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IntroductionThe accurate distinction between periprosthetic joint infections (PJI) and aseptic failures (AF) is of paramount importance due to differences in treatment. However, this could be challenging by using the current criteria. Various synovial fluid biomarkers are being assessed to improve the diagnostic accuracy. Myeloperoxidase (MPO), an enzyme contained in the granules of neutrophils, may be a promising biomarker for PJI.MethodsSynovial fluids of 99 patients (n = 65 PJI according to EBJIS criteria; n = 34 AF) were collected in two specialized orthopedic centers. PJI were divided into acute (n = 33) and low-grade (n = 32) according to previously published classification. An activity assay specific for active MPO was performed in each sample. Ability of MPO to correctly discriminate patients with PJI from AF was determined by ROC analysis. The best discriminating cut-off value was determined by calculating the J Youden index. For all analyses, a P value < 0.05 was considered statistically significant.ResultsActive MPO was higher in PJI than AF (P < 0.0001). The ROC analysis revealed a significant area under the curve (AUC: 0.86; 95% CI: 0.78–0.93, P < 0.0001). A cut-off value of 561.9 U/mL, with good sensitivity (0.69) and specificity (0.88), discriminated between AF and PJI (accuracy 75.76%, 95% CI: 66.11–83.81%, positive likelihood ratio 5.88, 95% CI: 2.31–14.98 and negative likelihood ratio 0.35, 95%CI: 0.24–0.51). No difference in MPO levels was found between acute and chronic low-grade PJI.ConclusionThe proposed assay appears to be a reliable and affordable tool for detecting the active MPO in synovial fluid, with promising characteristics of sensitivity and specificity in discriminating both acute and low-grade PJI from AF. Further studies are needed to confirm MPO diagnostic cut-off values and validate their use in the routine clinical practice.

Paraoxonase 1 (PON1) and Paraoxonase 3 (PON3) are enzymes located on the surface of high-density lipoprotein (HDL) and share similar antioxidant properties, possibly modulated by other proteins such as Myeloperoxidase (MPO), which drives the shift from functional to dysfunctional HDL. PON1 has been extensively studied in relation to Alzheimer’s Disease (AD), but the role of PON3 remains unknown. To fill this knowledge gap, the study analyzed PON3 protein levels and PON1-arylesterase activity in 99 AD patients, 100 patients with mild cognitive impairment (MCI), and 79 cognitively normal controls. The results showed that serum PON3 levels remained unchanged across all groups. In contrast, serum arylesterase activity was significantly reduced in both AD and MCI patients compared to controls (p < 0.001 for both comparisons). Surprisingly, there was no correlation between arylesterase activity and MPO protein concentration or activity. However, PON3 was found to have a significant positive correlation with both MPO concentration (r = 0.507, p < 0.0001) and MPO activity (r = 0.264, p < 0.01). In conclusion, we demonstrated for the first time that PON1 and PON3 have distinct relationships with AD, with only PON1 showing a decrease in activity in this disease, while PON3 levels remained unchanged. Another noteworthy finding was the selective correlation between PON3 and MPO, which may suggest a preferential physical association of PON3 with dysfunctional HDL.

Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the two major neurodegenerative diseases causing dementia. Due to similar clinical phenotypes, differential diagnosis is challenging without specific biomarkers. Beta-site Amyloid Precursor Protein cleaving enzyme 1 (BACE1) is a β-secretase pivotal in AD pathogenesis. In AD and mild cognitive impairment subjects, BACE1 activity is increased in brain/cerebrospinal fluid, and plasma levels appear to reflect those in the brain. In this study, we aim to evaluate serum BACE1 activity in FTD, since, to date, there is no evidence about its role. The serum of 30 FTD patients and 30 controls was analyzed to evaluate (i) BACE1 activity, using a fluorescent assay, and (ii) Glial Fibrillary Acid Protein (GFAP) and Neurofilament Light chain (NfL) levels, using a Simoa kit. As expected, a significant increase in GFAP and NfL levels was observed in FTD patients compared to controls. Serum BACE1 activity was not altered in FTD patients. A significant increase in serum BACE1 activity was shown in AD vs. FTD and controls. Our results support the hypothesis that serum BACE1 activity is a potential biomarker for the differential diagnosis between AD and FTD.

HDL-cholesterol quality, including cholesterol distribution in HDL subfractions, is emerging as a key discriminant in dictating the effects of these lipoproteins on cardiovascular health. This study aims at elucidating the relationship between cholesterol distribution in HDL subfractions and CVD risk factors as well as diet quality and energy density in a population of pre- and postmenopausal women. Seventy-two women aged 52 ± 6 years were characterized metabolically and anthropometrically. Serum HDL-C subfractions were quantified using the Lipoprint HDL System. Cholesterol distribution in large HDL subfractions was lower in overweight individuals and study participants with moderate to high estimated CVD risk, hypertension, or insulin resistance. Cholesterol distribution in large, as opposed to small, HDL subfractions correlated negatively with insulin resistance, circulating triglycerides, and visceral adipose tissue (VAT). VAT was an independent positive and negative predictor of cholesterol distribution in large and small HDL subfractions, respectively. Furthermore, an increase in energy intake could predict a decrease in cholesterol levels in large HDL subfractions while lipid intake positively predicted cholesterol levels in small HDL subfractions. Cholesterol distribution in HDL subfractions may represent an additional player in shaping CVD risk and a novel potential mediator of the effect of diet on cardiovascular health.

The aim of this study was to investigate whether the presence of Staphylococcus aureus (SA) producing the Panton–Valentine leukocidin (PVL) affects the outcome of Prosthetic Joint Infection (PJI). Patients with acute and chronic PJI sustained by SA were prospectively enrolled at the orthopedic unit of “Casa di Cura Santa Maria Maddalena”, from January 2019 to October 2021. PJI diagnosis was reached according to the diagnostic criteria of the International Consensus Meeting on PJI of Philadelphia. Synovial fluid obtained via joint aspirations was collected in order to isolate SA. The detection of PVL was performed via real-time quantitative PCR (RT-qPCR). The outcome assessment was performed using the criteria of the Delphi-based International Multidisciplinary Consensus. Twelve cases of PJI caused by SA were included. Nine (75%) cases were acute PJI treated using debridement, antibiotic and implant retention (DAIR); the remaining three (25%) were chronic PJI treated using two-stage (n = 2) and one-stage revision (n = 1), respectively. The SA strains that tested positive for PVL genes were 5/12 (41.6%,). Treatment failure was documented in three cases of acute PJI treated using DAIR, all supported by SA–PVL strains (p < 0.045). The remaining two cases were chronic PJI treated with a revision arthroplasty (one and two stage, respectively), with a 100% eradication rate in a medium follow-up of 24 months. Although a small case series, our study showed a 100% failure rate in acute PJI, probably caused by SA PVL-producing strains treated conservatively (p < 0.04). In this setting, toxin research should guide radical surgical treatment and targeted antibiotic therapy.

Abstract Background Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line. Methods Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues. Results We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed. Conclusions This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.

While human and animal leishmaniasis affect several millions of people worldwide, L. infantum is the species responsible for visceral leishmaniasis in Europe, Middle East, and America. Antileishmanial drugs present issues associated with drug toxicity and increasing parasite resistance. Therefore, the study of this parasite with a focus on new potential drug targets is extremely useful. Accordingly, we purified and characterized a transglutaminase (TGase) from L. infantum promastigotes. While Tgases are known to be involved in cell death and autophagy, it appears that these functions are very important for parasites’ virulence. For the first time, we showed a Ca2+- and GTP-dependent TGase in Leishmania corresponding to a 54 kDa protein, which was purified by two chromatographic steps: DEAE-Sepharose and Heparin-Sepharose. Using polyclonal antibodies against a 50-amino-acid conserved region of the catalytic core of human TGase 2, we revealed two other bands of 66 and 75 kDa. The 54 kDa band appears to be different from the previously reported TGase, which was shown to be Ca2+- independent. Future research should address the identification of the purified enzyme sequence and, subsequently, its cloning to more comprehensively investigate its pathophysiological function and possible differences from mammal enzymes.

Abstract Background The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood–cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40–60 and 9.0 over 60 years. Results 1209 subjects were included in the study. 718 females and 491 males (age: 15–88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p

Purpose. The success of total joint arthroplasty (TJA) has led to consistent growth in the use of arthroplasty in progressively younger patients. However, more than 10 percent of patients require revision surgery due to implant failure caused by aseptic or septic inflammation. Among the latter, surgical site infection (SSI) represents one of the worst complications of TJA, potentially resulting in the removal of the prosthesis. The aim of our study was to identify potential risk factors for SSIs in a population of patients undergoing TJA. Methods. TJA were prospectively recruited at Casa di Cura Santa Maria Maddalena from February 2019 to April 2020. Age, sex, major comorbidities, American Society of Anesthesiologists (ASA) class, length of surgery, type of surgical suture, total hospital length of stay, and clinical laboratory data were collected. The study population was then divided into two groups: Group A, normal postoperative course, and Group B, patients who developed SSI at follow-up (17-25 days). Results. 25/760 (3.3%) patients developed SSIs at follow-up. Clinical and demographic parameters were not different between the two groups. Total leucocyte and neutrophil values at discharge resulted to be significatively higher in Group B compared to Group A (p=0.025 and p=0.016, respectively). Values of 7860/μL for total leucocyte and 5185/μL for neutrophil count at discharge significantly predicted the future development of SSI (AUC 0.623 and AUC 0.641, respectively; p

A wealth of evidence suggests that Lipoprotein-associated phospholipase A2 (Lp-PLA2) plays a relevant role in atherogenesis and inflammation, which in turn are associated with the risk of developing dementia. The aim of this study was to evaluate whether serum Lp-PLA2 activity might be an early and/or late biomarker for different forms of dementia. Serum Lp-PLA2 activity was assessed in older patients with mild cognitive impairment (MCI, n = 166; median clinical follow-up = 29 months), Late-Onset Alzheimer’s disease (LOAD, n = 176), vascular dementia (VAD, n = 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) (n = 136), other dementia subtypes (n = 45), and cognitively normal controls (n = 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA, p = 0.028). Similarly, Lp-PLA2 activity was greater in MCI converting to VAD compared with those that did not or did convert to the other types of dementia (ANOVA, p = 0.011). After adjusting for potential confounders, high levels of Lp-PLA2 activity were associated with the diagnosis of VAD (O.R. = 2.38, 95% C.I. = 1.06–5.10), but not with other types of dementia. Our data suggest that increased serum Lp-PLA2 activity may represent a potential biomarker for the diagnosis of VAD.

Background: Patients with acute respiratory failure (ARF) may need mechanical ventilation (MV), which can lead to diaphragmatic dysfunction and muscle wasting, thus making difficult the weaning from the ventilator. Currently, there are no biomarkers specific for respiratory muscle and their function can only be assessed trough ultrasound or other invasive methods. Previously, the fast and slow isoform of the skeletal troponin I (fsTnI and ssTnI, respectively) have shown to be specific markers of muscle damage in healthy volunteers. We aimed therefore at describing the trend of skeletal troponin in mixed population of ICU patients undergoing weaning from mechanical ventilation and compared the value of fsTnI and ssTnI with diaphragmatic ultrasound derived parameters.Methods: In this prospective observational study we enrolled consecutive patients recovering from acute hypoxemic respiratory failure (AHRF) within 24 h from the start of weaning. Every day an arterial blood sample was collected to measure fsTnI, ssTnI, and global markers of muscle damage, such as ALT, AST, and CPK. Moreover, thickening fraction (TF) and diaphragmatic displacement (DE) were assessed by diaphragmatic ultrasound. The trend of fsTnI and ssTnI was evaluated during the first 3 days of weaning.Results: We enrolled 62 consecutive patients in the study, with a mean age of 67 ± 13 years and 43 of them (69%) were male. We did not find significant variations in the ssTnI trend (p = 0.623), but fsTnI significantly decreased over time by 30% from Day 1 to Day 2 and by 20% from Day 2 to Day 3 (p < 0.05). There was a significant interaction effect between baseline ssTnI and DE [F(2) = 4.396, p = 0.015], with high basal levels of ssTnI being associated to a higher decrease in DE. On the contrary, the high basal levels of fsTnI at day 1 were characterized by significant higher DE at each time point.Conclusions: Skeletal muscle proteins have a distinctive pattern of variation during weaning from mechanical ventilation. At day 1, a high basal value of ssTnI were associated to a higher decrease over time of diaphragmatic function while high values of fsTnI were associated to a higher displacement at each time point.

While Biochemistry textbooks for University degree courses do not deal with oligosaccharides, this subject is now becoming essential in Biomedical Sciences for several reasons. Oligosaccharides are currently used in foods and beverages for their useful physicochemical and prebiotic qualities, albeit their excessive consumption may have side effects. They are also essential components of milk, where they exert a protective role on infants acting as stimulants for the development of immune system and gut microbiota. Oligosaccharides are seen as an alternative to improperly used antibiotics in the diet for monogastric animals and considered promising safe anti-parasite treatments in agriculture. Besides, they are widely used in both cosmetics and pharmaceutics. For these reasons, biotechnological research is hardworking on new enzymes able to synthesize them in a great variety. At the same time, oligosaccharides belong to the so-called FODMAP (Fermentable Oligo-, Di- and Monosaccharides And Polyols) group of compounds, whose decreased use in diet is beneficial to several syndromes of the digestive tract. The scope of this review is to give a general and schematic view of oligosaccharides. We describe the structure, source and use of several of the most known oligosaccharides, focusing on their health implications. Main groups in human milk and their substitutes in infant formulas are also reported. In the end some of the most recent studied oligosaccharides and their promising applications are discussed.

Accumulating evidence suggests that high consumption of natural antioxidants promotes health by reducing oxidative stress and, thus, the risk of developing cardiovascular diseases. Similarly, fermentation of natural compounds with lactic acid bacteria (LAB), such as Lactiplantibacillus plantarum, enhances their beneficial properties as regulators of the immune, digestive, and cardiovascular system. We investigated the effects of fermentation with Lactiplantibacillus plantarum on the antioxidant and immunomodulatory effects of Pushgay berries (Vaccinium floribundum, Ericaceae family) in human umbilical vein endothelial cells (HUVECs) and macrophage cell line RAW264.7. Polyphenol content was assayed by Folin–Ciocalteu and HPLC-MS/MS analysis. The effects of berries solutions on cell viability or proliferation were assessed by WST8 (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt and Lactate dehydrogenase (LDH) release, Trypan blue exclusion test, and Alamar blue assay. Antioxidant activity was evaluated by a cell-based chemiluminescent probe for the detection of intracellular H2O2 production in HUVECs. Heme oxygenase-1 (HO-1) expression levels were investigated by RT-qPCR. Glutathione reductase (GR), glutathione peroxidase (Gpx), superoxide dismutase (SOD), and catalase (CAT) activities, as markers of intracellular antioxidant defense, were evaluated by spectrophotometric analysis. The immunomodulatory activity was examined in RAW 264.7 by quantification of inducible nitric oxide synthase (iNOS) and Tumor Necrosis Factor—alpha (TNFα) by RT-qPCR. Data showed that fermentation of Pushgay berries (i) enhances the content of quercetin aglycone, and (ii) increases their intracellular antioxidant activity, as indicated by the reduction in H2O2-induced cell death and the decrease in H2O2-induced HO-1 gene expression in HUVECs treated for 24 h with fermented berries solution (10 µg/mL). Moreover, treatment with Pushgay berries for 72 h (10 µg/mL) promotes cells growth in RAW 264.7, and only fermented Pushgay berries increase the expression of iNOS in the same cell line. Taken together, our results show that LAB fermentation of Pushgay berries enhances their antioxidant and immunomodulatory properties.

Background: Oxidative stress (OxS) has been linked to several pregnancy-related complications. Previous studies demonstrated that lactoferrin (LF) has the ability to modulate inflammation, OxS and the immune function. Therefore, we aimed to observe whether vaginal LF administration was able to decrease OxS in the amniotic fluid (AF) of pregnant women undergoing mid-trimester genetic amniocentesis.Methods: In this open-label clinical study, 60 pregnant women were divided into three groups: CONTROLS (n = 20), not treated with LF; LACTO 4HRS (n = 20), treated with LF 4 h prior to amniocentesis; LACTO 12HRS (n = 20), treated with LF 12 h prior to amniocentesis. Thiobarbituric acid reactive substances (TBARS), total antioxidant status (TAS) and oxidative stress index (OSI) were measured in AF samples. In addition, the in vitro antioxidant activity of LF on a cell line was tested.Results: LF decreased the concentration of TBARS in the AF, with LACTO 4HRS demonstrating the lowest value compared with CONTROLS (P < 0.0001). LACTO 4HRS had higher TAS and lower OSI than CONTROLS (P < 0.0001 for both). In vitro, LF was effective against the oxidative challenge regardless of the time of pretreatment.Conclusion: In conclusion, LF decreased both in vivo and in vitro OxS. LF administration may represent an intriguing clinical solution as an adjuvant to treat complications of pregnancy related to inflammation and OxS.Trial Registration:Clinicaltrials.gov, NCT02695563. Registered 01 March 2016—Retrospectively registered, https://clinicaltrials.gov/show/NCT02695563.

Purpose: Tick-Borne Encephalitis (TBE), a disease caused by Tick-Borne Encephalitis Virus (TBEV), is emerging in Italy. This study aimed to characterize the epidemiological, clinical, laboratory, imaging and electroencephalogram characteristics in Belluno, North-East Italy. Results: 76% were males, mean age 53 years; 50% did not report tick bite. 72% had a biphasic course, 42% a monophasic one, 8 cases of abortive TBE. Mostly no specific symptoms were observed, together with neurological signs and symptoms. None died, but 35% had sequelae at the one-month follow-up. Men had a higher risk of having neurological/neurocognitive sequelae; paresthesia or tremors were associated independently with sequelae. In terms of laboratory data, thrombocytopenia, neutropenia and lymphocytosis were associated with the first phase (p

Background: Sex and gender-related factors have been under-investigated as relevant determinants of health outcomes across non-communicable chronic diseases. Poor medication adherence results in adverse clinical outcomes and sex differences have been reported among patients at high cardiovascular risk, such as diabetics. The effect of diabetes and gender-related factors on medication adherence among women and men at high risk for ischemic heart disease (IHD) has not yet been fully investigated.Aim: To explore the role of sex, gender-related factors, and diabetes in pre-admission medication adherence among patients hospitalized for IHD.Materials and Methods: Data were obtained from the Endocrine Vascular disease Approach (EVA) (ClinicalTrials.gov Identifier: NCT02737982), a prospective cohort of patients admitted for IHD. We selected patients with baseline information regarding the presence of diabetes, cardiovascular risk factors, and gender-related variables (i.e., gender identity, gender role, gender relations, institutionalized gender). Our primary outcome was the proportion of pre-admission medication adherence defined through a self-reported questionnaire. We performed a sex-stratified analysis of clinical and gender-related factors associated with pre-admission medication adherence.Results: Two-hundred eighty patients admitted for IHD (35% women, mean age 70), were included. Around one-fourth of the patients were low-adherent to therapy before hospitalization, regardless of sex. Low-adherent patients were more likely diabetic (40%) and employed (40%). Sex-stratified analysis showed that low-adherent men were more likely to be employed (58 vs. 33%) and not primary earners (73 vs. 54%), with more masculine traits of personality, as compared with medium-high adherent men. Interestingly, women reporting medication low-adherence were similar for clinical and gender-related factors to those with medium-high adherence, except for diabetes (42 vs. 20%, p = 0.004). In a multivariate adjusted model only employed status was associated with poor medication adherence (OR 0.55, 95%CI 0.31–0.97). However, in the sex-stratified analysis, diabetes was independently associated with medication adherence only in women (OR 0.36; 95%CI 0.13–0.96), whereas a higher masculine BSRI was the only factor associated with medication adherence in men (OR 0.59, 95%CI 0.35–0.99).Conclusion: Pre-admission medication adherence is common in patients hospitalized for IHD, regardless of sex. However, patient-related factors such as diabetes, employment, and personality traits are associated with adherence in a sex-specific manner.

Background: Matrix metalloproteinases (MMPs) are pleiotropic enzymes involved in extracellular protein degradation and turnover. MMPs are implicated in the pathogenesis of many neurological diseases, including multiple sclerosis (MS).Objective: To search the level of MMPs in the cerebrospinal fluid (CSF) of MS patients and detect possible disease-specific patterns.Methods: CSF samples from 32 MS patients and, from 15 control subjects with other inflammatory neurological diseases (OIND) were analyzed. The Bio-Plex Pro Human MMP 9-Plex Panel (Bio-Rad) was used for the quantification of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13.Results: CSF MMP-1 and MMP-12 levels were significantly reduced in MS as compared with OIND. In MS patients' CSF: (i) MMP-1 levels were significantly higher in women vs. men; (ii) MMP-10 concentrations were higher in patients with CSF-restricted IgG oligoclonal bands, and (iii) MMP-7 levels were increased in patients with longer disease duration. In the OIND group MMP-7 and MMP-12 levels significantly and directly correlated with age.Conclusions: Our study contributes to investigating the role of MMPs in MS, with regard to CSF immunological features and disease duration. Sex-specific differences were also detected in MMPs CSF levels.

Background: A wealth of experimental and epidemiological evidence suggest that Apolipoprotein A-I (ApoA-I), the main protein constituent of high-density lipoprotein (HDL), may protect against Alzheimer disease (AD). To investigate this potential role, we conducted a meta-analysis of the published studies on the relationship between serum ApoA-I and AD occurrence. Methods: We screened MEDLINE, EMBASE, Web of Science, and Scopus, for cross-sectional studies published from inception to 1 March 2021, comparing the ApoA-I serum levels between patients with AD and cognitively normal controls. Results: From an initial screening of 245 articles, 5 studies, including 397 AD patients (mean age 75.0 years, 234 females) and 367 controls (mean age 69.2 years, 182 females), met the inclusion criteria. Compared to healthy controls, AD subjects had a lower ApoA-I serum level. The pooled weighted mean difference from a random-effects model was −0.31 g/L (p < 0.0001) (95% Confidence Interval: [−0.62–0.01], with high heterogeneity (I2 = 100%). The Egger’s test confirmed an absence of publication bias (t = 0.62, p = 0.576). Conclusions: Our study showed that AD patients present lower serum levels of ApoA-I compared to cognitively normal individuals. Further studies on large population samples are required to support this finding.

Type-2 diabetes (T2D) and its cardiovascular complications are related to sex. Increasing evidence suggests that paraoxonase 1 (PON1) activity, an antioxidant enzyme bound to high-density lipoproteins (HDL), is implicated in the onset and clinical progression of T2D. Since we previously showed that PON1 is a sexual dimorphic protein, we now investigated whether sex might impact the relationship between PON1 and this chronic disease. To address this aim, we assessed PON1 activity in the sera of 778 patients, including controls (women, n = 383; men, n = 198) and diabetics (women, n = 79; men = 118). PON1 activity decreased in both women and men with T2D compared with controls (p < 0.05 and p > 0.001, respectively), but the change was 50% larger in the female cohort. In line with this result, the enzyme activity was associated with serum glucose level only in women (r = −0.160, p = 0.002). Notably, only within this gender category, lower PON1 activity was independently associated with increased odds of being diabetic (odds ratio (95% Confidence interval: 2.162 (1.075–5.678)). In conclusion, our study suggests that PON1-deficiency in T2D is a gender-specific phenomenon, with women being more affected than men. This could contribute to the partial loss of female cardiovascular advantage associated with T2D.

Background: It has been suggested that circulating Paraoxonase-1 (PON1) and apolipoprotein A1 (APOA1), which closely interacts with the antioxidant enzyme, could be implicated in Alzheimer’s disease (AD) and vascular dementia (VaD) development. This study aimed to evaluate PON1 changes in serum and cerebrospinal fluid (CSF) as evidence for its association with AD or VaD. Methods: Serum PON-arylesterase activity was measured in patients with AD, VaD, and CONTROLS distributed in two cohorts: Ferrara cohort (FC: n = 503, age = 74 years) and Amsterdam Dementia cohort (ADC: n = 71, age = 65 years). In the last cohort, CSF PON-arylesterase, CSF β-amyloid1-42, p-tau and t-tau, and imaging biomarkers were also measured. Results: AD and VaD patients of FC showed significantly lower levels of serum PON-arylesterase compared to CONTROLS, but this outcome was driven by older subjects (>71 years, p < 0.0001). In the younger ADC, a similar decreasing (but not significant) trend was observed in serum and CSF. Intriguingly, PON-arylesterase per APOA1 correlated with t-tau in AD group (r = −0.485, p = 0.002). Conclusion: These results suggest that decreased peripheral PON-arylesterase might be a specific feature of older AD/VaD patients. Moreover, we showed that PON-arylesterase/APOA1 is inversely related to neurodegeneration in AD patients, suggesting a prognostic usefulness of this composite parameter.

Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, ‘sex’ and ‘gender’ are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs’ identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. “Being a male or being a female” is indeed important from a health point of view and it is no longer possible to avoid “sex and gender lens” when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

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

Several studies showed that hydroxyethyl starch (HES), a synthetic colloid used in volume replacement therapies, interferes with leukocyte-endothelium interactions. Although still unclear, the mechanism seems to involve the inhibition of neutrophils’ integrin. With the aim to provide direct evidence of the binding of HES to neutrophils and to investigate the influence of HES on neutrophil chemotaxis, we isolated and treated the cells with different concentrations of fluorescein-conjugated HES (HES-FITC), with or without different stimuli (N-Formylmethionine-leucyl-phenylalanine, fMLP, or IL-8). HES internalization was evaluated by trypan blue quenching and ammonium chloride treatment. Chemotaxis was evaluated by under-agarose assay after pretreatment of the cells with HES or a balanced saline solution. The integrin interacting with HES was identified by using specific blocking antibodies. Our results showed that HES-FITC binds to the plasma membrane of neutrophils without being internalized. Additionally, the cell-associated fluorescence increased after stimulation of neutrophils with fMLP (p < 0.01) but not IL-8. HES treatment impaired the chemotaxis only towards fMLP, event mainly ascribed to the inhibition of CD-11b (Mac-1 integrin) activity. Therefore, the observed effect mediated by HES should be taken into account during volume replacement therapies. Thus, HES treatment could be advantageous in clinical conditions where a low activation/recruitment of neutrophils may be beneficial, but may be harmful when unimpaired immune functions are mandatory.

Inflammation plays an important role in pregnancy, and cytokine and matrix metalloproteases (MMPs) imbalance has been associated with premature rupture of membranes and increased risk of preterm delivery. Previous studies have demonstrated that lactoferrin (LF), an iron-binding protein with anti-inflammatory properties, is able to decrease amniotic fluid (AF) levels of IL-6. Therefore, we aimed to evaluate the effect of vaginal LF administration on amniotic fluid PGE2 level and MMP-TIMP system in women undergoing genetic amniocentesis. One hundred and eleven women were randomly divided into controls (n=57) or treated with LF 4 hours before amniocentesis (n=54). Amniotic fluid PGE2, active MMP-9 and MMP-2, and TIMP-1 and TIMP-2 concentrations were determined by commercially available assays and the values were normalized by AF creatinine concentration. PGE2, active MMP-9, and its inhibitor TIMP-1 were lower in LF-treated group than in controls (p