Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation.

Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.

Ineffective correction of PPARγ signaling in cystic fibrosis airway epithelial cells undergoing repair.

Peroxisome proliferator-activated receptor gamma (PPARγ) represents a potential target to treat airway mucus hypersecretion in cystic fibrosis (CF). We aimed to determine if PPARγ is altered in CF human airway epithelial cells (HAECs), if PPARγ contributes to mucin expression and HAEC differentiation, and if PPARγ ligand therapy corrects the CF phenotype. To this end, well-differentiated CF and NCF HAEC primary cultures were wounded to monitor the expression of key genes involved in PPARγ activation and mucus homeostasis, and to evaluate the effect of a PPARγ agonist, at different times of repair. Hydroxyprostaglandin dehydrogenase (HPGD) converts prostaglandin E2 to 15-keto PGE2 (15kPGE2), an endogenous PPARγ ligand. Interestingly, PPARγ and HPGD expression dramatically decreased in CF HAECs. These changes were accompanied by an increase in the expression of MUC5B. The correlation between PPARγ and MUC5B was confirmed in an airway epithelial cell line after CFTR knock-down. Exposure of HAECs to 15kPGE2 did not correct the CF phenotype but revealed a defect in the process of basal cell (BC) differentiation. The HPGD/PPARγ axis is deregulated in primary HAEC cultures from CF patients, which may impact the maturation of BCs to differentiated luminal cells. Importantly, PPARγ therapy was inefficient in correcting the CF defect.

Is it safe to leave an ECMO circuit primed?

Extracorporeal membrane oxygenation (ECMO) is a means of life support for failing patients who require extreme life-saving measures due to failure of their heart, lungs or both organs. In a patient suffering cardiac arrest, the faster circulation via cardiopulmonary resuscitation (CPR) can be instituted the better the outcome is. If an ECMO circuit needs to be built and primed it may add significant minutes to the response time. The purpose of this study is to test for any growth in primed ECMO circuits at given time intervals to prove the safety of leaving an ECMO circuit primed. This, in turn, may lead to decreased response time, with an arrest and the placement of the arresting patient on ECMO. Five ECMO circuits were set up, primed and sampled for bacterial growth at 0, 24, 48 and 72 hours and then at one-week intervals, with an end point of four weeks. No bacterial growth was found at any point during the sampling process.

Extracorporeal membrane oxygenation use in patients with traumatic brain injury.

Venovenous extracorporeal membrane oxygenation (ECMO) is used for patients with severe, potentially reversible, respiratory failure unresponsive to conventional management. It is relatively contraindicated in patients with traumatic brain injury (TBI) due to bleeding complications and use of anticoagulation. We report two cases of TBI patients treated with ECMO.

Cx26 regulates proliferation of repairing basal airway epithelial cells.

The recovery of an intact epithelium following injury is critical for restoration of lung homeostasis, a process that may be altered in cystic fibrosis (CF). In response to injury, progenitor cells in the undamaged areas migrate, proliferate and re-differentiate to regenerate an intact airway epithelium. The mechanisms regulating this regenerative response are, however, not well understood. In a model of circular wound injury of well-differentiated human airway epithelial cell (HAEC) cultures, we identified the gap junction protein Cx26 as an important regulator of cell proliferation. We report that induction of Cx26 in repairing HAECs is associated with cell proliferation. We also show that Cx26 is expressed in a population of CK14-positive basal-like cells. Cx26 silencing in immortalized cell lines using siRNA and in primary HAECs using lentiviral-transduced shRNA enhanced Ki67-labeling index and Ki67 mRNA, indicating that Cx26 acts a negative regulator of HAEC proliferation. Cx26 silencing also markedly decreased the transcription of KLF4 in immortalized HAECs. We further show that CF HAECs exhibited deregulated expression of KLF4, Ki67 and Cx26 as well enhanced rate of wound closure in the early response to injury. These results point to an altered repair process of CF HAECs characterized by rapid but desynchronized initiation of HAEC activation and proliferation.

Venoarterial extracorporeal membrane oxygenation for the management of massive amlodipine overdose.

A 50-year-old man was admitted to the intensive care unit with respiratory failure and shock after suffering a massive overdose of amlodipine, lisinopril and hydrochlorothiazide. Despite mechanical ventilation, vasopressors, calcium gluconate, hyperinsulinemia-euglycemia therapy, methylene blue and intravenous fat emulsion, the patient's respiratory and hemodynamic status deteriorated. Venoarterial extracorporeal membrane oxygenation (ECMO) was initiated to provide cardiopulmonary support in the setting of profound respiratory failure and refractory shock. The patient was placed on ECMO 19 hours after arrival to the hospital, after which vasopressor and ventilatory requirements decreased significantly. The patient was decannulated from ECMO after 8 days and was discharged home after a 56-day hospitalization. Early institution of ECMO should be considered for the management of respiratory failure and refractory shock in the setting of calcium channel blocker overdose when medical therapies are insufficient.

Extracorporeal membrane oxygenation for diffuse alveolar hemorrhage and severe hypoxemic respiratory failure from silicone embolism.

Liquid silicone is an inert material that may be used for cosmetic procedures by physicians as well as illegally by non-medical personnel. The use of silicone may result in severe complications, disfigurement, and even death. In addition, the indications for extracorporeal membrane oxygenation (ECMO) support have been increasing as a salvage therapy for a variety of life-threatening conditions. The patient is a 27-year-old woman with no significant medical conditions who developed silicone emboli, and subsequent diffuse alveolar hemorrhage after being injected with silicone in her gluteal region without medical supervision. She became profoundly hypoxemic and suffered a brief asystolic cardiac arrest in this setting. The patient was placed on veno-venous ECMO support for 14 days. Medical care during ECMO was complicated by pulmonary hemorrhage, hemothorax, pneumothorax, and blood clot, resulting in oxygenator change-out. A modified adult ECMO circuit (Jostra QuadroxD, Maquet Cardiopulmonary, Rastatt, Germany) was used to transport the patient from a nearby community affiliate hospital and then reconfigured for the medical intensive care unit on a standard HL-20 heart-lung console. Although the use of ECMO for severe hypoxemic respiratory failure has been widely reported, to our knowledge, this is the first reported successful use of ECMO for silicone embolism syndrome associated with diffuse alveolar hemorrhage and severe hypoxemic respiratory failure.

Endothelial-specific deletion of connexin40 promotes atherosclerosis by increasing CD73-dependent leukocyte adhesion.

BACKGROUND: Endothelial dysfunction is the initiating event of atherosclerosis. The expression of connexin40 (Cx40), an endothelial gap junction protein, is decreased during atherogenesis. In the present report, we sought to determine whether Cx40 contributes to the development of the disease. METHODS AND RESULTS: Mice with ubiquitous deletion of Cx40 are hypertensive, a risk factor for atherosclerosis. Consequently, we generated atherosclerosis-susceptible mice with endothelial-specific deletion of Cx40 (Cx40del mice). Cx40del mice were indeed not hypertensive. The progression of atherosclerosis was increased in Cx40del mice after 5 and 10 weeks of a high-cholesterol diet, and spontaneous lesions were observed in the aortic sinuses of young mice without such a diet. These lesions showed monocyte infiltration into the intima, increased expression of vascular cell adhesion molecule-1, and decreased expression of the ecto-enzyme CD73 in the endothelium. The proinflammatory phenotype of Cx40del mice was confirmed in another model of induced leukocyte recruitment from the lung microcirculation. Endothelial CD73 is known to induce antiadhesion signaling via the production of adenosine. We found that reducing Cx40 expression in vitro with small interfering RNA or antisense decreased CD73 expression and activity and increased leukocyte adhesion to mouse endothelial cells. These effects were reversed by an adenosine receptor agonist. CONCLUSIONS: Cx40-mediated gap junctional communication contributes to a quiescent nonactivated endothelium by propagating adenosine-evoked antiinflammatory signals between endothelial cells. Alteration in this mechanism by targeting Cx40 promotes leukocyte adhesion to the endothelium, thus accelerating atherosclerosis.

Simultaneous pulmonary embolectomy and aortic root replacement.

Massive pulmonary embolism (PE) is characterized by hypotension and cardiogenic shock due to right ventricular failure, and is associated with a high mortality rate. In this case study, we report a simultaneous pulmonary embolectomy and aortic root replacement in a 71-year-old woman with a known ascending aortic aneurysm who sustained a massive PE following a VATS left upper lobectomy for non-small cell lung cancer.

The VEPSY UPDATED Project: clinical rationale and technical approach.

More than 10 years ago, Tart (1990) described virtual reality (VR) as a technological model of consciousness offering intriguing possibilities for developing diagnostic, inductive, psychotherapeutic, and training techniques that can extend and supplement current ones. To exploit and understand this potential is the overall goal of the "Telemedicine and Portable Virtual Environment in Clinical Psychology"--VEPSY UPDATED--a European Community-funded research project (IST-2000-25323, www.cybertherapy.info). Particularly, its specific goal is the development of different PC-based virtual reality modules to be used in clinical assessment and treatment of social phobia, panic disorders, male sexual disorders, obesity, and eating disorders. The paper describes the clinical and technical rationale behind the clinical applications developed by the project. Moreover, the paper focuses its analysis on the possible role of VR in clinical psychology and how it can be used for therapeutic change.

Six-month follow-up of in-patient experiential cognitive therapy for binge eating disorders.

Treating binge eating disorders is not easy: the disordered eating is usually combined with a patient who is overweight and often obese. As underlined by the current literature, treatment outcome must focus, at a minimum, on the binge eating characterizing this disorder, on weight changes, and preferably also changes in co-morbid psychopathology. To address these issues, cognitive behavioral therapy (CBT) is still considered the best approach. However, if we check the results of follow-up studies, different authors reported some relapse in the frequency of binge eating and small weight gains over the follow-up period. This paper describes the 6-month follow-up outcome of the Experiential Cognitive Therapy (ECT), a multi factorial treatment for binge eating disorders, including virtual reality therapy. These results are compared in a randomized controlled trial (n = 36) with the ones obtained by CBT and nutritional groups only. The results showed that 77% of the ECT group quit binging after 6 months versus 56% for the CBT sample and 22% for the nutritional group sample. Moreover, the ECT sample reported better scores in most psychometric tests including EDI-2 and body image scores.

The VEPSY UPDATED project: technical and clinical rationale.

The emergence of new shared media, such as the Internet and virtual reality are changing the ways in which people relate, communicate, and live. Health care, and in particular clinical psychology, is one of the areas that could be most dramatically reshaped by these new technologies. To exploit and understand this potential is the overall goal of the "Telemedicine and Portable Virtual Environment in Clinical Psychology"--VEPSY UPDATED--an European Community funded research project (IST-2000-25323, http://www.vepsy.com) whose specific goal is the development of different PC based virtual reality modules to be used in clinical assessment and treatment. In particular the developed modules have been using to address the following pathologies: anxiety disorders; male impotence and premature ejaculation; obesity, bulimia and binge-eating disorders. The chapter details the general technical and clinical characteristics of the developed modules.

The VEPSY updated project: virtual reality in clinical psychology.

Many of us grew up with the naive assumption that couches are the best used therapeutic tools in psychotherapy. But tools for psychotherapy are evolving in a much more complex environment than a designer's chaise lounge. In particular, virtual reality (VR) devices have the potential for appearing soon in many consulting rooms. The use of VR in medicine is not a novelty. Applications of virtual environments for health care have been developed in the following areas: surgical procedures (remote surgery or telepresence, augmented or enhanced surgery, and planning and simulation of procedures before surgery); preventive medicine and patient education; medical education and training; visualization of massive medical databases; and architectural design for health care facilities. However, there is a growing recognition that VR can play an important role in clinical psychology, too. To exploit and understand this potential is the main goal of the Telemedicine and Portable Virtual Environment in Clinical Psychology--VEPSY Updated--a European Community-funded research project (IST-2000-25323, http://www.vepsy.com). The project will provide innovative tools-telemedicine and portable-for the treatment of patients, clinical trials to verify their viability, and action plans for dissemination of its results to an extended audience-potential users and influential groups. The project will also develop different personal computer (PC)-based virtual reality modules to be used in clinical assessment and treatment. In particular, the developed modules will address the following pathologies: anxiety disorders; male impotence and premature ejaculation; and obesity, bulimia, and binge-eating disorders.

Virtual reality-based multidimensional therapy for the treatment of body image disturbances in obesity: a controlled study.

The main goal of this paper is a preliminary evaluation of the efficacy of a virtual reality VR-based multidimensional approach to the treatment of body image attitudes and related constructs. The female obese patients (n = 28) involved in a residential weight control treatment, including low-calorie diet (1,200 kcal/day) and physical training, were randomly assigned either to the VR treatment or to psychonutritional groups based on the cognitive-behavior approach. Patients were administered a battery of outcome measures assessing eating disorders symptomatology, attitudes toward food, body dissatisfaction, level of anxiety, motivation for change, level of assertiveness, and general psychiatric symptoms. In the short-term, the VR treatment was more effective than the traditional cognitive-behavioral psychonutritional groups in improving the overall psychological state of the patients. In particular, it was more effective in improving body satisfaction, self-efficacy, and motivation for change. The improvement was associated with a reduction in problematic eating and social behaviors. The possibility of inducing a significant change in body image and its associated behaviors using a VR-based short-term therapy can improve body satisfaction in traditional weight reduction programs. However, given that this research that does not include a follow-up study, the obtained results are preliminary.

The contemporary surgical intensive care unit. Structure, staffing, and issues.

Modern ICUs present unique challenges to physician-administrators in the current health care environment. Several models of care (e.g., open versus closed ICUs, physician extenders in the ICU) are used throughout the country, with varying degrees of success. Although all care models may work, the ideal model for a given ICU can be found only through ongoing performance improvement.

The use of PC based VR in clinical medicine: the VREPAR projects.

Virtual reality (VR) is an emerging technology that alters the way individuals interact with computers: a 3D computer-generated environment in which a person can move about and interact as if he actually was inside it. Given to the high computational power required to create virtual environments, these are usually developed on expensive high-end workstations. However, the significant advances in PC hardware that have been made over the last three years, are making PC-based VR a possible solution for clinical assessment and therapy. VREPAR - Virtual Reality Environments for Psychoneurophysiological Assessment and Rehabilitation - are two European Community funded projects (Telematics for health - HC 1053/HC 1055 - http://www.psicologia.net) that are trying to develop a modular PC-based virtual reality system for the medical market. The paper describes the rationale of the developed modules and the preliminary results obtained.

End-of-life decision-making in the hospital: current practice and future prospects.

Chart review of patients who died in the hospital was used to describe the pattern of end-of-life decision-making and care for hospitalized dying patients and to propose a structured process of assessing the suitability of patients for palliative care. The setting was a large urban academic medical center, and the sample comprised 200 of 205 consecutive adult deaths during the first 4 months of 1996. The main outcome measures were identification of the patient as dying, do-not-resuscitate (DNR) orders, and comfort care plans. Charts of 72% of the patients had evidence that they were considered dying. DNR orders were in place for 77% of all the patients, and 46% had comfort care plans. Presence of a health care proxy was significantly associated with DNR orders and comfort care plans (P < 0.001). On average, comfort care plans were put in place 15 days after admission, as compared with an overall mean length of stay of 17 days. Substantial proportions of patients with comfort care plans continued to receive antibiotics (41%) and blood draws (30%). Only 13% of the patients on mechanical ventilation and 19% of those on artificial nutrition and hydration underwent withdrawal of these interventions prior to death. These findings suggest opportunities and challenges for improving practice patterns for hospitalized dying patients. We recommend several measurable objectives for evaluating end-of-life decision-making and care and propose the development of a goals of care assessment tool to guide appropriate transitions from life-sustaining treatment to comfort care and plan palliative services.

Virtual reality based experiential cognitive treatment of anorexia nervosa.

The treatment of a 22-year old female university student diagnosed with Anorexia Nervosa is described. In the study the Experiential Cognitive Therapy (ECT) was used: a relatively short-term, integrated, patient oriented approach that focuses on individual discovery. Main characteristic of this approach is the use of Virtual Reality, a new technology that allows the user to be immersed in a computer-generated virtual world. At the end of the in-patient treatment, the subject increased her bodily awareness joined to a reduction in her level of body dissatisfaction. Moreover, the patient presented a high degree of motivation to change. The results are discussed with regard to Vitousek, Watson and Wilson (1998, Clinical Psychology Review, 18(4), 391-420) proposal of using the Socratic Method to face denial and resistance of anorectic patients.