Paradoxical upgrading reaction in extra-pulmonary tuberculosis: association with vitamin D therapy.

SETTING: Glasgow, Scotland, UK. BACKGROUND: Paradoxical reactions in tuberculosis (TB) are a notable example of our incomplete understanding of host-pathogen interactions during anti-tuberculosis treatment. OBJECTIVES: To determine risk factors for a TB paradoxical reaction, and specifically to assess for an independent association with vitamin D use. DESIGN: Consecutive human immunodeficiency virus (HIV) negative adult patients treated for extra-pulmonary TB were identified from an Extended Surveillance of Mycobacterial Infections database. In our setting, vitamin D was variably prescribed for newly diagnosed TB patients. A previously published definition of paradoxical TB reaction was retrospectively applied to, and data on all previously described risk factors were extracted from, centralised electronic patient records. The association with vitamin D use was assessed using multivariate logistic regression. RESULTS: Of the 249 patients included, most had TB adenopathy; 222/249 had microbiologically and/or histologically confirmed TB. Vitamin D was prescribed for 57/249 (23%) patients; 37/249 (15%) were classified as having paradoxical reactions. Younger age, acid-fast bacilli-positive invasive samples, multiple disease sites, lower lymphocyte count and vitamin D use were found to be independent risk factors. CONCLUSION: We speculate that vitamin D-mediated signalling of pro-inflammatory innate immune cells, along with high antigenic load, may mediate paradoxical reactions in anti-tuberculosis treatment.

Sarcoid panuveitis associated with etanercept treatment, resolving with adalimumab.

We presented a case of a 54-year-old woman, who developed sarcoidosis uveitis while on treatment with the tumour necrosis factor α (TNFα) antagonist etanercept for rheumatoid arthritis. Her condition improved, but did not recover completely after the medication was stopped. After starting her on another TNFα antagonist, adalimumab, the uveitis recovered completely. Etanercept and adalimumab are from the same class of medication, but have different effects on other mediators and cells, which may explain these discrepancies.

Validación de una escala para evaluar factores vinculados a la adherencia terapéutica en pacientes oncológicos / Validation of a scale to assess factors related to therapeutic adherence in cancer patients

El objetivo del presente estudio fue construir una escala que evaluara factores vinculados a la adherencia terapéutica en pacientes oncológicos y evaluar sus propiedades psicométricas. A la muestra conformada por 120 participantes provenientes del Servicio de Oncología del Hospital Clínico Regional de Antofagasta, se aplicó el cuestionario creado y validado previamente en una muestra piloto en similar tipo de pacientes. Se analizó la consistencia interna y la estructura factorial del cuestionario, así como la relación entre las dimensiones evaluadas. De acuerdo a los resultados, la escala presenta un alfa superior a 0.9, tanto a nivel total como en las diversas dimensiones, y una estructura factorial consistente con los factores teóricos elegidos. La conclusión de la investigación es que la escala construida puede constituirse en una herramienta de utilidad pronóstica de uso en pacientes oncológicos.

The aim of this study was to build and evaluate the psychometric properties of a scale to assess factors related to adherence in patients with cancer. In a sample of 120 patients from the Oncology Service from Hospital Clínico Regional de Antofagasta, we applied the questionnaire developed and previously validated in a pilot sample in similar patients. The internal consistency and factor structure of the questionnaire, and the relationship between the dimensions was assessed. According to the results, the scale has an alpha greater than 0.9, both overall and in various dimensions, and a factor structure consistent with the theoretical factors chosen. The research concluded that the scale is constructed can become a useful prognostic tool for use in cancer patients.

A summary of recent findings on birth outcomes and developmental effects of prenatal ETS, PAH, and pesticide exposures.

Inner-city minority populations are high-risk groups for adverse birth outcomes and also more likely to be exposed to environmental contaminants, including environmental tobacco smoke (ETS), benzo[a]pyrene B[a]P, other ambient polycyclic aromatic hydrocarbons (global PAHs), and residential pesticides. The Columbia Center for Children's Environmental Health (CCCEH) is conducting a prospective cohort study of 700 northern Manhattan pregnant women and newborns to examine the effects of prenatal exposure to these common toxicants on fetal growth, early neurodevelopment, and respiratory health. This paper summarizes results of three published studies demonstrating the effects of prenatal ETS, PAH, and pesticides on birth outcomes and/or neurocognitive development [Perera FP, Rauh V, Whyatt RM, Tsai WY, Bernert JT, Tu YH, et al. Molecular evidence of an interaction between prenatal environment exposures on birth outcomes in a multiethnic population. Environ Health Perspect 2004;12:630-62; Rauh VA, Whyatt RM, Garfinkel R, Andrews H, Hoepner L, Reyes A, et al. Developmental effects of exposure to environmental tobacco smoke and material hardship among inner-city children. Neurotoxicol Teratol 2004;26:373-85; Whyatt RM, Rauh V, Barr DB, Camann DE, Andrews HF, Garfinkel R, et al. Prenatal insecticide exposures, birth weight and length among an urban minority cohort. Environ Health Perspect, in press]. To evaluate the effects of prenatal exposure to ETS, PAHs, and pesticides, researchers analyzed questionnaire data, cord blood plasma (including biomarkers of ETS and pesticide exposure), and B[a]P-DNA adducts (a molecular dosimeter of PAHs). Self-reported ETS was associated with decreased head circumference (P = 0.04), and there was a significant interaction between ETS and adducts such that combined exposure had a significant multiplicative effect on birth weight (P = 0.04) and head circumference (P = 0.01) after adjusting for confounders. A second analysis examined the neurotoxic effects of prenatal ETS exposure and postpartum material hardship (unmet basic needs in the areas of food, housing, and clothing) on 2-year cognitive development. Both exposures depressed cognitive development (P < 0.05), and there was a significant interaction such that children with exposure to both ETS and material hardship exhibited the greatest cognitive deficit (7.1 points). A third analysis found that cord chlorpyrifos, and a combined measure of cord chlorpyrifos, diazinon, and propoxur-metabolite, were inversely associated with birth weight and/or length (P < 0.05). These results underscore the importance of policies that reduce exposure to ETS, air pollution, and pesticides with potentially adverse effects on fetal growth and child neurodevelopment.

Na+-K+-ATPase properties in rat heart and skeletal muscle 3 mo after coronary artery ligation.

This study was designed to determine whether chronic heart failure (CHF) results in changes in Na(+)-K(+)-ATPase properties in heart and skeletal muscles of different fiber-type composition. Adult rats were randomly assigned to a control (Con; n = 8) or CHF (n = 8) group. CHF was induced by ligation of the left main coronary artery. Examination of Na(+)-K(+)-ATPase activity (means +/- SE) 12 wk after the ligation measured, using the 3-O-methylfluorescein phosphatase assay (3-O-MFPase), indicated higher (P < 0.05) levels in soleus (Sol) (250 +/- 13 vs. 179 +/- 18 nmol.mg protein(-1).h(-1)) and lower (P < 0.05) levels in diaphragm (Dia) (200 +/- 12 vs. 272 +/- 27 nmol.mg protein(-1).h(-1)) and left ventricle (LV) (760 +/- 62 vs. 992 +/- 16 nmol.mg protein(-1).h(-1)) in CHF compared with Con, respectively. Na(+)-K(+)-ATPase protein content, measured by the [(3)H]ouabain binding technique, was higher (P < 0.05) in white gastrocnemius (WG) (166 +/- 12 vs. 135 +/- 7.6 pmol/g wet wt) and lower (P < 0.05) in Sol (193 +/- 20 vs. 260 +/- 8.6 pmol/g wet wt) and LV (159 +/- 10 vs. 221 +/- 10 pmol/g wet wt) in CHF compared with Con, respectively. Isoform content in CHF, measured by Western blot techniques, showed both increases (WG; P < 0.05) and decreases (Sol; P < 0.05) in alpha(1). For alpha(2), only increases [red gastrocnemius (RG), Sol, and Dia; P < 0.05] occurred. The beta(2)-isoform was decreased (LV, Sol, RG, and WG; P < 0.05) in CHF, whereas the beta(1) was both increased (WG and Dia; P < 0.05) and decreased (Sol and LV; P < 0.05). For beta(3), decreases (P < 0.05) in RG were observed in CHF, whereas no differences were found in Sol and WG between CHF and Con. It is concluded that CHF results in alterations in Na(+)-K(+)-ATPase that are muscle specific and property specific. Although decreases in Na(+)-K(+)-ATPase content would appear to explain the lower 3-O-MFPase in the LV, such does not appear to be the case in skeletal muscles where a dissociation between these properties was observed.

Malleability of human skeletal muscle Na(+)-K(+)-ATPase pump with short-term training.

To investigate the hypothesis that short-term submaximal training would result in changes in Na(+)-K(+)-ATPase content, activity, and isoform distribution in skeletal muscle, seven healthy, untrained men [peak aerobic power (peak oxygen consumption; Vo(2 peak)) = 45.6 ml x kg(-1) x min(-1) (SE 5.4)] cycled for 2 h/day at 60-65% Vo(2 peak) for 6 days. Muscle tissue, sampled from the vastus lateralis before training (0 days) and after 3 and 6 days of training and analyzed for Na(+)-K(+)-ATPase content, as assessed by the vanadate facilitated [(3)H]ouabain-binding technique, was increased (P < 0.05) at 3 days (294 +/- 8.6 pmol/g wet wt) and 6 days (308 +/- 15 pmol/g wet wt) of training compared with 0 days (272 +/- 9.7 pmol/g wet wt). Maximal Na(+)-K(+)-ATPase activity as evaluated by the 3-O-methylfluorescein phosphatase assay was increased (P < 0.05) by 6 days (53.4 +/- 5.9 nmol x h(-1) x mg protein(-1)) but not by 3 days (35.9 +/- 4.5 nmol x h(-1) x mg protein(-1)) compared with 0 days (37.8 +/- 3.7 nmol x h(-1) x mg protein(-1)) of training. Relative isoform distribution, measured by Western blot techniques, indicated increases (P < 0.05) in alpha(2)-content by 3 days and beta(1)-content by 6 days of training. These results indicate that prolonged aerobic exercise represents a potent stimulus for the rapid adaptation of Na(+)-K(+)-ATPase content, isoform, and activity characteristics.

Measurement of children's exposure to pesticides: analysis of urinary metabolite levels in a probability-based sample.

The Minnesota Children's Pesticide Exposure Study is a probability-based sample of 102 children 3-13 years old who were monitored for commonly used pesticides. During the summer of 1997, first-morning-void urine samples (1-3 per child) were obtained for 88% of study children and analyzed for metabolites of insecticides and herbicides: carbamates and related compounds (1-NAP), atrazine (AM), malathion (MDA), and chlorpyrifos and related compounds (TCPy). TCPy was present in 93% of the samples, whereas 1-NAP, MDA, and AM were detected in 45%, 37%, and 2% of samples, respectively. Measured intrachild means ranged from 1.4 microg/L for MDA to 9.2 microg/L for TCPy, and there was considerable intrachild variability. For children providing three urine samples, geometric mean TCPy levels were greater than the detection limit in 98% of the samples, and nearly half the children had geometric mean 1-NAP and MDA levels greater than the detection limit. Interchild variability was significantly greater than intrachild variability for 1-NAP (p = 0.0037) and TCPy (p < 0.0001). The four metabolites measured were not correlated within urine samples, and children's metabolite levels did not vary systematically by sex, age, race, household income, or putative household pesticide use. On a log scale, mean TCPy levels were significantly higher in urban than in nonurban children (7.2 vs. 4.7 microg/L; p = 0.036). Weighted population mean concentrations were 3.9 [standard error (SE) = 0.7; 95% confidence interval (CI), 2.5, 5.3] microg/L for 1-NAP, 1.7 (SE = 0.3; 95% CI, 1.1, 2.3) microg/L for MDA, and 9.6 (SE = 0.9; 95% CI, 7.8, 11) microg/L for TCPy. The weighted population results estimate the overall mean and variability of metabolite levels for more than 84,000 children in the census tracts sampled. Levels of 1-NAP were lower than reported adult reference range concentrations, whereas TCPy concentrations were substantially higher. Concentrations of MDA were detected more frequently and found at higher levels in children than in a recent nonprobability-based sample of adults. Overall, Minnesota children's TCPy and MDA levels were higher than in recent population-based studies of adults in the United States, but the relative magnitude of intraindividual variability was similar for adults and children.

Levels of methyleugenol in a subset of adults in the general U.S. population as determined by high resolution mass spectrometry.

We developed a sensitive and accurate analytical method for quantifying methyleugenol (ME) in human serum. Our method uses a simple solid-phase extraction followed by a highly specific analysis using isotope dilution gas chromatography-high resolution mass spectrometry. Our method is very accurate; its limit of detection is 3.1 pg/g and its average coefficient of variation is 14% over a 200-pg/g range. We applied this method to measure serum ME concentrations in adults in the general U.S. population. ME was detected in 98% of our samples, with a mean ME concentration of 24 pg/g (range < 3.1-390 pg/g). Lipid adjustment of the data did not alter the distribution. Bivariate and multivariate analyses using selected demographic variables showed only marginal relationships between race/ethnicity and sex/fasting status with serum ME concentrations. Although no demographic variable was a good predictor of ME exposure or dose, our data indicate prevalent exposure of U.S. adults to ME. Detailed pharmacokinetic studies are required to determine the relationship between ME intake and human serum ME concentrations.

Arachnoid cyst of the cavernous sinus resulting in third nerve palsy.

A 67-year-old man exhibited long-standing left third nerve palsy. Magnetic resonance imaging revealed a cystic lesion in the left cavernous sinus with signal characteristics typical of arachnoid cyst. Intradural cavernous sinus arachnoid cyst has not reported previously. Pathogenetic mechanisms are discussed.

Measuring worksite resources for employee heart health.

PURPOSE: Intervention at the organizational rather than the individual level is gaining greater attention in worksite health promotion efforts. However, little research has been done on instruments to measure this domain. Therefore, the purpose of this study was to further test the utility of an existing organizational heart health support instrument by examining relationships among worksite structural characteristics and comparing these results to other survey findings. DESIGN: One-time cross-sectional. SETTING: New York State. SUBJECTS: One hundred fifteen volunteer worksites in the New York State Healthy Heart Program, representing manufacturing, government, education, health care, and other industries. MEASURES: A survey was conducted using HeartCheck, an organizational assessment of employee support for heart health. HeartCheck contains 175 items measuring organizational support for tobacco control, nutrition, physical activity, stress, screening, and administrative support structure. RESULTS: On average, only 22% of all worksite resources assessed were present in the sample. Having a workforce greater than 250 provided a 12% increase in predicted overall worksite resources. A predominantly female workforce (> 75%) provided 10% higher levels of worksite stress resources. Worksites with unions had higher levels of resources for physical activity (10%), screening (13%), and general supportive structures (10%). The presence of manual labor diminished support for tobacco control resources (-13%). Finally, manufacturing worksites demonstrated a clear advantage for all types of worksite resources, except for stress. CONCLUSION: A number of trends found in this study are consistent with earlier work. Industry type and size both predict worksite supports similar to previous studies. Other findings that appear to contradict previous work, including the relatively low level of support observed in this sample, can be explained by the comprehensive nature of the instrument. Overall, these findings demonstrate the utility of HeartCheck.

Reference range concentrations of N-acetyl-S-(2-hydroxyethyl)-L-cysteine, a common metabolite of several volatile organic compounds, in the urine of adults in the United States.

N-acetyl-S-(2-hydroxyethyl)-L-cysteine (2-hydroxyethyl mercapturic acid, HEMA) is a urinary metabolite of several hazardous chemicals, including vinyl chloride (VC), ethylene oxide (EO), and ethylene dibromide (EDB). Information about the levels of HEMA in the general population is useful for assessing human exposures to HEMA parent compounds, including VC, EO, and EDB. To establish reference range concentrations for HEMA, we analyzed urine samples from 412 adult participants in the Third National Health and Nutrition Examination Survey (NHANES II) by using isotope-dilution high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). HEMA was detected in 71% of the samples examined. Creatinine-corrected concentrations ranged from less than 0.68 microg/g creatinine to 58.7 microg/g creatinine; the 95th percentile concentration was 11.2 microg/g creatinine; and the geometric mean and median creatinine-corrected concentrations were both 1.6 microg/g creatinine. We observed a statistically significant difference (P=0.0001) in the creatinine-corrected geometric mean concentration values of HEMA between smokers (2.8 microg/g creatinine) and nonsmokers (1.1 microg/g creatinine). The high levels of HEMA seen among smokers likely originated from HEMA-producing chemicals known to be present in tobacco smoke.

Strategies for biological monitoring of exposure for contemporary-use pesticides.

Pesticides are used on a massive scale in the United States. The widespread use of these pesticides has made it virtually impossible for the average person to avoid exposure at some level. Generally, it is believed that low-level exposure to these pesticides does not produce acute toxic effects; however, various cancers and other noncancer health endpoints have been associated with chronic exposure to several groups of pesticides. Therefore, it is imperative that well-designed studies investigate the potential relationship between contemporary pesticide exposure and health effects. For these studies to be accurate, reliable methods for determining individual exposure must be used. Biological monitoring is a useful tool for assessing exposure to some contemporary pesticides. As with any analytical method, biological monitoring entails many difficulties, but, in many instances, they can be overcome by the logical use of available information and information acquired in carefully designed studies. At the Centers for Disease Control and Prevention (CDC), we have acquired extensive experience in the development and application of specific techniques for biological monitoring of a variety of toxicants, including many of the contemporary-use pesticides. We have used these methods to measure the internal dose of pesticides received by people in acute and chronic incidents resulting from both environmental and industrial exposure. Additionally, we have established normative values, or reference ranges, of several pesticides based on measurements of their metabolites in the urine of randomly selected adults in the US population. These data have been successfully used to distinguish overt exposures from 'background' exposure. In this paper, we present several examples of the usefulness of biological monitoring in urine and blood and describe the difficulties involved with developing methods in these matrices. We also present a general strategy, considerations, and recommendations for developing biological monitoring techniques for measuring the internal dose of contemporary-use pesticides.

Assessing prenatal hepatitis B screening in Illinois with an inexpensive study design adaptable to other jurisdictions.

OBJECTIVES: This study estimated, using an economical survey design adaptable to other jurisdictions, the proportion of birth admissions in Illinois hospitals in which mothers were not screened for hepatitis B surface antigen prior to delivery. It also identified factors associated with lack of screening. METHODS: Based on a cluster sampling design, 1372 birth records were sampled, and data were abstracted by local personnel at 56 hospitals. Selected data elements were reabstracted on a subsample to evaluate recording errors. RESULTS: Reabstracted data demonstrated 95% agreement among reviewers. Hepatitis B surface antigen screening was documented for 90.7% of mothers; 11% of responding hospitals accounted for 45% of nonscreened mothers. Risk factors for not being screened included no prenatal care, Medicaid or no insurance, and delivery at a hospital lacking a written hepatitis B surface antigen policy. CONCLUSIONS: In Illinois, prenatal hepatitis B surface antigen screening rates were high and similar to those in other states. Births without screening or transferred information clustered in a few hospitals. The methods used here can economically identify underscreened populations by sampling a large number of hospitals within designated areas.

The fate of the oxidizing tyrosyl radical in the presence of glutathione and ascorbate. Implications for the radical sink hypothesis.

Cellular systems contain as much as millimolar concentrations of both ascorbate and GSH, although the GSH concentration is often 10-fold that of ascorbate. It has been proposed that GSH and superoxide dismutase (SOD) act in a concerted effort to eliminate biologically generated radicals. The tyrosyl radical (Tyr.) generated by horseradish peroxidase in the presence of hydrogen peroxide can react with GSH to form the glutathione thiyl radical (GS.). GS. can react with the glutathione anion (GS-) to form the disulfide radical anion (GSSG-). This highly reactive disulfide radical anion will reduce molecular oxygen, forming superoxide and glutathione disulfide (GSSG). In a concerted effort, SOD will catalyze the dismutation of superoxide, resulting in the elimination of the radical. The physiological relevance of this GSH/SOD concerted effort is questionable. In a tyrosyl radical-generating system containing ascorbate (100 microM) and GSH (8 mM), the ascorbate nearly eliminated oxygen consumption and diminished GS. formation. In the presence of ascorbate, the tyrosyl radical will oxidize ascorbate to form the ascorbate radical. When measuring the ascorbate radical directly using fast-flow electron spin resonance, only minor changes in the ascorbate radical electron spin resonance signal intensity occurred in the presence of GSH. These results indicate that in the presence of physiological concentrations of ascorbate and GSH, GSH is not involved in the detoxification pathway of oxidizing free radicals formed by peroxidases.

Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome.

Neonatal diabetes mellitus is a rare condition, the causes of which are mostly unknown. One well defined though very rare entity is the autosomal recessive Wolcott-Rallison syndrome, in which permanent neonatal diabetes, osteopenia, and epiphyseal dysplasia occur. Only five previous families have been reported, and here we describe the second in which parental consanguinity was present. The proband was born to first cousin parents and died at 2 years from the sequelae of poorly controlled diabetes. To test the hypothesis that mutation of PAX4, required in the mouse for pancreatic islet beta cell development, might cause WRS, the structure of the human PAX4 gene was deduced and DNA from two unrelated WRS patients sequenced. No PAX4 mutation was present, though the entire coding region was sequenced in both patients. It therefore appears unlikely that PAX4 is involved in the aetiology of Wolcott-Rallison syndrome, though it remains a good candidate for other forms of neonatal diabetes mellitus.

Characterization of cytochrome c free radical reactions with peptides by mass spectrometry.

The reactions of horse heart cytochrome c, hydrogen peroxide, and the spin trap 3,5-dibromo-4-nitrosobenzenesulfonic acid with a series of polypeptides were investigated using mass spectrometry. The mass spectra obtained from these reactions revealed that after a free radical has been generated on the heme-containing protein horse heart cytochrome c, it can be transferred to other biomolecules. In addition, the number of free radicals transferred to the target molecule could be determined. Recipient peptides/proteins that contained a tyrosine and/or tryptophan amino acid residue were most susceptible to free radical transfer. Using tandem mass spectrometry, the location of the 3,5-dibromo-4-nitrosobenzenesulfonic acid radical adduct on the nonapeptide RWIILGLNK was unequivocally determined to be at the tryptophan residue. We also demonstrated that the presence of an antioxidant in the reaction mixture not only inhibits free radical formation on horse heart cytochrome c, but also interferes with the transfer of the free radical, once it has been formed on cytochrome c.

A rapid, sensitive method for the quantitation of N-acetyl-S-(2-hydroxyethyl)-L-cysteine in human urine using isotope-dilution HPLC-MS-MS.

Because of increasing concern about exposure to carcinogens and other toxicants, reliable methods for biological monitoring of potentially exposed populations must be developed. For biological monitoring to be useful, appropriate biomarkers of exposures to xenobiotics must be identified, and sensitive, specific methods for quantifying the targeted biomarker must be developed. We have developed a sensitive and selective method for the analysis of N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA), urinary metabolite of at least three different known human carcinogens (vinyl chloride, ethylene oxide, and ethylene dibromide). The method uses strong anion-exchange solid-phase extraction and isotope-dilution high-performance liquid chromatography-tandem mass spectrometry. Our method is simple and is not labor intensive; the preparation time per sample is less than 10 min. Because urine samples vary in both their concentration and ion strength, intersample variability in HEMA recovery during the extraction is large. To overcome this inherent limitation, we use the isotope-dilution technique, which allows a complete correction for the extraction recovery for each sample. The limit of detection of the method is 0.68 microgram/L in a 1-mL urine sample with a coefficient of variation of 22% (determined by replicate analyses at both 4 and 11 micrograms/L) and an accuracy indistinguishable from 100%. Preliminary analyses of urine from a population with no known overt exposure to the parent toxicants show a frequency of detection of approximately 75%, which indicates that this method has the sensitivity to detect urinary HEMA derived from environmental exposure. We are currently using this method to establish a reference range of background exposure to these toxicants in the U.S. population.