Pre-hospital glycemia as a biomarker for in-hospital all-cause mortality in diabetic patients - a pilot study.

BACKGROUND: Type 2 Diabetes Mellitus (T2DM) presents a significant healthcare challenge, with considerable economic ramifications. While blood glucose management and long-term metabolic target setting for home care and outpatient treatment follow established procedures, the approach for short-term targets during hospitalization varies due to a lack of clinical consensus. Our study aims to elucidate the impact of pre-hospitalization and intra-hospitalization glycemic indexes on in-hospital survival rates in individuals with T2DM, addressing this notable gap in the current literature. METHODS: In this pilot study involving 120 hospitalized diabetic patients, we used advanced machine learning and classical statistical methods to identify variables for predicting hospitalization outcomes. We first developed a 30-day mortality risk classifier leveraging AdaBoost-FAS, a state-of-the-art ensemble machine learning method for tabular data. We then analyzed the feature relevance to identify the key predictive variables among the glycemic and routine clinical variables the model bases its predictions on. Next, we conducted detailed statistical analyses to shed light on the relationship between such variables and mortality risk. Finally, based on such analyses, we introduced a novel index, the ratio of intra-hospital glycemic variability to pre-hospitalization glycemic mean, to better characterize and stratify the diabetic population. RESULTS: Our findings underscore the importance of personalized approaches to glycemic management during hospitalization. The introduced index, alongside advanced predictive modeling, provides valuable insights for optimizing patient care. In particular, together with in-hospital glycemic variability, it is able to discriminate between patients with higher and lower mortality rates, highlighting the importance of tightly controlling not only pre-hospital but also in-hospital glycemic levels. CONCLUSIONS: Despite the pilot nature and modest sample size, this study marks the beginning of exploration into personalized glycemic control for hospitalized patients with T2DM. Pre-hospital blood glucose levels and related variables derived from it can serve as biomarkers for all-cause mortality during hospitalization.

Diagnostic accuracy of Point Of Care UltraSound (POCUS) in clinical practice: A retrospective, emergency department based study.

AIMS: Point-of-care ultrasound (POCUS) is the acquisition and interpretation of ultrasound imaging at the bedside to solve specific clinical questions based on signs and symptoms of presentation. While several studies evaluated POCUS diagnostic accuracy for a variety of clinical pictures in the emergency department (ED), only a few data are available on POCUS diagnostic accuracy performed by physicians with different POCUS skills. The objective of this research was to evaluate the diagnostic accuracy of POCUS compared to standard diagnostic imaging in the ED. MATERIALS AND METHODS: This was a retrospective study conducted in the ED of a third-level university hospital. Patients who underwent cardiac, thoracic, abdominal, or venous lower limb POCUS and a standard imaging examination between June 2021 and January 2022 were included. RESULTS: 1047 patients were screened, and 844 patients included. A total of 933 POCUS was included (102, 12.09%, cardiac; 466, 55.21%, thoracic; 336, 39.8%, abdominal; 29, 3.44%, lower limb venous POCUS), accounting for 2029 examinations. POCUS demonstrated 96.6% (95% CI 95.72-97.34) accuracy, 47.73 (95% CI 33.64-67.72) +LR, 0.09 (95% CI 0.06-0.12) -LR. +LR was greater than 10 for all investigations but for hydronephrosis (5.8), and -LR never exceeded 0.4. CONCLUSIONS: POCUS exhibited high diagnostic accuracy for virtually all conditions when performed by emergency department physicians.

Sarcopenia parameters in active older adults - an eight-year longitudinal study.

BACKGROUD: Sarcopenia is a common skeletal muscle syndrome that is common in older adults but can be mitigated by adequate and regular physical activity. The development and severity of sarcopenia is favored by several factors, the most influential of which are a sedentary lifestyle and physical inactivity. The aim of this observational longitudinal cohort study was to evaluate changes in sarcopenia parameters, based on the EWGSOP2 definition in a population of active older adults after eight years. It was hypothesized that selected active older adults would perform better on sarcopenia tests than the average population. METHODS: The 52 active older adults (22 men and 30 women, mean age: 68.4 ± 5.6 years at the time of their first evaluation) participated in the study at two time points eight-years apart. Three sarcopenia parameters were assessed at both time points: Muscle strength (handgrip test), skeletal muscle mass index, and physical performance (gait speed), these parameters were used to diagnose sarcop0enia according to the EWGSOP2 definition. Additional motor tests were also performed at follow-up measurements to assess participants' overall fitness. Participants self-reported physical activity and sedentary behavior using General Physical Activity Questionnaire at baseline and at follow-up measurements. RESULTS: In the first measurements we did not detect signs of sarcopenia in any individual, but after 8 years, we detected signs of sarcopenia in 7 participants. After eight years, we detected decline in ; muscle strength (-10.2%; p < .001), muscle mass index (-5.4%; p < .001), and physical performance measured with gait speed (-28.6%; p < .001). Similarly, self-reported physical activity and sedentary behavior declined, too (-25.0%; p = .030 and - 48.5%; p < .001, respectively). CONCLUSIONS: Despite expected lower scores on tests of sarcopenia parameters due to age-related decline, participants performed better on motor tests than reported in similar studies. Nevertheless, the prevalence of sarcopenia was consistent with most of the published literature. TRIAL REGISTRATION: The clinical trial protocol was registered on ClinicalTrials.gov, identifier: NCT04899531.

COVID-19 induced aorto duodenal fistula following evar in the so called "negative" patient.

OBJECTIVES: Since October 2019, SARS-CoV-2 pandemic represents a challenge for the international healthcare system and for the treatment and survival of patients. We normally focus on symptomatic patients, and symptoms can range from the respiratory to the gastrointestinal system. In addition, we consider patients without fever and respiratory symptoms, with both a negative RT nasopharyngeal swab and lung CT, as a "Covid-19 negative patient." In this article, we present a so called Covid-19 "negative" patient, with an unsuspected vascular clinical onset of the viral infection. METHODS: An 80 y.o. man, who previously underwent endovascular aortic repair for an infrarenal abdominal aortic aneurysm, presented to our department with an atypical presentation of an aorto-enteric fistula during the pandemic. While in hospital, weekly nasopharyngeal swab tests were always negative for SARS-CoV-2. However, the absence of aortic endograft complications, the gross anatomy of duodenal ischemic injury, and the recent history of the patient who lived the last months in Bergamo, the Italian city with the highest number of COVID-19 deaths, lead the senior Author to suspect an occult SARS-CoV-2 infection. The patient underwent to resection of the fourth portion of the duodenum and the first jejunal loop, with subsequent duodenum-jejunal latero-lateral anastomosis and the direct suture of the aortic wall. The intestinal specimen was investigated as suspected SARS-CoV-2 bowel infection by the means of immune-histochemistry (IHC). An ileum sample obtained in the pre-COVID-19 era was used as a control tissue. RESULTS: The histological analysis of the bowel revealed sustained wall ischemia and liponecrosis of the duodenal wall, with intramural blood vessels thrombosis. Blood vessel endotheliitis and neo-angiogenesis were also observed. Finally, the IHC was strongly positive for SARS-CoV-2 RNA and for HLA-G presence, with a particular concentration both in blood vessels and in the intestinal villi. The control tissue sample was not positive for both SARS-CoV-2 and HLA-G. CONCLUSIONS: Coronavirus pandemic continues to be an international challenge and more studies and trials must be done to learn its pathogenesis and its complications. As for thromboembolic events caused by SARS-COV-2, vascular surgeons are involved in treatment and prevention of the complications of this syndrome and must be ready with general surgeons to investigate atypical and particular cases such as the one discussed in this article.

Bowel ischemia as onset of COVID-19 in otherwise asymptomatic patients with persistently negative swab.

BACKGROUND: Asymptomatic patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can develop hypercoagulable conditions and acute vascular events. The objective of this study is to determine whether SARS-CoV-2 was present in resected specimens from patients with acute bowel ischemia, but asymptomatic for Coronavirus Disease 2019 (COVID-19) and with persistently real-time polymerase chain reaction negative pharyngeal swab. METHODS: Three consecutive patients presented severe abdominal symptoms due to extensive ischemia and necrosis of the bowel, with co-existent thrombosis of abdominal blood vessels. None had the usual manifestations of COVID-19, and repeated pharyngeal swabs tested negative. They underwent emergency surgery with intestinal resection. Immunohistochemical testing for SARS-CoV-2 on resected tissue was performed. RESULTS: All tested samples were strongly positive for SARS-CoV-2. CONCLUSIONS: This is the first case report in which patients with severe intestinal symptoms presented a marked SARS-CoV-2 positivity in the resected tissues, without any usual clinical manifestations of COVID-19. These results suggest that the patients might be infected with SARS-CoV-2 presenting acute abdominal distress but without respiratory or constitutional symptoms.

Relevance of VEGF and CD147 in different SARS-CoV-2 positive digestive tracts characterized by thrombotic damage.

Several evidence suggests that, in addition to the respiratory tract, also the gastrointestinal tract is a main site of severe acute respiratory syndrome CoronaVirus 2 (SARS-CoV-2) infection, as an example of a multi-organ vascular damage, likely associated with poor prognosis. To assess mechanisms SARS-CoV-2 responsible of tissue infection and vascular injury, correlating with thrombotic damage, specimens of the digestive tract positive for SARS-CoV-2 nucleocapsid protein were analyzed deriving from three patients, negative to naso-oro-pharyngeal swab for SARS-CoV-2. These COVID-19-negative patients came to clinical observation due to urgent abdominal surgery that removed different sections of the digestive tract after thrombotic events. Immunohistochemical for the expression of SARS-CoV-2 combined with a panel of SARS-CoV-2 related proteins angiotensin-converting enzyme 2 receptor, cluster of differentiation 147 (CD147), human leukocyte antigen-G (HLA-G), vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 was performed. Tissue samples were also evaluated by electron microscopy for ultrastructural virus localization and cell characterization. The damage of the tissue was assessed by ultrastructural analysis. It has been observed that CD147 expression levels correlate with SARS-CoV-2 infection extent, vascular damage and an increased expression of VEGF and thrombosis. The confirmation of CD147 co-localization with SARS-CoV-2 Spike protein binding on gastrointestinal tissues and the reduction of the infection level in intestinal epithelial cells after CD147 neutralization, suggest CD147 as a possible key factor for viral susceptibility of gastrointestinal tissue. The presence of SARS-CoV-2 infection of gastrointestinal tissue might be consequently implicated in abdominal thrombosis, where VEGF might mediate the vascular damage.

COVID-19 inpatients with gastrointestinal onset: sex and care needs' differences in the district of Ferrara, Italy.

BACKGROUND: COVID-19 is characterized by interstitial pneumonia, but a presentation of the disease with digestive symptoms only may occur. This work was aimed at evaluating: (1) the prevalence of presentation with digestive symptoms only in our cohort of COVID-19 inpatients; (2) differences between patients with and without gastrointestinal onset; (3) differences among males and females with gastrointestinal presentation; (4) outcomes of the groups of subjects with and without gastrointestinal onset. METHOD: We retrospectively divided the patients hospitalized with COVID-19 into two groups: (1) the one with digestive symptoms (DSG) and (2) the other without digestive symptoms (NDSG). We compared the subjects of DSG with those of NDSG and males with females in the DSG group only, in terms of demographics (age, sex), inflammation and organ damage indexes, length of stay, in-hospital and 100-day mortality. RESULTS: The prevalence of gastrointestinal symptoms at presentation was 12.5%. The DSG group showed a prevalence of females, and these tended to a shorter hospital stay; DSG patients were younger and with a higher load of comorbidities, but no differences concerning inflammation and organ damage indexes, need for intensification of care, in-hospital and 100-day mortality were detected. Among DSG patients, males were younger than females, more comorbid, with higher serum CRP and showed a longer length of hospital stay. Survival functions of DSG patients, in general, are more favourable than those of NDSG if adjusted for sex, age and comorbidities. CONCLUSIONS: (1) The prevalence of gastrointestinal presentation among hospitalized COVID-19 patients was 12.5%; (2) DSG patients were on average younger, more comorbid and with a prevalence of females, with a shorter hospital stay; (3) in the DSG group, males had a higher Charlson Comorbidity Score and needed a longer hospital stay; (4) DSG subjects seem to survive longer than those of the NDSG group.

Risk of dementia in patients with atrial fibrillation: Short versus long follow-up. A systematic review and meta-analysis.

BACKGROUND: No previous meta-analyses have compared the risk of dementia, due to an underlying atrial fibrillation (AF), in the short-term versus the long-term period. AIM: To perform an update meta-analysis of studies examining the association between AF and dementia and the relative impact of follow-up period. METHODS: Data were obtained searching MEDLINE and Scopus for all investigations published between 1 January 2000 and March 1, 2021 reporting the risk of dementia in AF patients. The following MeSH terms were used for the search: "Atrial Fibrillation" AND "Dementia" OR "Alzheimer's disease". From each study, the adjusted hazard ratio (aHR) with the related 95% confidence interval (CI) was pooled using a random effect model. RESULTS: The analysis was carried out on 18 studies involving 3.559.349 subjects, of which 902.741 (25.3%) developed dementia during follow-up. A random effect model revealed an aHR of 1.40 (95% CI: 1.27-1.54, p < 0.0001; I2  = 93.5%) for dementia in subjects with AF. Stratifying the studies according to follow-up duration, those having a follow-up ≥10 years showed an aHR for dementia of 1.37 (95% CI: 1.21-1.55, p < 0.0001, I2  = 96.6%), while those with a follow-up duration <10 years has a slightly higher aHR for dementia (HR: 1.59, 95%CI: 1.51-1.67, p < 0.0001, I2  = 49%). Nine studies showed that the aHR for Alzheimer's disease (AD) in AF patients was 1.30 (95%CI: 1.12-1.51, p < 0.0001, I2  = 87.6%). CONCLUSIONS: Evidence suggests that patients with AF have an increased risk of developing dementia and AD. The risk of dementia was slightly higher when the follow-up was shorter than 10 years.

Clinical and demographic parameters predict the progression from mild cognitive impairment to dementia in elderly patients.

OBJECTIVES: To evaluate the possibility of predicting the risk of progression from mild cognitive impairment (MCI) to dementia using a combination of clinical/demographic parameters. METHODS: A total of 462 MCI elderly patients (follow-up: 33 months). Variable measured included cognitive functions, age, gender, MCI type, education, comorbidities, clinical chemistry, and functional status. RESULTS: Amnestic type (aMCI) represented 63% of the sample, non-amnestic (naMCI) 37%; 190 subjects progressed to dementia, 49% among aMCI, and 28% among naMCI. At Cox multivariate regression analysis, only MMSE (one point increase HR 0.84; 95% CI 0.79-0.90), aMCI (HR 2.35; 95% CI 1.39-3.98), and age (1 year increase HR 1.05; 95% CI 1.01-1.10) were independently associated with progression to dementia. A score was created based on these dichotomized variables (score 0-3): age (≥ or < 78 years), MMSE score (≥ or < 25/30) and aMCI type. The conversion rate progressed from 6% in subjects with score 0 (negative predictive value: 0.94), to 31% in individuals with score 1, to 53% in subjects with score 2, to 72% in individuals with score 3 (positive predictive value: 0.72). ROC curve analysis showed an area under the curve of 0.72 (95% CI 0.66-0.75, p 0.0001). CONCLUSIONS: We have described a simple score, based on previously recognized predictors such as age, MMSE, and MCI type, which may be useful for an initial stratification of the risk of progression to dementia in patients affected by MCI. The score might help the clinicians to evaluate the need for more expansive/invasive examinations and for a closer follow-up in MCI patients.

Development, optimization and validation of an absolute specific assay for active myeloperoxidase (MPO) and its application in a clinical context: role of MPO specific activity in coronary artery disease.

Background Myeloperoxidase (MPO) is an enzyme with a recognized prognostic role in coronary artery disease (CAD), which is also emerging as a promising biomarker for cardiac risk stratification. However, the lack of a consensus method for its quantification has hindered its implementation in clinical practice. The aim of our work was to optimize an absolute sensitive assay for active MPO without external standards, to validate the method in the clinical context of CAD patients, and to estimate the enzyme specific activity. Methods In order to determine the MPO concentration using fluorescence readings, this ELISA assay exploits the activity of the enzyme recognized by specific antibodies. The assay was validated in a small cohort of patients that included: healthy subjects (n=60); patients with acute myocardial infarction (AMI, n=25); patients with stable CAD (SCAD, n=25) and a concomitant chronic obstructive pulmonary disease (COPD). Then, total MPO concentration and specific activity (activity/total MPO) were determined. Results The assay showed an intra- and inter-assay coefficient of variation of 5.8% and 10.4%, respectively, with a limit of detection (LoD) of 0.074 µU. Both AMI and SCAD patients had higher active and total MPO than controls (p<0.0001 and p<0.01, respectively). The specific activity of MPO was higher in SCAD patients compared to both controls and AMI (p<0.0001). Conclusions The study presents a robust and sensitive method for assaying MPO activity in biological fluids with low variability. Moreover, the determination of the specific activity could provide novel insight into the role of MPO in cardiovascular diseases (CVDs).

Effects of 3-month high-intensity interval training vs. moderate endurance training and 4-month follow-up on fat metabolism, cardiorespiratory function and mitochondrial respiration in obese adults.

PURPOSE: The purpose of this study was to investigate, in obese adults, changes in body composition, physical capacities, fat oxidation and ex vivo mitochondrial respiration induced by a 3-month either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT); afterwards, the patients were followed for four months. METHODS: Thirty-two patients (mean age 39 years; mean body mass index [BMI] 36 kg∙m-2) participated in this study attending ~ 34 sessions of training. At baseline (PRE), at the end of the program (POST) and after follow-up, body composition, peak O2 uptake (V'O2peak) and fat oxidation rate were measured. Vastus lateralis biopsies for the evaluation of mitochondrial respiration were performed only at PRE and POST. RESULTS: At POST, body mass (BM) and fat mass (FM) decreased (- 6 and - 14%, respectively, P < 0.05) in MICT and HIIT; V'O2peak increased in both groups (+ 6 and + 16%, respectively, P < 0.05). Maximal fat oxidation rate increased only after HIIT (P < 0.001). Maximal ADP-stimulated mitochondrial respiration normalized by citrate synthase increased (P < 0.05) by 67% and 36% in MICT and HIIT, respectively, without significant difference. After follow-up, BM and FM were still lower (- 4 and - 20%, respectively, P < 0.050) compared with baseline in both groups. Only after HIIT, V'O2peak (+ 8%) and maximal fat oxidation rate were still higher (P < 0.05). CONCLUSIONS: HIIT was more effective in improving and maintaining V'O2peak and fat oxidation. These results may be relevant for an appropriate prescription of training programs designed to optimize aerobic fitness in obese subjects.

Sex difference: an important issue to consider in epidemiological and clinical studies dealing with serum paraoxonase-1.

The aim of this study was to evaluate the influence of sex on serum paraoxonase-1 (PON1) activities and on its relationship with cardiovascular disease risk factors such as overall and central obesity. Arylesterase and lactonase activities of PON1 were assessed in 374 women and 92 men. Both arylesterase and lactonase activities were significantly higher in women compared to men (p<0.001), irrespectively of confounders such as high density lipoprotein-cholesterol, age, smoking and body mass index or waist circumference. Sex also strongly influenced the interplay between PON1 and both fat measures, with only the arylesterase showing a significant and independent inverse correlation with the former parameter (r = -0.248, p<0.001) and the risk of overall obesity (odds ratio: 0.559, 95% confidence interval: 0.340-0.919) in women, but not in men; conversely, neither of the two activities remained associated with waist circumference in men or women after full adjustment. Noteworthy, the association between arylesterase and BMI in the female subsample was significant among women younger than forty-five years (r = -0.453, p<0.001, R 2 = 0.207). In conclusion, our study suggests that sex might chiefly influence PON1 activity and its contribution to cardiovascular disease risk. Further studies are needed to confirm and clarify our preliminary findings.

Loss of maximal explosive power of lower limbs after 2 weeks of disuse and incomplete recovery after retraining in older adults.

KEY POINTS: Disuse in older adults can critically decrease lower limb muscle power, leading to compromised mobility and overall quality of life. We studied how muscle power and its determinants (muscle mass, single muscle fibre properties and motor control) adapted to 2 weeks of disuse and subsequent 2 weeks of physical training in young and older people. Disuse decreased lower limb muscle power in both groups; however, different adaptations in single muscle fibre properties and co-contraction of leg muscles were observed between young and older individuals. Six physical training sessions performed after disuse promoted the recovery of muscle mass and power. However, they were not sufficient to restore muscle power to pre-disuse values in older individuals, suggesting that further countermeasures are required to counteract the disuse-induced loss of muscle power in older adults. ABSTRACT: Disuse-induced loss of muscle power can be detrimental in older individuals, seriously impairing functional capacity. In this study, we examined the changes in maximal explosive power (MEP) of lower limbs induced by a 14-day disuse (bed-rest, BR) and a subsequent 14-day retraining, to assess whether the impact of disuse was greater in older than in young men, and to analyse the causes of such adaptations. Sixteen older adults (Old: 55-65 years) and seven Young (18-30 years) individuals participated in this study. In a subgroup of eight Old subjects, countermeasures based on cognitive training and protein supplementation were applied. MEP was measured with an explosive ergometer, muscle mass was determined by magnetic resonance, motor control was studied by EMG, and single muscle fibres were analysed in vastus lateralis biopsy samples. MEP was ∼33% lower in Old than in Young individuals, and remained significantly lower (-19%) when normalized by muscle volume. BR significantly affected MEP in Old (-15%) but not in Young. Retraining tended to increase MEP; however, this intervention was not sufficient to restore pre-BR values in Old. Ankle co-contraction increased after BR in Old only, and remained elevated after retraining (+30%). Significant atrophy occurred in slow fibres in Old, and in fast fibres in Young. After retraining, the recovery of muscle fibre thickness was partial. The proposed countermeasures were not sufficient to affect muscle mass and power. The greater impact of disuse and smaller retraining-induced recovery observed in Old highlight the importance of designing suitable rehabilitation protocols for older individuals.

Adipokines levels in HIV infected patients: lipocalin-2 and fatty acid binding protein-4 as possible markers of HIV and antiretroviral therapy-related adipose tissue inflammation.

BACKGROUND: Metabolic and cardiovascular diseases (CVD) represent a major problem in HIV infection. The aim of this study was to evaluate the relationship of HIV infection and antiretroviral therapy (ART) with circulating levels of two adipokines (Lipocalin-2 and Fatty Acid Binding Protein-4, FABP-4), known to be associated with adipose tissue dysfunction and cardiovascular disease in the general population. METHODS: We enrolled 40 non-obese HIV-infected patients and 10 healthy controls of similar age and Body Mass Index (BMI). Body composition, metabolic syndrome, lipid profile, 10-years CVD risk score, and adipokines levels were compared between groups. ART-regimen status (naïve, non-nucleoside reverse transcriptase inhibitors - NNRTIs - and protease inhibitors - PIs) association with adipokines levels was tested with linear regression models. RESULTS: HIV patients showed a worse metabolic profile than controls. Lipocalin-2 levels were higher in HIV-infected subjects (+53%; p = 0.007), with a significant trend (p = 0.003) for higher levels among subjects taking NNRTIs. Association of lipocalin-2 with fat-mass and BMI was modulated by ART regimens, being positive among subjects treated with NNRTIs and negative among those treated with PIs ("ART-regimens-by-BMI" interaction p = 0.0009). FABP-4 levels were correlated with age, fat mass, BMI, lipid profile and CVD risk (all R ≥ 0.32, p < 0.05), but not influenced by HIV-status (+20%; p = 0.12) or ART-regimen (p = 0.4). CONCLUSIONS: Our data confirm that HIV-infection is associated with adipose tissue inflammation, as measured by Lipocalin-2 levels, and ART does not attenuate this association. While FABP-4 is a marker of worse metabolic and CVD profile independently of HIV status or ART regimen, lipocalin-2 could represent a useful marker for HIV- and ART-related adipose tissue dysfunction.

Lower Plasma Klotho Concentrations Are Associated with Vascular Dementia but Not Late-Onset Alzheimer's Disease.

BACKGROUND: The protein Klotho is involved in biological processes related to longevity, cardiovascular health, and cognition. Serum Klotho levels have been associated with better cognition in animal models; moreover, lower Klotho concentrations in cerebrospinal fluid from subjects with late-onset Alzheimer's disease (LOAD) have been reported. OBJECTIVE: Our study aimed to examine the possible relationship between Klotho plasma concentrations and cognitive status in the elderly. METHODS: We evaluated plasma Klotho levels in a sample of 320 elderly patients admitted to a Memory Clinic. Four groups of subjects were enrolled, including cognitively intact individuals complaining about memory loss (controls) and patients affected by LOAD, mild cognitive impairment, or vascular dementia (VD). The sample was stratified by plasma Klotho tertiles. RESULTS: Lower levels of plasma Klotho (1st tertile) were associated with older age, higher prevalence of VD, single/multiple lacunar infarcts and leukoaraiosis, coronary heart disease and stroke, and higher levels of creatinine, homocysteine, and high-sensitivity C-reactive protein. On multivariate logistic regression analysis, the risk of VD was 3- and 4-fold in subjects belonging to the 1st tertile (≤514.8 pg/mL, OR 3.54, 95% CI 1.05-11.93) and 2nd tertile (> 514.8, < 659.1 pg/mL, OR 4.28, 95% CI 1.30-14.06) compared to the 3rd tertile (≥659.1 pg/mL). A significantly increased VD risk was found for Klotho values < 680 pg/mL. CONCLUSION: In a sample of elderly individuals, we found a significant association between low plasma Klotho levels and VD, but not LOAD. This finding suggests that, although these 2 forms of dementia might overlap, some physiopathological mechanisms related to VD and LOAD remain distinct.

Paraoxonase, arylesterase and lactonase activities of paraoxonase-1 (PON1) in obese and severely obese women.

Obesity is independently associated with disturbances in lipid and lipoprotein metabolism, oxidative stress, and is a well-established independent risk factor for cardiovascular diseases (CVD). Human paraoxonase 1 (PON1) is a pleotropic high-density lipoprotein (HDL)-associated enzyme with antioxidant and anti-inflammatory proprieties that have been suggested to contribute to the athero-protective function of the lipoprotein. The aim of this study was to investigate whether obesity is associated with PON1 activity and whether this association is influenced by oxidative stress, inflammation and HDL cholesterol (HDL-C) concentration. The promiscuous activities, arylesterase and paraoxonase, and the putative physiological activity, lactonase, of PON1 were assessed in the serum of 214 obese and severely obese, 101 overweight and 129 normal-weight women. Levels of high-sensitivity C-reactive protein (hs-CRP), hydroperoxides (by-products of lipid oxidative damage) and lipid profiles were also evaluated. Arylesterase activity was the only activity that significantly differed across the groups (ANOVA, p < .01), with the greatest decrease observed in individuals with body mass index (BMI) > 40 kg/m2 compared to controls (p < .001). This activity was also inversely, although weakly (r = -0.160, p < .001) correlated with the BMI, and the association was independent of age and levels of oxidative stress and inflammation, but not of HDL-C concentration. In conclusion, our results suggest that the apparent obesity-associated decrement of PON1 activity might simply reflect the decrease in concentration of its plasmatic carrier.

TRAIL and Ceruloplasmin Inverse Correlation as a Representative Crosstalk between Inflammation and Oxidative Stress.

OBJECTIVE: "Oxinflammation" is a recently coined term that defines the deleterious crosstalk between inflammatory and redox systemic processes, which underlie several diseases. Oxinflammation could be latently responsible for the predisposition of certain healthy individuals to disease development. The oxinflammatory pathway has been recently suggested to play a crucial role in regulating the activity of TNF-related apoptosis-inducing ligand (TRAIL), a TNF superfamily member that can mediate multiple signals in physiological and pathological processes. Therefore, we investigated the associations between TRAIL and key players of vascular redox homeostasis. METHODS: We measured circulating TRAIL levels relative to praoxonas-1, lipoprotein phospholipase-A2, and ceruloplasmin levels in a cohort of healthy subjects (n = 209). RESULTS: Multivariate analysis revealed that ceruloplasmin levels were significantly inversely associated with TRAIL levels (r = -0.431, p < 0.001). The observed association retained statistical significance after adjustment for additional confounding factors. After stratification for high-sensitivity C-reactive protein levels, the inverse association between TRAIL and ceruloplasmin levels remained strong and significant (r = -0.508, p < 0.001, R2 = 0.260) only in the presence of inflammation, confirming the role of inflammation as emerged in in vitro experiments where recombinant TRAIL decreased ceruloplasmin expression levels in TNF-treated PBMC cultures. CONCLUSION: The results indicated that in an inflammatory milieu, TRAIL downregulates ceruloplasmin expression, highlighting a signaling axis involving TRAIL and ceruloplasmin that are linked via inflammation and providing important insights with potential clinical implications.

Gene expression regional differences in human subcutaneous adipose tissue.

BACKGROUND: Accumulation of visceral adipose tissue (VAT) is clearly associated with an increased risk of obesity-related diseases and all-cause mortality, whereas gluteal subcutaneous fat accumulation (g-SAT) is associated with a lower risk. The relative contribution, in term of cardiovascular risk, of abdominal subcutaneous adipose tissue (a-SAT) is still controversial with studies showing both a detrimental effect and a protective role. Animal and in vitro studies demonstrated that adipocytes from visceral and subcutaneous depots have distinct morphological, metabolic and functional characteristics. These regional differences have a key role in the pathogenesis of obesity-related diseases. There is recent evidence that differentiation between upper-body and lower-body adipose tissues might be under control of site-specific sets of developmental genes, such as Homebox (HOX) genes, a group of related genes that control the body plan of an embryo along the anterior-posterior axis. However, the possible heterogeneity between different subcutaneous regions has not been extensively investigated. Here we studied global mRNA expression in g-SAT and a-SAT with a microarray approach. RNA was isolated from g-SAT and a-SAT biopsy, from eight healthy subjects, and hybridized on RNA microarray chips in order to detect regional differences in gene expression. RESULTS: A total of 131 genes are significantly and differently (>1.5 fold change, p < 0.05) expressed in a-SAT and g-SAT. Expression profiling reveals significant differences in expression of several HOX genes. Interestingly, two molecular signature of visceral adipocyte lineage, homebox genes HOXA5 and NR2F1, are up-regulated in a-SAT versus g-SAT by a 2.5 fold change. CONCLUSIONS: Our study shows that g-SAT and a-SAT have distinct expression profiles. The finding of a different expression of HOX genes, fundamental during the embryo development, suggests an early regional differentiation of subcutaneous adipose depots. Moreover, the higher expression of HOXA5 and NR2F1, two molecular signatures of visceral adipocytes, in a-SAT suggests that this subcutaneous adipose depot could be more similar to VAT than g-SAT. Our data suggest that we should look at SAT as composed of distinct depots with possibly different impact in obesity associated metabolic complications.

Interleukin-6 "Trans-Signaling" and Ischemic Vascular Disease: The Important Role of Soluble gp130.

Inflammation plays a major role in the onset of cardiovascular disease (CVD). Interleukine-6 (IL-6) is a multifunctional cytokine involved both in the beneficial acute inflammatory response and in the detrimental chronic low-grade systemic inflammation. Large genetic human studies, using Mendelian randomization approaches, have clearly showed that IL-6 pathway is causally involved in the onset of myocardial infarction. At the same time, IL-6 pathway is divided into two arms: classic signaling (effective in hepatocytes and leukocytes) and trans-signaling (with ubiquitous activity). Trans-signaling is known to be inhibited by the circulating soluble glycoprotein 130 (sgp130). In animal and in vitro models, trans-signaling inhibition with sgp130 antibody clearly shows a beneficial effect on inflammatory disease and atherosclerosis. Conversely, epidemiological data report inconsistent results between sgp130 levels and CV risk factors as well as CV outcome. We have reviewed the literature to understand the role of sgp130 and to find the evidence in favor of or against a possible clinical application of sgp130 treatment in the prevention of cardiovascular disease.

Mutual relationship between serum ferroxidase activity and hemoglobin levels in elderly individuals.

The identification of hemoglobin (Hb) biological determinants is of primary clinical interest, in particular in the elderly because of the well-documented relationship between anemia and cognitive and functional decline. Ceruloplasmin (Cp) and non-Cp ferroxidase activity might influence Hb production because of its role in modulating iron mobilization. This potential connection has never been explored so far. Therefore, in the present study, we evaluated the possible association between serum ferroxidase activity (sFeOx) and Hb in a sample of 136 apparently healthy older individuals. The results revealed that nonlinear (quadratic) regression explained the relationship between the two variables of interest better than did the linear one (R (2) = 0.09 vs. R (2) = 0.03). The same analysis highlighted a linear behavior for the relationship between Hb and sFeOx, for two separate subsamples stratified on the basis of the Hb value (141 g/L) corresponding to the parabola vertex. In the subset with higher Hb (high Hb), sFeOx was positively associated (r = 0.44, p = 0.003) while in the low Hb subset, the association was negative (r = -0.26, p = 0.01). Notably, we found that the concentration of Cp was significantly higher in Low Hb compared to High Hb subsample (p < 0.05), with this multicopper oxidase selectively contributing to sFeOx in the former group (r = 0.348, p = 0.001). Collectively, this exploratory study suggests that ferroxidases might play a role in dispatching the body's iron toward erythropoietic tissues, with Cp contribution that might become more important in stress-like conditions.