Combined suicide and cytokine gene therapy for peritoneal carcinomatosis

BACKGROUND: Gene therapy is a novel approach for the treatment of cancers, and tumours disseminated in the peritoneal cavity are suitable for in situ delivery of a therapeutic gene. AIMS: The efficacy of a therapy combining a suicide gene (herpes simplex virus type I thymidine kinase (HSV-TK)) and cytokine genes was investigated in a model of peritoneal carcinomatosis induced by colon carcinoma cells in syngeneic rats. MATERIAL AND METHODS: Pre-established macroscopic tumours in BDIX rats were treated by intraperitoneal injections of retrovirus producing cells (FLYA13 TK, FLYA13 granulocyte macrophage-colony stimulating factor (GM-CSF), FLYA13 interleukin 12 (IL-12)) and ganciclovir (GCV). RESULTS: TK/GCV treated animals showed a slight increase in survival time (72 days) compared with the control group (63 days) while the association of cytokine and TK/GCV gene therapy resulted in significantly improved survival, with a large proportion of animals remaining tumour free on day 480 (60% and 40% for TK/GCV/GM-CSF and TK/GCV/IL-12 treated animals, respectively). Histological analysis of treated animals showed that the remaining tumour nodes were infiltrated by mononuclear cells but no major differences were observed between the various treatments. Immunohistochemical analysis revealed that lymphoid CD4(+) and CD8(+) T cells as well as macrophages accumulated outside untreated tumour nodes while CD8(+) and CD25(+) activated T cells and macrophages heavily infiltrated the tumours after the different treatments. CONCLUSIONS: Our data indicate that combined suicide and cytokine gene therapy is a powerful approach for the treatment of macroscopic peritoneal carcinomatosis.     

Wire fractures in Solysafe septal occluders: a single center experience

Objectives : To determine the incidence of device fractures (DF) after implantation of a Solysafe® Septal Occluder (iSSO) and to assess the spectrum of associated problems. Background : In August 2010, after initial unpublished reports on DF, the manufacturer issued an “urgent field safety notice,” prompting all medical care providers to re‐examine all patients after iSSO. Methods : Prospective single center study. Extended follow‐up examination, including standardized fluoroscopy (sF), was performed in all patients after iSSO. Results : A total of 111 patients had undergone iSSO at our institution between June 2005 and July 2010. Median age and body weight were 50 years (9.3–79.6) and 75 kg (29–122), respectively. Indications for iSSO were (1) patent foramen ovale in patients with a history of cryptogenic stroke (n = 84; 76%) and (2) hemodynamically significant atrial septal defect of the secundum type (n = 27; 24%). A total of 113 devices were implanted. Complete follow‐up was available in 103 patients (92.8%). Median follow‐up was 1.9 years (0–5.2). There were no postimplantation neurological events or symptoms. The closure rate was 97.1%. DF was suspected on a chest X‐ray in one patient and documented in 10 patients by sF. The overall probability of freedom from DF was 82.3% after 5 years. One patient had embolization of a device fragment to the right pulmonary artery. So far, all patients with DF have been managed conservatively. Conclusions : The incidence of DF after iSSO is unacceptably high. sF is imperative for accurate diagnosis of DF. Further, follow‐up is needed to determine the risk of clinical complications and to optimize management. © 2012 Wiley Periodicals, Inc.     

Solute diffusion is hindered in the mitochondrial matrix

Intracellular chemical reactions generally constitute reaction-diffusion systems located inside nanostructured compartments like the cytosol, nucleus, endoplasmic reticulum, Golgi, and mitochondrion. Understanding the properties of such systems requires quantitative information about solute diffusion. Here we present a novel approach that allows determination of the solvent-dependent solute diffusion constant (D(solvent)) inside cell compartments with an experimentally quantifiable nanostructure. In essence, our method consists of the matching of synthetic fluorescence recovery after photobleaching (FRAP) curves, generated by a mathematical model with a realistic nanostructure, and experimental FRAP data. As a proof of principle, we assessed D(solvent) of a monomeric fluorescent protein (AcGFP1) and its tandem fusion (AcGFP1(2)) in the mitochondrial matrix of HEK293 cells. Our results demonstrate that diffusion of both proteins is substantially slowed by barriers in the mitochondrial matrix (cristae), suggesting that cells can control the dynamics of biochemical reactions in this compartment by modifying its nanostructure.     

Exercise training in coronary artery disease and coronary vasomotion

Exercise training has assumed a major role in cardiac rehabilitation, mostly because of its positive effects on myocardial perfusion in patients with coronary artery disease. The mechanisms involved in mediating this key effect have long been debated: both regression of coronary artery stenosis and improvement of collateralization have been suggested as potential adaptations. However, the comparatively minute changes in luminal diameter and myocardial contrast staining do not fully explain the significant changes in myocardial perfusion. During the last decade, endothelial dysfunction was identified as a trigger of myocardial ischemia. The impaired production of endothelium-derived nitric oxide (NO) in response to acetylcholine and flow leads to paradoxic vasoconstriction and exercise-induced ischemia. Recently, it was confirmed in humans that training attenuates paradoxic vasoconstriction in coronary artery disease and increases coronary blood flow in response to acetylcholine. Data from cell-culture and animal experiments suggest that shear stress acts as a stimulus for the endothelium to increase the transport capacity for L-arginine (the precursor molecule for NO), to enhance NO synthase activity and expression, and to increase the production of extracellular superoxide dismutase, which prevents premature breakdown of NO. Exercise also affects the microcirculation, where it sensitizes resistance arteries for the vasodilatory effects of adenosine. These novel findings provide a pathophysiological framework to explain the improvement of myocardial perfusion in the absence of changes in baseline coronary artery diameter. Because endothelial dysfunction has been identified as a predictor of coronary events, exercise may contribute to the long-term reduction of cardiovascular morbidity and mortality.     

Promoting Condom Use With Main Partners: A Behavioral Intervention Trial for Women

The Stages of Change (SOC) model was used to implement and evaluate a condom promotion intervention for HIV-positive and at-risk women who were recruited from clinic and community settings in Baltimore and Philadelphia. Participants were assigned to receive standard reproductive health services or enhanced services (standard plus SOC peer advocate intervention). Women who had a main partner at baseline and at a 6-month follow-up were included in the analysis (70 HIV positive, 471 at risk). Compared with the standard group, HIV-positive women in the enhanced group were significantly more likely to have progressed in the SOC model or to have maintained consistent condom use, and less likely to have relapsed or stayed in the precontemplation stage. Among the at-risk women, exposure to the intervention was associated with being at a higher SOC and being less likely to relapse relative to the standard group. The SOC model has promise for use in social and public health service settings that serve women at risk or living with HIV.     

Aging and heart failure--similar syndromes of exercise intolerance? Implications for exercise-based interventions

A classic hallmark of chronic heart failure (CHF) is exercise intolerance; however, the extent of exercise limitation is not correlated with the degree of left ventricular dysfunction. Over the past 2 decades it has become more and more evident that peripheral factors, such as skeletal muscle dysfunction, ventilatory abnormalities, and endothelial dysfunction, contribute the greater part to the limitation of exercise capacity. The molecular and pathophysiological changes observed in these organ systems are not always specific to the underlying CHF but rather represent a common pathway that is activated in several chronic disease processes, including severe chronic obstructive pulmonary disease, cancer, and in the normal aging process. A major contributing factor for skeletal muscle catabolism (i.e. elevated cytokine expression in the skeletal muscle) can be found in both normal healthy aging and in heart failure patients. It is reasonable to assume that the overlap of aging and CHF-associated changes in the skeletal muscle partially explains the disabling consequences of the CHF syndrome among elderly patients (nearly 80% of all patients hospitalized for CHF are >65 years old). Peripheral alterations in CHF are often not adequately treated in routine clinical care since standard pharmacological therapy is still focused on the cardiac function and neurohormonal alteration. Exercise training is a guideline-oriented adjuvant therapy with well-documented beneficial effects on exercise tolerance, skeletal muscle function, endothelial function, and respiration. In this review, the effects of exercise in aging and in CHF are compared and the parallel mechanisms are explored.     

Kommentar zu den Leitlinien der Europ?ischen Gesellschaft für Kardiologie (ESC) zur Diagnostik und Therapie des akuten Koronarsyndroms ohne persistierende ST-Streckenhebung

Non-ST-elevation acute coronary syndromes (NSTE-ACS) comprise a wide spectrum of disease severities and mortality risks. Next to establishing the diagnosis, clinical management therefore also requires risk stratification in order to adequately select the intensity and urgency of further work-up and treatment. In September 2011 updated recommendations for the management of patients with NSTE-ACS were published by the European Society of Cardiology. Major innovations included the use of highly sensitive troponin assays, including the resulting possibility of establishing a fast-track protocol, the routine recommendation of echocardiography in all patients and the introduction of coronary computed tomography (CT) angiography as a possibility to rule out coronary disease in selected individuals. The importance of risk stratification is emphasized throughout the document and routine use of the GRACE risk score as well as the CRUSADE bleeding risk score is encouraged. The recommendations reflect the availability of new antithrombotic agents and new timelines for invasive work-up are introduced. This comment in German summarizes the ESC guidelines and highlights relevant amendments as compared to the previous version.     

Inhomogeneous activation of motoneurone pools as revealed by co-contraction of antagonistic human arm muscles

Summary Perceived motion may be a stimulus for anticipatory slow eye movements. To test this possibility, the production of anticipatory slow eye movements in humans was studied using apparent motion stimuli. Short range apparent motion was produced with random dot stimuli and the anticipatory slow eye movements were isolated from the smooth pursuit responses by occasionally including trials in which the random dot stimulus did not appear. Long range apparent motion was produced with subjective contour stimuli. Both short range and long range apparent motion were found to be effective stimuli for anticipatory slow eye movements. The prominence of perceived motion was altered by changing the spatiotemporal displacement intervals in the short range apparent motion stimuli. Changing the subjective contours also changed the motion percepts of the long range apparent motion stimuli. With both stimuli, the peak anticipatory slow eye velocities that were achieved decreased as the prominence of the motion percepts decreased, while the timecourse of the anticipatory responses were similar under the different conditions. These findings indicate that the expectation of perceived motion is necessary for anticipatory slow eye movements.Supported by research grant EY03387 from the National Eye Institute     

A model for the peripheral auditory nervous system of the grassfrog

A model is presented which incorporates several data from the literature on isolated parts of the peripheral auditory nervous system into a coherent model. The usefulness of the model lies in the fact that it describes the functional properties of eighth nerve fibres and dorsal medullary nucleus neurons in response to monaural stimuli. The components are: a middle ear filter, transduction and tuning of the haircell, short-term adaptation, event generation with refractory properties, and coincidence detection. In a previous paper [Van Stokkum (1987), Hear. Res. 29, 223-235] a class of dorsal medullary nucleus neurons was described, which preferred fast intensity changes. Using a coincidence detection mechanism the proposed model reproduces the same preference. Variation of the parameters of the model successfully reproduces the range of response patterns which have been obtained from eighth nerve fibres and dorsal medullary nucleus neurons. With one set of parameters the output of the model in response to a set of spectrally and temporally structured stimuli qualitatively resembles the response of a single neuron. In this way the responses to the different stimuli are synthesized into a framework, which functionally describes the neuron.