The non-euphoric phytocannabinoid cannabidivarin counteracts intestinal inflammation in mice and cytokine expression in biopsies from UC pediatric patients.

Patients with ulcerative colitis (UC) using marijuana have been reported to experience symptomatic benefit. Cannabidivarin (CBDV) is a safe non-psychoactive phytocannabinoid able to activate and desensitize TRPA1, a member of the TRP channels superfamily, which plays a pivotal role in intestinal inflammation. Here, we have investigated the potential intestinal anti-inflammatory effect of CBDV in mice and in biopsies from pediatric patients with active UC. Colonic inflammation was induced in mice by dinitrobenzenesulfonic acid (DNBS). The effect of orally administered CBDV on macroscopic and microscopic damage, inflammatory parameters (i.e. myeloperoxidase activity, intestinal permeability and cytokine production) and faecal microbiota composition, was evaluated 3 days after DNBS administration. TRPA1 expression was studied by RT-PCR in inflamed colons of mice as well as in mucosal colonic biopsies of children with active UC, whose response to incubation with CBDV was also investigated. CBDV attenuates, in a TRPA1-antagonist sensitive manner, DNBS-induced signs of inflammation including neutrophil infiltration, intestinal permeability, and cytokine (i.e. IL-1ß, IL-6 and the chemokine MCP-1) production. CBDV also alters the dysregulation of gut microbiota associated to colitis. Finally, CBDV lessens cytokine expression in colonic biopsies from pediatric patients with ulcerative colitis, a condition in which TRPA1 was up-regulated. Our preclinical study shows that CBDV exerts intestinal anti-inflammatory effects in mice via TRPA1, and in children with active UC. Since CBDV has a favorable safety profile in humans, it may be considered for possible clinical trials in patients with UC.

Diagnostic accuracy and cost-effectiveness of different strategies to triage women with adnexal masses: a prospective study.

OBJECTIVE: Transvaginal sonography (TVS) and serum biomarkers are used widely in clinical practice to triage women with adnexal masses, but the effectiveness of current biomarkers is weak. The aim of this study was to determine the best method of diagnosing patients with adnexal masses, in terms of diagnostic accuracy and economic costs, among four triage strategies: (1) the International Ovarian Tumor Analysis group's simple rules (SR) for interpretation of TVS with subjective assessment (SA) by an experienced ultrasound operator when TVS results are inconclusive (referred to hereafter as SR ± SA), (2) SR ± SA and cancer antigen 125 (CA 125), (3) SR ± SA and human epididymis protein 4 (HE4) and (4) SR ± SA and the risk of malignancy algorithm (ROMA). Our main hypothesis was that the addition of the biomarkers to SR ± SA could improve triaging of these patients in terms of diagnostic accuracy (i.e. malignant vs benign). As secondary analyses, we estimated the cost effectiveness of the four strategies and the diagnostic accuracy of SR ± SA at the study hospitals. METHODS: Between February 2013 and January 2015, 447 consecutive patients who were scheduled for surgery for an adnexal mass at the S. Anna and Mauriziano Hospitals in Turin were enrolled in this multicenter prospective cohort study. Preoperative TVS was performed and preoperative CA 125 and HE4 levels were measured. Pathology reports were used to assess the diagnostic accuracy of the four triage strategies and the cost of each strategy was calculated. RESULTS: A total of 391 patients were included in the analysis: 57% (n = 221) were premenopausal and 43% (n = 170) were postmenopausal. The overall prevalence of malignancy was 21%. SR were conclusive in 89% of patients and thus did not require SA; the overall performance of SR ± SA showed a sensitivity of 82%, specificity of 92% and positive and negative predictive values and positive and negative likelihood ratios of 74%, 95%, 10.5 and 0.19, respectively. In premenopausal women, mean cost among the four triage strategies varied from €36.41 for SR ± SA to €70.12 for SR ± SA + ROMA. The addition of biomarkers to SR ± SA showed no diagnostic advantage compared with SR ± SA alone and was more costly. Among postmenopausal women, mean cost among the four triage strategies varied from €39.52 for SR ± SA to €73.23 for SR ± SA + ROMA. Among these women, SR ± SA + CA 125 and SR ± SA + ROMA had a higher sensitivity (both 92% (95% CI, 85-99%)) than SR ± SA (81% (95% CI, 71-91%)), but SR ± SA had a higher specificity (84% (95% CI, 77-91%)). SR ± SA + CA 125 and SR ± SA + ROMA improved diagnostic accuracy, each diagnosing a third more malignant adnexal masses. In postmenopausal women, compared with SR ± SA alone, SR ± SA + CA 125 showed a net reclassification improvement (NRI) of 28.8% at an extra cost of €13.00, while the extra cost for SR ± SA + ROMA was €33.71, with a comparable gain, in terms of NRI, as that of SR ± SA + CA 125. CONCLUSIONS: In our study sample, SR ± SA seems to be the best strategy to triage women with adnexal masses for surgical management. Among postmenopausal women, SR ± SA + CA 125 increased the NRI at a reasonable extra cost. Our data do not justify the use of HE4 and ROMA in the initial triage of women with adnexal masses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The relative burden of diabetes complications on healthcare costs: The population-based CINECA-SID ARNO Diabetes Observatory.

BACKGROUND AND AIMS: In the present population-based study, we aimed to describe the per patient annual healthcare cost of people with diabetes in 2007-2012, to assess the relative burden of diabetes complications and other potential determinants on healthcare costs in the 2012 cohort, and to describe and analyse the determinants of the cost of incident cases diagnosed in 2012. METHODS AND RESULTS: We analysed data from a retrospective cohort of residents in four Italian areas that were served by Local Health Units participating in the ARNO Observatory. Per patient annual healthcare costs (Euros) were estimated as the sum of all the resources supplied during that year (drugs, outpatient care, and hospitalisations). The mean per patient annual healthcare cost increased from €2752 in 2007 to €3191 in 2010, before decreasing to €2791 in 2012. The largest component of these costs was represented by hospitalisations (around €1550, on average; 51.7% of total cost), followed by outpatient care (€422; 14.6%) and drugs (€973; 33.7%). In 2012, the most relevant cost determinants were chronic diabetes complications, with an additional cost due to nephropathy/end stage renal disease (€4683), amputations (€5042), lower extremity revascularization (€4808), and cerebrovascular diseases (€3861). Costs associated with incidence cases were higher than those associated with prevalent. CONCLUSION: The present study provides evidence on the excess of healthcare costs due to diabetes complications in both prevalent and incident cases.

Incidence, prevalence, costs and quality of care of type 1 diabetes in Italy, age 0-29 years: The population-based CINECA-SID ARNO Observatory, 2002-2012.

BACKGROUND AND AIMS: To assess temporal trend in incidence (2003-12) and prevalence (2002-12) of type 1 diabetes in children and young adults, direct costs and selected indicators of quality of care under the coverage of the universalistic Italian National Health System (NHS). METHODS AND RESULTS: The ARNO Observatory, a healthcare monitoring system based on administrative data, identified a population-based multiregional cohort of subjects aged 0-29 years. Type 1 diabetes was defined by at least two prescriptions of insulin over 12 months and continuous insulin-treatment in the following year. Indicators of quality of care and directs costs were assessed in persons with diabetes and in people without diabetes, individually matched for age, gender and health unit (1:4 ratio). We identified 2357 incident cases of type 1 diabetes aged 0-29 years (completeness of ascertainment, 99%). Incidence rates were similar in ages 0-14 (15.8, 95% CI 14.9-16.8) and 15-29 years (16.3, 15.4-17.2), with no significant trend. Prevalence increased from 137 to 166.9/100,000, particularly in the age 15-29 years. Direct costs accounted for € 2117 in persons with diabetes and € 292 in control individuals. A statistically significant decreasing trend in hospitalization for acute complications was evident (p < 0.001), which was almost completely due to ketoacidosis. People with at least one HbA1c measurement over the year were 48.5%. CONCLUSION: We showed high incidence and increasing prevalence of type 1 diabetes in young adults in Italy, which impact on direct costs under the universalistic coverage of the NHS.

Bone substitutes in orthopaedic surgery: from basic science to clinical practice.

Bone substitutes are being increasingly used in surgery as over two millions bone grafting procedures are performed worldwide per year. Autografts still represent the gold standard for bone substitution, though the morbidity and the inherent limited availability are the main limitations. Allografts, i.e. banked bone, are osteoconductive and weakly osteoinductive, though there are still concerns about the residual infective risks, costs and donor availability issues. As an alternative, xenograft substitutes are cheap, but their use provided contrasting results, so far. Ceramic-based synthetic bone substitutes are alternatively based on hydroxyapatite (HA) and tricalcium phosphates, and are widely used in the clinical practice. Indeed, despite being completely resorbable and weaker than cortical bone, they have exhaustively proved to be effective. Biomimetic HAs are the evolution of traditional HA and contains ions (carbonates, Si, Sr, Fl, Mg) that mimic natural HA (biomimetic HA). Injectable cements represent another evolution, enabling mininvasive techniques. Bone morphogenetic proteins (namely BMP2 and 7) are the only bone inducing growth factors approved for human use in spine surgery and for the treatment of tibial nonunion. Demineralized bone matrix and platelet rich plasma did not prove to be effective and their use as bone substitutes remains controversial. Experimental cell-based approaches are considered the best suitable emerging strategies in several regenerative medicine application, including bone regeneration. In some cases, cells have been used as bioactive vehicles delivering osteoinductive genes locally to achieve bone regeneration. In particular, mesenchymal stem cells have been widely exploited for this purpose, being multipotent cells capable of efficient osteogenic potential. Here we intend to review and update the alternative available techniques used for bone fusion, along with some hints on the advancements achieved through the experimental research in this field.

Prediction of mortality and macrovascular complications in type 2 diabetes: validation of the UKPDS Outcomes Model in the Casale Monferrato Survey, Italy.

AIMS/HYPOTHESIS: The United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model can be used to estimate the lifetime occurrence of major diabetes-related complications in order to calculate health economic outcomes. The aim of the study was to assess the performance of the model by comparing the predicted and observed mortality and the incidence of macrovascular complications in an Italian population-based cohort with type 2 diabetes. METHODS: We used data from the Casale Monferrato Survey, a cohort enrolled in 1988 and surveyed in 1991 (n = 1,967) to assess the prevalence of cardiovascular risk factors. In 2000, a new survey included all the members of the original cohort who were still alive (n = 860), and in addition all individuals identified with a new diagnosis of type 2 diabetes since 1993 (n = 2,389). We compared the mortality predicted by the model for the 1991 survey over the subsequent 17-year period with the observed risk. The following outcomes were analysed in the 2000 survey: myocardial infarction (MI), other ischaemic heart disease, stroke, congestive heart failure (CHF) and amputation. RESULTS: For all-cause mortality, the predictions from the model at 5 and 10 years (23% and 47%, respectively) were identical to the observed risks. At 15 years, the risk of death was slightly overestimated (an estimate of 67% vs 64% observed, 95% CI 61%, 66%). The performance of the model was best for patients with a recent history of disease (duration <6 years). Among the complications, the predicted cumulative incidences of MI and CHF were very close to those observed. CONCLUSIONS/INTERPRETATION: External validation is essential to assess the accuracy of simulation models. The UKPDS Outcomes Model satisfactorily predicted a set of actual incidences of mortality and complications in an Italian diabetes cohort up to a duration of approximately 12 years. The longer term performance of such models should be carefully evaluated.

Collatamp sponges in the management of open fractures.

Open fractures are at high risk of infection and the prompt treatment of these injuries is critical to the success and is crucial to reduce the rate of complications. The basic steps of treatment include the immediate administration of systemic antibiotics, early surgical stabilization of the fracture associated with copious irrigation and radical debridement of the site of exposure, and when possible adequate soft tissue coverage. The systemic antibiotic therapy significantly improves the prognosis and reduces the occurrence of complications. However, in order to ensure adequate and sustained local concentration of antibiotic agent, high doses and for a long time are necessary. This increases the risk of side effects and bacterial resistance. The introduction of the antibiotic-loaded collagen sponges offers the advantages of a high local concentrations of antibiotic carrier delivering system with reduced systemic drug diffusion (less risk of side effects and resistance rate). Sponges are also biodegradable and fully resorbable and do not require additional surgery for their removal.

An overview of Clinical Quality Registries (CQRs) on gynecological oncology worldwide.

INTRODUCTION: Clinical Quality Registries (CQRs) were initiated in order to compare clinical outcomes between hospitals or regions within a country. To get an overview of these CQRs worldwide the aim of this study was to identify these CQRs for gynecological oncology and to summarize their characteristics, processes and QI's and to establish whether it is feasible to make an international comparison in the future. METHODS: To identify CQRs in gynecological oncology a literature search in Pubmed was performed. All papers describing the use of a CQR were included. Administrative, epidemiological and cancer registries were excluded as these registries do not primarily serve to measure quality of care through QI's. The taskforce or contact person of the included CQR were asked to participate and share information on registered items, processes and indicators. RESULTS: Five nations agreed to collaborate: Australia, Denmark, Italy, the Netherlands and Sweden. Denmark, Netherlands and Sweden established a nationwide registry, collecting data on multiple tumor types, and various QI's. Australia and Italy included patients with ovarian cancer only. All nations had a different process to report feedback results to participating hospitals. CONCLUSION: CQRs serve the same purpose to improve quality of care but vary on different aspects. Although similarities are observed in the topics measured by the QI's, an international comparison was not feasible as numerators or denominators differ between registries. In order to compare on an international level it would be useful to harmonize these registries and to set an international standard to measure the quality of care with similar indicators.

Bioplasty for vertebral fractures: preliminary results of a pre-clinical study on goats using autologous modified skin fibroblasts.

The debate is still ongoing about the long term effects of the mininvasive vertebral augmentation techniques and their usefulness in treating more complex cases where a bone inducing effect more than a merely bone substitution would be suitable, such as the vertebral fractures in young patients. We previously developed a clinically relevant gene therapy approach using modified dermal fibroblasts for inducing bone healing and bone formation in different animal models. The aim of this study is to show the feasibility of a minimally invasive percutaneous intrasomatic ex vivo gene therapy approach to treat thoracolumbar vertebral fractures and anterior column bone defects in a goat model.

The use of collatamp in total hip arthroplasty.

Total Hip Arthroplasty (THA) is one of the most common orthopedic operations in the world. The number of THA is expected to grow and with it the number of associated complications. Although improved surgical technique and the development of more scrupulous asepsis has decreased the incidence of periprosthetic joint infection (PJI), it remains one of the most feared complications of joint arthroplasty. The purpose of this study is to present the use of antibiotic-loaded collagen sponges (Collatamp EG) in the prophylaxis and treatment of PJI. For this scope a case report is described. The advantages offered by the antibiotic loaded sponges in terms of high and sustained concentration of antibiotic at the site of infection, diffused by the fully reabsorbable carrier, showed to be a an important adjuvant therapy in the treatment of PJI. Low systemic concentration of the drug and a wide versatility in surgical application are other advantages of this dispositive.

Bilateral nephrectomy as an extreme measure management for methicillin-resistant staphylococcus aureus (MRSA): A case report.

Methicillin-resistant Staphylococcus aureus (MRSA) infections are cases of urgent management that often leads to hospitalizations in intensive care and prolonged management of antibiotic therapy. In this occasion, we present the case of a 38-year-old female patient with sepsis secondary to banal dermal infection due MRSA that complicates with infectious thrombus of the left renal vein associated with multiple foci of bilateral renal abscesses. As an extreme and exceptional measure, emergency bilateral radical nephrectomy was performed to save the patient's life.

Appropriateness of early breast cancer management in relation to patient and hospital characteristics: a population based study in Northern Italy.

Administrative data may provide valuable information for monitoring the quality of care at population level and offer an efficient way of gathering data on individual patterns of care, and also to shed light on inequalities in access to appropriate medical care. The aim of the study was to investigate the role of patient and hospital characteristics in the initial treatment of early breast cancer using administrative data. Incident breast cancer patients were identified from hospital discharge records and linked to the radiotherapy outpatient database during 2000-2004 in the Piedmont region of Northwestern Italy. Women treated with breast-conserving surgery followed by radiotherapy (BCS + RT) were compared to those treated with BCS without radiotherapy (BCS w/o RT) or mastectomy using multinomial logistic regression models. Out of 16,022 incident cases, 46.2% received BCS + RT, 20.3% received BCS w/o RT, and 33.5% received a mastectomy. Compared to BCS + RT, the factors associated with BCS w/o RT were: increased age (OR = 1.54; 95% CI = 1.29-1.85, for ages 70-79 vs. <50), being unmarried (1.24; 1.13-1.36), presence of co-morbidities (1.32; 1.10-1.58), being treated at hospitals with low surgical volume (1.31; 1.07-1.60 for hospitals with less than 50 vs. > or =150 interventions/year), and living far from radiotherapy facilities (1.75; 1.39-2.20 for those at a distance of >45 min). These same factors were also associated with mastectomy. During the 5-year period observed, there was a trend of reduced probability of receiving a mastectomy (0.70; 0.56-0.88 for 2004 vs. 2000). The presence or absence of nodal involvement was positively associated with mastectomy (2.28; 1.83-2.85) and negatively associated with BCS w/o RT (0.65; 0.56-0.76). After adjustment for potential confounders, education level did not show any association with the type of treatment. Social and geographical factors, in addition to hospital specialization, should be considered to reduce inappropriateness of care for breast cancer.

NADPH oxidase 2 inhibitors CPP11G and CPP11H attenuate endothelial cell inflammation & vessel dysfunction and restore mouse hind-limb flow.

First described as essential to the phagocytic activity of leukocytes, Nox2-derived ROS have emerged as mediators of a range of cellular and tissue responses across species from salubrious to deleterious consequences. Knowledge of their role in inflammation is limited, however. We postulated that TNFα-induced endothelial reactive oxygen species (ROS) generation and pro-inflammatory signaling would be ameliorated by targeting Nox2. Herein, we in silico-modelled two first-in-class Nox2 inhibitors developed in our laboratory, explored their cellular mechanism of action and tested their efficacy in in vitro and mouse in vivo models of inflammation. Our data show that these inhibitors (CPP11G and CPP11H) disrupted canonical Nox2 organizing factor, p47phox, translocation to Nox2 in the plasma membrane; and abolished ROS production, markedly attenuated stress-responsive MAPK signaling and downstream AP-1 and NFκB nuclear translocation in human cells. Consequently, cell adhesion molecule expression and monocyte adherence were significantly inhibited by both inhibitors. In vivo, TNFα-induced ROS and inflammation were ameliorated by targeted Nox2 inhibition, which, in turn, improved hind-limb blood flow. These studies identify a proximal role for Nox2 in propagated inflammatory signaling and support therapeutic value of Nox2 inhibitors in inflammatory disease.

The cost of foreign body injuries in the upper aero-digestive tract: need for a change from a clinical to a public health perspective?

OBJECTIVE: This paper addressed the impact in terms of direct costs of the injuries in children due to foreign bodies in the upper aero-digestive tract. METHODS: Two thousand one hundred and three consecutive cases were collected from 2000 to 2002 in 16 European hospitals, 1 hospital for each participating country, and referred to children aged until 14 who had FB injuries. Costs were based on the extraction of the FB procedures and on hospitalization length, based on DRGs. Determinants of costs and of length of stay (LOS) were analyzed using a multilevel model. RESULTS: The major cost of the treatment of FB injuries is covered by the ENT Departments, which are usually the first choice of referral, directly from the patients. Children had a mean LOS of 2.13 days (95% C.I. 1.99-2.29). Treatment of the FB was associated with a mean cost of euro 1017.37 (95% C.I. 963.27-1073.51). In the multivariable analysis higher costs are related to the modality of arrival to the hospital by walk, to the site of the injury (ICD-933, ICD-934, ICD-935 in particular) and to the use of surgery in removing the FB. DISCUSSION: Foreign bodies injuries are posing a great threat not only with regards to the clinical aspects but also from the public health perspective, their treatment being associated with high costs, in particular when surgery is needed.

Five novel hormone-responsive cell lines derived from murine mammary ductal carcinomas: in vivo and in vitro effects of estrogens and progestins.

We have developed an experimental model of mammary carcinogenesis in which the administration of medroxyprogesterone acetate (MPA) to female BALB/c mice induces progestin-dependent ductal metastatic mammary tumors with high levels of estrogen receptor (ER) and progesterone receptor (PR). Through selective transplants in untreated mice, we have obtained progestin-independent variants, still expressing high levels of ER and PR. Primary cultures of the MPA-induced carcinomas C4-HD and C7-HI were set up, and after 3-4 months, several different cell lines were obtained. Four of these, MC4-L1, MC4-L2, MC4-L3, and MC4-L5 were established from C4-HD and a fifth, MC7-L1, from C7-HI. All cells were of epithelial origin, as demonstrated by electron microscopy and by immunocytochemical identification of cytokeratin and cadherin. In vitro MC4-L1, MC4-L3, and MC4-L5 showed a typical epithelial morphology; when transplanted in vivo, they originated metastatic carcinomas with different degrees of differentiation. MC4-L2 and MC7-L1 deviated from the standard epithelial picture; they disclosed a spindle-shaped morphology in vitro and in vivo gave rise to a biphasic spindle cell/tubular carcinoma and an anaplastic carcinoma, respectively; both lines gave rise to metastases. This differential morphology correlated with a higher degree of aggressiveness, as compared with MC4-L1, MC4-L3, and MC4-L5. ERs and PRs were detected by binding, immunocytochemistry, and Western blot. In vitro, MC4-L2 and MC7-L1 were stimulated by MPA (nM to microM) and 17beta-estradiol (nM and 10 nM); no significant stimulation was observed in MC4-L1, MC4-L3, and MC4-L5 under the same experimental conditions. In vivo, MPA significantly stimulated tumor growth in all epithelioid lines but not in MC4-L2 and MC7-L1. A progestin-dependent growth pattern was confirmed for MC4-L1, MC4-L3, and MC4-L5 in successive transplants, whereas MC4-L2 and MC7-L1 behaved as progestin independent. This is the first description of mouse mammary carcinoma cell lines expressing ER and PR. The different in vitro hormone responses as compared with in vivo and the differential effects of 17beta-estradiol in the parental tumors and in cell lines render these lines useful tools for the in vitro and in vivo study of hormone regulation of tumor growth and metastases.

IFN-beta1a modulates the expression of CTLA-4 and CD28 splice variants in human mononuclear cells: induction of soluble isoforms.

Recently, mRNA encoding soluble isoforms of CD28 and CTLA-4 have been described in human lymphocytes. We demonstrate that interferon-beta1a (IFN-beta1a) can enhance the expression of these transcripts in human mononuclear cells. Because soluble CD28 and CTLA-4 molecules might affect T cell activation, our findings suggest an additional means whereby IFN-beta therapy might exert its immunomodulatory effects in multiple sclerosis (MS).

An economic evaluation of the optimal workload in treating surgical patients in a breast unit.

A breast unit is a cancer centre specialised in the diagnosis and treatment of patients with breast cancer. The high level of specialised skills involved in running a breast unit makes it an expensive pattern of care. The European Society of Mastology (EUSOMA) recommends a minimum caseload of 150 cases sufficient to maintain expertise for each team member and to ensure cost-effective working of the breast unit. Specific economic analysis evaluating main diagnostic services (radiology and pathology) and treatment are needed. The present study assesses the activity level at which the breast unit represents good value for money in surgically-treated patients. Cost assessment is realised by defining a cost function according to the following assumptions: cost function input is personnel costs and technical equipment and output is the number of newly diagnosed cases of primary breast cancer admitted to the breast care unit each year. The increase from 50 new cancer cases per year to 100 will reduce average costs by almost 50%. Cost reduction is important up to a volume of 200 new cases per year. For economic investment to be justified, it is desirable that intake rises to at least 200 new cases per year. Our result is in-line with the EUSOMA recommendation.

The relationship of erythrocyte sodium-lithium countertransport to blood pressure and metabolic abnormalities in a sample of untreated middle-aged male workers.

OBJECTIVES: To investigate the relationship between erythrocyte sodium-lithium countertransport and blood pressure in a randomly selected sample of untreated male workers and to evaluate the influence of a set of metabolic abnormalities commonly associated with hypertension on this relationship. DESIGN: A cross-sectional investigation of a randomly selected sample of untreated male workers (n = 216, age range 21-59 years) at the Olivetti factory in Pozzuoli, Naples. METHODS: Standardized measurements of anthropometric and metabolic parameters, blood pressure and Na(+)-Li+ countertransport were performed. RESULTS: In a simple linear correlation analysis Na(+)-Li+ countertransport was directly related to plasma triglycerides and uric acid concentrations, body mass index (BMI) and systolic and diastolic blood pressure. Significantly higher values of Na(+)-Li+ countertransport were observed in the two upper quintiles of the serum triglycerides and uric acid distributions, and of the BMI distribution. Na(+)-Li+ countertransport accounted for approximately 2% of the blood pressure variation in this study population, but its contribution to the effect of metabolic covariates was not statistically significant. Hypertensive individuals with one or more metabolic abnormality had a significantly higher mean level of Na(+)-Li+ countertransport than those hypertensives who were free of such alterations. CONCLUSIONS: The results of the present study suggest that a high level of Na(+)-Li+ countertransport is more common in those hypertensive individuals who have concomitant metabolic abnormalities than in hypertensives who are free of such abnormalities.

Altered renal sodium handling in men with abdominal adiposity: a link to hypertension.

OBJECTIVES: Central adiposity, insulin resistance and hypertension are clearly interrelated but the mechanisms underlying this association have not been thoroughly elucidated. As renal sodium handling plays a central role in salt-sensitive forms of hypertension, we investigated the relation of renal tubular sodium handling to abdominal adiposity, blood pressure and insulin sensitivity. DESIGN: Population-based study. PARTICIPANTS: Five hundred and fifty-five untreated Olivetti male workers, aged 25-75 years. SETTING: Olivetti factory medical centers in Pozzuoli and Marcianise (Naples, Italy) MAIN OUTCOME MEASURES: Anthropometric indices, serum insulin, homeostatic model assessment index of insulin sensitivity, blood pressure, fractional excretions of uric acid and exogenous lithium (as markers of renal tubular sodium handling). RESULTS: In univariate analysis, measures of central adiposity (i.e. sagittal abdominal diameter and umbilical circumference) were directly correlated with serum insulin (P < 0.001) and blood pressure levels (P < 0.001) and inversely associated with the fractional excretions of uric acid and lithium (P = 0.01-0.001). In multiple linear regression analysis, the same anthropometric indices but not the measures of peripheral adiposity (arm circumference and tricipital skinfold thickness), were significant predictors of the fractional excretion of uric acid and lithium, independently of age, blood pressure and serum insulin levels (P = 0.01-0.001). CONCLUSIONS: Abdominal adiposity was associated with altered renal tubular sodium handling apart from insulin resistance and high blood pressure. The data indicate that men with prevalent abdominal adiposity have an enhanced rate of tubular sodium reabsorption, mainly at proximal sites. These findings provide a possible mechanistic link between central adiposity and salt-dependent hypertension.

Blood pressure and metabolic changes during dietary L-arginine supplementation in humans.

Dietary L-arginine supplementation has been proposed to reverse endothelial dysfunction in such diverse pathophysiologic conditions as hypercholesterolemia, coronary heart disease, and some forms of animal hypertension. In particular, chronic oral administration of L-arginine prevented the blood pressure rise induced by sodium chloride loading in salt-sensitive rats. To investigate the effects of L-arginine-rich diets on blood pressure and metabolic and coagulation parameters we performed a single-blind, controlled, crossover dietary intervention in six healthy volunteers. The subjects (aged 39+/-4 years, body mass index [BMI] 26+/-1 kg/m2, mean +/- SEM) received, in random sequence, three different isocaloric diets, each for a period of 1 week (Diet 1: control; Diet 2: L-arginine enriched by natural foods; Diet 3: identical to Diet 1 plus oral L-arginine supplement). Sodium intake was set at a constant level (about 180 mmol/day) throughout the three study periods. A blood pressure decrease was observed with both L-arginine-rich diets (Diet 2 v 1, SBP: -6.2 mm Hg [95% CI: -0.5 to -11.8], DBP: -5.0 mm Hg [-2.8 to -7.2]; Diet 3 v 1, SBP: -6.2 mm Hg [-1.8 to -10.5], DBP: -6.8 mm Hg [-3.0 to -10.6]). A slight increase in creatinine clearance (P = .07) and a fall in fasting blood glucose (P = .008) occurred after Diet 3 and, to a lesser extent, after Diet 2. Serum total cholesterol (P = .06) and triglyceride (P = .009) decreased and HDL cholesterol increased (P = .04) after Diet 2, but not after Diet 3. These results indicate that a moderate increase in L-arginine significantly lowered blood pressure and affected renal function and carbohydrate metabolism in healthy volunteers.