. 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. "
" is indeed important from a health point of view and it is no longer possible to avoid "
" 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.
Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that β-amyloid (Aβ) accumulation, that initiates ...LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that β-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.
It is now established that sex differences occur in clinical manifestation, disease progression, and prognosis for both cardiovascular (CVDs) and central nervous system (CNS) disorders. As such, a ...great deal of effort is now being put into understanding these differences and turning them into “advantages”: (a) for the discovery of new sex-specific biomarkers and (b) through a review of old biomarkers from the perspective of the “newly” discovered sex/gender medicine. This is also true for matrix metalloproteinases (MMPs), enzymes involved in extracellular matrix (ECM) remodelling, which play a role in both CVDs and CNS disorders. However, most of the studies conducted up to now relegated sex to a mere confounding variable used for statistical model correction rather than a determining factor that can influence MMP levels and, in turn, disease prognosis. Consistently, this approach causes a loss of information that might help clinicians in identifying novel patterns and improve the applicability of MMPs in clinical practice by providing sex-specific threshold values. In this scenario, the current review aims to gather the available knowledge on sex-related differences in MMPs levels in CVDs and CNS conditions, hoping to shed light on their use as sex-specific biomarkers of disease prognosis or progression.
Converging lines of evidence suggest that paraoxonase‐1 (PON‐1) may confer protection against inflammatory and oxidative challenge which, in turn, plays a key‐role in the onset and progression of ...dementia. The aim of this study was to evaluate whether serum PON‐1 paraoxonase/arylesterase activities might predict the clinical conversion of mild cognitive impairment (MCI) to late‐onset Alzheimer's disease (LOAD) or vascular dementia (VAD). Serum paraoxonase and arylesterase activities were measured by spectrophotometric assays at baseline in 141 MCI patients (median age: 77 years; interquartile range 71–81) and in 78 healthy controls (median age: 76 years; interquartile range 73–79). After 2 years of follow‐up, 86 MCI remained stable (MCI/MCI), 34 converted to LOAD (MCI/LOAD), whereas 21 converted to VAD (MCI/VAD). Baseline arylesterase activity was lower in all MCI groups compared with controls (all p < 0.01), whereas paraoxonase activity was lower in MCI/VAD group compared to controls (p < 0.05) and MCI/MCI patients (p = 0.009). Low paraoxonase and arylesterase activities (I quartile) were associated to higher risk of conversion to VAD (OR: 3.74, 95% CI: 1.37–10.25 and OR: 3.16, 95% CI: 1.17–8.56, respectively). Our results suggest that in MCI patients low PON‐1 activity might contribute to identify individuals susceptible to develop vascular dementia.
Our study showed that in patients with mild cognitive impairment (MCI) low serum levels of paraoxonase‐1 (PON‐1) activity is associated with a higher likelihood of developing Vascular Dementia, but not Alzheimer's Disease. The observed connection might be explained by the ability of PON‐1 to retard low‐density lipoprotein (LDL) oxidation, decrease oxidative stress, attenuate inflammation, and increase cholesterol efflux.
Our study showed that in patients with mild cognitive impairment (MCI) low serum levels of paraoxonase‐1 (PON‐1) activity is associated with a higher likelihood of developing Vascular Dementia, but not Alzheimer's Disease. The observed connection might be explained by the ability of PON‐1 to retard low‐density lipoprotein (LDL) oxidation, decrease oxidative stress, attenuate inflammation, and increase cholesterol efflux.
Although HIV-related deaths have decreased dramatically following the introduction of antiretroviral therapy (ART), HIV infection itself causes increased morbidity and mortality for both ...non-AIDS-related events or chronic inflammation and immune activation. The use of certain antiretroviral drugs can contribute to this process.
We investigated 26 potential biomarkers in serum samples from HIV-1 infected patients virologically suppressed under ART. The main objective of our study was to evaluate if virological suppression achieved with a triple drug regimen containing tenofovir disoproxil fumarate co-formulated with emtricitabine (TDF/FTC) as backbone, could correlate with a better immunological and inflammatory profile in relation to the third class of antiretroviral drug administered. The eligible patients were then divided into 3 groups in relation to the third drug associated with TDF/FTC: nucleoside reverse transcriptase inhibitors (NNRTI) (Group 1, n = 16), protease inhibitors (PI) (Group 2, n = 17) and integrase inhibitors (INI) (Group 3, n = 16).
Inflammatory cytokines and chemokines were more represented in Group 2 than in Group 3 (IL-1Ra, p = 0.013; IL-12p70 p = 0.039; TNF-α p = 0.041; IL-8, p = 0.027; MIP1 β, p = 0.033). Eotaxin showed lower levels in Group 1 compared to Group 2 (p = 0.010), while IP-10 was significantly lower in Group 1 compared to both Group 2 and Group 3 (p = 0.003 and p = 0.007, respectively).
Our results seem to discourage the administration of PI as a third drug in a virologically effective antiretroviral regimen, as its use is linked to the detection of higher levels of pro-inflammatory mediators in comparison with INI and NNRTI.
Background
Acute ischaemic stroke (AIS) triggers both systemic and neurovascular inflammation, influencing poststroke recovery. In smokers with AIS, inflammation might be further upregulated, ...increasing ischaemia/reperfusion injury. Here, the predictive value of leucocyte and adhesion molecules levels on poststroke outcomes was investigated.
Materials and methods
A total of 89 patients with AIS (n = 30 smokers and n = 59 nonsmokers) were recruited and evaluated 1, 7 and 90 days after the onset to assess stroke severity by the National Institute of Health Stroke Scale (NIHSS) score as well as clinical recovery at 90 days by the modified Rankin Scale (mRS). Lesion volume was assessed by noncontrast computed tomography. Haematological parameters, blood chemistry and soluble adhesion molecules were measured.
Results
Smokers experienced a more severe stroke and at a younger age with respect to nonsmokers, moreover, they had higher circulating levels of monocytes, neutrophils and soluble adhesion molecules. Baseline monocytes positively correlated with stroke severity and disability across all time points in the overall cohort. No correlation was shown between adhesion molecules and poststroke outcomes. A monocyte count >0·63 × 109/L predicted worse stroke severity (defined as NIHSS ≥5) at day 90 independently of age, hypertension, thrombolysis and active smoking in the overall cohort. Similarly, a monocyte count >0·64 × 109/L predicted poor neurological recovery at day 90 (defined as mRS > 2).
Conclusions
Smoker had more severe AIS and higher leucocytes and adhesion molecule levels. In the overall cohort, monocyte count was an independent predictor of worse poststroke outcome. Although larger trials are needed, monocyte count might be a cheap prognostic parameter in AIS.
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<0.05) independently from confounding factors (total leukocytes: O.R.=3,69 95% C.I. 1,63-8,32; neutrophils: O.R.=3,98 95% C.I. 1,76-8,97). Deep SSIs has been diagnosed significantly before superficial SSIs (p=0,008), with a median advance of 9 days. Conclusion. Total leukocytes and neutrophils at discharge seem useful to identify a population at risk for the development of septic inflammation at the surgical site following TJA. Further studies with larger populations are needed to develop a predictive SSIs risk score that should include those variables.
Introduction The 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. Methods Synovial 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. Results Active 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. Conclusion The 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.
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.
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.
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 < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group.
Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.
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,
= 166; median clinical follow-up = 29 months), Late-Onset Alzheimer's disease (LOAD,
= 176), vascular dementia (VAD,
= 43), dementia characterized by an overlap between LOAD and VAD (AD-VAD MIXED dementia) (
= 136), other dementia subtypes (
= 45), and cognitively normal controls (
= 151). We found a significant trend towards higher levels of Lp-PLA2 activity in VAD compared with the other groups (ANOVA,
= 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,
= 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.
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