Central hemodynamic effects of diuretic therapy in chronic heart failure

In chronic heart failure diuretic drugs improve central hemodynamic variables and cardiac pumping secondary to altered plasma and extracellular volumes; humoral markers of these changes include increased plasma renin and aldosterone levels. The latter increases are maximal over the first week but decline with chronic therapy. The plasma alpha-ANP levels show a reciprocal effect; these data are compatible with a rapid contraction of the plasma volume which is sustained during chronic therapy.The acute hemodynamic actions of diuretic agents reflect both immediate and direct vascular actions and also effects secondary to diuresis (volume redistribution). At rest substantial reductions in pulmonary wedge pressure (–29%), with a consequent fall in cardiac output (–10%), are described. Total systemic vascular resistance initially increases but reverse autoregulation over subsequent weeks returns this elevation gradually towards control values. Tolerance to these initial hemodynamic effects does not occur with maintained therapy; moreover, echocardiographic markers of contractility and exercise capacity may increase. The early venodilator effects of diuretic drugs can be attributed to prostaglandin release and the initial pressor actions to activation of the renin angiotensin system; these vascular actions may have limited relevance to long-term beneficial effects on hemodynamics. Direct pulmonary vasodilation and improved pulmonary compliance remain an interesting finding. Although most patients are both symptomatically and hemodynamically improved at rest, the actions during exercise are more varied. Some individuals with severely impaired left ventricular function show little hemodynamic improvement, whereas those with milder dysfunction usually benefit; in the main this is probably related to the latter being on a steeper cardiac function curve. The impact of diuretic therapy on the underlying disease process is unclear; however, there is little convincing evidence of remodelling or improvement in intrinsic performance (as distinct from that induced by altered loading conditions).     

Hemodynamic interactions of a new beta blocker,celiprolol, with nifedipine in angina pectoris

The hemodynamic consequences of blockade at both beta-adrenoceptors and slow calcium channels is of therapeutic importance for patients with angina pectoris. The hemodynamic interaction of a new cardioselective beta blocker, celiprolol, and nifedipine was examined in an acute hemodynamic study using three prospectively matched groups with angiographically confirmed coronary artery disease (n = 10/group). Patients were randomly allocated to intravenous celiprolol (8 mg), sublingual nifedipine (20 mg), or their combination. Rest and exercise (supine bicycle) hemodynamics were determined before and following each therapy. At rest, celiprolol did not alter pumping function; nifedipine reduced diastolic blood pressure and systemic vascular resistance index (SVRI), with a small increase in heart rate. Combination therapy reduced systemic arterial pressure and SVRI; heart rate and cardiac stroke volume index increased. During exercise celiprolol tended to reduce heart rate and cardiac index; nifedipine reduced exercise SVR and cardiac stroke work indices. Combination therapy reduced all components of blood pressure; cardiac stroke work and SVR indices fell. These hemodynamic data suggest that beta blockade with celiprolol may result in a slight depression of cardiac pumping during exercise; however, such effects are offset by the vasodilating actions of nifedipine (reflex sympathetic action offsetting cardiodepression). Thus the acute hemodynamic effects of this combination were seemingly safe in these patients; the longer term effects during maintained therapy should be further assessed.     

Association between Lp-PLA2 and coronary artery disease: focus on its relationship with lipoproteins and markers of inflammation and hemostasis

Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates pro-inflammatory molecules from oxidized LDL. We examined the association between Lp-PLA2 plasma concentrations and risk of stable coronary artery disease (CAD) in a large case-control study and further assessed the relationship between Lp-PLA2 and various lipid, inflammatory and hemostatic parameters. Lp-PLA2 concentrations were measured in 312 patients with CAD and in 479 age- and gender-matched blood donors. Various sensitive inflammatory and hemostatic markers and a complete lipoprotein profile were obtained. Lp-PLA2 concentrations were significantly higher in cases than in controls (296.1 ng/mL versus 266.0 ng/mL, p<0.0001). In multivariable logistic regression, the age- and gender-adjusted OR for the presence of CAD was 1.61 (95% CI, 1.07-2.44) if the top quartile of the Lp-PLA2 distribution was compared to the bottom quartile. Adjustment for traditional cardiovascular risk factors and statin use resulted in an OR of 2.04 (95% CI, 1.19-3.48). After additional controlling for vWF, the OR was slightly attenuated but still remained statistically significant (OR 1.91; 95% CI, 1.12-3.28). Thus, elevated Lp-PLA2 concentrations were associated with the presence of stable CAD, independent of various biochemical markers. Our results support the hypothesis that Lp-PLA2 may be a novel, independent risk marker for CAD.     

Dynamic changes of the neurogenic potential in the rat cochlear nucleus during post-natal development

Neuronal stem cells have been described in the post-natal cochlear nucleus recently. The aim of the study was to analyse the neurogenic potential in the cochlear nucleus from the early post-natal days until adulthood. Cochlear nuclei from Sprague–Dawley rats from post-natal day P3 up to P40 were examined. Neurosphere assays showed persistent neurosphere formation from the early post-natal days until adulthood. The numbers of generated neurospheres were fewer in older ages. Neurospheres were smaller, but displayed the same pattern of neuronal stem cell markers. The markers GFAP, MBP and ß-III Tubulin showed differentiation of dissociated cells from the neurospheres in all cells of the neuronal lineage. BrdU incorporation could be detected, in an age-dependent decrease, in whole-mount experiments of the cochlear nucleus on all examined days. BrdU co-labelled with Atoh1 and ß-III Tubulin. In addition, gene expression and cellular distribution studies of the neuronal stem cell markers displayed an age-dependent reduction in both quantity and numbers. The presented results display a possible neurogenic potential until adulthood in the cochlear nucleus by in vitro and in vivo experiments. The fact that this potential is highest at a critical period of development reveals possible functional importance for the development of the cochlear nucleus and the auditory function. The persistent neurogenic potential displayed until adulthood could be a neurogenic niche in the adult cochlear nucleus, which might be used for potential therapeutic strategies.     

Postmortem coronary artery calcium score in cases of myocardial infarction

International Journal of Legal Medicine - Sudden cardiac death (SCD) related to atherosclerotic coronary artery disease (ACAD) resulting in myocardial infarction is the most prevalent cause of...     

Influence of MRE11, RAD50 and NIBRIN protein expression on survival in pancreatic carcinoma after curative resection

The MRE11/RAD50/NIBRIN complex, a protein complex that repairs DNA double-strand breaks, could serve as an early marker for new lesions in pancreatic cancer. We determined the expression of MRE11, RAD50 and NIBRIN, and their possible prognostic value regarding survival.     

QRICH1 variants in Ververi‐Brady syndrome—delineation of the genotypic and phenotypic spectrum

Ververi‐Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss‐of‐function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail.