Molecular targeting of proteins by homocysteine: implications in familial and clinical hypercholesterolemia

Cardiovascular diseases (CVDs) are one of the leading causes of death and disability worldwide and one of its underlying causes is hypercholesterolemia. Hypercholesterolemia can have genetic (familial hypercholesterolemia, FH) and non-genetic causes (clinical hypercholesterolemia, CH), the first much more severe, with occurrence of premature atherosclerosis. While the pathophysiological role of homocysteine (Hcy) on CVD is still controversial, molecular targeting of protein by S and N-homocysteinylation offers a new paradigm to be considered in the vascular pathogenesis of hypercholesterolemia. On this regard, the present study aims to give new insights on protein targeting by Hcy in both CH and FH conditions. A total of 187 subjects were included: 65 normolipidemic and 122 hypercholesterolemic. Total (tHcy) and free (fHcy) fractions were quantified in serum samples after validation of an HPLCFD method, to assess S-homocysteinylation. Also, the lactonase (LACase) activity of paraoxonase-1 (PON1) was quantified by a colorimetric assay, as a surrogate of N-homocysteinylation. tHcy does not differ among groups. Nevertheless, fHcy declines in the hypercholesterolemic groups, with more evidence to the FH population. Consequently, there seems to be an increase of Shomocysteinylation, regardless of lipid lowering therapy (LLT). Also, despite of LLT use, LACase activity is lower in FH, thus the risk for protein N-homocysteinylation seems to be higher. Moreover, the decrease in LACase/ApoA1 and LACase/HDL ratios in FH, shows that HDL is dysfunctional in this population, despite its normal concentration values. Data supports that the pathophysiological role of Hcy on hypercholesterolemia may reside in its ability to post-translationally modify proteins. This role is particularly evident in FH condition. In the future, it will be interesting to identify which target proteins are modified and thus involved in vascular pathology progression.

Pathophysiology of cancer cachexia

Cancer cachexia is a frequent complication observed in patients with malignant tumors. Although several decades have passed since the first focus on the metabolic dysfunction's associated with cancer, few effective therapeutic interventions have been successfully introduced into the medical armamentarium. The present study thoroughly reviews the basic pathophysiology of cancer cachexia and the treatment options already investigated in that field. Experimental and clinical studies were evaluated individually in order to clarify the intricate alterations observed in tumor-bearing patients. The difficulties in introducing sound and effective nutritional support or metabolic manipulation to reverse cancer cachexia are outlined in this review.

Analysis of Plasma Homocysteine Levels in Patients with Unstable Angina

OBJECTIVE - To determine the prevalence of hyperhomocystinemia in patients with acute ischemic syndrome of the unstable angina type. METHODS - We prospectively studied 46 patients (24 females) with unstable angina and 46 control patients (19 males), paired by sex and age, blinded to the laboratory data. Details of diets, smoking habits, medication used, body mass index, and the presence of hypertension and diabetes were recorded, as were plasma lipid and glucose levels, C-reactive protein, and lipoperoxidation in all participants. Patients with renal disease were excluded. Plasma homocysteine was estimated using high-pressure liquid chromatography. RESULTS - Plasma homocysteine levels were significantly higher in the group of patients with unstable angina (12.7±6.7 µmol/L) than in the control group (8.7±4.4 µmol/L) (p<0.05). Among males, homocystinemia was higher in the group with unstable angina than in the control group, but this difference was not statistically significant (14.1±5.9 µmol/L versus 11.9±4.2 µmol/L). Among females, however, a statistically significant difference was observed between the 2 groups: 11.0±7.4 µmol/L versus 6.4±2.9 µmol/L (p<0.05) in the unstable angina and control groups, respectively. Approximately 24% of the patients had unstable angina at homocysteine levels above 15 µmol/L. CONCLUSION - High homocysteine levels seem to be a relevant prevalent factor in the population with unstable angina, particularly among females.

Lipoprotein (a): Structure, Pathophysiology and Clinical Implications

The chemical structure of lipoprotein (a) is similar to that of LDL, from which it differs due to the presence of apolipoprotein (a) bound to apo B100 via one disulfide bridge. Lipoprotein (a) is synthesized in the liver and its plasma concentration, which can be determined by use of monoclonal antibody-based methods, ranges from < 1 mg to > 1,000 mg/dL. Lipoprotein (a) levels over 20-30 mg/dL are associated with a two-fold risk of developing coronary artery disease. Usually, black subjects have higher lipoprotein (a) levels that, differently from Caucasians and Orientals, are not related to coronary artery disease. However, the risk of black subjects must be considered. Sex and age have little influence on lipoprotein (a) levels. Lipoprotein (a) homology with plasminogen might lead to interference with the fibrinolytic cascade, accounting for an atherogenic mechanism of that lipoprotein. Nevertheless, direct deposition of lipoprotein (a) on arterial wall is also a possible mechanism, lipoprotein (a) being more prone to oxidation than LDL. Most prospective studies have confirmed lipoprotein (a) as a predisposing factor to atherosclerosis. Statin treatment does not lower lipoprotein (a) levels, differently from niacin and ezetimibe, which tend to reduce lipoprotein (a), although confirmation of ezetimibe effects is pending. The reduction in lipoprotein (a) concentrations has not been demonstrated to reduce the risk for coronary artery disease. Whenever higher lipoprotein (a) concentrations are found, and in the absence of more effective and well-tolerated drugs, a more strict and vigorous control of the other coronary artery disease risk factors should be sought.

Top Three Pharmacogenomics and Personalized Medicine Applications at the Nexus of Renal Pathophysiology and Cardiovascular Medicine.

Pharmacogenomics is a field with origins in the study of monogenic variations in drug metabolism in the 1950s. Perhaps because of these historical underpinnings, there has been an intensive investigation of 'hepatic pharmacogenes' such as CYP450s and liver drug metabolism using pharmacogenomics approaches over the past five decades. Surprisingly, kidney pathophysiology, attendant diseases and treatment outcomes have been vastly under-studied and under-theorized despite their central importance in maintenance of health, susceptibility to disease and rational personalized therapeutics. Indeed, chronic kidney disease (CKD) represents an increasing public health burden worldwide, both in developed and developing countries. Patients with CKD suffer from high cardiovascular morbidity and mortality, which is mainly attributable to cardiovascular events before reaching end-stage renal disease. In this paper, we focus our analyses on renal function before end-stage renal disease, as seen through the lens of pharmacogenomics and human genomic variation. We herein synthesize the recent evidence linking selected Very Important Pharmacogenes (VIP) to renal function, blood pressure and salt-sensitivity in humans, and ways in which these insights might inform rational personalized therapeutics. Notably, we highlight and present the rationale for three applications that we consider as important and actionable therapeutic and preventive focus areas in renal pharmacogenomics: 1) ACE inhibitors, as a confirmed application, 2) VDR agonists, as a promising application, and 3) moderate dietary salt intake, as a suggested novel application. Additionally, we emphasize the putative contributions of gene-environment interactions, discuss the implications of these findings to treat and prevent hypertension and CKD. Finally, we conclude with a strategic agenda and vision required to accelerate advances in this under-studied field of renal pharmacogenomics with vast significance for global public health.

Association of serum homocysteine with major depressive disorder: results from a large population-based study.

BACKGROUND: Studies on the association between homocysteine levels and depression have shown conflicting results. To examine the association between serum total homocysteine (tHcy) levels and major depressive disorder (MDD) in a large community sample with an extended age range. METHODS: A total of 3392 men and women aged 35-66 years participating in the CoLaus study and its psychiatric arm (PsyCoLaus) were included in the analyses. High tHcy measured from fasting blood samples was defined as a concentration ≥15μmol/L. MDD was assessed using the semi-structured Diagnostic Interview for Genetics Studies. RESULTS: In multivariate analyses, elevated tHcy levels were associated with greater odds of meeting the diagnostic criteria for lifetime MDD among men (OR=1.71; 95% CI, 1.18-2.50). This was particularly the case for remitted MDD. Among women, there was no significant association between tHcy levels and MDD and the association tended to be in the opposite direction (OR=0.61; 95% CI, 0.34-1.08). CONCLUSIONS: In this large population-based study, elevated tHcy concentrations are associated with lifetime MDD and particularly with remitted MDD among men.

Portal hypertension in schistosomiasis: pathophysiology and treatment

In heavily infected young patients, there is a "non-congestive" phase of the disease with splenomegaly which can improve after chemoterapy. A strong correlation between hepatosplenic form and worm burden in young patients has been repeatedly shown. The pattern of vascular intrhepatic lesions seems to depend on two mechanisms: (a) egg embolization, with a partial blocking of the portal vasculature; (b) the appearance of small portal collaterals along the intrahepatic portal sistem. The role played by hepatitis B virus (HBV) and C virus infections in the pathogenesis of liver lesions is variably considered. Selective arteriography shows a reduced diameter of hepatic artery with thin and arched branches outlining vascular gaps. A rich arterial network , as described in autopsy cases, is usually not seen in vivo, except after splenectomy or shunt surgery. An augmented hepatic arterial flow was demonstrated in infected animals. These facts suggest that the poor intrahepatic arterial vascularization demonstrated by selective arteriography in humans is due to a "functional deviation"of arterial blood to the splenic territory. The best results obtained in treatment of portal hypertension were: esophagogastric desvascularization and splenectomy (EGDS), although risk of rebleeding persists; classical (proximal) splenorenal shunt (SRS) should be abandoned; distal splenorenal shunt may complicate with hepatic encephalopaty, although later and in a lower percentage than in SRS. Propranolol is currently under investigation. In our Department, schistosomotic patients with esophageal varices bleeding are treated by EGDS and, if rebleeding occurs, by sclerosis of the varices.

High altitude, a natural research laboratory for the study of cardiovascular physiology and pathophysiology.

High altitude constitutes an exciting natural laboratory for medical research. Although initially, the aim of high-altitude research was to understand the adaption of the organism to hypoxia and find treatments for altitude-related diseases, during the past decade or so, the scope of this research has broadened considerably. Two important observations led the foundation for the broadening of the scientific scope of high-altitude research. First, high-altitude pulmonary edema represents a unique model that allows studying fundamental mechanisms of pulmonary hypertension and lung edema in humans. Second, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary and systemic vascular dysfunction at an early stage. Here, we will review studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning lung edema and pulmonary hypertension and to the first direct demonstration of fetal programming of vascular dysfunction in humans.

Beyond sepsis pathophysiology with cytokines: what is their value as biomarkers for disease severity?

Sepsis is a major challenge in medicine. It is a common and frequently fatal infectious condition. The incidence continues to increase, with unacceptably high mortality rates, despite the use of specific antibiotics, aggressive operative intervention, nutritional support, and anti-inflammatory therapies. Typically, septic patients exhibit a high degree of heterogeneity due to variables such as age, weight, gender, the presence of secondary disease, the state of the immune system, and the severity of the infection. We are at urgent need for biomarkers and reliable measurements that can be applied to risk stratification of septic patients and that would easily identify those patients at the highest risk of a poor outcome. Such markers would be of fundamental importance to decision making for early intervention therapy or for the design of septic clinical trials. In the present work, we will review current biomarkers for sepsis severity and especially the use of cytokines as biomarkers with important pathophysiological role.

Pathophysiology and classification of the vibration white finger.

Skin, arteries and nerves of the upper extremities can be affected by vibration exposure. Recent advances in skin and vascular biology as well as new investigative methods, have shown that neurovascular symptoms may be due to different vascular and neurological disorders which should be differentiated if proper management is to be evaluated. Three types of vascular disorder can be observed in the vibration white finger: digital organic microangiopathy, a digital vasospastic phenomenon and arterial thrombosis in the upper extremities. An imbalance between endothelin-1 and calcitonin-gene-related peptide is probably responsible for the vasospastic phenomenon. Moreover, paresthesiae can be due to either a diffuse vibration neuropathy or a carpal tunnel syndrome. A precise diagnosis is then necessary to adapt the treatment to individual cases. A classification describing the type and severity of the vascular lesions is presented. Asymptomatic lesions are included for adequate epidemiological studies and risk assessment of vibrating tools. Monitoring of vibration exposed workers should include not only a questionnaire about symptoms, but also a clinical evaluation including diagnostic tests for the screening of early asymptomatic neurovascular injuries.

Influence of low-protein dietetic foods consumption on quality of life and levels of B vitamins and homocysteine in patients with chronic renal failure.

OBJECTIVE The aim of the study was to determine whether the consumption of low protein dietetic foods improved the quality of life and nutritional status for vitamins B and homocysteine in patients with chronic renal failure. METHODOLOGY This nutritional-intervention involved 28 men and 21 women, divided into two groups. The control-group consumed a low-protein diet prescribed, and the experimental-group consumed a diet in which some commonly used foods were replaced by low-protein dietetic foods. The study lasted 6 months. Food consumption was assessed by 24-h recall. Vitamin B6 as alphaEAST was measured in blood. Creatinine, urea, vitamin B12, folate and homocysteine were measured in plasma. The impact on the patients' quality of life from consuming the dietetic foods was assessed via the SF-36 questionnaire. RESULTS After 6 months, the protein intake among the experimental-group had decreased by 40%, and the urea/creatinine ratio and alphaEAST activity were also lower. The results of the SF-36 questionnaire show that the patients in the experimental-group obtained higher scores in the categories of general health and physical status. CONCLUSIONS The dietetic foods were very well accepted by all patients and their use allowed a better control of the protein intake, improved B6 status and a better quality of life.

Evaluation of an online, case-based interactive approach to teaching pathophysiology

AIM: The aim of this study was to evaluate a new pedagogical approach in teaching fluid, electrolyte and acid-base pathophysiology in undergraduate students. METHODS: This approach comprises traditional lectures, the study of clinical cases on the web and a final interactive discussion of these cases in the classroom. When on the web, the students are asked to select laboratory tests that seem most appropriate to understand the pathophysiological condition underlying the clinical case. The percentage of students having chosen a given test is made available to the teacher who uses it in an interactive session to stimulate discussion with the whole class of students. The same teacher used the same case studies during 2 consecutive years during the third year of the curriculum. RESULTS: The majority of students answered the questions on the web as requested and evaluated positively their experience with this form of teaching and learning. CONCLUSIONS: Complementing traditional lectures with online case-based studies and interactive group discussions represents, therefore, a simple means to promote the learning and the understanding of complex pathophysiological mechanisms. This simple problem-based approach to teaching and learning may be implemented to cover all fields of medicine.