Origins of nonword phonological errors in aphasic picture naming

A recent theory of lexical access in picture naming maintains that all nonword errors are generated during the retrieval of phonemic segments from the lexicon (Dell, Schwartz, Martin, Saffran, & Gagnon, 1997b). This theory is challenged by "dual origin" theories that postulate a second, post-lexical mechanism, whose disruption gives rise to "phonemic paraphasias" bearing close resemblance to the target. We tested the dual origin theory in a corpus of 457 nonword errors drawn from 18 subjects with fluent aphasia. The corpus was divided into two parts, based on degree of phonological overlap between error and target, and these parts were separately examined for proposed diagnostic characteristics of the postlexical error mechanism: serial order effects across the word, sensitivity to target length, and insensitivity to target frequency. Results did not support the dual origin theory but were consistent with a single, lexical origin account in which segment retrieval operates from left to right, rather than in parallel. Findings from this study also shed new light on how individual differences in the severity of the retrieval deficit modulate the expression of phonological errors in relation to target characteristics.     

Serum progesterone at the time of human chorionic gonadotrophin does not predict pregnancy in in-vitro fertilization and embryo transfer

Controversy exists as to whether the serum concentration ofprogesterone on the day of human chorionic gonadotrophin (HCG)administration following ovarian stimulation for in-vitro fertilization(IVF) and embryo transfer can be used to predict the likelihoodof success. This retrospective study was undertaken to answerthis question by analysing a large population of IVF and embryotransfer cycles (n = 756). In addition to the concentrationof progesterone on the day of HCG administration, all variablesknown to impact on IVF and embryo transfer success (such aspatient age), indication for IVF and embryo transfer, numberof oocytes retrieved and the number of embryos generated andtransferred were examined. There was a significant increasein the number of oocytes retrieved with increasing progesteroneconcentration at the time of HCG administration. However, therewas no correlation of progesterone concentration at HCG administrationwith pregnancy and implantation rates. It is concluded thatprevious reports associating a slight elevation of progesteronein gonadotrophin- releasing hormone agonist ovarian stimulationcycles for IVF and embryo transfer may be misleading becauseof a small sample size or the presence of confounding variablesthat affect IVF and embryo transfer success.     

Construction of cosmid contigs and high-resolution restriction mapping of the Huntington disease region of human chromosome 4

The gene responsible for Huntington disease (HD) has been localizedto a 2.2 million base pair (Mbp) region between the loci D4S10and D4S98 on the short arm of human chromosome 4. As part ofa strategy originally designed to clone the gene based on itschromosomal location, we and others previously identified overlappingyeast artificial chromosome (YAC) clones covering most of thisregion. While these YAC clones were useful for initially obtaininglong-range clone continuity, a number of features of the YACsindicated that smaller clones are generally more useful in thesubsequent steps of the positional cloning strategy. In thispaper, we use these YAC clones to generate sets of overlappingcosmid clones covering most of the HD region. We Isolated alarge number of cosmids by screening a chromosome 4-specificcosmld library with labeled DNA from a minimal overlapping setof YAC clones. These cosmid clones were further analyzed byrestriction mapping and hybridization experiments, leading tothe assembly of 185 cosmids Into eleven contigs covering morethan 1.65 Mbp and to a fine-structure restriction map of theregion. Nine of these contigs cover 90 percent of the 1.7 Mbpsubregion between loci D4S125 and D4S98 where the HD gene isnow known to lie. The detailed restriction map and the cosmidclones should facilitate the identification and localizationof cDNAs and polymorphic markers, and they provide reagentsfor large scale DNA sequencing of this region of the human genome.Our results suggest that this strategy should be generally usefulfor converting YAC clones into cosmid contigs and generatinghigh-resolution restriction maps of genomioc regions of interest.     

Parasite-susceptibility phenotypes of F1 Biomphalaria glabrataprogeny derived from interbreeding Schistosoma mansoni-resistant and -susceptible snails

In an effort to investigate the 'flow' of parasite-resistance genes through laboratory snail populations, we determined the susceptibility of progeny snails from freely interbreeding parasite-susceptible and parasite-resistant parents. Five parental populations of Biomphalaria glabrata were used to generate the progeny snails. Three of them contained different proportions of Schistosoma mansoni-susceptible albino snails (NMRI stock) and S. mansoni-resistant pigmented snails (BS-90), while single stock controls comprised the other two parental populations. F(1) snails from each parental population were exposed to S. mansoni miracidia. Some of the progeny snails were exposed as juveniles, others as adults. According to Hardy-Weinberg principle predictions, the F(1) generation from the three pigmented/albino parental populations displayed higher than expected numbers of pigmented (resistant) snails and lower than expected numbers of albino (susceptible) snails. Among the assumptions of the Hardy-Weinberg principle that were not met within these populations could include non-random mating, unequal fecundity, different hatching and survival rates of different genotypes, or other life-history differences between snail stocks. It is clear, though, that for these two laboratory snail stocks there is no fitness cost attached to genetic resistance to the parasite.     

Inclusion of CpG adjuvant with plasmid DNA coding for NcGRA7 improves protection against congenital neosporosis

The present study showed that incorporation of CpG adjuvant into plasmid DNA coding for NcGRA7 antigen resulted in a twofold increase in the level of protection against congenital transfer of Neospora caninum. The level of protection was considerably higher than that observed in pups born from dams immunized with nonrecombinant plasmid.     

Quantitation of hepatitis B viral DNA by solution hybridization: Comparison with DNA polymerase and hepatitis B e antigen during antiviral therapy

Serological markers of hepatitis B virus (HBV) replication were assessed in a randomized, controlled trial of prednisone withdrawal followed by α -interferon in the treatment of chronic hepatitis B. HBV DNA levels in more than 700 serial serum samples from 41 patients were determined by a sensitive and quantitative solution hybridization assay. Results were compared with HBV DNA polymerase (DNAp) activity and hepatitis B e antigen (HBeAg) in 21 untreated controls and 20 treated patients. Among treated patients, the mean pretherapy HBV DNA values were higher in nonresponders than in responders. During prednisone treatment, DNA levels increased an average of 2.1-fold in responders and 1.4-fold in nonresponders. During the 2-week rest interval between prednisone and interferon, DNA values fell an average of 57% in responders. In contrast, the mean DNA values in nonresponders did not change during the same interval. This early distinction between responders and nonresponders was not apparent from DNAp or HBeAg results. During interferon treatment, HBV DNA became undetectable in responders and remained negative during a 1-year follow-up. DNA in nonresponders declined to 14% of baseline during interferon treatment but increased to pretherapy levels after treatment. DNAp values generally paralleled HBV DNA values, but DNAp activity showed more variability and lower sensitivity than did the hybridization assay results. HBeAg values varied independently of HBV DNA and DNAp with a much delayed decline in responders. These results indicate that HBV DNA, when measured quantitatively by a sensitive solution hybridization assay, is an early predictor of the effects of antiviral agents on replication.     

Outcomes of unrelated umbilical cord blood transplantation for X-linked adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a defect in the metabolism of long chain fatty acids leading to demyelination, neurodegeneration, and death. The disease typically presents in young boys and adolescent boys. Allogeneic bone marrow transplantation has been used to halt progression of the disease. However, many patients lack suitable HLA- matched related donors and must rely on unmatched donors for a source of stem cells. The purpose of this study was to evaluate outcomes of unrelated donor umbilical cord blood transplantation after chemotherapy-based myeloablative conditioning and retrospectively determine if baseline studies correlate and help predict outcome. Between November 22, 1996, and November 3, 2005, 12 boys with X-linked ALD who lacked HL- matched related donors were referred to Duke University Medical Center for transplantation. These children were conditioned with myeloablative therapy including busulfan, cyclophosphamide, and antithymocyte globulin before receiving umbilical cord-blood transplants from unrelated donors. Baseline studies of neurophysiologic, neuroimaging, and neurodevelopmental status were performed and patients were subsequently evaluated for survival, engraftment, graft-versus-host disease, and neurodevelopmental outcomes. A substudy evaluated whether baseline neuroimaging and neurophysiologic studies correlated with cognitive and motor function and if these studies were predictive of posttransplantation outcomes. The umbilical cord blood grafts had normal levels of very long chain fatty acids. They delivered a median of 6.98 x 10(7) nucleated cells per kilogram of recipient body weight and were discordant for up to 4 of 6 HLA markers. Neutrophil engraftment occurred at a median of 22.9 days after transplantation. Three patients had grade II-IV acute graft-versus-host disease; 2 had extensive chronic graft-versus-host disease. Cumulative incidence of overall survival of the group at 6 months is 66.7% (95% confidence interval 39.9-93.3%). Median follow-up was 3.3 years (range 12 days to 6.3 years). As previously reported with bone marrow transplantation, symptomatic patients faired poorly with lower survival and rapid deterioration of neurologic function. This study included 3 patients transplanted at a very young age (2.6-3.5 years) before the onset of clinical symptoms who continue to develop at a normal rate for 3-5 years posttransplant. Although baseline Loes scores correlated with cognitive and motor outcome, neurophysiologic studies failed to show statistically significant differences. Transplantation of boys with X-linked ALD using partial HLA-matched umbilical cord blood yields similar results to those previously reported after bone marrow transplantation. Superior outcomes were seen in neurologically asymptomatic boys less than 3.5 years of age at the time of transplantation. Baseline Loes scores were a strong predictor of cognitive and motor outcome.     

Velo-cardio-facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both also have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletions has not been reported previously. An accurate diagnosis of the 22q11 deletions is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions. © 1994 Wiley-Liss, Inc.     

Rapid array-based genomic characterization of a subtle structural abnormality: a patient with psychosis and der(18)t(5;18)(p14.1;p11.23)

Array-based copy number analysis has recently emerged as a rapid means of mapping complex and/or subtle chromosomal abnormalities. We have compared two such techniques, using bacterial artificial chromosome (BAC) and single nucleotide polymorphism (SNP) arrays in the evaluation of a 45-year-old woman with dysmorphic features, mental retardation, psychosis, and an unbalanced derivative chromosome 18, (46,XX, der(18)t(18;?)(p12;?)). Both array-based methods demonstrated that the additional material on chromosome 18 was of 5p origin. The 5p duplication mapped telomeric to 25.320 Mb (BAC array) and 25.607 Mb (SNP array), corresponding to the band 5p14.1. Both BAC and SNP arrays also showed a deletion involving chromosome 18p extending telomeric from 8.437 Mb (BAC array) and 8.352 Mb (SNP array), corresponding to the band 18p11.23. Molecular cytogenetic mapping using fluorescence in situ hybridization (FISH) supported the array findings and further refined the breakpoint regions, confirming that the BAC and SNP chips were both useful in this regard. Both case reports and linkage analyses have implicated these chromosomal intervals in psychosis. The array-based experiments were completed over the course of several days. While these methods do not eliminate the requirement for traditional fine-mapping, they provide an efficient approach to identifying the origin and extent of deleted and duplicated material in chromosomal rearrangements.     

Breast cancer risk associated with ovulation-stimulating drugs

BACKGROUND: Despite the recognized role of hormones in the aetiology of breast cancer, there has been little evaluation of hormonal preparations used to treat infertility. METHODS: A retrospective cohort study of 12,193 women evaluated for infertility between 1965 and 1988 at five clinical sites identified 292 in situ and invasive breast cancers in follow-up through 1999. Standardized incidence ratios (SIRs) compared breast cancer risks with those of the general population. Analyses within the cohort estimated rate ratios (RRs) associated with medications after adjustment for other breast cancer predictors. RESULTS: Infertile patients had a significantly higher breast cancer risk than the general population [SIR = 1.29, 95% confidence interval (CI) 1.1-1.4]. Analyses within the cohort showed adjusted RRs of 1.02 for clomiphene citrate and 1.07 for gonadotrophins, and no substantial relationships to dosage or cycles of use. Slight and non-significant elevations in risk were seen for both drugs after > or = 20 years of follow-up (RRs = 1.39 for clomiphene and 1.54 for gonadotrophins). However, the risk associated with clomiphene for invasive breast cancers was statistically significant (RR = 1.60, 95% CI 1.0-2.5). CONCLUSIONS: Although there was no overall increase in breast cancer risk associated with use of ovulation-stimulating drugs, long-term effects should continue to be monitored.