Reduced neural baroreflex sensitivity is related to enhanced endothelial function in patients with end-stage liver disease

Objectives: Reduced baroreflex sensitivity (BRS) is a frequent complication in end-stage liver disease, but the underlying mechanism is unknown. We investigated the mechanical and neural components of BRS. Increased nitric oxide (NO) production has been reported in end-stage liver failure. Based on earlier experiments, we hypothesised that enhanced endothelial function might affect baroreflex function. Therefore, we explored the relation between endothelial function and the components of BRS.

Materials and methods: We enrolled 24 patients and 23 controls. BRS was determined by the spontaneous sequence method. Mechanical component was characterised by the distensibility coefficient (DC) of common carotid artery. Neural component was estimated as the ratio of integrated BRS and DC. Endothelial function was quantified by flow-mediated dilation (FMD) of the brachial artery.

Results: Integrated BRS was reduced in patients [7.00 (5.80–9.25) vs. 11.1 (8.50–14.80) ms/mmHg]. The mechanical component was not different in the two groups, whereas neural component showed significant reduction in patients (3.54?±?1.20 vs. 4.48?±?1.43?ms/10^?3). FMD was higher in patients (9.81?±?3.77 vs. 5.59?±?1.36%). FMD and neural BRS were directly related in controls (r?=?0.62), but inversely related in patients (r?=?–0.49).

Conclusions: Baroreflex impairment in end-stage liver disease might be explained by deterioration of the neural component, while the mechanical component appears to be preserved. Endothelial NO may enhance BRS in health; however, central endothelial overproduction of NO likely contributes to the reduction of neural component of BRS in patients awaiting liver transplantation.     

Determination of urinary NAG to detect renal ischemia-reperfusion injury and the protective effect of Allopurinol

We analysed the effect of ischemia-reperfusion injury to renal parenchyma after unilateral renal artery clamping using urinary N-acetyl-beta-D-glucosaminidase (NAG) that is a sensitive parameter of early renal tubular injury. In the study 60 mongrel dogs were divided into 3 groups: in the 1st group the left renal artery was clamped for 45 minutes, in the 2nd group Allopurinol was administered before the clamping, the 3rd was the control group, where only laparotomy and closure of the abdomen was performed. Urinary NAG activity referring to urinary creatinine (NAG index) was determined before the operation, at the beginning of the reperfusion, in the 60th and 120th minute of the reperfusion then 1, 2, 3 and 5 days after the operation. The highest NAG indices relating to injury of the proximal tubuli were found at the beginning of the reperfusion, in the 60th and 120th minutes of the reperfusion, then NAG returned to preoperative level in each group. Significantly higher NAG indices were found in the ischemia-reperfusion group compared to the group with Allopurinol pretreatment. Renal ischemia-reperfusion injury and the protective effect of Allopurinol could be detected by lysosomal NAG enzyme. The injury of the tubular function was reversible so it could be a change in tubular function.     

CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca²⁺ mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca²⁺ mobilization. Ca²⁺ mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P_2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P_2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.In regional hypoventilation of the lung, hypoxic pulmonary vasoconstriction (HPV) protects against systemic hypoxemia by redistributing blood flow from poorly to better ventilated areas of the lung, thereby minimizing ventilation-perfusion (V_A/Q) mismatch (1). In chronic hypoxemia-associated lung disease, however, HPV contributes to pulmonary hypertension (PH), characterized by increased resistance and progressive remodeling of the pulmonary arteries, eventually leading to right ventricular hypertrophy and, ultimately, right heart failure.In the lung, hypoxia is initially sensed at the alveolocapillary level (2). The signal is then propagated retrogradely via gap junctions to upstream arterioles, where it is transmitted to adjacent pulmonary arterial smooth muscle cells (PASMCs) for initiation of HPV (2). Contraction of PASMCs is ultimately triggered by RhoA/rho kinase (RhoK)-mediated Ca²⁺ sensitization and concomitant cytosolic Ca²⁺ increase (1), for which transient receptor potential canonical 6 (TRPC6) plays a predominant role (3). TRPC6 is a nonselective cation channel (4) that is highly expressed in PASMCs (3) and colocalizes with caveolin-1 (5). Upon hypoxia, TRPC6 translocates to caveolin- and sphingolipid-rich lipid rafts (6), where it is activated by diacylglycerol (DAG) via phospholipase C (PLC) (4, 7). However, the signaling pathways that translocate TRPC6 to caveolae and activate PLC and RhoA in response to hypoxia remain obscure. Here, we provide evidence for a previously unrecognized role of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in HPV and mechanistically link this finding to a newly identified, dual role of sphingolipids in both the activation of PLC and RhoA and the translocation of TRPC6.Gene mutations in CFTR cause CF, an autosomal recessive genetic disorder leading to viscous mucus secretion and recurring lung infections. CF is typically associated with profound pulmonary V_A/Q mismatches (8) and intrapulmonary shunts (9), which led us to hypothesize that HPV may be impaired in this condition. Indeed, arterial hypoxemia in CF patients can be accounted for by V_A/Q inequalities and shunts, yet not by impaired O₂ diffusion (10). Intriguingly, HPV is also abrogated in pneumonia (11) or sepsis (12) caused by Pseudomonas aeruginosa, which phenocopy CF disease via secretion of the virulence factor CFTR inhibitory factor (Cif) (13). Robert et al. reported the expression of CFTR in PASMCs and demonstrated its involvement in the modulation of pulmonary arterial tone (14). In the systemic circulation, CFTR-F508del, the most common mutation underlying human CF disease, has recently been associated with diminished Ca²⁺ release in vascular smooth muscle cells, decreased aortic tone, and responsiveness (15). Of specific relevance for HPV, CFTR was recently shown to directly interact with TRPC6, thus regulating TRPC6-dependent Ca²⁺ influx (16). Based on these considerations, we postulated that CFTR may play a crucial, yet so far unrecognized, role in hypoxia-induced Ca²⁺ mobilization underlying PASMC contraction and HPV.Interestingly, CFTR is considered to regulate homeostasis and lipid raft concentrations of sphingolipids (17, 18), which have recently become implicated in HPV in that HPV is blocked by inhibition of neutral sphingomyelinase (nSMase), which releases ceramide from sphingomyelin (19). nSMase is activated upon oxidative stress (20), possibly via arachidonic acid liberation by phospholipase A₂ (21), which all have been linked to HPV (1). In addition, ceramide accumulates in PASMCs upon hypoxia (22), mediates caveolar TRPC6 translocation in lung endothelial cells (23), and contributes to constriction of pulmonary artery rings (19, 24). Although ceramide may thus potentially act as a direct mediator of HPV, it may also serve as substrate for the formation of other, bioactive sphingolipids, most notably sphingosine-1-phosphate (S1P). S1P is generated by conversion of ceramide to sphingosine and its subsequent phosphorylation by sphingosine kinase (SphK) (25), which is known to be up-regulated upon hypoxia (26). In the lung, SphK1 is the predominant SphK isoform (27) and has been shown to modulate pulmonary vascular responsiveness and remodeling (28). S1P acts intracellularly as a second messenger or extracellularly via activation of five G protein-coupled receptors (GPCRs) termed S1P_1–5 (25), of which S1P₂ (29) and S1P₄ (30) mediate pulmonary vasoconstriction. Because S1P₂ (29, 31) and S1P₄ (32) receptor engagement activates PLC and RhoK, and S1P is a known activator of TRPC5 (33), we hypothesized that S1P may trigger both central pathways of HPV, DAG formation and consecutive TRPC6-induced Ca²⁺ mobilization, as well as RhoK-mediated Ca²⁺ sensitization (1). A potential role of S1P in HPV is particularly intriguing in consideration of its potential tie to CFTR, in that CFTR is one of only two transporters shown to translocate S1P across biological membranes (17). In the present study, we hence probed for the functional role of CFTR and its mechanistic link to sphingolipid signaling in HPV.     

Psychoactive Substance Use and Problematic Internet Use as Predictors of Bullying and Cyberbullying Victimization

Research exploring the relationship between addictions and experiences of bullying suggests that problem behaviors may generally be associated with an increased risk of victimization. The aim of the present study was to examine the role of psychoactive substance use, excessive Internet use, and social support in both traditional offline bullying and online “cyberbullying” victimization in a nationally representative sample of adolescents (N = 6237; 51% male; M _age = 16.62 years, SD = 0.95). Results demonstrated that traditional bullying victimization was associated with cyberbullying victimization. Furthermore, psychoactive substance use and problematic Internet use predicted both traditional bullying and cyberbullying victimization. Finally, perceived social support was found to be an important protective factor against both traditional and cyberbullying victimization. However, psychoactive substance use and problematic Internet use accounted for only a small proportion of variance in victimization.     

The 8.1 ancestral MHC haplotype is strongly associated with colorectal cancer risk

Many recent data indicate that some alleles encoded in the central major histocompatibility complex (MHC) region (Class III) of short arm of chromosome 6 may modify the risk of cancer development. Therefore we determined 4 single nucleotide polymorphisms (SNPs) of this region (TNF-alpha -308 G > A, RAGE -429 T > C, HSP70-2 -1267 A > G, LTA 252 A > G) in genomic DNA samples from 183 Hungarian patients with colorectal cancer and 141 age matched control subjects representing the Hungarian population of the same age and gender. No significant differences were found in either SNP tested. When, however, three- or four-locus haplotypes consisting of known constituents of the so-called 8.1 ancestral haplotype (8.1AH) were considered, marked differences were observed. Frequency of TNF-alpha -308A, RAGE -429C, HSP70-2 -1267G, LTA 252G (8.1AH) haplotype was significantly (p = 0.006) more frequent (19.1%) among patients than in the controls (7.7%). Age- and gender-adjusted ratio of the 8.1AH carriers vs. non-carriers to have colorectal cancer was 2.514 (1.130-5.594). This risk was higher in 相似文献   

Adverse perinatal outcome in teenage pregnancies: an analysis of a 5-year period in Southeastern Hungary

Objective: To determine the risks of adverse perinatal outcomes of teenage mothers.

Material and methods: A retrospective analysis was performed on teenage mothers (under 20 years of age) who delivered in the period of 2010–2014 at the Department of Obstetrics and Gynecology, University of Szeged (study group). All mothers who delivered in Hungary during the same period were studied as a control group. The following parameters were analyzed: demographic data of the mothers, maternal complications, perinatal outcome and congenital malformations of the newborns. The binominal test, Student’s t-test and Poisson’s regression were applied using STATA 9.0 (StataCorp, College Station, TX, USA) statistical software (p?Results: During this 5-year period, 12,845 births were recorded at the Department, of these 274 (2.1%) were teenage pregnancies with 275 newborns. The offsprings of teenage mothers had significantly lower mean birth weight (3110.2?±?564.03?g versus 3247?g), higher rate of congenital malformations (8.0 versus 5.0%) and higher admission to neonatal intensive care unit (12.4 versus 8.0%) than the infants in the control group.

Conclusions: Younger maternal age was significantly associated with lower mean birth weight, higher risk of congenital malformations, and increased admission rate to neonatal intensive care unit.     

The role of methylglyoxal metabolism in type-2 diabetes and its complications

Transient or chronic hyperglycaemia increases the formation of intracellular reactive oxygen species and aldehydes. The accumulation of reactive aldehydes is implicated in the development of diabetic complications. Methylglyoxal, a glucose dependent α-dicarbonyl might be the most important reactive aldehyde in diabetes and its complications. Diabetes was the first disease in which evidence emerged for the increased formation of methylglyoxal in the cells and in the serum. Methylglyoxal has a toxic effect on insulin secretion from pancreatic beta-cells, and on modifications of proteins and nucleic acids. Moreover, methylglyoxal is one of the major precursors of advanced glycation end-products. The glyoxalase enzyme system that exists in all mammalian cells is catalyzing the detoxification of methylglyoxal. This review summarizes the methylglyoxal metabolism in normoglycaemic and hyperglycamic conditions and the role of methylglyoxal in the development of late diabetic microvascular complications.     

Effect of warfarin on survival in small cell carcinoma of the lung. Veterans Administration Study No. 75

In a controlled, randomized study, survival of patients with small cell carcinoma of the lung (SCCL) was prolonged on addition of warfarin sodium to combination chemotherapy plus radiation therapy. Median survival for 25 control patients was 24 weeks and for 25 warfarin-treated patients was 50 weeks. This difference could not be accounted for by differences between groups in performance status, extent of disease, age, or sex. The survival advantage associated with warfarin administration was observed both for patients with extensive disease and for those who failed to achieve complete or partial remission. The warfarin-treated group also demonstrated a significantly increased time to first evidence of disease progression. These results suggest that warfarin may be useful in the treatment of SCCL and also support the hypothesis that the blood coagulation mechanism may be involved in the growth and spread of cancer in man.