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Aims Elevated sympathetic outflow is associated with primary hypertension. However, the mechanisms involved in heightened sympathetic outflow in hypertension are unclear. The central amygdala (CeA) regulates autonomic components of emotions through projections to the brainstem. The neuronal Kv7 channel is a non-inactivating voltage-dependent K+ channel encoded by KCNQ2/3 genes involved in stabilizing the neuronal membrane potential and regulating neuronal excitability. In this study, we investigated if altered Kv7 channel activity in the CeA contributes to heightened sympathetic outflow in hypertension. Methods and results The mRNA and protein expression levels of Kv7.2/Kv7.3 in the CeA were significantly reduced in spontaneously hypertensive rats (SHRs) compared with Wistar-Kyoto (WKY) rats. Lowering blood pressure with celiac ganglionectomy in SHRs did not alter Kv7.2 and Kv7.3 channel expression levels in the CeA. Fluospheres were injected into the rostral ventrolateral medulla (RVLM) to retrogradely label CeA neurons projecting to the RVLM (CeA-RVLM neurons). Kv7 channel currents recorded from CeA-RVLM neurons in brain slices were much smaller in SHRs than in WKY rats. Furthermore, the basal firing activity of CeA-RVLM neurons was significantly greater in SHRs than in WKY rats. Bath application of specific Kv7 channel blocker 10, 10-bis (4-pyridinylmethyl)-9(10H)-anthracnose (XE-991) increased the excitability of CeA-RVLM neurons in WKY rats, but not in SHRs. Microinjection of XE-991 into the CeA increased arterial blood pressure (ABP) and renal sympathetic nerve activity (RSNA), while microinjection of Kv7 channel opener QO-58 decreased ABP and RSNA, in anesthetized WKY rats but not SHRs. Conclusions Our findings suggest that diminished Kv7 channel activity in the CeA contributes to elevated sympathetic outflow in primary hypertension. This novel information provides new mechanistic insight into the pathogenesis of neurogenic hypertension. Translational perspective This study reveals a novel mechanistic insight into the pathogenesis of primary hypertension and provides a rationale to develop therapeutic strategies targeting Kv7 channels in the amygdala for treating hypertension. Viral vector-mediated overexpression of Kv7 channels in the amygdala is a potential approach to decrease blood pressure and inhibit sympathetic outflow in hypertension. However, this approach is not feasible to apply to hypertension patients at the current stage. Further studies to determine the molecular mechanism underlying downregulation of Kv7 channels may identify agents that increase expression levels of Kv7 channels in hypertension.

Background Continuous infusion of doxorubicin or dexrazoxane pre-treatment prior to bolus doxorubicin are proven strategies to protect against doxorubicin-induced cardiotoxicity. Recently, global longitudinal peak systolic strain (GLS) measured with speckle tracking echocardiography (STE) and high-sensitivity troponin T (hs-TnT) have been validated as sensitive indicators of doxorubicin-induced cardiotoxicity. Here, we asked whether changes in hs-TnT and/or GLS can be detected in patients who were treated with continuous infusion of doxorubicin or pre-treated with dexrazoxane followed by bolus doxorubicin. Methods Twenty-nine patients with newly diagnosed sarcoma were assigned to receive either 72-h doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. Eight patients received dexrazoxane pre-treatment; eleven patients received continuous doxorubicin infusion; ten patients crossed over from continuous infusion to dexrazoxane. Bloods were collected for hs-TnT at baseline, 24 h or 72 h after initiation of doxorubicin treatment in each chemotherapy cycle. All blood samples were assayed in batch using hs-TnT kit from Roche diagnostics. 2D Echo and STE were performed before doxorubicin, after cycle 3, and at the end of chemotherapy. Results Seven patients in the cross-over group have at least one hs-TnT measurement between 5 ng/L to 10 ng/L during and after chemotherapy. Ten patients have at least one hs-TnT measurement above 10 ng/ml during and after chemotherapy (six in dexrazoxane group, three in continuous infusion group, one in cross-over group). The average hs-TnT level increases with each additional cycle of doxorubicin treatment. Eight patients had a more than 5% reduction in LVEF at the end of chemotherapy (four in dexrazoxane group, three in continuous infusion group, and one in cross-over group). Four out of these eight patients had a change of GLS by more than 15% (three in the dexrazoxane group). Conclusion Elevation in hs-TnT levels were observed in more than 59% of patients who had received either continuous doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. However, changes in LVEF and GLS were less frequently observed. Thus, continuous doxorubicin infusion or dexrazoxane pre-treatment do not completely ameliorate subclinical doxorubicin-induced cardiotoxicity as detected by more sensitive techniques.

In this second part of a 2-part review, we will review cancer or cancer therapy–associated systemic and pulmonary hypertension, QT prolongation, arrhythmias, pericardial disease, and radiation-induced cardiotoxicity. This review is based on a MEDLINE search of published data, published clinical guidelines, and best practices in major cancer centers. Newly developed targeted therapy can exert off-target effects causing hypertension, thromboembolism, QT prolongation, and atrial fibrillation. Radiation therapy often accelerates atherosclerosis. Furthermore, radiation can damage the heart valves, the conduction system, and pericardium, which may take years to manifest clinically. Management of pericardial disease in cancer patients also posed clinical challenges. This review highlights the unique opportunity of caring for cancer patients with heart problems caused by cancer or cancer therapy. It is an invitation to action for cardiologists to become familiar with this emerging subspecialty.

Session II of the Second International Colloquium on Cardio-Oncology, chaired by Dr Breccia (Rome, Italy) and Dr Jurczak (Krakow, Poland), focused on mechanisms and clinical course of cardiovascular toxicity of cancer treatment. Whereas the venerable anthracyclines keep challenging patients and clinicians with risk of left ventricular dysfunction and heart failure, other newer drugs cause substantially different clinical phenotypes of cardiovascular toxicity. In particular, Session II not only focused on arterial thrombosis and venous thromboembolism, but also hypertension or cardiomyopathy or atrial fibrillation induced by many otherwise life-saving drugs. Dr Breccia (Rome, Italy) reviewed incidence, mechanisms, risk factors, and principles for prevention of cardiovascular events induced by tyrosine kinase inhibitors of hematologic interest, such as those used to treat chronic myeloid leukemia. Dr Carver (Philadelphia) reviewed the incidence, predisposing factors, and principles for proactive management of cardiovascular events in patients treated by conventional chemotherapy or new drugs for treatment of multiple myeloma. Dr Szmit (Warsaw, Poland) discussed on how coagulation disorders should be classified according to patient- or drug-related factors and how they should be diagnosed and treated in patients with solid or hematologic tumors. Dr Minotti (Rome. Italy) illustrated some potential pitfalls of accelerated drug development and approval and their possible impact on clinical incidence of cardiovascular events induced by tyrosine kinase inhibitors of hematologic interest. Session II therefore offered a broad perspective of the risk-benefit ratio of new drugs that are plagued with concerns about cardiovascular events.

INTRODUCTION Approximately 50% of patients with sepsis-induced acute lung injury and acute respiratory distress syndrome require mechanical ventilation. Patients with extended mechanical ventilator use routinely develop reinfections, which increases hospital stay, mortality, and health care cost. Some studies have pointed out inflammatory factors concentrations can affect ventilator weaning, but do not indicate changed inflammatory factors related to ventilator weaning during using ventilators. OBJECTIVES This study aimed to investigate during period of septic patients using ventilators, the inflammatory cytokines concentrations related with weaning rate. METHODS Blood was collected from 35 septic patients before and during ventilator use on days 1, 7, 14, and 21 (or weaning). RESULTS 58.3% (N = 20) of septic patients with mechanical ventilators were weaned successfully within 21 days (ventilator weaned group, VW), 16.7% (N = 6) did not wean within 21 days (ventilator dependent group, VD), and 25% died (death group) in hospital. Before ventilator use, higher C-reactive protein (CRP), IL-6, and IL-8 levels were measured in the death group than in all other groups (P

Importance Oncocardiology is a medical discipline that focuses on the identification, prevention, and treatment of cardiovascular complications related to cancer therapy. This discipline has gained interest from the cardiology community in recent years because of a remarkable increase in the number of cancer survivors and the proliferation of new cancer therapies causing cardiovascular complications, such as hypertension, heart failure, vascular complications, and cardiac arrhythmia. In this review, we provide historical perspectives, highlight new discoveries, and speculate on the opportunity created by merging the research interests and clinical practices of cardiology and oncology. Observations The old paradigm of anthracycline cardiotoxic effects is replaced by new insights that anthracycline targets topoisomerase II β to cause DNA double-strand breaks and a profound change in the transcriptome leading to the generation of reactive oxygen species and the development of mitochondriopathy. Prevention of anthracycline cardiotoxic effects should be based on inhibiting or degrading topoisomerase II β. New challenges were posed by the introduction of trastuzumab and tyrosine kinase inhibitors that revolutionized cancer therapy. The on-target cardiotoxic effects of trastuzumab were owing to a prosurvival benefit of Her2 that binds to neuregulin, whereas the off-target effect of multitargeted tyrosine kinase inhibitors may be mediated by disruption of the vascular endothelial growth factor signaling pathway or the stress-induced angiogenesis. Sensitive imaging techniques, such as global strain, and biomarkers have allowed for early detection of cardiotoxic effects. Early treatment with heart failure medications may be beneficial in preventing the development of late cardiotoxic effects. Conclusions and Relevance Close collaboration between cardiologists and oncologists is required to meet the demand of an increasing number of cancer survivors. New insights based on mechanistic studies or genetic discoveries will pave the way for better prevention, diagnosis, and treatment of cancer therapy-induced cardiovascular complications.

Pain is a major presenting symptom in patients with rheumatic diseases. It is difficult, however, to define pain precisely because there are both objective and subjective components to the experience of pain. Thus, patients with the same degree of tissue inflammation may experience different levels of pain. The variation in individual pain experience often presents us with a diagnostic and therapeutic dilemma. Pain management, therefore, must be based on a solid understanding of the pathophysiology of pain and on a careful review of the risks, benefits, cost, and efficacy of available treatments.

Pain is the most common reason patients seek medical care. While pain may be a symptom of an underlying disease or injury, pain can also become a persistent symptom of an autonomous neurophysiological process constituting a unique neurobiological disorder. It has been demonstrated that all forms of pain, including acute, chronic, and that associated with terminal illness, are often poorly managed with consequent needless suffering, functional impairment and disability. The American Academy of Pain Medicine, in its position …

Cancer is the second leading cause of death in the United States. About 1.2 million new cancer cases were diagnosed in 1998. One out of every four deaths, approximately half a million people, will be the result of cancer in 1999. Pain is often inadequately treated in patients with cancer. Sixty-seven percent of outpatients with metastatic cancer have pain, and 36% of these patients have pain severe enough to impair their ability to function. 6 Sixty percent of terminally ill cancer patients suffer from pain. 11 Eighty-six percent of practicing physicians surveyed believed that the majority of cancer patients with pain were undermedicated. 32 On a global scale, the World Health Organization Cancer Pain Relief Program reported that approximately 5 million people worldwide experience cancer pain on a daily basis, with 25% of them dying without relief from severe pain. Cancer pain can be controlled through relatively simple means in most patients. Unrelieved pain can lessen the patients' activity, function, appetite, and sleep. It can also induce fear and increase suffering in patients with cancer. Chronic unrelieved pain depresses patients and increases the risk of suicide. In addition to playing a major role in the quality of care for cancer patients at the end of their life, pain management is also vital to cancer survivors and patients with stable disease status. Although they have survived the disease, patients may have chronic pain from disease or therapy. Adequate pain control is important to ensure that patients are able to function productively, maintain social relationships, and improve their quality of life. The most recent report on cancer incidence and mortality showed the first decline after nearly 20 years of a steady increase 35 ; thus, pain control in cancer survivors and patients with stable disease is an important part of the total care of cancer patients. The majority of cancer pain can be controlled with oral pharmacologic management. Both physicians and patients should understand that the long-term use of opioids for pain relief is different from substance abuse. Studies have shown that the number of individuals who become addicted to drugs by introducing them through medical use is extremely small. 24 Clinicians should assess patients and, if pain is present, provide them with optimal relief throughout the course of illness. The treatment plan should include patient and family education about pain and its management and encourage patients to be active participants in pain management. 7 Comprehensive management of cancer patients with pain is best accomplished through interdisciplinary coordination. Whenever possible, the primary care physician should coordinate the services of medical, surgical, and radiation oncologists; pain specialists; psychologists; psychiatrists; physical therapists; social workers; nurses; and hospice workers.

Since 1997, the Institute of Medicine of the National Academy of Sciences has released two reports regarding the need to provide more educational programs that stress the importance of end-of-life care and that train clinicians to provide such care [1,2]. The Summary and Recommendations for Improving Palliative Care for Cancer, released by the Institute of Medicine in 2001, listed “inadequate training of health care personnel in symptom management and other palliative care skills” as a barrier to ensure excellent palliative and end-of-life care [2]. Pain is a common symptom of patients with cancer, and pain control is an important clinical goal for this patient group as well as for patients with nonmalignant diseases. All patients expect reliable skillful care from their physicians when experiencing pain and approaching death. The Joint Commission on Accreditation of Healthcare Organizations ( JCAHO) first established pain management standards for all hospitals in 2001. These standards require all physicians to assess and manage pain for all patients. However, pain medicine and palliative care are not a part of the required curriculum at most of the United State's medical schools. Billings et al. [3] reviewed articles, and Barzansky et al. [4] reviewed the Liaison Committee on Medical Education (LCME) and Association of American Medical Colleges (AAMC) Annual Medical School Questionnaires regarding medical education … Reprint requests to: Hui-Ming Chang, MD, MPH, Department of Palliative Care and Rehabilitation, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard Box 8, Houston, TX 77030. Tel: (713) 500-3559; Fax: (713) 500-0336; E-mail: Hui-Ming.Chang{at}uth.tmc.edu.