Interannual Variability in Baseline Ozone and Its Relationship to Surface Ozone in the Western U.S.

Baseline ozone refers to observed concentrations of tropospheric ozone at sites that have a negligible influence from local emissions. The Mount Bachelor Observatory (MBO) was established in 2004 to examine baseline air masses as they arrive to North America from the west. In May 2012, we observed an O3 increase of 2.0-8.5 ppbv in monthly average maximum daily 8-hour average O3 mixing ratio (MDA8 O3) at MBO and numerous other sites in the western U.S. compared to previous years. This shift in the O3 distribution had an impact on the number of exceedance days. We also observed a good correlation between daily MDA8 variations at MBO and at downwind sites. This suggests that under specific meteorological conditions, synoptic variation in O3 at MBO can be observed at other surface sites in the western U.S. At MBO, the elevated O3 concentrations in May 2012 are associated with low CO values and low water vapor values, consistent with transport from the upper troposphere/lower stratosphere (UT/LS). Furthermore, the Real-time Air Quality Modeling System (RAQMS) analyses indicate that a large flux of O3 from the UT/LS in May 2012 contributed to the observed enhanced O3 across the western U.S. Our results suggest that a network of mountaintop observations, LiDAR and satellite observations of O3 could provide key data on daily and interannual variations in baseline O3.

Screening electrocardiograms in psychiatric research: implications for physicians and healthy volunteers.

AIMS: While there is controversy regarding utility of screening electrocardiograms (ECGs) in competitive athletes and children exposed to psychostimulants, there is no data on the use of screening ECGs in psychiatric research. We aimed to examine the prevalence and clinical significance of ECG abnormalities and their impact on eligibility for studies. METHODS: We analysed 500 consecutive ECG reports from physically healthy volunteers who had a negative cardiac history, normal cardiovascular examination and no other significant medical illnesses. For the purpose of this report, all ECGs were over-read by one cardiologist. RESULTS: The mean age of our cohort was 28.3 ± 8.0 years. A total of 112 (22.4%) ECGs were reported as abnormal (14.2%) or borderline (8.2%). These abnormalities were considered clinically insignificant in all but eight subjects (1.6%) who underwent evaluation with an echocardiogram. All echocardiograms were normal. No subject was excluded from studies. After the over-reading, no abnormalities or isolated bradycardia were present in 37 of 112 (33%) ECGs that were initially reported as abnormal or borderline, while minor abnormalities were found in 7 of 204 (3.4%) ECGs that were reported as normal. CONCLUSIONS: Although screening ECGs did not detect significant cardiac pathology or affect eligibility for our studies, over 20% of subjects were labelled as having an abnormal or borderline ECG which was incorrect in one-third of cases. Strategies to minimise unintended consequences of screening are discussed.

The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus.

BACKGROUND: A common functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) was previously associated with diminished episodic memory performance in healthy people. As cognitive function is commonly impaired in patients with systemic lupus erythematosus (SLE), the association of the BDNF Val66Met with neurocognitive function was studied. OBJECTIVE: To study the association of the BDNF Val66Met with neurocognitive function in a cohort of patients with SLE. METHODS: Cognitive function was assessed in 59 patients with SLE with no previous or current central nervous system involvement. Cognitive tests were grouped into five domains (memory, attention/executive function, visuospatial skills, motor function and psychomotor speed) and used to obtain domain Z scores, reflecting the difference between averaged scores of performance on individual tests and published norms in each domain. Genotyping was carried out using a 5'-nuclease assay with 99.9% accuracy. Unpaired t test was used to assess the relationship between genotypes and cognitive function, whereas the effect of possible confounders was assessed in a multivariate analysis. RESULTS: Patients carrying the Met66 allele scored significantly higher on psychomotor, attention/executive and motor function tests, resulting in significantly higher domain Z scores for the psychomotor (p = 0.005) and motor (p = 0.002) domains. CONCLUSIONS: The BDNF Met66 allele was associated with better cognitive functioning in the psychomotor and motor domains, even after controlling for differences in ethnicity, sex, depression status and prednisone treatment. These data suggest that the BDNF Met66 allele confers protection against the decline of motor and psychomotor cognitive functions in patients with longstanding SLE.

The use of a bioactive skin substitute decreases length of stay for pediatric burn patients.

BACKGROUND: To optimize burn care for children, the authors introduced a protocol incorporating the use of a bioactive skin substitute, TransCyte (Advanced Tissue Sciences, La Jolla, CA). This study was designed to determine whether this management plan was safe, efficacious, and decreased hospital inpatient length of stay (LOS) compared with conventional burn management in children. METHODS: All pediatric burns greater than 7% total body surface area (TBSA) that occurred after October 1999 underwent wound closure with TransCyte (n = 20). These cases were compared with the previous 20 consecutive burn cases greater than 7% TBSA that received standard therapy. Standard therapy consisted of application of antimicrobial ointments and hydrodebridement. The following information was obtained: burn mechanism, age, size of burn, requirement of autograft, and LOS. Data were analyzed using the student's t test. RESULTS: Data for age, percent TBSA burn and LOS are reported as means +/- SEM. The children who received standard therapy were 2.99 +/- 0.7 years compared with those receiving TransCyte were 3.1 +/- 0.8 years. There was no difference between the treatment groups with regard to percent TBSA burn: standard therapy, 14.3 +/- 1.4% TBSA versus TransCyte, 12.7 +/- 1.3% TBSA. There was no difference in the type of burns in each group, the majority were liquid scald type, 70% in the standard therapy group versus 90% in the TransCyte group. Only 1 child in the TransCyte group required autografting (5%) compared with 7 children in the standard therapy group (35%). Children treated with TransCyte had a statistically 6 significant decreaed LOS compared with those receiving standard therapy, 5.9 +/- 0.9 days versus 13.8 +/- 2.2 days, respectively (P =.002). CONCLUSIONS: This is the first study using TransCyte in children. The authors found that this protocol of burn care was safe, effective, and significantly reduced the LOS. This new approach to pediatric burn care is effective and improves the quality of care for children with burns.

The endothelin receptor B (EDNRB) promoter displays heterogeneous, site specific methylation patterns in normal and tumor cells.

The 5' region for the endothelin receptor B (EDNRB) gene is a complex CpG island giving rise to four individual transcripts initiating within the island. Here, for the first time, we analyze the relationship between methylation and gene expression in a CpG island located in the 5' region of a gene with multiple transcription start sites. The CpG island was unmethylated in normal prostate and bladder tissue, whereas it became methylated in apparently normal colonic epithelium. Tumors derived from these tissues were frequently hypermethylated relative to the respective normal tissues. Analysis of 11 individual CpG sites located throughout the CpG island showed that specific sites with high methylation levels in several tumors were also methylated in normal tissues, suggesting that they might serve as foci for further de novo methylation. This region also had high levels of methylation in several cancer cell lines, and we found that a low methylation level in a small region within the 5' region correlated with expression of the 5'-most transcript. Interestingly, almost complete methylation 200-1000 bp downstream of the transcriptional start site did not block expression of this transcript. Finally, we show that treatment with 5-aza-2'-deoxycytidine can induce transcriptional activation of the four EDNRB transcripts. Our results show the existence of differential, tissue-dependent methylation at the EDNRB 5' region, suggest the existence of a spreading mechanism for de novo methylation, starting from methylation hotspots, and show that hypermethylation immediately 3' to a transcriptional start site does not prevent initiation.

Children and adolescents living with HIV and AIDS: a review.

Worldwide, more than one million children are infected with human immunodeficiency virus (HIV) and in the United States it has become the sixth leading cause of death among 15-24-year-olds. Despite the trend of increasing rates of infection, advances in therapies have led to survival past 5 years of age for more than 65% of infected children. This global health threat will therefore continue to have a significant impact on child and adolescent psychiatry and psychology. This paper reviews current studies and reports on the consequences of the acquired immunodeficiency syndrome (AIDS) epidemic in the psychiatric care and development of children and adolescents infected by HIV. From a search of all the English-language-based literature on pediatric AIDS, 140 studies are reviewed which address HIV infection and its psychological and social implications. Several topics of mental health significance are examined: (1) the epidemiology of HIV, (2) neurocognitive development among those infected, (3) psychological impact of infection, and (4) the family and social context of HIV. The transition of HIV from an acute, lethal disease to a subacute, chronic disease has enormous implications for the neurocognitive and psychosocial development of children and families. As children and adolescents infected with HIV continue to live longer, normal developmental milestones and educational needs will take on new significance. Many children will continue to be adversely impacted by non-HIV factors such as poverty, inadequate medical services, and a lack of social support. This review outlines recent developments that hold promise to effectively reduce the treatment burden on the infected, their families, and health care providers and to decrease the incidence of transmission to the uninfected.

DNA methylator and mismatch repair phenotypes are not mutually exclusive in colorectal cancer cell lines.

A potential link between DNA repair and de novo methylation of exogenous sequences in colorectal cancer cell lines suggested that cells deficient in mismatch repair (MMR-) had an increased ability to silence the introduced virus promoter by DNA methylation due to the presence of a methylator phenotype (MET+) (Lengauer et al., 1997a). We explored this relationship in more detail and found that although there was a clear difference in the abilities of MMR+ cells to express the viral promoter compared to their MMR- counterparts, this difference was not consistently explained by levels of methylation in the viral promoter. Furthermore, we were unable to distinguish differences between the levels of methylation of six endogenous known CpG islands or 100 random DNA fragments containing CCGG sites within the cells. No consistent differences between the abilities of the cells to methylate the CpG island in exon 2 of the p16 gene were observed after transient demethylation by 5-aza-2'-deoxycytidine nor in the levels of expression of three human methyltransferase enzymes. Our results do not therefore support the existence of mutually exclusive DNA methylation (MET) and DNA repair (MMR) phenotypes. Oncogene (2000) 19, 943 - 952.

Psychiatric diagnoses in adolescents seropositive for the human immunodeficiency virus.

OBJECTIVE: To provide a descriptive analysis of the prevalence of past and current psychiatric disorders in adolescents positive for the human immunodeficiency virus (HIV). DESIGN: Structured interview in a convenience sample in a primary care urban adolescent clinic in Washington, DC. PARTICIPANTS: Thirty-four HIV-seropositive adolescents ranging in age from 16 to 21 years. MAIN OUTCOME MEASURES: The Structured Clinical Interview for DSM-IV Axis I Disorders-Patient Edition (SCID-P) was administered by a child psychiatrist or a clinical child psychologist. Extensive review of medical records was also conducted. RESULTS: A majority of the HIV-infected adolescents in our sample had received psychiatric diagnoses prior to their treatment at the clinic (53%), had a documented history of sexual abuse (50%), and had a history of substance use (82%). Psychiatric diagnoses determined by the SCID-P indicated that 85% of the sample had a current Axis I disorder, with 44% reporting ongoing depressive disorders. CONCLUSIONS: The majority of subjects in this sample had had a previous psychiatric diagnosis, and almost half had a current affective disorder. Psychiatric disorders, especially affective disorders, may be a risk factor for high-risk sexual behaviors and substance use that increases the risk for HIV infection in adolescent populations.

Analphoid marker chromosome in a patient with hyper-IgE syndrome, autism, and mild mental retardation.

Hyper-IgE syndrome with recurrent infections (HIES) is a primary immunodeficiency disease characterized by recurrent skin and lung abscesses and extreme elevations of serum IgE, but also involving dentition, bones, and connective tissue. Although the etiology of HIES is unknown, autosomal dominant inheritance has been observed in multiple kindreds. A 17 year old male with sporadic HIES, autism, and mild mental retardation was found to have a supernumerary marker chromosome in peripheral blood lymphocytes and skin fibroblasts. Microdissection and FISH analysis of the marker chromosome showed that it was derived from a small interstitial deletion of one homologue of chromosome 4q21. Lack of hybridization of probes specific for telomeres and alphoid centromeres, including a centromere 4 specific probe, established that the marker was an analphoid ring chromosome. Comparative genotyping of transformed B-cell subclones with (M+) and without (M-) the marker chromosome showed loss of the maternal alleles in M- cells between markers D4S1569 and D4S3010. FISH using YAC clones from 4q21 confirmed the size and location of the interstitial deletion. Thus our patient's phenotypes were associated with de novo formation of a marker chromosome containing 15-20 cM of DNA deleted from his maternally derived chromosome 4. Proximal chromosome 4q therefore is a candidate region for disease genes for both HIES and autism. Identification of genes disrupted or lost during the formation of the marker chromosome as well as linkage studies in kindreds with HIES or autism may help us to understand the etiology of these complex phenotypes.

The role of DNA methylation in expression of the p19/p16 locus in human bladder cancer cell lines.

Methylation of CpG sites in the control regions of tumor suppressor genes may be an important mechanism for their heritable, yet reversible, transcriptional inactivation. These changes in methylation may impair the proper expression and/or function of cell cycle regulatory genes and confer a selective growth advantage to affected cells. Detailed methylation analysis using genomic bisulfite sequencing was performed on a series of subclones of a bladder cancer cell line in which a hypermethylated p16 gene had been reactivated by transient treatment with 5-aza-2'-deoxycytidine. Methylation of the CpG island in the promoter of the p16 gene in human bladder cancer cells did not stop the formation of a transcript initiated 20 kb upstream by the p19 promoter but did prevent the expression of a p16 transcript. Furthermore, we show that reactivant clones that expressed p16 at varying levels contained heterogeneous methylation patterns, suggesting that p16 expression can occur even in the presence of a relatively heavily methylated coding region. We also present the first functional evidence that methylation of only a small number of CpG sites can significantly down-regulate p16 promoter activity, thus providing support for the model of progressive inactivation of this tumor suppressor gene by DNA methylation.

Inhibition of DNA methylation by 5-aza-2'-deoxycytidine suppresses the growth of human tumor cell lines.

Alterations in DNA methylation patterns accompany the establishment of immortal cell lines. De novo methylation of CpG islands within the control regions of growth-regulatory genes may inactivate their transcription, giving cells selective growth advantages in culture. We exposed seven human tumor cell lines and two human fibroblast cell strains to the demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-CdR), to determine whether the silencing of growth-regulatory genes by de novo methylation in immortalized cell lines could be reversed, possibly restoring growth control. After recovery from the immediate cytotoxic effects of 5-Aza-CdR, this agent suppressed cellular growth in all seven tumor lines but not in either fibroblast strain. Because alterations in the p16 (CDKN2/MTS1) cell cycle regulatory gene are associated with numerous cancers, we analyzed expression of this gene before and after 5-Aza-CdR treatment. The gene was reactivated by 5-Aza-CdR treatment in three of four tumor cell lines not expressing p16, whereas the fourth tumor line contained a p16 homozygous deletion. p16 was shown to be hypermethylated only in the cell lines and its up-regulation by 5-Aza-CdR was associated with demethylation of the p16 promoter. The remaining tumor lines expressed p16 at constant levels before and after 5-Aza-CdR treatment and showed minimal p16 promoter methylation, suggesting that other growth-regulatory genes may have been silenced by de novo methylation in these cells. p16 expression, cell growth inhibition, and G1 cell cycle arrest by 5-Aza-CdR in the T24 bladder tumor cell line were also heritable after prolonged passage in culture. Furthermore, a dormant p16 gene was reactivated in T24 cells growing in nu/nu rats, and 5-Aza-CdR treatment of T24 cells before inoculation into nu/nu mice decreased the rate of tumor growth. These results suggest that 5-Aza-CdR may slow the growth of tumor cells by reactivating growth-regulatory genes silenced by de novo methylation.

Effect of search experience on sustained MEDLINE usage by students.

PURPOSE: While educators agree that medical students should learn to use MEDLINE for clinical application, there is a lack of consensus on an optimal level of exposure to this resource during training that will result in sustained usage. This study sought to identify the level of search experience (1) to increase the odds that the student searcher will continue to search MEDLINE in the absence of search assignments, and (2) to make an appreciable difference in the odds of retrieving items of relevance from the MEDLINE database. METHOD: Search frequencies of MEDLINE via the PaperChase interface by 184 fourth-year students (class of 1992) at the University of Michigan Medical School were analyzed using the log cross-product technique. The students were required to take the Comprehensive Clinical Assessment, an examination that included a search assignment, as they entered their fourth year of medical school. Their levels of MEDLINE use and their retrieval performances before the examination were compared with those achieved during the subsequent five months as fourth-year medical students. RESULTS: For those who searched an average of at least once a month during their first three years of medical school, there was a 7.38:1 chance that they would conduct three searches per month in the fourth year, compared with those who searched less frequently. The odds of retrieving at least one item of definite relevance were 8.27:1 for those who had searched at least one and one-half times per month before the search assignment. CONCLUSION: Searching once a month through the first few years of medical school provided an experience level that improved the odds that a student would continue to search MEDLINE: Data indicated that a history of a minimum of 1.5 online sessions per month increased the odds of retrieving relevant items to 8.27:1. Implications for educational strategy are clear.

Factors affecting students' use of MEDLINE.

MEDLINE search transcripts by a class of third-year medical students were analyzed. The 184 students were divided into three groups according to their search experience in terms of the number of sessions logged at the time of a search assignment. A strong relation was found between the level of search experience and the frequency of use in the subsequent 5 months. Over 80% of the students were able to retrieve a few useful items for an emergency clinical situation. More experienced searchers were able to retrieve more relevant items than less experienced searchers. However, no relation was found between search effectiveness and clinical knowledge as indicated by two scores derived from the University of Michigan's Comprehensive Clinical Assessment examination and Part II of NBME. Similarly, clinical knowledge also did not appear to relate to MEDLINE search experience. More exposure to MEDLINE during medical school could play an important role in developing effective literature searching skills for lifelong learning, which is essential for today's health professionals.

Perusing the literature via citation links.

While MEDLINE searching is recognized as the single most effective means to identify relevant items to solve clinical and research problems, the clinician should also consider the complementary strategy to search for relevant items citing a known key paper. This study reports on the usefulness of citation searching based on the analysis of 89 searches. For each topic, the citations linked to an average of 24% additional relevant materials. At least one relevant item was added to 85% of the searches. The additional effort of scanning another printout is minimal since citation searching for 42% of the searches produced less than 7 additional items, half of which were judged to be useful. Duplicate retrievals were mostly of definite relevance. This alternate strategy appeared to be effective in interdisciplinary topics. Furthermore, the online version of the citation index is known for short turn-around time in processing, a feature important for many rapidly developing specialties.

Importance of platelet serologic testing for defining the cause of neonatal thrombocytopenia.

This report illustrates the importance of serologic techniques for defining the etiology of neonatal thrombocytopenia. In Case 1 the maternal count was low normal to normal during the first postpartum week. Several weeks later the appearance of persistent maternal thrombocytopenia led to the demonstration of anti-GP IIb-IIIa in stored and freshly obtained maternal sera, suggesting that the mother had an autoimmune type of thrombocytopenia. The mother of Case 2 had systemic lupus erythematosus. However, serologic testing revealed that the infant's thrombocytopenia was not related to the mother's lupus but was secondary to alloimmunization with the PlA1 antigen. An algorithm for defining etiologic mechanisms in infants with antibody-mediated forms of thrombocytopenia is presented.

A quality filtering system for medical literature.

An algorithmic method for selecting quality journal articles is presented. The procedures are based on formalizations of existing evaluation mechanisms in scientific publication. The method was actually applied to the journal literature of the pharmacology of cardiac arrhythmias for the period 1967 to 1970. A comparison with the selected bibliographies of four recent publications showed that the method approximated some of the selections made by conventional subjective judgment.