Association of oxidative stress and PON1 with LDL and HDL particle size in middle-aged subjects

BACKGROUND: Alterations in plasma lipoprotein subclass distributions affect atherosclerosis risk. Smaller, denser low-density lipoprotein (LDL) particles (sdLDL) are more susceptible to oxidation. In contrast, most of the protective effects of high-density lipoproteins (HDL) are attributable to larger particles. This study investigates the connection between LDL and HDL particle heterogeneity and oxidative stress, antioxidative defence (AOD) and paraoxonase (PON1) status in a healthy middle-aged Serbian population. MATERIALS AND METHODS: LDL and HDL particle sizes and subclass distributions were measured by gradient gel electrophoresis in 104 men and 103 women, aged 53 +/- 9.4 years. PON1 activities and PON1(Q192R) phenotypes were determined with paraoxon and diazoxon as substrates. The oxidative stress/AOD status was estimated by measuring malondialdehyde (MDA) and superoxide-anion (O2*(-)) levels and superoxide-dismutase (SOD) activity. RESULTS: Subjects with sdLDL had significantly higher MDA (P < 0.001) and O2*(-)(P < 0.05) levels and greater diazoxonase (DZOase) activity (P < 0.05) compared to subjects with larger LDL particles. A high MDA concentration was a significant predictor of the sdLDL phenotype (P < 0.005). Increased levels of and MDA were associated with smaller HDL(3) subclass abundance. Reduced HDL particle size was associated with lower DZOase activity (P < 0.01). CONCLUSIONS: Even in the absence of symptoms of atherosclerosis, sdLDL particles are associated with increased oxidative stress, which may stimulate a compensatory rise in PON1 DZOase activity. Elevated oxidative stress may significantly affect HDL subclass distribution, resulting in the accumulation of smaller, denser HDL particles with diminished antioxidative capacity.     

The association of PC-1 (ENPP1) K121Q polymorphism with metabolic syndrome in patients with coronary heart disease

BACKGROUND: Metabolic syndrome (MS) is a clinical feature, closely associated with insulin resistance, one of the prime underlying causes of overall cardiovascular morbidity, including coronary heart disease (CHD). Considering the association between PC-1 121Q genotype and insulin resistance phenotype, the aim of the present study was to investigate the contribution of PC-1 K121Q polymorphism to the development of MS and its concomitant disorders in CHD patients. METHODS: A total of 130 Caucasians from Serbia, including 80 CHD patients (aged 59.4+/-8.6 years, of a mean BMI 28.9+/-3.9 kg/m2) and 50 control subjects (aged 48.0+/-6.4 years, of a mean BMI 29.6+/-2.1 kg/m2), were genotyped for PC-1 K121Q using a mutagenic separated PCR assay, in order to determine the prevalence of the PC 121Q variant in individuals suffering from CHD and its association with MS. RESULTS: The frequency of PC-1 121Q allele found in CHD patients was 28.5%, with significantly (P<0.01) higher prevalence in those with MS (40% vs. 10%). Both MS (P<0.01) and its components [central obesity (P<0.01), low HDL-cholesterol (P<0.01) and high triglycerides (P<0.05)] were significantly more prevalent in CHD 121Q carriers compared to CHD patients who exhibited the wild-type genotype. A binary logistic regression model has revealed that PC-1 121Q allele carriers had a 5.5 fold increased odds (95%CI: 1.4-20.9, P=0.01) for the MS compared to wild-type carriers. The PC-1 121Q allele contributed to MS components as well, although these associations did not reach statistical significance. CONCLUSION: The findings of the present study support the hypothesis that the PC-1 (ENPP1) 121Q allele is associated with the genetic susceptibility for MS in patients with CHD. Further studies and more extensive research in this area are needed, not only to confirm this association, but to elucidate it in more details.     

Clinical evaluation of Functional Electrical Therapy in acute hemiplegic subjects

This paper describes a clinical randomized single-blinded study of the effects of Functional Electrical Therapy (FET) on the paretic arms of subjects with acute hemiplegia caused by strokes. FET is an exercise program that comprises voluntary arm movements and opening, closing, holding, and releasing of objects that are assisted by a neural prosthesis (electrical stimulation). FET consisted of a 30 min everyday exercise for 3 consecutive weeks in addition to conventional therapy. Twenty-eight acute hemiplegic subjects participated in a 6 mo study. The subjects were divided into lower functioning groups (LFGs) and higher functioning groups (HFGs) based on their capacity to voluntarily extend the wrist and fingers against the gravity, and were randomly assigned to controls or FET groups. The outcomes included the Upper Extremity Function Test, the coordination of elbow and shoulder movements, spasticity of key muscles of the paretic arm, and Reduced Upper Extremity Motor Activity Log. FET and control groups showed a recovery trend in all outcome measures. The gains in FET groups were much larger compared with the gains in control groups. The speed of recovery in FET groups was substantially faster compared with the recovery rate in control groups during the first 3 weeks (treatment). The LFG subjects showed less improvement than the HFG in both the FET and control groups.     

Impact of depression on sexual dysfunction and HRQoL in CAD patients

Background

The aim of this study was to assess the impact of the depression on sexual dysfunction and the health-related quality of life (HRQoL) in coronary artery disease (CAD) patients admitted for cardiovascular rehabilitation within 3 months after an acute myocardial infarction (AMI). Methods. In all, 745 consecutive CAD patients (502 men and 243 women, aged 60.9 ± 9.3 years) admitted for cardiovascular rehabilitation within 3 months after an AMI, were enrolled in the study and divided into 4 groups according to Beck depression inventory (BDI) score range. HRQoL was estimated using the SF-36 questionnaire for total QoL and dimensions for physical and mental health [physical and mental component summary scores (PCS, MCS)]. Sexual dysfunction was assessed using the ASEX scale.

Results

The HRQoL decreased following the range of depression, as demonstrated for significantly higher PCS in minimal compared to mild, moderate and severe depression groups (P<0.001). The MCS was significantly higher in minimal compared to mild, moderate and severe depression groups (P<0.001). The ASEX score was significantly higher in minimal, compared to mild, moderate and severe depression groups, as well as in mild and moderate compared to severe depression group. A significant association was found between depression score range and age, self-reported regular exercise, type 2 diabetes mellitus, and cigarette smoking.

Conclusions

Depression significantly affected HRQoL and sexual dysfunction in CAD patients, as demonstrated by the significant decrease of PCS, MCS, and significant increase of ASEX score following the range of the depression according to BDI.     

Krukenberg tumor of gastric origin in pregnancy with dismal outcome

Krukenberg tumors are mostly found as metastatic signet-ring cell adenomucinous carcinomas in young, premenopausal women. They are bilateral in 80% of the cases, and thus can be expected in pregnancy. A 31-year-old female was diagnosed by explorative laparotomy at 27 weeks of gestation with a Krukenberg tumor due to bilateral adnexal masses and a large amount of ascites. At surgery cesarean section with total abdominal hysterectomy, bilateral salpingo-oophorectomy, total omentectomy and pelvic lymphadenectomy was performed. The neonate died 24 hours later due to prematurity and respiratory distress syndrome. The primary site of the cancer was detected metachronously two months after surgery and postoperative chemotherapy, as stomach adenomucinous carcinoma. In spite of surgery and postoperative multiagent chemotherapy, the patient died six months from the diagnosis of Krukenberg.     

Two-photon fluorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood�Cbrain barrier opening

Blood–brain barrier (BBB) disruption can be achieved with ultrasound (US) and circulating microbubble (MB) contrast agent. Using dorsal US sonication and Definity, an MB contrast agent, responses of the cortical cerebral vasculature to BBB opening were observed with varying acoustic peak negative pressure (0.071 to 0.25 MPa) under two-photon microscope. Wistar rats with a craniotomy were sonicated with a single piezoelectric transducer following the intravenous injection of Texas Red for visualization of vasculature and leakage from BBB opening. Based on time-dependent intensity change in the extravascular area, the leakage was classified into three types: fast, sustained, and slow. Fast leakage was characterized by a rapid increase to peak intensity during sonication, but a decrease afterwards, occurring at all pressures and vessels sizes analyzed in our study. Sustained leakage was indicated by a similar, immediate increase to peak intensity but one that remained elevated for the duration of imaging, occurring at low-to-intermediate pressures. Slow leakage began 5 to 15 minutes after sonication, dominating at low pressures, and was more prevalent among smaller vessels than fast and sustained leakage. Our study showed the possibility of controlling leakage type and vessel size in US-induced BBB opening through varying acoustic pressure.     

IFIT1 is an antiviral protein that recognizes 5'-triphosphate RNA

Antiviral innate immunity relies on the recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5' terminus (PPP-RNA). By an affinity proteomics approach with PPP-RNA as the 'bait', we found that the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members. IFIT1 bound PPP-RNA with nanomolar affinity and required the arginine at position 187 in a highly charged carboxy-terminal groove of the protein. In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA. On the basis of this specificity and the great abundance of IFIT proteins after infection, we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids.     

Quantitative estimates of stimulation-induced perfusion response using two-photon fluorescence microscopy of cortical microvascular networks

Functional hyperemia, or the increase in focal perfusion elicited by neuronal activation, is one of the primary functions of the neurovascular unit and a hallmark of healthy brain functioning. While much is known about the hemodynamics on the millimeter to tenths of millimeter-scale accessible by MRI, there is a paucity of quantitative data on the micrometer-scale changes in perfusion in response to functional stimulation. We present a novel methodology for quantification of perfusion and intravascular flow across the 3D microvascular network in the rat somatosensory cortex using two-photon fluorescence microscopy (2PFM). For approximately 96% of responding microvessels in the forelimb representation of the primary somatosensory cortex, brief (~2s) forepaw stimulation resulted in an increase of perfusion 20±4% (mean±sem). The perfusion levels associated with the remaining 4% of the responding microvessels decreased 10±9% upon stimulation. Vessels irrigating regions of lower vascular density were found to exhibit higher flow (p<0.02), supporting the notion that local vascular morphology and hemodynamics reflect the metabolic needs of the surrounding parenchyma. High dispersion (~77%) in perfusion levels suggests high spatial variation in tissue susceptibility to hypoxia. The current methodology enables quantification of absolute perfusion associated with individual vessels of the cortical microvascular bed and its changes in response to functional stimulation and thereby provides an important tool for studying the cellular mechanisms of functional hyperemia, the spatial specificity of perfusion response to functional stimulation, and, broadly, the micrometer-scale relationship between vascular morphology and function in health and disease.     

Sunitinib-induced microangiopathic hemolytic anemia with fatal outcome

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated activity in renal cell carcinoma and is now widely used in the palliative treatment of patients with metastatic renal cell carcinoma. It is generally well tolerated but has been associated with a low incidence of grade 3 and 4 toxicities including fatigue, diarrhea, anorexia, mucositis, skin toxicity, immune thrombocytopenic purpura, hypertension, hypothyroidism, cytopenias, and decreased cardiac ejection fraction. Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is a rare condition that is severe and may be fatal. Several medications have been implicated in causing TTP-HUS including clopidogrel, mitomycin C, cisplatin. In this report, we describe a case of atypical HUS-microangiopathic hemolytic anemia during treatment with sunitinib in a patient with metastatic renal cell carcinoma. To our knowledge, this is the fourth case of microangiopathic hemolytic anemia associated with sunitinib described in the literature and the first case with fatal outcome despite treatment with plasmapheresis, dialysis, and withdrawal of sunitinib.