Non-Natural Death Associated with Sexual Activity: Results of a 25-Year Medicolegal Postmortem Study.

INTRODUCTION: Non-natural deaths associated with sexual activity may occur either with or without the involvement of other persons. AIM: The present study provides an overview of cases of non-natural death related to sexual activities as well as recommendations of how to handle these cases and to identify potentially dangerous pleasure-enhancing techniques. METHODS: This medicolegal, postmortem, retrospective, and prospective study is based on data of autopsies performed at the Institute of Legal Medicine at University Hospital, Goethe University, Frankfurt, Germany. MAIN OUTCOME MEASURE: Identification of circumstances, sexual practices, and gender distribution of cases of non-natural death in this context. RESULTS: Between 1993 and 2017 (25 years), 16,437 medicolegal autopsies were performed, of which 74 cases (43 males, 31 females) of non-natural death were found to relate to sexual activities (0.45%). One female and 21 males had died in the course of autoerotic practices (group I, n = 22). Nine males and 14 females had performed sexual practices with mutual consent (group II, n = 23), and 13 males and 16 females without mutual consent (group III, n = 29). The average age in group I was 45.4 years; in group II, 40.6 years; and in group III, 39.2 years. Most of the deceased were found in their own apartments. Forms of stimulation included vaginal, anal, and oral intercourse; insertion of foreign bodies; use of chemical substances; and tools for respiratory depression/hypoxia. Three cases of death occurred during sexual activities involving bondage and discipline, sadism, and masochism (BDSM). Death due to strangulation was the main cause in group I, whereas intoxications were predominant in group II. Sharp force (eg, knife) was mainly responsible for death in group III. Anogenital injuries were documented in all groups in approximately equal percentages. CLINICAL IMPLICATIONS: The cases presented show a high variety of circumstances in which non-natural death connected to sexual activity may occur. STRENGTHS & LIMITATIONS: This study presents a large postmortem collection of non-natural death cases with associated sexual activity. As the main limiting factor, it must be stated that mutual consent for a sexual practice or consumption of substances was presumed based on the information provided and a lack of evidence against this assumption. CONCLUSION: In cases of death associated with sexual activity, medical staff should perform thorough unbiased examinations and documentations. Strangulation and the consumption of stimulants should be classified as life-threatening, pleasure-enhancing techniques. Patients and young people should be informed about these risks. Bunzel L, Koelzer SC, Zedler B, et al. Non-Natural Death Associated with Sexual Activity: Results of a 25-Year Medicolegal Postmortem Study. J Sex Med 2019;16:1547-1556.

Validation of an administrative claims coding algorithm for serious opioid overdose: A medical chart review.

PURPOSE: A standardized definition for serious opioid overdose has not been clearly established for disease surveillance or assessing the impact of risk mitigation strategies. The purpose of this study was to use medical chart review to clinically validate a claims-based algorithm to identify serious opioid overdose events. METHODS: The algorithm for serious opioid overdose required an opioid poisoning or external cause ICD-9-CM code occurring within 1 day of (a) an adverse effect code for serious central nervous system or respiratory depression or (b) a mechanical ventilation or critical care CPT code. The claims coding algorithm identified a sample of 145 individuals 18 years or older among patients that presented to the emergency department of two large hospitals in metropolitan Atlanta, Georgia from January 2014 to August 2015. Claims-defined cases were evaluated against rigorous clinical definitions for serious opioid overdose using (a) literature-based criteria for typical clinical manifestations of opioid overdose and/or (b) clinical response to the opioid-specific reversal agent naloxone. The positive predictive value (PPV) for a serious opioid overdose was calculated as the percentage of clinically confirmed cases (definite or probable). RESULTS: Among 140 evaluable claims-defined cases, 107 fulfilled clinical criteria for a serious opioid overdose [95 definite and 12 probable; PPV of 76.4% (95% CI 69.4%, 83.5%)]. Among 30 nonconfirmed cases, 20 were polyintoxications involving one or more nonopioid psychoactive agents. CONCLUSIONS: An administrative claims coding algorithm for serious opioid overdose had high clinical predictive performance in a medical chart review.

Risk Factors for Serious Prescription Opioid-Induced Respiratory Depression or Overdose: Comparison of Commercially Insured and Veterans Health Affairs Populations.

Objective: To characterize the risk factors associated with overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids in a commercially insured population (CIP) and to compare risk factor profiles between the CIP and Veterans Health Administration (VHA) population. Subjects and Methods: Analysis of data from 18,365,497 patients in the IMS PharMetrics Plus health plan claims database (CIP) who were dispensed a prescription opioid in 2009 to 2013. Baseline factors associated with an event of serious OIRD among 7,234 cases and 28,932 controls were identified using multivariable logistic regression. The CIP risk factor profile was compared with that from a corresponding logistic regression among 817 VHA cases and 8,170 controls in 2010 to 2012. Results: The strongest associations with serious OIRD in CIP were diagnosed substance use disorder (odds ratio [OR] = 10.20, 95% confidence interval [CI] = 9.06-11.40) and depression (OR = 3.12, 95% CI = 2.84-3.42). Other strongly associated factors included other mental health disorders; impaired liver, renal, vascular, and pulmonary function; prescribed fentanyl, methadone, and morphine; higher daily opioid doses; and concurrent psychoactive medications. These risk factors, except depression, vascular disease, and specific opioids, largely aligned with VHA despite CIP being substantially younger, including more females and less chronic disease, and having greater prescribing prevalence of higher daily opioid doses, specific opioids, and most selected nonopioids. Conclusions: Risk factor profiles for serious OIRD among US medical users of prescription opioids with private or public health insurance were largely concordant despite substantial differences between the populations in demographics, clinical conditions, health care delivery systems, and clinical practices.

Validation of a Screening Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in a US Commercial Health Plan Claims Database.

Objective: To validate a risk index that estimates the likelihood of overdose or serious opioid-induced respiratory depression (OIRD) among medical users of prescription opioids. Subjects and Methods: A case-control analysis of 18,365,497 patients with an opioid prescription from 2009 to 2013 in the IMS PharMetrics Plus commercially insured health plan claims database (CIP). An OIRD event occurred in 7,234 cases. Four controls were selected per case. Validity of the Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (RIOSORD), developed previously using Veterans Health Administration (VHA) patient data, was assessed. Multivariable logistic regression was used within the CIP study population to develop a slightly refined RIOSORD. The composition and performance of the CIP-based RIOSORD was evaluated and compared with VHA-based RIOSORD. Results: VHA-RIOSORD performed well in discriminating OIRD events in CIP (C-statistic = 0.85). Additionally, re-estimation of logistic model coefficients in CIP yielded a 0.90 C-statistic. The resulting comorbidity and pharmacotherapy variables most highly associated with OIRD and retained in the CIP-RIOSORD were largely concordant with VHA-RIOSORD. These variables included neuropsychiatric and cardiopulmonary disorders, impaired drug excretion, opioid characteristics, and concurrent psychoactive medications. The average predicted probability of OIRD ranged from 2% to 83%, with excellent agreement between predicted and observed incidence across risk classes. Conclusions: RIOSORD had excellent predictive accuracy in a large population of US medical users of prescription opioids, similar to its performance in VHA. This practical risk index is designed to support clinical decision-making for safer opioid prescribing, and its clinical utility should be evaluated prospectively.

Love Death-A Retrospective and Prospective Follow-Up Mortality Study Over 45 Years.

BACKGROUND: Although sexual activity can cause moderate stress, it can cause natural death in individuals with pre-existing illness. The aim of this study was to identify additional pre-existing health problems, sexual practices, and potential circumstances that may trigger fatal events. METHODS: This medicolegal postmortem, retrospective, and prospective study is based on data of autopsies performed at the Institute of Legal Medicine of the University hospital, Goethe-University, Frankfurt/Main, Germany. OUTCOMES: Identification of pre-existing health problems, sexual practices, and potential circumstances than could trigger fatal events. RESULTS: From 1972 to 2016 (45 years) approximately 38,000 medicolegal autopsies were performed, of which 99 cases of natural death were connected to sexual activities (0.26%). Except for eight women, men represented most cases. The women's mean age was 45 years (median = 45) and the men's mean age was 57.2 years (median = 57). Causes of death were coronary heart disease (n = 28), myocardial infarction (n = 21) and reinfarction (n = 17), cerebral hemorrhage (n = 12), rupture of aortic aneurysms (n = 8), cardiomyopathy (n = 8), acute heart failure (n = 2), sudden cardiac arrest (n = 1), myocarditis (n = 1), and a combination of post myocardial infarction and cocaine intoxication (n = 1). Most cases showed increased heart weights and body mass indices. Death occurred mainly during the summer and spring and in the home of the deceased. If sexual partners were identified, 34 men died during or after sexual contact with a female prostitute, two cases at least two female prostitutes. Nine men died during or after sexual intercourse with their wife, in seven cases the sexual partner was a mistress, and in four cases the life partner. Five men died during homosexual contacts. Based on the situation 30 men were found in, death occurred during masturbation. Of the women, five died during intercourse with the life partner, two died during intercourse with a lover or friend, and in one case no information was provided. CLINICAL TRANSLATION: Natural deaths connected with sexual activity appear to be associated with male sex and pre-existing cardiovascular disorders. Most cases recorded occurred with mistresses, prostitutes, or during masturbation. If death occurs, the spouse or life partner might need psychological support. STRENGTH AND LIMITATIONS: To our knowledge, the present study contains the largest collection of postmortem data on natural deaths connected with sexual activities. However, the cases presented were of forensic interest; a larger number of undetected cases especially in the marital or stable relationship sector must be assumed. CONCLUSION: Patients should be informed about the circumstances that could trigger the "love death." Lange L, Zedler B, Verhoff MA, Parzeller M. Love Death-A Retrospective and Prospective Follow-Up Mortality Study Over 45 Years. J Sex Med 2017;14:1226-1231.

Development of a Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Veterans' Health Administration Patients.

OBJECTIVE: Develop a risk index to estimate the likelihood of life-threatening respiratory depression or overdose among medical users of prescription opioids. SUBJECTS, DESIGN, AND METHODS: A case-control analysis of administrative health care data from the Veterans' Health Administration identified 1,877,841 patients with a pharmacy record for an opioid prescription between October 1, 2010 and September 30, 2012. Overdose or serious opioid-induced respiratory depression (OSORD) occurred in 817. Ten controls were selected per case (n = 8,170). Items for an OSORD risk index (RIOSORD) were selected through logistic regression modeling, with point values assigned to each predictor. Modeling of risk index scores produced predicted probabilities of OSORD; risk classes were defined by the predicted probability distribution. RESULTS: Fifteen variables most highly associated with OSORD were retained as items, including mental health disorders and pharmacotherapy; impaired drug metabolism or excretion; pulmonary disorders; specific opioid characteristics; and recent hospital visits. The average predicted probability of experiencing OSORD ranged from 3% in the lowest risk decile to 94% in the highest, with excellent agreement between predicted and observed incidence across risk classes. The model's C-statistic was 0.88 and Hosmer-Lemeshow goodness-of-fit statistic 10.8 (P > 0.05). CONCLUSION: RIOSORD performed well in identifying medical users of prescription opioids within the Veterans' Health Administration at elevated risk of overdose or life-threatening respiratory depression, those most likely to benefit from preventive interventions. This novel, clinically practical, risk index is intended to provide clinical decision support for safer pain management. It should be assessed, and refined as necessary, in a more generalizable population, and prospectively evaluated.

Total Exposure Study Analysis consortium: a cross-sectional study of tobacco exposures.

BACKGROUND: The Total Exposure Study was a stratified, multi-center, cross-sectional study designed to estimate levels of biomarkers of tobacco-specific and non-specific exposure and of potential harm in U.S. adult current cigarette smokers (≥one manufactured cigarette per day over the last year) and tobacco product non-users (no smoking or use of any nicotine containing products over the last 5 years). The study was designed and sponsored by a tobacco company and implemented by contract research organizations in 2002-2003. Multiple analyses of smoking behavior, demographics, and biomarkers were performed. Study data and banked biospecimens were transferred from the sponsor to the Virginia Tobacco and Health Research Repository in 2010, and then to SRI International in 2012, for independent analysis and dissemination. METHODS: We analyzed biomarker distributions overall, and by biospecimen availability, for comparison with existing studies, and to evaluate generalizability to the entire sample. We calculated genome-wide statistical power for a priori hypotheses. We performed clinical chemistries, nucleic acid extractions and genotyping, and report correlation and quality control metrics. RESULTS: Vital signs, clinical chemistries, and laboratory measures of tobacco specific and non-specific toxicants are available from 3585 current cigarette smokers, and 1077 non-users. Peripheral blood mononuclear cells, red blood cells, plasma and 24-h urine biospecimens are available from 3073 participants (2355 smokers and 719 non-users). In multivariate analysis, participants with banked biospecimens were significantly more likely to self-identify as White, to be older, to have increased total nicotine equivalents per cigarette, decreased serum cotinine, and increased forced vital capacity, compared to participants without. Effect sizes were small (Cohen's d-values ≤ 0.11). Power for a priori hypotheses was 57 % in non-Hispanic Black (N = 340), and 96 % in non-Hispanic White (N = 1840), smokers. All DNA samples had genotype completion rates ≥97.5 %; 68 % of RNA samples yielded RIN scores ≥6.0. CONCLUSIONS: Total Exposure Study clinical and laboratory assessments and biospecimens comprise a unique resource for cigarette smoke health effects research. The Total Exposure Study Analysis Consortium seeks to perform molecular studies in multiple domains and will share data and analytic results in public repositories and the peer-reviewed literature. Data and banked biospecimens are available for independent or collaborative research.

Risk factors for serious prescription opioid-related toxicity or overdose among Veterans Health Administration patients.

OBJECTIVE: Prescription opioid use and deaths related to serious toxicity, including overdose, have increased dramatically in the United States since 1999. However, factors associated with serious opioid-related respiratory or central nervous system (CNS) depression or overdose in medical users are not well characterized. The objective of this study was to examine the factors associated with serious toxicity in medical users of prescription opioids. DESIGN: Retrospective, nested, case-control analysis of Veterans Health Administration (VHA) medical, pharmacy, and health care resource utilization administrative data. SUBJECTS: Patients dispensed an opioid by VHA between October 1, 2010 and September 30, 2012 (N=8,987). METHODS: Cases (N=817) experienced life-threatening opioid-related respiratory/CNS depression or overdose. Ten controls were randomly assigned to each case (N=8,170). Logistic regression was used to examine associations with the outcome. RESULTS: The strongest associations were maximum prescribed daily morphine equivalent dose (MED)≥ 100 mg (odds ratio [OR]=4.1, 95% confidence interval [CI], 2.6-6.5), history of opioid dependence (OR=3.9, 95% CI, 2.6-5.8), and hospitalization during the 6 months before the serious toxicity or overdose event (OR=2.9, 95% CI, 2.3-3.6). Liver disease, extended-release or long-acting opioids, and daily MED of 20 mg or more were also significantly associated. CONCLUSIONS: Substantial risk for serious opioid-related toxicity and overdose exists at even relatively low maximum prescribed daily MED, especially in patients already vulnerable due to underlying demographic factors, comorbid conditions, and concomitant use of CNS depressant medications or substances. Screening patients for risk, providing education, and coprescribing naloxone for those at elevated risk may be effective at reducing serious opioid-related respiratory/CNS depression and overdose in medical users of prescription opioids.

[The Patient Rights Act (PatRG)--Part 3: Burden of proof in liability questions and critical resumé]. / Das Patientenrechtegesetz (PatRG)--Teil 3: Beweislast in Haftungsfragen und kritisches Fazit.

The article deals with the new regulations in the German Civil Code (Bürgerliches Gesetzbuch - BGB), which came into effect in Germany as the Patient Rights Act (PatRG) on the 2/26/2013. In the third part, the burden of proof in liability questions (and 630h BGB) are discussed and critically analysed. In the discussion and a final resume points of criticism of the new law are pointed out.

[The medicolegal relevance of benign and malignant coronary artery anomalies]. / Uber die Relevanz von benignen und malignen Koronaranomalien in der Rechtsmedizin.

Isolated coronary anomalies are rare abnormalities that can be divided into benign and malignant forms. Malignant coronary artery abnormalities generally present already during infancy or early childhood by causing symptoms or sudden death. Benign abnormalities often remain asymptomatic because they are hemodynamically irrelevant. Among the 12,985 autopsies performed at the Institute of Legal Medicine at the University of Frankfurt (Germany) between 1995 and 2013, there were eight cases (0.062%) with isolated coronary artery abnormalities. Five of these cases (0.039%) could be included in our retrospective study. These involved one deceased female and four deceased male subjects, aged between 2 and 57 years. In three of these cases (aged 6, 9, and 11 years old), the coronary anomaly was classified as malignant and was recorded as the cause of death. Benign isolated coronary anomalies are often incidental findings during autopsies. However, in one of the cases in our study, coronary sclerosis in precisely the anomalous vessel was found to be the origin of a fatal myocardial infarction. Malignant isolated coronary artery anomalies attain medicolegal significance when they remain undetected despite advanced early detection protocols and cause sudden death in childhood.

Anthropometrical differences between suicide and other non-natural death circumstances: an autopsy study.

BACKGROUND: In international epidemiological studies, associations between suicides and body height, or body mass index (BMI) were found. Because of the recently growing number of suicides in Germany, a closer look on different anthropometric measures of suicide victims autopsied at the Institute of Forensic Medicine of the Goethe-University in Frankfurt/Main, Germany, was taken. METHOD: A retrospective analysis of 1,271 non-natural death cases autopsied between 2006 and 2010 was performed. A total of 566 other than suicide (control group) and 245 suicide cases (study group) with a given body height and weight aged between 18 and 96 years were examined. RESULTS: Body mass indices of the 18-59-year-old male and 60-79-year-old female suicide victims were significantly lower. Old-aged women who committed suicide exhibited beside a significant lower body mass a significantly slender body shape measured as smaller pelvic circumference, waist circumference, and waist-to-tallness ratio. Self-poisoning was by far the leading suicide method in both genders. The victims of the suicide method hanging were the youngest on average, and this method was most common in the male underweight and female lightly normal weight BMI categories, whereas old, overweight, and obese men killed themselves predominantly with firearms. CONCLUSION: The analysis showed that body measures of suicide cases in comparison to other non-natural death circumstance cases differ. For criminal procedural reasons, all suicide cases should be autopsied. But high autopsy rates are also needed for scientific research and to ensure a high level of patient safety.

[The Patient Rights Act (PatRG)--part 1: legislative procedure, treatment contract, contracting parties and their obligations to cooperate and inform]. / Das Patientenrechtegesetz (PatRG)--Teil 1: Gesetzgebungsverfahren, Behandlungsvertrag, Vertragspartner und deren Mitwirkungs- und Informationspflichten.

The article deals with the new regulations in the German Civil Code (BGB) which came into effect in Germany on 26 Feb 2013 as the Patient Rights Act (PatRG). In Part I, the legislative procedure, the treatment contract and the contracting parties (Section 630a Civil Code), the applicable regulations (Section 630b Civil Code) and the obligations to cooperate and inform (Section 630c Civil Code) are discussed and critically analysed.

[The Patient Rights Act (PatRG)--part 2: informed consent, duty to inform, documentation of treatment, access to the patient file]. / Das Patientenrechtegesetz (PatRG)--Teil 2: Einwilligung, Aufklärungspflichten, Dokumentation der Behandlung, Einsichtnahme in die Patientenakte.

The article deals with the new regulations in the German Civil Code (BGB) which came into effect in Germany on 26 Feb 2013 as the Patient Rights Act (PatRG). In the second part, the consent of the patient (Section 630d Civil Code), the physician's duties to inform the patient (Section 630e Civil Code), the documentation of treatment (Section 630f Civil Code), and the right of access to the patient file (Section 630g Civil Code) are discussed and critically analysed.

[Medical and legal aspects of genital mutilation and circumcision. Part II: Male circumcision]. / Medizinische und rechtliche Aspekte der Genitalverstümmelung bzw. Beschneidung. Tell II: Die rituelle Zirkumzision.

In the last few years, male circumcision has become the subject of controversial discussion. On the one hand, medical and hygienic arguments, ideology, freedom of religion, cultural identity and social adequacy are claimed by those supporting male circumcision. On the other hand, the justification of this practice also has to be critically scrutinized just as the question whether the parents have the right to consent to the operation. Today, opinions range from those who claim that religion and culture alone justify the practice to those who consider circumcision of minors unable to give their consent as bodily injury subject to punishment. In contrast to female genital mutilation, most positions do not postulate that circumcision violates morality. If the person concerned is able to give his consent, freedom of religion may also justify circumcision after weighing its pros and cons as well as its risks and potential side effects.

[Medical and legal aspects of genital mutilation and circumcision part I: female genital mutilation (FGM)]. / Medizinische und Rechtliche Aspekte der Genitalverstiimmelung bzw. Beschneidung Teil I: Weibliche Genitalversttimmelung.

Female genital mutilation (FGM) is considered to be against the law and against morality not only in Western countries, although a woman of age and able to consent may sometimes think differently. The procedure may have serious physical and emotional consequences for the girl or woman. Nevertheless there are attempts to justify the procedure with medical and hygienic pseudoarguments, ideology, freedom of religion, cultural identity and social adequacy. Outside the Western world, some people claim that religion and culture alone justify the practice. In Germany, parents can lose the right to determine the residence of their daughter, if she is faced with the risk of genital mutilation in order to prevent that the child or girl is taken to her home country. Genital mutilation as a gender-specific threat is recognized as a reason to grant asylum or prevent deportation. Proposals to make genital mutilation a separate punishable offence are presently discussed by the legislator.

A statistical method for excluding non-variable CpG sites in high-throughput DNA methylation profiling.

BACKGROUND: High-throughput DNA methylation arrays are likely to accelerate the pace of methylation biomarker discovery for a wide variety of diseases. A potential problem with a standard set of probes measuring the methylation status of CpG sites across the whole genome is that many sites may not show inter-individual methylation variation among the biosamples for the disease outcome being studied. Inclusion of these so-called "non-variable sites" will increase the risk of false discoveries and reduce statistical power to detect biologically relevant methylation markers. RESULTS: We propose a method to estimate the proportion of non-variable CpG sites and eliminate those sites from further analyses. Our method is illustrated using data obtained by hybridizing DNA extracted from the peripheral blood mononuclear cells of 311 samples to an array assaying 1505 CpG sites. Results showed that a large proportion of the CpG sites did not show inter-individual variation in methylation. CONCLUSIONS: Our method resulted in a substantial improvement in association signals between methylation sites and outcome variables while controlling the false discovery rate at the same level.

(1)H nuclear magnetic resonance metabolomics analysis identifies novel urinary biomarkers for lung function.

Chronic obstructive pulmonary disease (COPD), characterized by chronic airflow limitation, is a serious public health concern. In this study, we used proton nuclear magnetic resonance ((1)H NMR) spectroscopy to identify and quantify metabolites associated with lung function in COPD. Plasma and urine were collected from 197 adults with COPD and from 195 without COPD. Samples were assayed using a 600 MHz NMR spectrometer, and the resulting spectra were analyzed against quantitative spirometric measures of lung function. After correcting for false discoveries and adjusting for covariates (sex, age, smoking) several spectral regions in urine were found to be significantly associated with baseline lung function. These regions correspond to the metabolites trigonelline, hippurate and formate. Concentrations of each metabolite, standardized to urinary creatinine, were associated with baseline lung function (minimum p-value = 0.0002 for trigonelline). No significant associations were found with plasma metabolites. Urinary hippurate and formate are often related to gut microflora. This could suggest that the microbiome varies between individuals with different lung function. Alternatively, the associated metabolites may reflect lifestyle differences affecting overall health. Our results will require replication and validation, but demonstrate the utility of NMR metabolomics as a screening tool for identifying novel biomarkers of pulmonary outcomes.

Gene expression profiling of peripheral blood leukocytes identifies potential novel biomarkers of chronic obstructive pulmonary disease in current and former smokers.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease with associated systemic effects. OBJECTIVE: To use gene expression microarrays in peripheral blood leukocytes of current and former cigarette smokers to identify differences associated with COPD. MATERIALS AND METHODS: Random forest modelling and a split-sample case-control approach were used to identify candidate predictors. RESULTS: We identified 1013 genes and one smoking exposure variable that differentiated current and former smokers with or without COPD. This predictor set was reduced to a nine-gene classifier (IL6R, CCR2, PPP2CB, RASSF2, WTAP, DNTTIP2, GDAP1, LIPE and RPL14). CONCLUSION: These gene expression profiles represent potential biomarkers for COPD and may help increase mechanistic understanding of the disease.

High-resolution mass spectrometry proteomics for the identification of candidate plasma protein biomarkers for chronic obstructive pulmonary disease.

Although cigarette smoking is recognized as the most important cause of chronic obstructive pulmonary disease (COPD), the pathophysiological mechanisms underlying the lung function decline are not well understood. Using off-line strong cation exchange fractionation with RP-LC-ESI-MS/MS and robust database searching, 1758 tryptic peptides were identified in plasma samples from cigarette smokers. Using two statistical approaches, 30 peptides were identified to be associated with the annualized rate of lung function decline over 5 years among smokers with COPD characterized as having rapid (n = 18) or slow (n = 18) decline and 18 smokers without COPD. The identified peptides belong to proteins that are involved in the complement or coagulation systems or have antiprotease or metabolic functions. This research demonstrates the utility of proteomic profiling to improve the understanding of molecular mechanisms involved in cigarette smoking-related COPD by identifying plasma proteins that correlate with decline in lung function.

Proteomic biomarkers in plasma that differentiate rapid and slow decline in lung function in adult cigarette smokers with chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of morbidity and mortality in the United States and cigarette smoking is a primary determinant of the disease. COPD is characterized by chronic airflow limitation as measured by the forced expiratory volume in one second (FEV(1)). In this study, the plasma proteomes of 38 middle-aged or older adult smokers with mild to moderate COPD, with FEV(1) decline characterized as either rapid (RPD, n = 20) or slow or absent (SLW, n = 18), were interrogated using a comprehensive high-throughput proteomic approach, the accurate mass and time (AMT) tag technology. This technology is based upon a putative mass and time tag database (PMT), high-resolution LC separations and high mass accuracy measurements using FT-ICR MS with a 9.4-T magnetic field. The peptide and protein data were analyzed using three statistical approaches to address ambiguities related to the high proportion of missing data inherent to proteomic analysis. The RPD and SLW groups were differentiated by 55 peptides which mapped to 33 unique proteins. Twelve of the proteins have known roles in the complement or coagulation cascade and, despite an inability to adjust for some factors known to affect lung function decline, suggest potential mechanistic biomarkers associated with the rate of lung function decline in COPD. Whether these proteins are the cause or result of accelerated decline will require further research.