Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins

Preeclampsia is a potentially fatal complication of human pregnancy characterized by hypertension, proteinuria, and edema. Placental oxidative stress is a key element in the pathogenesis of the syndrome and results in the release of a cocktail of factors, including proinflammatory cytokines and apoptotic debris, that in turn cause activation of the maternal endothelium. The intermediary molecular mechanisms underlying this release are unknown, but they represent a potential target for therapeutic interventions. We examined activation of signaling pathways during hypoxia-reoxygenation of villous explants in vitro. Hypoxia-reoxygenation activated the p38 and stress-activated protein kinase mitogen-activated protein kinase (MAPK) and the nuclear factor-kappaB pathways. Downstream consequences included increased tissue concentrations and secretion of tumor necrosis factor-alpha and interleukin-1 beta, increased expression of cyclooxygenase-2, and increased apoptosis. Administration of vitamins C and E to explants blocked activation of the p38 and stress-activated protein kinase MAPK and nuclear factor-kappaB pathways. Vitamin administration or p38 pathway inhibition also reduced cyclooxygenase-2 expression, tumor necrosis factor-alpha and interleukin-1 beta secretion, and the levels of apoptosis. We conclude that oxidative stress is a potent inducer of placental synthesis and release of proinflammatory factors. Most of these effects are mediated through the p38 MAPK and nuclear factor-kappaB pathways and can be effectively blocked by vitamins C and E in vitro.     

The denoising of Monte Carlo dose distributions using convolution superposition calculations

Monte Carlo (MC) dose calculations can be accurate but are also computationally intensive. In contrast, convolution superposition (CS) offers faster and smoother results but by making approximations. We investigated MC denoising techniques, which use available convolution superposition results and new noise filtering methods to guide and accelerate MC calculations. Two main approaches were developed to combine CS information with MC denoising. In the first approach, the denoising result is iteratively updated by adding the denoised residual difference between the result and the MC image. Multi-scale methods were used (wavelets or contourlets) for denoising the residual. The iterations are initialized by the CS data. In the second approach, we used a frequency splitting technique by quadrature filtering to combine low frequency components derived from MC simulations with high frequency components derived from CS components. The rationale is to take the scattering tails as well as dose levels in the high-dose region from the MC calculations, which presumably more accurately incorporates scatter; high-frequency details are taken from CS calculations. 3D Butterworth filters were used to design the quadrature filters. The methods were demonstrated using anonymized clinical lung and head and neck cases. The MC dose distributions were calculated by the open-source dose planning method MC code with varying noise levels. Our results indicate that the frequency-splitting technique for incorporating CS-guided MC denoising is promising in terms of computational efficiency and noise reduction.     

Clinical application of growth factors and cytokines in wound healing

Wound healing is a complex and dynamic biological process that involves the coordinated efforts of multiple cell types and is executed and regulated by numerous growth factors and cytokines. There has been a drive in the past two decades to study the therapeutic effects of various growth factors in the clinical management of nonhealing wounds (e.g., pressure ulcers, chronic venous ulcers, diabetic foot ulcers). For this review, we conducted an online search of Medline/PubMed and critically analyzed the literature regarding the role of growth factors and cytokines in the management of these wounds. We focused on currently approved therapies, emerging therapies, and future research possibilities. In this review, we discuss four growth factors and cytokines currently being used on and off label for the healing of wounds. These include granulocyte‐macrophage colony‐stimulating factor, platelet‐derived growth factor, vascular endothelial growth factor, and basic fibroblast growth factor. While the clinical results of using growth factors and cytokines are encouraging, many studies involved a small sample size and are disparate in measured endpoints. Therefore, further research is required to provide definitive evidence of efficacy.     

Overexpression of oxytocin receptors in the hypothalamic PVN increases baroreceptor reflex sensitivity and buffers BP variability in conscious rats

Background and Purpose

The paraventricular nucleus (PVN) of the hypothalamus is an important integrative site for neuroendocrine control of the circulation. We investigated the role of oxytocin receptors (OT receptors) in PVN in cardiovascular homeostasis.

Experimental Approach

Experiments were performed in conscious male Wistar rats equipped with a radiotelemetric device. The PVN was unilaterally co-transfected with an adenoviral vector (Ad), engineered to overexpress OT receptors, and an enhanced green fluorescent protein (eGFP) tag. Control groups: PVN was transfected with an Ad expressing eGFP alone or untransfected, sham rats (Wt). Recordings were obtained without and with selective blockade of OT receptors (OTX), during both baseline and stressful conditions. Baroreceptor reflex sensitivity (BRS) and cardiovascular short-term variability were evaluated using the sequence method and spectral methodology respectively.

Key Results

Under baseline conditions, rats overexpressing OT receptors (OTR) exhibited enhanced BRS and reduced BP variability compared to control groups. Exposure to stress increased BP, BP variability and HR in all rats. In control groups, but not in OTR rats, BRS decreased during stress. Pretreatment of OTR rats with OTX reduced BRS and enhanced BP and HR variability under baseline and stressful conditions. Pretreatment of Wt rats with OTX, reduced BRS and increased BP variability under baseline and stressful conditions, but only increased HR variability during stress.

Conclusions and Implications

OT receptors in PVN are involved in tonic neural control of BRS and cardiovascular short-term variability. The failure of this mechanism could critically contribute to the loss of autonomic control in cardiovascular disease.     

Potential causes of insufficient bladder contrast opacification and premature microbubble destruction during contrast-enhanced voiding urosonography in children

Contrast-enhanced voiding urosonography (ceVUS) has been recognized as a child-friendly examination with high diagnostic accuracy for vesicoureteric reflux detection. A single bolus and the infusion techniques of ceVUS are described. Insufficient bladder contrast opacification during the filling phase and premature destruction of SonoVue microbubbles might occur. Data regarding SonoVue's features, doses, bladder contrast opacification, US bladder parameters, urine catheter, antibiotic prophylaxis, and childrens behaviors were collected to discover the possible causes of the contrast vanishing observed during bladder filling in 10% of examinations and in the later phase of ceVUS in 5% of examinations. An updated ceVUS examination protocol is suggested.     

Replication of ϕX174 DNA by Escherichia coli polA-In Vitro

Lysates of an Escherichia coli polA^- strain convert single-stranded DNA from ϕX174 virus to the double-stranded replicative form with high efficiency on cellophane discs. The initiation of synthesis of the complementary strand appears to be rate limiting; once initiation occurs, the chain is propagated rapidly. Under these conditions, the unsealed replicative form accumulates and is slowly converted to the sealed form; this conversion requires the activity of the DPN-dependent DNA ligase.     

Clinical and epidemiological features of Guillain‐Barré syndrome in the Western Balkans

The aim of this study was to define features of Guillain‐Barré syndrome in a large cohort of patients from three Western Balkans countries. Data from adult Guillain‐Barré syndrome (GBS) cases from 2009 to 2013 were retrospectively obtained from all tertiary health care centers. During the 5‐year period, 327 new cases of GBS were identified with a male to female ratio of 1.7 : 1. The most common GBS variants were demyelinating (65%) and axonal (12%). At nadir 45% of patients were chair‐bound, confined to bed, or required assisted ventilation, while 5% died. The crude incidence of GBS in Serbia and Montenegro was 0.93 per 100,000 population, and age‐adjusted incidence according to the world standard population was 0.86 per 100,000. Incidence was particularly high in 50‐ to 80‐year‐old men. Statistically significant seasonal variations of GBS were not observed. This study of patients with GBS in the Western Balkans allows us to prepare the health system better and to improve the management of patients. This study also opens opportunities for international collaboration and for taking part in the multinational studies on GBS.     

Palladium(II) Complexes with N‐Heteroaromatic Bidentate Hydrazone Ligands: The Effect of the Chelate Ring Size and Lipophilicity on in vitro Cytotoxic Activity

Novel Pd(II) complex with N‐heteroaromatic Schiff base ligand, derived from 8‐quinolinecarboxaldehyde (q8a) and ethyl hydrazinoacetate (haOEt), was synthesized and characterized by analytical and spectroscopy methods. The structure of novel complex, as well as structures of its quinoline and pyridine analogues, was optimized by density functional theory calculations, and theoretical data show good agreement with experimental results. A cytotoxic action of the complexes was evaluated on cultures of human promyelocytic leukemia (HL‐60), human glioma (U251), rat glioma (C6), and mouse fibrosarcoma (L929) cell lines. Among investigated compounds, only complexes with quinoline‐based ligands reduce the cell numbers in a dose‐dependent manner in investigated cell lines. The observed cytotoxic effect of two isomeric quinoline‐based complexes is predominantly mediated through the induction of apoptotic cell death in HL‐60 cell line. The cytotoxicity of most efficient novel Pd(II) complex is comparable to the activity of cisplatin, in all cell lines investigated.