A novel eco-friendly polymeric photosensitizer based on chitosan and flavin mononucleotide.

Flavin mononucleotide (FMN) is a dye belonging to the flavin family. These dyes produce photosensitized degradation of organic compounds via reaction with the excited states of the dye or with reactive oxygen species photogenerated from the triplet of the dye. This article presents a new polymeric dye (FMN-CS) composed of the photosensitizer FMN covalently bonded to chitosan polysaccharide (CS). FMN-CS obtained has a molecular weight of 230 × 103 g mol-1 and a deacetylation degree of 74.8%. The polymeric dye is an environmentally friendly polymer with spectroscopic and physicochemical properties similar to those of FMN and CS, respectively. Moreover, under sunlight, it is capable of generating 1O2 with a quantum yield of 0.31. FMN-CS, like CS, is insoluble in basic media. This allows easy recovery of the polymeric dye once the photosensitized process has been carried out and makes FMN-CS a suitable photosensitizer for the degradation of pollutants in contaminated waters. To evaluate whether FMN-CS may be used for pollutant degradation, the photosensitized degradation of two trihydroxybenzenes by FMN-CS was studied.

Polymorphonuclear phenotypical expression of CD18, at baseline and after in vitro activation, in several clinical disorders: Revision of our case series.

BACKGROUND: In relation to the different and important roles of the beta2 integrins, we have revisited the expression of polymorphonuclear leukocyte CD18 in several clinical disorders, at baseline and after in vitro activation. SUBJECTS: we have examined subjects with type 1 diabetes mellitus, vascular atherosclerotic disease, type 2 diabetes mellitus without and with macrovascular complications, chronic renal failure on conservative treatment, essential hypertension, deep venous thrombosis, acute ischemic stroke and subjects with venous leg ulcers. METHODS: unfractioned leukocyte suspension was prepared according to the Mikita's method, while the leukocyte were separated into mononuclear and polymorphonuclear cells with a Ficoll-Hypaque medium. Using specific monoclonal antibody, the CD18 expression was evaluated with cytofluorimetric analysis, using FACScan (Becton Dickinson) be Cellquest software; the activation in vitro with PMA was effected according to modified Yasui and Masuda methods. RESULTS: in type 1 diabetes mellitus, at baseline CD18 is under expressed in comparison with normal control, and not changes after PMA activation were observed; in subjects with vascular atherosclerotic disease, in type 2 diabetes mellitus CD18 is over expressed at baseline but does not vary after activation; in subjects with chronic renal failure, essential hypertension and in subjects with acute ischemic stroke the CD18 up-regulate at baseline compared to normal control, and it increases further after activation; in subjects with deep venous thrombosis the CD18 expression is not different from control group at baseline, but it increases after activation; finally, in subjects with venous leg ulcers the CD18 is normally expressed at baseline, and it does not change after PMA activation. CONCLUSIONS: in the different clinical disorders, the trend of this integrin subunit provides some specific information, useful to select the best therapeutic strategy in clinical practice.

Red Cell Distribution Width and Elongation Index in a Cohort of Patients With Juvenile Acute Myocardial Infarction.

In a cohort of patients with juvenile myocardial infarction, we considered the red cell distribution width (RDW), hematocrit, hemoglobin, and elongation index values at the initial phase and at 3 and 12 months from the acute event. In the initial phase, only the elongation index values turn out reduced if compared with those of the control group, and that only turn out to discriminate the infarcted ST-segment elevation myocardial infarction (STEMI) from non-STEMI. Dividing the patients according to the traditional risk factors and the extent of coronary heart disease, there are no significant variations in the analyzed parameters. No major changes are observed after 12 months from the acute event. Both to 3 and to 12 months from the infarct episode, the negative statistical correlation between RDW and the value of elongation index remains. These data make us reflect on the role of the degree of anisocytosis of red blood cell expressed by the RDW on the determinism of erythrocyte deformability, which plays its role in the microcirculation district and that is essential in the transfer of tissue oxygen.

Use of telehealth for psychosocial oncology: A mixed methods study about barriers to and opportunities with Latino patients from Latin America, Spain, and the United States.

OBJECTIVES: Telehealth for mental healthcare expanded rapidly with the COVID-19 pandemic's onset; however, global access disparities emerged. Telehealth challenges and opportunities for Latino cancer patients from different geographical regions must be explored. METHODS: A cross-sectional online survey (March-July 2021) of mental health providers, serving Latino cancer patients in Latin America, United States, and Spain, contained close-ended questions related to the use of telehealth during the pandemic and open-ended questions on recommending/not recommending telehealth. RESULTS: In a sample of 148 providers from 21 countries, 60.5% reported that at least some of their patients had difficulties with Internet speed and connectivity and lacked knowledge about using electronic devices (43.2%) or the Internet (45.4%). Lacking privacy at home (66.0%) and childcare (26.0%) were reported patient challenges. Internet connectivity or speed were issues for providers (43.2%) themselves. Improving patient reach was a reported telehealth benefit (64.2%). Geographical access (43.2%) and physical limitations (35.8%) were considerations in offering telehealth. Considerations for not recommending telehealth were patient age (24.3%) and lacking technological knowledge (29.1%). CONCLUSIONS: Telehealth for mental healthcare may improve patient access issues caused by geographical and transportation conditions and patient functionality. Findings provide insight into telehealth benefits and challenges in Latino patient populations. Future studies should examine patient access and use by region.

Photocatalytic evaluation and characterization of TiO2-riboflavin phosphate film: analysis of reactive oxygen species.

The effect of Riboflavin-5'-phosphate (RFPO4) sensitization on photocatalytic properties of TiO2 film was studied. RFPO4 was adsorbed on film surface to investigate the photophysical properties of TiO2 upon blue-light photoexcitation. The film was characterized through scanning electron microscopy, energy dispersive spectroscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, thermogravimetric analysis, and diffuse reflectance spectroscopy. The efficiency of the TiO2/RFPO4 film was tested for pollutant elimination in aqueous media in a visible-light-driven system. The phenol paradigmatic model was employed in an aqueous solution as a contaminant target. TiO2/RFPO4 sensitized photodegradation of phenol, which produces catechol, hydroquinone, and benzophenone, was monitored by absorption spectroscopy and HPLC. The results indicated that phenol degradation with TiO2/RFPO4 film was due to the photogeneration of two reactive oxygen species, singlet molecular oxygen (O2(1Δg)) and superoxide radical anion (O2·-) identified through specific detection techniques. The presence of O2(1Δg) is reported here for the first time as generated from a sensitized TiO2 film upon visible-light photoirradiation. Based on the photophysical determinations, a photocatalytic mechanism for TiO2/RFPO4 was established.

Metalloproteinases and Tissue Inhibitors in Generalized Myasthenia Gravis. A Preliminary Study.

INTRODUCTION: Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) have recently been proposed as promising biomarkers in different immune-mediated disorders. We evaluated the plasma levels of MMP-9 and MMP-2 and their tissue inhibitors TIMP-1 and TIMP-2 in a patients' cohort with generalized myasthenia gravis (MG). METHODS: Plasma concentrations of MMP-9, MMP-2, TIMP-1 and TIMP-2 were evaluated in 14 patients with generalized MG and 13 age- and sex-matched healthy controls. The severity of disease was assessed by the modified Osserman classification. RESULTS: Compared to the healthy subjects, MG patients had increased plasma concentrations of MMP-9, but reduced plasma levels of MMP-2 and TIMP-1. MG patients also showed a positive correlation between MMP-2 concentrations and disease severity. An increase in MMP-9 levels and MMP-9/TIMP-1 ratio and a decrease in MMP-2 levels and MMP-2/TIMP-2 ratio were detected in patients with generalized MG. Higher levels of MMP-2 correlated with greater disease severity. DISCUSSION: Our preliminary findings suggest that MMPs and TIMPs could play a role in the pathogenesis of MG and might be associated with the risk of clinical deterioration.

Trombólisis intraarterial en paciente COVID-19 con isquemia aguda en extremidadinferior / Intraarterial thrombolysis in a COVID-19 patient with acute lower limb ischemia

La trombólisis dirigida por catéter es un procedimiento considerado de elección y aceptado, con muy buenos resultados en los casos de trombosis arteriales del lecho distal. Los pacientes con infección por COVID-19 y trombosisarteriales representan una subpoblación de pacientes críticos que condiciona el uso de determinadas técnicasquirúrgicas de revascularización.

Catheter-directed thrombolysis is an accepted procedure with very good results in cases of arterial thrombosis ofthe distal territory, being considered of choice. Patients with COVID-19 infection and arterial thrombosis representa subpopulation of critically ill patients that conditions the use of certain revascularization surgical techniques.

Expression pattern of matrix metalloproteinases-2 and -9 and their tissue inhibitors in patients with chronic inflammatory demyelinating polyneuropathy.

BACKGROUND: Matrix metalloproteinases (MMPs) are a heterogeneous family of endopeptidases that play a role in many physiological functions, including the immune response. An imbalance between the activity of MMPs and their physiological tissue inhibitors (TIMPs) has been proposed in the pathophysiology of different autoimmune disorders. We aimed to assess the plasmatic levels of MMP-2, MMP-9, and their inhibitors TIMP-1 and -2 in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). SUBJECTS AND METHODS: Twenty patients with CIDP and 20 age- and sex-matched healthy controls were enrolled. Plasma concentrations of MMP-2, MMP-9, TIMP-1, and TIMP-2 were determined by the enzyme-linked immunosorbent assay. RESULTS: CIDP subjects had higher MMP-9 concentrations along with TIMP-1 downregulation when compared to controls, with the consequent increase in the MMP-9/TIMP-1 ratio (p<0.000002 for all measures). Conversely, the concentration of MMP-2 was lower in the CIDP group (p<0.01) without changes in the TIMP-2 concentration. The MMP-2/TIMP-2 ratio was decreased in the patients' group (p<0.02). DISCUSSION: We provide first preliminary evidence that the plasmatic pattern of MMPs and TIMPs is markedly altered in patients with CIDP. Future studies are needed to assess the potential usefulness of these new biomarkers in the clinical setting.

The function of matrix metalloproteinase-9 (MMP-9) and its tissue inhibitor (TIMP-1) in several clinical conditions: Results and analysis of our survey.

The goal of this research was to evaluate the plasma concentration of MMP-9 and its tissue inhibitor (TIMP-1) in different clinical conditions. It included several groups of subjects: 31 overweight subjects; 91 obese adults divided into two subgroups according to the BMI value (BMI 30-35 Kg/m2 and BMI > 35 Kg/m2); 90 subjects with metabolic syndrome (MS) divided into two subgroups (with and without diabetes mellitus); 100 subjects with preclinical carotid atherosclerosis (PCA) divided according to the number of cardiovascular risk factors and to the insulin resistance degree; 48 subjects with obstructive sleep apnoea syndrome (OSAS) divided according to the apnoea/hypopnea index (AHI); 27 subjects with chronic kidney disease (CKD) on conservative management; 31 subjects with CKD on regular haemodialysis treatment. We have found a significant increase of MMP-9 and TIMP-1 in overweight subjects, in obese adult and in MS subjects. In obese adults, the behaviour of these two parameters was not influenced by the degree of obesity, while in the group of MS subjects both these parameters were clearly influenced by the presence of diabetes mellitus. In subjects with PCA, we observed an increase of MMP-9 associated with a significant decrease of TIMP-1; the same trend was found by subdividing the entire group in accordance with the number of cardiovascular risk factors and with the insulin resistance degree. In subjects with OSAS, we noted an increase in MMP-9 and TIMP-1; this increase was more evident in subjects with OSAS having AHI > 30. In individuals with CKD on conservative and haemodialysis treatment we have found, at baseline, a marked increase in MMP-9 and a significant decrease of TIMP-1. In dialyzed subjects, after a standard dialysis session was noted, a significant increase in MMP-9 was associated with a further decrease in TIMP-1.

Oregano Essential Oil Interactions with Photogenerated Singlet Molecular Oxygen.

Essential oils are a mixture of volatile compounds, products of the secondary metabolism of plants. Once extracted, they can be deteriorated losing their organoleptic and therapeutic properties due to various environmental factors, being light exposure in aerobic conditions the main cause. In this work, the oregano essential oil extraction and characterization from Origanum vulgare plants grown in the experimental field of the FTU-UNSL and its photodegradation in MeOH:H2 O 60:40 v/v solvent were studied. Characterization by EIMS and NIST Mass Spectrometry indicates the main compounds of oregano essential oil, quantified in the extracted oil by GC-MS, are carvacrol (7.14%) and thymol (47.37%). Degradation of essential oil and its two major components can be caused by reactive oxygen species photogenerated from endogenous sensitizers as riboflavin. Our results suggest degradation occurs involving singlet molecular oxygen. Interaction of carvacrol and thymol with singlet oxygen is mainly a physical process, while essential oil has an important reactive component, which indicates there might be other constituents which could contribute to reactive photoprotection. The effect of simultaneous presence of oregano essential oil and tryptophan amino acid-used as a photooxidizable model under riboflavin-photosensitizing conditions-was studied in order to evaluate the possible photoprotection exerted by the essential oil.

Experimental and Theoretical Study of the Stability of the Complex Fisetin-Cu(II) and A Comparative Study of Free Ligand and Complex Interaction with Molecular Singlet Oxygen.

In this work, the flavonol fisetin was selected in order to study its reactivity against Cu(II), a metal ion of interest in biological media and industry. The stoichiometry and apparent formation constant of the complex in ethanolic medium at 25°C were evaluated using spectrophotometric techniques. The resulting stoichiometry was a 1:1 ligand:metal complex, and a log K = 5.17 ± 0.12 was determined. Since two possible chelation sites can be proposed for the complex formation, quantum chemistry calculations were performed on these structures. Calculations suggest that the hydroxyl-keto site is more stable for the complex formation than the catechol site. Flavonoids could exert protection against oxidative damage caused by reactive oxygen species, and this biological activity could be affected by chelation with metal ions. This led us to perform a study on the interaction of both, free flavonoid and complex, with reactive oxygen species. Our results showed both compounds quench molecular singlet oxygen photogenerated with visible light, mainly in a physical fashion. In order to analyze a possible protective effect of flavonoid and its complex against oxidative damage in biological environments, the amino acid tryptophan was selected as a model oxidation system. Free flavonoid does not have a marked protective effect, whereas its complex showed a relevant protective effect.

Behaviour of carbonyl groups in several clinical conditions: Analysis of our survey.

Protein carbonylation is a marker of oxidative protein damage, that is likely involved in the pathogenesis of several diseases. The aim of this study was to evaluate the protein carbonyl (PC) groups in different clinical conditions. It included different groups of subjects: 81 trained subjects; 23 subjects with mild essential hypertension; 31 middle-aged subjects with metabolic syndrome (MS); 106 subjects with MS not selected for age (subdivided into two subgroups, with and without diabetes mellitus); 91 obese adults subdivided in two subgroups (BMI 30-35 Kg/m2 and BMI > 35 kg/m2); 48 subjects with obstructive sleep apnea syndrome (OSAS) subdivided in accordance with the apnea/hypopnea index (AHI); 27 subjects with chronic kidney disease (CKD) on conservative therapy; 31 subjects with CKD on haemodialysis treatment; and 50 subjects with juvenile myocardial infarction. PC groups were reduced in trained subjects in comparison with sedentary controls, while no variation was observed in mild essential hypertension. PC groups were increased in MS subjects and in adult obese subjects. In MS subjects the PC groups were not influenced by the presence of diabetes mellitus and in adult obese subjects were not influenced by the obesity degree. In OSAS subjects only those with AHI > 30 showed an increase of PC groups. PC groups increased in CKD subjects undergoing conservative treatment and haemodialysis therapy. In dialyzed subjects, after a standard dialysis session, there was a marked increase in PC groups. In juvenile myocardial infarction PC groups were higher than in controls; there was no difference between STEMI and NSTEMI and their concentration was unaffected by the number of cardiovascular risk factors or stenosed coronary vessels.

Plasma Viscosity and NLR in Young Subjects with Myocardial Infarction: Evaluation at the Initial Stage and at 3 and 12 Months.

In the "Sicilian study on juvenile myocardial infarction," we had evaluated plasma viscosity (PV) and neutrophil/lymphocyte ratio (NLR) in patients with acute myocardial infarction (AMI) at the age of ⩽45 years. Now, we examined the relationship between these 2 parameters in 120 subjects (109 men and 11 women) aged ⩽45 years with recent AMI. The patients were classified according to the number of cardiovascular risk factors, the electrocardiographic criteria (ST-segment elevation myocardial infarction [STEMI] or non-ST-segment elevation myocardial infarction [NSTEMI]), and the extent of coronary stenosis, evaluated with coronary angiography. On fasting venous blood, we measured PV at the shear rate of 450 s-1 and NLR. The control group included 50 healthy subjects (mean age = 35.1 ± 7.8 years). At the initial stage, PV and NLR were significantly increased in comparison with controls. Subdividing AMI patients according to the median value of NLR, in the group with high NLR PV was significantly higher, whereas subdividing the patients according to the PV median value, NLR was not different between the 2 groups; 3 and 12 months after AMI, we observed only a significant decrease in NLR. Only PV was discriminant regarding the cardiovascular complications registered during an 18-month follow-up. The evaluation of PV may be of prognostic value in juvenile AMI.

Neuroanatomía funcional de la escala de coma de Glasgow / Functional neuroanatomy of the Glasgow coma scale

Introducción: La escala de coma de Glasgow (ECG) es una escala mundialmente reconocida para la clasificación de pacientes con trauma craneoencefálico de acuerdo a su compromiso neurológico. Esta escala evalúa la apertura ocular, la respuesta verbal y la respuesta motora. La neuroanatomía funcional representa un compromiso secuencial para el descenso en el puntaje de cada uno de estos ítems. El objetivo de esta revisión es describir la anatomía del sistema reticular activador ascendente (SRAA), la anatomía funcional del lenguaje, la anatomía del tallo cerebral y de las vías motoras que representan cada ítem evaluado por la ECG. Materiales y métodos: Se hizo una revisión narrativa bibliográfica de las principales vías para cada ítem de la ECG. Resultados: Las principales vías en relación con la apertura ocular se concentran en las vías del SRAA, las vías de la respuesta verbal incluyen las vías del lenguaje y las vías que provienen del putamen y del cerebelo que regulan la emisión del lenguaje, mientras que las vías que regulan la respuesta motora principalmente se relacionan con la vía piramidal, el sistema rubro-espinal y vestíbulo-espinal. Conclusiones: El descenso del puntaje en los tres ítems que evalúa la ECG se relacionan con vías específicas que predominan en los ganglios basales y en el tallo cerebral.

Introduction: The Glasgow Coma Scale (GCS) is a globally recognized scale for the classification of patients with traumatic brain injury according to their neurological impairment. This scale evaluates the ocular opening, the verbal response and the motor response. Functional neuroanatomy represents a sequential decrease in the score of each of these items. The objective of this review is to describe the anatomy of the ascending reticular activating system (ARAS), the functional anatomy of the language, and the anatomy of the brainstem and the motor pathways that represent each item evaluated by the GCS. Materials and methods: A narrative literature review of the main routes for each item of the scale was performed. Results: The main pathways in relation to the ocular opening are concentrated in the ARAS, the verbal response pathways include the language pathways and the connections that come from the putamen and the cerebellum that regulate the production of the language, while the pathways that regulate the motor response mainly relate to the pyramidal tract, the rubro-spinal and vestibulo-spinal systems. Conclusions: The decline of the score in the three items that evaluates the GCS is related to specific pathways that predominate in the basal ganglia and in the brainstem.

Lipid Peroxidation, Protein Oxidation, Gelatinases, and Their Inhibitors in a Group of Adults with Obesity.

The association between obesity and cardiovascular diseases has a multifactorial pathogenesis, including the synthesis of inflammatory molecules, the increase in oxidative stress and the dysregulation of the matrix metalloprotease (MMP) concentration and activity. In a group of adults with obesity, divided in 2 subgroups according to the body mass index (BMI), we examined lipid peroxidation, expressed as thiobarbituric acid-reactive substances (TBARS), protein oxidation, expressed as protein carbonyl groups (PCs), plasma gelatinases (MMP-2 and MMP-9), and their tissue inhibitors (TIMP-1 and TIMP-2). In the whole group, as well as in the 2 subgroups (with BMI 30-35 or BMI>35) of obese subjects, we observed an increase in TBARS, PCs, MMP-2, and MMP-9, and also TIMP-1 and TIMP-2 in comparison with the control group. A positive correlation between TBARS and PCs emerged in obese subjects and persisted after dividing obese subjects according to BMI. The correlation between MMP-2 and TIMP-2 was not statistically significant, while a significant correlation was present between MMP-9 and TIMP-1. The correlations between the markers of oxidative stress (TBARS and PCs) and those of the MMP/TIMP profile indicated a more marked influence of protein oxidation on MMPs and TIMPs in comparison with TBARS. The innovative aspect of our study was the simultaneous evaluation of oxidative stress markers and MMP/TIMP profile in adult obese subjects. We observed significant alterations and correlations that may negatively influence the clinical course of the disease.

From San Luis, A Few Words of Gratitude.

The Photochemical Research Group from San Luis (Argentina) highlights the contributions of Dr. Norman Andino García to the development of the group as a way to show him our gratitude for all his support.

Analysis of the Blood Viscosity Behavior in the Sicilian Study on Juvenile Myocardial Infarction.

Considering the role of hemorheology in coronary circulation, we studied blood viscosity in patients with juvenile myocardial infarction. We examined whole blood viscosity at high shear rate using the cone-on-plate viscosimeter Wells-Brookfield ½ LVT and at low shear rate employing a viscometer Contraves LS30 in 120 patients (aged <46 years) with myocardial infarction, at the initial stage and subsequently 3 and 12 months after. At the initial stage, patients had an increased whole blood viscosity in comparison to normal controls. This hemorheological profile was not influenced by the cardiovascular risk factors, nor by the extent of coronary lesions, even if some differences were evident between patients with ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). The blood viscosity pattern at the initial stage did not influence recurring ischemic events or the onset of heart failure during an 18 months' follow-up. The neutrophil to lymphocyte ratio did not affect the blood viscosity pattern. We reevaluated 83 patients 3 months after and 70 patients 12 months after the acute coronary syndrome, and we found that the hemorheological parameters were still altered in comparison to normal controls at both times. We observed an impairment of the hemorheological pattern in young patients with myocardial infarction, partially influenced by the infarction type (STEMI and NSTEMI) and persisting in the long term.

Red blood cell deformability in multiple myeloma1.

The aim of this study was the evaluation of the erythrocyte deformability in multiple myeloma (MM). We enrolled 29 MM patients and we evaluated, on fasting venous blood, the erythrocyte deformability, expressed as elongation index, and examined using the diffractometric method. By comparing normal controls and MM patients, a significant decrease in erythrocyte deformability, especially at low shear stresses, was found. In this research paper we evaluated all the hypothesis for a possible explanation of the behaviour of red blood cell deformability in MM, even considering how the alteration of erythrocyte deformability worsens the microcirculatory flow in these patients in association with the marked increase in plasma viscosity.

Gelatinases and their tissue inhibitors in a group of subjects with obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) is associated with an elevated risk of cardiovascular events and stroke. Matrix metalloproteinases (MMPs) are endopeptidases involved in extracellular matrix degradation and then in the development and progression of cardiovascular diseases. Our aim was to evaluate plasma levels of gelatinases (MMP-2 and MMP-9) and their tissue inhibitors (TIMP-1 and TIMP-2) in a group of subjects with OSAS. We enrolled 48 subjects (36 men and 12 women; mean age 49.7 ± 14.68 yrs) with OSAS diagnosed with a 1-night cardiorespiratory study and then we subdivided these subjects into two subgroups according to the apnea/hypopnea index (AHI): Low (L = 21 subjects with AHI <30) and High (H = 27 subjects with AHI >30). We measured plasma concentration of the gelatinases and their inhibitors using ELISA kits. We observed a significant increase in plasma concentration of MMP-9, MMP-2, TIMP-1 and TIMP-2 in the entire group of OSAS subjects and in the two subgroups, with higher levels in the H in comparison with the L subgroup. In the whole group of OSAS subjects we also noted a significant decrease in MMP-9/TIMP-1 ratio in comparison with normal controls. Only MMP-9 was significantly correlated with the severity of the disease, expressed as AHI, with the oxygen desaturation index and also with the mean oxygen saturation. MMPs pattern is altered in OSAS and significantly influenced by the severity of the disease; it probably contributes to the vascular remodeling that leads to the atherosclerotic disease and cardiovascular complications.