Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates.

The filamentous fungus Aspergillus nidulans has been a primary workhorse used to understand fungal genetics. Much of this work has focused on elucidating the genetics of biosynthetic gene clusters (BGCs) and the secondary metabolites (SMs) they produce. SMs are both niche defining in fungi and of great economic importance to humans. Despite the focus on A. nidulans, very little is known about the natural diversity in secondary metabolism within this species. We determined the BGC content and looked for evolutionary patterns in BGCs from whole-genome sequences of two clinical isolates and the A4 reference genome of A. nidulans Differences in BGC content were used to explain SM profiles determined using liquid chromatography-high-resolution mass spectrometry. We found that in addition to genetic variation of BGCs contained by all isolates, nine BGCs varied by presence/absence. We discovered the viridicatumtoxin BGC in A. nidulans and suggest that this BGC has undergone a horizontal gene transfer from the Aspergillus section Nigri lineage into Penicillium sometime after the sections Nigri and Nidulantes diverged. We identified the production of viridicatumtoxin and several other compounds previously not known to be produced by A. nidulans One isolate showed a lack of sterigmatocystin production even though it contained an apparently intact sterigmatocystin BGC, raising questions about other genes and processes known to regulate this BGC. Altogether, our work uncovers a large degree of intraspecies diversity in BGC and SM production in this genetic model species and offers new avenues to understand the evolution and regulation of secondary metabolism.IMPORTANCE Much of what we know about the genetics underlying secondary metabolite (SM) production and the function of SMs in the model fungus Aspergillus nidulans comes from a single reference genome. A growing body of research indicates the importance of biosynthetic gene cluster (BGC) and SM diversity within a species. However, there is no information about the natural diversity of secondary metabolism in A. nidulans We discovered six novel clusters that contribute to the considerable variation in both BGC content and SM production within A. nidulans We characterize a diverse set of mutations and emphasize how findings of single nucleotide polymorphisms (SNPs), deletions, and differences in evolutionary history encompass much of the variation observed in nonmodel systems. Our results emphasize that A. nidulans may also be a strong model to use within-species diversity to elucidate regulatory cross talk, fungal ecology, and drug discovery systems.

Atmospheric peroxyacetyl nitrate (PAN): a global budget and source attribution.

Peroxyacetyl nitrate (PAN) formed in the atmospheric oxidation of non-methane volatile organic compounds (NMVOCs) is the principal tropospheric reservoir for nitrogen oxide radicals (NOx = NO + NO2). PAN enables the transport and release of NOx to the remote troposphere with major implications for the global distributions of ozone and OH, the main tropospheric oxidants. Simulation of PAN is a challenge for global models because of the dependence of PAN on vertical transport as well as complex and uncertain NMVOC sources and chemistry. Here we use an improved representation of NMVOCs in a global 3-D chemical transport model (GEOS-Chem) and show that it can simulate PAN observations from aircraft campaigns worldwide. The immediate carbonyl precursors for PAN formation include acetaldehyde (44% of the global source), methylglyoxal (30 %), acetone (7 %), and a suite of other isoprene and terpene oxidation products (19 %). A diversity of NMVOC emissions is responsible for PAN formation globally including isoprene (37 %) and alkanes (14 %). Anthropogenic sources are dominant in the extratropical Northern Hemisphere outside the growing season. Open fires appear to play little role except at high northern latitudes in spring, although results are very sensitive to plume chemistry and plume rise. Lightning NOx is the dominant contributor to the observed PAN maximum in the free troposphere over the South Atlantic.

The role of CRE1 in nucleosome positioning within the cbh1 promoter and coding regions of Trichoderma reesei.

Nucleosome positioning within the promoter and coding regions of the cellobiohydrolase-encoding cbh1 gene of Trichoderma reesei was investigated. T. reesei is a filamentous fungus that is able to degrade dead plant biomass by secreting enzymes such as cellulases, a feature which is exploited in industrial applications. In the presence of different carbon sources, regulation of one of these cellulase-encoding genes, cbh1, is mediated by various transcription factors including CRE1. Deletion or mutation of cre1 caused an increase in cbh1 transcript levels under repressing conditions. CRE1 was shown to bind to several consensus recognition sequences in the cbh1 promoter region in vitro. Under repressing conditions (glucose), the cbh1 promoter and coding regions are occupied by several positioned nucleosomes. Transcription of cbh1 in the presence of the inducer sophorose resulted in a loss of nucleosomes from the coding region and in the re-positioning of the promoter nucleosomes which prevents CRE1 from binding to its recognition sites within the promoter region. Strains expressing a non-functional CRE1 (in strains with mutated CRE1 or cre1-deletion) exhibited a loss of positioned nucleosomes within the cbh1 coding region under repressing conditions only. This indicates that CRE1 is important for correct nucleosome positioning within the cbh1 coding region under repressing conditions.

Sinais e sintomas de disfuncao temporomandibular em criancas portadoras de paralisia cerebral / Signs and symptoms of temporomandibular dysfunction in children wit cerebral palsy

O objetivo deste estudo foi analisar os sinais e sintomas de disfuncao temporomandibular em criancas portadoras de paralisia cerebral. Material e metodos: Foram avaliadas 22 criancas entre 5 e 13 anos, sendo 10 portadoras de paralisia cerebral espastica (9,1+-2,64 anos) e 12 normais (7,91+-0,99 anos). Foram colhidas informacoes sobre mastigacao, dor muscular e articular e ruidos articulares. Tambem foi determinado o indice de disfuncao clinica de Helkimo e o grau de espasticidade por meio da Escala de Espasticidade Ashworth Modificada. Resultados: os resultados indicam que nao ha diferenca significativa (p=0,231) na maxima abertura bucal entre os grupos. Contudo, no movimento lateral direito (p=0,001), no movimento lateral esquerdo (p=0,048) e na protusao (p=0,009) observou-se significativa diferenca. Conclusao: muitas criancas com paralisia cerebral nao realizaram o movimento de protrusao (50 por cento) e a lateralidade par um dos lados (40 por cento) , mas a severidade da disfuncao temporomandibular nao esta relacionada com a severidade da espasticidade

A comparison of population-based cancer incidence rates in Israel and Jordan.

Reliable information about comparative cancer incidence in the Middle East has been lacking. The Middle East Cancer Consortium (MECC) has formed a network of population-based registries with standardized basic data. Here the age-adjusted cancer incidences are compared for four populations: Israeli Jews, Israeli non-Jews, Jordanians and the US Surveillance Epidemiology and End Results (SEER) population, for the years 1996-1997 (Israel) and 1996-1998 (other populations). The all-sites rate of cancer is approximately twice as high in Israeli Jews and SEER, compared with Israeli non-Jews and Jordanians. Rates of lung cancer are similar among Israeli Jews and non-Jews and about twice as high as in Jordanians. Childhood leukaemia rates in Jordan are higher than in Israeli Jews, but lower than SEER. Hodgkin lymphoma rates in Israeli non-Jews and Jordanians are similar to SEER, but non-Hodgkin lymphoma rates are lower than SEER. The previous suspicion of higher overall leukaemia and lymphoma rates in Jordan is thus not confirmed.

Comparing frequency of content-bearing words in abstracts and texts in articles from four medical journals: an exploratory study.

BACKGROUND: Retrieval tests have assumed that the abstract is a true surrogate of the entire text. However, the frequency of terms in abstracts has never been compared to that of the articles they represent. Even though many sources are now available in full-text, many still rely on the abstract for retrieval. METHODS: 1,138 articles with their abstracts were downloaded from Journal of the American Medical Association, New England Journal of Medicine, Lancet, and the British Medical Journal. Words were extracted from the articles and their abstracts and the frequency of each word was counted in both sources. Each article and its abstract were tested using a chi-squared test to determine if the words in the abstract occurred as frequently as would be expected. RESULTS: 96% of the abstracts tested as samples of the article they represented. CONCLUSION: In these four journals, the abstracts are lexical, as well as intellectual, surrogates for the documents they represent.

Frequency distributions of breast cancer characteristics classified by estrogen receptor and progesterone receptor status for eight racial/ethnic groups.

BACKGROUND: The National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer registries have been collecting data regarding estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer since 1990. The current study reports on some of these data for eight racial/ethnic groups. METHODS: Stratified by ER and PR status, the frequency distributions of 112,588 breast cancer cases diagnosed between 1992--1997 in 11 SEER cancer registries were examined by age at diagnosis, stage at diagnosis, histologic grade, and tumor type for white, black, Hispanic, Japanese, Chinese, Filipino, Native Hawaiian, and American Indian and Alaska Native (AI/AN) females. RESULTS: For each racial/ethnic group, the percentage of ER positive (+)/PR+ was > ER-PR- > ER+PR- > ER-PR+ tumors. For the two major ER/PR groups, the ER+PR+ tumors were different from the ER-PR- tumors in several ways. For white females, there were differences in the age distributions, stage at diagnosis, and histologic grade. For black females, the differences involved the age distributions and tumor grades. For Hispanic and Japanese females, there were differences with regard to the age distributions and tumor grades. For Filipino, Chinese, and AI/AN females, the tumor stages and grades differed. For Native Hawaiians, the histologic tumor grades were different. CONCLUSIONS: For each racial/ethnic group, the ER/PR status appeared to divide breast cancer patients into two or more subgroups with unique tumor characteristics. In general, ER status appeared to have the greatest impact on delineating these subgroups, whereas in some cases, PR status was able to modify the subgroups further. It is hoped that reporting these tumor characteristics by ER/PR status for each racial/ethnic group will spur more investigation into the significance of ER/PR status in each racial/ethnic group.

Annual report to the nation on the status of cancer (1973 through 1998), featuring cancers with recent increasing trends.

BACKGROUND: The American Cancer Society, the National Cancer Institute (NCI), the North American Association of Central Cancer Registries, and the Centers for Disease Control and Prevention, including the National Center for Health Statistics (NCHS), collaborate to provide an annual update on cancer occurrence and trends in the United States. This year's report contains a special feature that focuses on cancers with recent increasing trends. METHODS: From 1992 through 1998, age-adjusted rates and annual percent changes are calculated for cancer incidence and underlying cause of death with the use of NCI incidence and NCHS mortality data. Joinpoint analysis, a model of joined line segments, is used to examine long-term trends for the four most common cancers and for those cancers with recent increasing trends in incidence or mortality. Statistically significant findings are based on a P value of.05 by use of a two-sided test. State-specific incidence and death rates for 1994 through 1998 are reported for major cancers. RESULTS: From 1992 through 1998, total cancer death rates declined in males and females, while cancer incidence rates declined only in males. Incidence rates in females increased slightly, largely because of breast cancer increases that occurred in some older age groups, possibly as a result of increased early detection. Female lung cancer mortality, a major cause of death in women, continued to increase but more slowly than in earlier years. In addition, the incidence or mortality rate increased in 10 other sites, accounting for about 13% of total cancer incidence and mortality in the United States. CONCLUSIONS: Overall cancer incidence and death rates continued to decline in the United States. Future progress will require sustained improvements in cancer prevention, screening, and treatment.

Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older.

CONTEXT: Postmenopausal women aged 55 years and older have 66% of incident breast tumors and experience 77% of breast cancer mortality, but other age-related health problems may affect tumor prognosis and treatment decisions. OBJECTIVE: To document the comorbidity burden of postmenopausal breast cancer patients and evaluate its relationship with age on disease stage, treatment, and early mortality. DESIGN AND SETTING: Data were collected on breast cancer patients' comorbidities by retrospective hospital medical records review and merged with information on patients' tumor characteristics collected from 6 regional National Cancer Institute Surveillance, Epidemiology, and End Results cancer registries. Patients were followed up until death or for 30 months from breast cancer diagnosis. PARTICIPANTS: Population-based random sample of 1800 postmenopausal breast cancer patients diagnosed in 1992 stratified by 3 age groups: 55 to 64 years, 65 to 74 years, and 75 years and older. MAIN OUTCOME MEASURES: Extent of disease, therapy received, comorbidity, cause of death, and survival. RESULTS: Seventy-three percent (1312 of 1800) of the sample was diagnosed with stage I and II breast cancer, 10% (n = 188) with stage III and IV breast cancer, and 17% (n = 300) did not have a stage assignment. Of the 1017 patients with stage I and stage II node-negative breast cancer, 95% received therapy in agreement with the National Institutes of Health consensus statement recommendation for early-stage breast cancer. Patients in older age groups were less likely to receive therapy consistent with the consensus statement (P<.001), and women aged 70 years and older were significantly less likely to receive axillary lymph node dissection as determined by logistic regression analysis (P<.01). Diabetes, renal failure, stroke, liver disease, a previous malignant tumor, and smoking were significant in predicting early mortality in a statistical model that included age and disease stage. Breast cancer was the underlying cause of death for 135 decedents (51.3%). Heart disease (n = 45, 17.1%) and previous cancers (n = 22, 8.4%) were the next major underlying causes. In the 30-month follow-up period, 263 patients (15%) died. CONCLUSION: Patient care decisions occur in the context of breast cancer and other age-related conditions. Comorbidity in older patients may limit the ability to obtain prognostic information (ie, axillary lymph node dissection), tends to minimize treatment options (eg, breast-conserving therapy), and increases the risk of death from causes other than breast cancer.

Genetic analysis of Brugada syndrome in Israel: two novel mutations and possible genetic heterogeneity.

Idiopathic ventricular fibrillation in patients with an electrocardiogram (ECG) pattern of right bundle branch block and ST-segment elevation in leads V1 to V3 (now frequently called Brugada syndrome) is associated with a high incidence of syncopal episodes or sudden death. The disease is inherited as an autosomal dominant trait. Mutations in SCN5A, a cardiac sodium channel gene, have been recently associated with Brugada syndrome. We have analyzed 7 patients from Israel affected with Brugada syndrome. The families of these patients are characterized by a small number of symptomatic members. Sequencing analysis of SCN5A revealed two novel mutations, G35S and R104Q, in two Brugada patients, and a possible R34C polymorphism in two unrelated controls. No mutations were detected in 5 other patients, suggesting genetic heterogeneity. Low penetrance is probably the cause for the small number of symptomatic members in the two families positive for the SCN5A mutations.

Comparing frequency of word occurrences in abstracts and texts using two stop word lists.

Retrieval tests have assumed that the abstract is a true surrogate of the entire text. However, the frequency of terms in abstracts has never been compared to that of the articles they represent. Even though many sources are now available in full-text, many still rely on the abstract for retrieval. 1,138 articles with their abstracts were downloaded from Journal of the American Medical Association, New England Journal of Medicine, the British Medical Journal, and the Lancet. Based on two stop word lists, one long and one short, content bearing words were extracted from the articles and their abstracts and the frequency of each word was counted in both sources. Each article and its abstract were tested using a chi-squared test to determine if the words in the abstract occurred as frequently as would be expected. 96% to 98% of the abstracts tested were not significantly different than random samples of the articles they represented. In these four journals, the abstracts are lexical, as well as intellectual, surrogates for the articles they represent.

Prenatal diagnosis of a novel COL1A1 mutation in osteogenesis imperfecta type I carried through full term pregnancy.

Prenatal diagnosis was performed in a family where the father has osteogenesis imperfecta (OI) type I, with a novel mutation in the COL1A1 gene: a C to T change at position c3076 (c.3076C-->T) leading to a change of arginine at codon 848 to a stop codon (R848X). Prenatal diagnosis by chorionic villous sampling (CVS) was performed during the fourth pregnancy, and revealed that the fetus is a carrier of the same COL1A1 mutation. The possibility of phenotypic variability was discussed with the parents. They elected to carry the pregnancy to term, and a male child with mild OI was born. This is the first reported case where OI was diagnosed prenatally, and the parents opted to carry the pregnancy to term. It illustrates the potential use of DNA-based analysis for early prenatal diagnosis of OI, and the complexities of genetic counselling.

Achondroplasia in diverse Jewish and Arab populations in Israel: clinical and molecular characterization.

BACKGROUND: Achondroplasia is the most frequent form of disproportionate short stature, characterized by rhizomelic shortening of the limbs. This disorder is inherited as an autosomal dominant trait, although most of the cases are sporadic, a result of a de novo mutation. A recurrent glycine to arginine mutation at codon 380 (G380R) in the transmembrane domain of the fibroblast growth factor receptor 3 gene was found to cause achondroplasia among different populations. This is most uncommon in other autosomal dominant genetic diseases. OBJECTIVES: To determine whether this mutation is also common among Jewish patients from diverse ethnic groups and among the Arab population in Israel. METHODS: We examined the G380R mutation (G > A and G > C transition) and the mutation G375C (G > T transition at codon 375) in 31 sporadic patients and in one family diagnosed clinically to have achondroplasia. RESULTS: We found the G > A transition at codon 380 in 30 of our patients and the G > C transition in one patient. We were not able to detect any of the three mutations in two patients with an atypical form of achondroplasia. CONCLUSIONS: Our results further support the unusual observation that nucleotide 1138 of the FGFR3 gene is the most mutable nucleotide discovered to date across different populations.

Toward a comparison of survival in American and European cancer patients.

BACKGROUND: Only recently have extensive population-based cancer survival data become available in Europe, providing an opportunity to compare survival in Europe and the United States. METHODS: The authors considered 12 cancers: lung, breast, stomach, colon, rectum, melanoma, cervix uteri, corpus uteri, ovary, prostate, Hodgkin disease, and non-Hodgkin lymphoma. The authors analyzed 738,076 European and 282,398 U.S. patients, whose disease was diagnosed in 1985-1989, obtained from 41 EUROCARE cancer registries in 17 countries and 9 U.S. SEER registries. Relative survival was estimated to correct for competing causes of mortality. RESULTS: Europeans had significantly lower survival rates than U.S. patients for most cancers. Differences in 5-year relative survival rates were higher for prostate (56% vs. 81%), skin melanoma (76% vs. 86%), colon (47% vs. 60%), rectum (43% vs. 57%), breast (73% vs. 82%), and corpus uteri (73% vs. 83%). Survival declined with increasing age at diagnosis for most cancers in both the U.S. and Europe but was more marked in Europe. CONCLUSIONS: Survival for most major cancers was worse in Europe than the U.S. especially for older patients. Differences in data collection, analysis, and quality apparently had only marginal influences on survival rate differences. Further research is required to clarify the reasons for the survival rate differences.

The annual report to the nation on the status of cancer, 1973-1997, with a special section on colorectal cancer.

BACKGROUND: This annual report to the nation addresses progress in cancer prevention and control in the U.S. with a special section on colorectal cancer. This report is the joint effort of the American Cancer Society, the National Cancer Institute (NCI), the North American Association of Central Cancer Registries (NAACCR), and the Centers for Disease Control and Prevention (CDC), including the National Center for Health Statistics (NCHS). METHODS: Age-adjusted rates were based on cancer incidence data from the NCI and NAACCR and underlying cause of death as compiled by NCHS. Joinpoint analysis was based on NCI Surveillance, Epidemiology, and End Results (SEER) program incidence rates and NCHS death rates for 1973-1997. The prevalence of screening examinations for colorectal cancer was obtained from the CDC's Behavioral Risk Factor Surveillance System and the NCHS's National Health Interview Survey. RESULTS: Between 1990-1997, overall cancer incidence and death rates declined. Joinpoint analyses of cancer incidence and death rates confirmed the declines described in earlier reports. The incidence trends for colorectal cancer have shown recent steep declines for whites in contrast to a leveling off of the rates for blacks. State-to-state variations occurred in colorectal cancer screening prevalence as well as incidence and death rates. CONCLUSIONS: The continuing declines in overall cancer incidence and death rates are encouraging. However, a few of the top ten incidence or mortality cancer sites continued to increase or remained level. For many cancer sites, whites had lower incidence and mortality rates than blacks but higher rates than Hispanics, Asian and Pacific Islanders, and American Indians/Alaska Natives. The variations in colorectal cancer incidence and death rates by race/ethnicity, gender, age, and geographic area may be related to differences in risk factors, demographic characteristics, screening, and medical practice. New efforts currently are underway to increase awareness of screening benefits and treatment for colorectal cancer.

Aging and cancer in America. Demographic and epidemiologic perspectives.

It has been stated in this article and elsewhere that cancer patients aged 65 years and older deserve special attention as a target group for research efforts across the cancer-control spectrum. The available data show that the vulnerability of older persons to cancer is unmistakable. Clinicians will be treating more older patients as the nation ages. The future needs of this segment of the population must be anticipated. In this context, the following generic treatment questions are pertinent. What are the peculiarities of the aged host of which clinicians must be aware in evaluating the older cancer patient? Do various forms of cancer present differently in the elderly? How can be complications caused by the multiple pathologies inherent in the older patient be anticipated? What are the potential hazards and limitations of surgery, radiotherapy, and chemotherapy for older persons with cancer? What is known regarding increased risk of adverse reactions to medications, drugs, and interaction of drugs in older patients? The surveillance data and population estimates and projections presented in this article illustrate the extent of the problems of cancer in the elderly at the macro level. For the individual patient, the special knowledge of aging individuals and their health status based on geriatric medicine and gerontology that has been accumulating for the past several decades needs to be incorporated into the oncology armamentarium that has developed during the same period. The information and expertise from both fields must converge, and new knowledge must be developed at the aging/cancer interface and applied for the optimal treatment of cancer in the elderly.

Partitioning linear trends in age-adjusted rates.

OBJECTIVE: Surveillance of chronic diseases includes monitoring trends in age-adjusted rates in the general population. Statistics that are calculated to describe and compare trends include the annual percent change and the percent change for a specified time period. However, it is also of interest to determine the contribution specific diseases make to an overall trend in order to better understand the impact of interventions and changes in the prevalence of risk factors. The objective here is to provide a method for partitioning a linear trend in age-adjusted rates into disease-specific components. METHODS: The method presented is based on linear regression. The decreasing trend in age-adjusted cancer mortality rates for the total United States during the period 1991-96 is analyzed to illustrate the method. RESULTS: Trends in mortality for cancers of the colon/rectum, breast, lung/bronchus, and prostate are found to be responsible for 75% of the decreasing trend in cancer mortality. CONCLUSIONS: It is possible to partition an overall trend in age-adjusted rates under the assumption that it and the trends for all mutually exclusive and exhaustive subgroups of interest are linear.

Cancer surveillance series [corrected]: brain and other central nervous system cancers: recent trends in incidence and mortality.

BACKGROUND: During the 1980s, the incidence of primary malignant brain and other central nervous system tumors (hereafter called brain cancer) was reported to be increasing among all age groups in the United States, while mortality was declining for persons younger than 65 years. We analyzed these data to provide updates on incidence and mortality trends for brain cancer in the United States and to examine these patterns in search of their causes. METHODS: Data on incidence, overall and according to histology and anatomic site, and on relative survival were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute for 1975 through 1995. Mortality data were obtained from the National Center for Health Statistics. Medicare procedure claims from the National Cancer Institute's SEER-Medicare database were used for imaging trends. Statistically significant changes in incidence trends were identified, and annual percent changes were computed for log linear models. RESULTS/CONCLUSIONS: Rates stabilized for all age groups during the most recent period for which SEER data were available, except for the group containing individuals 85 years of age or older. Mortality trends continued to decline for the younger age groups, and the steep increases in mortality seen in the past for the elderly slowed substantially. Patterns differed by age group according to the site and grade of tumors between younger and older patients. During the last decade, use of computed tomography scans was relatively stable for those 65-74 years old but increased among those 85 years old or older. IMPLICATIONS: Improvements in diagnosis and changes in the diagnosis and treatment of elderly patients provide likely explanations for the observed patterns in brain cancer trends.