Associations between asthma trigger reports, mental health conditions, and asthma morbidity among world trade center rescue and recovery workers.

Aim: There is limited information regarding asthma triggers in World Trade Center (WTC) rescue and recovery workers (RRW) or how mental health conditions affect the perception of triggers. Methods: We included 372 WTC workers with asthma. The Asthma Trigger Inventory (ATI) assessed triggers along five domains: psychological, allergens, physical activity, infection, and pollution. We administered the Structured Clinical Interview to diagnose post-traumatic stress disorder (PTSD), major depression and panic disorder (PD). The Asthma Control Questionnaire (ACQ) and Mini Asthma Quality of Life Questionnaire (AQLQ) measured asthma control and quality of life, respectively. Linear regression models were fitted to examine the association of ATI total and subdomain scores with mental health conditions as well as the percent of ACQ and AQLQ variance explained by ATI subscales. Results: The most common triggers were air pollution (75%) and general allergens (68%). PTSD was significantly associated with psychological triggers (partial r2=0.05, p < 0.01), physical activity (partial r2=0.03, p < 0.01) and air pollution (partial r2=0.02, p = 0.04) subscales while PD was significantly associated with air pollution (partial r2=0.03, p = 0.03) and general allergens (partial r2=0.02, p = 0.03). ATI subscales explained a large percentage of variance in asthma control (r2=0.37, p < 0.01) and quality of life scores (r2=0.40, p < 0.01). Psychological subscale scores explained the largest portion of the total variability in ACQ (partial r2= 0.11, p = 0.72) and AQLQ (partial r2=0.14, p = 0.64) scores. Conclusion: RRW with mental health conditions reported more asthma triggers and these triggers were associated with asthma morbidity. These data can help support interventions in RRW with asthma.

Post-traumatic stress disorder dimensions and asthma morbidity in World Trade Center rescue and recovery workers.

OBJECTIVE: Using data from a cohort of World Trade Center (WTC) rescue and recovery workers with asthma, we assessed whether meeting criteria for post-traumatic stress disorder (PTSD), sub-threshold PTSD, and for specific PTSD symptom dimensions are associated with increased asthma morbidity. METHODS: Participants underwent a Structured Clinical Interview for Diagnostic and Statistical Manual to assess the presence of PTSD following DSM-IV criteria during in-person interviews between December 2013 and April 2015. We defined sub-threshold PTSD as meeting criteria for two of three symptom dimensions: re-experiencing, avoidance, or hyper-arousal. Asthma control, acute asthma-related healthcare utilization, and asthma-related quality of life data were collected using validated scales. Unadjusted and multiple regression analyses were performed to assess the relationship between sub-threshold PTSD and PTSD symptom domains with asthma morbidity measures. RESULTS: Of the 181 WTC workers with asthma recruited into the study, 28% had PTSD and 25% had sub-threshold PTSD. Patients with PTSD showed worse asthma control, higher rates of inpatient healthcare utilization, and poorer asthma quality of life than those with sub-threshold or no PTSD. After adjusting for potential confounders, among patients not meeting the criteria for full PTSD, those presenting symptoms of re-experiencing exhibited poorer quality of life (p = 0.003). Avoidance was associated with increased acute healthcare use (p = 0.05). Sub-threshold PTSD was not associated with asthma morbidity (p > 0.05 for all comparisons). CONCLUSIONS: There may be benefit in assessing asthma control in patients with sub-threshold PTSD symptoms as well as those with full PTSD to more effectively identify ongoing asthma symptoms and target management strategies.

Estimating medical costs of work-related diseases in the Basque Country (2008).

OBJECTIVES: To estimate the medical costs of work-attributable diseases (WAD) treated by the public health care system for one of the Spanish Autonomous Communities, the Basque Country, in 2008. METHODS: We calculated the burden of disease attributable to work for each category of diseases according to ICD-9-CM by using estimates of attributable fractions. Hospital and specialized outpatient care cost data were derived from the Spanish National Health System analytical accountability system. Secondary sources of information were used to estimate primary health care and drug prescriptions. RESULTS: Direct costs of work-attributable diseases borne by the Basque Regional Health Service totalled 106 million Euros in 2008, representing 3.3% of Basque public expenditures on health and 0.16% of Basque GDP in 2008. Specialized care, including hospitalizations, absorbed the highest proportion of costs (52%), followed by drug prescriptions and primary health care (27% and 21%, respectively). Diseases of the musculoskeletal system and connective tissues accounted for 47.3% of total costs, followed by cardiovascular diseases (19.6%) and cancer (15%). CONCLUSIONS: Occupational diseases and accidents are costly in the Basque Region of Spain, generating a severe deviation of public expenditures and overburdening of the Public Health System because they should really be the responsibility of the Social Security System. Proper identification and assignment of costs of work-related diseases would result in significant savings for the National Health System (Spanish and European), would provide an incentive for the prevention of these avoidable causes of illness and thus contribute to the sustainability of social systems.

Identification and functional characterization of p130Cas as a substrate of protein tyrosine phosphatase nonreceptor 14.

Protein tyrosine phosphatase nonreceptor type 14 (PTPN14) is frequently mutated in a variety of human cancers. However, the cell signaling pathways regulated by PTPN14 largely remain to be elucidated. Here, we identify a list of potential substrates of PTPN14 using a phospho-proteomic approach. We show that p130 Crk-associated substrate (p130Cas) is a direct substrate of PTPN14 and that PTPN14 specifically regulates p130Cas phosphorylation at tyrosine residue 128 (Y128) in colorectal cancer (CRC) cells. We engineered CRC cells homozygous for a p130Cas Y128F knock-in mutant and found that these cells exhibit significantly reduced migration and colony formation, impaired anchorage-independent growth, slower xenograft tumor growth in nude mice and have decreased phosphorylation of AKT. Furthermore, we demonstrate that SRC phosphorylates p130Cas Y128 and that CRC cell lines harboring high levels of pY128Cas are more sensitive to SRC family kinase inhibitor Dasatinib. These findings suggest that p130Cas Y128 phosphorylation may be exploited as a predictive marker for Dasatinib response in cancer patients. In aggregate, our studies reveal a novel signaling pathway that has an important role in colorectal tumorigenesis.

Removal of uracil by uracil DNA glycosylase limits pemetrexed cytotoxicity: overriding the limit with methoxyamine to inhibit base excision repair.

Uracil DNA glycosylase (UDG) specifically removes uracil bases from DNA, and its repair activity determines the sensitivity of the cell to anticancer agents that are capable of introducing uracil into DNA. In the present study, the participation of UDG in the response to pemetrexed-induced incorporation of uracil into DNA was studied using isogenic human tumor cell lines with or without UDG (UDG(+/+)/UDG(-/-)). UDG(-/-) cells were very sensitive to pemetrexed. Cell killing by pemetrexed was associated with genomic uracil accumulation, stalled DNA replication, and catastrophic DNA strand breaks. By contrast, UDG(+/+) cells were >10 times more resistant to pemetrexed due to the rapid removal of uracil from DNA by UDG and subsequent repair of the resultant AP sites (abasic sites) via the base excision repair (BER). The resistance to pemetrexed in UDG(+/+) cells could be reversed by the addition of methoxyamine (MX), which binds to AP sites and interrupts BER pathway. Furthermore, MX-bound AP sites induced cell death was related to their cytotoxic effect of dual inactivation of UDG and topoisomerase IIα, two genes that are highly expressed in lung cancer cells in comparison with normal cells. Thus, targeting BER-based therapy exhibits more selective cytotoxicity on cancer cells through a synthetic lethal mechanism.

Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer.

MicroRNAs are small, non-coding RNAs that influence gene regulatory networks by post-transcriptional regulation of specific messenger RNA targets. MicroRNA expression is dysregulated in human malignancies, frequently leading to loss of expression of certain microRNAs. We report that expression of hsa-miR-342, a microRNA encoded in an intron of the gene EVL, is commonly suppressed in human colorectal cancer. The expression of hsa-miR-342 is coordinated with that of EVL and our results indicate that the mechanism of silencing is CpG island methylation upstream of EVL. We found methylation at the EVL/hsa-miR-342 locus in 86% of colorectal adenocarcinomas and in 67% of adenomas, indicating that it is an early event in colorectal carcinogenesis. In addition, we observed a higher frequency of methylation (56%) in histologically normal colorectal mucosa from individuals with concurrent cancer compared to mucosa from individuals without colorectal cancer (12%), suggesting the existence of a 'field defect' involving methylated EVL/hsa-miR-342. Furthermore, reconstitution of hsa-miR-342 in the colorectal cancer cell line HT-29 induced apoptosis, suggesting that this microRNA could function as a proapoptotic tumor suppressor. In aggregate, these results support a novel mechanism for silencing intronic microRNAs in cancer by epigenetic alterations of cognate host genes.

Incidence of epilepsy in a racially diverse, community-dwelling, elderly cohort: results from the Einstein aging study.

OBJECTIVE: To determine age-specific incidence and cumulative incidence of epilepsy in a well-defined cohort of elderly people, and to examine how rates of epilepsy are modified by sex, race, stroke, dementia, head injury, and depression. METHODS: The authors examined data from a reconstructed cohort based on 1919 community-dwelling volunteers, followed as part of a large ongoing prospective aging study. RESULTS: Age-specific incidence was 10.6 (per 100,000 person-years) between ages 45 and 59, 25.8 between ages 60 and 74, and 101.1 between ages 75 and 89. Cumulative incidence was 0.15% from age 45 to age 60, 0.38% to age 70, 1.01% to age 80, and 1.47% to age 90. In addition, the difference in cumulative incidence among African-American subjects approached statistical significance (57.6/100,000 person-years versus 26.1 in Caucasian, p=0.10), and the difference in incidence among subjects reporting a history of stroke was significantly elevated (p=0.029). Incidence of epilepsy was not statistically elevated among males, those with dementia, or individuals reporting a history of head injury or treatment for depression. Among "healthy" subjects without history of stroke, head injury, or dementia, we observed a cumulative risk of epilepsy with onset after age 60 of only 1.1%. CONCLUSIONS: The incidence of epilepsy was low in this relatively healthy cohort of elderly people, especially among subjects without known risk factors. In this study we identified African-American race as a risk factor in the elderly for epilepsy independent of stroke.

Recruitment of patients into an internet-based clinical trials database: the experience of OncoLink and the National Colorectal Cancer Research Alliance.

PURPOSE: In March 2001, the National Colorectal Cancer Research Alliance (NCCRA) and OncoLink (http://www.oncolink.org) established a database to facilitate patient enrollment onto clinical trials. This study describes the population registering with the database and identifies discrepancies between individuals registering through the Internet and those registering through a telephone call center. METHODS: Participants registered with the NCCRA/OncoLink database through the Internet or a telephone call center. All participants entering the database completed a questionnaire regarding basic demographics, colon cancer risk factors, and indicated how they became aware of the database. Comparisons were made between individuals registering through the Internet and those registering through the telephone call center. RESULTS: A total of 2,162 participants registered during the first 16 months of the database. Most patients registered through the Internet rather than the telephone call center (88% v 12%; P < .001). More females than males registered (73% v 27%; P < .001). The majority (89%) were white. Participants registering through the Internet were younger than those registering through the call center (mean, 48.8 v 55.0 years; P < .001). There was no difference between the two groups with regard to sex or ethnicity. CONCLUSION: The Internet has the potential to increase the likelihood that interested individuals find appropriate clinical trials. Some of the discrepancies that are known to exist for access to the Internet were also seen for those registering with the database through the Internet. Despite these differences, the potential to increase clinical trial enrollment with this type of Internet-based database is high.

Electrophysiologic effects of a novel selective adenosine A1 agonist (CVT-510) on atrioventricular nodal conduction in humans.

BACKGROUND: CVT-510, N-(3(R)-tetrahydrofuranyl)-6-aminopurine riboside, is a selective A(1)-adenosine receptor agonist with potential potent antiarrhythmic effects in tachycardias involving the atrioventricular (AV) node. This study, the first in humans, was designed to determine the effects of CVT-510 on AV nodal conduction and hemodynamics. METHODS AND RESULTS: Patients in sinus rhythm with normal AV nodal function at electrophysiologic study (n = 32) received a single intravenous bolus of CVT-510. AH and HV intervals were measured during sinus rhythm and during atrial pacing at 1, 5, 10, 15, 20, 30, 45, and 60 minutes after the bolus. Increasing doses of CVT-510 (0.3 to 10 microg/kg) caused a dose-dependent increase in the AH interval. At 1 minute, a dose of 10 microg/kg increased the AH interval during sinus rhythm from 93 +/- 23 msec to 114 +/- 37 msec, p = 0.01 and from 114 +/- 31 msec to 146 +/- 44 msec during atrial pacing at 600 msec, p = 0.003). The AH interval returned to baseline by 20 minutes. CVT-510 at doses of 0.3 to 10 microg/kg had no effect on sinus rate, HV interval, or systemic blood pressure, and was not associated with serious adverse effects. At doses of 15 and 30 microg/kg, CVT-510 produced transient second/third degree AV heart block in all four patients treated. One of these patients also had a prolonged sedative effect that was reversed with aminophylline. CONCLUSIONS: CVT-510 promptly prolongs AV nodal conduction and does not affect sinus rate or blood pressure. Selective stimulation of the A(1)-adenosine receptor by CVT-510 may be useful for immediate control of heart rate in atrial fibrillation/flutter and to convert paroxysmal supraventricular tachycardia to sinus rhythm, while avoiding vasodilatation mediated by the A(2)-adenosine receptor, as well as the vasodepressor and negative inotropic effects associated with beta-adrenergic receptor blockade and/or calcium channel blockers.

MMTV promoter hypomethylation is linked to spontaneous and MNU associated c-neu expression and mammary carcinogenesis in MMTV c-neu transgenic mice.

The erbB family of receptor tyrosine kinases is frequently implicated in neoplasia. Amplification and overexpression of erbB2/neu has been found in 20 to 40% of human breast cancers. Previous studies using MMTV/c-neu transgenic mice have linked rat neu overexpression to mammary tumor development. In this study, we provide evidence that rat neu overexpression in mammary tumors of MMTV/c-neu transgenic mice is always associated with demethylation of the MMTV promoter, whereas the normal mammary glands of these transgenic mice always contain specific methylated regions of the MMTV promoter. In addition, after exposure to N-methyl-N-nitrosourea (MNU), the latency of mammary tumor development is significantly reduced and again is also associated with MMTV promoter demethylation. Thus, the transition from methylation to hypomethylation of the MMTV promoter induces high-level expression of c-neu and appears to be a prerequisite for transformation from normal to malignant mammary epithelium, either spontaneously or after carcinogen exposure. Expression of transgenic c-neu from the demethylated MMTV promoter appears to be an early event that allows outgrowth of mammary epithelium predisposed to malignant transformation.

The impact of maternal alcohol and illicit drug use on children's behavior problems: evidence from the children of the national longitudinal survey of youth.

This study uses Children of the National Longitudinal Survey of Youth to test for evidence of a causal relationship between maternal alcohol, marijuana, and cocaine use, and children's behavior problems. Ordinary least squares (OLS) results provide strong evidence that substance use is associated with behavior problems. However, OLS estimation fails to account for unobserved factors that may be correlated with substance use and child behavior. To account for this problem, mother-child and family fixed-effects models are tested. The results suggest that maternal illicit drug use is positively associated with children's behavior problems, while alcohol use has a less consistent impact.

Significance of inducible ventricular fibrillation in patients with coronary artery disease and unexplained syncope.

OBJECTIVES: This study was designed to determine the incidence and prognostic significance of inducible ventricular fibrillation (VF) in patients with coronary artery disease (CAD) and unexplained syncope. BACKGROUND: Current American College of Cardiology/American Heart Association practice guidelines recommend implantation of internal cardioverter-defibrillators (ICDs) in patients with unexplained syncope in whom either ventricular tachycardia (VT) or VF is inducible during electrophysiologic (EP) testing. Although the prognostic significance of inducible monomorphic VT is known, the significance of inducible VF remains undefined. METHODS: We evaluated 118 consecutive patients with CAD and unexplained syncope who underwent EP testing. Sustained monomorphic VT was inducible in 53 (45%) patients; in 20 (17%) patients, VF was the only inducible arrhythmia; and no sustained ventricular arrhythmia was inducible in the remaining 45 (38%) patients. The latter two groups of 65 (55%) patients make up the study population. RESULTS: There were 16 deaths among the study population during a follow-up period of 25.3 +/- 19.6 months. The overall one- and two-year survival in these patients was 89% and 81%, respectively. No significant difference in survival was observed between patients with and without inducible VF (80% power to detect a fourfold survival difference). CONCLUSIONS: In 17% of patients with CAD and unexplained syncope, VF is the only inducible ventricular arrhythmia. Within the limits of this pilot study, long-term follow-up of patients with and without inducible VF demonstrates no difference in survival between the two groups. Therefore, the practice of ICD implantation in patients with CAD, unexplained syncope and inducible VF, especially with triple ventricular extrastimuli, may merit reconsideration.

Complex AV nodal dynamics during ventricular-triggered atrial pacing in humans.

In vitro experiments have shown that the complexity of atrioventricular nodal (AVN) conduction dynamics increases with heart rate. Although complex AVN dynamics (e.g., alternans) have been observed clinically, human AVN dynamics during rapid pacing have not been systematically investigated. We studied such dynamics during ventricular-triggered atrial pacing in 37 patients with normal AVN function (18 patients with dual AVN pathway physiology and 19 patients without). Alternans, which always resulted from single pathway conduction, occurred in 18 patients. In 16 patients (3 of whom also had alternans), quasisinusoidal AVN conduction oscillations occurred (mean frequency 0.02 Hz); such oscillations have not been previously reported. There were no significant differences in the dynamics for patients with or without dual AVN pathways. To illuminate the governing dynamic mechanism, a second atrial pacing trial was performed on 12 patients after autonomic blockade. Blockade facilitated alternans but inhibited oscillations. This study suggests that rapid AVN excitation in vivo can lead to autonomically mediated AVN conduction oscillations or single pathway alternans that are a function of inherent nonlinear dynamic AVN tissue properties.

Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammation of the gastrointestinal tract caused by an abnormal and uncontrolled immune response to one or more normally occurring gut constituents. AIM: Given the effects of transforming growth factor beta1 (TGF-beta1) on both the immune system and extracellular matrix, we postulated that alterations in TGF-beta signalling in intestinal epithelial cells may play an important role in the development of IBD. METHODS: TGF-beta signalling was inactivated in mouse intestine by expressing a dominant negative mutant form of the TGF-beta type II receptor under the control of the mouse intestinal trefoil peptide (ITF)/TFF3 promoter. Transgenic mice (ITF-dnRII) developed spontaneous colitis presenting with diarrhoea, haematochezia, and anal prolapse when not maintained under specific pathogen free (SPF) conditions. Under SPF conditions we induced colitis by mixing dextran sodium sulphate (DSS) in drinking water to examine the significance of loss of TGF-beta signalling in the pathogenesis of IBD. RESULTS: Transgenic mice showed increased susceptibility to DSS induced IBD, and elicited increased expression of major histocompatibility complex class II, generation of autoantibodies against intestinal goblet cells, and increased activity of matrix metalloproteinase in intestinal epithelial cells compared with wild-type littermates challenged with DSS. CONCLUSIONS: Deficiency of TGF-beta signalling specifically in the intestine contributes to the development of IBD. Maintenance of TGF-beta signalling may be important in regulating immune homeostasis in the intestine

Fast-tracking after outpatient laparoscopy: reasons for failure after propofol, sevoflurane, and desflurane anesthesia.

IMPLICATIONS: In this study, although 41%-94% of the patients were fast-track eligible after laparoscopic surgery, only 35%-53% of the patients actually bypassed the postanesthesia care unit (PACU) because of anesthetic-related factors and surgical complications. Residual sedation was the most common anesthetic-related cause of failure to bypass thePACU.

Testing for colon neoplasia susceptibility variants at the human COX2 locus.

BACKGROUND: Siblings and other first-degree relatives of patients with "sporadic" (i.e., apparently nonfamilial) colorectal cancer or precursor adenomatous colon polyps have an increased risk of developing colon neoplasia. This observation suggests the presence of inherited genetic determinants for sporadic colon neoplasia. Mice homozygous for a null cyclooxygenase 2 (COX2) (also called PTGS2) allele have a dramatically reduced susceptibility to the development of intestinal adenomas. In humans, use of pharmacologic inhibitors of COX2 enzyme activity are associated with reduced risk of colon neoplasia. This study examined whether the human COX2 locus may be linked to colon neoplasia in humans. METHODS: We used the affected sibling-pair method to test for linkage of the human COX2 locus to colon neoplasia. RESULTS: We examined 74 concordantly affected sibling pairs from 46 sibships with colon neoplasia. One hundred five siblings from these sibships were diagnosed with either colorectal cancer or colon adenomatous polyps before age 65 years. No linkage between COX2 and colon neoplasia was found by use of a multipoint model-free linkage analysis (estimate of allele sharing was 0.44; standard error = +/-0.04; 95% confidence interval = 0.36 to 0.52). Moreover, even allowing for heterogeneity, the potential that a COX2 colon neoplasia susceptibility variant was present within a substantial subset of these sibships was strongly excluded under either a recessive or a dominant inheritance model (95% confidence to exclude a model in which 2.7% or more of the sibling pairs harbor a dominant susceptibility allele). CONCLUSIONS: This study of concordantly affected sibling pairs thus demonstrates that variations in the COX2 gene are unlikely to be a source of individual susceptibility to colon neoplasia in humans.

Searching for microsatellite mutations in coding regions in lung, breast, ovarian and colorectal cancers.

RepX represents a new informatics approach to probe the UniGene database for potentially polymorphic repeat sequences in the open reading frame (ORF) of genes, 56% of which were found to be actually polymorphic. We now have performed mutational analysis of 17 such sites in genes not found to be polymorphic (<0.03 frequency) in a large panel of human cancer genomic DNAs derived from 31 lung, 21 breast, seven ovarian, 21 (13 microsatellite instability (MSI)+ and eight MSI-) colorectal cancer cell lines. In the lung, breast and ovarian tumor DNAs we found no mutations (<0.03-0.04 rate of tumor associated open reading frame mutations) in these sequences. By contrast, 18 MSI+ colorectal cancers (13 cancer cell lines and five primary tumors) with mismatch repair defects exhibited six mutations in three of the 17 genes (SREBP-2, TAN-1, GR6) (P<0.000003 compared to all other cancers tested). We conclude that coding region microsatellite alterations are rare in lung, breast, ovarian carcinomas and MSI (-) colorectal cancers, but are relatively frequent in MSI (+) colorectal cancers with mismatch repair deficits.

Nonlinear-dynamical arrhythmia control in humans.

Nonlinear-dynamical control techniques, also known as chaos control, have been used with great success to control a wide range of physical systems. Such techniques have been used to control the behavior of in vitro excitable biological tissue, suggesting their potential for clinical utility. However, the feasibility of using such techniques to control physiological processes has not been demonstrated in humans. Here we show that nonlinear-dynamical control can modulate human cardiac electrophysiological dynamics by rapidly stabilizing an unstable target rhythm. Specifically, in 52/54 control attempts in five patients, we successfully terminated pacing-induced period-2 atrioventricular-nodal conduction alternans by stabilizing the underlying unstable steady-state conduction. This proof-of-concept demonstration shows that nonlinear-dynamical control techniques are clinically feasible and provides a foundation for developing such techniques for more complex forms of clinical arrhythmia.