Lung cancer is the leading cause of cancer death. Results of therapeutic interventions are particularly discouraging when the disease is discovered in an advanced stage. Early diagnosis is limited by the fact that the disease usually develops asymptomatically and available screening methods do not fulfil the requirements for reliable discrimination between patients with lung cancer and subjects not suffering from the disease. Breath sampling is completely noninvasive and provides a potentially useful approach to screening lung cancer. Exhaled biomarkers contain both volatile and nonvolatile molecules. The profile of volatile organic compounds is different in patients with lung cancer than in control subjects. In exhaled breath condensate, the proteomic profile of breath from cancer patients differs from that of healthy smokers. We reviewed the scientific evidence demonstrating that a unique chemical signature can be detected in the breath of patients with lung cancer and that the exhaled breath biomarker profile could aid clinical decision making.KEYWORDS: Biomarker, electronic nose, exhaled breath, exhaled breath condensate, lung cancer, smell L ung cancer is the leading cause of global cancer death in both males and females. According to the most recent projection of global mortality, by 2030 it will emerge as the third and the fifth leading cause of death in highand middle-income countries, respectively [1,2]. Figures on disease outcome measures are very discouraging as even with the most advanced treatment strategies ,86% of lung cancer patients die within 5 yrs of diagnosis. With early detection and treatment, however, the 5-yr survival rate improves dramatically from 20% in patients with stage III lung cancer to 70% in patients with stage I disease [3]. Researchers, therefore, have sought out screening tests to detect lung cancer in the earliest stages and several promising new approaches have been proposed for this purpose, such as computer-assisted image analysis of chest radiographs, spiral computed tomography (CT) scanning, PCR-based assays of sputum and fluorescence bronchoscopy [4][5][6][7].Breath chemical tests have a broad spectrum of applications ranging from the US Food and Drug Administration-approved exhaled nitric oxide fraction (FeNO) measurement to monitor the effect of anti-inflammatory treatment in asthma, to volatile organic compound (VOC) determination and nonvolatile biomarker profiling in the cooled breath sample called exhaled breath condensate (EBC) [8][9][10][11]. Being completely noninvasive, sampling of the breath allows clinicians and researchers to assess different body functions in a flexible manner. Breath collection can be performed even in very severe patients and also repeated within short intervals. Therefore, breath testing is considered to be a potentially ideal candidate for screening purposes. Besides widely known constituents such as nitrogen, oxygen, carbon dioxide, inert gases and water vapour, exhaled breath also consists of thousands of volatile and nonv...

Respiratory sinus arrhythmia (RSA) is frequently employed as an intra- and interindividual index of cardiac parasympathetic tone, although the relationship of RSA to interindividual differences in cardiac vagal tone remains questionable. Our study examined between- and within-subject relations among RSA, cardiac vagal tone, and respiratory parameters. Twenty-nine young adults performed two sessions of tasks under no medication and single and double autonomic blockade (intravenously administered propranolol and atropine). Parasympathetic tone was determined from heart period responses to complete vagal blockade. Results indicated the following. Resting RSA does not accurately predict individual differences in cardiac vagal tone. However, RSA and heart period together do predict such individual differences reasonably well. The relationship between individual variations in RSA and vagal tone is not improved by controlling respiratory parameters. Substantial cardiac vagal activity occurs during inspiration, and intraindividual variations in respiratory measures confound the association between RSA and cardiac vagal tone.

Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here, we report that the gender-specific inflammatory response is preferentially down-regulated by PARP in male animals. Female mice produce less tumor necrosis factor-␣ and macrophage inflammatory protein-1␣ in response to systemic inflammation induced by endotoxin than male mice and are resistant to endotoxin-induced mortality. Pharmacological inhibition of PARP is effective in reducing inflammatory mediator production and mortality in male, but not in female, mice. Ovariectomy partially reverses the protection seen in female mice. Endotoxin-induced PARP activation in circulating leukocytes is reduced in male, but not female, animals by pharmacological PARP inhibition, as shown by flow cytometry. Pretreatment of male mice with 17-␤-estradiol prevents endotoxin-induced hepatic injury and reduces poly(ADPribosyl)ation in vivo. In male, but not female, animals, endotoxin induces an impairment of the endothelium-dependent relaxant responses, which is prevented by PARP inhibition. In vitro oxidant-induced PARP activation is reduced in cultured cells placed in female rat serum compared with male serum. Estrogen does not directly inhibit the enzymatic activity of PARP in vitro. However, PARP and estrogen receptor ␣ form a complex, which binds to DNA in vitro, and the DNA binding of this complex is enhanced by estrogen. Thus, estrogen may anchor PARP to estrogen receptor ␣ and to the DNA and prevent its recognition of DNA strand breaks and hence its activation. In conclusion, the gender difference in the inflammatory response shows preferential modulation by PARP in male animals.

Aging is associated with profound changes in the structure and function of the heart. A fundamental understanding of these processes, using relevant animal models, is required for effective prevention and treatment of cardiovascular disease in the elderly. Here, we studied cardiac performance in 4-to 5-mo-old (young) and 24-to 26-mo-old (old) Fischer 344 male rats using the Millar pressurevolume (P-V) conductance catheter system. We evaluated systolic and diastolic function in vivo at different preloads, including preload recruitable stroke work (PRSW), maximal slope of the systolic pressure increment (+dP/dt), and its relation to end-diastolic volume (+dP/dt-EDV) as well as the time constant of left ventricular pressure decay, as an index of relaxation. The slope of the enddiastolic P-V relation (EDPVR), an index of left ventricular stiffness, was also calculated. Aging was associated with decrease in left ventricular systolic pressure, +dP/dt, maximal slope of the diastolic pressure decrement, +dP/dt-EDV, PRSW, ejection fraction, stroke volume, cardiac and stroke work indexes, and efficiency. In contrast, total peripheral resistance, left ventricular enddiastolic volume, left ventricular end-diastolic pressure, and EDPVR were greater in aging than in young animals. Taken together, these data suggest that advanced aging is characterized by decreased systolic performance accompanied by delayed relaxation and increased diastolic stiffness of the heart in male Fischer 344 rats. P-V analysis is a sensitive method to determine cardiac function in rats. Keywords systolic dysfunction; diastolic dysfunctionIn the absence of obvious disease, the major anatomic changes seen in the aging human heart are primarily an increase in ventricular wall thickness, myocardial fibrosis, and valvular fibrocalcification, which lead to reduced ventricular compliance (26). In addition, loss of Address for reprint requests and other correspondence: P. Pacher, National Institute on Alcohol Abuse and Alcoholism, 12420 Parklawn Dr., MSC-8115, Bethesda, MD 20892-8115 (pacher@mail.nih.gov arterial elasticity produces a widening of arterial pulse pressure and reduction of the diastolic pressure that largely determines coronary artery perfusion. Aging also imposes a ceiling on maximal cardiac output (CO) that reflects both reduced maximal heart rate (HR) and the agerelated prolongation of time required for both myocardial contraction and relaxation (25,26). In a variety of mammals, including dogs and rodents, aging is also associated with hypertrophy, dilatation, and fibrosis of the left ventricle (LV) (1)(2)(3)(5)(6)(7)(8)(9)(10)(11)21,25,(37)(38)(39). A fundamental understanding of these processes, using relevant animal models, is required for more effective prevention and treatment of cardiovascular disease in the elderly. The Fischer 344 (F344) rat, developed by the National Institute on Aging, is an inbred rat model that is commonly used for aging studies. It has a longer lifespan, smaller body size, and lower spontaneous tumor rat...

Background-Cardiovagal autonomic control declines with age in adult subjects, which is related in part to increasing stiffness of the barosensory vessel wall. It is not known, however, whether autonomic function changes with age in children. Methods and Results-We studied 137 healthy subjects divided into 4 age groups: group 1, 7 to 14 years; group 2, 11 to 14 years; group 3, 15 to 18 years; and group 4, 19 to 22 years. Brachial artery pressure was measured by sphygmomanometry and continuous radial artery pressure and carotid artery pulse pressure (⌬P) by applanation tonometry. The R-R interval was derived from the ECG. Autonomic function was assessed by spontaneous sequence and frequency-domain indices, which indicate the extent of coupling between fluctuations in heart rate and systolic pressure. Carotid artery diastolic diameter (DD) and pulsatile distension (⌬D) were measured by echo wall tracking; carotid compliance coefficient (CC) was defined as ⌬D/⌬P and distensibility coefficient as 2⌬D/DD · ⌬P. , with no significant changes afterward. CC and DC were inversely proportional to age (rϭϪ0.49 and Ϫ0.62, respectively, PϽ0.001). The efficiency of neural integrative mechanisms, estimated as the ratio of spontaneous indices and CC, more than doubled from group 1 to group 3. Spontaneous indices were linearly related to measures of cardiac vagal activity. Conclusions-The increase in spontaneous indices from early childhood to adolescence, despite gradual stiffening of the carotid artery, may indicate improved cardiovagal autonomic function, which is most likely a result of maturation of neural mechanisms, attaining peak level at adolescence.