest extension of life, the disease remains progressive. As progeria is associated with stem cell depletion and mesenchymal stem cell (MSC) therapy has shown efficacy in treating atherosclerosis, we aimed to evaluate its efficacy and safety in HGPS. Methods: A 7-year-old male with classic HGPS and preexisting severe cerebrovascular disease received four intravenous infusion of bone marrow-derived MSCs (2.5 × 10⁵ cells/kg) over 8 months. Growth, metabolic, cardiovascular, musculoskeletal, auditory, and inflammatory cytokines were monitored throughout the study. Prophylactic enoxaparin was administered to prevent vascular complications. Results: MSC therapy was associated with improved lean body mass (11.5%), bone mineral density (L-spine z-score: 0.55 → 2.03), reduced arterial stiffness (9.98% reductionin pulse wave velocity), joint range of motion, dentition, and decreased sICAM-1 levels. However, Cardiovascular deterioration continued, and the patient passed away 10 months after the fourth dose, likely due to progression of the underlying vascular disease. No severe adverse effects were attributed to MSC therapy. Conclusions: MSC therapy may offer short-term benefits in arterial stiffness, bone health and inflammation in HGPS without notable safety concerns. Further studies are warranted to validate these findings, explore earlier intervention, and determine long-term efficacy and optimal dosing strategies. Full article

Background/Objectives: Preterm infants represent a population group at increased risk for vitamin D deficiency (VDD) and for its negative impact on various outcomes like metabolic bone disease or rickets, respiratory complications like respiratory distress syndrome and the development of bronchopulmonary dysplasia, necrotizing enterocolitis, or retinopathy of prematurity. Methods: Despite the growing interest in vitamin D research, there is still uncertainty regarding clear recommendations for each high-risk category of premature infants concerning the optimal dosage, optimal product, and timing for initiating vitamin D supplementation to prevent VDD. Results: An analysis of the literature suggests that early intervention for the optimal enteral supplementation of vitamin D is not only successful in achieving higher 25-hydroxi-vitamin D (25(OH)D) at one month but is also linked with improved outcomes. Conclusions: The traditional concepts and current recommendations for assessing vitamin D status and optimal supplementation need to be revised. Since parenteral nutrition, fortified mothers’ own milk, and special formula for preterm infants cannot provide adequate vitamin D levels, initiating oral supplementation soon after birth is essential to correct VDD in preterm infants. Full article

Background/Objectives: Sodium glycerophosphate improves the adverse side effects of parenteral nutrition. Therefore, this study aimed to evaluate different outcomes, including metabolic bone disease and electrolyte imbalance, associated with the use of sodium glycerophosphate or inorganic phosphate in parenteral nutrition for preterm neonates. Methods: This retrospective cohort study enrolled 402 newborns admitted to the neonatal intensive care unit of one medical center between January 2019 and September 2021. Of them, 205 received sodium glycerophosphate as parenteral nutrition, while the other 197 received inorganic phosphate. Baseline characteristics and growth parameters, including body weight, body length, and head circumference in the first year of life; calcium and phosphate content of parenteral nutrition in the first 4 weeks; calcium, phosphorus, alkaline phosphatase (ALP), and creatinine levels; and morbidities were compared. Results: During the first 4 weeks, the calcium and phosphate contents of parenteral nutrition were significantly higher in the sodium glycerophosphate vs. inorganic phosphate group. Growth parameters did not differ significantly between groups. The sodium glycerophosphate group showed a higher mean serum phosphate level (4.0 ± 1.2 mg/dL vs. 3.5 ± 1.3 mg/dL, p = 0.001), lower serum ALP level (402.8 ± 202.8 U/L vs. 466.4 ± 228.6 U/L, p = 0.004), lower seizure incidence (4.9% vs. 13.2%, p = 0.003), and higher hypocalcemia incidence (41.5% vs. 31.5%, p = 0.038). However, there were no significant intergroup differences in other common morbidities such as metabolic bone diseases of prematurity, bronchopulmonary dysplasia, electrolyte imbalance, hypoglycemia, retinopathy of prematurity, or intraventricular hemorrhage. Conclusions: Compared to inorganic phosphate, sodium glycerophosphate is associated with higher serum phosphate levels, lower ALP levels, and reduced seizure incidence in premature infants. However, as the study was retrospective and single-center, further randomized controlled trials are needed to confirm these findings. Full article

Background: Metabolic Bone Disease of Prematurity (MBDP) is common in extremely preterm infants (≤28 weeks gestation). Parenteral nutrition (PN) with higher calcium (Ca) and phosphorus (P) concentration started soon after birth may improve bone health in preterm infants. We compared the effect of two standard PN formulations on the incidence of MBDP and explored the predictive ability of biochemical markers for diagnosing MBDP. Methods: This retrospective study included eligible preterm infants ≤ 28 weeks gestation. Infants in group 1 (January 2016–December 2017) received PN 1 formulation with lower Ca (1.6 mmol/kg/day) and P concentration (1.4 mmol/kg/day). Infants in group 2 (June 2018–May 2020) received PN 2 formulation with higher Ca (2.3 mmol/kg/day) and P concentration (1.8 mmol/kg/day). We reviewed the biochemical and radiological investigations performed for diagnosing MBDP. Results: The incidence of MBDP reduced from 82.8% (77/93) in group 1 to 47.3% (27/57) in group 2. Grade 2–3 MBDP reduced significantly from 14% in group 1 to none in group 2 (p < 0.01). Serum phosphate < 1.5 mmol/L had a sensitivity of 79% and specificity of 77%, and alkaline phosphatase > 500 U/L showed a sensitivity of 72% and specificity of 71% for diagnosing radiological MBDP. There was no increase in hypercalcemia, hypophosphatemia or nephrocalcinosis from PN 2 formulation. Conclusions: A higher Ca and P concentration in PN reduced MBDP and eliminated grade 2–3 MBDP in our cohort without an increase in adverse events. Low serum phosphate and high serum alkaline phosphatase were the best predictors for diagnosing MBDP. Full article

Thalassemia is an autosomal recessive hereditary chronic hemolytic anemia characterized by a partial or complete deficiency in the synthesis of alpha- or beta-globin chains, which are essential components of adult hemoglobin. Mutations in the globin genes lead to the production of unstable globin chains that precipitate within cells, causing hemolysis. This shortens the lifespan of mature red blood cells (RBCs) and results in the premature destruction of RBC precursors in the bone marrow. Regular red blood cell transfusions are the standard treatment for thalassemia. However, these transfusions can lead to increased iron overload, which can impair vital systems such as the liver, heart, ovaries, and endocrine system. Focusing on female reproductive endocrinology, recurrent blood transfusions can cause iron accumulation in the pituitary and hypothalamus, leading to hypogonadotropic hypogonadism (HH), the most common endocrinopathy in these patients, affecting 40–91% of women. Recurrent transfusions and the resulting iron overload can also lead to oxidative stress and ovarian damage in patients with beta-thalassemia major (BTM). Despite advancements in iron chelation therapy, hypothalamic–pituitary damage associated with HH contributes to subfertility and sexual dysfunction, often with little to no recovery. In women exposed to gonadotoxic drugs, particularly those with BTM, anti-Mullerian hormone (AMH)—a marker of ovarian reserve—is frequently used to assess ovarian damage. This review aims to explore the pathophysiology of β-thalassemia and its major clinical manifestations, with a focus on endocrine complications and their impact on ovarian reserve. It also investigates how metabolomics can provide insights into the disease’s metabolic alterations and inform current and emerging therapeutic strategies to mitigate complications and optimize patient outcomes, potentially leading to more effective and personalized treatments. Full article

Background: Significant improvement in neonatal care has enabled increasing survival of preterm infants. Metabolic bone disease of prematurity is often overlooked due to other comorbidities of preterm birth. The best approach is screening and prevention of the disease in high-risk infants such as preterm infants. Aim: We followed up the clinical, radiological, and serum biochemical markers of metabolic bone disease in extremely preterm infants (<28 weeks of gestation). The clinical applicability and validation of C-terminal telopeptide of type I collagen (CTX-I) as a novel bone turnover marker were assessed. Standard and novel biochemical bone turnover markers and quantitative ultrasound were compared. Method: Patients’ data were collected from medical records. Assessments of calcium, phosphate, alkaline phosphatase, bone-alkaline phosphatase, CTX-I, and quantitative ultrasound were prospectively performed twice in 42 extremely preterm infants at postmenstrual ages of 30–32 weeks and 36–40 weeks. Bone mineral density was measured by quantitative ultrasound. Conclusion: Phosphate, alkaline phosphatase, bone alkaline phosphatase, calcium, or ionized calcium are not related to gestational age, but bone mineral density, measured by quantitative ultrasound, is related. There is no correlation between standard and novel biochemical markers and quantitative ultrasound for the identification of metabolic bone disease. Full article

Tooth eruption is an essential process for the development of the oral and maxillofacial system. Several inherited and acquired diseases might affect this tightly regulated process, resulting in premature, delayed, or even failed tooth eruption. The purpose of this article is to review the literature and the clinical parameters of metabolic bone diseases that affect tooth eruption. It examines the physiological aspects of tooth eruption and the pathophysiological changes induced by metabolic bone diseases, including changes in bone metabolism, density, and structure. The search strategy for this review included an electronic search in PubMed, Google Scholar, Medline, Scopus, and the Cochrane Library using the following keywords: “metabolic bone diseases”, “tooth eruption”, “delayed tooth eruption”, and each reported disease in combination with “tooth eruption disorders”, covering publications up to March 2024 and limited to English-language sources. Understanding the influence of metabolic bone diseases on tooth eruption is crucial for managing both dental and skeletal manifestations associated with these disorders. This review suggests that a multidisciplinary approach to treatment may significantly improve oral outcomes for patients suffering from such conditions. Clinicians should be aware of the specific dental abnormalities that may arise and consider comprehensive evaluations and individualized treatment plans. These findings underscore the need for further research into targeted therapies that address these abnormalities. Full article

The purpose of the present study was to evaluate the concentrations of some bone turnover markers in preterm neonates with uncomplicated clinical course in the first month of life. Samples from 13 preterm neonates were collected at three different times: at birth (T0) from umbilical cord blood (UCB); and at 15 (T1) and 30 (T2) days of life from peripheral blood (PB). The concentrations of calcium (Ca), phosphate (P), total alkaline phosphatase (ALP), Collagen Type 1 Amino-terminal Propeptide (PINP), osteocalcin (OC), Collagen Type 1 Carboxyl-Terminal Telopeptide (CTX) and Leptin were assessed. A statistically significant difference for ALP concentration at birth versus T1 and T2 was found. An evident increase in the median concentrations of CTX, OC and PINP from T0 to T2 were observed. A significant difference was also found for Leptin concentration at T0 compared to T1. In preterm infants, in the absence of acute or chronic medical conditions and without risk factors for metabolic bone disease (MBD) of prematurity, there is a significant increase in bone turnover markers during the first month of life. The knowledge of the variations in these markers in the first weeks of life, integrated by the variations in the biochemical indicators of bone metabolism, could help in recognizing any conditions at risk of developing bone diseases. Full article

Vitamin D deficiency can escalate prematurity bone disease in preterm infants and negatively influence their immature immunology system. Infants born at 24 + 0/7 weeks to 32 + 6/7 weeks of gestation will be considered for inclusion. Cord or vein blood samples will be obtained within 48 h after birth for 25-hydroxyvitamin D level measurements. Parathyroid hormone and interleukin-6 levels will be measured. Infants will be randomized to the monitored group (i.e., an initial dose of 1000 IU/day and possible modification) or the controlled group (i.e., 250 IU/day or 500 IU/day dose, depending on weight). Supplementation will be monitored up to a postconceptional age of 35 weeks. The primary endpoint is the percentage of infants with deficient or suboptimal 25-hydroxyvitamin D levels at 28 ± 2 days of age. 25-Hydroxyvitamin D levels will be measured at postconceptional age 35 ± 2 weeks. Secondary goals encompass assessing the occurrence of sepsis, osteopenia, hyperparathyroidism, and interleukin-6 concentration. The aim of this study is to evaluate the efficacy of monitored vitamin D supplementation in a group of preterm infants and ascertain if a high initial dosage of monitored vitamin D supplementation can decrease the occurrence of neonatal sepsis and metabolic bone disease. Full article

Chronic immune activation has a significant role in HIV-1 disease pathogenesis and CD4+ T-cell depletion. The causes of chronic inflammation and immune activation are incompletely understood, but they are likely multifactorial in nature, involving both direct and indirect stimuli. Possible explanations include microbial translocation, coinfection, and continued presence of competent replicating virus. In fact, long-term viral suppression treatments are unable to normalize elevated markers of systemic immune activation. Furthermore, high levels of pro-inflammatory cytokines increase susceptibility to premature aging of the immune system. The phenomenon of “inflammaging” has begun to be evident in the last decades, as a consequence of increased life expectancy due to the introduction of cART. Quality of life and survival have improved substantially; however, PLWH are predisposed to chronic inflammatory conditions leading to age-associated diseases, such as inflammatory bowel disease, neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities, and non-HIV-associated cancers. Several approaches have been studied in numerous uncontrolled and/or randomized clinical trials with the aim of reducing immune activation/inflammatory status in PLWH, none of which have achieved consistent results. Full article

Metabolic bone disease of prematurity (MBD) is a condition of reduced bone mineral content (BMC) compared to that expected for gestational age (GA). Preterm birth interrupts the physiological process of calcium (Ca) and phosphorus (P) deposition that occurs mostly in the third trimester of pregnancy, leading to an inadequate bone mineralization during intrauterine life (IUL). After birth, an insufficient intake of Ca and P carries on this alteration, resulting in overt disease. If MBD is often a self-limited condition, in some cases it could hesitate the permanent alteration of bone structures with growth faltering and failure to wean off mechanical ventilation due to excessive chest wall compliance. Despite advances in neonatal intensive care, MBD is still frequent in preterm infants, with an incidence of 16–23% in very-low-birth-weight (VLBW, birth weight <1500 g) and 40–60% in extremely low-birth-weight (ELBW, birth weight <1000 g) infants. Several risk factors are associated with MBD (e.g., malabsorption syndrome, parenteral nutrition (PN), pulmonary bronchodysplasia (BPD), necrotizing enterocolitis (NEC), and some chronic medications). The aim of this study was to evaluate the rate of MBD in a cohort of VLBWI and the role of some risk factors. We enrolled 238 VLBWIs (107 male). 52 subjects were classified as increased risk (G1) and 186 as standard risk (G2) according to serum alkaline phosphatase (ALP) and phosphorus (P) levels. G1 subjects have lower GA (p < 0.01) and BW (p < 0.001). Moreover, they need longer PN support (p < 0.05) and invasive ventilation (p < 0.01). G1 presented a higher rate of BPD (p = 0.026). At linear regression analysis, BW and PN resulted as independent predictor of increased risk (p = 0.001, p = 0.040, respectively). Preventive strategies are fundamental to prevent chronic alteration in bone structures and to reduce the risk of short stature. Screening for MBD based on serum ALP could be helpful in clinical practice to identify subjects at increased risk. Full article

In preterm newborns, secondary hyperparathyroidism (HPTH) is an underdiagnosed and undertreated entity. Its detection in the context of metabolic bone mineral disease (MBD) screening programs may be important to guide nutritional treatment. We designed a retrospective cohort study to determine the incidence of HPTH in very premature infants. As secondary objectives, we studied the risk factors, morbidities, and biochemical alterations associated with HPTH. A total of 154 preterm newborns ≤32 weeks gestational age (GA) were included. Of these, 40.3% (n = 62) presented with HPTH. In the multivariate analysis, independent risk factors for HPTH were cesarean section (OR: 4.00; 95% CI: 1.59–10.06), oxygen during resuscitation (OR: 3.43; 95% CI: 1.09–10.81), invasive mechanical ventilation (OR: 3.56; 95% CI: 1.63–7.77) and anemia requiring transfusion (OR: 2.37; 95% CI: 1.01–5.57). Among the analytical variables, serum calcium (OR: 0.53; 95% CI: 0.29–0.97), serum phosphate (OR: 2.01; 95% CI: 1.39–2.92), vitamin D (OR: 0.96; 95% CI: 0.93–1), and the calcium/creatinine ratio in urine (OR: 0.05; 95% CI: 0.01–0.28) were independently associated with HPTH. The simplified predictive model included GA and calcium/creatinine ratio in urine and demonstrated an AUC of 0.828. We concluded that HPTH is a frequent entity among very premature infants and that further studies are required to determine the role of HPTH in MBD and the clinical applicability of prediction models. Full article

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the CTNS gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns^−/− mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the CTNS cDNA, pCCL-CTNS, and showed its efficacy in Ctns^−/− mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34⁺ HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis. Full article