Filipe Palavra

Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women

BackgroundThe aim of this study is to evaluate the effect of gender and menopause in cardiometabolic risk in a type 2 diabetes mellitus (T2DM) population, based on classical and non-traditional markers.MethodsSeventy four volunteers and 110 T2DM patients were enrolled in the study. Anthropometric data, blood pressure, body mass index (BMI), waist circumference (WC) and the following serum markers were analyzed: glucose, Total-c, TGs, LDL-c, Oxidized-LDL, total HDL-c and large and small HDL-c subpopulations, paraoxonase 1 activity, hsCRP, uric acid, TNF-α, adiponectin and VEGF.ResultsNon-diabetic women, compared to men, presented lower glycemia, WC, small HDL-c, uric acid, TNF-α and increased large HDL-c. Diabetes abrogates the protective effect of female gender, since diabetic women showed increased BMI, WC, small HDL-c, VEGF, uric acid, TNF-α and hsCRP, as well as reduced adiponectin, when compared with non-diabetic. In diabetic females, but not in males, WC is directly and significantly associated with TNF-α, VEGF, hsCRP and uric acid; TNF-α is directly associated with VEGF and hsCRP, and inversely with adiponectin. Postmenopausal females presented a worsen cardiometabolic profile, viewed by the increased WC, small HDL-c, VEGF, uric acid, TNF-α and hsCRP. In this population, WC is directly and significantly associated with TNF-α, VEGF, hsCRP; TNF-α is directly associated with VEGF; and uric acid is inversely associated with large HDL-c and hsCRP with adiponectin, also inversely.ConclusionsDiabetes abrogates the protective effect of gender on non-diabetic women, and postmenopausal diabetic females presented worsen cardiometabolic risk, including a more atherogenic lipid sketch and a pro-inflammatory and pro-angiogenic profile. The classical cardiovascular risk factors (CVRFs) fail to completely explain these differences, which are better clarified using “non-traditional” factors, such as HDL-c subpopulations, rather than total HDL-c content, and markers of inflammation and angiogenesis, namely TNF-α, hsCRP, uric acid and VEGF. Multi-therapeutic intervention, directed to obesity, atherogenic lipid particles and inflammatory mediators is advisory in order to efficiently prevent the serious diabetic cardiovascular complications.

New markers of early cardiovascular risk in multiple sclerosis patients: Oxidized-LDL correlates with clinical staging

OBJECTIVES: This study aimed to characterize a population of multiple sclerosis (MS) patients in terms of traditional and new cardiovascular risk factors and assess their putative correlation with clinical disease activity (evaluated by the Expanded Disability Status Scale [EDSS]). METHODS: Thirty relapsing MS patients and 66 subjects, matched by age and sex, were enrolled in this cross-sectional study. For each subject, anthropometric data were collected and classical biochemical (including lipid profile, glucose and C reactive protein [CRP] levels) and novel markers (paraoxonase 1 [PON1] enzyme activity and contents of high-density lipoprotein [HDL] cholesterol, oxidized low-density lipoprotein [Ox-LDL], tumor necrosis factor [TNF]-alfa, vascular endothelial growth factor [VEGF] and adiponectin) were studied. RESULTS: In patients group, 23 women and 7 men were included, aged 35.00 (28.25–40.25) years and scoring a median of 2.00 (1.50–3.13) in EDSS. Comparing with controls, the most relevant differences encountered were: increased serum triglycerides (P < 0.001), Ox-LDL (P < 0.001) as well as Ox-LDL/LDL ratio and reduced small HDL (P = 0.040), accompanied by a trend to increased VEGF concentration. LDL content, especially Ox-LDL, showed positive and significant correlation with EDSS (r = 0.458; P = 0.011) and VEGF (r = 0.453; P = 0.014). CONCLUSIONS: MS patients presented a profile of early CV risk, being Ox-LDL contents a putative good marker and having correlation with the clinical activity of the disease.

Recent Advances and Challenges of mTOR Inhibitors Use in the Treatment of Patients with Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) is a genetic condition characterized by the presence of benign, noninvasive, and tumor-like lesions called hamartomas that can affect multiple organ systems and are responsible for the clinical features of the disease. In the majority of cases, TSC results from mutations in the TSC1 and TSC2 genes, leading to the overactivation of the mammalian target of rapamycin (mTOR) signalling pathway, which controls several cell functions, including cell growth, proliferation, and survival. The establishment of a connection between TSC and mTOR led to the clinical use of drugs known as mTOR inhibitors (like rapamycin, also known as sirolimus and everolimus), which are becoming an increasingly interesting tool in the management of TSC-associated features, such as subependymal giant cell astrocytomas, renal angiomyolipomas, and also epilepsy. However, the intrinsic characteristics of these drugs and their systemic effects in such a heterogeneous condition pose many challenges in clinical practice, so that some questions remain unanswered. This article provides an overview of the pharmacological aspects of mTOR inhibitors about the clinical trials leading to their approval in TSC-related conditions and exposes current challenges and future directions associated with this promising therapeutic line.

Obesity and brain inflammation: a focus on multiple sclerosis.

The increase in prevalence of obesity in industrialized societies is an indisputable fact. However, the apparent passive role played by adipocytes, in pathophysiological terms, has been gradually substituted by a metabolically active performance, relevant to many biochemical mechanisms that may contribute to a chronic low‐grade inflammatory status, which increasingly imposes itself as a key feature of obesity. This chronic inflammatory status will have to be integrated into the complex equation of many diseases in which inflammation plays a crucial role. Multiple sclerosis (MS) is a chronic inflammatory condition typically confined to the central nervous system, and many work has been produced to find possible points of contact between the biology of this immune‐mediated disease and obesity. So far, clinical data are not conclusive, but many biochemical features have been recently disclosed. Brain inflammation has been implicated in some of the mechanisms that lead to obesity, which has also been recognized as an important player in inducing some degree of immune dysfunction. In this review, we collected evidence that allows establishing bridges between obesity and MS. After considering epidemiological controversies, we will focus on possible shared mechanisms, as well as on the potential contributions that disease‐modifying drugs may have on this apparent relationship of mutual interference.

Emergent Biomarkers of Residual Cardiovascular Risk in Patients with Low HDL-c and/or High Triglycerides and Average LDL-c Concentrations: Focus on HDL Subpopulations, Oxidized LDL, Adiponectin, and Uric Acid

This study intended to determine the impact of HDL-c and/or TGs levels on patients with average LDL-c concentration, focusing on lipidic, oxidative, inflammatory, and angiogenic profiles. Patients with cardiovascular risk factors (n = 169) were divided into 4 subgroups, combining normal and low HDL-c with normal and high TGs patients. The following data was analyzed: BP, BMI, waist circumference and serum glucose, Total-c, TGs, LDL-c, oxidized-LDL, total HDL-c and HDL subpopulations, paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF-α, adiponectin, VEGF, and iCAM1. The two populations with increased TGs levels, regardless of the normal or low HDL-c, presented obesity and higher waist circumference, Total-c, LDL-c, Ox-LDL, and uric acid. Adiponectin concentration was significantly lower and VEGF was higher in the population with cumulative low values of HDL-c and high values of TGs, while HDL quality was reduced in the populations with impaired values of HDL-c and/or TGs, viewed by reduced large and increased small HDL subfractions. In conclusion, in a population with cardiovascular risk factors, low HDL-c and/or high TGs concentrations seem to be associated with a poor cardiometabolic profile, despite average LDL-c levels. This condition, often called residual risk, is better evidenced by using both traditional and nontraditional CV biomarkers, including large and small HDL subfractions, Ox-LDL, adiponectin, VEGF, and uric acid.

Cardiometabolic Risk, Inflammation, and Neurodegenerative Disorders

Inflammation has been recognized as an important character in the underlying mechanisms leading to the development of various types of neurodegenerative disorders. In this sense, both inflammation of the nervous system itself and systemic inflammation act in the complex pathophysiology of these neurological diseases. The nervous system does not play a passive role in the complexity of these mechanisms and can itself be responsible for perpetuating pro-inflammatory stimuli – it is today recognized the important role that specific brain areas play in the so-called metabolic inflammation. This dialectical relationship will be the focus of this chapter.

Listeria rhombencephalitis mimicking a demyelinating event in an immunocompetent young patient

As physicians, we know that, in clinical practice, the diagnosis of multiple sclerosis (MS) can be very challenging. Still, the development of diagnostic criteria based on the inclusion of multiple data coming from clinical grounds and from complementary exams (primarily from magnetic resonance imaging (MRI)) has been contributing to the optimization of this process of differential diagnosis and, in practice, results in high sensitivity and specificity, allowing clinicians to make a more accurate diagnosis. Nevertheless, one should not forget that there is no MS-specific diagnostic test and the intermittent nature of the disease and high variability in presenting symptoms can make diagnosis difficult and can contribute to bring some degree of uncertainty to all this, which is contained in the axiomatic expression that it can only be made if there is no better explanation for patient’s neurological signs and symptoms.

mTOR and Neuroinflammation

Abstract During the last decade, the insight into the mechanisms linking inflammation to diseases of the nervous system has increased, and so-called neuroinflammation has assumed a key pathophysiological role in many acute or chronic neurological conditions. Therefore, neuroinflammatory processes have been investigated with the aim of better understanding the mechanisms of those diseases but, above all, of identifying molecular therapeutic targets that can contribute to change the natural history of some conditions with increasing prevalence. Signaling pathways mediated by the mammalian target of rapamycin (mTOR) have been ever more implicated in processes occurring in neuroinflammation. Since it assumes a key role as a signal integrator in several complex processes of cell physiology, mTOR arises as an interesting target, whose pharmacological modulation could have clinical interest. Focusing on the main consequences of neuroinflammation, this chapter describes how mTOR participates in them and how the modulation of its activity could become clinically interesting.

Inflammation Biomarkers and Cardiometabolic Risk

The ominous presence of inflammation in all phases of atherosclerosis has prompted the evaluation of emergent biomarkers of inflammation as tools to help in identifying patients at high risk for future cardiovascular events, to improve diagnostic and prognostic abilities, and to monitor disease activity and efficacy of therapy. Acute-phase reactants, pro- and anti-inflammatory cytokines, cell adhesion molecules, chemokines, and other mediators involved in the pathogenesis of atherosclerosis have been shown to have predictive value to determine future cardiovascular events and/or death, but until now, none, with the exception of hsCRP, has demonstrated additive value to the Framingham Risk Score.