The value of waist circumference as a preditor of cardiovascular risk in adult patients with classic phenylketonuria.

BACKGROUND AND AIMS: We aimed to evaluate the differences in some cardiovascular risk (CVR) factors between adult patients without and with phenylketonuria (PKU) and to explore the correlation between waist circumference (WC) and body mass index (BMI) with the previous variables. METHODS: This was an observational case-control study that included patients older than 18 years with a diagnosis of classic PKU. The controls were age- and sex-matched individuals. We collected demographic, epidemiological, clinical, and laboratory variables, including WC, BMI, and lipid profile parameters. RESULTS: A total of 72 patients (25 controls and 47 cases) were included with a mean age of 36 years, of which 45 (62%) were women. Adult PKU patients showed lower high-density lipoprotein cholesterol (HDL-c) and higher triglyceride (TG) levels than the control group. We found an association between WC and uric acid (B=0.024, P=0.013, 95%CI: 0.005-0.043), TG (B=0.768, P=0.024, 95%CI: 0.107-1.428), and HDL-c (B=-0.254, P=0.026, 95%CI: -0.477 to (-0.032)) levels in PKU patients. However, we did not find any trend between WC and uric acid, TG and HDL-c levels that reached statistical significance (P<0.05) in patients without PKU. CONCLUSIONS: Waist circumference rather than BMI may better represent the CVR in patients with PKU.

Assessment of Oxidative Stress Markers in Hypertensive Patients under the Use of Renin-Angiotensin-Aldosterone Blockers.

As in other fields, chronotherapy applied to arterial hypertension (AHT) may have implications on oxidative stress. We compared the levels of some redox markers between hypertensive patients with morning and bedtime use of renin-angiotensin-aldosterone system (RAAS) blockers. This was an observational study that included patients older than 18 years with a diagnosis of essential AHT. Blood pressure (BP) figures were measured using twenty-four-hour ambulatory BP monitoring (24-h ABPM). Lipid peroxidation and protein oxidation were assessed using the thiobarbituric acid reactive substances (TBARS) and reduced thiols assays. We recruited 70 patients with a median age of 54 years, of whom 38 (54%) were women. In hypertensive patients with bedtime use of RAAS blockers, reduced thiol levels showed a positive correlation with nocturnal diastolic BP decrease. TBARS levels were associated with bedtime use of RAAS blockers in dipper and non-dipper hypertensive patients. In non-dipper patients, bedtime use of RAAS blockers was also associated with a decrease in nocturnal diastolic BP. Chronotherapy applied to bedtime use of some BP-lowering drugs in hypertensive patients may be linked to a better redox profile.

Implications of Inflammatory and Oxidative Stress Markers in the Attenuation of Nocturnal Blood Pressure Dipping.

To date, no model has jointly encompassed clinical, inflammatory, and redox markers with the risk of a non-dipper blood pressure (BP) profile. We aimed to evaluate the correlation between these features and the main twenty-four-hour ambulatory blood pressure monitoring (24-h ABPM) indices, as well as to establish a multivariate model including inflammatory, redox, and clinical markers for the prediction of a non-dipper BP profile. This was an observational study that included hypertensive patients older than 18 years. We enrolled 247 hypertensive patients (56% women) with a median age of 56 years. The results showed that higher levels of fibrinogen, tissue polypeptide-specific antigen, beta-2-microglobulin, thiobarbituric acid reactive substances, and copper/zinc ratio were associated with a higher risk of a non-dipper BP profile. Nocturnal systolic BP dipping showed a negative correlation with beta-globulin, beta-2-microglobulin, and gamma-globulin levels, whereas nocturnal diastolic BP dipping was positively correlated with alpha-2-globulin levels, and negatively correlated with gamma-globulin and copper levels. We found a correlation between nocturnal pulse pressure and beta-2-microglobulin and vitamin E levels, whereas the day-to-night pulse pressure gradient was correlated with zinc levels. Twenty-four-hour ABPM indices could exhibit singular inflammatory and redox patterns with implications that are still poorly understood. Some inflammatory and redox markers could be associated with the risk of a non-dipper BP profile.

The role of phenylalanine levels in the neuropsychological and neuroanatomical status of adult patients with phenylketonuria: The impact of fluctuations.

We aimed to evaluate the role of plasma phenylalanine (Phe) levels and its fluctuations in some neurocognitive domains and brain magnetic resonance imaging (MRI) findings in adult patients with phenylketonuria (PKU). It was an observational study that included patients older than 18 years with early-treated classical PKU. Plasma Phe levels were measured every other month throughout 2 years and predictor variables were the mean, maximum (max), minimum (min), range (min-max), and plasma Phe levels at the time of cognitive testing. Patients were evaluated for executive function, processing speed, visual attention, and fluid cognitive abilities using the Trail Making Test (TMT) and for the presence of brain MRI abnormalities. In all, 22 patients with a mean age of 34 years were included, of which 18 (81%) were women. Patients with higher range and maximum Phe levels had a poorer time-based performance on TMT form A and form B. Patients with brain MRI abnormalities had higher range, maximum, and mean Phe levels. Range of Phe levels showed a good performance for MRI abnormalities (area under the curve (AUC): 0.881, standard error (SE): 0.095, 95% CI: 0.695-0.999, p = 0.044) and for the poorest time-based performances on TMT form A (AUC: 0.822, SE: 0.092, 95% CI: 0.641-0.999, p = 0.024) and B (AUC: 0.816, SE: 0.094, 95% CI: 0.632-0.999, p = 0.021). Greater Phe variability may have a negative impact on some neurocognitive domains and could be related to the severity of brain structural damage in adult patients with PKU.

The correlation of lipid profile and waist circumference with phenylalanine levels in adult patients with classical phenylketonuria.

INTRODUCTION AND OBJECTIVES: Some studies have pointed to a relationship between Phenyketonuria (PKU) and an increased cardiovascular risk (CVR). This study aimed to evaluate the influence of metabolic control on classical CVR factors in adult patients with PKU. MATERIAL AND METHODS: It was a cross-sectional study conducted in patients older than 18 years with a diagnosis of classical PKU and under strict dietary control. Demographic, epidemiological and laboratory variables related to CVR were collected. The variables of metabolic control were some parameters related to phenylalanine (Phe) plasma levels. RESULTS: A total of 47 patients were included with a mean age of 36±10 years of which 30 (64%) were women. Multivariate analysis revealed that range Phe (B=-2.211, P=0.044, 95%CI: -4.354-(-0.068)) levels were within the model for triglyceride concentrations, while minimum (B=-2.803, P=0.051, 95%CI: -5.612-0.007) and range (B=-1.515, P=0.039, 95%CI: -2.945-(-0.084)) Phe levels were within the model for high-density lipoprotein cholesterol concentrations. Median Phe levels showed a stronger correlation with waist circumference (WC) (B=1.216, P=0.002, 95%CI: 0.462-1.969) than with body mass index (B=0.355, P=0.052, 95%CI: -0.004-0.714). CONCLUSIONS: High Phe levels and wide Phe fluctuations were related to weight gain, increased WC and lipid profile abnormalities. Systematic CVR assessments and comprehensive monitoring of Phe levels may be desirable to prevent or delay cardiovascular disease in PKU patients.

Correlation between Blunted Nocturnal Decrease in Diastolic Blood Pressure and Oxidative Stress: An Observational Study.

An impaired nocturnal decrease in diastolic blood pressure (DBP) increases the blood pressure (BP) load, which is a main factor in endothelial dysfunction, atherosclerosis, and arterial stiffness. We aimed to quantify some markers of oxidative stress in hypertensive patients, to compare their levels between individuals with dipper and non-dipper DBP profiles, and to assess their correlation with the nocturnal DBP (nDBP) dipping. It was an observational study that included patients older than 18 years with a diagnosis of essential hypertension who consented to participate. The collected variables were some indices of 24-h ambulatory blood pressure monitoring, demographic, epidemiological, clinical, and laboratory variables. Plasma thiobarbituric acid reactive substances (TBARS) and reduced thiols, together with serum vitamin E, vitamin A, copper (Cu), and zinc (Zn) levels were assessed as oxidative stress markers. We recruited 248 patients with a median age of 56 years (56% women). The percentage of nDBP dipping showed a weak positive correlation with reduced thiol, vitamin E, and vitamin A levels; and a weak negative correlation with Cu levels. We also found a negative correlation between nDBP dipping and the TBARS/Thiol, TBARS/Vitamin E, and TBARS/Vitamin A ratios. After multivariate analysis, we found that increased TBARS/Thiol ratio and serum Cu levels were associated with a higher risk of a non-dipper DBP profile. As in other situations of increased cardiovascular risk, an impaired nDBP decrease may coincide with abnormalities in redox status.

Assessment of oxidative stress markers in elderly patients with SARS-CoV-2 infection and potential prognostic implications in the medium and long term.

We aimed to evaluate the correlation of plasma levels of thiobarbituric acid reactive substances (TBARS) and reduced thiols with morbidity, mortality and immune response during and after SARS-CoV-2 infection. This was an observational study that included inpatients with SARS-CoV-2 infection older than 65 years. The individuals were followed up to the twelfth month post-discharge. Plasma levels of TBARS and reduced thiols were quantified as a measure of lipid and protein oxidation, respectively. Fatal and non-fatal events were evaluated during admission and at the third, sixth and twelfth month post-discharge. Differences in oxidative stress markers between the groups of interest, time to a negative RT-qPCR and time to significant anti-SARS-CoV-2 IgM titers were assessed. We included 61 patients (57% women) with a mean age of 83 years old. After multivariate analysis, we found differences in TBARS and reduced thiol levels between the comparison groups in fatal and non-fatal events during hospital admission. TBARS levels were also correlated with fatal events at the 6th and 12th months post-discharge. One year after hospital discharge, other predictors rather than oxidative stress markers were relevant in the models. The median time to reach significant anti-SARS-CoV-2 IgM titers was lower in patients with low levels of reduced thiols. Assessment of some parameters related to oxidative stress may help identify groups of patients with a higher risk of morbidity, mortality and delayed immune response during and after SARS-CoV-2 infection.

Are Differences in Inflammatory Markers between Patients with and without Hypertension-Mediated Organ Damage Influenced by Circadian Blood Pressure Abnormalities?

We aimed to explore the influence that the circadian blood pressure (BP) profile could exert on the correlation between some inflammatory markers and hypertension-mediated organ damage (HMOD). This was a cross-sectional study that included patients with primary arterial hypertension older than 18 years old. We included some parameters of 24 h ambulatory blood pressure monitoring collection and several inflammatory markers, as follows: platelet count (PTC), erythrocyte sedimentation rate (ESR), ultrasensitive C-reactive-protein, ferritin, fibrinogen, and uric acid. Myocardial hypertrophy, albuminuria, carotid intima-media thicknesses and ankle brachial index were assessed as HMOD presentations. Individuals were divided into two groups: patients with and without HMOD. We included 522 patients (47% women, mean age of 54 years). Multivariate logistic regression analysis showed that male patients older than 50 years old with uric acid levels above 7 mg/dL, ESR higher than 20 mm/h, fibrinogen greater than 320 mg/dL and PTC lower than 275 × 103/µL were associated with HMOD (p < 0.05). The circadian BP profile (dipper versus non-dipper pattern) did reach neither statistical significance nor influence the odds ratio of those inflammatory markers for HMOD. We found that differences in some inflammatory markers between patients with and without HMOD were not explained by a different circadian BP profile.

Copper Increases Brain Oxidative Stress and Enhances the Ability of 6-Hydroxydopamine to Cause Dopaminergic Degeneration in a Rat Model of Parkinson's Disease.

Redox properties enable copper to perform its essential role in many biological processes, but they can also convert it into a potentially hazardous element. Its dyshomeostasis may have serious neurological consequences, and its possible involvement in Parkinson's disease and other neurodegenerative disorders has been suggested. The in vitro and ex vivo ability of copper to increase oxidative stress has already been demonstrated, and the aim of the present study was to assess in vivo the capacity of copper to cause brain oxidative damage and its ability to increase the dopaminergic degeneration induced by 6-hydroxydopamine. We found that chronic copper administration (10 mg Cu2+/kg/day, IP) causes its accumulation in different brain areas (cortex, striatum, nigra) and was accompanied by an increase in TBARS levels and a decrease in protein free-thiol content in the cortex. A decrease in catalase activity and an increase in glutathione peroxidase activity were also observed in the cortex. The intrastriatal administration of Cu2+ caused an increase in some indices of oxidative stress (TBARS and protein free-thiol content) in striatum and nigra, but was unable to induce dopaminergic degeneration. However, when copper was intrastriatally coadministered with 6-hydroxydopamine, it increased dopaminergic degeneration, a fact that was also accompanied by an increase in the assayed indices of oxidative stress, a decrease in catalase activity, and an augmentation in glutathione activity. Evidently, copper cannot cause neurodegeneration per se, but may potentiate the action of other factors involved in the pathogenesis of Parkinson's disease through oxidative stress.

Copper increases the ability of 6-hydroxydopamine to generate oxidative stress and the ability of ascorbate and glutathione to potentiate this effect: potential implications in Parkinson's disease.

Copper is an essential metal for the function of many proteins related to important cellular reactions and also involved in the synaptic transmission. Although there are several mechanisms involved in copper homeostasis, a dysregulation in this process can result in serious neurological consequences, including degeneration of dopaminergic neurons. 6-Hydroxydopamine is a dopaminergic neurotoxin mainly used in experimental models of Parkinson's disease, whose neurotoxicity has been related to its ability to generate free radicals. In this study, we examined the effects induced by copper on 6-OHDA autoxidation. Our data show that both Cu+ and Cu2+ caused an increase in • OH production by 6-OHDA autoxidation, which was accompanied by an increase in the rate of both p-quinone formation and H2 O2 accumulation. The presence of ascorbate greatly enhanced this process by establishing a redox cycle which regenerates 6-OHDA from its p-quinone. However, the presence of glutathione did not change significantly the copper-induced effects. We observed that copper is able to potentiate the ability of 6-OHDA to cause both lipid peroxidation and protein oxidation, with the latter including a reduction in free-thiol content and an increase in carbonyl content. Ascorbate also increases the lipid peroxidation induced by the action of copper and 6-OHDA. Glutathione protects against the copper-induced lipid peroxidation, but does not reduce its potential to oxidize free thiols. These results clearly demonstrate the potential of copper to increase the capacity of 6-OHDA to generate oxidative stress and the ability of ascorbate to enhance this potential, which may contribute to the destruction of dopaminergic neurons.