Age, gender, and racial differences in incidence and survival in primary CNS lymphoma.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma that accounts for ~4% of newly diagnosed central nervous system (CNS) tumours. The objective of this study was to analyse the epidemiology, incidence, and outcome of these rare tumours. METHODS: Primary brain and CNS lymphoma cases were identified from the Surveillance, Epidemiology, and End Results (SEER) research data sets for the years 1980-2008 for analysis of trends in incidence and survival. SEER(*)Stat v. 7.0.4 software was used to analyse the data. RESULTS: The overall incidence rate of PCNSL was 0.47 per 100,000 person-years. The incidence was significantly higher in males compared with females, blacks aged 0-49 years at diagnosis compared with whites, and whites aged 50 years and older at diagnosis compared with blacks. After a significant decline in incidence between 1995 and 1999, incidence rates rose slightly; those aged 75+ years at diagnosis had the most dramatic increase in incidence rates over time. Five-year survival rates were significantly higher in whites compared with blacks aged 0-49 years at diagnosis, but was primarily driven by white women aged 0-49 years. CONCLUSION: There is an increase in incidence of PCNSL in the elderly, and elderly blacks have lower incidence compared with white population. Survival remains poor and is negatively dominated by factors associated with HIV infection and advanced age.

Risk of renal cell carcinoma in relation to blood telomere length in a population-based case-control study.

BACKGROUND: There are few known risk factors for renal cell carcinoma (RCC). Two small hospital-based case-control studies suggested an association between short blood telomere length (TL) and increased RCC risk. METHODS: We conducted a large population-based case-control study in two metropolitan regions of the United States comparing relative TL in DNA derived from peripheral blood samples from 891 RCC cases and 894 controls. Odds ratios and 95% confidence intervals were estimated using unconditional logistic regression in both unadjusted and adjusted models. RESULTS: Median TL was 0.85 for both cases and controls (P=0.40), and no differences in RCC risk by quartiles of TL were observed. Results of analyses stratified by age, sex, race, tumour stage, and time from RCC diagnosis to blood collection were similarly null. In multivariate analyses among controls, increasing age and history of hypertension were associated with shorter TL (P<0.001 and P=0.07, respectively), and African Americans had longer TL than Caucasians (P<0.001). CONCLUSION: These data do not support the hypothesis that blood TL is associated with RCC. This population-based case-control study is, to our knowledge, the largest investigation to date of TL and RCC.

Low plasma cholesterol levels caused by a short deletion in the apolipoprotein B gene.

Familial hypobetalipoproteinemia is a syndrome in which the plasma levels of apolipoprotein B (apo-B) and cholesterol are abnormally low. A truncated species of apo-B was identified in the plasma lipoproteins of members of a kindred with familial hypobetalipoproteinemia. DNA sequencing studies on genomic clones and enzymatically amplified genomic DNA samples revealed a four-base pair deletion in the apo-B gene. This short deletion, which results in a frameshift and a premature stop codon, accounts for the truncated apo-B species and explains the low apo-B and low cholesterol levels in this family.

Type III hyperlipoproteinemia associated with apolipoprotein E phenotype E3/3. Structure and genetics of an apolipoprotein E3 variant.

A family has been described in which type III hyperlipoproteinemia is associated with apo E phenotype E3/3 (Havel, R. J., L. Kotite, J. P. Kane, P. Tun, and T. Bersot. 1983. J. Clin. Invest. 72:379-387). In the current study, the structure of apo E from the propositus of this family was determined using both protein and DNA analyses. The propositus is heterozygous for two different apo E alleles, one coding for normal apo E3 and one for a previously undescribed variant apo E3 in which arginine replaces cysteine at residue 112 and cysteine replaces arginine at residue 142. Apo E gene analysis of nine other family members spanning four generations indicated that only those five members having type III hyperlipoproteinemia possess the variant apo E3. Like the propositus, all five are heterozygous for this variant, suggesting that the disorder in this family is transmitted in a dominant fashion. The variant apo E3 was defective in its ability to bind to lipoprotein receptors, and this functional defect probably contributes to the expression of type III hyperlipoproteinemia in this family.

DNA sequence analysis of a mouse pro alpha 1 (I) procollagen gene: evidence for a mouse B1 element within the gene.

In a 3.8-kilobase mouse DNA sequence encoding amino acid sequences for the pro alpha 1(I) chain of type I procollagen, 14 coding sequences were identified which specify a sequence 95% homologous to amino acid residues 568 to 963 of the bovine alpha 1(I) chain. All of these coding sequences were flanked by appropriate splice junctions following the GT/AG rule. These observations suggest, but do not prove, that this pro alpha 1(I) gene is transcriptionally active. Of the 14 coding sequences, 7 were 54 base pairs in length, whereas the remainder were higher multiples of 54 base pairs. Nonrandom utilization of codons pertained throughout all of the coding sequences showing a preference (56%) for U in the wobble position. Two of the intervening sequences encoded imperfect vestiges of coding sequences which exhibited a codon preference different from that of the pro alpha 1(I) gene proper and were not flanked by splice junctions. One intervening sequence encoded a member of the mouse B1 family of middle repetitive sequences. It was flanked by 8-base-pair direct repeats and had a truncated A-rich region, suggesting that it may be a mobile element. Within this element were sequences which could function as a RNA polymerase III split promoter.

DNase I- and micrococcal nuclease-hypersensitive sites in the human apolipoprotein B gene are tissue specific.

We have mapped the DNase I- and micrococcal nuclease-hypersensitive sites present in the 5' end of the human apolipoprotein B (apo-B) gene in nuclei from cells expressing or not expressing the gene. Four DNase I-hypersensitive sites were found in nuclei from liver-derived HepG2 cells and intestine-derived CaCo-2 cells, which express the apo-B gene, but not in HeLa cells, which do not. These sites are located near positions -120, -440, -700, and +760 base pairs relative to the transcriptional start site. Undifferentiated CaCo-2 cells exhibited another site, near position -540. Six micrococcal nuclease-hypersensitive sites were found in nuclei from HepG2 and CaCo-2 cells, but not in HeLa cells or free DNA. These sites are located near positions -120, -390, -530, -700, -850, and +210. HepG2 cells exhibited another site, near position +460. Comparison of the DNA sequence of the 5' flanking regions of the human and mouse apo-B genes revealed a high degree of evolutionary conservation of short stretches of sequences in the immediate vicinity of each of the DNase I- and most of the micrococcal nuclease-hypersensitive sites.

Acetylation and phosphorylation of Drosophila histones. Distribution of acetate and phosphate groups in fractionated chromatin.

The phosphorylation and acetylation patterns of Drosophila histones were studied after whole cell incubation with ortho [32P] phosphate or [3H] acetate. Radioactive phosphate associated mainly with H1, H3, and H4 and radioactive acetate was associated mainly with H3, H4, and H2B. H3 showed the highest specific activity of both labels. Two chromatin fractionation methods were employed to investigate the distribution of acetate and phosphate groups in histones form template-active and template-inactive regions. The levels of both acetate and phosphate groups were higher in histones from template-active regions.

Analysis of serpin inhibitory function by mutagenesis of ovalbumin and generation of chimeric ovalbumin/PAI-2 fusion proteins.

Ovalbumin is a non-inhibitory serpin which lacks the ability to undergo the S --> R transition or conformational change. Amino acid residues in the hinge region (P11 to P14) of ovalbumin and other non-inhibitory serpins differ from the concensus sequence of this region of inhibitory serpins, and have been proposed to be responsible for lack of inhibitory properties, particularly the P14 charged residue. Site directed mutagenesis using PCR overlap extension was performed on these residues in ovalbumin to create a mutant with three amino acid changes, R340T, V342A and V343A. However analysis of the mutant recombinant ovalbumin with the consensus residues failed to show inhibitory activity or decreased stability, indicating that the hinge region alone is not responsible for lack of inhibition. A series of three fusion proteins were then constructed by replacing varying C-terminal regions of ovalbumin with the corresponding region of the inhibitory ov-serpin PAI-2 in order to further analyse serpin inhibitory function. Fusion proteins F1 and F2 contained approximately 16% and 35% PAI-2, respectively. This resulted in the replacing of structural features such as the reactive site loop, hinge region and beta sheet strands 5A and 6A. However both fusion proteins showed no inhibitory activity with the PAI-2 target protease urokinase (uPA) and no decrease in stability as analysed by transverse urea gradient (TUG) gels. The third chimeric fusion protein constructed (F3) contained 64% PAI-2 and did demonstrate inhibition of uPA, SDS-PAGE stable complex formation with uPA and increased instability on TUG gels. Structural differences between the inactive F2 and active F3 include the replacement of helix F and beta sheet strand 3A of ovalbumin with those of PAI-2, suggesting that these features may have a key role in serpin beta-sheet opening and inhibitory function.

Two Drosophila actin genes in detail. Gene structure, protein structure and transcription during development.

DNA fragments representing the six Drosophila actin genes have been isolated by recombinant DNA techniques. We have compared the transcriptional characteristics of the actin genes at the cytological loci 79B and 88F. The activity of each gene in vivo was examined using gene-specific probes from transcribed, but non-translated 3' regions of each gene. The genes show similar patterns of transcriptional activity during development until the pupal stage, with two periods showing RNA accumulation at two to three hours and 12 to 15 hours during embryonic development, followed by large increases in the proportion of message from each gene in first and second instar larvae. During pupal development, the 88F gene apparently produces a larger proportion of transcripts than at any other developmental stage, while the transcripts of the 79B gene are reduced to a level lower than in first and second instar larvae. The 5' end of each messenger RNA in larvae has been mapped by nuclease S1 digestion of hybrids between restriction fragments of genes and homologous mRNAs. The two genes display widely differing capacities to serve as templates for transcription in vitro in HeLa cell extracts. The complete DNA sequences of both genes including the flanking regions immediately 3' and 5' to the gene are presented. These data permit comparison of the DNA sequences of these Drosophila actin genes with each other and with the DNA sequence and protein sequence information available for the actins of Drosophila and other organisms. These two genes share the common structural feature of an intervening sequence at amino acid 307, though the sequences within each intron differ greatly. This may be a reflection of a duplication event, followed by divergence of the intervening sequences. We discuss possible correlations between the DNA sequences of each 5' flanking region and the differences in transcriptional characteristics of these two distinct but closely related genes.

DNA from Maize with and without B Chromosomes: A Comparative Study.

DNA preparations from 5B and 0B maize seedlings are indistinguishable in their buoyant density distribution in CsCl gradients. Their renaturation kinetics are identical at several stringency criteria. DNA competition studies fail to detect any component in 5B DNA redundant sequences which is lacking in 0B DNA. Homologous and heterologous duplexes formed between 5B and 0B DNA have virtually identical melting profiles. The DNA of B chromosomes is concluded to be very closely related to that of A chromosomes.

Hashimoto's thyroiditis and insulin-dependent diabetes mellitus: differences among individuals with and without abnormal thyroid function.

Insulin-dependent diabetes mellitus probands from the Familial Autoimmune and Diabetes Study were evaluated for autoimmune thyroid disease (n = 265). The prevalence of Hashimoto's thyroiditis was 26.6%; 42.0% of these individuals were euthyroid, and 58.0% were hypothyroid. There was a female predominance among hypothyroid and euthyroid Hashimoto's cases compared to those with no thyroid disease (75% vs. 72.4% vs. 41.6%; P < 0.001). Insulin-dependent diabetes mellitus patients with hypothyroid Hashimoto's thyroiditis were more likely to report another autoimmune disease compared to euthyroid Hashimoto's patients or individuals with no thyroid disease (30.8% vs. 17.2% vs. 13.9%; P < 0.01). Sex-specific analysis revealed that this difference was significant for men but not for women. Both euthyroid and hypothyroid Hashimoto's cases were more likely to have a family history of the disease (66.7% vs. 69.2% vs. 47.7%; P < 0.05). No differences were observed in the prevalence of DQA1*0501-DQB1*0201 or DQA1*0301-DQB1*0302 across the three groups. Body mass index, lipid levels, glycemic control, and diabetes complications were also similar. However, euthyroid Hashimoto's women were more likely to report spontaneous abortions than those with hypothyroid Hashimoto's thyroiditis or no thyroid disease (23.8% vs. 61.5% vs. 29.1%; P < 0.05). These data suggest that gender-specific risk factors may be primary determinants of Hashimoto's thyroiditis and other autoimmune diseases among women. However, disease-specific determinants may also increase susceptibility to other autoimmune diseases.

Centralized databases available for describing primary brain tumor incidence, survival, and treatment: Central Brain Tumor Registry of the United States; Surveillance, Epidemiology, and End Results; and National Cancer Data Base.

Characteristics of three databases--the Central Brain Tumor Registry of the United States (CBTRUS) database; the Surveillance, Epidemiology and End Results (SEER) database; and the National Cancer Data Base (NCDB)--containing information on primary brain tumors are discussed. The recently developed population-based CBTRUS database comprises incidence data on all primary brain tumors from 11 collaborating state registries; however, follow-up data are not available. SEER, the population-based gold standard for cancer data, collects incidence and follow-up data on malignant brain tumors only. While not population-based, the NCDB identifies newly diagnosed cases and conducts follow-up on all primary brain tumors from hospitals accredited by the American College of Surgeons. The NCDB is the largest of the three databases and also contains more complete information regarding treatment of these tumors than either the SEER or CBTRUS databases. Additional strengths and limitations of each of these are described, and their judicious use for supporting research, education, and health care planning is encouraged.

Trends in incidence of primary brain tumors in the United States, 1985-1994.

Brain tumor incidence has increased over the last 20 years in all age groups, both overall and for specific histologies. Reasons attributed to these increases include increase in lymphoma due to HIV/AIDS, introduction of computed tomography/magnetic resonance imaging, and changes in coding/classification. The purpose of this study was to describe overall and histologic-specific incidence trends in a population-based series of primary benign and malignant brain tumors. Data from the Central Brain Tumor Registry of the United States from 1985 through 1994 were used to determine incidence trends in the broad age groups 0-19, 20-64, and > or = 65 years, both overall and for selected histologies. Poisson regression was used to express trends as average annual percentage change. Overall, incidence increased modestly (annual percentage change 0.9%, 95% confidence interval, 0.4, 1.4). When lymphomas were excluded, this result was not statistically significant (annual percentage change 0.5%, 95% confidence interval, -0.1, 1.1). Specific histologies that were increasing were lymphomas in individuals aged 20 to 64 years and in males aged 65 years or older, ependymomas in the population aged 20 to 64 years, nerve sheath tumors in males, and pituitary tumors in females. Increases that were not specific to any population subgroup were seen for glioblastoma, oligodendrogliomas, and astrocytomas, excluding not otherwise specified (NOS) tumors. Corresponding decreases were noted for NOS, astrocytoma NOS, and glioma NOS. Increasing incidence trends for lymphomas were consistent with previous literature. Improvements in diagnostic technology in addition to changes in classification and coding were likely to be responsible for decreases seen in incidence of NOS subgroups and corresponding increases in glioma subgroups. In contrast, the increases identified for ependymomas, nerve sheath tumors, and pituitary tumors were less likely to be artifacts of improvements in diagnosis, and they warrant further study.

Descriptive epidemiology of primary brain and CNS tumors: results from the Central Brain Tumor Registry of the United States, 1990-1994.

The Central Brain Tumor Registry of the United States (CBTRUS) obtained 5 years of incidence data (1990-1994)--including reports on all primary brain and CNS tumors--from 11 collaborating state cancer registries. Data were available for 20,765 tumors located in the brain, meninges, and other CNS sites, including the pituitary and pineal glands. The average annual incidence was estimated at 11.5 cases per 100,000 person-years. The higher incidence of tumors in male patients (12.1 per 100,000 person-years) than in female patients (11.0 per 100,000 person-years) was statistically significant (P < 0.05); the higher incidence in whites (11.6 per 100,000 person-years) compared with blacks (7.8 per 100,000 person-years) was statistically significant (P < 0.05). The most frequently reported histologies were meningiomas (24.0%) and glioblastomas (22.6%). Higher rates for glioblastomas, anaplastic astrocytomas, oligodendrogliomas, anaplastic oligodendrogliomas, ependymomas, mixed gliomas, astrocytomas not otherwise specified, medulloblastomas, lymphomas, and germ cell tumors in male than in female patients were statistically significant (P < 0.05), with relative risks (RR) ranging from 1.3 to 3.4. Meningiomas were the only tumors with a significant excess in females (RR = 0.5). We noted higher occurrence rates in whites than in blacks for the following histologies: diffuse astrocytomas, anaplastic astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, mixed gliomas, astrocytomas NOS, medulloblastomas, nerve sheath tumors, hemangioblastomas, and germ cell tumors, with RRs ranging from 1.5 to 3.4. Racial differences in occurrence rates were not observed for predominately benign meningiomas or pituitary tumors. This study represents the largest compilation of data on primary brain and CNS tumors in the United States. Standard reporting definitions and practices must be universally adopted to improve the quality and use of cancer registry data.

Altering the fine specificity of an anti-Legionella single chain antibody by a single amino acid insertion.

Antibody engineering provides the potential to clone and manipulate antibody genes to produce fragments with altered specificity. We have produced an anti- Legionella single chain fragment with broader specificity towards Legionella serotypes than the parent monoclonal antibody. Using this relationship between the parent monoclonal and the recombinant antibody derived from it as a model, we attempted to identify those residues responsible for this change in fine specificity. Sequence analysis of this recombinant antibody revealed the deletion of a conserved residue, Asp101, in the CDR-H3 region. Using site-directed mutagenesis, we have created a mutant form of this single chain fragment with an aspartic acid insertion mutation at position 101 of the antibody heavy chain. This mutant scFv demonstrates improved specificity compared to the wild-type recombinant antibody, indicating an important role for Asp101.

Congenital malformations and intrauterine growth retardation: a population study.

The relationship between congenital malformations and intrauterine growth retardation was investigated using data from the population-based Metropolitan Atlanta Congenital Defects Program. Between 1970 and 1984, the system ascertained 13,074 infants with major structural malformations diagnosed in the first year of life and born to metropolitan Atlanta residents. These infants were classified as having intrauterine growth retardation if their birth weight was below the race-, sex-, and gestational age-specific tenth percentile limits for all Atlanta births. Overall, the frequency of intrauterine growth retardation among malformed infants was 22.3% (relative risk 2.6). Of 48 defect categories evaluated, 46 were associated with excess intrauterine growth retardation, most notably chromosomal anomalies (eg, 83.7% for infants with trisomy 18, relative risk 46) and anencephaly (73.3%, relative risk 25). Only a few isolated defects (such as isolated polydactyly, pyloric stenosis, and congenital hip dislocation) were not associated with excess intrauterine growth retardation. Among infants with multiple malformations, the frequency of intrauterine growth retardation increased markedly with increasing number of defects--from 20% for infants with two defects to 60% for infants with nine or more defects. The relationship between malformations and intrauterine growth retardation can be explained by one or more of three mechanisms: (1) intrauterine growth retardation can be a secondary disturbance to the presence of malformations; (2) intrauterine growth retardation can predispose the fetus to malformations; and (3) intrauterine growth retardation can coexist with malformations because of common etiologic factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Another look at the black-white gap in gestation-specific perinatal mortality.

In the US, black infants born near or at term experience higher mortality than white infants. To extend our understanding of black-white differences in the relative advantages of growth (measured by birthweight) for gestational age, we compared race-specific rates of perinatal mortality by deviation in grams from the median birthweight for four categories of gestation (35-36, 37-38, 39-41, and 42-43 weeks). We also used race-specific standards to examine the difference between the median birthweight and the optimum birthweight (i.e. birthweight with the lowest mortality). The data, which were derived from vital records for singletons delivered in the US from 1983-1984, comprised 24,626 fetal and neonatal deaths among 5,157,197 white infants and 5973 fetal and neonatal deaths among 926,678 black infants. At all deviations from the median birthweight, black infants had relatively better survival at 35-36 weeks of gestation. This advantage was reversed among infants with gestations of 39-41 and 42-43 weeks. The optimum birthweight for black infants with gestations greater than or equal to 37 weeks was closer to their median birthweight than was that for white infants. For black infants with gestations of 39-41 weeks, the optimum birthweight was 187g (95% confidence interval (CI): 150-234) greater than the median birthweight (3289g); for comparable white infants the optimum birthweight was 397g (95% CI: 366-431) greater than the median birthweight (3487g). To reduce the black-white gap in perinatal mortality, we need a better understanding of aetiological relations between gestation, growth, and mortality.

Comparative analysis of sequences at the 5' end of the human and mouse apolipoprotein B genes.

A comparison was made between the DNA sequences in two regions of the mouse and the human apolipoprotein B genes: the 5'-flanking sequence and the region between the first exon and the second intron. Considerable homology was observed, particularly in the immediate 5' region and in the second intron. Because promoter and enhancer elements have been previously localized to these regions in the human apolipoprotein B gene, it is proposed that regions of conserved base sequence delineate binding regions for regulatory proteins. In some cases, contiguous regions of homology are longer than expected for regions designed as recognition sites for individual nuclear proteins, and may define regions recognizable by a cluster of interacting proteins. Both the human and mouse genes contain repetitive elements and a hypervariable dinucleotide repeat.

A randomized trial of nurse-midwifery prenatal care to reduce low birth weight.

In a randomized, controlled trial in five regional centers with state health department clinics, 1458 women at high risk for low birth weight (LBW) outcome received either prenatal interventions provided by nurse-midwives and nurses under their supervision or the standard high-risk prenatal care provided by obstetricians. The intervention administered by the nurse-midwives included patient education to identify the signs and symptoms of preterm labor, activity counseling in response to monitoring of the cervix by frequent examinations, stress reduction by enhancing social support, nutrition counseling with emphasis on weight gain, and substance-abuse counseling. For women in the control group, care was provided by obstetricians according to local standards for the management of high-risk pregnancies. We hypothesized that the LBW rate among live births to women who had received care from nurse-midwives would be lower than that in the control group. Although the LBW rate was lower in the intervention group than in the control group, the observed difference was not statistically significant. Race was not prespecified as a possible effect modifier, but examination of the data post hoc suggested that black women at high statistical risk of giving birth to an LBW infant may have derived benefit from the program. Although the results do not suggest any striking advantage of the nurse-midwifery intervention over standard obstetric care for women at high statistical risk of having an LBW infant, neither do they suggest any disadvantage. Nurse-midwives could provide care to certain populations of high-risk women and facilitate future coverage of these presently underserved populations.

Patterns of prenatal care initiation in Georgia, 1980-1992.

OBJECTIVE: To determine whether characteristics in a woman's first pregnancy were associated with the trimester in which she initiated prenatal care in her second pregnancy. METHODS: Data for white and black women whose first and second pregnancies resulted in singleton live births between 1980 and 1992 were obtained from Georgia birth certificates (n = 177,041). Adjusted relative risks (RRs) for early prenatal care in the second pregnancy were computed by logistic regression models that included trimester of prenatal care initiation, infant outcomes, or maternal conditions in the woman's first pregnancy as the exposure and controlled for maternal age, education, child's year of birth, interval between first and second pregnancy, presence of father's name on the birth certificate, and the interaction between prenatal care and education. Models were stratified by race. RESULTS: Women of both races who initiated prenatal care in the first trimester of their first pregnancies were more likely than those with delayed care to initiate prenatal care in the first trimester of their second pregnancies (RR = 1.25 and 1.63 for white and black women educated beyond high school, respectively). Both white and black women who delivered a baby with very low birth weight (RR = 1.06 and 1.15, respectively) or who suffered an infant death (RR = 1.09 and 1.31, respectively) in their first pregnancies were more likely than those who did not experience these events to begin prenatal care in the first trimester of their second pregnancies. CONCLUSION: Women with some potentially preventable adverse infant outcomes tend to obtain earlier care in their next pregnancy. Unfortunately, women who delayed prenatal care in their first pregnancy frequently delay prenatal care in their next.