Procarbazine, lomustine and vincristine toxicity in low-grade gliomas.

BACKGROUND: Procarbazine, lomustine, and vincristine (pcv) significantly improve survival outcomes in lgg (low-grade gliomas). Administration of pcv to lgg patients increased tremendously over the past years as it went from 2 patients per year between 2005 and 2012 to 23 patients in 2015 only in our centre. However, serious hematological and non-hematological adverse events may occur. The purpose of this study was to evaluate the toxicity of pcv and its clinical relevance in our practice. METHODS: We retrospectively reviewed the charts of 57 patients with lgg who received pcv at the Centre hospitalier de l'Université de Montréal between 1 January 2005 and 27 July 2016. RESULTS: Procarbazine, lomustine, and vincristine were associated with severe hematological toxicity as clinically significant grade 3 anemia, neutropenia, and thrombocytopenia occurred in 7%, 10%, and 28% of patients, respectively. Other frequent adverse events such as the increase of liver enzymes, cutaneous rash, neurotoxicity, and vomiting occurred in 65%, 26%, 60%, and 40% of patients, respectively. Patients with prophylactic trimethoprim/sulfamethoxazole had more grade 3 hematological toxicity with pcv, especially anemia (p = 0.040) and thrombocytopenia (p = 0.003) but we found no increase in pcv toxicity in patients on concurrent anticonvulsants. Patients with grade 3 neutropenia had a significantly lower survival (median survival 44.0 months vs. 114.0 months, p = 0.001). Patients who were given pcv at diagnosis had more grade 3 anemia than those who received it at subsequent lines of treatment (p = 0.042). CONCLUSION: Procarbazine, lomustine, and vincristine increase survival in lgg but were also associated with major hematologic, hepatic, neurologic, and cutaneous toxicity. Anti-Pneumocystis jiroveci pneumonia (pjp) prophylaxis, but not anticonvulsants, enhances hematologic toxicity.

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma.

OBJECTIVE: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. METHODS: The European Organization for Research and Treatment of Cancer (EORTC) 26981-22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. RESULTS: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). CONCLUSIONS: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

Canadian recommendations for the treatment of recurrent or progressive glioblastoma multiforme.

Recommendation 1: Multidisciplinary ApproachTo optimize treatment outcomes, the management of patients with recurrent glioblastoma should be individualized and should involve a multidisciplinary team approach, including neurosurgery, neuropathology, radiation oncology, neuro-oncology, and allied health professions.Recommendation 2: ImagingThe standard imaging modality for assessment of recurrent glioblastoma is Gd-enhanced magnetic resonance imaging (mri). Tumour recurrence should be assessed according to the criteria set out by the Response Assessment in Neuro-Oncology Working Group. The optimal timing and frequency of mri after chemoradiation and adjunctive therapy have not been established.Recommendation 3: Pseudo-progressionProgression observed by mri after chemoradiation can be pseudo-progression. Accordingly, treated patients should not be classified as having progressive disease by Gd-enhancing mri within the first 12 weeks after the end of radiotherapy unless new enhancement is observed outside the radiotherapy field or viable tumour is confirmed by pathology at the time of a required re-operation. Adjuvant temozolomide should be continued and follow-up imaging obtained.Recommendation 4: Repeat SurgerySurgery can play a role in providing symptom relief and confirming tumour recurrence, pseudo-progression, or radiation necrosis. However, before surgical intervention, it is essential to clearly define treatment goals and the expected impact on prognosis and the patient's quality of life. In the absence of level 1 evidence, the decision to re-operate should be made according to individual circumstances, in consultation with the multidisciplinary team and the patient.Recommendation 5: Re-irradiationRe-irradiation is seldom recommended, but can be considered in carefully selected cases of recurrent glioblastoma.Recommendation 6: Systemic TherapyClinical trials, when available, should be offered to all eligible patients. In the absence of a trial, systemic therapy, including temozolomide rechallenge or anti-angiogenic therapy, may be considered. Combination therapy is still experimental; optimal drug combinations and sequencing have not been established.

Phase I study of Aplidine in a dailyx5 one-hour infusion every 3 weeks in patients with solid tumors refractory to standard therapy. A National Cancer Institute of Canada Clinical Trials Group study: NCIC CTG IND 115.

BACKGROUND: Aplidine is a cyclic depsipeptide isolated from the marine tunicate Aplidium albicans. METHODS: This phase I study of Aplidine given as a 1-hour i.v. infusion daily for 5 days every 3 weeks was conducted in patients with refractory solid tumors. Objectives were to define the dose limiting toxicities, the maximal tolerated dose, and the recommended phase II dose. RESULTS: Thirty-seven patients were accrued on study. Doses ranged from 80 microg/m(2) to 1500 microg/m(2)/day. Eleven patients received more than three cycles of Aplidine. Dose-limiting toxicities occurred at 1500 microg/m(2) and 1350 microg/m(2)/day and consisted of nausea, vomiting, myalgia, fatigue, skin rash and diarrhea. Mild to moderate muscular pain and weakness was noted in patients treated with multiple cycles with no significant drug related neurotoxicity. Bone marrow toxicity was not observed. The recommended dose for phase II studies was 1200 microg/m(2) daily for 5 days, every 3 weeks. Pharmacokinetic studies performed during the first cycle demonstrated that therapeutic plasma levels of Aplidine are reachable well below the recommended dose. Nine patients with progressive disease at study entry had stable disease and two had minor responses, one in non-small cell lung cancer and one in colorectal cancer. CONCLUSIONS: Aplidine given at a dose of 1200 microg/m(2) daily for 5 days, every 3 weeks is well tolerated with few severe adverse events. This schedule of Aplidine is under evaluation in phase II studies in hematological malignancies and solid tumors.

The influence of air conditioning, humidity, temperature and other household characteristics on mite allergen concentrations in the northeastern United States.

BACKGROUND: Information about the influence of housing and occupant characteristics on mite allergen concentrations is crucial to determine which methods could be used to decrease exposure of susceptible subjects. OBJECTIVES: To identify housing and occupant characteristics that are associated with mite allergen concentrations in house dust collected from living rooms and mattresses. METHODS: We collected dust samples from 750 homes in the northeastern US. The influence of various characteristics on concentrations of mite allergens (Der p 1 and Der f 1) was studied using multiple linear regression analysis. RESULTS: Some characteristics, like absence of air conditioners, the presence of mold or mildew, and a lower temperature were consistently associated with higher concentrations of both mite allergens in dust from all sampling locations. However, none of these factors changed Der p 1 or Der f 1 concentrations by more than a factor of 2. People of white ethnic background had roughly two times higher mite allergen concentrations, while family income, family size, and education level only marginally influenced mite allergen concentrations. CONCLUSIONS: Various housing characteristics have some influence on mite allergen concentrations, and could possibly be used to decrease exposure of susceptible subjects. However, only a limited percentage of the variation in mite allergen concentrations was explained by these characteristics.

Phase II study of troxacitabine (BCH-4556) in patients with advanced and/or metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada-Clinical Trials Group.

PURPOSE: A multi-institution phase II study was undertaken by National Cancer Institute of Canada-Clinical Trials Group to evaluate the efficacy and toxicity of intravenous troxacitabine (Troxatyl; Shire Pharmaceuticals Plc, Laval, Quebec, Canada), in patients with renal cell carcinoma. PATIENTS AND METHODS: Between June 1999 and March 2000, 35 patients (24 male) with a mean age of 60 years who had advanced and/or metastatic disease were treated with troxacitabine given as an intravenous infusion over 30 minutes at a dose of 10 mg/m2 intravenously, once every 3 weeks. RESULTS: Of the 33 of 35 patients evaluable for response, there were two confirmed partial responses, 21 patients had stable disease (median duration, 4.4 months), and 10 patients had progressive disease. Eight patients remained stable for more than 6 months, of whom six remain free of progression. The most common drug-related nonhematologic toxicities observed were skin rash (77.1%), hand-foot syndrome (68.6%), alopecia (51.4%), fatigue (51.4%), and nausea (57.1%). Out of a total of 145 cycles of treatment, 98 were given without steroid premedication, whereas 47 cycles were given with steroid premedication. Without premedication, skin rash occurred in 37% of cycles compared with 26% when steroids were given prophylactically. CONCLUSION: Troxacitabine given at a dose of 10 mg/m2 once every 3 weeks was well tolerated in patients with metastatic renal cell cancer, with common toxicities being a moderate to severe granulocytopenia and skin rash. Steroid premedication may reduce the frequency and severity of the skin rash. Our current study suggests that the nucleoside analog troxacitabine may have modest activity against renal cell carcinoma; however, larger studies are required to confirm this.

Risk factors for asthma prevalence among urban and nonurban African American children.

Urban residence is a risk factor for asthma. We examined multiple risk factors simultaneously among African American children. We interviewed 2409 African American mothers of newborns who had at least 1 child at home under 18 years of age. Sixteen percent reported at least 1 child with physician-diagnosed asthma. Significantly associated with an asthmatic child were maternal asthma and allergies, maternal cigarette smoking, a humidifying device, and a gas range or oven in the home. Urban residence was related to asthma but became nonsignificant once other factors were controlled for. Asthma associated with urban residence may be explained by identifiable factors.

Use of health services by insurance status among children with asthma.

OBJECTIVES: It is well known that asthmatic children receiving Medicaid use the emergency department (ED) more frequently than otherwise-insured asthmatic children. However, the extent to which this difference is attributable to provider characteristics, medication use, access to primary care, and symptomatology is poorly understood. These factors were explored as independent predictors of health care utilization. METHODS: Baseline data from a prospective cohort study of childhood asthma severity were used. Subjects were recruited from seven New England hospitals. Home interviews collected data on monthly symptoms, health care visits, insurance status, as well as sociodemographics and asthma-related risk factors (n = 804). Characteristics of providers' practices, board certifications, and asthma specialty were obtained from Folio's Medical Dictionaries for Connecticut and Massachusetts. RESULTS: After adjusting for frequency of asthma-related primary care visits, primary provider practice type, use of asthma specialist, age, gender, medication use, and symptomatology, Medicaid children still used the ED more frequently for asthma services than privately insured children (RR, 1.7; 95% CI, 1.1, 2.5). In general, race/ethnicity did not modify the relationship between insurance status and health care use, except that black children receiving Medicaid were 90% (95% CI, 0.0, 0.7) less likely to have had > or = 3 routine primary care visits for asthma in the previous year than black privately insured children. White children receiving Medicaid were 2.5 (95% CI, 1.0, 6.9) times more likely to use the ED for asthma than privately insured white children. CONCLUSIONS: The results suggest that enabling, structural, and need factors do not necessarily explain observed differences in pediatric asthma health care use by insurance status. Future investigation must explore other explanatory factors such as maternal attitudes and beliefs and patient-provider communication.

Maternal caffeine intake and intrauterine growth retardation.

This study estimates the effect of maternal caffeine consumption throughout pregnancy on fetal growth. We studied 2,714 women who delivered a liveborn infant between 1988 and 1991. Detailed information regarding coffee, tea, and soda drinking during the first and third trimesters of pregnancy was obtained. Average caffeine intake during month 1 of pregnancy was higher than for month 7 (72.4 vs 54.0 mg per day). Consumption of >300 mg caffeine per day during month 1 (adjusted odds ratio = 0.91; 95% confidence interval = 0.44--1.90) and during month 7 (adjusted odds ratio = 1.00; 95% confidence interval = 0.37--2.70) was not associated with intrauterine growth retardation. There was little evidence for any effect modification due to cigarette smoking on the caffeine associations. This study provides evidence that antenatal caffeine consumption has no adverse effect on fetal growth.

A childhood asthma severity scale: symptoms, medications, and health care visits.

BACKGROUND: Although there are current measures to evaluate childhood asthma severity for clinical diagnosis and treatment, there is no standard valid measure to evaluate childhood asthma severity for large-scale epidemiologic studies. OBJECTIVES: To develop and test a childhood asthma severity scale (CHAS) for clinimetric validity and to determine differences in symptoms, medication use, and health care visits by participant characteristics. METHODS: Eight hundred ninety-seven actively asthmatic children under the age of 12 years were selected from a general population of children. Children were selected from a screening questionnaire administered at six Connecticut hospitals that serve large minority populations in Bridgeport, New Haven, Hartford, and Danbury and one hospital serving south central Massachusetts. Twelve-month baseline data for a prospective cohort study of childhood asthma severity were collected on a monthly basis through home interviews. Home interviews addressed questions on daily symptoms, medication use, and health care visits. A severity scale was constructed using three dimensions: symptoms, medication use, and health care visits. RESULTS: CHAS has sufficient preliminary content, construct, and predictive validity. Despite similarities in symptoms, there were health care utilization and medication differentials according to race and ethnicity, insurance status, family income, and maternal education. CONCLUSIONS: CHAS is a potentially useful measure of asthma severity for large-scale epidemiologic studies. It seems that CHAS has sufficient clinimetric properties.

The relation between fungal propagules in indoor air and home characteristics.

BACKGROUND: Questionnaires are commonly used in epidemiologic studies to obtain information about house characteristics in order to predict the household aeroallergen exposure levels. However, the reliability of the predictions made with the questionnaires has not been evaluated. To address this issue, we compared objectively measured fungal propagules including the most frequently isolated mold genera (i.e., Alternaria, Aspergillus, Cladosporium, Penicillium, etc.) in a large sample of homes and compared these measured values to the questionnaire-determined household characteristics. METHODS: As part of a prospective cohort study on the relation between residential allergen exposure and development of asthma in neonates, fungal air samples were collected from infant bedrooms and main living areas in 1000 homes in the Northeast USA, from December 1996 to January 1999. A Burkard portable air sampler was used in combination with DG-18 and MEA agars. A questionnaire was used to obtain information on host and house characteristics that may have an impact on the presence of fungal propagules in the air. This included information on observation of moisture problems (e.g., water leakage or damage, and mold or mildew growth), ventilation and heating facilities, building age and type, number of occupants, annual household income, presence of pets and pests, cleaning regimens, etc. RESULTS: The number of CFU/m3 air collected on MEA was significantly higher than on DG-18 (means, respectively, 1033.5 and 846.0 CFU/m3) (P < 0.0005). However, there was no significant difference between the numbers of CFU/m3 air collected from the main living area and from the infant bedroom. There was only a very weak relationship between the house characteristics, as described by questionnaire, and the presence of fungal propagules in indoor air. Only the temperature, relative humidity, season, and cats inside homes had a statistically significant impact on the presence of fungal propagules in indoor air. CONCLUSION: The presence of fungal propagules in indoor air cannot be reliably predicted by home characteristics. Actual measurements are required for fungal exposure assessment, and the use of only one medium to collect samples in one location in a home might be adequate to represent residential levels of fungi in indoor air.

Two types of recombination hotspots in bacteriophage T4: one requires DNA damage and a replication origin and the other does not.

Recombination hotspots have previously been discovered in bacteriophage T4 by two different approaches, marker rescue recombination from heavily damaged phage genomes and recombination during co-infection by two undamaged phage genomes. The phage replication origin ori(34) is located in a region that has a hotspot in both assays. To determine the relationship between the origin and the two kinds of hotspots, we generated phage carrying point mutations that should inactivate ori(34) but not affect the gene 34 reading frame (within which ori(34) is located). The mutations eliminated the function of the origin, as judged by both autonomous replication of plasmids during T4 infection and two-dimensional gel analysis of phage genomic replication intermediates. As expected from past studies, the ori(34) mutations also eliminated the hotspot for marker rescue recombination from UV-irradiated genomes. However, the origin mutations had no effect on the recombination hotspot that is observed with co-infecting undamaged phage genomes, demonstrating that some DNA sequence other than the origin is responsible for inflated recombination between undamaged genomes. The hotspots for marker rescue recombination may result from a replication fork restart process that acts upon origin-initiated replication forks that become blocked at nearby DNA damage. The two-dimensional gel analysis also revealed phage T4 replication intermediates not previously detected by this method, including origin theta forms.

NCIC-CTG phase II study of gemcitabine in patients with malignant glioma (IND.94).

PURPOSE: We conducted a phase II multicentre study of gemcitabine in patients with anaplastic astrocytoma and glioblastoma multiforme at first relapse. PATIENTS AND METHODS: Patients with anaplastic astrocytoma or glioblastoma multiforme receiving a stable dose of steroids and ECOG performance status < or = 3 were eligible for this study at the time of first relapse. One adjuvant chemotherapy regimen was permissible. Patients received gemcitabine 1000 mg/m2 i.v. weekly x 3, repeated on a four-weekly cycle. RESULTS: Of 20 patients enrolled, 15 were evaluable for response, 19 for non-hematological toxicity and 18 for hematological toxicity. Seven patients had anaplastic astrocytoma (AA) and twelve glioblastoma multiforme (GBM). Age ranged from 28-71 years (median 50). Fifteen patients discontinued therapy due to disease progression. The median number of cycles administered was 1 (range 1-11); only two patients received more than three cycles. Hematologic toxicity was acceptable and no grade 4 toxicity was seen. One patient developed Pneumocystis pneumonia and eventual pulmonary embolism; one died of gastric hemorrhage related to steroid therapy. No objective responses were seen. Nine patients had stable disease (median duration 2.7 months, range 0.9-11.2). CONCLUSIONS: Gemcitabine given in this dose and schedule seems well tolerated but is not active in patients with recurrent high-grade gliomas.

Reducing the risk of transfusion-transmitted rickettsial disease by WBC filtration, using Orientia tsutsugamushiin a model system.

BACKGROUND: Careful donor screening and infectious disease marker testing have significantly reduced the incidence of transfusion-transmitted diseases and improved the safety of the blood supply. However, transfusion-transmitted diseases resulting from the use of asymptomatic yet infectious donors continue to put patients at risk. This study was undertaken to determine if third-generation WBC filters could remove Orientia tsutsugamushi-infected cells from contaminated blood. STUDY DESIGN AND METHODS: Packed RBCs were inoculated with human MNCs infected with O. tsutsugamushi at levels estimated to occur in asymptomatic infectious donors. WBC reduction was accomplished with a third-generation WBC filter. Prefiltration and postfiltration specimens were collected, serially diluted, and injected into mice to determine the infectivity of the samples. RESULTS: Mice receiving WBC-reduced packed RBCs showed no signs of illness or markers of infectivity, which suggested that a reduction of as much as 10(5) infectious rickettsiae could be achieved by filtration. CONCLUSION: The high-efficiency, third-generation, WBC-reduction filters that were tested may provide protection against the transfusion transmission of scrub typhus rickettsiae by removing from contaminated blood cells that contain intracellular bacteria.

Polarity: the role of localized secretion.

Studies of single cells from brown algae suggest that localized secretions stabilize the polar axis resulting in an asymmetry in the cell wall. This cortical asymmetry appears to play a role in orienting the plane of cell division and in determining the different fates of the resulting daughter cells. Recent studies indicate that similar processes may operate in seed plants.

Psoralen photochemical inactivation of Orientia tsutsugamushi in platelet concentrates.

BACKGROUND: The risk of transfusion transmission of disease has been reduced by the combination of predonation questions and improved transfusion-transmitted disease assays, but the risk is still present. This study was conducted to determine if psoralen photochemistry could inactivate an obligate intracellular bacterium, with documented potential for transfusion, in PCs to further improve safety. STUDY DESIGN AND METHODS: PCs were inoculated with MNCs infected with Orientia tsutsugamushi. The concentrates were treated with amounts ranging from 0.86 to 138 micromol per L of 4'-(aminomethyl)-4,5',8-trimethylpsoralen hydrochloride (AMT) combined with a constant long-wave UVA light (320-400 nm) exposure of 5 J per cm(2). The effects of photochemical treatment were analyzed by using a mouse infectivity assay along with in vitro testing by PCR, indirect fluorescence antibody, direct fluorescence antibody, and Giemsa staining. RESULTS: AMT, at 0.86 micromol per L or more, combined with UVA light of 5 J per cm(2), inactivated O. tsutsugamushi that contaminated PCs. The PCs that did not receive the combined treatment caused infection. CONCLUSIONS: The psoralen AMT, in conjunction with UVA light exposure, effectively abolished the infectivity of PCs deliberately contaminated with the scrub typhus organism O. tsutsugamushi, as tested in a mouse infectivity assay.

The yeast nucleoporin Nup2p is involved in nuclear export of importin alpha/Srp1p.

The importin alpha.beta heterodimer mediates nuclear import of proteins containing classical nuclear localization signals. After carrying its cargo into the nucleus, the importin dimer dissociates, and Srp1p (the yeast importin alpha subunit) is recycled to the cytoplasm in a complex with Cse1p and RanGTP. Nup2p is a yeast FXFG nucleoporin that contains a Ran-binding domain. We find that export of Srp1p from the nucleus is impaired in Deltanup2 mutants. Also, Srp1p fusion proteins accumulate at the nuclear rim in wild-type cells but accumulate in the nuclear interior in Deltanup2 cells. A deletion of NUP2 shows genetic interactions with mutants in SRP1 and PRP20, which encodes the Ran nucleotide exchange factor. Srp1p binds directly to an N-terminal domain of Nup2p. This region of Nup2p is sufficient to allow accumulation of an Srp1p fusion protein at the nuclear rim, but the C-terminal Ran-binding domain of Nup2p is required for efficient Srp1p export. Formation of the Srp1p.Cse1p. RanGTP export complex releases Srp1p from its binding site in Nup2p. We propose that Nup2p may act as a scaffold that facilitates formation of the Srp1p export complex.

Environmental tobacco smoke exposure and small-for-gestational-age birth.

The aim of this analysis was to examine the effect of environmental tobacco smoke exposure on the risk of small-for-gestational-age (SGA) birth. The study population included 2,283 nonsmokers from a nested cohort study undertaken in southern Connecticut from 1988 to 1992. The duration and intensity of exposures incurred at multiple locations during the third trimester of pregnancy were measured by postpartum interview. The effect of exposure on birth weight and on incidence of SGA birth was assessed by multivariate logistic and linear regression. An estimated 26.5% of the women had been exposed to environmental tobacco smoke for at least 1 hour per week during the third trimester. The median duration of exposure among the exposed over all locations was 5 hours per week. The adjusted odds ratio for SGA birth in exposed mothers compared with unexposed mothers, using a dichotomous exposure variable, was 0.82 (95% confidence interval: 0.51, 1.33). The adjusted birth weight difference associated with exposure was -1.2 g (95% confidence interval: -43.3, 41.0). No effect of environmental tobacco smoke exposure on fetal growth was seen in this relatively homogeneous upper middle class group of women exposed at low levels. This is reassuring for women exposed at low levels, but it does not exclude the possibility of an effect in women exposed to higher levels of environmental tobacco smoke.

Healthy women's PEF variations with ambient summer concentrations of PM10, PM2.5, SO42-, H+, and O3.

The relationship between ambient air pollution and daily change in peak expiratory flow (PEF) was studied in a sample of 473 nonsmoking women (age 19 to 43 yr) in Virginia over summers 1995- 1996. Daily 24-h averages of particulate matter (PM2.5 and PM10), fine particulate sulfate (SO42-) and strong acid (H+), hourly ozone (O3), and select meteorologic variables (e.g., temperature) were collected at a regional outdoor monitoring site. Subjects took PEF measurements twice daily for a 2-wk period using a standard MiniWright peak flow meter. Concurrent measures for summer periods of 24-h PM2.5 (micrograms/m3) ranged from 3.5 to 59.7; H+ (nmol/m3) from 0 to 250; maximal daily 8-h average O3 (ppb) from 17.0 to 87.6. Morning PEF decrements were significantly associated with H+ and PM2. 5. An increase of 50 etamol/m3 of H+ and 10 micrograms/m3 of PM2.5 related to decreases of 0.89 (95% CI = 0.21 to 1.57) and 0.73 (95% CI = 0.07 to 1.38) L/min in morning PEF, respectively. Ozone was the only exposure related to evening PEF with 5-d cumulative lag exposure showing the greatest effect; 7.65 L/ min (95% CI = 2.25 to 13.0) decrease per 30 ppb O3 increase. Separate physiologic effects were observed for summer ambient concentrations of two different pollutants (PEF decrements related to PM2.5 in morning and O3 in evening) at concentrations below the new U.S. EPA 24-h ambient air quality standard for PM2.5 and 8-h standard for O3.

Bacteriophage T4 initiates bidirectional DNA replication through a two-step process.

Two-dimensional gel analysis of the bacteriophage T4 ori(uvsY) region revealed a novel "comet" on the Y arc. This comet contains simple Y molecules in which the branch points map to the ori(uvsY) transcript region. The comet depends on the the origin and DNA synthesis and is abolished by a mutation that reduces replication without affecting transcription. These results argue that the branched molecules are intermediates in replication initiation. A transcriptional terminator, cloned just downstream of the origin promoter, shortened the tail of the comet. Therefore, the location of the transcript determines the DNA branch points. We conclude that the comet DNA consists of intermediates in which unidirectional replication has been triggered by priming from the RNA of the origin R loop.