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The training of soldiers for urban conflict involves marksmanship instruction on outdoor flat ranges and the teaching of close-quarter battle techniques in indoor facilities, referred to as shoot houses, where intense firing exercises can generate high air lead levels from small arms ammunition, flash bang grenades, and explosive devices. Levels of lead and copper in air were evaluated during five training activities of a 45-day training course using both stationary general area and breathing zone sampling over a 2-year period. Individual blood lead values were determined prior to and at course completion. Mean breathing zone lead concentrations for the five training activities ranged from 0.014 on the outdoor flat range to 0.064 mg/m 3 inside shoot houses; with a change to lead-free ammunition the values were reduced to a range of 0.006-0.022 mg/m 3 . Isolated flash bang grenades generated very high general area lead concentrations (2.0 mg/m 3 ), which in training were associated with the highest measured breathing zone concentration (0.16 mg/m 3 ). For copper, mean breathing zone concentrations increased from 0.010 to 0.037 mg/m 3 with the change to lead-free frangible ammunition on the outdoor range, but remained below the permissible exposure limit for copper fume. Inside shoot houses, mean breathing zone copper concentrations exceeded the permissible exposure limit with ball and lead-free frangible ammunition, ranging from 0.077-0.13 mg/m 3 . With the introduction of lead-free ammunition, when comparing the blood lead differences between start and finish of the course, there was a significant reduction in the mean blood lead difference from 13.3 µg/dL to 5.4 µg/dL. Options for mitigation of potentially high exposure areas using improved ventilation designs are discussed. These results advocate for improved designs for shoot house training facilities, stress the importance of removing lead from ammunition and explosive devices for training, and promote the continued need for implementation of controls to mitigate and manage metal exposures during training.

Introduction: Ongoing studies are investigating the potential link between deployment to Operation Iraqi Freedom and Operation Enduring Freedom and relationship to increases in pulmonary disease. While increases in certain diseases such as asthma and airway hyperreactivity are well established, data on other chronic pulmonary diseases such as sarcoidosis have not been defined., Material and Methods: A retrospective chart review was conducted of all active duty military personnel diagnosed with sarcoidosis from 2005 to 2010. Deployment dates and locations were obtained through the Armed Forces Health Surveillance Branch. Electronic medical records were reviewed to determine the following parameters: dates of diagnosis, temporal relationship of diagnosis and deployment, symptoms (pre- and/or post-deployment), spirometry, diffusing capacity, radiographic staging, and treatment course. Pulmonary sarcoidosis incidence rates were estimated using International Classification of Diseases (ICD-9) coded medical encounter data from the Defense Medical Surveillance System and compared between Army and nonArmy personnel, as well as between ever-deployed and never-deployed personnel., Results: A cohort of 478 Army soldiers was identified with sarcoidosis based on ICD-9 codes and individual review of the medical records. The cohort was 80% male. 38.7% of soldiers with sarcoidosis never deployed. 11.7% were diagnosed prior to deployment, and 50.2% were diagnosed postdeployment. The diagnosis of sarcoidosis was established with a tissue diagnosis in 68% of the deployed cohort. Overall differences in spirometry were not identified. Obstructed spirometry was similar in all deployment groups (never, pre, and post) at 9.2%, 15.8% and 8.7%, respectively. Restrictive patterns based on total lung capacity (<70%) were similar at 9.2%, 12.5%, and 11.0%, respectively. Radiographic staging showed a similar distribution in the populations with the never/pre versus postdeployment groups having Stage 0 = 2.3 versus 3.5%, Stage I = 43.8 versus 41.6%, Stage II = 33.1 versus 41.0%, Stage III = 15.1 versus 12.1%, and Stage IV = 2.2 versus 1.7%, respectively. During 2005-2010, the estimated incidence rate of pulmonary sarcoidosis was low among active duty Army personnel (16.5 cases/100,000 person-years), and no trend in annual rates was observed, p = 0.89. Based on overall Department of Defense medical data, estimated pulmonary sarcoidosis rates were lower among ever-deployed personnel, relative to nondeployed personnel., Conclusion: Based on this analysis of Army sarcoidosis patients, there was no difference in the rates of sarcoidosis diagnosis in deployed and nondeployed soldiers. Spirometry values, total lung capacity, and radiographic staging did not show significant differences between deployment groups., (© The Association of Military Surgeons of the United States. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Since 2001, more than 2.7 million U.S. military personnel have been deployed in support of operations in Southwest Asia and Afghanistan. Land-based personnel experienced elevated exposures to particulate matter and other inhalational exposures from multiple sources, including desert dust, burn pit combustion, and other industrial, mobile, or military sources. A workshop conducted at the 2018 American Thoracic Society International Conference had the goals of: 1 ) identifying key studies assessing postdeployment respiratory health, 2 ) describing emerging research, and 3 ) highlighting knowledge gaps. The workshop reviewed epidemiologic studies that demonstrated more frequent encounters for respiratory symptoms postdeployment compared with nondeployers and for airway disease, predominantly asthma, as well as case series describing postdeployment dyspnea, asthma, and a range of other respiratory tract findings. On the basis of particulate matter effects in other populations, it also is possible that deployers experienced reductions in pulmonary function as a result of such exposure. The workshop also gave particular attention to constrictive bronchiolitis, which has been reported in lung biopsies of selected deployers. Workshop participants had heterogeneous views regarding the definition and frequency of constrictive bronchiolitis and other small airway pathologic findings in deployed populations. The workshop concluded that the relationship of airway disease, including constrictive bronchiolitis, to exposures experienced during deployment remains to be better defined. Future clinical and epidemiologic research efforts should address better characterization of deployment exposures; carry out longitudinal assessment of potentially related adverse health conditions, including lung function and other physiologic changes; and use rigorous histologic, exposure, and clinical characterization of patients with respiratory tract abnormalities.

Objective: To develop and validate a simple geriatric screening tool that performs as well as more complex assessments BACKGROUND:: Many tools that predict treatment risk in older adults are impractical for routine clinical use., Methods: We prospectively conducted comprehensive preoperative evaluations on 1025 patients age ≥75 years who presented to Sinai Hospital of Baltimore for major elective surgery, then retrospectively reviewed patients' medical records for occurrence of postoperative outcomes. Using logistic regression modeling and receiver operating characteristic curve analysis we selected the best combination of simple tests, labeling this the Sinai Abbreviated Geriatric Evaluation (SAGE). The performance of the SAGE was then compared with 3 standard tools in its power to predict postoperative outcomes., Results: The SAGE is a statistically significant predictor of postoperative outcomes. Each unit decrease in SAGE score was significantly associated with a 51% (95% CI 1.30-1.77) increase in odds of a complication, a 2-fold increase in odds of postoperative delirium (95% CI 1.65-2.66), a 27% increase in odds of length of hospital stay >2 days (95% CI 1.10-1.47), a 54% increase in odds of a hospital readmission within 30 days (95% CI 1.25-2.88), and a 38% increase in odds of an unanticipated discharge to higher-level care (95% CI 1.18-1.61). We estimated the receiver operating characteristic curve area under the curve (AUC) for the SAGE of 0.69, 0.77, 0.73, 0.66, and 0.78 for the above outcomes, respectively. The SAGE performed as well in predicting postoperative outcomes as Fried's frailty phenotype, Charlson Comorbidity Index, and American Society of Anesthesiologists Physical Status Class (ASA)., Conclusion: The SAGE performs as well as other geriatric evaluations that require equipment or memorization.

Background: Service members deploying to Afghanistan (OEF) and Iraq (OIF) often return with respiratory symptoms. We sought to determine prevalence of lung function abnormalities following OEF/OIF., Methods: We identified OEF/OIF patients who had unexplained respiratory symptoms evaluated using lung function testing. Lung function data were summarized and analyzed for associations with demographic and deployment characteristics., Results: We found 267 patients with unexplained cough or dyspnea, lung function testing and a history of OEF/OIF deployment. All patients had basic spirometry performed and 82 had diffusion capacity for carbon dioxide (DLCO) measured. The median (IQR) number of deployments and total days deployed were 1 (1-2) and 352.0 (209-583), respectively. There were 83 (36.6%) patients with abnormal spirometry, 53 (63.9%) of whom had an abnormal FEV1/FVC. Only one (1.2%) patient had an abnormal DLCO adjusted for alveolar volume. Of 104 patients who had post bronchodilator (BD) testing performed, six (5.8%) had a positive response by ATS criteria. We found no relationships between lung function and time in theater, deployment location, deployment frequency, or land based-deployment. Dyspnea and enlisted rank were associated with tobacco use and lower FEV1, and cough was associated with total number of deployments., Conclusions: Service members with respiratory complaints following OEF/OIF have a high prevalence of abnormalities on spirometry. Tobacco use, enlisted rank and total number of deployments were associated with symptoms or spirometric abnormalities., (Published by Elsevier Ltd.)

Objective: The aim of this study was to determine the relationship between deployment length and indices of airflow obstruction in Iraq and Afghanistan veterans with airborne hazards exposure., Methods: One hundred twenty-four post-9/11 veterans completed pulmonary function testing and questionnaires. We examined the association of airflow limitation [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC)] and bronchodilator responsiveness (ΔFEV1 and ΔFVC) with deployment length, adjusting for smoking., Results: Longer deployment length was associated with lower FEV1/FVC [β = -0.19; 95% confidence interval (95% CI), -0.39 to 0.01], greater ΔFEV1 (β = 0.27; 95% CI, 0.09 to 0.45) and ΔFVC (β = 0.19; 95% CI, 0.05 to 0.33). In our model adjusted for smoking history, longer deployment length remained associated with greater ΔFEV1 and ΔFVC (P < 0.01), but not with FEV1/FVC (P = 0.059)., Conclusion: In our sample of post-9/11 veterans, longer deployment lengths were associated with significant bronchodilator responsiveness and a trend toward airflow limitation independent of tobacco use.

Objective: Human milk is the best form of nutrition for preterm infants and has been associated with a lower incidence of necrotizing enterocolitis (NEC). Infants that develop NEC have a higher incidence of feeding intolerance and longer hospitalizations. The combination of a donor milk bank and donor milk-derived fortifier has changed feeding practices in neonatal intensive care units (NICU). The purpose of this study is to assess the benefits and cost of an exclusive human milk (EHM) diet in very low birth weight (VLBW) infants in a community level III NICU., Study Design: This is a retrospective study including preterm infants ⩽28 weeks and/or VLBW (⩽1500 g) who were enrolled from March 2009 until March 2014. Infants were grouped as follows: group H (entirely human milk based, born March 2012 to 2014), group B (bovine-based fortifier and maternal milk, born March 2009 to 2012), group M (mixed combination of maternal milk, bovine-based fortifier and formula, born March 2009 to 2012) and group F (formula fed infants, born March 2009 to 2012). Baseline characteristics among the four groups were similar., Result: The study included 293 infants between gestational ages 23 to 34 weeks and birth weights between 490 and 1700 g. Feeding intolerance occurred less often (P<0.0001), number of days to full feeds was lower (P<0.001), incidence of NEC was lower (P<0.011), and total hospitalization costs were lower by up to $106,968 per infant (P<0.004) in those fed an EHM diet compared with the other groups. Average weight gain per day was similar among the four groups (18.5 to 20.6 g per day)., Conclusions: Implementing an EHM diet in our VLBW infants has led to a significant decrease in the incidence of NEC. Other benefits of this diet include: decreased feeding intolerance, shorter time to full feeds, shorter length of stay, and lower hospital and physician charges for extremely premature and VLBW infants.

Inhalational hazards are numerous in operational environments. A retrospective cohort study was conducted to investigate associations between deployment to Kabul, Afghanistan and subsequent respiratory health among U.S. military personnel. The study population consisted of personnel who deployed to Kabul, select Operation Enduring Freedom locations, personnel stationed in the Republic of Korea, and U.S.-stationed personnel. Incidence rate ratios (IRRs) were estimated for respiratory symptoms, signs, and ill-defined conditions, asthma, and chronic obstructive pulmonary disease. A significantly elevated rate of symptoms, signs, and ill-defined conditions was observed among Kabul-deployed personnel compared to personnel deployed or stationed in Bagram (IRR 1.12; 95% confidence interval [CI], 1.05-1.19), Republic of Korea (IRR 1.20; 95% CI, 1.10-1.31), and the United States (IRR 1.52; 95% CI, 1.43-1.62). A statistically elevated rate of asthma was observed among personnel deployed to Kabul, relative to U.S.-stationed personnel (IRR 1.61; 95% CI, 1.22-2.12). Statistically significant rates were not observed for chronic obstructive pulmonary disease among Kabul-deployed personnel compared to other study groups. These findings suggest that deployment to Kabul is associated with an elevated risk of postdeployment respiratory symptoms and new-onset asthma., (Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.)

Background: The US military has been continuously engaged in combat operations since 2001. Assessing trends in respiratory health diagnoses during this time of prolonged military conflict can provide insight into associated changes in the burden of pulmonary conditions in the US military population., Purpose: To estimate and evaluate trends in rates of chronic obstructive pulmonary diseases in the active duty US military population from 2001 through 2013., Methods: A retrospective analysis of ambulatory medical encounter diagnosis data corresponding to a study base of over 18 million personnel-years was performed to estimate average rates and evaluate temporal trends in rates of chronic obstructive lung conditions. Differences in rates and the time trends of those rates were evaluated by branch of military service, military occupation, and military rank., Results: During the 13-year period, we observed 482,670 encounters for chronic obstructive pulmonary disease and allied conditions (ICD-9 490-496) among active duty military personnel. Over half (57%) of the medical encounters in this category were for a diagnosis of bronchitis, not specified as acute or chronic. There was a statistically significant 17.2% average increase in the annual rates of this nonspecific bronchitis diagnosis from 2001-2009 (95% CI: 13.5% to 21.1%), followed by a 23.6% annual decline in the rates from 2009 through 2013 (95% CI: 8.6% to 36.2%). Statistically significant declines were observed in the rates of chronic bronchitis over time (annual percentage decline: 3.1%; 95% CI: 0.5% to 6.6%) and asthma (annual percentage decline: 5.9%; 95% CI: 2.5% to 9.2%). A 1.6% annual increase in the rate of emphysema and a 0.1% increase in the rate of chronic airways obstruction (not elsewhere classified) over the study period were not statistically significant (P>.05). The magnitude of the estimated rates of these chronic obstructive lung conditions, and, to a lesser extent, the temporal trends in these rates, were sensitive to the requirement that there be persistence of the diagnosis evidenced in the medical record in order qualify as an incident case., Conclusions: We observed decreases in the rates of asthma and chronic bronchitis over the 13-year study period. The increase, and then decrease, over time in rates of bronchitis that has not been specified as acute or chronic drives the overall trends in chronic respiratory disease trends.

Deployed military personnel are exposed to inhalational hazards that may increase their risk of chronic lung conditions. This evaluation assessed associations between Operation Iraqi Freedom (OIF) deployment and postdeployment medical encounters for respiratory symptoms and medical conditions. This retrospective cohort study was conducted among military personnel who, between January 2005 and June 2007, were deployed to either of two locations with burn pits in Iraq, or to either of two locations without burn pits in Kuwait. Incidence rate ratios (IRRs) were estimated using two nondeployed reference groups. Rates among personnel deployed to burn pit locations were also compared directly to those among personnel deployed to locations without burn pits. Significantly elevated rates of encounters for respiratory symptoms (IRR = 1.25; 95% confidence interval [CI]: 1.20-1.30) and asthma (IRR = 1.54; 95% CI: 1.33-1.78) were observed among the formerly deployed personnel relative to U.S.-stationed personnel. Personnel deployed to burn pit locations did not have significantly elevated rates for any of the outcomes relative to personnel deployed to locations without burn pits. These results are consistent with the hypothesis that OIF deployment is associated with subsequent risk of respiratory conditions. Elevated medical encounter rates were not uniquely associated with burn pits., (Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.)

Purpose: Use of the word "cure" in cancer care reflects a balance of physician and patient optimism, realism, medico-legal concerns, and even superstition. This study surveyed a group of oncology specialists regarding the frequency and determinants of using the word cure., Methods: Oncology clinicians at the Dana-Farber Cancer Institute (n = 180) were invited to complete a survey regarding the word cure in cancer care. Participants completed a 19-question survey regarding how commonly their patients are cured, how often they use the word cure in their practice, and details about its use. Three case scenarios were presented to elicit participants' views., Results: Of the 117 participants (65%) who provided responses, 81% were hesitant to tell a patient that they are cured, and 63% would never tell a patient that they are cured. Only 7% felt that greater than 75% of their patients are, or will be, cured. The participating clinicians reported that only 34% of patients ask if they are cured. For 20-year survivors of testicular cancer, large-cell lymphoma, and estrogen receptor-positive breast cancer, 84%, 76%, and 48% of clinicians, respectively, believed that the patients were cured, and 35%, 43%, and 56% recommended annual oncology follow-up of the patients. Twenty-three percent of oncology clinicians believed that patients should never be discharged from the cancer center., Conclusion: Oncology clinicians report that patients are hesitant to ask whether they are cured, and the clinicians are hesitant to tell patients they are cured. Annual oncology follow-up was frequently endorsed, even after 20 years in remission.

Objective: To evaluate the impact of ambient particulate matter (PM) on acute cardiorespiratory morbidity among US military personnel in southwest Asia., Methods: We linked ambient PM data collected between December 2005 and June 2007 with personnel, medical, and meteorological data. We implemented a case-crossover analysis to estimate base-specific associations and pooled those estimates using meta-analytic methods., Results: The adjusted odds ratios for a 10-μg/m increase in ambient PM2.5 and a qualifying medical encounter were 0.92 (95% confidence interval [CI]: 0.77 to 1.11) and 1.01 (95% CI: 0.95 to 1.07) for the current (lag&#95;0) and previous (lag&#95;1) days. The estimates for a 10-μg/m increase in PM10 were 0.99 (95% CI: 0.97 to 1.03) at lag&#95;0, and 1.00 (95% CI: 0.97 to 1.02) at lag&#95;1., Conclusions: No statistically significant associations between PM and cardiorespiratory outcomes were observed in this young, relatively healthy, deployed military population.

Objective: To evaluate the association between postdeployment respiratory conditions and deployment to Iraq or Afghanistan., Methods: We linked deployment history of US military personnel with postdeployment medical records. We then conducted a nested case-control study., Results: Relative to a single deployment, multiple deployments were not significantly associated with obstructive pulmonary disease (odds ratio, 1.08; 95% confidence interval, 0.82 to 1.42). Cumulative time deployed was also not significantly associated with obstructive pulmonary disease. Nevertheless, we did note that the rate of respiratory symptoms and encounters for obstructive pulmonary diseases (predominantly asthma and bronchitis) increased from before to after deployment., Conclusions: In a population of active duty US military personnel, we observed an increase in postdeployment respiratory symptoms and medical encounters for obstructive pulmonary diseases, relative to predeployment rates, in the absence of an association with cumulative deployment duration or total number of deployments.

Objective: To assess the impact of exposure to a 2003 sulfur plant fire on the health of deployed US Army personnel., Methods: The authors identified a small firefighter group known to be at the fire source and a larger, more dispersed population. Self-reported health status and respiratory health outcomes for these two groups were reviewed compared with two unexposed groups., Results: Self-reported health concerns, difficulty breathing, and shortness of breath were common in the exposed. Rates for chronic respiratory conditions increased in all groups from before to after deployment. Postdeployment medical encounters for chronic respiratory conditions among the exposed did not differ significantly from the unexposed comparison groups., Conclusion: Potential exposure to the sulfur fire was positively associated with self-reported health concerns and symptoms but not with clinical encounters for chronic respiratory health conditions.

There is a recognized need to identify the potential impact of air pollution exposure on the health of military personnel deployed to Southwest Asia (SWA). The exposure characterization reported by Engelbrecht et al. in this issue summarizes the results of a remarkable effort to conduct environmental sampling at locations where US military personnel are deployed in support of Operation Enduring Freedom and Operation Iraqi Freedom. This is an important first step in better understanding the relationship between the health of soldiers deployed in SWA and air pollution in the area of operations. We discuss here what is currently known about the effects of particulate matter (PM) on human health, focusing on the limited evidence specific to US military personnel, and outline current and planned efforts to utilize sampling data to assess health outcomes in deployed military populations.

Endotoxin exposure has been proposed as an environmental determinant of allergen responses in children. To better understand the implications of using a single measurement of house dust endotoxin to characterize exposure in the first year of life, we evaluated room-specific within-home and between-home variability in dust endotoxin obtained from 470 households in Boston, Massachusetts. Homes were sampled up to two times over 5-11 months. We analyzed 1,287 dust samples from the kitchen, family room, and baby's bedroom for endotoxin. We fit a mixed-effects model to estimate mean levels and the variation of endotoxin between homes, between rooms, and between sampling times. Endotoxin ranged from 2 to 1,945 units per milligram of dust. Levels were highest during summer and lowest in the winter. Mean endotoxin levels varied significantly from room to room. Cross-sectionally, endotoxin was moderately correlated between family room and bedroom floor (r = 0.30), between family room and kitchen (r = 0.32), and between kitchen and bedroom (r = 0.42). Adjusting for season, the correlation of endotoxin levels within homes over time was 0.65 for both the bedroom and kitchen and 0.54 for the family room. The temporal within-home variance of endotoxin was lowest for bedroom floor samples and highest for kitchen samples. Between-home variance was lowest in the family room and highest for kitchen samples. Adjusting for season, within-home variation was less than between-home variation for all three rooms. These results suggest that room-to-room and home-to-home differences in endotoxin influence the total variability more than factors affecting endotoxin levels within a room over time.

Background: Infant endotoxin exposure has been proposed as a factor that might protect against allergy and the early childhood immune responses that increase the risk of IgE production to allergens., Objective: Using a prospective study design, we tested the hypothesis that early-life endotoxin exposure is associated with allergen- and mitogen-induced cytokine production and proliferative responses of PBMCs isolated from infants with a parental history of physician-diagnosed asthma or allergy., Methods: We assessed household dust endotoxin at age 2 to 3 months and PBMC proliferative and cytokine responses to cockroach allergen (Bla g 2), dust mite allergen (Der f 1), cat allergen (Fel d 1), and the nonspecific mitogen PHA at age 2 to 3 years., Results: We found that increased endotoxin levels were associated with decreased IL-13 levels in response to cockroach, dust mite, and cat allergens, but not mitogen stimulation. Endotoxin levels were not correlated with allergen- or mitogen-induced IFN-gamma, TNF-alpha, or IL-10. Increased endotoxin levels were associated with decreased lymphocyte proliferation after cockroach allergen stimulation. An inverse, although nonsignificant, association was also found between endotoxin and proliferation to the other tested stimuli., Conclusion: Increased early-life exposure to household endotoxin was associated with reduced allergen-induced production of the TH2 cytokine IL-13 and reduced lymphoproliferative responses at age 2 to 3 years in children at risk for allergy and asthma. Early-life endotoxin-related reduction of IL-13 production might represent one pathway through which increased endotoxin decreases the risk of allergic disease and allergy in later childhood.

Spontaneous and provoked nonrespiratory arousals can be accompanied by a patterned hemodynamic response. To investigate whether a patterned response is also elicited by respiratory arousals, we compared nonrespiratory arousals (NRA) to respiratory arousals (RA) induced by airway occlusion during non-rapid eye movement sleep. We monitored mean arterial blood pressure (MAP), heart rate, iliac and renal blood flow, and sleep stage in 7 pigs during natural sleep. Iliac and renal vascular resistance were calculated. Airway occlusions were obtained by manually inflating a chronically implanted tracheal balloon during sleep. The balloon was quickly deflated as soon as electroencephalogram arousal occurred. As previously reported, NRA generally elicited iliac vasodilation, renal vasoconstriction, little change in MAP, and tachycardia. In contrast, RA generally elicited iliac and renal vasoconstriction, an increase in MAP and tachycardia. The frequent occurrence of iliac vasoconstriction and arterial pressure elevation following RA but not NRA suggests that sleep state change alone does not account for the hemodynamic response to airway occlusion during sleep.

We examined the influence of two common polymorphic forms of the beta(2)-adrenergic receptor (beta(2)AR): the Gly16 and Glu27 alleles, on acute and long-term beta(2)AR desensitization in human airway smooth muscle (HASM) cells. In cells from 15 individuals, considered without respect to genotype, pretreatment with Isoproterenol (ISO) at 10(-7) M for 1 h or 24 h caused approximately 25% and 64% decreases in the ability of subsequent ISO (10(-6) M) stimulation to reduce HASM cell stiffness as measured by magnetic twisting cytometry. Similar results were obtained with ISO-induced cyclic adenosine monophosphate (cAMP) as the outcome indicator. Data were then stratified post hoc by genotype. Cells containing at least one Glu27 allele (equivalent to presence of the Gly16Glu27 haplotype) showed significantly greater acute desensitization than did cells with no Glu27 allele, whether ISO-induced cell stiffness (34% versus 19%, p < 0.03) or cAMP formation (58% versus 11%, p < 0.02) was measured. Likewise, cells with any Glu27 allele showed greater long-term desensitization of cell stiffness and cAMP formation responses than did cells without the Glu27 allele. The distribution of genotypes limited direct conclusions about the influence of the Gly16 allele. However, presence of the Gly16Gln27 haplotype was associated with less acute and long-term desensitization of ISO-induced cAMP formation than was seen in cells without the Gly16Gln27 haplotype (14% versus 47%, p < 0.09 for short-term desensitization; 32% versus 84%, p < 0.01 for long-term desensitization), suggesting that the influence of Glu27 is not through its association with Gly16. The Glu27 allele was in strong linkage disequilibrium with the Arg19 allele, a polymorphic form of the beta(2)AR upstream peptide of the 5'-leader cistron of the beta(2)AR, and this polymorphism in the beta(2)AR 5'-flanking region may explain the effects of the Glu27 allele. Cells with any Arg19 allele showed significantly greater acute and long-term desensitization of ISO-induced cAMP formation than did cells without the Arg19 allele (54% versus 2%, p < 0.01 for short-term desensitization; 73% versus 35%, p < 0.05 for long-term desensitization). Similar results were obtained for ISO-induced changes in cell stiffness. Thus, the presence of the Glu27 allele is associated with increased acute and long-term desensitization in HASM.

During ozone (O(3)) exposure, adult rats decrease their minute ventilation (VE). To determine whether such changes are also observed in immature animals, Sprague-Dawley rats, aged 2, 4, 6, 8, or 12 wk, were exposed to O(3) (2 ppm) in nose-only-exposure plethysmographs. Baseline VE normalized for body weight decreased with age from 2.1 +/- 0.1 ml. min(-1). g(-1) in 2-wk-old rats to 0. 72 +/- 0.03 ml. min(-1). g(-1) in 12-wk-old rats, consistent with the higher metabolic rates of younger animals. In adult (8- and 12-wk-old) rats, O(3) caused 40-50% decreases in VE that occurred primarily as the result of a decrease in tidal volume. In 6-wk-old rats, O(3)-induced changes in VE were significantly less, and in 2- and 4-wk-old rats, no significant changes in VE were observed during O(3) exposure. The increased baseline VE and the smaller decrements in VE induced by O(3) in the immature rats imply that their delivered dose of O(3) is much higher than in adult rats. To determine whether these differences in O(3) dose influence the extent of injury, we measured bronchoalveolar lavage protein concentrations. The magnitude of the changes in bronchoalveolar lavage induced by O(3) was significantly greater in 2- than in 8-wk-old rats (267 +/- 47 vs. 165 +/- 22%, respectively, P < 0.05). O(3) exposure also caused a significant increase in PGE(2) in 2-wk-old but not in adult rats. The results indicate that the ventilatory response to O(3) is absent in 2-wk-old rats and that lack of this response, in conjunction with a greater specific ventilation, leads to greater lung injury.

We have previously reported that interleukin (IL)-1beta causes beta-adrenergic hyporesponsiveness in cultured human airway smooth muscle cells by increasing cyclooxygenase-2 (COX-2) expression and prostanoid formation. The purpose of this study was to determine whether extracellular signal-regulated kinases (ERKs) are involved in these events. Levels of phosphorylated ERK (p42 and p44) increased 8.3- and 13-fold, respectively, 15 min after treatment with IL-1beta (20 ng/ml) alone. Pretreating cells with the mitogen-activated protein kinase kinase inhibitor PD-98059 or U-126 (2 h before IL-1beta treatment) decreased ERK phosphorylation. IL-1beta (20 ng/ml for 22 h) alone caused a marked induction of COX-2 and increased basal PGE(2) release 28-fold (P < 0.001). PD-98059 (100 microM) and U-126 (10 microM) each decreased COX-2 expression when administered before IL-1beta treatment. In control cells, PD-98059 and U-126 had no effect on basal or arachidonic acid (AA; 10 microM)-stimulated PGE(2) release, but both inhibitors caused a significant decrease in bradykinin (BK; 1 microM)-stimulated PGE(2) release, consistent with a role for ERK in the activation of phospholipase A(2) by BK. In IL-1beta-treated cells, prior administration of PD-98059 caused 81, 92 and 40% decreases in basal and BK- and AA-stimulated PGE(2) release, respectively (P < 0.01), whereas administration of PD-98059 20 h after IL-1beta resulted in only 38 and 43% decreases in basal and BK-stimulated PGE(2) release, respectively (P < 0.02) and had no effect on AA-stimulated PGE(2) release. IL-1beta attenuated isoproterenol-induced decreases in human airway smooth muscle stiffness as measured by magnetic twisting cytometry, and PD-98059 or U-126 abolished this effect in a concentration-dependent manner. These results are consistent with the hypothesis that ERKs are involved early in the signal transduction pathway through which IL-1beta induces PGE(2) synthesis and beta-adrenergic hyporesponsiveness and that ERKs act by inducing COX-2 and activating phospholipase A(2).

The case of a young female presenting severe mental problems and episodic neurological symptoms is described. Obsessive-compulsive disorder was diagnosed upon psychiatric treatment for eight months. No neurological condition was found. Hypoglycaemia was observed during an episode of long-lasting somnolescence and the patient referred for endocrinological examination. Reactive hypoglycaemia was ruled out in an oral glucose tolerance test. A test of prolonged starvation revealed hypoglycaemia associated with neuropsychiatric symptoms. Glucose abolished this condition, suggesting an insulinoma as the basis of the spontaneous hypoglycaemia. Subsequently, two insulinomas were resected from the tail of the pancreas. The patient has recovered completely after her surgery, with no signs of mental or neurological disease and blood glucose within normal limits. As insulinoma is often associated to the MEN1-syndrome, the patient and her relatives are now being investigated for this condition.

Patients with obstructive sleep apnea experience marked cardiovascular changes with apnea termination. Based on this observation, we hypothesized that sudden sleep disruption is accompanied by a specific, patterned hemodynamic response, similar to the cardiovascular defense reaction. To test this hypothesis, we recorded mean arterial blood pressure, heart rate, iliac blood flow and vascular resistance, and renal blood flow and vascular resistance in five pigs instrumented with chronic sleep electrodes. Cardiovascular parameters were recorded during quiet wakefulness, during non-rapid-eye-movement and rapid-eye-movement sleep, and during spontaneous and induced arousals. Iliac vasodilation (iliac vascular resistance decreased by -29.6 +/- 4.1% of baseline) associated with renal vasoconstriction (renal vascular resistance increased by 10.3 +/- 4.0%), tachycardia (heart rate increase: +23.8 +/- 3.1%), and minimal changes in mean arterial blood pressure were the most common pattern of arousal response, but other hemodynamic patterns were observed. Similar findings were obtained in rapid-eye-movement sleep and for acoustic and tactile arousals. In conclusion, spontaneous and induced arousals from sleep may be associated with simultaneous visceral vasoconstriction and hindlimb vasodilation, but the response is variable.

GABAA agonist-induced formation of low-affinity GABAA receptors in cultured cerebellar granule cells was studied in the presence or absence of alpha-difluoromethylornithine (DFMO), a blocker of polyamine formation. High- and low-affinity GABAA receptors were monitored by Scatchard analysis of [3H]GABA binding to membranes from cells cultured for either 4 or 10 days in the presence or absence of the GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). Cultures grown for 4 days were exposed to THIP and DFMO for an additional period of 6 hr (acute exposure), whereas cultures grown for 10 days were exposed to the same agents during the entire culture period (chronic exposure). Regardless of the culture period or drug exposure protocol, control cells expressed only a high-affinity (KD 7 nM) binding site for GABA, whereas the cultures treated with THIP for either 6 hr or 10 days exhibited an additional low-affinity binding site (KD approximately 500 nM). Chronic exposure to DFMO prevented the THIP induction of low-affinity GABAA receptors, whereas acute exposure to DFMO had no effect on the ability of THIP to induce low-affinity GABAA receptors. Measurements of the intracellular polyamine concentration demonstrated a slight decrease in the putrescine level in the granule cells exposed to DFMO or THIP + DFMO for 6 hr. In contrast, granule cells chronically (10 days) exposed to DFMO or THIP + DFMO were depleted of putrescine and spermidine. Hence, the ability of THIP to induce low-affinity GABAA receptors was prevented by the simultaneous depletion of the cellular content of putrescine and spermidine, whereas inhibition of ornithine decarboxylase and of putrescine formation was not sufficient to prevent THIP-induced receptor formation.

Objective: To test treatment regimens for Lyme arthritis., Methods: Patients were randomly assigned to treatment with doxycycline or amoxicillin plus probenecid for 30 days. Patients who had persistent arthritis for at least 3 months after treatment with oral antibiotics or parenteral penicillin were given intravenous ceftriaxone for 2 weeks., Results: Eighteen of the 20 patients treated with doxycycline and 16 of the 18 patients who completed the amoxicillin regimen had resolution of the arthritis within 1-3 months after study entry. However, neuroborreliosis later developed in 5 patients, 4 of whom had received the amoxicillin regimen. Of 16 patients (2 from the oral antibiotic study and 14 additional patients) who had persistent arthritis despite previous oral antibiotics or parenteral penicillin, none had resolution of the arthritis within 3 months after ceftriaxone therapy. The HLA-DR4 specificity and OspA reactivity were associated with a lack of response., Conclusion: Lyme arthritis can usually be treated successfully with oral antibiotics, but patients may still develop neuroborreliosis. Patients with certain genetic and immune markers may have persistent arthritis despite treatment with oral or intravenous antibiotics.

The recent literature pertaining to tumors of articular structures and bone is reviewed. In pigmented villonodular synovitis, the bone resorptive cell is a macrophage polykaryon rather than an osteoclast. Complete arthroscopic synovectomy was successful in most diffuse articular forms of the disease. The early synovial changes in synovial chondromatosis were described; the lesion may be difficult to distinguish from synovial chondrosarcoma. Free body removal may be sufficient to treat synovial chondromatosis. Magnetic resonance imaging has been found useful in association with plain radiographs in the diagnosis of hemangioma and synovial sarcoma. Intracapsular osteoid osteoma, a benign neoplasm, may cause chronic monoarthritis. Computed tomography is essential in the diagnosis of this lesion. Aneurysmal bone cysts frequently show fluid-fluid levels on magnetic resonance imaging. Osteosarcoma, predominantly a tumor of childhood or adolescence, may occur in individuals over age 40 with underlying bone conditions. Computed tomography and magnetic resonance imaging are complementary in defining the extent of this lesion.

Effects of polyamine depletion by alpha-difluoromethylornithine (DFMO) were studied on the GABA-agonist mediated enhancement of the morphological development of cultured rat cerebellar granule cells. An increase in the number of neurite extending cells and in the cytoplasmic density of organelles relevant for protein synthesis was observed upon culturing in the presence of 4,5,6,7-tetrahydro-isoxazole[5,4-c]pyridin-3-ol (THIP) for 4 days. The intracellular concentrations of putrescine, spermidine, and spermine in these cultures were similar to the concentrations of the polyamines observed in cultures grown in a plain culture medium for 1, 2, 3 or 4 days, respectively. Upon culturing in the simultaneous presence of THIP and DFMO, the concentrations of putrescine and spermadine were reduced to less than 20% of the levels in the controls. This depletion was associated with a severely impaired morphological development of the granule cell cultures. Thus, the number of neurite extending cells was reduced to 50% of the number in the control cultures upon culturing in the presence of DFMO alone or in combination with THIP. Moreover, the THIP mediated increase in the cytoplasmic density of rough endoplasmic reticulum, Golgi apparatus and different types of vesicles was prevented by the exposure to DFMO.

Effects of taurine and THIP were studied on the development of cultured cerebellar granule cells with regard to GABA receptor expression and morphological development. Culturing in the presence of taurine or THIP led to the formation of low affinity GABA receptors as revealed from Scatchard analysis of [3H]GABA binding. This formation of receptors was susceptible to inhibition upon culturing in the simultaneous presence of taurine and bicuculline demonstrating the involvement of the high affinity GABA receptors which are present on the cells regardless of the culture condition. Superfusion experiments on cells cultured under the different conditions demonstrated that the low affinity GABA receptors expressed after culturing in the presence of THIP or taurine mediated an inhibition by GABA of evoked transmitter release from the granule cells. Cells cultured in either plain culture media or in the presence of taurine were indistinguishable with respect to the number of neurite extending cells observed after 4 days in culture. In contrast, culturing in the presence of THIP increased the number of neurite extending cells by 8% relative to the controls.

Of 2135 elderly residents of nursing homes in Arkansas (mean age, 79.4 years) who have been treated with isoniazid for prevention of tuberculosis, data from 1935 were suitable for analysis. About 12 months of therapy was successfully completed in 1600 persons. Therapy could not be completed in 84 persons (4.4%) because of incipient hepatic toxicity and in 116 (6.0%) because of other types of drug intolerance. Although 135 persons (7.0%) died during the course of therapy, no evidence was found that isoniazid contributed to any death. The ratio of benefit (reduction of risk for tuberculosis) to risk (for nonfatal isoniazid-related hepatitis) was clearly favorable in persons who had definite conversions (1.6 for women, 3.4 for men) but less so for persons who had tuberculin reactions of unknown duration and for persons with minor increases in size of tuberculin reaction (less than 12 mm increase from an initially negative reaction).