Exposure to manganese (Mn) is associated with neurobehavioral effects. There is disagreement on whether commonly occurring exposures in welding, ferroalloy, and other industrial processes produce neurologically significant neurobehavioral changes representing parkinsonism. A review of methodological issues in the human epidemiological literature on Mn identified: (1) studies focused on idiopathic Parkinson disease without considering manganism, a parkinsonian syndrome; (2) studies with healthy worker effect bias; (3) studies with problematic statistical modeling; and (4) studies arising from case series derived from litigation. Investigations with adequate study design and exposure assessment revealed consistent neurobehavioral effects and attributable subclinical and clinical signs and symptoms of impairment. Twenty-eight studies show an exposure-response relationship between Mn and neurobehavioral effects, including 11 with continuous exposure metrics and six with three or four levels of contrasted exposure. The effects of sustained low-concentration exposures to Mn are consistent with the manifestations of early manganism, i.e., consistent with parkinsonism. This is compelling evidence that Mn is a neurotoxic chemical and there is good evidence that Mn exposures far below the current US standard of 5.0 mg/m3 are causing impairment.
Bias (Epidemiology) ; Healthy Worker Effect ; Humans ; Jurisprudence ; Manganese* ; Models, Statistical ; Neurobehavioral Manifestations ; Neuropsychological Tests ; Occupations* ; Parkinson Disease ; Parkinsonian Disorders* ; Welding

Foundry workers are potentially exposed to a number of carcinogens. This study was conducted to describe the cancer incidence associated with employment in small-sized Korean iron foundries and to compare those findings to the Korean population. Cancer morbidity in 208 Korean foundries was analyzed using the Standardized Incidence Ratio (SIR) and Standardized Rate Ratio (SRR). Overall cancer morbidity in foundry workers (SIR=1.11, 95% confidence interval [CI]=1.01-1.21) was significantly higher than that of Korean general population. Lung cancer (SIR=1.45, 95%CI=1.11-1.87) and lymphohematopoietcic cancer (SIR=1.58, 95%CI=1.00-2.37) in production workers were significantly high compared to Korean general population. Stomach cancer in fettling (SRR=2.10, 95%CI=1.10-4.01) and lung cancer in molding (SRR=3.06, 95%CI=1.22-7.64) and in fettling (SRR=2.63, 95%CI=1.01-6.84) were there significant elevations compared to office workers. In this study, statistically significant excess lung cancer was observed in production workers comparing to Korean general population and office workers. Also, cancer morbidity of overall cancer, lung cancer and stomach cancer was significantly increased with duration of employment at ten and more years comparing to Korean general population. These findings suggest in causal association between exposure to carcinogens during foundry work and cancer morbidity.
Adult ; Aged ; Carcinogens/toxicity ; Cohort Studies ; Female ; Humans ; Iron/toxicity ; Lung Neoplasms/epidemiology/mortality ; Male ; Middle Aged ; Morbidity ; Neoplasms/*epidemiology/mortality ; Occupational Diseases/*epidemiology ; Occupational Exposure ; Republic of Korea ; Stomach Neoplasms/epidemiology/mortality

BACKGROUND: Metalworking fluids (MWFs) are mixtures with inhalation exposures as mists, dusts, and vapors, and dermal exposure in the dispersed and bulk liquid phase. A quantitative risk assessment was performed for exposure to MWF and respiratory disease.METHODS: Risks associated with MWF were derived from published studies and NIOSH Health Hazard Evaluations, and lifetime risks were calculated. The outcomes analyzed included adult onset asthma, hypersensitivity pneumonitis, pulmonary function impairment, and reported symptoms. Incidence rates were compiled or estimated, and annual proportional loss of respiratory capacity was derived from cross-sectional assessments.RESULTS: A strong healthy worker survivor effect was present. New-onset asthma and hypersensitivity pneumonitis, at 0.1 mg/m3 MWF under continuous outbreak conditions, had a lifetime risk of 45%; if the associated microbiological conditions occur with only 5% prevalence, then the lifetime risk would be about 3%. At 0.1 mg/m3, the estimate of excess lifetime risk of attributable pulmonary impairment was 0.25%, which may have been underestimated by a factor of 5 or more by a strong healthy worker survivor effect. The symptom prevalence associated with respiratory impairment at 0.1 mg/m3 MWF was estimated to be 5% (published studies) and 21% (Health Hazard Evaluations).CONCLUSION: Significant risks of impairment and chronic disease occurred at 0.1 mg/m3 for MWFs in use mostly before 2000. Evolving MWFs contain new ingredients with uncharacterized long-term hazards.
Adult ; Alveolitis, Extrinsic Allergic ; Asthma ; Asthma, Occupational ; Chronic Disease ; Dust ; Humans ; Incidence ; Inhalation Exposure ; National Institute for Occupational Safety and Health (U.S.) ; Prevalence ; Risk Assessment ; Survivors

Background: Toluene diisocyanate (TDI) is a highly reactive chemical that causes sensitization and has also been associated with increased lung cancer. A risk assessment was conducted based on occupational epidemiologic estimates for several health outcomes. Methods: Exposure and outcome details were extracted from published studies and a NIOSH Health Hazard Evaluation for new onset asthma, pulmonary function measurements, symptom prevalence, and mortality from lung cancer and respiratory disease. Summary exposure–response estimates were calculated taking into account relative precision and possible survivor selection effects. Attributable incidence of sensitization was estimated as were annual proportional losses of pulmonary function. Excess lifetime risks and benchmark doses were calculated. Results: Respiratory outcomes exhibited strong survivor bias. Asthma/sensitization exposure response decreased with increasing facility-average TDI air concentration as did TDI-associated pulmonary impairment. In a mortality cohort where mean employment duration was less than 1 year, survivor bias pre-empted estimation of lung cancer and respiratory disease exposure response. Conclusion Controlling for survivor bias and assuming a linear dose–response with facility-average TDI concentrations, excess lifetime risks exceeding one per thousand occurred at about 2 ppt TDI for sensitization and respiratory impairment. Under alternate assumptions regarding stationary and cumulative effects, one per thousand excess risks were estimated at TDI concentrations of 10 – 30 ppt. The unexplained reported excess mortality from lung cancer and other lung diseases, if attributable to TDI or associated emissions, could represent a lifetime risk comparable to that of sensitization.

Background: Toluene diisocyanate (TDI) is a highly reactive chemical that causes sensitization and has also been associated with increased lung cancer. A risk assessment was conducted based on occupational epidemiologic estimates for several health outcomes. Methods: Exposure and outcome details were extracted from published studies and a NIOSH Health Hazard Evaluation for new onset asthma, pulmonary function measurements, symptom prevalence, and mortality from lung cancer and respiratory disease. Summary exposure–response estimates were calculated taking into account relative precision and possible survivor selection effects. Attributable incidence of sensitization was estimated as were annual proportional losses of pulmonary function. Excess lifetime risks and benchmark doses were calculated. Results: Respiratory outcomes exhibited strong survivor bias. Asthma/sensitization exposure response decreased with increasing facility-average TDI air concentration as did TDI-associated pulmonary impairment. In a mortality cohort where mean employment duration was less than 1 year, survivor bias pre-empted estimation of lung cancer and respiratory disease exposure response. Conclusion Controlling for survivor bias and assuming a linear dose–response with facility-average TDI concentrations, excess lifetime risks exceeding one per thousand occurred at about 2 ppt TDI for sensitization and respiratory impairment. Under alternate assumptions regarding stationary and cumulative effects, one per thousand excess risks were estimated at TDI concentrations of 10 – 30 ppt. The unexplained reported excess mortality from lung cancer and other lung diseases, if attributable to TDI or associated emissions, could represent a lifetime risk comparable to that of sensitization.

BACKGROUND/AIMS: Smooth muscle cells (SMCs) characteristically express serum response factor (SRF), which regulates their development. The role of SRF in SMC plasticity in the pathophysiological conditions of gastrointestinal (GI) tract is less characterized. METHODS: We generated SMC-specific Srf knockout mice and characterized the prenatally lethal phenotype using ultrasound biomicroscopy and histological analysis. We used small bowel partial obstruction surgeries and primary cell culture using cell-specific enhanced green fluorescent protein (EGFP) mouse lines to study phenotypic and molecular changes of SMCs by immunofluorescence, Western blotting, and quantitative polymerase chain reaction. Finally we examined SRF change in human rectal prolapse tissue by immunofluorescence. RESULTS: Congenital SMC-specific Srf knockout mice died before birth and displayed severe GI and cardiac defects. Partial obstruction resulted in an overall increase in SRF protein expression. However, individual SMCs appeared to gradually lose SRF in the hypertrophic muscle. Cells expressing low levels of SRF also expressed low levels of platelet-derived growth factor receptor alpha (PDGFRalphalow) and Ki67. SMCs grown in culture recaptured the phenotypic switch from differentiated SMCs to proliferative PDGFRalphalow cells. The immediate and dramatic reduction of Srf and Myh11 mRNA expression confirmed the phenotypic change. Human rectal prolapse tissue also demonstrated significant loss of SRF expression. CONCLUSIONS: SRF expression in SMCs is essential for prenatal development of the GI tract and heart. Following partial obstruction, SMCs down-regulate SRF to transition into proliferative PDGFRalphalow cells that may represent a phenotype responsible for their plasticity. These findings demonstrate that SRF also plays a critical role in the remodeling process following GI injury.
Animals ; Blotting, Western ; Fluorescent Antibody Technique ; Gastrointestinal Tract ; Heart ; Humans ; Mice ; Mice, Knockout ; Microscopy, Acoustic ; Muscle Cells ; Muscle, Smooth* ; Myocytes, Smooth Muscle ; Parturition ; Phenotype* ; Plastics ; Polymerase Chain Reaction ; Primary Cell Culture ; Receptors, Platelet-Derived Growth Factor ; Rectal Prolapse ; RNA, Messenger ; Serum Response Factor*

Background/Aims: Insomnia is common in people with chronic medical conditions, such as inflammatory bowel disease (IBD), and is readily treatable through cognitive behavioral therapy for insomnia. This study aimed to describe the associations with insomnia in people with IBD and its relationship to IBD-related disability. Methods: An online questionnaire was administered through 3 tertiary IBD centers, social media, and Crohn’s Colitis Australia. The questionnaire included the Insomnia Severity Index (ISI), a validated assessment of insomnia. Measures of anxiety, depression, physical activity, and disability were also included. IBD activity was assessed using validated patient reported scores. A multivariate model was constructed for clinically significant insomnia and ISI scores. Subpopulations of Crohn’s disease and ulcerative colitis were considered. Results: In a cohort of 670 respondents the median age was 41 years (range, 32–70 years), with the majority female (78.4%), the majority had Crohn’s disease (57.3%). Increasingly severe disability was associated with worse insomnia score. Clinically significant insomnia was associated with clinically active IBD, abdominal pain, anxiety, and depression, in a multivariate model. In an ulcerative colitis population, Simple Clinical Colitis Activity Index components of general well-being and urgency were associated with worse ISI score in a model including depression and anxiety. In those with Crohn’s disease, the multivariate model included Harvey Bradshaw Index score in addition to depression and anxiety. Conclusions Insomnia is common in people with IBD and is associated with increased disability. Abdominal pain and mental health conditions should prompt consideration for screening for insomnia and referral for cognitive behavioral therapy for insomnia.

No abstract available.
Germ Cells* ; Humans ; Neoplasms, Germ Cell and Embryonal* ; Treatment Outcome* ; Biomarkers, Tumor*

To develop a more appropriate therapeutic strategy for treatment of nonpulmonary visceral metastatic testicular seminoma based on the International Germ Cell Consensus Classification, we reviewed the medical records of patients with nonpulmonary visceral metastatic testicular seminoma who were treated over a 20-year period. Only 15 (2.2%) of the 686 cases of testicular seminoma were nonpulmonary visceral metastatic seminoma. The median age of patients was 38 years (range, 22-53 years). Ten (67%) of the patients had an initial diagnosis of supradiaphragmatic or visceral metastatic disease. In addition to nonpulmonary visceral metastasis, all patients had lymph node metastasis as well, the majority of which involved the retroperitoneal lymph nodes. The median and mean progression-free survival durations after chemotherapy for advanced disease were 19 months and 63.7 months, respectively. Six patients (40%) survived, five relapsed after radiation therapy and four died of chemorefractory disease not dependent on the specific regimen. Although the number of cases reviewed in this study was small, we conclude that the choice of chemotherapeutic regimen among the current treatments for nonpulmonary visceral metastatic seminoma of testis primary does not present a different outcome. Therefore, multimodality therapies using new strategies or new agents are well indicated.
Adult ; Antineoplastic Agents, Combined/administration & dosage* ; Bone Neoplasms/secondary ; Bone Neoplasms/radiotherapy ; Bone Neoplasms/drug therapy ; Combined Modality Therapy ; Human ; Lung Neoplasms/secondary ; Lung Neoplasms/radiotherapy ; Lung Neoplasms/drug therapy ; Lymphatic Metastasis ; Male ; Middle Age ; Retroperitoneal Neoplasms/secondary* ; Retroperitoneal Neoplasms/radiotherapy ; Retroperitoneal Neoplasms/drug therapy* ; Retrospective Studies ; Seminoma/secondary* ; Seminoma/radiotherapy ; Seminoma/drug therapy* ; Testicular Neoplasms/pathology*

We wanted to present the results of our experience with bilateral testis tumor and to suggest the effects of chemotherapy in suppressing the development of second primary testicular tumors. Between 1978 and 1997, 2,345 patients were treated for testicular tumor at The University of Texas M. D. Anderson Cancer Center. Of these, 2,107 had germ cell cancers. There were 22 (0.94%) cases of bilateral testicular tumor in the overall patient population and 21 (1.0%) cases among patients with germ cell cancer. We reviewed the medical records to determine the incidence of the histological subtype, the incidence of metachronous versus synchronous formation of contralateral tumors, and tumor stage in this patient population. We also examined the effect of chemotherapy in treating the first tumor and preventing the occurrence of a second tumor. Finally, we compared the effect of ultrasonography, serum tumor marker elevation, and physical examination in detecting second tumors. Only one contralateral germ cell tumor developed synchronously; all others developed metachronously. Fifty percent of first tumors were seminomas, compared to 55% of second tumors. The histologic concordance rate for first and second tumors was 35%. Tumor stage was higher among first tumors than second tumors. The majority of second tumors in patients who received chemotherapy for first malignancies tended to be metachronous seminomas. Ultrasonography detected 6 of 21 (28.6%) contralateral tumors before they were evident by physical examination or serum tumor marker elevation. Seminomas were more prevalent among patients with bilateral germ cell disease than patients with unilateral disease. Chemotherapy, when used as treatment for first tumors, may have some effect in preventing the development of nonseminomatous germ cell tumors in the contralateral testicle. Close follow-up of the contralateral testis with ultrasonography is essential for early detection of second tumors. The outcome for patients with bilateral testicular germ cell cancer is excellent, secondary to early detection.
Adolescence ; Adult ; Antineoplastic Agents/therapeutic use* ; Human ; Incidence ; Male ; Neoplasms, Multiple Primary/epidemiology ; Neoplasms, Second Primary/prevention & control* ; Neoplasms, Second Primary/epidemiology ; Testicular Neoplasms/pathology ; Testicular Neoplasms/drug therapy*