A practical approach for anabolic treatment of bone fragility with romosozumab.

BACKGROUND: Romosozumab, a fully humanized anti-sclerostin-antibody, is a bone-builder stimulating osteoblasts and inhibiting osteoclast by activation of the canonical Wnt-beta catenin signaling. This unique mechanism of action has the potential to address unmet needs in osteoporosis management. METHODS: The multifaceted practical clinical issues related to romosozumab are discussed, especially focusing on the rationale of employing a sclerostin inhibitor to target bone fragility as first line or second line treatment in post-menopausal osteoporosis and in males at increased risk of fractures. RESULTS: Four randomized clinical trials with several post-hoc analyses and more than ten observational studies have consistently demonstrated that romosozumab is effective in rapidly increasing bone mineral density (BMD) and decreasing risk of vertebral, non-vertebral and hip fractures in post-menopausal women at very-high risk of fractures. In male osteoporosis, only data on BMD are available. Noteworthy, romosozumab was shown to be more effective and rapid than teriparatide in improving BMD, bone structure and strength at the hip, especially in women already treated with anti-resorptive drugs. Interestingly, even if romosozumab displays best results in treatment-naïve patients, its favourable effects on BMD were observed even in women previously treated with teriparatide or denosumab, although to a lesser extent. CONCLUSIONS: Based on the available evidence, romosozumab could be proposed as ideal drug in several clinical settings, such as non-fractured post-menopausal women at very-high risk of fractures, patients with recent hip fracture, patients non responder to bisphosphonates and short-term denosumab therapy.

Local Polarization and Isothermal Local Equilibrium in Relativistic Heavy Ion Collisions.

We show that the inclusion of a recently found additional term of the spin polarization vector at local equilibrium which is linear in the symmetrized gradients of the velocity field, and the assumption of hadron production at constant temperature restore the quantitative agreement between hydrodynamic model predictions and local polarization measurements in relativistic heavy ion collisions at sqrt[s_{NN}]=200 GeV. The longitudinal component of the spin polarization vector turns out to be very sensitive to the temperature value, with a good fit around 155 MeV. The implications of this finding are discussed.

Cancer prevalence in the subcategories of the indeterminate class III (AUS/FLUS) of the Bethesda system for thyroid cytology: a meta-analysis.

PURPOSE: The indeterminate cytologic report represents a major challenge in the field of thyroid nodule. The indeterminate class III of the Bethesda classification system (i.e., AUS/FLUS) includes a heterogeneous group of subcategories characterized by doubtful nuclear and/or architectural atypia. The study aim was to  conduct a systematic review and meta-analysis to evaluate the rate of malignancy in each subcategory of Bethesda III. METHODS: PubMed, CENTRAL, and Scopus databases were searched until April 2020. Original articles reporting data on the subcategories of Bethesda III were included. The histological diagnosis was the reference standard to classify true/false negative and true/false positive cases. RESULTS: The pooled cancer prevalence in each subcategory of Bethesda III was estimated using a random-effects model. Twenty-three papers with 4241 nodules were included. Overall, 1163 (27.4%) were malignant. The cancer rate observed in the subcategories ranged from 15%, in "Hürthle cell aspirates with low risk pattern", to 44%, in "Focal cytologic atypia". CONCLUSIONS: The overall cancer rate found in the Bethesda III ranged more largely than that originally estimated (10-30%) and varied among any scenarios. These evidence-based data represent a reference for the clinical management of these patients.

Autologous tooth graft: a histological comparison between dentin mixed with xenograft and dentin alone grafts in socket preservation.

The aim of this study is to compare the histological results after socket preservation between dentin mixed with xenograft and dentin alone in tooth graft procedure. Six patients were included in this prospective case series study and treated in three clinical centers using standardized clinical procedures. This clinical trial enrolled patients with three walls post-extractive defects requiring the restoration of bone dimension and shape in mandibular zone. The patients were divided in two groups: extracted teeth alone (first group) and extracted teeth mixed with equal quantity of xenograft (second group). The extracted tooth was cleaned and processed by a recently introduced automated device, that allows fragmentation and partial demineralization of the tooth matrix and used as graft material. The graft obtained in this way, was inserted at the time of the extraction. A covering membrane was used to protect the graft. Implants were placed after 4 months of healing. Bone biopsies of the all grafted sites were taken at the time of implant surgery, for histological analysis. Descriptive statistics was used to synthesize the results, using mean values and standard deviations. Six patients (5 women, mean age at surgery 50.3±12.1 years) were treated and after 4 months of healing both groups, grafts height appeared stable. No signs of infection were present. Bone biopsy were taken in all grafted sites (3 with group one and 3 with group two). The histologic analysis revealed no inflammatory or infective reaction against both groups. The histomorphometry results between the two groups are different. The first group show an amount of new bone greater than the second group (+85.29%) and minor quantity of residual graft (-83.59%). The dentin alone shows a larger amount of new bone.

Nodule size as predictive factor of efficacy of radiofrequency ablation in treating autonomously functioning thyroid nodules.

CONTEXT: No defined pre-treatment factors are able to predict the response to radiofrequency ablation (RFA) of an autonomously functioning thyroid nodule (AFTN). OBJECTIVE: Primary endpoint was to evaluate the success rate of RFA to restore euthyroidism in a cohort of adult patients with small solitary AFTN compared with medium-sized nodules. Secondary endpoints included nodule volume reduction and rate of conversion from hot nodules to cold using scintiscan. METHODS: This was a 24-month prospective monocentric open parallel-group trial. Twenty-nine patients with AFTN were divided into two groups based on thyroid volume: 15 patients with small nodules (<12 mL) in group A and 14 patients with medium nodules (>12 mL) in group B. All patients underwent a single session of RFA and were clinically, biochemically, and morphologically evaluated at baseline and at 1, 6, 12 and 24 months after treatment. RESULTS: After RFA, there was greater nodule volume reduction in group A compared with group B (p < 0.001 for each follow-up point). In group A, there was a greater increase in TSH levels than in group B at 6 (p = 0.01), 12 (p = 0.005), and 24 months (p < 0.001). At 24 months, the rate of responders was greater in group A than in group B (86 vs. 45%; p < 0.001). In group A, 86% of nodules converted from hot to cold compared with 18% in group B (p < 0.001). CONCLUSIONS: A single session of RFA was effective in restoring euthyroidism in patients with small AFTNs. Nodule volume seems to be a significant predictive factor of the efficacy of RFA in treating AFTN.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

Serum chitotriosidase in postmenopausal women with severe osteoporosis.

UNLABELLED: Human chitotriosidase (Chit) increases during the osteoclast differentiation and their activity. We demonstrated that serum Chit was significantly higher in osteoporotic subjects than in healthy control ones and revealed a negative correlation between Chit and bone mineral density (BMD). This is the first study showing a correlation between Chit and severe postmenopausal osteoporosis. INTRODUCTION: Mammalian chitinases exert important biological roles in the monocyte lineage and chronic inflammatory diseases. In particular, Chit seems to promote bone resorption in vitro. No in vivo studies have been performed to confirm this finding. We aim to evaluate Chit activity in postmenopausal women affected by severe osteoporosis. METHODS: In this cross-sectional study, 91 postmenopausal women affected by osteoporosis and 61 with either osteopenia or normal BMD were screened. All subjects were assessed by dual-energy X-ray absorptiometry (DXA) and X-ray vertebral morphometry. Osteoporotic subjects were considered eligible if they were affected by at least one vertebral osteoporotic fracture (group A = 57 subjects). Osteopenic or healthy subjects were free from osteoporotic fractures (group B = 51 subjects). Enzymatic Chit and serum ß-CrossLaps (CTX) were measured in the whole population. RESULTS: Group A showed higher serum levels of beta-CTX compared to group B (0.40 ± 0.26 ng/mL vs 0.29 ± 0.2 ng/mL, p = 0.022). Chit was significantly higher in group A than in group B (1042 ± 613 nmol/mL/h vs 472 ± 313 nmol/mL/h, p < 0.001, respectively) even after adjustment for age (p < 0.001). Spearman correlation test revealed a negative correlation between Chit and BMD at each site (lumbar spine: r = -0.38, p = 0.001, femoral neck: r = -0.35, p = 0.001, total femur: r = -0.39, p < 0.001). Furthermore, a positive correlation between Chit and PTH was observed (r = 0.26, p = 0.013). No significant correlation was found between Chit and beta-CTX (r = 0.12, p = 0.229). After a multivariate analysis, a positive correlation between severe osteoporosis and Chit (p < 0.001), beta-CTX (p = 0.013), and age (p < 0.001) was observed. CONCLUSION: This is the first clinical study showing a correlation between Chit and severe postmenopausal osteoporosis. Larger and prospective studies are needed to evaluate if Chit may be a promising clinical biomarker and/or therapeutic monitor in subjects with osteoporosis.

Temperature and time variations during osteotomies performed with different piezosurgical devices: an in vitro study.

AIM: The aim of this experimental in vitro study was to evaluate the effects of the piezoelectric device in temperature and time variations in standardized osteotomies performed with similar tip inserts in bovine bone blocks. METHODS: Two different piezosurgical devices were used the OE-F15(®) (Osada Inc., Los Angeles, California, USA) and the Surgybone(®) (Silfradent Inc., Sofia, Forli Cesena, Italy). Serrated inserts with similar geometry were coupled with each device (ST94 insert/test A and P0700 insert/test B). Osteotomies 10 mm long and 3 mm deep were performed in bone blocks resembling type II (dense) and type IV (soft) bone densities with and without irrigation. Thermal changes and time variations were recorded. The effects of bone density, irrigation, and device on temperature changes and time necessary to accomplish the osteotomies were analyzed. RESULTS: Thermal analysis showed significant higher temperatures during piezosurgery osteotomies in hard bone without irrigation (P < 0.05). The type of piezosurgical device did not influence thermal variations (P > 0.05). Time analysis showed that the mean time values necessary to perform osteotomies were shorter in soft bone than in dense bone (P < 0.05). CONCLUSIONS: Within the limitations of this in vitro study, it may be concluded that the temperature increases more in piezosurgery osteotomies in dense bone without irrigation; the time to perform the osteotomy with piezosurgery is shorter in soft bone compared to hard bone; and the piezosurgical device have a minimal influence in the temperature and time variations when a similar tip design is used during piezosurgery osteotomies.

Italian association of clinical endocrinologists (AME) position statement: drug therapy of osteoporosis.

Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration.

Oral anti-diabetic drugs and fracture risk, cut to the bone: safe or dangerous? A narrative review.

Fracture risk is higher in older adults with type 2 diabetes and may be influenced by treatments for diabetes. Oral anti-diabetic drugs have different effects on bone metabolism. The purpose of this review is to describe the effects of these drugs on bone metabolism and fracture risk. Osteoporosis is a progressive skeletal disorder that is characterized by compromised bone strength and increased risk of fracture. This condition has become an important global health problem, affecting approximately 200 million people worldwide. Another chronic and highly prevalent condition is diabetes mellitus, which affects more than 380 million people; both type 1 and type 2 diabetes are risk factors for fracture. Type 2 diabetes, in particular, is associated with impaired bone strength, although it is characterized by normal or elevated bone mineral density. Several therapeutic strategies are available to achieve the best outcomes in the management of diabetes mellitus but these have different effects on bone metabolism. The purpose of this narrative review is to describe the effects of oral hypoglycemic agents (metformin, sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-dependent glucose transporter 2 inhibitors) on bone metabolism and on the risk of developing fragility fractures in patients with type 2 diabetes. Both diabetes and osteoporosis represent a significant burden in terms of healthcare costs and quality of life. It is very important to choose therapies for diabetes that ensure good metabolic control whilst preserving skeletal health.

Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism.

UNLABELLED: No data on the pharmacological treatment of normocalcemic hyperparathyroidism (NPHPT) are available. We treated 30 NPHPT postmenopausal women with alendronate/cholecalciferol (treated group) or vitamin D alone (control group). Over 1 year, bone mineral density (BMD) increased significantly in treated group, but not in control group. Both treatments did not affect serum or urinary calcium. INTRODUCTION: Normocalcemic primary hyperparathyroidism (NPHPT) is defined by normal serum calcium and consistently elevated PTH levels after ruling out the causes of secondary hyperparathyroidism. It is likely that subjects with NPHPT may develop kidney and bone disease. As no data on the pharmacological treatment of NPHPT are available, we aimed to investigate the effects of alendronate and cholecalciferol on both BMD and bone biochemical markers in postmenopausal women with NPHPT. Safety of vitamin D was evaluated as secondary endpoint. METHODS: The study was a prospective open label randomized trial comparing 15 postmenopausal women with NPHPT (PMW-NPHPT), treated with oral alendronate plus cholecalciferol (treated group) and 15 PMW-NPHPT treated only with cholecalciferol (control group). Blood samples were obtained at baseline and after 3, 6, and 12 months. Bone turnover markers (BTM) were measured at baseline, 3, and 6 months, respectively. BMD was assessed at baseline and after 12 months. RESULTS: After 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group (p = 0.001). No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. BTM significantly decreased in the treated group but not in the control group, at 3 and 6 months (p < 0.001), respectively. No cases of hypercalcemia or hypercalciuria were detected during the study. CONCLUSION: The results of this study indicate that alendronate/cholecalciferol increases BMD in postmenopausal women with NPHPT. Alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium.

In vivo corneal confocal microscopy as a novel non-invasive tool to investigate cardiac autonomic neuropathy in Type 1 diabetes.

AIMS: To investigate whether small nerve fibre degeneration detected using corneal confocal microscopy is associated with cardiac autonomic neuropathy in people with Type 1 diabetes. METHODS: Thirty-six people with Type 1 diabetes and 20 age- and sex-matched healthy control subjects were enrolled. Tests to determine heart rate response to deep-breathing (expiratory-to-inspiratory ratio), heart rate response to lying-to-stand test (30:15 ratio) and blood pressure response to standing were performed to detect cardiac autonomic neuropathy. Corneal confocal microscopy was performed to assess: corneal nerve density and corneal nerve beadings; branching pattern; and nerve fibre tortuosity. RESULTS: Compared with control participants, participants with Type 1 diabetes had fewer (mean ± SD 45.4 ± 20.2 vs 92.0 ± 22.7 fibres/mm²; P < 0.001) and more tortuous corneal nerve fibres (20 participants with Type 1 diabetes vs four control participants had nerve tortuosity grade 2/3; P = 0.022) and fewer beadings (mean ± SD 15.1 ± 3.5 vs 20.6 ± 5.0; P < 0.001). Of the participants with Type 1 diabetes, 11 met the criteria for the diagnosis of cardiac autonomic neuropathy. Corneal nerve density was significantly lower in participants with cardiac autonomic neuropathy than in those without (mean ± SD 32.8 ± 16.4 vs 51.7 ± 18.9 fibres/mm²; P = 0.008). This difference remained significant after adjustment for age (P = 0.02), gender (P = 0.04), disease duration (P = 0.005), insulin requirement (P = 0.02) and neuropathy disability score (P = 0.04). CONCLUSION: This study suggests that corneal confocal microscopy could represent a new and non-invasive tool to investigate cardiac autonomic neuropathy in people with Type 1 diabetes. Larger studies are required to define the role of corneal confocal microscopy in the assessment of cardiac autonomic neuropathy.

[Benefit of skull vibration-induced nystagmus test in occupational medicine]. / Intérêt du test de vibration osseux vestibulaire en médecine du travail.

BACKGROUND: Nystagmus induced by vibrations (NIV), has been optimized by the present authors this last decade. The skull vibration-induced nystagmus test (SVINT) can be designated as a high-frequency global "vestibular Weber test" and can be considered as an office-based examination to detect vestibular asymmetry. The aim of this study is to define the tolerance of the SVINT as well as its comparison to the simplified caloric test of Veits (CTV) in normal workers during the pre-employment visit at the occupational medicine center. MATERIAL AND METHODS: The vestibular function has been evaluated by the SVINT and the CTV in 87 healthy workers. The tolerance of the two procedures has been evaluated by a 4-items questionnaire (nausea, vomiting, sweating, asthenia). RESULTS: The caloric test was normal in each worker. The SVINT was positive in one patient who had a partial unilateral vestibular dysfunction related to trauma. The mean duration of the procedure was 15 min for CTV and 1 min for SVINT. Side effects (nausea, vomiting, sweating, asthenia) were present in 50% of the workers following CTV and in only one patient after SVINT. The SVINT demonstrated significantly less side effects for each item (p < 0.0001). CONCLUSIONS: SVINT is a valid, rapid, low-cost clinical screening test and does not cause patient discomfort. It is suggested that this test which explores vestibular high frequencies and is not modified by vestibular compensation is useful for the diagnostic screening of workers' vestibular dysfunction, when combined with other vestibular tests and complements the CTV.

Correlation between vegetarian diet and oral health: a systematic review.

OBJECTIVE: Nutrition plays a significant role in preserving the balance of the human body. Considering each person's particular characteristics, diet can directly and indirectly alter the body's immune response. The purpose of this study is to draw attention to the connection between a vegetarian diet and its impact on oral health. MATERIALS AND METHODS: To determine the connection between a vegetarian diet and dental health, a search of the literature was conducted on the PubMed, Scopus, and Web of Science databases. English language and a publication year between January 1, 2013, and March 1, 2023, were the inclusion criteria for the search. RESULTS: There were 167 articles in total that addressed the subject of interest, and 18 of them were chosen for qualitative analysis. CONCLUSIONS: This study suggests that a vegetarian diet may alter oral health, namely periodontal health, tooth erosion, and oral microbiome. Even if the data collected prevents the effect of a vegetarian diet on oral health from being confirmed, this study acts as a starting point for future, more focused research.

Pharmacological Sedation in Paediatric Dentistry.

AIM: This research aims to explore and evaluate various sedation strategies used in paediatric dentistry, focusing on effectively and safely addressing dental anxiety to improve cooperation during dental treatment in paediatric patients. MATERIALS: To identify relevant studies for this systematic review, the Scopus, Web of Science and PubMed databases were used, combining the terms "sedation" with "pediatric dentistry" or "pedodontics" through the Boolean operators "AND" and "OR". Only literature published in English within the last ten years was included. The inclusion criteria were clinical studies, case reports and in vivo studies, while systematic reviews, meta-analyses and studies conducted on animals or in vitro were excluded. After eliminating duplicates, 544 articles were identified, of which 501 were excluded for not meeting the inclusion criteria. A further 27 articles were excluded for various reasons, including lack of retrieval, in vitro nature or being reviews. Finally, 16 articles were selected for inclusion in the review. CONCLUSION: These findings underscore the importance of pharmacological management in paediatric dental care, offering valuable insights into the selection and application of sedation techniques to mitigate dental anxiety and enhance patient outcomes.

Ceramic biomaterials in dentistry: chemical structure and biosafety - a review and a bibliometric visual mapping on Scopus database.

OBJECTIVE: A biomaterial is any non-pharmaceutical substance or a mixture of synthetic or natural substances used independently or as part of a system for any amount of time with the aim of mending, supporting the growth, or replacing tissues, organs, or functions of the body. It is a non-renewable material that interacts with biological systems. The purpose of this study was to assess the advances in ceramic biomaterials and perform a bibliometric mapping of the literature on the subject. MATERIALS AND METHODS: The Scopus database was used for manuscript screening (Elsevier, Amsterdam, The Netherlands). The effect of the scientific production has been assessed using scientometric citational metrics. RESULTS: A total of 2,554 pieces of literature, including 2,234 papers, 170 conference proceedings, 109 reviews, 35 book chapters, 3 editorial letters, and 3 short surveys, were retrieved. Based on the research conducted, it is noted that ceramic materials are high-performing by being porous or glassy and can, therefore, serve as fillers, covering materials, and scaffolds in medicine and biotechnology. They are frequently employed not only in orthopedic and maxillofacial surgery but also in dentistry for dental prostheses. CONCLUSIONS: Materials monitoring methods enable us to track the three-dimensional evolution of ceramics' volume, as well as flaws or micro-cracks.

A study survey on molnupiravir treatment in COVID-19 patients at home in Ninh Thuan province, Vietnam.

OBJECTIVE: Molnupiravir (MOV) is an oral antiviral drug that received use authorization in Vietnam for the treatment of mild COVID-19 (F0). There was a need to develop alternative approaches that allowed patients to access medication, decongest hospitals, clinics, and facilities, and protect people from infection. During the COVID-19 crisis, the Ninh Thuan Health Authorities implemented the home delivery of medication by community health workers. This study conducted in collaboration with two important Italian entities [the Aldo Moro University of Bari City and the 118 Department of Territorial Emergency System (118 SET) of Taranto City] aimed to evaluate the implementation of home delivery F0 treatment package assessing the rate of infection recovering during the coronavirus pandemic in Ninh Thuan province, Vietnam. PATIENTS AND METHODS: A convergent mixed methods research, based on a longitudinal study with quantitative research and qualitative assessments, evaluated four implementation outcomes: the feasibility, fidelity, coverage, sustainability, and effectiveness of the initiative. Data sources included routinely collected data, a telephonic survey of patients, an analysis of set-up and recurrent costs, as well as descriptive exploratory qualitative and quantitative analysis. RESULTS: After taking the MOV for 5 days, only 35 out of the initial 400 F0 patients remained positive, while 365 patients (91.2%) were negative (CT≥30). Whilst, the successful rate after using the drug during the course accounted for 99.85% and 100% after the entire treatment course, without any death. After 5 days of taking the drug, a positive test result (CT<30) was associated with age group ≥60 (OR=2.7) and comorbidities (OR=3.0) (p<0.05) compared to negative and positive results (CT≥30). Negative factors impacting F0 at home include a shortage of healthcare workers, inadequate supply of thermometers and SpO2 meters, and insufficient financial support for healthcare workers. CONCLUSIONS: MOV caused a reduction in the risk of hospitalization or death in mild COVID-19 patients, and molnupiravir was also found to be well tolerated and safe without any major adverse events during the administration period.

HLA-dependent autoantibodies against post-translationally modified collagen type II in type 1 diabetes mellitus.

AIMS/HYPOTHESIS: In this study the involvement of oxidative stress in type 1 diabetes mellitus autoimmunity and the possible association with rheumatoid arthritis (RA) was investigated. We tested the hypothesis that oxidative stress induced by chronic hyperglycaemia triggers post-translational modifications and thus the formation of neo-antigens in type 1 diabetes, similar to the ones found in RA. METHODS: Collagen type II (CII), a known autoantigen in RA, was treated with ribose and various reactive oxygen species (ROS). Levels of antibodies specific to native and ROS-modified CII (ROS-CII) were compared in type 1 diabetes, type 2 diabetes and healthy controls, and related to the HLA genotype. RESULTS: Significantly higher binding to ROS-CII vs native CII was observed in type 1 diabetic patients possessing the HLA-DRB1*04 allele irrespective of variables of glucose control (blood glucose or HbA(1c)). Type 1 diabetic patients carrying a DRB1*04 allele with the shared epitope showed the highest risk for ROS-CII autoimmunity, while the DRB1*0301 allele was protective. Conversely, native CII autoimmunity was not associated with any specific DRB1 allele. Positive and inverse seroconversion rates of response to ROS-CII were high in DRB1*04-positive type 1 diabetic patients. CONCLUSION: Hyperglycaemia and oxidative stress may trigger genetically controlled autoimmunity to ROS-CII and may explain the association between type 1 diabetes mellitus and RA.