Formaldehyde production from isoprene oxidation across NOx regimes.

The chemical link between isoprene and formaldehyde (HCHO) is a strong, non-linear function of NOx (= NO + NO2). This relationship is a linchpin for top-down isoprene emission inventory verification from orbital HCHO column observations. It is also a benchmark for overall photochemical mechanism performance with regard to VOC oxidation. Using a comprehensive suite of airborne in situ observations over the Southeast U.S., we quantify HCHO production across the urban-rural spectrum. Analysis of isoprene and its major first-generation oxidation products allows us to define both a "prompt" yield of HCHO (molecules of HCHO produced per molecule of freshly-emitted isoprene) and the background HCHO mixing ratio (from oxidation of longer-lived hydrocarbons). Over the range of observed NOx values (roughly 0.1 - 2 ppbv), the prompt yield increases by a factor of 3 (from 0.3 to 0.9 ppbv ppbv-1), while background HCHO increases by a factor of 2 (from 1.6 to 3.3 ppbv). We apply the same method to evaluate the performance of both a global chemical transport model (AM3) and a measurement-constrained 0-D steady state box model. Both models reproduce the NOx dependence of the prompt HCHO yield, illustrating that models with updated isoprene oxidation mechanisms can adequately capture the link between HCHO and recent isoprene emissions. On the other hand, both models under-estimate background HCHO mixing ratios, suggesting missing HCHO precursors, inadequate representation of later-generation isoprene degradation and/or under-estimated hydroxyl radical concentrations. Detailed process rates from the box model simulation demonstrate a 3-fold increase in HCHO production across the range of observed NOx values, driven by a 100% increase in OH and a 40% increase in branching of organic peroxy radical reactions to produce HCHO.

Jaw complications associated with bisphosphonate use in patients with plasma cell dyscrasias.

Osteonecrosis of the jaw has been linked with bisphosphonate use in breast cancer and multiple myeloma patients. We report 17 cases of patients with plasma cell dyscrasia being treated with bisphosphonate who developed osteonecrosis/osteomyelitis of the jaw. Seventeen patients evaluated at our institution between 1998 and 2005 are reported. All were being treated with bisphosphonates for a median of 5 mo prior to the onset of jaw symptoms. Sixteen of the 17 patients are 51 yr or older. None of the patients had been irradiated in the jaw nor had obvious osseous manifestation of multiple myeloma in the jaw. Thirteen patients were receiving zoledronic acid and four patients were receiving pamidronate at the onset of jaw symptoms. Six of the 17 did receive both agents at some time and all of these individuals were receiving zoledronic acid at diagnosis. Microorganisms were isolated in 7/17 patients with the most common organism being actinomycosis. We have initiated the following guidelines in an effort to ameliorate the incidence of this complication. Patients should have a full dental examination at the time of diagnosis of the plasma cell dyscrasia especially if bisphosphonates are to be considered as part of the therapy. In addition, bisphosphonates are held for a period of 3 mo prior to invasive dental procedures to allow for the osteoclastic recovery, therefore enhanced debris removal and lessening the chance of creating a fertile bacterial medium. Following the dental procedure we would re-introduce bisphosphonates only after the healing process is complete. Finally, multiple myeloma patients diagnosed with jaw osteonecrosis probably have a concurrent infection and should be aggressively treated with antibiotics.

A descriptive study of urban rabies during the civil war in Sierra Leone: 1995-2001.

A study was conducted to assess the effects of the breakdown in internal infrastructure on the incidence of canine-transmitted human rabies in urban areas of Sierra Leone during the course of the civil war between 1995 and 2001. Data from provincial hospitals in the Western Area and Southern Province indicated that there was a significant increase in the incidence of canine-transmitted urban human rabies chi2 = 39.63, p < 0.0001, particularly among children chi2 = 23.73, p < 0.0001, over the course of the war. In the Western Area in 2001, towards the end of the war, there was a significant increase in adult cases, which was reflected in the observed versus the expected chi2 ratio (70 versus 53). Interview-based questionnaire surveys in Freetown administered between 2001 and 2002 indicated that dogs were commonly kept for security reasons, and were largely unrestrained and unlicensed, regardless of the socioeconomic status of the owner. Virtually all dogs were unvaccinated and were mainly living in close proximity with humans. This study indicated that there is an urgent requirement for appropriate mass rabies vaccination campaigns for pet dogs and for campaigns to manipulate the urban habitat to control free-roaming and wandering but owned dog populations in Freetown and other urban areas in the provinces of Sierra Leone. Interview-based questionnaires administered in three districts of Freetown indicated a relatively high degree of uniformity in dog husbandry and veterinary care habits across a wide range of socioeconomic status categories in dog owners.

Failed challenge with quetiapine after neuroleptic malignant syndrome with conventional antipsychotics.

Neuroleptic malignant syndrome (NMS) is an uncommon but potentially life-threatening adverse effect associated with conventional antipsychotic agents. The syndrome is characterized by muscular rigidity, hyperpyrexia, altered consciousness, and autonomic dysfunction. Few cases of quetiapine-induced NMS have been reported. A 54-year-old man was unsuccessfully challenged with quetiapine after conventional antipsychotic-induced NMS.

Hypoxia inhibits amino acid uptake in human lung fibroblasts.

Hypoxia and amino acid deprivation downregulate expression of extracellular matrix genes in lung fibroblasts. We examined the effect of hypoxia on amino acid uptake and protein formation in human lung fibroblasts. Low O(2) tension (0% O(2)) suppressed incorporation of [(3)H]proline into type I collagen without affecting [(35)S]methionine labeling of other proteins. Initial decreases in intracellular [(3)H]proline incorporation occurred after 2 h of exposure to 0% O(2), with maximal suppression of intracellular [(3)H]proline levels at 6 h of treatment. Hypoxia significantly inhibited the uptake of radiolabeled proline, 2-aminoisobutyric acid (AIB), and 2-(methylamino)isobutyric acid (methyl-AIB) while inducing minor decreases in leucine transport. Neither cycloheximide nor indomethacin abrogated hypoxia-related suppression of methyl-AIB uptake. Efflux studies demonstrated that hypoxia inhibited methyl-AIB transport in a bidirectional fashion. The downregulation of amino acid transport was not due to a toxic effect; function recovered on return to standard O(2) conditions. Kinetic analysis of AIB transport revealed a 10-fold increase in K(m) accompanied by a small increase in maximal transport velocity among cells exposed to 0% O(2). These data indicate that low O(2) tension regulates the system A transporter by decreasing transporter substrate affinity.

Hypoxia downregulates tropoelastin gene expression in rat lung fibroblasts by pretranslational mechanisms.

Elastolytic lung injury disrupts cell barriers, flooding alveoli and producing regional hypoxia. Abnormal O2 tensions may alter repair of damaged elastin fibers. To determine the effect of hypoxia on extravascular elastin formation, we isolated rat lung fibroblasts and cultured them under a variety of O2 conditions. Hypoxia downregulated tropoelastin mRNA in a dose- and time-related fashion while upregulating glyceraldehyde-3-phosphate dehydrogenase mRNA levels. The changes in tropoelastin gene expression were not due to cell toxicity as measured by chromium release and cell proliferation studies. Neither cycloheximide nor actinomycin D abrogated this effect. Hypoxia induced early decreases in tropoelastin mRNA stability; minor suppression of gene transcription occurred later. When returned to 21% O2, tropoelastin mRNA recovered to control levels in part by upregulating tropoelastin gene transcription. Taken together, these data indicate that hypoxia regulates tropoelastin gene expression and may alter repair of acutely injured lung.

Perceived value of providing peer reviewers with abstracts and preprints of related published and unpublished papers.

CONTEXT: Many journals provide peer reviewers with written instructions regarding review criteria, such as the originality of results, but little research has been done to investigate ways to improve or facilitate the peer review task. OBJECTIVE: To assess the value that peer reviewers place on receipt of supplemental materials (eg, abstracts of related papers and preprints of related unpublished manuscripts). DESIGN: Questionnaire survey sent to all 733 peer reviewers recruited by the Journal of the National Cancer Institute to review 356 manuscripts consecutively sent out for review from February 24, 1997, through January 16, 1998. The inclusion of supplemental materials with manuscript review packages was optional. MAIN OUTCOME MEASURE: The peer reviewers' assessment of the actual or potential usefulness of supplemental materials on the performance of peer review. RESULTS: A total of 481 (66%) of 733 questionnaires were returned. Of the 471 respondents' questionnaires that could be used, 217 (46%) indicated that they received abstracts, and 44 (10%) of 458 respondents indicated that they received preprints. Higher proportions of peer reviewers who received supplemental materials than those who had not received them felt that they were (or would be) useful to them when reviewing the manuscript (63% [95% confidence interval (CI), 57%-69%] vs 45% [95% CI, 38%-52%]; P<.001) and to the peer review process in general (80% [95% CI, 75%-85%] vs 64% [95% CI, 58%-70%]; P<.001). CONCLUSION: The majority of respondents indicated that supplemental materials helped (or would have helped) them evaluate manuscripts and valued them more highly when they actually received them.

Pharmacology of the pulmonary diseases.

The management of patients with pulmonary diseases may pose a challenge to the dentist. A thorough understanding of the major respiratory diseases is paramount to the successful treatment of these individuals. Morbidity and mortality for COPD patients have increased over time. There has been a decline in the number of smokers in the United States, but it may take two or three decades before health care systems notice a decrease in associated health care visits. Smoking tobacco is the major cause of COPD. Health care providers need to inform patients about smoking cessation programs and motivate them toward that end. The most important factor in preventing COPD is helping patients stop smoking. Mainstays in the treatment of COPD include inhaled anticholinergics and supplemental oxygen, when indicated. For certain patients, beta2-agonists, mucolytics, anti-inflammatory agents, and antibiotics are indicated. Asthma morbidity and mortality continue to rise significantly despite scientific advances and improved understanding of the disease and ability to render effective treatment. The reasons for this are not entirely clear. Asthma treatment has been revolutionized over the past decade. If proper preventive environmental measures and medications are prescribed, and the patients are carefully educated and complaint, their prognosis is good, and their condition should rarely require emergency treatment or hospitalization. The management of TB in the dental office involves several aspects of the disease. The dentist should be able to refer properly a patient with signs and symptoms of disease or to follow up on inadequate treatment. The medications taken for TB do not usually modify the dental management of the patient. The complications of the medications may, however, affect some drugs the dentist could prescribe. The resurgence of TB in the United States mandates that every dentist understand this disease and its importance.

An upstream region of the H2AZ gene promoter modulates promoter activity in different cell types.

Human H2AZ gene promoter fragments that included sequences upstream from the core promoter resulted in decreased activity of reporter constructs transfected into several human cell lines, but increased activity in the undifferentiated human embryonal carcinoma cell line Tera-2. Differentiation of Tera-2 cells in media containing retinoic acid restored the ability of the upstream region to downregulate H2AZ gene promoter activity. Levels of endogenous H2AZ mRNA were also found to be 2.5-fold higher in undifferentiated Tera-2 cells than in differentiated Tera-2 cells. A 128 bp region located 234 to 361 bp upstream from the transcription start site of the H2AZ gene was found to be responsible for the modulation of reporter activity. The upstream region also functioned similarly when removed from the H2AZ gene promoter and inserted upstream of the SV40 promoter in reporter constructs. Gel mobility shift studies of fragments of this region revealed two sequence elements, CTCCTCC and CACGTG, that bound nuclear factors in vitro.

Characterization of the proximal promoter of the human histone H2A.Z gene.

Histone H2A.Z is a distinct and evolutionarily conserved member of the histone H2A family whose synthesis, in contrast to that of most other histone species, is not dependent on DNA replication. The gene for H2A.Z lacks the signals involved in the 3' processing of replication-linked histone mRNA species and contains introns as well as polyadenylation signals. The H2A.Z gene proximal promoter, a 200-bp region upstream of the transcription start site that provides maximal activity in CAT reporter studies, contains three CCAAT and two GGGCGG elements as well as a consensus TATA element. In vitro DNase I footprint analysis of this region indicated that the central CCAAT and the distal GGGCGG elements were protected by factors present in HeLa nuclear extract. Site-directed mutations of selected promoter elements were generated in the H2A.Z gene promoter region of a CAT reporter construct by a novel one-step PCR procedure. Of the elements examined, the central CCAAT element was found to be the most important determinant of promoter activity; its disruption decreased CAT reporter activity by 65%. Disruption of the proximal CCAAT or the distal GGGCGG elements led to decreases in activity of 40%, while disruption of any of the other examined led to smaller decreases. Gel-mobility shift analysis showed that the three CCAAT elements had overlapping but not identical binding specificities for nuclear factors. The two GGGCGG elements both were found to bind transcription factor Sp1, but the distal element bound Sp1 with higher affinity. The findings show that the central and proximal CCAAT elements and the distal GGGCGG element appear to be the major determinants of the transcriptional activity of the H2A.Z gene.

Characterization of the human histone H2A.X gene. Comparison of its promoter with other H2A gene promoters.

The human gene for the replication-unlinked histone protein H2A.X is a naturally occurring chimera that contains a replication-unlinked promoter yet produces a stemloop mRNA characteristic of replication-linked histone genes. Consistent with the latter attribute, the H2A.X gene was found to lack introns. The promoter of the H2A.X gene was localized to a 120-base pair region upstream of the transcription start site, a region which included a TATA and two CCAAT sequence elements. The proximal of the two CCAAT elements was shown to be an important determinant of H2A.X gene promoter activity. In a comparative study with the CCAAT elements from the replication-linked H2A.1a gene and the replication-unlinked H2A.Z gene, the proximal CCAAT element of the H2A.X gene was found to bind nuclear factors also bound by CCAAT elements in the latter but not in the former. The specificity of the replication-unlinked H2A.X and H2A.Z gene promoters for CCAAT-binding transcription factors appeared to also reside in short homologous sequences about 10 base pairs away on either side of the CCAAT sequence.

The relative expression of human histone H2A genes is similar in different types of proliferating cells.

To help elucidate the factors regulating the expression of histone multigene families in proliferating cells, we asked whether the relative expression of different members of such a family was dependent upon or independent of the type of proliferating cell. This question was examined by measuring the relative expression of seven members of the human histone H2A multigene family in four cell lines of diverse origin. Two previously uncharacterized members of the H2A gene family were found to be the most abundantly expressed of the seven in all four cell lines. One of these encodes an H2A.2 species containing methionine. The lines examined in the study were Jurkat (a lymphoma line), N-tera (a pluripotent embryonic carcinoma line), HeLa (originally isolated as a cervical carcinoma), and IMR90 (a normal embryonic fibroblastic line). The amount of each mRNA species was quantitated using oligonucleotides about 30 bases long complementary to the 5' or 3' untranslated regions. In each cell line, there was at least an eight-fold difference in the amount of the most and least highly expressed of the seven H2A mRNA species. In addition, there were up to five-fold differences among the cell lines in the amount of the H2A mRNA species as a fraction of total RNA. However, in contrast to those differences, the four cell lines were found to express the seven H2A mRNAs in similar relative amounts. These findings suggest that the relative expression of the individual members of a histone gene family is independent of the type of replicating cell.

Histone H2A.X gene transcription is regulated differently than transcription of other replication-linked histone genes.

Histone H2A.X is a replication-independent histone H2A isoprotein species that is encoded by a transcript alternatively processed at the 3' end to yield two mRNAs: a 0.6-kb mRNA ending with the stem-loop structure characteristic of the mRNAs for replication-linked histone species, and a second, polyadenylated 1.6-kb mRNA ending about 1 kb further downstream (C. Mannironi, W. M. Bonner, and C. L. Hatch, Nucleic Acids Res. 17:9113-9126, 1989). Of the two, the 0.6-kb H2A.X stem-loop mRNA predominates in many cell lines, indicating that the presence of two types of mRNA may not completely account for the replication independence of H2A.X protein synthesis. The ambiguity is resolved by the finding that the level of the 0.6-kb H2A.X mRNA is only weakly downregulated during the inhibition of DNA replication and only weakly upregulated during the inhibition of protein synthesis, while the levels of other replication-linked mRNAs are strongly down- or upregulated under these two conditions. Analysis of the nuclear transcription rates of specific H2A genes showed that while the rates of transcription of replication-linked H2A genes decreased substantially during the inhibition of DNA synthesis and increased substantially during the inhibition of protein synthesis, the rate of H2A.X gene transcription decreased slightly under both conditions. These differences in transcriptional regulation between the H2A.X gene and other replication-linked histone genes are sufficient to account for the differences in regulation of their respective stem-loop mRNAs.

Risk indicators for periodontitis in a military treatment population.

The association between the periodontal diagnosis and a variety of subject characteristics was studied in a group of 1,783 patients examined at a large military dental clinic. In order of importance, age greater than 30, smoking, male sex, and Filipino racial background were all found to be statistically significant risk indicators for the presence of moderate or advanced periodontitis. A logistic regression equation serving as a predictive model employing these four variables was presented. The strong association found between smoking and advanced periodontitis is consistent with the hypothesis that smoking has cumulative detrimental effects on periodontal health. While these and other risk indicators are neither causative, diagnostic, nor prognostic, they may be helpful in alerting the clinician to more carefully evaluate other clinical signs or laboratory findings of disease.

The prevalence of periodontitis in a military treatment population.

A group of 1,984 males and females (age range 13 to 84) at a military dental clinic were given oral examinations with full-mouth circumferential periodontal probing. Diagnoses were made both for individual quadrants and for the entire mouth using clearly defined diagnostic criteria. The results showed 37% of the subjects had gingivitis only, 33% had early periodontitis, 14% had moderate periodontitis, 15% had advanced periodontitis, 0.5% had juvenile periodontitis, and 0.5% had necrotizing gingivitis. The prevalence of periodontitis increased with age to a peak in the 45- to 50-year-age group. The proportion of periodontitis-affected quadrants, although initially lagging behind the overall case diagnoses, also increased with age.

The human histone H2A.Z gene. Sequence and regulation.

The gene encoding the human basal histone variant H2A.Z has been cloned and sequenced. There is a single functional H2A.Z gene with several pseudogene copies. No other histone genes were found in the 3 kilobases of upstream sequence or in the 0.7 kilobase of downstream sequence. In the upstream region, there are regions of Alu sequences, located about 1375 and 2650 base pairs before the transcription start site. The amount of the H2A.Z transcript is unlinked to DNA replication; however, the amount of the H2A.Z transcript is greatly decreased as proliferating cell cultures become quiescent due in part to a decrease in the rate of transcription. Promoter sequences upstream from the H2A.Z gene have been delineated in IMR-90 cells by chloramphenicol acetyltransferase gene expression. Maximal promoter activity was found in a chloramphenicol acetyltransferase construct that contained 234 base pairs just upstream from the transcription start site. This region includes two GC boxes and three CCAAT boxes as well as a properly positioned TATA box. The organization of the human gene is similar to that of the recently characterized chicken gene (Dalton, S., Robins, A. J., Harvey, R. P., and Wells, J. R. E. (1989) Nucleic Acids Res. 17, 1745-1756). Both have four introns with identical exon-intron borders, but three of the introns in the chicken gene are much longer than those in the human. The promoter regions of the two genes have little overall homology; however, two GC boxes and one of the CCAAT boxes are conserved.

H2A.X. a histone isoprotein with a conserved C-terminal sequence, is encoded by a novel mRNA with both DNA replication type and polyA 3' processing signals.

A full length cDNA clone that directs the in vitro synthesis of human histone H2A isoprotein H2A.X has been isolated and sequenced. H2A.X contains 142 amino acid residues, 13 more than human H2A.1. The sequence of the first 120 residues of H2A.X is almost identical to that of human H2A.1. The sequence of the carboxy-terminal 22 residues of H2A.X is unrelated to any known sequence in vertebrate histone H2A; however, it contains a sequence homologous with those of several lower eukaryotes. This homology centers on the carboxy-terminal tetrapeptide which in H2A.X is SerGlnGluTyr. Homologous sequences are found in H2As of three types of yeasts, in Tetrahymena and Drosophila. Seven of the nine carboxy-terminal amino acids of H2A.X are identical with those of S. cerevisiae H2A.1. It is suggested that this H2A carboxy-terminal motif may be present in all eukaryotes. The H2A.X cDNA is 1585 bases long followed by a polyA tail. There are 73 nucleotides in the 5' UTR, 432 in the coding region, and 1080 in the 3' UTR. Even though H2A.X is considered a basal histone, being synthesized in G1 as well as in S-phase, and its mRNA contains polyA addition motifs and a polyA tail, its mRNA also contains the conserved stem-loop and U7 binding sequences involved in the processing and stability of replication type histone mRNAs. Two forms of H2A.X mRNA, consistent with the two sets of processing signals were found in proliferating cell cultures. One, about 1600 bases long, contains polyA; the other, about 575 bases long, lacks polyA. The short form behaves as a replication type histone mRNA, decreasing in amount when cell cultures are incubated with inhibitors of DNA synthesis, while the longer behaves as a basal type histone mRNA.

Glossodynia as an oral manifestation of diabetes mellitus.

The oral signs and symptoms of glossodynia and xerostomia present a diagnostic problem for the clinician. One of the etiologic considerations in the differential diagnosis should be diabetes mellitus. When diabetes mellitus is suspected, appropriate blood tests should be ordered. If diabetes mellitus is the cause, proper control of the disease will minimize these and other complications and improve the patient's quality of life.