Rankl genetic deficiency and functional blockade undermine skeletal stem and progenitor cell differentiation.

BACKGROUND: Skeletal Stem Cells (SSCs) are required for skeletal development, homeostasis, and repair. The perspective of their wide application in regenerative medicine approaches has supported research in this field, even though so far results in the clinic have not reached expectations, possibly due also to partial knowledge of intrinsic, potentially actionable SSC regulatory factors. Among them, the pleiotropic cytokine RANKL, with essential roles also in bone biology, is a candidate deserving deep investigation. METHODS: To dissect the role of the RANKL cytokine in SSC biology, we performed ex vivo characterization of SSCs and downstream progenitors (SSPCs) in mice lacking Rankl (Rankl-/-) by means of cytofluorimetric sorting and analysis of SSC populations from different skeletal compartments, gene expression analysis, and in vitro osteogenic differentiation. In addition, we assessed the effect of the pharmacological treatment with the anti-RANKL blocking antibody Denosumab (approved for therapy in patients with pathological bone loss) on the osteogenic potential of bone marrow-derived stromal cells from human healthy subjects (hBMSCs). RESULTS: We found that, regardless of the ossification type of bone, osteochondral SSCs had a higher frequency and impaired differentiation along the osteochondrogenic lineage in Rankl-/- mice as compared to wild-type. Rankl-/- mice also had increased frequency of committed osteochondrogenic and adipogenic progenitor cells deriving from perivascular SSCs. These changes were not due to the peculiar bone phenotype of increased density caused by lack of osteoclast resorption (defined osteopetrosis); indeed, they were not found in another osteopetrotic mouse model, i.e., the oc/oc mouse, and were therefore not due to osteopetrosis per se. In addition, Rankl-/- SSCs and primary osteoblasts showed reduced mineralization capacity. Of note, hBMSCs treated in vitro with Denosumab had reduced osteogenic capacity compared to control cultures. CONCLUSIONS: We provide for the first time the characterization of SSPCs from mouse models of severe recessive osteopetrosis. We demonstrate that Rankl genetic deficiency in murine SSCs and functional blockade in hBMSCs reduce their osteogenic potential. Therefore, we propose that RANKL is an important regulatory factor of SSC features with translational relevance.

Home mobile radiography service in the COVID-19 era.

Demographic changes in the Western world linked to the increase in the elderly population, life expectancy and above all cancer patients and chronically ill patients, often entrusted to home care or in healthcare residences, highlight an exponential increase in requests for diagnostic tests at home. Conventional radiographic examinations, such as thoracic, musculoskeletal and abdominal images are the most requested and are important first level diagnostic tests. To date and, in particular, in times of COVID-19 emergency, these patients need to be transferred to the hospital to perform radiological examinations which involve an increase in costs for the health system and an increased risk for the health of these patients, already often debilitated and immunocompromised. This article discussed the benefits of taking conventional chest x-rays directly at the patient's home.

Sterile carbon particle suspension vs India ink for endoscopic tattooing of colonic lesions: a randomized controlled trial.

BACKGROUND: Different markers have been used preoperatively to mark colonic lesions, especially India ink. In recent years, another kind of marker has been developed: sterile carbon particle suspension (SCPS). No comparison between these two markers has yet been made. The aim of the present study was to compare the pyrogenic, inflammatory and intraperitoneal effect of these two markers. METHODS: From September 2015 to December 2018, adult patients who were candidates for elective laparoscopic colon resection were randomized to the SCPS or conventional India ink injection group using computer-based randomization. The primary endpoint of the study was the presence of intraoperative adhesions related to the endoscopic tattoo. Secondary endpoints were differences in white blood cell, C-reactive protein, and fibrinogen levels as well as, abdominal pain and body temperature at baseline (before endoscopic tattooing) and 6 and 24 h after colonoscopy. Finally, the visibility of the tattoo during the minimally invasive intervention was assessed. RESULTS: Ninety-four patients were included in the study, 47 for each arm. There were 45/94 females (47.9%) and 49/94 males (52.1%), with a median age of 67.85 ± 9.22 years. No differences were found between groups in WBC, fibrinogen levels, body temperature or VAS scores, but we documented significantly higher CRP values at 6 and 24 h after endoscopic tattooing with India ink injection. There were significantly fewer adhesions in the SCPS Endoscopic Marker group. All the endoscopic tattoos were clearly visible. CONCLUSIONS: SCPS is an effective method for tattooing colonic lesions and has a better safety profile than traditional India ink in terms of post-procedure inflammatory response and intraoperative bowel adhesions. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (ID: NCT03637933).

Robotic versus laparoscopic approach to treat symptomatic achalasia: systematic review with meta-analysis.

Minimally invasive Heller myotomy is considered the gold standard surgical approach for symptomatic achalasia because it is a safe and effective procedure. Over the last years, several studies comparing the laparoscopic and robotic approach for Heller myotomy have been published. Although the robotic approach appears to have some advantages over standard laparoscopy, data on this topic are still controversial and no definite conclusions have been drawn. This metanalysis has been designed to systematically evaluate and compare the effectiveness and safety of the robot-assisted Heller myotomy as compared to the standard laparoscopic approach. According to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, a systematic search on both laparoscopic and robotic Heller myotomy was performed in all the major electronic databases (PubMed, Web of Science, Scopus, EMBASE), using the following search string: (achalasia OR Dor) AND robotic. Six articles were included in the final analysis. A metaregression analysis was performed to assess the possible effects of demographic variables (age, gender, body mass indes (BMI)) and previous abdominal surgery or endoscopic intervention on the analyzed outcomes. No statistical difference was observed in operative times (mean difference (MD) = 20.79, P = 0.19, 95% confidence interval (CI) -10.05,51,62), estimated blood loss (MD = -17.10, P = 0.13, 95% CI -40.48,5.08), conversion rate to open surgery (risk difference (RD) = -0.01, P = 0.33, 95% CI -0.05,0.02), length of hospital stay (MD = -0.73, P = 0.15, 95% CI -1.71,0.25) and long-term recurrence (odds ratio (OR) = 0.59, P = 0.45, 95% CI 0.15,2.33). On the contrary, the robotic approach was found to be associated with a significantly significant lower rate of intraoperative esophageal perforations (OR = 0.13, P < 0.001, 95% CI 0.04, 0.45). Our results suggest that the robotic approach is safer than the laparoscopic Heller myotomy, encouraging the use of robot-assisted surgery. However, our analysis is limited because of the exiguous number of comparative studies and because most of the included studies were statistically underpowered, given the small sample size. Moreover, a high degree of heterogeneity was observed in most of published studies. Taking in consideration the additional costs of robot-assisted procedures, larger Randomized Controlled Trials (RCTs) are advocated to confirm the safety and effectiveness of the robotic approach, and its advantages over standard laparoscopic surgery. In conclusion, well-designed prospective trials and RCTs with homogeneous parameters are needed to draw definitive conclusions about the best surgical approach to pursue in treating symptomatic achalasia.

Relationship between skeletal muscle function, body composition, and weight loss in patients with advanced pancreatic and gastrointestinal cancers.

BACKGROUND: Muscle function and its correlation with body composition and weight loss have not been studied deeply in pancreas and gastrointestinal cancers. This research aims to determine the skeletal muscle function and its relationship with body compartments, significant weight loss, and performance status (ECOG) 0-2 in a population with advanced digestive cancers. METHODS: A cross-sectional study was designed to determine the relationship between muscular function, weight loss, and body composition. Patients with advanced digestive adenocarcinomas were evaluated. Muscle strength was examined by hand grip technique and body composition by bioimpedance analysis. Values of hemoglobin and albumin were measured in plasma. RESULTS: A sample of 81 patients was included. They had adenocarcinoma of stomach (n = 9), pancreas (n = 28), or colorectum (n = 44). With regard to skeletal muscle function, sub-maximal strength increased when percentage of weight loss decreased (p = 0.002) or when any of the following variables increased: skeletal muscle (p < 0.001), waist-hip ratio (p < 0.001), body surface area (p < 0.001), and body mass index (p = 0.001). According to multivariate analysis of these variables, only percentage of weight loss and skeletal muscle remained statistically significant. Endurance had no correlation with any of the variables. Higher weight loss was found in tumors of the upper tract (stomach and pancreas) in comparison with those of the lower tract (colorectal) (p = 0.005). CONCLUSIONS: In advanced digestive cancer, sub-maximal strength correlated inversely with weight loss and directly with skeletal muscle such as in lung and head and neck cancers. On the other hand, endurance had no correlation with any of the variables considered.

Weight loss facilitates reduction of left ventricular mass in obese hypertensive patients: The Campania Salute Network.

BACKGROUND AND AIMS: Reduction of left ventricular mass index (LVMi) during antihypertensive treatment is less likely to occur in obese subjects. The aim of the study was to assess whether weight loss influences reduction of LVMi in treated, obese, hypertensive patients. METHODS AND RESULTS: From the Campania Salute Network registry, we identified 1546 obese hypertensive patients (50 ± 9 years, 43% women) with more than 12 months follow-up. Echocardiographic reduction of LVMi was considered as achievement of normal values (<47 g/m2.7 in women or <50 g/m2.7 in men) or a reduction of ≥10% during follow-up. Weight loss was considered as ≥5% reduction in body weight, and occurred in 403 patients (26%) during a median follow-up of 50 months (IQrange:31-93). Median weight loss was 8.6% (IQrange:6.5-12). Patients with weight loss had higher baseline body mass index (p < 0.05), while there was no difference in age, sex, duration of hypertension, prevalence of diabetes, metabolic syndrome and average blood pressure during follow-up. During follow-up, 152 patients (9.8%) exhibited reduction of LVMi. Reduction of LVMi was more frequent (12.9% vs 9.1%, p < 0.030) in patients losing weight than in those who did not. In logistic regression analysis, weight loss was associated with reduction of left ventricular mass index (OR 1.51 [95%CI 1.02-2.23], p = 0.039), independent of significant associations with younger age, lower average systolic blood pressure during follow-up, longer follow-up time and higher LVMi at baseline. CONCLUSION: In treated obese hypertensive patients, weight loss during follow-up promotes significant reduction of LVMi, independent of baseline characteristics and blood pressure control.

Is increased uric acid a risk factor or a defensive response? The Campania Salute Network.

BACKGROUND AND AIMS: Circulating uric acid (UA) is positively associated with body mass index (BMI), blood glucose, blood pressure (BP), markers of inflammation, and altered lipid profile. UA has also anti-oxidative properties which might be beneficial for cardiovascular (CV) system. It is still debated whether or not UA is independently associated with increased CV morbidity and/or mortality. METHODS AND RESULTS: We studied prognostic impact of UA in 8833 hypertensive adults (mean age 53 ± 12 yrs, 3857 women) from the Campania Salute Network, without prevalent CV disease and more than stage 3 CKD. We calculated standardized UA Z-score, adjusted for age, sex, glomerular filtration rate, and BMI. Low and high UA and UA Z-score quartiles were compared to the 2 middle quartiles assumed to be "normal". Prevalence of obesity and diabetes was higher in low and high than in normal UA Z-score group (all p < 0.001). Systolic BP, left ventricular mass, carotid intima thickness were significantly higher and ejection fraction was reduced in the presence of high UA Z-score (all p < 0.001). Over 33-months average follow-up, incident major CV end-points (MACE) were not significantly different among low, normal and high UA or UA Z-score. In the latter analysis, however, incident MACE tended to be more frequent in the low than the high UA Z-score. Despite the results of multivariable analyses, the effect of less aggressive therapy in low UA Z-score cannot be excluded with certainty. CONCLUSION: In treated hypertensive patients, high levels of UA normalized for major biological determinants do not independently predict CV outcome. CLINICALTRIALS. GOV IDENTIFIER: NCT02211365.

A new index to simplify the screening of hypertension in overweight or obese youth.

BACKGROUND AND AIMS: Hypertension (HTH) is a frequent complication in pediatric obesity. To simplify the screening of HTH in overweight/obese (Ow/Ob) youth, we compared the performance of a new index (High Blood Pressure index, HBPi) with respect to the standard criteria of the IV Report [systolic BP (SBP) and/or diastolic BP (DBP) ≥95th percentile for age, gender and height]. We also compared the performance of HBPi with other simplified indices such as the BP/height ratio and the absolute height-specific BP thresholds. Ten pediatrics' outpatient centers participating in the "CARdiometabolic risk factors in ITALY study" provided medical records of 4225 Ow/Ob children and adolescents (age 6-16 years). METHODS AND RESULTS: Centers were divided into two groups: training set (TS) (n = 2204 participants) and validation set (VS) (n = 2021 participants). The simplified HBPi (mmHg) was: (SBP/2 + DBP/10) - age + (1 × female gender). In the TS, a HBPi value ≥57 mmHg in both children and adolescents had high sensitivity (0.89), specificity (0.97), positive (0.89) and negative (0.97) predictive values in classifying youth at high risk of HTN compared with the IV Report. In the VS, the HBPi showed a better performance than high levels of BP/height ratio and height-specific BP thresholds in classifying individuals at risk of HTN: area under curves 0.95 (0.93-0.96), 0.80 (0.78-0.82), 0.76 (0.74-0.79), respectively; specificities 0.95 (0.94-0.96), 0.69 (0.67-0.72), 0.60 (0.57-0.62), respectively. CONCLUSIONS: HBPi, combining SBP and DBP, gender and age, may help pediatricians to implement HTN screening in Ow/Ob youth.

Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network.

Reduced myocardial mechano-energetic efficiency (MEE), estimated as stroke volume/heart rate ratio per g of left ventricular (LV) mass (LVM), and expressed in µl s-1 g-1 (MEEi), is a strong predictor of cardiovascular (CV) events, independently of LV hypertrophy and other confounders, including type II diabetes (DM). Decreased MEEi is more frequent in patients with diabetes. In the present analysis we evaluated the interrelation among MEEi, DM and metabolic syndrome (MetS) in the setting of arterial hypertension. Hypertensive patients from the Campania Salute Network, free of prevalent CV disease and with ejection fraction >50% (n=12 503), were analysed. Coexistence of MetS and DM was ordinally categorized into 4 groups: 8235 patients with neither MetS nor DM (MetS-/DM-); 502 without MetS and with DM (MetS-/DM+); 3045 with MetS and without DM (MetS+/DM-); and 721 with MetS and DM (MetS+/DM+). After controlling for sex, systolic blood pressure, body mass index, relative wall thickness (RWT), antihypertensive medications and type of antidiabetic therapy, MEEi was 333 µl s-1 g-1 in MetS-/DM-, 328 in MetS-/DM+, 326 in MetS+/DM- and 319 in MetS+/DM+ (P for trend <0.0001). In pairwise comparisons (Sidak-adjusted), all conditions, except MetS-/DM+, were significantly different from MetS-/DM- (all P<0.02). No statistical difference was detected between MetS-/DM+ and MetS+/DM-. Both MetS and DM are associated with decreased MEEi in hypertensive patients, independently to each other, but the reduction is statistically less evident for MetS-/DM+. MetS+/DM+ patients have the lowest levels of MEEi, consistent with the alterations of energy supply associated with the combination of insulin resistance with insulin deficiency.

Correcting for H2O interference using a RAD7 electrostatic collection-based silicon detector.

The effect of water molecules on the electrostatic collection of 218Po ions onto the surface of silicon detectors (neutralization) is evaluated through the comparison with a scintillation cell (ZnS), not affected by air humidity. A radon monitor (RAD7, Durridge Company) was connected to a stainless steel radon chamber, equipped with the scintillation cell. Radon gas, extracted from an acidified RaCl2 source, was injected into the chamber and the amount of water molecules in the system was alternatively lowered or increased (from 0.00075 to 0.014 g of water in RAD7) by connecting the chamber to a desiccant or to a bubbling water bottle. The relative efficiency of the silicon detector with respect to the scintillation cell decreases with the growth of water molecules inside RAD7. This dependence, with a fixed i) electrostatic chamber geometry and ii) nominal high voltage, diverges during the humidification or the drying phase because it is in turn influenced by the length of interaction of polonium atoms with water molecules, which impacts on the size of 218Po clusters and thus on the neutralization process. For water contents higher that 0.01 g in RAD7, this effect is greatly enhanced. Temperature in the investigated range (18.5-35.6 °C) does not affect the efficiency of electrostatic collection-based silicon detectors. Based on these experiments, admitting a certain error on the efficiency (from 1.8 to 7.5%, depending on the water content), proper corrections were developed to adjust soil radon readings, when a desiccant is removed. This operation is necessary if recent Non-Aqueous Phase Liquids (NAPLs) leakage has occurred in the subsoil to avoid the sorption and possible later release of radon by Drierite, with related partition between the solid and liquid phases (water and NAPL).

Identification of phenotypes at risk of transition from diastolic hypertension to isolated systolic hypertension.

Little is known about the potential progression of hypertensive patients towards isolated systolic hypertension (ISH) and about the phenotypes associated with the development of this condition. Aim of this study was to detect predictors of evolution towards ISH in patients with initial systolic-diastolic hypertension. We selected 7801 hypertensive patients free of prevalent cardiovascular (CV) diseases or severe chronic kidney disease and with at least 6-month follow-up from the Campania Salute Network. During 55±44 months of follow-up, incidence of ISH was 21%. Patients with ISH at the follow-up were significantly older (P<0.0001), had longer duration of hypertension, higher prevalence of diabetes and were more likely to be women (all P<0.0001). They exhibited higher baseline left ventricular mass index (LVMi), arterial stiffness (pulse pressure/stroke index), relative wall thickness (RWT) and carotid intima-media thickness (IMT; all P<0.001). Independent predictors of incident ISH were older age (odds ratio (OR)=1.14/5 years), female gender (OR=1.30), higher baseline systolic blood pressure (OR=1.03/5 mm Hg), lower diastolic blood pressure (OR=0.89/5 mm Hg), longer duration of hypertension (OR=1.08/5 months), higher LVMi (OR=1.02/5 g m(-2.7)), arterial stiffness (OR=2.01), RWT (OR=1.02), IMT (OR=1.19 mm(-1); all P<0.0001), independently of antihypertensive treatment, obesity, diabetes and fasting glucose (P>0.05). Our findings suggest that ISH is a sign of aggravation of the atherosclerotic disease already evident by the target organ damage. Great efforts should be paid to prevent this evolution and prompt aggressive therapy for arterial hypertension should be issued before the onset of target organ damage, to reduce global CV risk.

X-ray crystallographic and kinetic investigations of 6-sulfamoyl-saccharin as a carbonic anhydrase inhibitor.

6-Sulfamoyl-saccharin was investigated as an inhibitor of 11 α-carbonic anhydrase (CA, EC 4.2.1.1) isoforms of human (h) origin, hCA I-XIV, and X-ray crystallographic data were obtained for its adduct with hCA II, the physiologically dominant isoform. This compound possesses two potential zinc-binding groups, the primary sulfamoyl one and the secondary, acylatedsulfonamide. Saccharin itself binds to the Zn(II) ion from the CA active site coordinating with this last group, in deprotonated (SO2N(-)CO) form. Here we explain why 6-sulfamoyl-saccharin, unlike saccharin, binds to the metal ion from the hCA II active site by its primary sulfonamide moiety and not the secondary one as saccharin itself. Our study is useful for shedding new light to the structure-based drug design of isoform-selective CA inhibitors of the sulfonamide type.

Type of myocardial infarction presentation in patients with chronic kidney disease.

BACKGROUND AND AIM: Association of coronary and renal disease has been frequently found in epidemiological studies. Whether ECG-graphic presentation of myocardial infarction [S-T Elevated MI (STEMI) or Non S-T Elevated MI (NSTEMI)] is related to the degree of renal dysfunction is still unclear. METHODS AND RESULTS: We examined 146 patients with acute myocardial infarction, consecutively entering the Coronary Care Unit of our ward. At entry, patients underwent clinical, ECG-graphic and echocardiographic examination, and blood samples were withdrawn for cardiac markers and general biochemistry. GFR was calculated using the CKD-EPI equation. STEMI was found in 71 cases and NSTEMI in 75 cases. Renal function was normal in 61 patients (stage 1), mildly impaired (<90 mL/min/1.73 m(2) and ≥ 60 mL/min/1.73 m(2)) in 60 (stage 2) and moderately to severely impaired (GFR <60 mL/min/1.73 m(2)) in 25 cases (stages 3-4). Patients were, thereafter, clustered into two groups (stages 1-2 and stages 3-4). Compared to stage 1-2 subjects, stages 3-4 patients were older, were more likely to be diabetic and had more frequently previous cardiovascular diseases. The probability of presentation of NSTEMI for stage 3-4 patients was 4-fold greater than for stage 1-2 patients (p = 0.02). CONCLUSIONS: These data support the evidence that 1) NSTEMI is associated with more severe kidney dysfunction, likely due to more severe and/or longer lasting exposition to risk factors; 2) cardiac and renal impairment are strongly associated. ClinicalTrials.gov Identifier: NCT01636427.

Transient bacteraemia due to Chryseobacterium indologenes in an immunocompetent patient: a case report and literature review.

A 51-year-old woman was admitted to the emergency unit with diffuse headache, visus reduction, and paraesthesias of the trigeminal area and the left hand. Three days after admission she showed shaking chills, vomiting, and sudden onset of fever (39·4°C). Blood cultures were performed soon after fever onset. Fever persisted for the whole day, decreasing slowly after 12 hours. No empirical antibiotic treatment was started in order to better define the diagnosis. Fever completely disappeared the day after. Two blood cultures for aerobes were positive for Chryseobacterium indologenes. The patient was discharged with the diagnosis of transient bacteraemia and transferred to the neurology unit for further investigations. C. indologenes infections are described in 31 studies with a total of 171 cases (pneumonia and bacteraemia being the most frequent). Our case is the first report of transient bacteraemia caused by C. indologenes in an immunocompetent, non-elderly patient without needing medical devices.

Serum uric acid does not predict incident metabolic syndrome in a population with high prevalence of obesity.

AIM: To evaluate whether uric acid (UA) predicts 4-yr incidence of metabolic syndrome (MetS) in non-diabetic participants of the Strong Heart Study (SHS) cohort. METHODS AND RESULTS: In this population-based prospective study we analyzed 1499 American Indians (890 women), without diabetes or MetS, controlled during the 4th SHS exam and re-examined 4 years later during the 5th SHS exam. Participants were divided into sex-specific tertiles of UA and the first two tertiles (group N) were compared with the third tertile (group H). Body mass index (BMI = 28.3 ± 7 vs. 31.1 ± 7 kg/m(2)), fat-free mass (FFM = 52.0 ± 14 vs. 54.9 ± 11 kg), waist-to-hip ratio, HOMA-IR (3.66 vs. 4.26), BP and indices of inflammation were significantly higher in group H than in group N (all p < 0.001). Incident MetS at the time of the 5th exam was more frequent in group H than group N (35 vs. 28%, OR 1.44 (95% CI = 1.10-1.91; p < 0.01). This association was still significant (OR = 1.13, p = 0.04) independently of family relatedness, sex, history of hypertension, HOMA-IR, central adiposity and renal function, but disappeared when fat-free mass was included in the model. CONCLUSIONS: In the SHS, UA levels are associated to parameters of insulin resistance and to indices of inflammation. UA levels, however, do not predict incident MetS independently of the initial obesity-related increased FFM.

Modulation of polyfunctional HIV-specific CD8 T cells in patients responding differently to antiretroviral therapy.

Antiretroviral therapy allows a restoration of immune cell homeostasis associated with a normal immune competence. Our goal was to analyze the modulation of polyfunctional HIV-specific CD8+ T-cell responses during antiretroviral therapy. HIV-infected individuals were divided into four groups according to CD4+ cell count and viral load at the moment of recruitment. Whole blood was stimulated with a pool of CD8-specific HIV-antigens to assess cytokine/chemokine production and cytotoxicity activity by using flow cytometry. The groups show different modulation in HIV-specific CD8+ T-cell responses. In particular, immunological failure showed different distributions of polyfunctional HIVspecific CD8+ responses, mainly due to an increase of cells producing CD107alpha/IFNgamma/IL-2/MIP-1beta. Our results indicate that this particular 4+ functional subset is a possible correlate of immunological failure. Considering the complexity of interactions among HAART, immune system and HIV, work is in progress to find correlates of therapy efficacy.

Cardiometabolic risk in overweight subjects with or without relative fat-free mass deficiency: the Strong Heart Study.

BACKGROUND AND AIM: Sarcopenia is a condition mainly due to loss of fat-free mass (FFM) in elderly individuals. RFFMD, however, is also frequent in obese subjects due to abnormal body composition. Objective of this study was to evaluate the impact of relative fat-free mass deficiency (RFFMD) on cardiometabolic (CM) risk in obese normoglycemic individuals. METHODS AND RESULTS: Overweight/obese American Indians from the Strong Heart Study population, without diabetes and with FBG ≤ 110 mg/dL and with GFR >60 mg/mL/1.73 m(2) were selected for this analysis (n = 742). RFFMD was defined on the basis of a multivariable equation previously reported. Fasting glucose and 2 h-OGTT were measured together with urine albumin/creatinine excretion, laboratory and anthropometric parameters. In addition to lower FFM and greater adipose mass, participants with RFFMD had higher body mass index, waist circumference, C-reactive protein, fibrinogen, insulin resistance and urinary albumin/creatinine than participants with normal FFM (all p < 0.001); they also had a greater prevalence of hypertension, impaired glucose tolerance (IGT) or OGTT-diabetes than participants with normal FFM (all p < 0.003) and a near 2-fold greater probability of significant proteinuria (p < 0.01). RFFMD was more frequent in women than in men: significant sex-RFFMD interactions were found for BMI and waist circumference (both p < 0.0001). CONCLUSIONS: RFFMD in overweight/obese normoglycemic individuals is associated with greater probability of hypertension, abnormalities of glucose tolerance and proteinuria. Assessment of RFFRMD might, therefore, help stratifying cardiometabolic risk among normoglycemic individuals with overweight/obesity.