Associations between hypovitaminosis D and COVID-19: a narrative review.

In the search for factors affecting incidence and lethality of the current COVID-19 pandemic, recent association studies explored the possible role of vitamin D deficiency. Altogether, these studies, in most cases based on cross-sectional analyses, could not yet provide a convincing demonstration of a cause-effect relationship. In this editorial, the authors describe the scientific evidence underlying a possible role of vitamin D in the prevention and development of the pandemic, considering its immunomodulatory role and antiviral effects. They conclude that further studies are needed to (1) better explore possible associations between vitamin D deficiency and COVID-19 morbidity and lethality, and (2) assess if compensating such deficiency could avoid or mitigate the worst manifestations of COVID-19. They highlight the need for public health campaigns to promote consumption of vitamin D-rich foods and proper sunlight exposition or, when this is not possible, controlled pharmaceutical supplementation, especially in countries with high prevalence of hypovitaminosis D.

Circulating Long Non-Coding RNA GAS5 Is Overexpressed in Serum from Osteoporotic Patients and Is Associated with Increased Risk of Bone Fragility.

Osteoporosis (OP) is a multifactorial disorder in which environmental factors along with genetic variants and epigenetic mechanisms have been implicated. Long non-coding RNAs (lncRNAs) have recently emerged as important regulators of bone metabolism and OP aetiology. In this study, we analyzed the expression level and the genetic association of lncRNA GAS5 in OP patients compared to controls. Quantitative RT-PCR analysis of GAS5 was performed on the serum of 56 OP patients and 28 healthy individuals. OP subjects were divided into three groups of analysis: 29 with fragility fractures of lumbar spine (OP_VF), 14 with fragility fractures of femoral neck (OP_FF) and 13 without fractures (OP_WF). Genotyping of the rs145204276 insertion/deletion polymorphism has also been performed by Restriction fragment length polymorphism (RFLP) and direct sequencing analyses. Expression of circulating GAS5 is significantly increased in OP patients compared to controls (p < 0.01), with a statistically higher significance in fractured OP individuals vs. healthy subjects (p < 0.001). No statistically significant change was found in female OP patients; conversely, GAS5 is upregulated in the subgroup of fractured OP women sera (p < 0.01) and in all OP males (p < 0.05). Furthermore, a direct correlation between GAS5 expression level and parathyroid hormone (PTH) concentration was found in OP patients (r = 0.2930; p = 0.0389). Genetic analysis of rs145204276 revealed that the deletion allele was correlated with a higher expression of GAS5 in OP patients (0.22 ± 0.02 vs. 0.15 ± 0.01, ** p < 0.01). Our results suggest circulating GAS5 as a putative biomarker for the diagnosis and prognosis of OP and OP-related fractures.

How the knowledge of fracture risk might influence adherence to oral therapy of osteoporosis in Italy: the ADEOST study.

UNLABELLED: The patients' adherence to osteoporosis treatments is low. In our study population a history of osteoporotic fractures was associated to better compliance and persistence; however, a 12-month randomized study carried out on 816 osteoporotic women showed that providing the patients with their individual fracture risk information did not prove effective. PURPOSE: Several drugs are currently available for the treatment of osteoporosis, but the patients' compliance and persistence with these treatments are low. This study aimed to both analyze the adherence to oral osteoporosis medications among Italian osteoporotic patients (cross-sectional study) and evaluate if providing patients with their individual fracture risk information may improve compliance and persistence (prospective study). METHODS: A total of 3379 osteoporotic patients referred as outpatients for a visit 1 year after receiving a prescription of oral osteoporosis medications for the first time, were enrolled for the retrospective study. Moreover, 816 postmenopausal women receiving an oral prescription for osteoporosis for the first time, were randomized into two groups: group 1 (managed according to standard clinical practice) and group 2 (managed with greater patient involvement and information on the individual risk of major osteoporotic fractures calculated by DeFRA algorithm). RESULTS: In the retrospective study, a history of osteoporotic fractures, the frequency of drug administration and a condition of being overweight/obese had a significant influence on both compliance and persistence. Of the 816 patients enrolled in the longitudinal study, 731 (374 of group 1 and 357 of group 2) attended the 1 year follow-up visit. The percentage of women with high compliance or persistence was greater in group 2 (64.2 vs. 58.1 % and 66.8 vs. 62.6 %, respectively), but without reaching any statistical significance. CONCLUSIONS: Although providing the patients with their individual fracture risk information was not statistically effective, further studies on additional interventions able to improve the patients' perceived risk of fracture are warranted.

[Technological advances and hospital-at-home care]. / L'innovazione tecnologica e l'ospedalizzazione a domicilio.

Advances in the miniaturization and portability of diagnostic technologies, information technologies, remote monitoring, and long-distance care have increased the viability of home-based care, even for patients with serious conditions. Telemedicine and teleradiology projects are active at the Hospital at Home Service of Torino.

Circulating MicroRNAs as Biomarkers of Osteoporosis and Fragility Fractures.

CONTEXT: Measurement of circulating microRNAs (miRNAs) as potential biomarkers of fragility fracture risk has recently become a subject of investigation. OBJECTIVE: Measure by next-generation sequencing (NGS), global miRNA expression in serum samples of osteoporotic subjects vs individuals with normal bone mineral density (BMD). DESIGN: Samples were collected from patients with different bone phenotypes and/or fragility fractures who did not receive any antiresorptive and/or bone-forming drug at the time of blood collection. SETTING: Samples and data were collected at 7 medical centers in Italy. PATIENTS: NGS prescreening: 50 osteoporotic patients vs 30 individuals with normal BMD. Droplet digital polymerase chain reaction (ddPCR) validation: 213 patients with different bone phenotypes, including the NGS-analyzed cohort. RESULTS: NGS identified 5 miRNAs (miR-8085, miR-320a-3p, miR-23a-3p, miR-4497, miR-145-5p) differentially expressed in osteoporosis cases without fractures vs controls. ddPCR validation confirmed lower c-miR-23a-3p expression in osteoporotic patients, with or without fracture, than in osteopenic and normal subjects and increased c-miR-320a-3p expression in osteoporotic patients with fracture and lower expression in osteoporotic patients without fracture. ddPCR analysis showed a significantly increased expression of miR-21-5p in osteoporotic patients, with or without fracture, than in osteopenic and normal subjects, not evidenced by the NGS prescreening. DISCUSSION: Our study confirmed levels of c-miR-23a-3p and c-miR-21-5p as able to distinguish osteoporotic patients and subjects with normal BMD. Increased levels of c-miR-320a-3p specifically associated with fractures, independently by BMD, suggesting c-miR-320a-3p as a prognostic indicator of fracture risk in osteoporotic patients, to be confirmed in prospective studies on incident fractures.

Proinflammatory cytokine gene polymorphisms and susceptibility to Paget's disease of bone: an association study.

BACKGROUND: Recent studies suggested that proinflammatory cytokines are involved in the pathophysiology of Paget's disease of bone (PDB). The purpose of this study was to evaluate whether functionally active polymorphisms of the interleukin-1α (IL-1α), interleukin-1ß (IL-ß), interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) genes would modify the occurrence and the clinical features of PDB. METHODS: Genomic DNA was extracted from 144 PDB patients and 115 healthy controls. All subjects were genotyped for the following functionally active polymorphisms in the proinflammatory cytokine genes: IL-1α-889 C>T, IL-1ß-511 C>T, IL-6-174 G>C, and TNF-α-308 G>A. Allele and genotype frequencies were compared between cases and controls. The clinical characteristics of the disease were compared according to the different genotypes. RESULTS: Allele and genotype frequencies of the examined polymorphism resulted nearly identical in cases and controls. Examining the association with the clinical features, PDB patients carrying the C/C genotype of the IL-6 gene showed a significantly (p<0.001) higher frequency of hearing loss and primary hyperparathyroidism. No significant difference in the remaining clinical features was found. In conclusion, this study do not support the hypothesis that the examined proinflammatory genes are major genetic risk factor for PDB. However, our data suggests a role for the IL-6 gene in modifying the clinical features of the disease.

Percutaneous vertebroplasty in osteoporotic patients: an institutional experience of 1,634 patients with long-term follow-up.

PURPOSE: To assess long-term clinical outcome of percutaneous vertebroplasty (PV). MATERIALS AND METHODS: PV was performed in 1,634 patients (1,387 women; median age 73 years ± 9.3) with painful osteoporotic vertebral compression fractures (VCFs). All patients had back pain that persisted for ≥ 2 months with a concordant magnetic resonance imaging study. After PV, medical therapy for osteoporosis was continued, and patients were prospectively evaluated (follow-up 11.8-44.9 months, mean 25.0 months). Visual analog scale (VAS), Oswestry Disability Index (ODI), analgesic drug use, and use of external brace support were recorded at baseline and during follow-up. New occurrences of symptomatic vertebral fractures were recorded. RESULTS: The mean VAS score of 7.94 significantly improved to 1.12 at the primary endpoint (P < .001). Differences in patterns of analgesic usage compared with baseline values were highly statistically significant (marginal homogeneity test, P < .001). Median ODI values of 82% before treatment significantly decreased to 6% (P < .001). Before intervention, 1,279 patients wore a brace; 1,167 (91.2%) patients did not wear a brace after PV (χ(2) = 31.005, P < .0001). A new painful fracture with a significant higher proportion of contiguous vertebrae (63.6%) occurred in 214 (13.1%) patients (z = 7.59, P = .025). CONCLUSIONS: PV can provide durable pain relief and improvement in ambulation in patients with VCFs.

Does solar ultraviolet radiation play a role in COVID-19 infection and deaths? An environmental ecological study in Italy.

A significantly stronger impact in mortality and morbidity by COVID-19 has been observed in the northern Italian regions compared to the southern ones. The reasons of this geographical pattern might involve several concurrent factors. The main objective of this work is to investigate whether any correlations exist between the spatial distribution of COVID-19 cases and deaths in the different Italian regions and the amount of solar ultraviolet (UV) radiation at the Earth's surface. To this purpose, in this environmental ecological study a mixed-effect exponential regression was built to explain the incidence of COVID-19 based on the environmental conditions, and demographic and pathophysiologic factors. Observations and estimates of the cumulative solar UV exposure have been included to quantify the amount of radiation available e.g., for pre-vitamin D3 synthesis or SARS-CoV-2 inactivation by sunlight. The analysis shows a significant correlation (p-value <5 × 10-2) between the response variables (death percentage, incidence of infections and positive tests) and biologically effective solar UV radiation, residents in nursing homes per inhabitant (NHR), air temperature, death percentage due to the most frequent comorbidities. Among all factors, the amount of solar UV radiation is the variable contributing the most to the observed correlation, explaining up to 83.2% of the variance of the COVID-19 affected cases per population. While the statistical outcomes of the study do not directly entail a specific cause-effect relationship, our results are consistent with the hypothesis that solar UV radiation impacted on the development of the infection and on its complications, e.g. through the effect of vitamin D on the immune system or virus inactivation by sunlight. The analytical framework used in this study, based on commonly available data, can be easily replicated in other countries and geographical domains to identify possible correlations between exposure to solar UV radiation and the spread of the pandemic.

Genetic epidemiology of Paget's disease of bone in italy: sequestosome1/p62 gene mutational test and haplotype analysis at 5q35 in a large representative series of sporadic and familial Italian cases of Paget's disease of bone.

Families affected by Paget's disease of bone frequently harbor mutations in the SQSTM1/p62 gene. In this multicentric study we collected 345 sporadic and 12 familial PDB cases throughout Italy, identifying 12 different mutations, 5 of which are newly reported and 3, D335E, A381V, and Y383X, external to the UBA domain. Subjects with truncating mutations, E396X, showed a significantly younger age at clinical diagnosis, while the Y383X subjects had a higher average number of affected skeletal sites. All the mutants exhibited the CGTG-H2 haplotype. In two pairs and one triad of unrelated Italian PDB families from different Italian regions, we detected a common SQSTM1/p62 mutation for each P392L, M404V, and G425R group. Since the CGTG-H2 haplotype frequency was also high in normal subjects, and genetic influence due to migratory fluxes of different ethnic groups exists in the Italian population, to refine the search for a more geographically specific founder effect, we extended the haplotype analysis in these families using polymorphic microsatellite repeat markers, within and flanking the SQSTM1/p62 locus, from chromosome 5q35, other than the exon 6 and 3'UTR polymorphisms. All mutant carriers from two of the three M404V families and from the G425R families exhibited common extended chromosome 5q35 haplotypes, IT01 and IT02, respectively, which may be reflecting influences of past migrations. This may be helpful in estimating the true rate of de novo mutations. We confirm the data on the existence of both a mutational hotspot at the UBA domain of SQSTM1/p62 and a founder effect in the PDB population.

Zoledronate in the prevention of Paget's (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to prevent SQSTM1-mediated Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget's disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carry SQSTM1 mutations. METHODS AND ANALYSIS: People with a family history of PDB aged >30 years who test positive for SQSTM1 mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events. ETHICS AND DISSEMINATION: The study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals with SQSTM1 mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis.

Compelling evidences suggest that increased production of osteoclastogenic cytokines by activated T cells plays a relevant role in the bone loss induced by estrogen deficiency in the mouse. However, little information is available on the role of T cells in post-menopausal bone loss in humans. To investigate this issue we have assessed the production of cytokines involved in osteoclastogenesis (RANKL, TNFalpha and OPG), in vitro osteoclast (OC) formation in pre and post-menopausal women, the latter with or without osteoporosis. We evaluated also OC precursors in peripheral blood and the ability of peripheral blood mononuclear cells to produce TNFalpha in both basal and stimulated condition by flow cytometry in these subjects. Our data demonstrate that estrogen deficiency enhances the production of the pro-osteoclastogenetic cytokines TNFalpha and RANKL and increases the number of circulating OC precursors. Furthermore, we show that T cells and monocytes from women with osteoporosis exhibit a higher production of TNFalpha than those from the other two groups. Our findings suggest that estrogen deficiency stimulates OC formation both by increasing the production of TNFalpha and RANKL and increasing the number of OC precursors. Women with post-menopausal osteoporosis have a higher T cell activity than healthy post-menopausal subjects; T cells thus contribute to the bone loss induced by estrogen deficiency in humans as they do in the mouse.

Bone mineral density and singh index predict bone mechanical properties of human femur.

The aim of our study was to assess the predictive value of the Singh index (SI), which estimates bone architecture, and bone density (BMD) when dealing with the mechanical competence of bone and to analze possible differences in bone properties between gender in humans. The relationship between SI, BMD, and mechanical competence was analyzed in 106 bone cylinders from 37 human femoral heads obtained during hip-joint replacement surgery for low energy fracture or for osteoarthritis. Bones from osteoporotic patients are less dense and more brittle compared with bones from osteoarthritic patients, as expected. Among osteoporotic patients female bones were more brittle than those from males, although BMD was similar. In osteoarthritic patients there were no significant differences among sexes. Bone mechanical competence varies according to BMD and to SI categories. Thus, our study suggests that bone strength is predicted by both BMD and bone architecture.

Allometric scaling and biomechanical behavior of the bone tissue: an experimental intraspecific investigation.

INTRODUCTION: Adaptation of bone to different loads has received much attention. This paper examines the consequences of differences in size on bones from the same animal species. METHODS: The study was conducted on 32 canine radii. Their geometry, densitometry and mechanical properties were determined and one-way ANOVA was used to analyze their distribution by sex. Bending failure was observed during the mechanical test. The bones were then likened to thin beams and the mechanical parameters of interest were appraised via beam theory. A multiple linear regression model with stepwise analyses was employed to determine which parameters rule the mechanical characteristics. The relationships between the bone mass and the parameters investigated were analyzed by means of a model II regression in order to state how the scaling of the bone characteristics act on its mechanical behavior. RESULTS: The linear regression model demonstrated that an animal's mass, its sex and the mineral content and the geometrical properties of its bones almost entirely predict their mechanical behavior. A close fit was found between the experimentally determined and the theoretical slopes of the log regressed allometric equations. The work to failure was found to scale almost linearly with the animal and bone mass and the macroscopical bone material properties were found to be mass invariant. The allometric equations showed that as the animal mass increases, employing proportionally the same amount of tissue, bones get proportionally shorter and proportionally distribute their tissue further from the cross-sectional centroid. CONCLUSIONS: Our results suggest that dimensional analysis on the assumption of geometrical self-similarity and mechanical testing according to classic elastic solutions are reasonable in bones tested in accordance to our set up. The bone geometry is the parameter able to curb the energy effects of an animal mass increase. The allometric scaling of the bone length and the cross-sectional layout, without an increase in the amount of material proportionally employed, preserves linear with the animal mass the amount of energy necessary to fracture a bone and restrain the rise of stresses and strains in the cross-section.

Fracture incidence and characterization in patients on osteoporosis treatment: the ICARO study.

UNLABELLED: None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D. INTRODUCTION: Osteoporotic fracture is one of the most important public health concerns among the elderly. Currently available therapies have been shown to significantly decrease the risk of fracture, although none of them completely abolishes this risk. In clinical practice, poor treatment response may also result from a number of other factors. MATERIALS AND METHODS: The Incidence and ChAracterization of inadequate clinical Responders in Osteoporosis (ICARO) is a multicenter, observational study carried out in Italy. It aimed to analyze, in postmenopausal women with established osteoporosis, the risk factors for an "inadequate clinical response" to drug therapy, defined as the occurrence of new vertebral or nonvertebral fragility fractures in patients prescribed, for at least 1 year, alendronate, risedronate, or raloxifene, with a compliance >50%. RESULTS: In 880 patients treated with antiresorptive agents for a median of 2.0 years (95% CI: 1.0-4.5) years, the "inadequate clinical responder (ICR)" subjects over the observation period were 220 (25%), with an annual incidence of 8.9%. ICRs, compared with "adequate clinical responders (ACRs)," had more pretreatment fractures and were treated longer (2.8 versus 1.8 years; p < 0.001). After multiple adjustment for these confounding factors, significant determinants of inadequate clinical response were a poorer treatment compliance and a less frequent co-administration of calcium and vitamin D supplements. CONCLUSIONS: The incidence of fractures during treatment with antiresorptive agents in a clinical setting is considerably higher than that observed in randomized clinical trials. Inadequate compliance to treatment and lack of supplementation of calcium and vitamin D are major determinants of this poor response.

Immune system and bone metabolism: Does thymectomy influence postmenopausal bone loss in humans?

Recent studies of animal models have suggested that an increase in the number of T cells due to both peripheral expansion and increased thymic T cell output plays a key role in the regulation of bone loss after ovariectomy. Osteoclastogenic cytokines which are either produced by T cells or activate T cells have also been implicated in ovx induced bone loss. Among them are TNF alpha and IL-7. The present study investigates the role of thymectomy (THX) and IL-7 in bone metabolism in humans. We studied T cells subsets, cytokine production and bone metabolism in 13 women thymectomized for Myasthenia gravis as compared to healthy controls. Our data demonstrate that the number of CD4+ and TNF-producing T cells is lower in THX women as compared to euthymic controls. However in THX women the residual T cells produce higher levels of IL-7 and RANKL. Furthermore, flow cytometry shows that IL-7 is produced by T and B cells. Serum levels of TNF alpha were unaffected by THX and both serum TNF alpha and the RANKL/OPG correlated inversely with BMD. There were no differences in bone turnover and bone mineral density between THX women and the controls. These data suggest that THX decreases the number of TNF-producing CD4+ T cells but does not alters serum TNF levels. The RANKL/OPG ratio and indices of bone metabolisms are also not affected by THX, although THX increases the levels of IL-7 and RANKL. Further studies are needed to clarify the role of thymus in bone metabolism and osteoclastogenesis in postmenopausal women.

Spontaneous osteoclast formation from peripheral blood mononuclear cells in postmenopausal osteoporosis.

Osteoclasts are cells involved in bone reabsorbing and hence in postmenopausal bone loss. There is no evidence of increased in vitro spontaneous osteoclast formation in postmenopausal osteoporosis. The aim of our study was to evaluate spontaneous osteoclastogenesis in osteoporosis. Bone mineral density, markers of bone turnover, and cultures of peripheral blood mononuclear cells (PBMC) on dentine slices with or without the addition of 1,25-OH vitamin D3 ([10(-8) M]) were obtained from 18 osteoporotic women and 15 controls. To verify cytokine production by PBMC cultures, supernatants were collected on days 3 and 6 and tested for TNF-alpha and RANKL. The data obtained were compared between patients and controls by one-way ANOVA and correlated by Pearson's coefficient. We found a significant increase in osteoclast formation and bone reabsorbing activity in patients with respect to controls; in addition, the production of TNF-alpha and RANKL is significantly higher in patients. Furthermore, osteoclast number is inversely correlated with bone mineral density and directly with RANKL in culture supernatants. Our data demonstrated an increased spontaneous osteoclastogenesis in women affected by postmenopausal osteoporosis: this increase may be explained by the higher production of TNF-alpha and RANKL by PBMC cultures of osteoporotic patients.

Prevalence of Paget's disease of bone in Italy.

UNLABELLED: We examined the prevalence of PDB in Italy from radiological, scintigraphic, and biochemical surveys in two Italian towns. Prevalence rates varied from 0.7% to 2.4%, were higher in males than in females, and slightly differed between the two towns. Unlike previous studies in populations of British descent, no secular trend for a decreasing prevalence emerged. INTRODUCTION: Clinical, radiological, and necropsy data from different countries suggested pronounced geographical variations in the prevalence of Paget's disease of bone (PDB). Despite the impact of the disease on the population, there are limited data on the prevalence of PDB in Italy. MATERIALS AND METHODS: The objective of this study was to estimate the prevalence of PDB in the district of Siena (Central Italy) and Turin (Northern Italy) from radiological, biochemical, and scintigraphic surveys. We examined a sample of 1778 consecutive pelvic radiographs performed between 1999 and 2000 at the Hospital Radiology Unit in Siena and 6609 pelvic radiographs performed in 1986-1987, 1992-1993, and 1999-2002 from the Radiology Department of Molinette Hospital in Turin. In Siena, 7906 consecutive (99m)TC-MDP bone scans performed over a 4-year period (January 2000 to May 2004) were also screened for the presence of PDB, and the prevalence of elevated alkaline phosphatase (ALP) levels (>300 UI/liter) was estimated from 7449 computerized medical records over a 3-year period (January 2000 to February 2003). The finding of PDB on the pelvic radiograph and bone scan was based on standardized radiological criteria. RESULTS: At the end of the radiological surveys, 16/1778 pelvic PDB cases (8 males and 8 females) were observed in Siena and 41/6609 (27 males and 14 females) in Turin. The crude prevalence of the disease was 0.89% in Siena and 0.62% in Turin. Given that pelvic involvement is commonly described in 60-90% of PDB patients, the estimated overall prevalence of PDB ranged from 1.0% to 1.5% in Siena and from 0.7% to 1.0% in Turin. No decrease in the prevalence of PDB was evident after comparison of prevalence rates from different periods. Biochemical analyses showed 296/7449 subjects with elevated ALP levels and normal liver enzymes, 87 of whom had confirmed diagnosis of PDB. The estimated prevalence of biochemical PDB was 1.5%. The scintigraphic survey showed a PDB prevalence of 194/7906 (2.4%), which was significantly higher than the radiological and biochemical estimates. CONCLUSIONS: Our surveys suggest that PDB in Italy has an estimated prevalence of at least 1%, comparable with that observed in United States and other European countries, but lower than that described in Britain and New Zealand. No secular trend for a decreasing prevalence of PDB was observed.

Body fat is the main predictor of fibrinogen levels in healthy non-obese men.

Previous studies have demonstrated that circulating levels of C-reactive protein (CRP), a marker of cardiovascular risk, are strictly related to body fatness. Elevated fibrinogen levels are also predictive of future cardiovascular events. The metabolic background of this relationship and the predictors of fibrinogen levels have not been well established. We aimed to evaluate whether fibrinogen levels are associated with body fat content and distribution and to determine the independent predictors of fibrinogen levels in a sample of healthy, non-obese, nonsmoking young adult men. Age, anthropometric measures (body mass index [BMI], waist-to-hip ratio [WHR]), total and regional fat content (determined by dual x-ray absorptiometry [DXA]), metabolic variables (total cholesterol [T-Chol], low-density lipoprotein cholesterol [LDL-C], and high-density lipoprotein cholesterol [HDL-C]; triglycerides [TG]; glucose and insulin levels; fasting insulin resistance index [FIRI]; blood pressure), interleukin-6 (IL-6), and acute-phase reactants levels (fibrinogen, highly sensitive [hs]-CRP) were determined in 87 healthy nonsmoking, non-obese subjects. Linear regression analysis was used to evaluate the association between body fat, fibrinogen, and metabolic variables, and multiple regression model analysis was used to examine the independent predictors of fibrinogen levels. Eighty-seven (30.5 +/- 3.5 years) non-obese (mean BMI 24.1 +/- 3.5) men were studied. Fibrinogen levels were strongly associated with measures of body fat and with metabolic variables. Total body fat (P < .0001) and LDL-cholesterol (P < .01) were the independent predictors of fibrinogen levels, accounting for 29.5% and 10.9% of its variance, respectively. Total body fat was the best independent predictor of hs-CRP levels, accounting for 32.5 % of its variance. We conclude that in healthy, non-obese subjects, body fat content is the main predictor of fibrinogen levels, as well of hs-CRP levels. These findings support the speculation that there is a direct mechanism by which adipose tissue might regulate the levels of circulating acute-phase reactants.

Inflammatory cytokines and VEGF measured in exhaled breath condensate are correlated with tumor mass in non-small cell lung cancer.

Inflammation mediated by the immune system is known to be important in carcinogenesis and, specifically, T helper 17 cells have been reported to play a role in tumor progression by promoting neo-angiogenesis. The aim of this study was to investigate whether inflammatory cytokines and vascular endothelial growth factor (VEGF) levels in exhaled breath condensate (EBC) and in serum were related to tumor size in patients with non-small cell lung cancer (NSCLC). Il-6, IL-17, TNF-α and VEGF levels were measured in EBC and serum of 15 patients with stage I-IIA NSCLC and in 30 healthy controls by immunoassay. The tumor size was measured by a CT scan. The concentrations of IL-6, IL-17 and VEGF were significantly higher in EBC of patients with lung cancer, compared with controls, while only serum IL-6 concentration was higher in patients compared to controls. A significant correlation (r = 0.78, p = 0.001) was observed between EBC levels of IL-6 and IL-17; IL-17 was also correlated to EBC levels of the VEGF (r = 0.83, p < 0.001) and TNF-α (r = 0.62, p = 0.014). The tumor diameter was significantly correlated with EBC concentrations of VEGF (r = 0.58, p = 0.039), IL-6 (r = 0.67, p = 0.013) and IL-17 (r = 0.66, p = 0.017). Our results show a significant relationship between inflammatory and angiogenic markers, measured in EBC by a non-invasive method, and tumor mass.

Common susceptibility alleles and SQSTM1 mutations predict disease extent and severity in a multinational study of patients with Paget's disease.

Paget's disease of bone (PDB) has a strong genetic component. Here, we investigated possible associations between genetic variants that predispose to PDB and disease severity. Allelic variants identified as predictors of PDB from genome-wide association studies were analyzed in 1940 PDB patients from the United Kingdom, Italy, Western Australia, and Spain. A cumulative risk allele score was constructed by adding the variants together and relating this to markers of disease severity, alone and in combination with SQSTM1 mutations. In SQSTM1-negative patients, risk allele scores in the highest tertile were associated with a 27% increase in disease extent compared with the lowest tertile (p < 0.00001) with intermediate values in the middle tertile (20% increase; p = 0.0007). The effects were similar for disease severity score, which was 15% (p = 0.01) and 25% (p < 0.00001) higher in the middle and upper tertiles, respectively. Risk allele score remained a significant predictor of extent and severity when SQSTM-positive individuals were included, with an effect size approximately one-third of that observed with SQSTM1 mutations. A genetic risk score was developed by combining information from both markers, which identified subgroups of individuals with low, medium, and high levels of severity with a specificity of 70% and sensitivity of 55%. Risk allele scores and SQSTM1 mutations both predict extent and severity of PDB. It is possible that with further refinement, genetic profiling may be of clinical value in identifying individuals at high risk of severe disease who might benefit from enhanced surveillance and early intervention.