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Porphyromonas gingivalis has been implicated in the etiology of adult periodontitis. In this study, we examined the viability of Drosophila melanogaster as a new model for examining P. gingivalis -host interactions. P. gingivalis (W83) infection of Drosophila resulted in a systemic infection that killed in a dose-dependent manner. Differences in the virulence of several clinically prevalent P. gingivalis strains were observed in the Drosophila killing model, and the results correlated well with studies in mammalian infection models and human epidemiologic studies. P. gingivalis pathobiology in Drosophila did not result from uncontrolled growth of the bacterium in the Drosophila hemolymph (blood) or overt damage to Drosophila tissues. P. gingivalis killing of Drosophila was multifactorial, involving several bacterial factors that are also involved in virulence in mammals. The results from this study suggest that many aspects of P. gingivalis pathogenesis in mammals are conserved in Drosophila , and thus the Drosophila killing model should be useful for characterizing P. gingivalis -host interactions and, potentially, polymicrobe-host interactions.

To evaluate the relationship between accommodation, visual acuity, and emmetropization in human infancy.Defocus at distance and near (57 cm) was assessed using Mohindra and dynamic retinoscopy, respectively, in 262 normal birthweight infants at 3, 9, and 18 months of age. Preferential looking provided acuity data at the same ages. The spherical equivalent refractive error was measured by cycloplegic retinoscopy (cyclopentolate 1%).Univariate linear regression analyses showed no associations between the change in refractive error and defocus at distance or near. Change in refractive error was linearly related to the accommodative response at distance (R = 0.17, p0.0001) and near (R = 0.13, p0.0001). The ten subjects with the poorest emmetropization relative to the change predicted by the linear effects of their refractive error had higher average levels of hyperopic defocus at distance and near (p0.043). Logistic regression showed a decrease in the odds of reaching +2.00 diopter or less hyperopia by 18 months with increasing levels of hyperopia at 3 months, or if Mohindra retinoscopy was myopic combined with acuity better than the median level of 1.25 logMAR [area under the receiver operating characteristic curve = 0.78 (95% CI = 0.68 to 0.88)].The level of cycloplegic refractive error was the best single factor for predicting emmetropization by 18 months of age, with smaller contributions from visual acuity and Mohindra retinoscopy. The lack of correlation between defocus and change in refractive error does not support a simple model of emmetropization in response to the level of hyperopic defocus. Infants were capable of maintaining accurate average levels of accommodation across a range of moderate hyperopic refractive errors at 3 months of age. The association between the change in refractive error and accommodative response suggests that accommodation is a plausible visual signal for emmetropization.

Purpose To evaluate the efficacy of prolonged intracerebral (i.c.) administration of carboplatin by means of ALZET osmotic pumps, in combination with radiotherapy for the treatment of intracranial F98 glioma in rats. Methods and Materials Seven days after stereotactic implantation of F98 glioma cells into the brains of Fischer rats, carboplatin was administrated i.c. by means of ALZET pumps over 6 days. Rats were treated at the European Synchrotron Radiation Facility with a single 15-Gy X-ray dose, either given alone or 24 h after administration of carboplatin. Results Untreated rats had a mean survival time (MST) ± SE of 23 ± 1 days, compared with 44 ± 3 days for X-irradiated animals and 69 ± 20 days for rats that received carboplatin alone, with 3 of 13 of these surviving >195 days. Rats that received carboplatin followed by X-irradiation had a MST of >142 ± 21 days and a median survival time of >195 days, with 6 of 11 rats (55%) still alive at the end of the study. The corresponding percentage increases in lifespan, based on median survival times, were 25%, 85%, and 713%, respectively, for carboplatin alone, radiotherapy alone, or the combination. Conclusions Our data demonstrate that i.c. infusion of carboplatin by means of ALZET pumps in combination with X-irradiation is highly effective for the treatment of the F98 glioma. They provide strong support for the approach of concomitantly administering chemo- and radiotherapy for the treatment of brain tumors.

The purpose of the present study was to evaluate the effectiveness of a 3-carboranyl thymidine analogue (3CTA), 3-[5-{2-(2,3-dihydroxyprop-1-yl)- o -carboran-1-yl}pentan-1-yl] thymidine, designated N5–2OH, for boron neutron capture therapy (BNCT) of brain tumors using the RG2 rat glioma model. Target validation was established using the thymidine kinase (TK) 1(+) wild-type, murine L929 cell line and its TK1(−) mutant counterpart, which were implanted s.c. (s.c.) into nude mice. Two intratumoral (i.t.) injections of 10 B-enriched N5–2OH were administered to tumor-bearing mice at 2-hour intervals, after which BNCT was carried out at the Massachusetts Institute of Technology (MIT) Research Reactor. Thirty days after BNCT, mice bearing TK1(+) L929 tumors had a 15× reduction in tumor volume compared with TK1(−) controls. Based on these favorable results, BNCT studies were then initiated in rats bearing intracerebral (i.c.) RG2 gliomas, after i.c. administration of N5–2OH by Alzet osmotic pumps, either alone or in combination with i.v. (i.v.) boronophenylalanine (BPA), a drug that has been used clinically. The mean survival times (MSTs) of RG2 glioma bearing rats were 45.6 ± 7.2 days, 35.0 ± 3.3days, and 52.9 ± 8.9 days, respectively, for animals that received N5–2OH, BPA, or both. The differences between the survival plots of rats that received N5–2OH and BPA alone were highly significant ( P = 0.0003). These data provide proof-of-principle that a 3CTA can function as a boron delivery agent for NCT. Further studies are planned to design and synthesize 3CTAs with enhanced chemical and biological properties, and increased therapeutic efficacy.

To correlate cardiovascular magnetic resonance (CMR)-based measurement of aortic pulse wave velocity (PWV) with serum markers for atherosclerosis and plaque burden in the thoracic aorta.Individuals with risk factors for coronary atherosclerosis underwent CMR pulse wave velocity examination of the descending thoracic aorta and computed tomography for coronary calcium scoring. Inversion recovery images allowed quantification of aortic plaque. Serum lipids and c-reactive protein levels were measured.Mean PWV did not correlate with presence of aortic plaque (p = 0.55). Subgroup analysis showed no significant correlation with PWV and total plaque. PWV and pulse pressure correlated (PP) (R2 0.38, p = 0.0003), but PWV and other predictor variables did not. Total plaque area correlated with aortic diameter (p = 0.0066).In patients with suspected coronary artery disease, aortic pulse wave velocity reflects increased aortic stiffness demonstrated by elevated pulse pressure, but does not directly correlate with aortic plaque or serum markers for arterial disease.

ObjectivesWe studied the modifier effect of platelet antigen polymorphism (PlA2) on platelet inhibition by acetylsalicylic acid (ASA, i.e., aspirin), clopidogrel, or their combination in patients with coronary heart disease.BackgroundClopidogrel, when administered with ASA, was shown to significantly improve the outcome of patients with acute coronary syndromes compared with patients receiving only ASA. We have shown previously that the effect of ASA on platelets is modified by the glycoprotein IIIa single nucleotide polymorphism PlA2. Hence, an important pharmacogenetic question remains whether the antiplatelet effect of clopidogrel is uniform for all patients or, like acetylsalicylic acid, more selective.MethodsThirty PlA1/A1and 30 PlA1/A2patients were assigned randomly to ASA 325 mg/day, clopidogrel 75 mg/day, or both. After 10 days, platelet function was studied.ResultsClopidogrel provided stronger platelet inhibition than ASA with adenosine diphosphate as the agonist, and combination therapy resulted in greater inhibition than either inhibitor used alone (p < 0.0001). The use of ASA resulted in greater inhibition compared with clopidogrel with epinephrine (p < 0.0001) and collagen as agonists (p < 0.0001). With collagen as the agonist, platelets from PlA1/A2donors were markedly and significantly less inhibited by ASA (p = 0.005). In contrast, with clopidogrel, no significant difference could be detected between inhibition of PlA1/A1and PlA1/A2platelets.ConclusionsThe combination of ASA and clopidogrel appears superior to either agent alone in inhibiting platelet function. PlA2functions as an important modifier for platelet responsiveness to ASA but not to clopidogrel. These findings could have significant impact on the future design of pharmacogenetic antithrombotic strategies for patients with coronary heart disease.

Complaints of excessive numbers of flies were reported by citizens living in a rural area surrounding a large (>2 million laying hens) egg-layer facility in northwestern Ohio. Sticky cylinder traps and hanging fly strips were used at outdoor and indoor locations, respectively, at known distances from the layer farm and from control sites to determine the most likely source of the flies and to determine the severity of the problem compared with fly populations in nearby rural settings. House flies, Musca domestica (L.), were the predominant flies captured on fly traps located within 6.4 km of the poultry operations. There was a significantly greater number of M. domestica trapped in the study area surrounding the layer facility than in the control areas. The quantity of house flies captured decreased with increased distance from the layer farm. Two years into the study, a second egg-layer facility opened in an area that was originally a control site. With regard to this second farm, after 4 yr of study, there was a significant difference shown between the population of house flies during the 2-yr control phase and the 2-yr period when the egg-layer facility was operational. This study documented that large egg layer facilities can significantly increase the house fly population in the surrounding community up to 6.4 km from the source of the flies and may result in a severe nuisance up to 3.2 km away.

The new book by Vittinghoff et al. (2005) is reviewed.

Purpose Boron neutron capture therapy (BNCT) has been used clinically as a single modality treatment for high-grade gliomas and melanomas metastatic to the brain. The purpose of the present study was to determine whether its efficacy could be enhanced by an X-ray boost administered after BNCT. Two brain tumor models were used, the F98 glioma as a model for primary brain tumors and the MRA 27 human melanoma as a model for metastatic brain tumors. Methods and materials For biodistribution studies, either 10 5 F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats or 10 6 MRA 27 melanoma cells were implanted intracerebrally into National Institutes of Health (NIH)-rnu nude rats. Biodistribution studies were performed 11–13 days after implantation of the F98 glioma and 20–24 days after implantation of the MRA 27 melanoma. Animals bearing the F98 glioma received a combination of two boron-containing drugs, sodium borocaptate at a dose of 30 mg/kg and boron phenylalanine (BPA) at a dose of 250 mg/kg. MRA 27 melanoma-bearing rats received BPA (500 mg/kg) containing an equivalent amount of 10 B (27 mg B/kg). The drugs were administered by either intracarotid or i.v. injection. Results The tumor boron concentration after intracarotid injection was ∼50% greater in the F98 glioma and MRA 27 melanoma after intracarotid injection (20.8 and 36.8 μg/g, respectively) compared with i.v. injection (11.2 and 19.5 μg/g, respectively). BNCT was carried out at the Brookhaven National Laboratory Medical Research Reactor ∼14 days after tumor implantation of either the F98 glioma or the MRA 27 melanoma. Approximately 7–10 days after BNCT, subsets of animals were irradiated with 6-MV photons, produced by a linear accelerator at a total dose of 15 Gy, delivered in 5-Gy daily fractions. F98 glioma-bearing rats that received intracarotid or i.v. sodium borocaptate plus BPA, followed 2.5 h later by BNCT and 7–10 days later by X-rays, had similar mean survival times (61 days and 53 days, respectively, p = 0.25), and the non X-irradiated, BNCT-treated animals had a mean survival time of 52 and 40 days, respectively, for intracarotid vs. i.v. injection; the latter was equivalent to that of the irradiated animals. The corresponding survival time for MRA 27 melanoma-bearing rats that received intracarotid or i.v. BPA, followed by BNCT and then X-irradiation, was 75 and 82 days, respectively ( p = 0.5), 54 days without X-irradiation ( p = 0.0002), 37 days for X-irradiation alone, and 24 days for untreated controls. In contrast to the data obtained with the F98 glioma, MRA 27 melanoma-bearing rats that received i.v. BPA, followed by BNCT, had a highly significant difference in mean survival time compared with the irradiated controls (54 vs. 37 days, p = 0.008). Conclusion Our data are the first to suggest that a significant therapeutic gain may be obtained when BNCT is combined with an X-ray boost. Additional experimental studies are required to determine the optimal combination of X-radiation and neutron doses and whether it is more advantageous to administer the photon boost before or after BNCT.

Recent investigations of the human subgingival oral flora based on ribosomal 16S cloning and sequencing have shown many of the bacterial species present to be novel species or phylotypes. The purpose of the present investigation was to identify potential periodontal pathogens among these newly identified species and phylotypes. Species-specific ribosomal 16S primers for PCR amplification were developed for detection of new species. Associations with chronic periodontitis were observed for several new species or phylotypes, including uncultivated clones D084 and BH017 from the Deferribacteres phylum, AU126 from the Bacteroidetes phylum, Megasphaera clone BB166, clone X112 from the OP11 phylum, and clone I025 from the TM7 phylum, and the named species Eubacterium saphenum, Porphyromonas endodontalis, Prevotella denticola, and Cryptobacterium curtum. Species or phylotypes more prevalent in periodontal health included two uncultivated phylotypes, clone W090 from the Deferribacteres phylum and clone BU063 from the Bacteroidetes, and named species Atopobium rimae and Atopobium parvulum.

Objectives: Several oral pathologists have described oral leukoplakia of the maxillary vestibule in patients with no traditional risk factors for the condition. On questioning these patients, it was determined that Viadent® mouthrinse or Viadent® toothpaste was commonly used by them. A hypothesis was developed that Viadent® or a component of Viadent® caused the lesions. This paper evaluates the association between oral leukoplakia and use of Viadent® products. Methods: A matched case-control study was designed to test the hypothesis that use of Viadent® products increases an individual's risk of oral leukoplakia. Cases included 58 patients diagnosed with oral leukoplakia identified through the biopsy service at the Ohio State University, College of Dentistry, Oral Pathology Section. The matched control was a friend or relative of the patient. Cases and controls were administered a questionnaire about their use of Viadent®, and other known risk factors for leukoplakia such as tobacco and excessive alcohol use. Results: An age difference was seen between cases and controls, the cases being older (P

Although substantial epidemiologic evidence links Streptococcus mutans to caries, the pathobiology of caries may involve more complex communities of bacterial species. Molecular methods for bacterial identification and enumeration now make it possible to more precisely study the microbiota associated with dental caries. The purpose of this study was to compare the bacteria found in early childhood caries (ECC) to those found in caries-free children by using molecular identification methods. Cloning and sequencing of bacterial 16S ribosomal DNAs from a healthy subject and a subject with ECC were used for identification of novel species or uncultivated phylotypes and species not previously associated with dental caries. Ten novel phylotypes were identified. A number of species or phylotypes that may play a role in health or disease were identified and warrant further investigation. In addition, quantitative measurements for 23 previously known bacterial species or species groups were obtained by a reverse capture checkerboard assay for 30 subjects with caries and 30 healthy controls. Significant differences were observed for nine species: S . sanguinis was associated with health and, in order of decreasing cell numbers, Actinomyces gerencseriae , Bifidobacterium , S . mutans , Veillonella , S . salivarius , S . constellatus , S . parasanguinis , and Lactobacillus fermentum were associated with caries. These data suggest that A . gerencseriae and other Actinomyces species may play an important role in caries initiation and that a novel Bifidobacterium may be a major pathogen in deep caries. Further investigation could lead to the identification of targets for biological interventions in the caries process and thereby contribute to improved prevention of and treatment for this significant public health problem.

Purpose : Multicentric cerebral metastases of melanoma represent an important clinical problem for which there currently is no satisfactory treatment. We previously developed a model for melanoma metastatic to the brain employing nude rats bearing intracerebral implants of the human MRA27 melanoma. The purpose of the present study was to determine if the efficacy of boron neutron capture therapy (BNCT) could be improved by either Cereport (RMP-7) mediated modulation of blood-brain barrier (BBB) permeability or hyperosmotic mannitol-induced BBB disruption using boronophenylalanine (BPA) as the capture agent. Methods and Materials : Biodistribution studies were carried out at 0.5, 2.5, and 4 h after intracarotid administration of Cereport (1.5 μg/kg) and intracarotid or i.v. administration of BPA (500 mg/kg). Peak tumor boron concentrations (65.4 μg/g) and the best composite tumor:brain (6.1:1) and tumor:blood (6.3:1) ratios were observed at 2.5 h after intracarotid administration. BNCT was initiated at the Brookhaven Medical Research Reactor 13–14 days after intracerebral implantation of 106 MRA27 cells. Results : Untreated control rats had a median survival time (MeST) of 22 days and for irradiated controls, it was 30 days. Rats that received i.v. or intracarotid BPA without Cereport followed by BNCT 2.5 h later had MeSTs of 41 days and 57 days, respectively, with 20% long-term survivors (>180 days) in the latter group. Rats that received intracarotid BPA with Cereport had an MeST of 86 days with 36% long-term survivors, which was very close to that of rats that had hyperosmotic mannitol-induced disruption of the BBB (85 days with 25% long-term survivors). When these two groups were combined, and survival times were compared, using the Wilcoxon rank sum test, to those of rats that received intracarotid BPA without blood-brain barrier disruption, these differences were significant at the level p = 0.01. Conclusions : Our data show that optimizing the delivery of BPA by means of intracarotid injection combined with opening the BBB by infusing Cereport or a hyperosmotic solution of mannitol significantly enhanced survival times and produced long-term cures of MRA27 melanoma-bearing rats. These observations are relevant to future clinical studies using BNCT for the treatment of intracerebral melanoma.

OBJECTIVE The purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODS BSH (non-10 B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTS Blood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 μg/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean ± standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1 ± 5.8 and 17.3 ± 10.1 μg/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 μg/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6 ± 5.1 and 5.5 ± 3.9 μg/g and the tumor/normal brain tissue ratios were 3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 μg/ml at 2 hours to 63 μg/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 μg/g, respectively, during the 3- to 7-hour sampling period. CONCLUSION When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

OBJECTIVE Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 microg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 10(3) F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean +/- standard deviation) were 55.7 +/- 9.6 microg/g with Cereport versus 33.6 +/- 3.9 microg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 +/- 9.9 microg/g with Cereport versus 15.4 +/- 3.5 microg/g without Cereport (P < 0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 +/- 0.6, and the tumor-to-brain ratio was 5.2 +/- 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 +/- 16 days for i.c. administration of BPA with Cereport versus 40 +/- 6 days without Cereport (P = 0.05), 38 +/- 4 days for i.v. administration of BPA with Cereport versus 34 +/- 3 days without Cereport (P = 0.02), 28 +/- 5 days for irradiated controls, and 23 +/- 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

We discuss a sample size calculation for a pair-matched case-control study to test for interaction between a specific exposure and a second risk factor. The second risk factor could be either binary or continuous. An algorithm for the calculation of sample size is suggested which is based on a logistic regression model that relates the logarithm of the disease-exposure odds ratio to the second risk factor. This problem is motivated by a study comparing the prevalence of GP-IIIa Pl(A2) polymorphism (the exposure) in individuals with and without myocardial infarction (case-control). One of the hypotheses in this study is whether or not there is an interaction between the prevalence of GP-IIIa Pl(A2) polymorphism and a second risk factor such as smoking status and homocysteine level. We introduce the algorithm in detail with several numerical examples.

Understanding the contribution of race to factors associated with cigarette smoking and nicotine metabolism is essential for the characterization of patterns of tobacco use, nicotine dependence and incidence of tobacco-related diseases. This paper reports an investigation of cotinine levels among Southeast Asian smokers in two separate studies. Study 1 included 327 male and female smokers who participated in community-based interviews where smoking history information was obtained and a saliva continine sample was collected. Results indicated that subjects smoked an average of 11.2 cigarettes/day, with men reporting significantly higher consumption rates as compared to women (p < 0.0001). Subjects' mean cotinine level was 65 ng/ml with an average cotinine/cigarette ratio of 8.2. In Study 2, plasma and saliva cotinine in six Southeast Asian adult smokers were measured during 2 days of smoking followed by 6 days of abstinence. On day 1, mean plasma and saliva continine levels were 268 and 235 ng/ml, respectively. After 6 days of abstinence, mean levels had dropped to 12 ng/ml for plasma and 8 ng/ml in saliva. On average, it required at least 4.7 days for saliva continine levels to reach < 14 ng/ml. Mean cotinine concentrations during smoking differed in these two separate studies. Implications of these findings are discussed and future research recommendations are presented.

Objective Using the well-characterized F98 rat glioma model, the purpose of the present study was to determine whether the delivery of boronophenylalanine (BPA) could be enhanced by prior administration of the bradykinin analog Cereport (Alkermes, Inc., Cambridge, MA) (previously known as Receptor-Mediated Permeabilizer-7), which produces a transient, pharmacologically mediated opening of the blood-brain barrier. Methods Two series of experiments were performed in F98 glioma-bearing rats that had received either intracarotid (i.c.) or intravenous infusions of Cereport (at doses ranging from 1.5 to 7.5 microg/kg of body weight), followed by i.c. (or intravenous) injection of BPA (300 mg/kg of body weight). Animals were killed 0.5, 2.5, or 4 hours later, samples of blood, skin, muscle, and eye were obtained, brains were removed, and tumors were excised for boron determination by direct current plasma-atomic emission spectroscopy. Results Averaged over all time points, i.c. infusion of Cereport significantly enhanced tumor boron uptake (P = 0.0001), compared with the excipient (saline) control values. Tumor boron values were equivalent at 0.5 (36.0 microg/g) and 2.5 hours (38.5 microg/g) after i.c. administration of Cereport and BPA and then decreased by 33% (to 25.7 microg/g) at 4 hours. These tumor boron uptake values were significantly different (alpha = 0.05), compared with values measured at the corresponding times after i.c. administration of BPA without Cereport (22.6, 21.8, and 15.3 microg/g, respectively). Although no time-related effects were observed, i.c. administration of Cereport followed by intravenous administration of BPA also significantly enhanced (alpha = 0.05) tumor boron uptake at 0.5, 2.5, and 4 hours (27.4, 30.3, and 28.0 microg/g, respectively), compared with values obtained without Cereport (11.3, 13.4, and 15.2 microg/g, respectively). Boron levels in normal brain tissue from tumor-bearing and non-tumor-bearing cerebral hemispheres and in blood were not significantly different from those measured in saline-treated control animals. Conclusion This study established that i.c. infusion of Cereport significantly increased delivery of BPA to F98 rat gliomas, and this could enhance the efficacy of boron neutron capture therapy of this tumor.

The agricultural industry has consistently been ranked among the most hazardous in the U.S. To date, few analytic studies of occupational injury among farm operators and workers have been conducted. A case control study was undertaken to investigate risk factors for agricultural work-related injury among Ohio farm operators. Cases were selected from among 1,793 respondents to a questionnaire administered during the first phase of the NIOSH-sponsored Ohio Farm Family Health and Hazard Study (OFFHHS). Analysis consisted of description of the injury experience of the sample as a whole, followed by logistic estimation of prevalence odds ratios (pORs) measuring the effect of potential risk factors on injury risk. The case series consisted of 90 white male principal operators (POs) injured doing farm work in the 12 months prior to questionnaire completion. Controls consisted of 1,475 white male POs who reported no injuries. The overall rate of injury was 5 per 100 person-years. The most notable result is the relationship between self-reported neurotoxic symptoms and injury, suggesting those with more reported symptoms were at greater risk of injury. The crude OR, when compared to the reference score of < or = 27, increased from 1.74 (95% CI = 0.60-5.09) in the 28-30 category, to 1.89 (95% CI = 0.71-5.03) in the 31-35 category, to 2.96 (95% CI = 1.10-7.96) in the highest category of test score. The P value for trend was 0.0218. These associations largely persisted after controlling for potential confounders with multiple logistic regression. Risk was inversely related to age. The results show marked increases in risk of injury associated with farmers younger than 30 and increased severity of self-reported neurological symptoms, controlling for potential confounding.

Boronophenylalanine (BPA) has been used for boron neutron capture therapy (BNCT) of brain tumors in both experimental animals and humans. The purpose of the present study was to determine if the efficacy of BNCT could be enhanced by means of intracarotid (i.c.) injection of BPA with or without blood-brain barrier disruption (BBB-D) and neutron irradiation using a rat brain tumor model. For biodistribution studies, F98 glioma cells were implanted stereotactically into the brains of Fischer rats, and12 days later BBB-D was carried out by i.c. infusion of 25% mannitol (1.373 mOsmol/ml), followed immediately by i.c. administration of 300, 500 or 800 mg of BPA/kg body weight (b.w.). At the 500 mg dose a fourfold increase in tumor boron concentration (94.5 μg/g) was seen at 2.5 hours after BBB-D, compared to 20.8 μg/g in i.v. injected animals. The best composite tumor to normal tissue ratios were observed at 2.5 hours after BBB-D, at which time the tumor: blood (T: Bl) ratio was10.9, and the tumor: brain (T: Br) ratio was 7.5, compared to 3.2 and 5.0 respectively for i.v. injected rats. In contrast, animals that had received i.c. BPA without BBB-D had T: Bl and T: Br ratios of 8.5 and 5.9, respectively, and the tumor boron concentration was 42.7μg/g. For therapy experiments, initiated 14 days after intracerebral implantation of F98 glioma cells, 500 mg/kg b.w. of BPA were administered i.v. or i.c. with or without BBB-D, and the animals were irradiated 2.5 hourslater at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. The mean survival time for untreated control rats was 24 ± 3 days, 30 ± 2 days for irradiated controls, 37 ± 3 days for those receiving i.v. BPA, 52 ± 15 days for rats receiving i.c. BPA without BBB-D, and 95 ± 95 days for BBB-D followed by i.c. BPA and BNCT. The latter group had a 246% increase in life span (ILS) compared to untreated controls and a 124% ILS compared to that of i.v. injected animals. These survival data are the best ever obtained with the F98 glioma model and suggest that i.c. administration of BPA with or without BBB-D may be useful as a means to increase the efficacy of BNCT.

The results of a Monte Carlo study of the size and power of parametric and semi-parametric approaches to inference on covariate effects in survival (time-to-events) models in the presence of model misspecification and an independent censoring mechanism are reported. Basic models employed are a parametric model, where both a baseline distribution and the dependence structure of covariates on the failure times are fully specified (exponential, Weibull, log logistic, log normal, and normal regression models are studied), and a semi-parametric approach (due to Cox) in which the baseline distribution is unspecified. The Cox model performs very well compared to the parametric models for distributions with proportional hazard rates and appears to be with regard to the proportional hazards assumption. Appropriate parametric models have the potential of improving the size and power of the tests, although overall they are not appreciably better than the Cox model. In comparing the small sample performance of three statistical tests, the likelihood ratio and Wald tests closely agree with each other (likelihood ratio having a slight advantage), while the score test tends to perform much poorer since it inflates the size and power more than the other two.

Using results from patients, we studied several methods for long-term (years) monitoring of the analytical stability of various chemistry tests. For each test, we obtained on a bimonthly basis histograms of > or = 200 to approximately 2000 data points and determined the median, mean, and mean of those data points in the reference range ("average of normal" or AON). Examining approximately 4 years' data, we found that the medians and AON are extremely stable for most tests, and that all observed shifts in the medians or in the AON could be explained by expected or unexpected changes in the laboratory. The means and peak values of the Erlang (gamma) distribution were less useful, owing to shifts caused by extreme outliers, especially for enzymes in serum. We assumed that the underlying patient population and testing patterns were stable. We recommend the use of medians or the AON of patients' data under defined conditions for monitoring the long-term analytical stability of certain tests involving serum or whole blood.

There has been increasing interest in the possible use of boronophenylalanine as a capture agent for boron neutron capture therapy of brain tumors. The purpose of the present study was to determine whether the uptake of boronophenylalanine in F98 glioma-bearing rats could be enhanced by means of intracarotid (i.c.) injection with or without blood-brain barrier disruption (BBB-D). Glioma cells (10(5)) were stereotactically implanted into the right cerebral hemisphere of Fischer rats, and 12 days later, BBB-D was performed by infusing 25% mannitol (1.373 mOsmol/ml) into the right carotid artery and then immediately injecting L-boronophenylalanine (300 mg/kg of body weight) intracarotidly. The animals were killed 0.5, 1, 2.5, and 4 hours later, and the brains were removed for boron determination by direct current plasma atomic emission spectroscopy. BBB-D was assessed by the intravenous injection of Evans blue or horseradish peroxidase, and the barrier-disrupted hemispheres and tumors showed intense staining with each. The mean tumor boron concentration after i.c. injection and BBB-D was 34.8 +/- 6.8 micrograms/g at 2.5 hours compared with 20.3 +/- 6.2 micrograms/g after i.c. injection without BBB-D and 10.7 +/- 0.7 micrograms/g after intravenous injection. No significant differences in boron concentration in muscle, skin, and eye were observed among the different groups. Boron concentrations in the ipsilateral, disrupted hemisphere increased transiently but rapidly returned to background levels by 2.5 hours after BBB-D. The tumor:brain and tumor:blood ratios were 5.2 and 5.6, respectively, compared to 3.2 and 2.1 for intravenous injection groups at 2.5 hours. The present study is the first to show that BBB-D combined with i.c. injection can enhance the tumor uptake of boron compounds for boron neutron capture therapy.

A total of 1,403 Southeast Asian adult immigrant males (n = 783) and females (n = 620) from Cambodia, Laos, and Vietnam who currently resided in Central Ohio were interviewed to determine the self-reported smoking prevalence among them, and underwent biochemical confirmation of their smoking status. Variables having to do with the subjects' sociodemography, acculturation, and smoking history that were related to the misclassification of smoking status were also investigated. Self-reported current smoking rates were 40.9% and 5.6% for males and females, respectively. After verification of the subjects' smoking status by saliva cotinine assay (smoker status > or = 14 ng/ml), the rates of smoking were found to be greater, at 43.7% for males and 14.8% for females. Years of education, self-reported smoking status, country of origin, and method of healthcare payment were significant predictors of misclassification. These findings suggest that the prevalence of smoking is higher among Southeast Asian adult females than has been previously reported. Variables that predict misclassification with regard to smoking status are presented, and their implications for clinicians and researchers are discussed.

Many biological and medical studies have as a response of interest the time to occurrence of some event, such as the occurrence of a particular symptom or disease, remission, relapse, death due to some specific disease, or simply death. In this paper we study the problem of assessing the effect of potential risk factors on the outcome event of interest through a parametric or semi-parametric frailty model where the lifetimes have a reason to be considered dependent. This dependence may arise because of multiple endpoints within the same individual or because, when studying a single endpoint, there are natural groupings between study subjects. The objective of this paper is to extend both parametric and semi-parametric approaches to regression analysis in which the lifetimes of individuals in a group are effected by the same random frailty which follows a positive stable distribution. Some comparisons of the properties of this frailty distribution with other frailty distributions are made and an example which assesses the effect of a treatment in a litter-matched tumorigenesis study is presented.

Many biological and medical studies have as a response of interest the time to occurrence of some event, X, such as the occurrence of cessation of smoking, conception, a particular symptom or disease, remission, relapse, death due to some specific disease, or simply death. Often it is impossible to measure X due to the occurrence of some other competing event, usually termed a competing risk. This competing event may be the withdrawal of the subject from the study (for whatever reason), death from some cause other than the one of interest, or any eventuality that precludes the main event of interest from occurring. Usually the assumption is made that all such censoring times and lifetimes are independent. In this case one uses either the Kaplan-Meier estimator or the Nelson-Aalen estimator to estimate the survival function. However, if the competing risk or censoring times are not independent of X, then there is no generally acceptable way to estimate the survival function. There has been considerable work devoted to this problem of dependent competing risks scattered throughout the statistical literature in the past several years and this paper presents a survey of such work.

The optical and structural development of the major dioptric components of the eye, the cornea and crystalline lens, has been well-documented from infancy through childhood. The cornea displays little difference as a function of age despite its importance as two-thirds of the dioptric power of the eye. At 47 D to 48 D, average corneal power is greater in infants than in children or adults for a relatively brief period,1–3 then by age 3 to 9 months reaches values of 43 D to 44 D that remain stable throughout childhood.4–7 The crystalline lens undergoes more substantial age-related changes in several parameters over a longer period of time. The anterior surface radius of curvature averages 7.2 mm in early infancy, then flattens by some 4.5 mm to reach 11–12 mm by age 14 years.4, 8–9 The posterior surface follows a similar time course, with radii in infancy averaging 4.7 mm, flattening to 6–7 mm by age 14 years.4, 8–9 Flattening radii of curvature over time contribute to an overall loss in equivalent power of about 18 D to 19 D; the average crystalline lens power of 41 D in infancy becomes about 22–23 D by age 14 years.4–6, 9 This power loss from flattening radii of curvature is facilitated by an accompanying decrease in the lens equivalent refractive index for much of infancy and early childhood. An equivalent refractive index of 1.45 in early infancy drops to 1.43 to 1.42 by age 10 years, responsible for nearly half of the decrease in crystalline lens equivalent power.4–6 After age 10 years, lens refractive index appears to be stable on average in white and Asian children, continues to decrease in Native Americans, but switches direction to increase in African-American and Hispanic children.6 Lens thickness also decreases in infancy and early childhood from an average of 3.7–4.0 mm in infancy to 3.4–3.5 mm at age 10 years.4–7, 10–11 Except for one report in Tibetan children,9 lens thinning reverses direction to become lens thickening after the age of 10–13 years in most ethnic groups.6–7, 12 The substantial decreases in crystalline lens power that take place with age are counter-balanced by a vitreous chamber depth (VCD) that elongates from 10–11 mm at birth to become 16–17 mm by age 14 years.5–7, 9–11 Precise balance between corneal and lenticular refractive power and the length of the eye should result in a stable refractive state. The ocular components that are in balance in emmetropia are obviously out of balance in myopia: the eye is too long for the optical power of the cornea and crystalline lens. Understanding the temporal pattern of how this imbalance develops requires data both before and after the onset of myopia. Numerous studies have documented average values by age for myopic and emmetropic individuals,13–17 longitudinal studies have reported change in ocular components as a function of age,5, 7, 18 but the behavior of the optical ocular components before and after the onset of myopia has not been reported in detail. One longitudinal study compared children at their last emmetropic visit before myopia onset to children who remained emmetropic. The average corneal power of the children who became myopic was about 0.8 D greater and there were no differences in lens thickness or power compared to those who remained emmetropic;19 however this study provided data at only one point in time before myopia onset. The purpose of the current paper is to document the temporal development of corneal power and several crystalline lens parameters (thickness, equivalent power, radii of curvature, and refractive index) across the years before, during, and after myopia onset in comparison to age-matched emmetropic values.

We present data on the effects of a heart health education intervention targeted at adult Southeast Asians. Within each of the Cambodian, Laotian, and Vietnamese groups who received the intervention, we obtained random samples approximately three to 18 months postintervention. Comparisons were made between preintervention and postintervention knowledge of blood pressure and awareness of behaviors to prevent heart disease. Within all three ethnic samples, we found significant increases in the pre-to-post percentages of individuals who could define blood pressure and identify ways to prevent heart diseases. [Am J Prev Med 1994;10:205–8]

Numerous experiments show that chronic exposure to lenses simulating hyperopic refractive error accelerates axial growth in a predictable manner in various species, suggesting that defocus at the fovea influences eye growth.1–5 Greater amounts of accommodative lag from a deficient accommodative response is the putative analogous source of hyperopic defocus during near work in children.6–8 Several studies have shown that myopic children or those undergoing more rapid myopic progression spend more time in near work than nonmyopes or more slowly progressing myopes,9–13 yet the association between refractive error and near work is not always statistically significant.14–17 In addition, the potency of accommodative lag in stimulating human ocular growth is not clear. Hyperopic defocus is less related to the rate of emmetropization in infancy than is the level of accommodative effort expended by hyperopic infants.18 In children, many attempts to reduce accommodative lag through plus lens corrections at near have had only modest results in slowing myopic progression.12,19–23 However, other studies and subsamples of myopic children—for example, esophores at near with high accommodative lag—have shown a larger treatment effect of plus at near.24–26 Whether a high accommodative lag increases the risk of onset of myopia in nonmyopic children is also unclear. One study found increased accommodative lag 2 years before the onset of myopia and in the year of onset.7 Our own larger investigation showed no increase in accommodative lag before myopia onset in children who became myopic compared with children who were emmetropic.8 Recent investigations of the effects of hyperopic defocus on ocular growth have shifted their attention away from measures at the fovea and moved toward the retinal periphery. Ablation and occlusion experiments in primates have shown that manipulation of the more extensive peripheral visual environment can guide not only peripheral ocular growth, but also axial growth, suggesting that perhaps peripheral hyperopic defocus can act as a guide for foveal refractive error.27,28 Myopes have relative peripheral hyperopia more often than other refractive error groups, at least in the lateral visual field, because of their relatively less oblate ocular shape.29–35 This exposure to peripheral hyperopic defocus appears about 2 years before myopia onset, on average.36 The degree of risk for myopia onset from peripheral hyperopia has not yet been quantified, nor has it been adjusted for foveal refractive error or ethnicity. The purpose of this analysis was to use longitudinal data from the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study to evaluate the following hypotheses: (1) nonmyopic children with more relative peripheral hyperopia are at higher risk for becoming myopic, and (2) myopic children with more relative peripheral hyperopia have a faster rate of myopic progression.

This article reports the development of an acculturation scale for Southeast Asian immigrants. From factor analyses of responses on 13 items obtained from samples of three different Southeast Asian ethnic groups, i.e., Cambodians, Laotians, and Vietnamese, two subscales were derived: (1) proficiency in languages (land of origin versus English), and (2) language, social and food (LSF) preferences. Inter-item reliability of the scales was demonstrated for each of the three ethnic groups, with Cronbach alpha coefficients of 0.76 or above. Construct validity was also established within each of the three ethnic groups by demonstrating expected associations of the subscales with current age, years in the USA, total years of education, percentage of lifetime in the USA, and age on entering the USA. Multivariate analyses within each of the ethnic groups revealed that, once controlling for years of education, percentage of lifetime in the USA, and type of health care coverage, although not significant for the Cambodians (P = 0.08) males tended to show higher scores for the proficiency in language subscale in comparison to females. Similar multivariate analyses for the LSF preference subscale showed that although slightly higher for the males, the differences between the genders was not significant for the Cambodians (P = 0.78); both the Laotian (P = 0.23) and Vietnamese (P = 0.01) females showed higher scores in comparison to males although only just reaching significance for the Vietnamese.

Bivariate survival analysis models that incorporate random effects or ‘frailty’ provide a useful framework for determining the effectiveness of interventions. These models are based on the notion that two paired survival times are correlated because they share a common unobserved value of a random variate from a frailty distribution. In some applications, however, investigators may have some information that characterizes pairs and thus provides information about their frailty. Alternatively, there may be an interest in assessing whether the correlation within certain types of pairs is different from the correlation within other types of pairs. In this paper, we present a method to incorporate ‘pair-wise’ covariate information into the dependence parameter of the bivariate survival function. We provide an example using data from the Framingham Heart Study to investigate the times until the occurrence of two events within an individual: the first detection of hypertension and the first cardiovascular disease event. We model the dependence between these two events as a function of the age of the individual at the time of enrolment into the Framingham Study.

Porphyromonas gingivalis is a Gram-negative obligate anaerobe that has been implicated in the etiology of adult periodontitis. We recently introduced a Drosophila melanogaster killing model for examination of P. gingivalis -host interactions. In the current study, the Drosophila killing model was used to characterize the host response to P. gingivalis infection by identifying host components that play a role during infection. Drosophila immune response gene mutants were screened for altered susceptibility to killing by P. gingivalis . The Imd signaling pathway was shown to be important for the survival of Drosophila infected by nonencapsulated P. gingivalis strains but was dispensable for the survival of Drosophila infected by encapsulated P. gingivalis strains. The P. gingivalis capsule was shown to mediate resistance to killing by Drosophila antimicrobial peptides (Imd pathway-regulated cecropinA and drosocin) and human beta-defensin 3. Drosophila thiol-ester protein II (Tep II) and Tep IV and the tumor necrosis factor (TNF) homolog Eiger were also involved in the immune response against P. gingivalis infection, while the scavenger receptors Eater and Croquemort played no roles in the response to P. gingivalis infection. This study demonstrates that the Drosophila killing model is a useful high-throughput model for characterizing the host response to P. gingivalis infection and uncovering novel interactions between the bacterium and the host.

Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98EGFR) or mutant receptors(F98npEGFRvIII).Experimental Design: A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering 125I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor.Results: Following CED of a mixture of 125I-BD-C225 and 125I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for 125I-BD-L8A4 and 34.7% ID/g for 125I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 μg/g for rats that received both mAbs, and 12.3 and 13.8 μg/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P < 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls.Conclusions: Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of 10B for BNCT of EGFRvIII-expressing gliomas.

Twenty-five patients with congestive heart failure (CHF) underwent a double-blind randomized study of the acute hemodynamic effects of orally administered nicorandil, a newly developed vasodilator drug. A dose range of 10 to 60 mg was studied. Nicorandil, at a dose of 60 mg, caused statistically significant decreases in systemic systolic and diastolic blood pressure, right atrial pressure, pulmonary capillary wedge pressure, systemic and pulmonary vascular resistance and systolic and diastolic pulmonary arterial pressure. A brief increase in cardiac index attributable to an increase in stroke volume without a change in heart rate was also observed. A dose of 40 mg produced similar results in cardiac index and systemic and pulmonary vascular resistance, but changes in other hemodynamic parameters were much smaller in magnitude and usually not of statistical significance. No significant hemodynamic response was seen to doses of 10 and 20 mg of nicorandil. Duration of action was short with nearly all hemodynamic parameters returning close to baseline within 3 hours. This rapid decrease in activity occurred in concert with a rapid plasma clearance of nicorandil as determined by serial measurements of plasma drug concentration. This study suggests that first-dose orally administered nicorandil elicits favorable, but brief, hemodynamic effects in CHF at doses greater than or equal to 40 mg.

To identify whether parental history of myopia and/or parent-reported children's visual activity levels can predict juvenile-onset myopia.Survey-based data from Orinda Longitudinal Study of Myopia subjects from 1989 to 2001 were used to predict future myopia. Univariate and multiple logistic regression analyses were performed, and receiver operator characteristic (ROC) curves were generated. Differences among the areas under the ROC curves were compared using the method of multiple comparison with the best.Of the 514 children eligible for this analysis, 111 (21.6%) became myopic. Differences in the third grade between eventual myopes and nonmyopes were seen for the number of myopic parents (P0.001) and for the number of sports and outdoor activity hours per week (11.65 +/- 6.97 hours for nonmyopes vs. 7.98 +/- 6.54 hours for future myopes, P0.001). Analysis of the areas under the ROC curves showed three variables with a predictive value better than chance: the number of myopic parents, the number of sports and outdoor activity hours per week, and the number of reading hours per week. After controlling for sports and outdoor hours per week and parental myopia history, reading hours per week was no longer a statistically significant factor. The area under the curve for the parental myopia history and sports and outdoor activities model was 0.73. A significant interaction in the logistic model showed a differential effect of sport and outdoor activity hours per week based on a child's number of myopic parents.Parental history of myopia was an important predictor in univariate and multivariate models, with a differential effect of sports and outdoor activity hours per week based on the number of myopic parents. Lower amounts of sports and outdoor activity increased the odds of becoming myopic in those children with two myopic parents more than in those children with either zero or one myopic parent. The chance of becoming myopic for children with no myopic parents appears lowest in the children with the highest amount of sports and outdoor activity, compared with those with two myopic parents.

This paper reviews the statistical analyses of competing risks data. There is an extensive history of this topic; however, the literature is often confusing partially because it evolved over time. The available data for competing risks is in the form of time until event occurrence where T is the time from some suitable starting point until some cause of failure for each individual who fails, and δi is an indicator variable equal to 1 if failure is due to the ith cause, 0 otherwise. In the latent failure time approach, one assumes that there are k potential failure times, X1, X2, …, Xk, associated with each risk. T is then the min (X1, X2, …, Xk) and δi is an indicator variable equal to 1 if failure is due to the ith cause, 0 otherwise. References for the latent failure time model prior to the 1970s may be found in David and Moeschberger (1978), and more recently in Klein and Moeschberger (2003). The direction of the statistical analyses of competing risks studies changed dramatically after the identifiability problem for marginal distributions of the latent failure time model was pointed out by Tsiatis (1975), Prentice et al. (1978), and many others. At that time, interest centered on estimating identifiable competing risk probabilities. Most of the references cited in this paper deal with the more recent attempts to analyze competing risks data.

The gingival sulcus contains a complex ecosystem that includes many uncultivated bacteria. Understanding the dynamics of this ecosystem in transitions between health and disease is important in advancing our understanding of the bacterial etiology of periodontitis. The objective of this longitudinal study was to examine the stability of bacterial colonization in the gingival crevice and to explore the relationship between shifts in microbial composition and changes in periodontal health status using a comprehensive, quantitative, culture-independent approach. Subgingival plaque samples and periodontal data were collected from 24 subjects over 2 years. Baseline and 2-year plaque samples were analyzed using quantitative ribosomal 16S cloning and sequencing. Ten subjects remained periodontally healthy over 2 years, the periodontal health of seven subjects worsened, and seven subjects showed clinical improvement. Bacterial stability was greatest among healthy, clinically stable subjects and lowest for subjects whose periodontal status worsened ( P = 0.01). Higher numbers of species lost or gained were also observed for subjects whose clinical status changed ( P = 0.009). This provides evidence that a change in periodontal status is accompanied by shifts within the bacterial community. Based on these data, measures of microbial stability may be useful in clinical diagnosis and prognosis. Regarding individual species, increases in levels of the uncultivated phylotype Veillonella sp. oral clone X042, a gram-negative bacterium and the most common member of the subgingival bacterial community, were associated with periodontal health ( P = 0.04), suggesting that this is an important beneficial species. Filifactor alocis , a gram-positive anaerobe, was found at higher levels in subjects with disease ( P = 0.01).

Purpose: The purpose of the present study was to evaluate a boronated EGFRvIII-specific monoclonal antibody, L8A4, for boron neutron capture therapy (BNCT) of the receptor-positive rat glioma, F98npEGFRvIII. Experimental Design: A heavily boronated polyamido amine (PAMAM) dendrimer (BD) was chemically linked to L8A4 by two heterobifunctional reagents, N-succinimidyl 3-(2-pyridyldithio)propionate and N-(k-maleimidoundecanoic acid)hydrazide. For in vivo studies, F98 wild-type receptor-negative or EGFRvIII human gene-transfected receptor-positive F98npEGFRvIII glioma cells were implanted i.c. into the brains of Fischer rats. Biodistribution studies were initiated 14 days later. Animals received [125I]BD-L8A4 by either convection enhanced delivery (CED) or direct i.t. injection and were euthanized 6, 12, 24, or 48 hours later. Results: At 6 hours, equivalent amounts of the bioconjugate were detected in receptor-positive and receptor-negative tumors, but by 24 hours the amounts retained by receptor-positive gliomas were 60.1% following CED and 43.7% following i.t. injection compared with 14.6% ID/g by receptor-negative tumors. Boron concentrations in normal brain, blood, liver, kidneys, and spleen all were at nondetectable levels (6 months) and those that received BD-L8A4 alone had a mean ± SE survival time of 70.4 ± 11.1 days with 10% long-term survivors compared with 40.1 ± 2.2 days for i.v. BPA and 30.3 ± 1.6 and 26.3 ± 1.1 days for irradiated and untreated controls, respectively. Conclusions: These data convincingly show the therapeutic efficacy of molecular targeting of EGFRvIII using either boronated monoclonal antibody L8A4 alone or in combination with BPA and should provide a platform for the future development of combinations of high and low molecular weight delivery agents for BNCT of brain tumors.

Complaints of excessive numbers of flies were reported by citizens living in a rural area surrounding a large (2 million laying hens) egg-layer facility in northwestern Ohio. Sticky cylinder traps and hanging fly strips were used at outdoor and indoor locations, respectively, at known distances from the layer farm and from control sites to determine the most likely source of the flies and to determine the severity of the problem compared with fly populations in nearby rural settings. House flies, Musca domestica (L.), were the predominant flies captured on fly traps located within 6.4 km of the poultry operations. There was a significantly greater number of M. domestica trapped in the study area surrounding the layer facility than in the control areas. The quantity of house flies captured decreased with increased distance from the layer farm. Two years into the study, a second egg-layer facility opened in an area that was originally a control site. With regard to this second farm, after 4 yr of study, there was a significant difference shown between the population of house flies during the 2-yr control phase and the 2-yr period when the egg-layer facility was operational. This study documented that large egg layer facilities can significantly increase the house fly population in the surrounding community up to 6.4 km from the source of the flies and may result in a severe nuisance up to 3.2 km away.

PURPOSE To evaluate the contribution made by the ocular components to the emmetropization of spherical equivalent refractive error in human infants between 3 and 9 months of age. METHODS Keratophakometry in two meridians was performed on 222 normal-birthweight infant subjects at 3 and 9 months of age. The spherical equivalent refractive error was measured by cycloplegic retinoscopy (cyclopentolate 1%). Anterior chamber depth, lens thickness, and vitreous chamber depth were measured by A-scan ultrasonography over the closed eyelid. RESULTS Both the mean and SD for spherical equivalent refractive error decreased between 3 and 9 months of age (+2.16 +/- 1.30 D at 3 months; +1.36 +/- 1.06 D at 9 months; P < 0.0001, for the change in both mean and SD). Average ocular component change was characterized by increases in axial length, thinning, and flattening of the crystalline lens, increases in lens equivalent refractive index, and decreases in lens and corneal power. Initial refractive error was associated in a nonlinear manner with the change in refractive error (R(2) = 0.41; P < 0.0001) and with axial growth (R(2) = 0.082; P = 0.0005). Reduction in hyperopia correlated significantly with increases in axial length (R(2) = 0.16; P < 0.0001), but not with changes in corneal and lenticular power. Decreases in lenticular and corneal power were associated with axial elongation (R(2) = 0.40, R(2) = 0.12, respectively; both P < 0.0001). CONCLUSIONS Modulation in the amount of axial growth in relation to initial refractive error appeared to be the most influential factor in emmetropization of spherical equivalent refractive error. The associations between initial refractive error, subsequent axial growth, and change in refractive error were consistent with a visual basis for emmetropization. The cornea and crystalline lens lost substantial amounts of dioptric power in this phase of growth, but neither appeared to play a significant role in emmetropization.

Most studies of the bacterial etiology of periodontitis have used either culture-based or targeted DNA approaches, and so it is likely that pathogens remain undiscovered. The purpose of this study was to use culture-independent, quantitative analysis of biofilms associated with chronic periodontitis and periodontal health to identify pathogens and beneficial species. Samples from subjects with periodontitis and controls were analyzed using ribosomal 16S cloning and sequencing. Several genera, many of them uncultivated, were associated with periodontitis, the most numerous of which were gram positive, including Peptostreptococcus and Filifactor . The genera Megasphaera and Desulfobulbus were elevated in periodontitis, and the levels of several species or phylotypes of Campylobacter , Selenomonas , Deferribacteres , Dialister , Catonella , Tannerella , Streptococcus , Atopobium , Eubacterium , and Treponema were elevated in disease. Streptococcus and Veillonella spp. were found in high numbers in all samples and accounted for a significantly greater fraction of the microbial community in healthy subjects than in those with periodontitis. The microbial profile of periodontal health also included the less-abundant genera Campylobacter , Abiotrophia , Gemella , Capnocytophaga , and Neisseria . These newly identified candidates outnumbered Porphyromonas gingivalis and other species previously implicated as periodontopathogens, and it is not clear if newly identified and more numerous species may play a more important role in pathogenesis. Finally, more differences were found in the bacterial profile between subjects with periodontitis and healthy subjects than between deep and shallow sites within the same subject. This suggests that chronic periodontitis is the result of a global perturbation of the oral bacterial ecology rather than a disease-site specific microbial shift.

Purpose. Many studies have characterized astigmatism in infancy, but few have been longitudinal or contained ocular component data. This study characterized the frequency, orientation, and longitudinal change with age of infant astigmatism. Additional factors investigated were the influence of early astigmatism on emmetropization and its relation to corneal and lenticular toricity. Methods. Three hundred two infants were enrolled in the study. Of these, 298 provided data for at least one visit at 3 ± 1 months, 9 ± 1 months, 18 ± 2 months, and 36 ± 3 months. Testing included cycloplegic retinoscopy (cyclopentolate 1 %), video-based keratophakometry, and ultrasonography over the closed eyelid. Results. Astigmatism ≥1.00 DC was common at 3 months of age (41.6%) but decreased in prevalence to 4.1 % by 36 months (p < 0.0001). The most common orientation was with-the-rule at 3 months (37.0% compared with 2.7% for against-the-rule) but against-the-rule at 36 months (3.2% compared with 0.9% for with-the-rule). Most of the change in the average value of the horizontal/vertical component of astigmatism (J 0 ) occurred between 3 and 9 months (-0.26 ± 0.36 D; p < 0.0001) with no significant change between 9 and 36 months (-0.05 ± 0.36 D; p = 0.09). Spherical equivalent refractive error was not correlated with J 0 at 3 and 9 months (R 2 = 0.002, p = 0.48 and R 2 = 0.001, p = 0.56, respectively). The two were only weakly correlated at 18 and 36 months (R 2 = 0.06 for each age, p < 0.0001, p = 0.0002, respectively). Changes in spherical equivalent between 3 and 9 months were unrelated to either the initial value of J 0 (partial R 2 for J 0 = 0.0001; p = 0.85) or the change in J 0 (partial R 2 for change in J 0 = 0.0031; p = 0.31). Across all the ages, corneal toricity was with-the-rule, and lenticular toricity was against-the-rule (produced by the toricity of the posterior lens surface). The cornea and anterior lens surface became more spherical with age, contributing to the shift away from with-the-rule refractive astigmatism. Toricity of all the refractive surfaces became less variable with age. Conclusions. Consistent with many reports, astigmatism was common in early infancy but decreased in prevalence with age, particularly when with-the-rule in orientation. The reduction in percentage of infants with astigmatism appeared to be caused by decreases in the toricity of the cornea and the anterior lens combined with decreases in the variability of corneal and lenticular surfaces. Astigmatism in infancy appeared to be unrelated to emmetropization of spherical equivalent refractive error.

The purpose of this report is to describe the normal growth pattern of the optical components of the eye in a cohort of emmetropic, school-aged children.Emmetropia was defined as refractive error (measured by cycloplegic autorefraction) in the vertical and horizontal meridians of the right eye between +1.00 D and -0.25 D at all the visits. This definition resulted in a sample of 194 children enrolled in the Orinda Longitudinal Study of Myopia (OLSM) between ages 6 and 14 years with at least 2 years of follow-up evaluation (across three annual visits) between 1989 and 2000. The optical components measured included corneal power, anterior chamber depth, crystalline lens thickness, Gullstrand lens power, calculated lens power, crystalline lens index, vitreous chamber depth, and axial length.Corneal power and anterior chamber depth were best modeled as quadratic functions of ln (age). The model involving the square of the inverse of age best described calculated lens power and crystalline lens index. The relationship between age and crystalline lens thickness was best described using a linear function of age with a point of inflection. A linear function of ln (age) with a point of inflection best described the relationship between age and axial length, Gullstrand lens power, and vitreous chamber depth. For five of the eight components (crystalline lens thickness, Gullstrand lens power, calculated lens power, corneal power, and crystalline lens index), the line modeling the data was negative in overall direction, indicating that the component value decreased with age. The upward trend of the line modeling axial length, anterior chamber depth, and vitreous chamber depth reflected the continued growth of the eye from age 6 years to age 15 years.A picture of normal eye growth in emmetropes from ages 6 to 15 years is provided based on a combination of cross-sectional and longitudinal data. Axial elongation, crystalline lens flattening and thinning, and decrease in lens power are its hallmarks.

This article describes the results from two studies of Chinese Americans. In one study, a convenience sample of patients completed face-to-face interviews to assess smoking patterns in the home, knowledge of tobacco, and ways in which health interventions could be communicated to the community. The other study involved two focus group discussions with the primary purpose of learning how spouses, health care workers, and the media can participate in smoking cessation interventions. A convenience sample of 795 patients at the Charles B. Wang Community Health Center in New York City's Chinatown was interviewed using face-to-face interviews. The focus group discussions were conducted using 15 volunteers. One discussion was conducted in Mandarin and the other in Cantonese. Although 92.7% of the respondents prefer people not smoke in the home, only 21% ban smoking with few exceptions. The focus group participants indicated that often the smoker is the oldest male and he also is the person who establishes the rules. Nearly half of the respondents receive most of their health-related information from their physician, and the focus group participants stated that physicians are highly regarded in their culture. Finally, the majority of respondents receive health-related information from Chinese language media. These results will assist in the planning of a smoking cessation intervention targeting Chinese Americans. The physician represents a key player in any intervention, and public health antismoking messages may be communicated effectively through Chinese language media.

To describe the refractive error and ocular components of a large group of school-aged children as a function of age and gender.In this report, we describe the refractive error and ocular components of 2583 school-aged children (49.3% girls, overall mean [+/-SD] age 10.0 +/- 2.3). Measurement methods included cycloplegic autorefraction, autokeratometry, videophakometry, and A-scan ultrasonography. For statistical comparisons across gender and age, a critical point of alpha = 0.005 was used to assess significance because of the large sample size and the large number of comparisons made.Of these 2583 children, 10.1% were myopic (-0.75 D or more myopia in both meridians), and 8.6% were hyperopic (+1.25 D or more hyperopia in both meridians). As would be expected, there was a significant effect of age on refractive error (spherical equivalent, p0.0001), toward less hyperopia/more myopia. There was no significant difference in the average refractive error between girls and boys (p = 0.0192). Girls had steeper corneas than boys (0.74 D steeper in the vertical meridian and 0.63 D steeper in the horizontal meridian, p0.0001). There were no significant differences in corneal power with age (p = 0.16). Both older age and male gender were significantly associated with deeper anterior chambers (p0.0001 for both). The crystalline lens showed significant thinning with age (p0.0001), however, there was no significant difference in the lens thickness between girls and boys (p = 0.66). Both Gullstrand lens power and calculated lens power showed significant effects of age and gender (p0.0001 for both). Girls, on average, had Gullstrand lens powers that were 0.28 D steeper and calculated lens powers that were 0.80 D more powerful than boys. Axial length also showed significant effects of age and gender (p0.0001 for both). Girls' eyes were, on average, 0.32 mm shorter than those of boys.These cross-sectional data show a general pattern of ocular growth, no change in corneal power, and crystalline lens thinning and flattening between the ages of 6 and 14 years. Girls tended to have steeper corneas, stronger crystalline lenses, and shorter eyes compared with boys.

Publisher Summary Survival analysis has become one of the most widely used statistical tools for analyzing clinical research data. It is specifically concerned with time-to-event data and is of particular value because of its intrinsic ability to handle censored observations. This chapter focuses on hypothesis-testing procedures because of their widespread use in the health sciences literature. The hypothesis test of the equality of Kaplan–Meier survival curves is typically accomplished using one of the available methods designed for this purpose, but, without doubt, the logrank test is the most commonly used. Perhaps the reason for the popularity of the logrank test rests in its ready availability in almost all statistical software packages. However, what many users do not appreciate is that the logrank test has very low power for some alternative hypotheses. The chapter presents the results of a systematic review of every article appearing in a major medical journal during a three-year period (1999–2001). Of the 1749 main articles reviewed, 184 (10.5%) employed survival analysis and, of these, 127 articles used Kaplan–Meier estimates of survival distributions. Hypothesis testing for the equality of the survival curves was presented in 107 of these 127 articles (84.3%). None of these papers mentioned anything about the underlying alternative hypothesis of interest to the investigator or assumptions of the chosen test.

In this chapter we shall examine techniques for drawing an inference about the distribution of the time to some event X, based on a sample of right-censored survival data. A typical data point consists of a time on study and an indicator of whether this time is an event time or a censoring time for each of the nindividuals in the study. We assume throughout this chapter that the potential censoring time is unrelated to the potential event time. The methods are appropriate for Type I, Type II, progressive or random censoring discussed in section 3.2.

To quantify the degree of association between juvenile myopia and parental myopia, near work, and school achievement.Refractive error, parental refractive status, current level of near activities (assumed working distance-weighted hours per week spent studying, reading for pleasure, watching television, playing video games or working on the computer), hours per week spent playing sports, and level of school achievement (scores on the Iowa Tests of Basic Skills [ITBS]) were assessed in 366 eighth grade children who participated in the Orinda Longitudinal Study of Myopia in 1991 to 1996.Children with myopia were more likely to have parents with myopia; to spend significantly more time studying, more time reading, and less time playing sports; and to score higher on the ITBS Reading and Total Language subtests than emmetropic children (chi(2) and Wilcoxon rank-sum tests; P0.024). Multivariate logistic regression models showed no substantial confounding effects between parental myopia, near work, sports activity, and school achievement, suggesting that each factor has an independent association with myopia. The multivariate odds ratio (95% confidence interval) for two compared with no parents with myopia was 6.40 (2.17-18.87) and was 1.020 (1.008-1.032) for each diopter-hour per week of near work. Interactions between parental myopia and near work were not significant (P = 0.67), indicating no increase in the risk associated with near work with an increasing number of parents with myopia.Heredity was the most important factor associated with juvenile myopia, with smaller independent contributions from more near work, higher school achievement, and less time in sports activity. There was no evidence that children inherit a myopigenic environment or a susceptibility to the effects of near work from their parents.