Tumor-induced Osteomalacia: A Systematic Review and Individual Patient's Data Analysis.

CONTEXT: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, usually caused by small, benign, and slow-growing phosphaturic mesenchymal tumors. Clinically, TIO is characterized by renal phosphate leak, causing hypophosphatemia and osteomalacia. This review was performed to assess the clinical characteristics of TIO patients described worldwide so far. EVIDENCE ACQUISITION: On June 26, 2021, a systematic search was performed in Medline, Google Scholar, Google book, and Cochrane Library using the terms: "tumor induced osteomalacia," "oncogenic osteomalacia," "hypophosphatemia." There were no language restrictions. This review was performed according to Preferred Reporting Items for Systematic reviews and Meta-Analyses criteria. EVIDENCE RESULTS: Overall, 1725 TIO cases were collected. TIO was more frequent in adult men, who showed a higher incidence of fractures compared with TIO women. The TIO-causing neoplasms were identified in 1493 patients. The somatostatin receptor-based imaging modalities have the highest sensitivity for the identification of TIO-causing neoplasms. TIO-causing neoplasms were equally located in bone and soft tissues; the latter showed a higher prevalence of fractures and deformities. The surgery is the preferred TIO definitive treatment (successful in > 90% of patients). Promising nonsurgical therapies are treatments with burosumab in TIO patients with elevated fibroblast growth factor-23 levels, and with radiolabeled somatostatin analogs in patients with TIO-causing neoplasm identified by somatostatin receptor-based imaging techniques. CONCLUSION: TIO occurs preferentially in adult men. The TIO clinical expressiveness is more severe in men as well as in patients with TIO-causing neoplasms located in soft tissues. Treatments with burosumab and with radiolabeled somatostatin analogs are the most promising nonsurgical therapies.

100% Fruit juice intake and cardiovascular risk: a systematic review and meta-analysis of prospective and randomised controlled studies.

PURPOSE: The relationship between 100% fruit juice (100%FJ) consumption and cardiovascular risk is object of debate: indeed, recently published investigations provided new but discrepant evidence on this important question and International dietary guidelines are not in agreement on recommendations about fruit juice consumption. Therefore, we performed a meta-analysis of the prospective studies and the randomised controlled trials (RCTs) that explored the relationship between 100%FJ intake, cardiovascular risk profile and risk of cardiovascular events. METHODS: We performed a systematic search of publications up to August 2019. Summary relative risks and exploration of linearity of the association were estimated for prospective studies and summary mean differences (MDs) calculated for RCTs. RESULTS: A total of 21 prospective studies and 35 RCTs met the inclusion criteria. Dose-response analysis detected a significant inverse association between low-moderate 100%FJ consumption and risk of stroke (up to 200 ml/day) or total CV events (up to 170 ml/day) compared with no consumption, with a non-linear relationship (p for non-linearity < 0.05). No significant association was found for coronary heart disease and diabetes risk. In RCTs, a favorable and significant effect of 100%FJ intake was detected on blood pressure (systolic, MD: - 3.14 mmHg; diastolic, MD: - 1.68 mmHg), arterial compliance (carotid-femoral pulse wave velocity, - 0.38 m/s) and endothelial function (flow-mediated dilation, 2.10%). Neutral effects were found on body weight, blood lipids and glucose metabolism. CONCLUSIONS: The results of these analyses indicate that 100%FJ consumption is not associated with higher CV risk. A non-linear inverse dose-response relationship occurs between 100%FJ consumption and CV disease, in particular for risk of stroke, probably mediated by the decrease in blood pressure. TRIAL REGISTRATION: PROSPERO registration number (CRD42019135577).

RE-AIM evaluation of a one-year trial of a combined educational and environmental workplace intervention to lower salt intake in Switzerland.

Reducing excessive dietary sodium may reduce cardiovascular disease risk. Environmental and behavioral interventions in workplaces may reduce salt consumption, but information on the effectiveness of workplace nutrition interventions is sparse. We used the RE-AIM framework to evaluate a one-year trial in 2015-2016 of an educational and environmental intervention to lower salt intake of employees in organizations with catering facilities in Switzerland. Five educational workshops for employees and assessments that included 24-hour urine collection were combined with five coaching sessions and food analyses in catering operations. We studied the adoption, reach, implementation, effectiveness, and maintenance of the intervention. Eight of 389 candidate organizations participated in the trial in which 145 (50% men) out of 5794 potentially eligible employees consented to participate, and 138 completed the trial with 13 in the control group. The overall mean change of daily salt intake was -0.6 g from 8.7 g to 8.1 g (6.9%). Though the mean daily salt intake of women was unaltered from 7 g, the mean intake of men declined by -1.2 g from 10.4 g to 9.2 g. Baseline salt intake, sex, and waist-to-height ratio were significant predictors of salt reduction. The analysis also highlighted pivotal determinants of low adoption and reach, and program implementation in catering operations. We conclude that a workplace program of nutrition intervention for employees and catering staff is feasible. The acceptance, effectiveness, and maintenance of nutrition interventions in the workplace require strong employer support. In a supportive food environment, interventions tailored to sex, age, and CVD risk inter alia could be successful.

Increased Microalbuminuria Risk in Male Cigarette Smokers: Results from the "Olivetti Heart Study" after 8 Years Follow-Up.

BACKGROUND/AIMS: Association between cigarette smoke and albuminuria (UA) was already demonstrated in cross-sectional studies and in selected population samples (i.e diabetic patients). This study aims to evaluate, prospectively, the relationship between cigarette smoke and UA in a male adult population sample, with basal normal kidney function, participating in the Olivetti Heart Study (OHS). METHODS: Among 994 participants, examined in both 1994-95 and 2002-04, were selected those resulted in both visits smokers (n=221) and non-smokers (n=416) and with basal normal kidney function (GFR> 60 mL/min) and basal albumin/creatinine ratio (ACR< 30 mg/g). RESULTS: At baseline, the prevalence of hypertension was 41%, diabetes affected 6.3% and obesity 17% of the whole sample. Smokers showed statistically significant lower levels of systolic (SBP) and diastolic blood pressure (DBP) and BMI (p< 0.001) compared to non-smokers. There were not basal differences in UA, GFR and metabolic profile. However, at follow-up examination, smokers showed a statistically significant increase in SBP and DBP (p< 0.05), but not in GFR and BMI. Moreover, smokers showed a higher risk compared to non-smokers to be in the higher median levels group of UA (OR: 2.17, C.I.95%: 1.51-3.13; p < 0.001), even after correction for major confounding factors. Further adjustment for basal antihypertensive and hypoglycemic treatment did not change these patterns of association. CONCLUSION: In a selected male adult population sample, cigarette smoke was independently associated with the development of higher levels of albuminuria over time.

Cow's Milk Consumption and Health: A Health Professional's Guide.

The most recent scientific evidence supports the consumption of cow's milk and dairy products as part of a balanced diet. However, these days, the public and practicing physicans are exposed to a stream of inconsistent (and often misleading) information regarding the relationship between cow's milk intake and health in the lay press and in the media. The purpose of this article, in this context, is to facilitate doctor-patient communication on this topic, providing physicians with a series of structured answers to frequently asked patient questions. The answers range from milk and milk-derived products' nutritional function across the life span, to their relationship with diseases such as osteoporosis and cancer, to lactose intolerance and milk allergy, and have been prepared by a panel of experts from the Italian medical and nutritional scientific community. When consumed according to appropriate national guidelines, milk and its derivatives contribute essential micro- and macronutrients to the diet, especially in infancy and childhood where bone mass growth is in a critical phase. Furthermore, preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes, and cardiovascular disease, while no clear data suggest a significant association between milk intake and cancer. Overall, current scientific literature suggests that an appropriate consumption of milk and its derivatives, according to available nutritional guidelines, may be beneficial across all age groups, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy. Key teaching points: Milk and its derivatives contribute essential micro and macronutrients to the diet, when consumed according to appropriate national guidelines, especially in infancy and childhood where bone mass growth is in a critical phase. Preliminary evidence suggests potentially protective effects of milk against overweight, obesity, diabetes and cardiovascular disease No clear data are available about the association between milk intake and cancer. Current scientific literature suggests that an appropriate consumption of milk and its derivatives may be beneficial at all ages, with the exception of specific medical conditions such as lactose intolerance or milk protein allergy.

Circulating leptin levels predict the decline in renal function with age in a sample of adult men (The Olivetti Heart Study).

Leptin (LPT) is associated with a number of cardiovascular risk factors, such as high blood pressure (BP), insulin resistance and excess in body weight. Some studies find an unfavorable cross-sectional association between LPT and renal disease, in particular in patients with already known kidney dysfunction. There are few data on the relationship between LPT and changes in renal function over time in subjects without evidence of kidney dysfunction. Hence, the aim of this study is to estimate the predictive role of LPT on the decline in renal function occurring in an 8-year follow-up observation of a sample of adult apparently healthy men (The Olivetti Heart Study). The study includes 319 untreated normotensive and nondiabetic men without clinical evidence of renal dysfunction (creatinine clearance-CrCl > 60 mL/min/1.73 m2) at baseline. At baseline, LPT is significantly and positively associated with BMI, abdominal circumference, BP and Homa index, no relationship is found with CrCl. At the end of the 8-year follow-up, a significant association is detected between baseline LPT and changes occurring in BP. Moreover, an inverse correlation with changes in CrCl is found (r = - 0.12). This unfavorable relationship between baseline LPT and decline in renal function is also confirmed in the multivariate analyses, after adjustment for all potential confounders (R2 = 0.42, p < 0.01). The results of this prospective investigation suggest a predictive role of circulating LPT levels on decline in renal function over time, independently of main potential confounders, in normotensive and nondiabetic men with normal renal function at baseline.

Interleukin-6 trans-signaling and pathological low back pain in patients with Paget disease of bone.

The interleukin (IL)-6 biological system plays a key role in the pathogenesis of Paget disease (PD) of bone and pathological bone pain. Bone pain, particularly in the lower back region, is the most frequent symptom in patients with PD. This case-control study aimed to evaluate the relationship between the IL-6 system and low back pain (LBP) in patients with PD. We evaluated 85 patients with PD, with the disease localized in the lumbar spine, pelvis, and/or sacrum, and classified them based on the presence or absence of LBP, before and after aminobisphosphonate treatment. We also examined 32 healthy controls without LBP. Before treatment, IL-6 levels in patients with PD were higher than those in the controls, without difference between patients with or without LBP. Patients with PD with LBP (35/85) showed higher IL-6-soluble receptor (sIL-6R) and lower soluble glycoprotein (sgp) 130 levels compared with both patients with PD without LBP and controls (sIL-6R: 46.9 ± 7.4 vs 35.4 ± 8.6 vs 29.9 ± 4.2 ng/mL; sgp130: 307.2 ± 35.4 vs 341.4 ± 41.4 vs 417.1 ± 58.5 ng/mL, respectively). Paget disease remission, 6 months after treatment, is associated with LBP improvement. This phenomenon is associated with reduced sIL-6R levels and increased sgp130 levels in patients with PD with LBP at the baseline. Considering the biological properties of IL-6, sIL-6R, and sgp130, the results of the study suggest that the perception of LBP in patients with PD could be linked to an enhanced transmission of IL-6 signal in the specialized neural system activated by nociceptors.

Study design and baseline characteristics of a combined educational and environmental intervention trial to lower sodium intake in Swiss employees.

BACKGROUND: Blood pressure is a primary cardiovascular disease risk factor. Population-wide governmental strategies aim to reduce lifestyle and dietary risk factors for hypertension, one of which is an unbalanced diet with high sodium and low potassium intakes. Nutrition interventions in the workplace are considered a promising approach in encouraging health-promoting behaviors. We developed and conducted the health promoting sodium reduction trial "Healthful & Tasty: Sure!" in worksites in the German-speaking part of Switzerland from May 2015 to Nov 2016, for which we present the study protocol and baseline characteristics. METHODS: Healthful & Tasty, a cluster nonrandomized single-arm trial with calibration arm, aimed to demonstrate the effectiveness of a combined educational and environmental intervention in the workplace in reducing employees' average daily sodium/salt intake by 15%. To this end, health and food literacy of employees and guideline compliance among the catering facility team needed to be improved. The primary outcome measure was sodium/salt intake estimated from sodium excretion in a 24-h urine sample. Secondary outcome measures included changes in the overall qualitative diet composition, blood pressure, anthropometric indices, and health and food literacy. Of eight organizations with catering facilities, seven organizations took part in the nutrition education and catering salt reduction interventions, and one organization participated as a control. Overall, 145 consenting employees were included in the staggered, one-year four-phase trial, of which 132 participated in the intervention group. In addition to catering surveys and food sampling, the trial included five follow-up health assessments including questionnaires, blood pressure measurements, anthropometrics, and sodium, potassium, and iodine intake measurements obtained from 24-h and spot urine samples, and a food record checklist. Exploratory and hypothesis generating baseline statistical analysis included 141 participants with adequate 24-h urine samples. DISCUSSION: Despite practice-driven limitations to the study design and small cluster and participant numbers, this trial has methodological strength and will provide important insights into the effectiveness of a combined educational and environmental intervention to reduce salt intake among female and male Swiss employees. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00006790 . Registered 23 September 2014.

Risk factors for silent myocardial ischemia in patients with well-controlled essential hypertension.

Silent myocardial ischemia (SMI) is frequently observed in patients with essential hypertension (EH). The major risk factor for SMI is uncontrolled blood pressure (BP), but SMI is also observed in patients with well-controlled BP. To evaluate the prevalence of SMI and the factors associated with SMI in EH patients with well-controlled BP. The medical records of 859 EH patients who underwent simultaneous 24-h ambulatory blood pressure monitoring (ABPM) and 24-h ambulatory electrocardiogram recording (AECG) were retrospectively evaluated. Each SMI episode was characterized by: (a) ST segment depression ≥0.5 mm; (b) duration of ST segment depression >60 s; and (c) reversibility of the ST segment depression. Overall 126 EH patients (14.7 %) had at least one episode of SMI. The SMI events were more frequent among patients with poorly controlled compared to those with well-controlled BP [86/479 (17.95 %) vs. 40/380 (10.52 %), p < 0.01]. Among EH patients with well-controlled BP, current and past smoking as well as the presence of an additional metabolic syndrome (MetS) constitutive element (obesity, impaired fasting glucose level or dyslipidemia) were significantly associated with the occurrence of SMI. In all EH patients with well-controlled BP and AECG evidence of SMI, there were one or more coronary artery stenotic lesions greater than 50 % found at coronary angiography. In EH patients who are current smokers, or have one or more additional components of a MetS there is markedly reduced benefit associated with good BP control with regard to the occurrence of myocardial ischemia: in this patient category, an AECG may help detect this condition.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

Dietary treatment of urinary risk factors for renal stone formation. A review of CLU Working Group.

OBJECTIVE: Diet interventions may reduce the risk of urinary stone formation and its recurrence, but there is no conclusive consensus in the literature regarding the effectiveness of dietary interventions and recommendations about specific diets for patients with urinary calculi. The aim of this study was to review the studies reporting the effects of different dietary interventions for the modification of urinary risk factors in patients with urinary stone disease. MATERIALS AND METHODS: A systematic search of the Pubmed database literature up to July 1, 2014 for studies on dietary treatment of urinary risk factors for urinary stone formation was conducted according to a methodology developed a priori. Studies were screened by titles and abstracts for eligibility. Data were extracted using a standardized form and the quality of evidence was assessed. RESULTS: Evidence from the selected studies were used to form evidence-based guideline statements. In the absence of sufficient evidence, additional statements were developed as expert opinions. CONCLUSIONS: General measures: Each patient with nephrolithiasis should undertake appropriate evaluation according to the knowledge of the calculus composition. Regardless of the underlying cause of the stone disease, a mainstay of conservative management is the forced increase in fluid intake to achieve a daily urine output of 2 liters. HYPERCALCIURIA: Dietary calcium restriction is not recommended for stone formers with nephrolithiasis. Diets with a calcium content ≥ 1 g/day (and low protein-low sodium) could be protective against the risk of stone formation in hypercalciuric stone forming adults. Moderate dietary salt restriction is useful in limiting urinary calcium excretion and thus may be helpful for primary and secondary prevention of nephrolithiasis. A low-normal protein intake decrease calciuria and could be useful in stone prevention and preservation of bone mass. Omega-3 fatty acids and bran of different origin decreases calciuria, but their impact on the urinary stone risk profile is uncertain. Sports beverage do not affect the urinary stone risk profile. HYPEROXALURIA: A diet low in oxalate and/or a calcium intake normal to high (800-1200 mg/day for adults) reduce the urinary excretion of oxalate, conversely a diet rich in oxalates and/or a diet low in calcium increase urinary oxalate. A restriction in protein intake may reduce the urinary excretion of oxalate although a vegetarian diet may lead to an increase in urinary oxalate. Adding bran to a diet low in oxalate cancels its effect of reducing urinary oxalate. Conversely, the addition of supplements of fruit and vegetables to a mixed diet does not involve an increased excretion of oxalate in the urine. The intake of pyridoxine reduces the excretion of oxalate. HYPERURICOSURIA: In patients with renal calcium stones the decrease of the urinary excretion of uric acid after restriction of dietary protein and purine is suggested although not clearly demonstrated. HYPOCITRATURIA: The administration of alkaline-citrates salts is recommended for the medical treatment of renal stone-formers with hypocitraturia, although compliance to this treatment is limited by gastrointestinal side effects and costs. Increased intake of fruit and vegetables (excluding those with high oxalate content) increases citrate excretion and involves a significant protection against the risk of stone formation. Citrus (lemons, oranges, grapefruit, and lime) and non citrus fruits (melon) are natural sources of dietary citrate, and several studies have shown the potential of these fruits and/or their juices in raising urine citrate levels. CHILDREN: There are enought basis to advice an adequate fluid intake also in children. Moderate dietary salt restriction and implementation of potassium intake are useful in limiting urinary calcium excretion whereas dietary calcium restriction is not recommended for children with nephrolithiasis. It seems reasonable to advice a balanced consumption of fruit and vegetables and a low consumption of chocolate and cola according to general nutritional guidelines, although no studies have assessed in pediatric stone formers the effect of fruit and vegetables supplementation on urinary citrate and the effects of chocolate and cola restriction on urinary oxalate in pediatric stone formers. Despite the low level of scientific evidence, a low-protein (< 20 g/day) low-salt (< 2 g/day) diet with high hydration (> 3 liters/day) is strongly advised in children with cystinuria. ELDERLY: In older patients dietary counseling for renal stone prevention has to consider some particular aspects of aging. A restriction of sodium intake in association with a higher intake of potassium, magnesium and citrate is advisable in order to reduce urinary risk factors for stone formation but also to prevent the loss of bone mass and the incidence of hypertension, although more hemodynamic sensitivity to sodium intake and decreased renal function of the elderly have to be considered. A diet rich in calcium (1200 mg/day) is useful to maintain skeletal wellness and to prevent kidney stones although an higher supplementation could involve an increase of risk for both the formation of kidney stones and cardiovascular diseases. A lower content of animal protein in association to an higher intake of plant products decrease the acid load and the excretion of uric acid has no particular contraindications in the elderly patients, although overall nutritional status has to be preserved.

Clinical characteristics and evolution of giant cell tumor occurring in Paget's disease of bone.

Patients with Paget's bone disease (PDB) have an increased risk of developing giant cell tumor (GCT). This study was performed to evaluate the clinical characteristics and evolution of GCT complicating PDB and to compare these clinical characteristics to those observed in two large PDB cohorts, the PDB Italian Registry and the United Kingdom's Multi-Centre Randomised Controlled Trial of Symptomatic Versus Intensive Bisphosphonate Therapy for Paget's Disease (PRISM) study. A systematic literature review identified 117 cases of PDB complicated by GCT (PDB-GCT), which involved the skeletal sites affected by PDB (110 patients) or the extraskeletal tissues adjacent to affected bones (7 patients). In contrast to what previously reported for GCT patients without GCT patients (83.2%) were white and one-fourth of them (24.8%) had multifocal GCTs. Compared to PDB patients without GCT, PDB-GCT patients showed a higher male/female ratio (2.1 versus 1.2) and more severe disease (age at PDB onset 52.1 ± 12.1 versus 63.3 ± 10.6 years; number of affected sites 6.1 ± 2.9 versus 2.34 ± 1.6; prevalence of polyostotic PDB 93.3% versus 60.6%). The mortality rate of PDB-GCT patients was higher than those occurring in GCT patients without PDB (about 50% versus 0% to 5% at 5 years) or in PDB patients without GCT (log rank = 29.002). Moreover, up to 98% of PDB-GCT cases had elevated total alkaline phosphatase levels at neoplasm diagnosis, suggestive of active PDB. Importantly, PDB-GCT patients from Southern Italy (45.6% of all GCT patients) showed a higher prevalence of multifocal GCT (51.7%) and of positive familial history for PDB (70.8%) and GCT (65.0%). Finally, indirect evidence suggests a decline in the incidence of GCT in PDB patients. The occurrence of GCT in PDB patients is associated with severe disease and reduced life expectancy of affected patients. The increased prevalence of familial diseases in PDB-GCT patients from Southern Italy suggests a founder effect. The observed changes over time in the incidence of GCT in PDB patients could be related to improved clinical management and/or living conditions of patients.

Not smoking is associated with lower risk of hypertension: results of the Olivetti Heart Study.

BACKGROUND: Few epidemiological investigations evaluated the role of smoking cessation on blood pressure (BP), and the results are not univocal. Therefore, the aim of this study was to assess the effect of smoking cessation on the risk to develop hypertension (HPT) and on BP values. METHODS: This longitudinal study, with a follow-up period of 8 years, included the participants of the Olivetti Heart Study. Participants were 430 untreated normotensive non-diabetic men with normal renal function, examined twice in 1994-95 and in 2002-04. The sample included current smokers (S, n = 212), former smokers (ES, n = 145) and never smokers (NS, n = 73) at baseline. RESULTS: Basal body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in ES than in S (ES vs. S; BMI: 27.0 ± 2.5 vs. 26.1 ± 2.9 kg/m2; P < 0.01; SBP/DBP: 121.2 ± 9.3/80.0 ± 5.8 vs. 19.1 ± 9.9/77.4 ± 6.7 mm Hg; P < 0.05; M ± SD). After 8 years of follow-up, BP changes (Δ) were significantly lower in ES than in S (ΔSBP/DBP: 12.6 ± 13.4/7.9 ± 8.1 vs. 16.0 ± 14.9/10.3 ± 10.1 mm Hg; P < 0.05; M ± SD), also after adjustment for potential confounders. Moreover, at the last examination, the overall HPT prevalence was 33%, with lower values in ES than in S (25 vs. 38%, P = 0.01). After accounting for age, BP and BMI at baseline, and changes in smoking habit over the 8-year period, ES still had significant lower risk of HPT than S (odds ratio 0.30, 95% confidence interval 0.15-0.58; P < 0.01). CONCLUSIONS: In this sample of healthy men, smoking cessation was associated with lower BP increment and minor HPT risk, independently of potential confounders.

Dietary salt intake and risk of gastric cancer.

Humans began to use large amounts of salt for the main purpose of food preservation approximately 5,000 years ago and, although since then advanced technologies have been developed allowing drastic reduction in the use of salt for food storage, excess dietary salt intake remains very common. Gastric cancer is a common neoplasia, and dietary factors, including salt consumption, are considered relevant to its causation. A number of experimental studies supported the cocarcinogenic effect of salt through synergic action with Helicobacter pylori infection, in addition to some independent effects such as increase in the rate of cell proliferation and of endogenous mutations. Many epidemiological studies analyzed the relationship between excess salt intake and risk of gastric cancer. Both cross-sectional and prospective studies indicated a possibly dose-dependent positive association. In particular, a comprehensive meta-analysis of longitudinal studies detected a strong adverse effect of total salt intake and salt-rich foods on the risk of gastric cancer in the general population. Altogether, the epidemiological, clinical, and experimental evidence supports the possibility of a substantial reduction in the rates of gastric cancer through progressive reduction in population salt intake.

Giant cell tumor occurring in familial Paget's disease of bone: report of clinical characteristics and linkage analysis of a large pedigree.

Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree.

Habitual salt intake and risk of gastric cancer: a meta-analysis of prospective studies.

BACKGROUND & AIMS: Systematic reviews of case-control studies evaluating the relationship between dietary salt intake and gastric cancer showed a positive association, however a quantitative analysis of longitudinal cohort studies is lacking. Therefore, we carried out a meta-analysis to assess the association between habitual salt intake and risk of gastric cancer in prospective studies. METHODS: We performed a systematic search of published articles (1966-2010). Criteria for inclusion were: original articles, prospective adult population studies, assessment of salt intake as baseline exposure and of gastric cancer as outcome, follow-up of at least 4 years, indication of number of participants exposed and events across different salt intake categories. RESULTS: Seven studies (10 cohorts) met the inclusion criteria (268 718 participants, 1474 events, follow-up 6-15 years). In the pooled analysis, "high" and "moderately high" vs "low" salt intake were both associated with increased risk of gastric cancer (RR = 1.68 [95% C.I. 1.17-2.41], p = 0.005 and respectively 1.41 [1.03-1.93], p = 0.032), with no evidence of publication bias. The association was stronger in the Japanese population and higher consumption of selected salt-rich foods was also associated with greater risk. Meta-regression analyses did not detect specific sources of heterogeneity. CONCLUSIONS: Dietary salt intake was directly associated with risk of gastric cancer in prospective population studies, with progressively increasing risk across consumption levels.

A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease.

Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for the T575C variant, yielding an odds ratio of 1.29 (p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p = 0.01), as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11A(A192) produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A(V192), confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.

Psoriatic arthritis is associated with increased arterial stiffness in the absence of known cardiovascular risk factors: a case control study.

The objective of the study was the evaluation of arterial stiffness, a cardiovascular risk factor, in patients with psoriatic arthritis (PsA). Twenty PsA patients classified on the basis of the CASPAR criteria (M/W, 14/6; mean age, 38.6 years; range, 22-53), attending our out-patient clinic, and 20 healthy control subjects (M/W, 14/6; mean age, 38.7 years; range, 22-53) matched for age, weight, height and with similar cardiometabolic profile entered the study. An exclusion criterion was the presence of known cardiovascular risk factors. Central hemodynamic parameters and aortic pulse wave velocity (aPWV) were assessed non-invasively by a SphygmoCor device. A significantly higher aPWV was recorded in PsA patients when compared to controls. The difference remained statistically significant after adjustment for age, weight, height, heart rate (HR) and central mean pressure (mean±SE; PsA, 8.3 ± 0.2 versus control, 6.8 ± 0.2 m/s; p < 0.0001). Among PsA patients, aPWV was related to known duration of disease (r = 0.63; p = 0.003). This result was confirmed after adjustment for the main confounders (ß = 0.011; p = 0.013). These results support the concept of psoriatic disease as a systemic condition involving not only the skin, joints and gastrointestinal tract but also arterial vessels. The involvement of the vascular system indicates the presence of pathogenetic mechanisms that could accelerate the atherosclerotic process in this condition.

Associations of selenium status with cardiometabolic risk factors: an 8-year follow-up analysis of the Olivetti Heart study.

OBJECTIVE: High selenium status has been associated with adverse cardiometabolic outcomes in selenium-replete populations such as the US. In populations with lower selenium status such as in Italy, there is little epidemiological evidence about the association of selenium with cardiometabolic risk factors. We therefore examined cross-sectional and prospective relationships of serum selenium concentrations with cardiometabolic risk factors including blood pressure, diabetes and blood lipids in the Olivetti Heart Study. METHODS: The study population consisted of 445 adult male individuals for whom baseline serum selenium measurement and cardiometabolic risk factors at baseline (1994-1995) and follow-up examination (2002-2004: average follow-up=8 years) were available. Serum selenium was measured by atomic absorption spectrophotometry. RESULTS: Average serum selenium concentration at baseline was 77.5 ± 18.4 µg/L. In cross-sectional analyses, serum selenium levels were positively associated with serum total cholesterol (p for trend <0.0001) and prevalent diabetes (p for trend <0.05). In prospective analysis, serum selenium at baseline was likewise a strong predictor of serum total cholesterol (p=0.002) and LDL-cholesterol (p=0.001) at follow-up, after adjustment for age, BMI, cigarette smoking, physical activity, and lipid-lowering medication. These associations, however, were no longer significant after additional adjustment for baseline blood lipids. Selenium at baseline did not predict changes in total cholesterol levels between the baseline and follow-up examinations [ß-coefficient (± SE)= 0.09 ± 0.12 (p=0.46)]. CONCLUSION: These findings corroborate previous cross-sectional associations of high selenium status with adverse blood lipid profile and diabetes. However, prospective analyses do not support the causality of these relations. Randomized and experimental evidence is necessary to clarify the mechanisms underlying the observed cross-sectional associations.