A Naturally Transmitted Epitheliotropic Polyomavirus Pathogenic in Immunodeficient Rats: Characterization, Transmission, and Preliminary Epidemiologic Studies.

We report the identification, pathogenesis, and transmission of a novel polyomavirus in severe combined immunodeficient F344 rats with null Prkdc and interleukin 2 receptor gamma genes. Infected rats experienced weight loss, decreased fecundity, and mortality. Large basophilic intranuclear inclusions were observed in epithelium of the respiratory tract, salivary and lacrimal glands, uterus, and prostate gland. Unbiased viral metagenomic sequencing of lesioned tissues identified a novel polyomavirus, provisionally named Rattus norvegicus polyomavirus 2 (RatPyV2), which clustered with Washington University (WU) polyomavirus in the Wuki clade of the Betapolyomavirus genus. In situ hybridization analyses and quantitative polymerase chain reaction (PCR) results demonstrated viral nucleic acids in epithelium of respiratory, glandular, and reproductive tissues. Polyomaviral disease was reproduced in Foxn1rnu nude rats cohoused with infected rats or experimentally inoculated with virus. After development of RatPyV2-specific diagnostic assays, a survey of immune-competent rats from North American research institutions revealed detection of RatPyV2 in 7 of 1,000 fecal samples by PCR and anti-RatPyV2 antibodies in 480 of 1,500 serum samples. These findings suggest widespread infection in laboratory rat populations, which may have profound implications for established models of respiratory injury. Additionally, RatPyV2 infection studies may provide an important system to investigate the pathogenesis of WU polyomavirus diseases of man.

The significance of closed kinematic chains to biological movement and dynamic stability.

Closed kinematic chains (CKCs) are widely used in mechanical engineering because they provide a simple and efficient mechanism with multiple applications, but they are much less appreciated in living tissues. Biomechanical research has been dominated by the use of lever models and their kinematic analysis, which has largely ignored the geometric organization of these ubiquitous and evolutionary-conserved systems, yet CKCs contribute substantially to our understanding of biological motion. Closed-chain kinematics couple multiple parts into continuous mechanical loops that allow the structure itself to regulate complex movements, and are described in a wide variety of different organisms, including humans. In a biological context, CKCs are modular units nested within others at multiple size scales as part of an integrated movement system that extends throughout the organism and can act in synergy with the nervous system, where present. They provide an energy-efficient mechanism that enables multiple mechanical functions to be optimized during embryological development and increases evolutionary diversity.

Risk, coping and PTSD symptom trajectories in World Trade Center responders.

Trajectories of disaster-related posttraumatic stress disorder (PTSD) symptoms are often heterogeneous, and associated with common and unique risk factors, yet little is known about potentially modifiable psychosocial characteristics associated with low-symptom and recovering trajectories in disaster responders. A total of 4487 rescue and recovery workers (1874 police and 2613 non-traditional responders) involved during and in the aftermath of the unprecedented World Trade Center (WTC) attacks, were assessed an average of 3, 6, 8, and 12 years post-9/11/2001. Among police responders, WTC-related PTSD symptoms were characterized by four trajectories, including no/low-symptom (76.1%), worsening (12.1%), improving (7.5%), and chronic (4.4%) trajectories. In non-traditional responders, a five-trajectory solution was optimal, with fewer responders in a no/low-symptom trajectory (55.5%), and the remainder in subtly worsening (19.3%), chronic (10.8%), improving (8.5%), and steeply worsening (5.9%) trajectories. Consistent factors associated with symptomatic PTSD trajectories across responder groups included Hispanic ethnicity, pre-9/11 psychiatric history, greater WTC exposure, greater medical illness burden, life stressors and post-9/11 traumas, and maladaptive coping (e.g., substance use, avoidance coping). Higher perceived preparedness, greater sense of purpose in life, and positive emotion-focused coping (e.g., positive reframing, acceptance) were negatively associated with symptomatic trajectories. Findings in this unique cohort indicate considerable heterogeneity in WTC-related PTSD symptom trajectories over 12 years post-9/11/2001, with lower rates of elevated PTSD symptoms in police than in non-traditional responders. They further provide a comprehensive risk prediction model of PTSD symptom trajectories, which can inform prevention, monitoring, and treatment efforts in WTC and other disaster responders.

Lumbopelvic muscle activation patterns in three stances under graded loading conditions: Proposing a tensegrity model for load transfer through the sacroiliac joints.

PURPOSE: According to the conventional arch model of the pelvis, stability of the sacroiliac joints may require a predominance of form and force closure mechanisms: the greater the vertical shear force at the sacroiliac joints, the greater the reliance on self-bracing by horizontally or obliquely oriented muscles (such as the internal oblique). But what happens to the arch model when a person stands on one leg? In such cases, the pelvis no longer has imposts, leaving both the arch, and the arch model theory, without support. Do lumbopelvic muscle activation patterns in one-legged stances under load suggest compatibility with a different model? This study compares lumbopelvic muscle activation patterns in two-legged and one-legged stances in response to four levels of graded trunk loading in order to further our understanding the stabilization of the sacroiliac joints. METHODS: Thirty male subjects experienced four levels of trunk loading (0%, 5%, 10% and 15% of body weight) by holding a bucket at one side, at three conditions: 1) two-legged standing with the bucket in the dominant hand, 2) ipsilateral loading: one-legged standing with the bucket in the dominant hand while using the same-side leg, and 3) contralateral loading: one-legged standing using the same leg used in condition 2, but with the bucket in the non-dominant hand. During these tasks, EMG signals from eight lumbopelvic muscles were collected. ANOVA with repeated design was performed on normalized EMG's to test the main effect of load and condition, and interaction effects of load by condition. RESULTS: Latissimus dorsi and erector spinae muscles showed an antagonistic pattern of activity toward the direction of load which may suggest these muscles as lateral trunk stabilizers. Internal oblique muscles showed a co-activation pattern with increasing task demand, which may function to increase lumbopelvic stability (P < 0.05). No unilateral pattern of the internal obliques was observed during all trials. CONCLUSIONS: Our results suggest that the lumbopelvic region uses a similar strategy for load transfer in both double and single leg support positions which is not compatible with the arch analogy. Our findings are more consistent with a suspensory system (wire-spoke wheel model). If our proposed model holds true, the pelvic ring can only be integrated by adjusting tension in the spokes and by preserving rim integrity or continuity. Thus, we propose that in order to restore tension integrity throughout the pelvic ring, efforts to unlock restrictions, muscular correction of positional faults and lumbopelvic or even respiratory exercises following sacroiliac joint dysfunctions must be taken into consideration. Our hypothetical model may initiate thinking and act as a guide to future work based on a biomechanical approach to the problem of sacroiliac joint dysfunction.

Rapid progression of pleural disease due to exposure to Libby amphibole: "Not your grandfather's asbestos related disease".

BACKGROUND: Residents and mine employees from Libby, Montana, have been exposed to asbestiform amphiboles from the vermiculite mine that operated in this location from the mid-1920s until 1990. Clinical observations show a different form of asbestos-related toxicity than other forms of asbestos. METHODS: Five illustrative cases from the Center for Asbestos-Related Diseases in Libby were selected. All had clear exposure histories, multiple follow-up visits, illustrative chest radiographic studies, serial pulmonary function tests, and sufficient length of follow-up to characterize disease progression. RESULTS: These cases developed increasing symptoms of dyspnea and chest pain, progressive radiological changes that were predominantly pleural, and a restrictive pattern of impaired spirometry that rapidly progressed with significant loss of pulmonary function. CONCLUSIONS: LA exposure can cause a non-malignant pleural disease that is more rapidly progressive and more severe than the usual asbestos-related disease.

Impact of anaesthetics and analgesics on fetal growth in the mouse.

Common anaesthetic and analgesic agents used during pregnancy in mice have been observed to cause fetal growth restriction. We investigated the impact of therapeutic doses of three anaesthetics (ketamine/xylazine, isoflurane, and tribromoethanol) and two analgesics (buprenorphine and meloxicam) on fetal and placental growth. Pregnant mice were treated with one of these agents at fertilization (E0), attachment (E4), beginning of organogenesis (E6), end of organogenesis (E12), or during the logarithmic growth phase (E15), or they were placed into an untreated control group. At term (E18), fetal and placental growth were evaluated, morphological analyses were performed, and skeletal measurements were conducted. Fetal growth was reduced significantly (P < 0.01) by ketamine/xylazine treatment at E0, E4, E12, or E15, by isoflurane administered at E0 or E6, and by tribromoethanol administered at E6 or E12. Two-day treatment with buprenorphine beginning at E4 or E6, or with meloxicam at E0 also significantly reduced fetal growth (P < 0.01). Neither placental growth nor litter size was significantly affected by any of these agents. The occurrence of microphthalmia was nearly eight-fold higher (P < 0.05) in response to buprenorphine administration at E6 compared with controls. The length of the humerus was reduced at most gestation times in response to each of these agents and was correlated (P < 0.01) with fetal weight for ketamine/xylazine, tribromoethanol, and meloxicam. These data reveal patterns of acceptable and detrimental anaesthetic and analgesic use during fetal development and have refined our capability to provide recommendations for the use of these agents during pregnancy in the mouse.

Asbestos, asbestosis, smoking, and lung cancer. New findings from the North American insulator cohort.

RATIONALE: Asbestos, smoking, and asbestosis increase lung cancer risk in incompletely elucidated ways. Smoking cessation among asbestos-exposed cohorts has been little studied. OBJECTIVES: To measure the contributions of asbestos exposure, asbestosis, smoking, and their interactions to lung cancer risk in an asbestos-exposed cohort and to describe their reduction in lung cancer risk when they stop smoking. METHODS: We examined lung cancer mortality obtained through the National Death Index for 1981 to 2008 for 2,377 male North American insulators for whom chest X-ray, spirometric, occupational, and smoking data were collected in 1981 to 1983 and for 54,243 non-asbestos-exposed blue collar male workers from Cancer Prevention Study II for whom occupational and smoking data were collected in 1982. MEASUREMENTS AND MAIN RESULTS: Lung cancer caused 339 (19%) insulator deaths. Lung cancer mortality was increased by asbestos exposure alone among nonsmokers (rate ratio = 3.6 [95% confidence interval (CI), 1.7-7.6]), by asbestosis among nonsmokers (rate ratio = 7.40 [95% CI, 4.0-13.7]), and by smoking without asbestos exposure (rate ratio = 10.3 [95% CI, 8.8-12.2]). The joint effect of smoking and asbestos alone was additive (rate ratio = 14.4 [95% CI, 10.7-19.4]) and with asbestosis, supra-additive (rate ratio = 36.8 [95% CI, 30.1-45.0]). Insulator lung cancer mortality halved within 10 years of smoking cessation and converged with that of never-smokers 30 years after smoking cessation. CONCLUSIONS: Asbestos increases lung cancer mortality among nonsmokers. Asbestosis further increases the lung cancer risk and, considered jointly with smoking, has a supra-additive effect. Insulators benefit greatly by quitting smoking.

Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma.

BACKGROUND: New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker. METHODS: We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay. RESULTS: Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105±7 ng per milliliter in the Detroit cohort and 113±8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14±1 ng per milliliter and 24±1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694±37 ng per milliliter in the Detroit cohort and 636±92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212±25 and 151±23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma. CONCLUSIONS: Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions. (Funded by the Early Detection Research Network, National Institutes of Health, and others.).

Early detection of malignant pleural mesothelioma in asbestos-exposed individuals with a noninvasive proteomics-based surveillance tool.

BACKGROUND: Malignant pleural mesothelioma (MM) is an aggressive, asbestos-related pulmonary cancer that is increasing in incidence. Because diagnosis is difficult and the disease is relatively rare, most patients present at a clinically advanced stage where possibility of cure is minimal. To improve surveillance and detection of MM in the high-risk population, we completed a series of clinical studies to develop a noninvasive test for early detection. METHODOLOGY/PRINCIPAL FINDINGS: We conducted multi-center case-control studies in serum from 117 MM cases and 142 asbestos-exposed control individuals. Biomarker discovery, verification, and validation were performed using SOMAmer proteomic technology, which simultaneously measures over 1000 proteins in unfractionated biologic samples. Using univariate and multivariate approaches we discovered 64 candidate protein biomarkers and derived a 13-marker random forest classifier with an AUC of 0.99±0.01 in training, 0.98±0.04 in independent blinded verification and 0.95±0.04 in blinded validation studies. Sensitivity and specificity at our pre-specified decision threshold were 97%/92% in training and 90%/95% in blinded verification. This classifier accuracy was maintained in a second blinded validation set with a sensitivity/specificity of 90%/89% and combined accuracy of 92%. Sensitivity correlated with pathologic stage; 77% of Stage I, 93% of Stage II, 96% of Stage III and 96% of Stage IV cases were detected. An alternative decision threshold in the validation study yielding 98% specificity would still detect 60% of MM cases. In a paired sample set the classifier AUC of 0.99 and 91%/94% sensitivity/specificity was superior to that of mesothelin with an AUC of 0.82 and 66%/88% sensitivity/specificity. The candidate biomarker panel consists of both inflammatory and proliferative proteins, processes strongly associated with asbestos-induced malignancy. SIGNIFICANCE: The SOMAmer biomarker panel discovered and validated in these studies provides a solid foundation for surveillance and diagnosis of MM in those at highest risk for this disease.

The burden of full and subsyndromal posttraumatic stress disorder among police involved in the World Trade Center rescue and recovery effort.

BACKGROUND: This study examined the prevalence, correlates, and perceived mental healthcare needs associated with subsyndromal PTSD in police involved in the World Trade Center (WTC) rescue and recovery effort. METHODS: A total of 8466 police completed an interview/survey as part of the WTC Medical monitoring and Treatment Program an average of four years after 9/11/2001. RESULTS: The past month prevalence of full and subsyndromal WTC-related PTSD was 5.4% and 15.4%, respectively. Loss of someone or knowing someone injured on 9/11 (odds ratios [ORs]=1.56-1.86), pre-9/11 stressors (ORs=1.30-1.50), family support (ORs=0.83-0.94), and union membership (ORs=0.50-0.52) were associated with both full and subsyndromal PTSD. Exposure to the dust cloud (OR=1.36), performing search and rescue work (OR=1.29), and work support (OR=0.89) were additionally associated with subsyndromal PTSD. Rates of comorbid depression, panic disorder, and alcohol use problems (ORs=3.82-41.74), and somatic symptoms and functional difficulties (ORs=1.30-1.95) were highest among police with full PTSD, with intermediate rates among police with subsyndromal PTSD (ORs=2.93-7.02; and ORs=1.18-1.60, respectively). Police with full and subsyndromal PTSD were significantly more likely than controls to report needing mental healthcare (41.1% and 19.8%, respectively, versus 6.8% in trauma controls). CONCLUSIONS: These results underscore the importance of a more inclusive and dimensional conceptualization of PTSD, particularly in professions such as police, as operational definitions and conventional screening cut-points may underestimate the psychological burden for this population. Accordingly, psychiatric clinicians should assess for disaster-related subsyndromal PTSD symptoms in disaster response personnel.

Persistence of multiple illnesses in World Trade Center rescue and recovery workers: a cohort study.

BACKGROUND: More than 50,000 people participated in the rescue and recovery work that followed the Sept 11, 2001 (9/11) attacks on the World Trade Center (WTC). Multiple health problems in these workers were reported in the early years after the disaster. We report incidence and prevalence rates of physical and mental health disorders during the 9 years since the attacks, examine their associations with occupational exposures, and quantify physical and mental health comorbidities. METHODS: In this longitudinal study of a large cohort of WTC rescue and recovery workers, we gathered data from 27,449 participants in the WTC Screening, Monitoring, and Treatment Program. The study population included police officers, firefighters, construction workers, and municipal workers. We used the Kaplan-Meier procedure to estimate cumulative and annual incidence of physical disorders (asthma, sinusitis, and gastro-oesophageal reflux disease), mental health disorders (depression, post-traumatic stress disorder [PTSD], and panic disorder), and spirometric abnormalities. Incidence rates were assessed also by level of exposure (days worked at the WTC site and exposure to the dust cloud). FINDINGS: 9-year cumulative incidence of asthma was 27·6% (number at risk: 7027), sinusitis 42·3% (5870), and gastro-oesophageal reflux disease 39·3% (5650). In police officers, cumulative incidence of depression was 7·0% (number at risk: 3648), PTSD 9·3% (3761), and panic disorder 8·4% (3780). In other rescue and recovery workers, cumulative incidence of depression was 27·5% (number at risk: 4200), PTSD 31·9% (4342), and panic disorder 21·2% (4953). 9-year cumulative incidence for spirometric abnormalities was 41·8% (number at risk: 5769); three-quarters of these abnormalities were low forced vital capacity. Incidence of most disorders was highest in workers with greatest WTC exposure. Extensive comorbidity was reported within and between physical and mental health disorders. INTERPRETATION: 9 years after the 9/11 WTC attacks, rescue and recovery workers continue to have a substantial burden of physical and mental health problems. These findings emphasise the need for continued monitoring and treatment of the WTC rescue and recovery population. FUNDING: Centers for Disease Control and Prevention and National Institute for Occupational Safety and Health.

Work-related injuries and illnesses reported by World Trade Center response workers and volunteers.

INTRODUCTION: In 2002, the Mount Sinai Center for Occupational and Environmental Medicine, with support from the National Institute for Occupational Safety and Health (NIOSH), began coordinating the World Trade Center (WTC) Worker and Volunteer Medical Screening Program (MSP) to monitor the health of qualified WTC responders. Enrolled participants were offered a clinical examination; interviewed to collect medical, mental health, and exposure information; and requested to complete a self-administered medical questionnaire. The objective of this study was to better understand work-related injuries and illnesses sustained on-site by WTC responders. METHODS: A descriptive analysis of select data from the MSP self-administered medical questionnaire was conducted. Data collected July 2002 through April 2004 from MSP participants enrolled at the Mount Sinai clinic were reviewed using univariate statistical techniques. RESULTS: Records from 7,810 participants were analyzed, with most participants associated with either the construction industry (n = 2,623, 34%) or law enforcement (n = 2,036, 26%). Approximately a third of the participants (n = 2,486, 32%) reported at least one injury or illness requiring medical treatment that was sustained during WTC work/volunteer activities. Of the total 4,768 injuries/illnesses reported by these participants, respiratory complaints were most common (n = 1,350, 28%), followed by traumatic injuries excluding eye injuries (n = 961, 20%), eye injuries/ailments (n = 709, 15%), chest pain (n = 375, 8%), headaches (n = 359, 8%), skin conditions (n = 178, 4%), and digestive system conditions (n = 163, 3%). Participants reported that 36% of injuries/illnesses were treated off-site and 29% were treated on-site, with the remaining not specifying treatment location. Off-site treatment was prevalent for respiratory complaints, psychological stress, and chest pain. On-site treatment was predominate for eye injuries/ailments and traumatic injuries excluding eye injuries. CONCLUSION: Study results underscore the need for rapid deployment of personal protective equipment for disaster responders and medical care stations mobilized near disaster worksites. Additionally, the results, many of which are comparable to findings from previous WTC studies where data were collected in real-time, indicate that a screening program such as the MSP may be effective in retrospectively providing general information on disaster responder demographics and work-related injuries and illnesses.

Longitudinal assessment of spirometry in the World Trade Center medical monitoring program.

BACKGROUND: Multiple studies have demonstrated an initial high prevalence of spirometric abnormalities following World Trade Center (WTC) disaster exposure. We assessed prevalence of spirometric abnormalities and changes in spirometry between baseline and first follow-up evaluation in participants in the WTC Worker and Volunteer Medical Monitoring Program. We also determined the predictors of spirometric change between the two examinations. METHODS: Prebronchodilator and postbronchodilator spirometry, demographics, occupational history, smoking status, and respiratory symptoms and exposure onset were obtained at both examinations (about 3 years apart). RESULTS: At the second examination, 24.1% of individuals had abnormal spirometry findings. The predominant defect was a low FVC without obstruction (16.1%). Between examinations, the majority of individuals did not have a greater-than-expected decline in lung function. The mean declines in prebronchodilator FEV(1) and FVC were 13 mL/yr and 2 mL/yr, respectively (postbronchodilator results were similar and not reported). Significant predictors of greater average decline between examinations were lack of bronchodilator responsiveness at examination 1 and weight gain [corrected]. CONCLUSIONS: Elevated rates of spirometric abnormalities were present at both examinations, with reduced FVC most common. Although the majority had a normal decline in lung function, lack of bronchodilator response at examination 1 and weight gain were significantly associated with greater-than-normal lung function declines [corrected]. Due to the presence of spirometric abnormalities > 5 years after the disaster in many exposed individuals, longer-term monitoring of WTC responders is essential.

Reflux symptoms and disorders and pulmonary disease in former World Trade Center rescue and recovery workers and volunteers.

BACKGROUND: Gastroesophageal reflux disease is one of the most prevalent conditions among former World Trade Center (WTC) rescue and recovery workers. The reason for this proposed association with an inhalation injury is unclear. In this study, we clinically characterized the reflux disorders in former WTC workers, and we investigated their association with pulmonary function abnormalities and with clinical diagnoses of other WTC-related diseases. METHODS: Forty-two former WTC workers underwent the following testing: symptom inventories, physical examination, spirometry, esophagogastroduodenoscopy, and 24-hour pH monitoring studies for the evaluation of chronic reflux-like symptoms. Patients were classified into two groups based on clinical evaluation: group 1 (reflux patients) including definitive reflux disorders (gastroesophageal reflux, nonerosive reflux, nonacid reflux, and laryngopharyngeal reflux diseases) and group 2 (no-reflux patients) patients without clinically significant reflux disease, including functional heartburn, and hypersensitive esophagus disorder. RESULTS: The reflux and no-reflux patients had significantly different Johnson-DeMeester scores and esophageal acid exposure times. Patients with reflux disorders were more likely to have reduced forced vital capacity (chi2 = 5.49, P = 0.031) and also more likely to have been diagnosed with a lower airway disease (chi2 = 7.14, P = 0.008). We found no significant association between reflux and psychiatric disorders (chi2 = 0.02, P = 0.89), levels of exposure at the WTC site, or incidence of dry cough, or other upper airway disorders. CONCLUSIONS: A spectrum of reflux symptoms and disorders are present in WTC responders. Our data suggest that the presence of reflux disease is related to that of pulmonary function abnormality suggestive of air trapping and a diagnosis of a lower respiratory disease.