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PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2004

Failure to induce oral tolerance in Crohn's and ulcerative colitis patients: possible genetic risk.

It has been proposed that defective activation of suppressor or regulatory T cells is one mechanism involved in the uncontrolled inflammatory process seen in inflammatory bowel disease (IBD). Because suppressor/regulatory T cells are thought to play a role in the promotion of oral tolerance, we attempted to induce oral tolerance in normal controls (n = 21) and patients with either Crohn's disease (CD; n = 12) or ulcerative colitis (UC; n = 13). In the first study, subjects were fed the neoantigen keyhole limpet hemocyanin (KLH) on days 1 to 5 and 11 to 15. Subcutaneous immunization with KLH was performed on day 26, with a booster immunization on day 35. Blood for KLH-induced T cell proliferation and serum for anti-KLH antibody production was obtained at baseline, on day 26 preimmunization (postfed), on day 35 after the first immunization, and again on day 42 after the second immunization. In normal individuals, KLH feeding prior to immunization and booster resulted in reduced KLH-specific T cell proliferation compared with the group that was not fed KLH. However, although on the same KLH-feeding protocol, both CD and UC patients demonstrated significantly enhanced proliferation without oral tolerance induction when compared with baseline values. These data suggest that oral tolerance induction is defective in patients with IBD. This may reflect an in vivo functional defect in mucosal suppression of immune responses in IBD. Both UC and CD appear to be multigenic disorders with evidence of familial segregation. We analyzed four multiplex Crohn's and two UC families to determine whether the defect in tolerance induction was genetically regulated. In three of the four CD families at least one unaffected family member also failed to tolerate (total 5 of 14 unaffected family members). In the UC families, the defect in tolerance segregated with disease. These data suggest a genetic defect in tolerance induction in Crohn's disease.

Administration, Oral↗
PubMed2002

Epithelial monolayer wounding stimulates binding of USF-1 to an E-box motif in the plasminogen activator inhibitor type 1 gene.

Several proteases and their co-expressed inhibitors modulate the interdependent processes of cell migration and matrix proteolysis during wound repair. Transcription of the gene encoding plasminogen activator inhibitor type 1 (PAI-1), a serine protease inhibitor important in the control of barrier proteolysis and cell-to-matrix adhesion, is spatially-temporally regulated following epithelial denudation injury in vitro as well as in vivo. Using a well-defined culture model of acute epidermal wounding and reepithelialization, PAI-1 mRNA/protein synthesis was induced early after monolayer scraping and restricted to cells comprising the motile cohort. PAI-1 levels in locomoting cells remained elevated (relative to the distal, contact-inhibited monolayer regions) throughout the time course of trauma repair. Targeted PAI-1 downregulation by transfection of antisense PAI-1 expression constructs significantly impaired keratinocyte migration and monolayer scrape wound closure. Injury-induced PAI-1 transcription closely paralleled growth state-dependent controls on the PAI-1 gene. An E-box motif (CACGTG) in the PAI-1 proximal promoter (located at nucleotides -160 to -165), previously shown to be necessary for serum-induced PAI-1 expression, was bound by nuclear factors from wound-stimulated but not quiescent, contact-inhibited, keratinocytes. UV crosslinking approaches to identify E-box-binding factors coupled with deoxyoligonucleotide affinity chromatography and gel retardation assays confirmed at least one major E-box-binding protein in both serum- and wound-activated cells to be USF-1, a member of the helix-loop-helix family of transcription factors. An intact hexanucleotide E-box motif was necessary and sufficient for USF-1 binding using nuclear extracts from both serum- and wound-simulated cells. Two species of immunoreactive USF-1 were identified by western blotting of total cellular lysates that corresponded to the previously characterized phosphorylated and non-phosphorylated forms of the protein. USF-1 isolated by PAI-1 promoter-DNA affinity chromatography was almost exclusively phosphorylated. Only a fraction of the total cellular USF-1 in proliferating cultures, by comparison, was phosphorylated at any given time. PAI-1 E-box binding activity, assessed by probe mobility shift criteria, increased within 2 hours of monolayer scrape injury, a time frame consistent with wound-stimulated increases in PAI-1 transcription. Relative to intact cultures, scrape site-juxtaposed cells had significantly greater cytoplasmic and nuclear USF-1 immunoreactivity correlating with the specific in situ-restricted expression of PAI-1 transcripts/protein in the wound-edge cohort. USF-1 immunocytochemical staining declined significantly with increasing distance from the denudation site. These data are the first to indicate that binding of USF-1 to its target motif can be induced by 'tissue' injury in vitro and implicate USF-1 as a transcriptional regulator of genes (e.g. PAI-1) involved in wound repair.

Animals↗
PubMed2002

Mitogen-activated protein kinase activation by oxidative and bacterial stress in an amphibian cell culture model.

The decline of many amphibian species could be caused by their susceptibility to environmental pollutants that cause cellular stress and cell death. A variety of intracellular signal transduction pathways are activated by environmental stress factors, which result in cell death. Mitogen-activated protein kinases are intracellular signaling molecules that include the extracellular signal-regulated kinases (ERK-1 and ERK-2). We used cultured (italic)Xenopus(/italic) tadpole cells (XTC-2 cells) to investigate the activation of ERK by oxidative or bacterial stress, two environmental factors that could contribute to pollution in aquatic systems. We exposed XTC-2 cell monolayers to hydrogen peroxide or bacterial lipopolysaccharide and measured ERK activation by Western blotting using antibodies raised against phosphorylated ERK-1 and ERK-2. Only ERK-2 was detected in XTC-2 cells. Both hydrogen peroxide and lipopolysaccharide caused ERK-2 phosphorylation in a time- and concentration-dependent manner. Hydrogen peroxide caused a 20- to 30-fold increase in ERK-2 activation that peaked 30 min after treatment, and lipopolysaccharide induced a 5- to 10-fold increase in ERK-2 activation that peaked 60 min after treatment. PD98059, an inhibitor of the ERK pathway, reduced the cytotoxic response of XTC-2 cells to hydrogen peroxide or lipopolysaccharide. These data suggest that ERK-2 is an intracellular target of oxidative and bacterial stress in amphibians that mediates, at least in part, the cytotoxic response to hydrogen peroxide or lipopolysaccharide. Moreover, the (italic)Xenopus(/italic) (XTC-2) cell culture system could serve as a useful model to identify agents that might threaten amphibian populations and human health.

Adaptation, Physiological↗
PubMed2005

Development of a new vaccine for the prevention of Lassa fever.

BACKGROUND: Recent importation of Lassa fever into Germany, the Netherlands, the United Kingdom, and the United States by travelers on commercial airlines from Africa underscores the public health challenge of emerging viruses. Currently, there are no licensed vaccines for Lassa fever, and no experimental vaccine has completely protected nonhuman primates against a lethal challenge. METHODS AND FINDINGS: We developed a replication-competent vaccine against Lassa virus based on attenuated recombinant vesicular stomatitis virus vectors expressing the Lassa viral glycoprotein. A single intramuscular vaccination of the Lassa vaccine elicited a protective immune response in nonhuman primates against a lethal Lassa virus challenge. Vaccine shedding was not detected in the monkeys, and none of the animals developed fever or other symptoms of illness associated with vaccination. The Lassa vaccine induced strong humoral and cellular immune responses in the four vaccinated and challenged monkeys. Despite a transient Lassa viremia in vaccinated animals 7 d after challenge, the vaccinated animals showed no evidence of clinical disease. In contrast, the two control animals developed severe symptoms including rashes, facial edema, and elevated liver enzymes, and ultimately succumbed to the Lassa infection. CONCLUSION: Our data suggest that the Lassa vaccine candidate based on recombinant vesicular stomatitis virus is safe and highly efficacious in a relevant animal model that faithfully reproduces human disease.

Animals↗
PubMed2006

Lateralization of the human mirror neuron system.

A cortical network consisting of the inferior frontal, rostral inferior parietal, and posterior superior temporal cortices has been implicated in representing actions in the primate brain and is critical to imitation in humans. This neural circuitry may be an evolutionary precursor of neural systems associated with language. However, language is predominantly lateralized to the left hemisphere, whereas the degree of lateralization of the imitation circuitry in humans is unclear. We conducted a functional magnetic resonance imaging study of imitation of finger movements with lateralized stimuli and responses. During imitation, activity in the inferior frontal and rostral inferior parietal cortex, although fairly bilateral, was stronger in the hemisphere ipsilateral to the visual stimulus and response hand. This ipsilateral pattern is at variance with the typical contralateral activity of primary visual and motor areas. Reliably increased signal in the right superior temporal sulcus (STS) was observed for both left-sided and right-sided imitation tasks, although subthreshold activity was also observed in the left STS. Overall, the data indicate that visual and motor components of the human mirror system are not left-lateralized. The left hemisphere superiority for language, then, must be have been favored by other types of language precursors, perhaps auditory or multimodal action representations.

Adolescent↗
PubMed2006

Genetic control of X chromosome inactivation in mice: definition of the Xce candidate interval.

In early mammalian development, one of the two X chromosomes is silenced in each female cell as a result of X chromosome inactivation, the mammalian dosage compensation mechanism. In the mouse epiblast, the choice of which chromosome is inactivated is essentially random, but can be biased by alleles at the X-linked X controlling element (Xce). Although this locus was first described nearly four decades ago, the identity and precise genomic localization of Xce remains elusive. Within the X inactivation center region of the X chromosome, previous linkage disequilibrium studies comparing strains of known Xce genotypes have suggested that Xce is physically distinct from Xist, although this has not yet been established by genetic mapping or progeny testing. In this report, we used quantitative trait locus (QTL) mapping strategies to define the minimal Xce candidate interval. Subsequent analysis of recombinant chromosomes allowed for the establishment of a maximum 1.85-Mb candidate region for the Xce locus. Finally, we use QTL approaches in an effort to identify additional modifiers of the X chromosome choice, as we have previously demonstrated that choice in Xce heterozygous females is significantly influenced by genetic variation present on autosomes (Chadwick and Willard 2005). We did not identify any autosomal loci with significant associations and thus show conclusively that Xce is the only major locus to influence X inactivation patterns in the crosses analyzed. This study provides a foundation for future analyses into the genetic control of X chromosome inactivation and defines a 1.85-Mb interval encompassing all the major elements of the Xce locus.

Alleles↗
PubMed2006

Tandem mass spectrometry program implementation challenges for state newborn screening programs: national survey of barriers and issues.

OBJECTIVE: A national survey was undertaken to identify the barriers faced by states that have already implemented tandem mass spectrometry (MS/MS) screening and those that have not yet done so. METHODS: In April 2004, a 10-question survey was mailed to 106 individuals identified as key newborn screening contacts in each state. The survey requested information on issues that affected the state's ability to expand newborn screening to include MS/MS technology. RESULTS: Representatives from 51 of 53 states/territories responded to the survey. Of the 51 responding states, 32 (63%) said that they are offering MS/MS screening currently. The top 2 issues that most affected the ability of states to add MS/MS screening were difficulty acquiring support within the organization (66%) and funding limitations (63%). The screening criteria that were most difficult to address were knowledge about the natural history of MS/MS-detectable disorders if untreated (37%), the short-term costs of screening and diagnosis (36%), and the long-term follow-up costs (34%). The top-ranked laboratory issues were the high costs of equipment and supplies (53%) and the development of appropriate population-specific cutoff values (41%). The top-ranked follow-up issues were the availability of accepted protocols and guidelines for MS/MS diagnostic evaluations (59%) and the availability of adequate educational materials describing the disorders (44%). CONCLUSIONS: Several of the issues identified can be addressed through improved, more-comprehensive, patient surveillance systems that track patient health status and health services utilization, although other approaches need to be developed. Through a better understanding of these issues and challenges, the community of professionals who are concerned with the quality and scope of newborn screening may be better able to help states develop strategies to overcome these barriers.

Data Collection↗
PubMed2006

California's experience implementing a pilot newborn supplemental screening program using tandem mass spectrometry.

OBJECTIVE: In response to a California legislative mandate, a pilot tandem mass spectrometry (MS/MS) screening program was undertaken by the Genetic Disease Branch of the California Department of Health Services between January 2002 and June 2003. This article outlines the Genetic Disease Branch approach to implementing the MS/MS pilot program and the program evaluation strategies used. METHODS: Through the use of multiple data collection methods, we were able to describe hospital participation patterns, screening test uptake, screening test performance, follow-up services utilization, and provider and family satisfaction with the educational materials and follow-up services provided. RESULTS: During the 18-month pilot program, just more than one half of California's 755,698 newborns were offered MS/MS screening; among this group, 90% of parents chose to have their newborns screened. Fifty-one newborns were identified with MS/MS-detectable disorders, among 461 patients referred for follow-up testing (0.13% of the screened population). One disorder was diagnosed successfully for every 6939 newborns screened and for every 9 infants referred (excluding phenylketonuria). The overall California population prevalence of MS/MS-detectable disorders was 1 case per 6500 infants (excluding phenylketonuria). The positive predictive value for medium-chain acyl-CoA dehydrogenase deficiency was 86.7%, whereas the positive predictive value for short-chain acyl-CoA dehydrogenase deficiency was 21.6%. For a sample from Hawaii, 1 isovaleric aciduria case was detected among 6132 newborns. CONCLUSIONS: Evaluation of the California MS/MS screening pilot program demonstrated that this technology was effective in identifying additional metabolic disorders. The positive predictive value of screening was particularly good for medium-chain acyl-CoA dehydrogenase deficiency. Overall, patient referral rates were very acceptable. The utility of the program was also demonstrated by positive reviews from patients and providers.

California↗
PubMed2002

Effect of telephone follow-up on the physical well-being dimension of quality of life in patients with cancer.

OBJECTIVE: To evaluate the effect of telephone follow-up on the physical well-being dimension of health-related quality of life in patients with cancer. DESIGN: Randomized, controlled trial. SETTING: Public teaching hospital. PATIENTS: One hundred fifty patients with cancer who were discharged to home from the hospital. INTERVENTION: Patients received a telephone follow-up call 48-72 hours after discharge. Information was solicited regarding drug-related (and other) problems. Problems were addressed, and advice and support were given. MEASUREMENTS AND MAIN RESULTS: Analysis of variance revealed no differences in the physical well-being dimension of health-related quality of life between patients who received telephone follow-up and a control group who did not. Sixty-eight percent of the follow-up group and 40% of the control group (p = 0.007) reported having had at least one contact with a health professional. CONCLUSION: One possible explanation for the lack of effect of the intervention is that high-risk patients in the control group received a similar intervention from other health care professionals. We suggest that telephone follow-up be coordinated among health professionals.

Adult↗
PubMed2005

X-inactivation status varies in human embryonic stem cell lines.

Human embryonic stem cells (hESCs) derived from human blastocysts have an apparently unlimited proliferative capacity and can differentiate into ectoderm, mesoderm, and endoderm. As such, hESC lines have enormous potential for use in cell replacement therapies. It must first be demonstrated, however, that hESCs maintain a stable karyotype and phenotype and that gene expression is appropriately regulated. To date, different hESC lines exhibit similar patterns of expression of markers associated with pluripotent cells. However, the evaluation of epigenetic status of hESC lines has only recently been initiated. One example of epigenetic gene regulation is dosage compensation of the X chromosome in mammalian females. This is achieved through an epigenetic event referred to as X-chromosome inactivation (XCI), an event initiated upon cellular differentiation. We provide the first evidence that undifferentiated hESC lines exhibit different patterns of XCI.

Aneuploidy↗
PubMed2004

Effects of porcine zona pellucida immunocontraceptives in zoo felids.

Methods of contraception are necessary for management of zoo felids; however, the most commonly used contraceptive (melengestrol acetate implant) is associated with serious adverse reactions with long-term use. Porcine zona pellucida (pZP) vaccines are promising as contraceptives, but their safety in zoo felids has not been tested. pZP vaccine was administered to 27 female felids representing 10 species, including African lion (Panthera leo), Asian leopard (P. pardus), jaguar (P. onca), tiger (P. tigris), snow leopard (P. uncia), cougar (Felis concolor), Siberian lynx (F. lynx), Canada lynx (F. canadensis), serval (F. serval), and bobcat (F. rufus), in 15 facilities. Over 6 wk, each animal received three i.m. injections of 65 microg pZP with Freund's complete adjuvant (FCA), Freund's incomplete adjuvant, or carbopol as the adjuvant. Behavioral signs of estrus were seen in 14 of the vaccinated felids. An unacceptably high incidence of adverse reactions was seen including injection site swelling, lameness, limb swelling, or abscessation (or all) in five felids after injection with FCA as the initial adjuvant. Adverse behavioral signs, including increased irritability and aggression, were seen in four felids. Six of the felids were assayed for antibodies against pZP during the 12 mo after vaccination; all showed antibody production. Antibody levels appeared to peak 1-4 mo after vaccination began, although elevated antibody levels persisted in two animals for > 12 mo after the first injection. All vaccinated felids were ovariohysterectomized 3-13 mo after vaccination. Folliculogenesis was present in all treated animals, and there was no histopathologic evidence of inflammatory damage to ovaries. Contraceptive efficacy was not specifically evaluated in this study; however, two of the three felids housed with an intact male became pregnant during the study, one of which gave birth to healthy cubs.

Animals↗
PubMed2002

Femoral intramedullary nailing: comparison of fracture-table and manual traction. a prospective, randomized study.

BACKGROUND: The purpose of this study was to compare manual traction and fracture-table traction for the reduction and nailing of femoral shaft fractures. We evaluated the quality of the reduction, operative time, complications, and functional status of the patient. METHODS: Eighty-seven consecutive adult patients with a unilateral fracture of the femoral diaphysis that did not extend into the knee joint or proximal to the lesser trochanter were enrolled in the study. Patients who were transferred to our institution more than forty-eight hours after injury; those with multiple-system injuries, injury to the ipsilateral lower extremity, or pathological fracture; and those who were unable or unwilling to provide consent or to return for follow-up were excluded. Forty-five patients were randomized to manual traction and forty-two, to fracture-table traction; all were treated in the supine position. The number of surgical assistants, operative and fluoroscopy time, complications, functional scores, and other outcomes were recorded. RESULTS: There were no significant differences between the groups with respect to age, gender, Glasgow Coma Score, Injury Severity Score, side or mechanism of injury, fracture type, or time from injury to treatment. Internal malrotation was significantly more common when the fracture table had been used: twelve (29%) of the forty-two femora were internally rotated by >10 compared with three (7%) of the forty-five treated with manual traction (p = 0.007). Total operative time, from the beginning of the patient positioning to the completion of the skin closure, was decreased from a mean of 139 minutes (range, 100 to 212 minutes) when the fracture table was used to a mean of 119 minutes (range, sixty-five to 180 minutes) when manual traction was used (p = 0.033). There was no significant difference between the two treatment groups with regard to the number of assistants per case (mean two; range, zero to three), fluoroscopy time, other complications including femoral shortening or lengthening, or functional status of the patient at one year. CONCLUSIONS: Compared with fracture-table traction with the patient in a supine position, manual traction for intramedullary nailing of isolated fractures of the femoral shaft is an effective technique that decreases operative time and improves the quality of the reduction.

Adolescent↗
PubMed2004

Interferon-beta 1a and SARS coronavirus replication.

A global outbreak of severe acute respiratory syndrome (SARS) caused by a novel coronavirus began in March 2003. The rapid emergence of SARS and the substantial illness and death it caused have made it a critical public health issue. Because no effective treatments are available, an intensive effort is under way to identify and test promising antiviral drugs. Here, we report that recombinant human interferon-beta 1a potently inhibits SARS coronavirus replication in vitro.

Animals↗
PubMed2004

Escherichia coli O157 cluster evaluation.

We investigated a multistate cluster of Escherichia coli O157:H7 isolates; pulsed-field gel electrophoresis subtyping, using a single enzyme, suggested an epidemiologic association. An investigation and additional subtyping, however, did not support the association. Confirmating E. coli O157 clusters with two or more restriction endonucleases is necessary before public health resources are allocated to follow-up investigations.

Adolescent↗
PubMed2005

Late recognition of SARS in nosocomial outbreak, Toronto.

Late recognition of severe acute respiratory syndrome (SARS) was associated with no known SARS contact, hospitalization before the nosocomial outbreak was recognized, symptom onset while hospitalized, wards with SARS clusters, and postoperative status. SARS is difficult to recognize in hospitalized patients with a variety of underlying conditions in the absence of epidemiologic links.

Aged↗
PubMed2006

Response and cardiac toxicity of trastuzumab given in conjunction with weekly paclitaxel after doxorubicin/cyclophosphamide.

BACKGROUND: Adjuvant trastuzumab improves relapse-free survival in HER2-overexpressing breast cancer but is associated with cardiac toxicity. This phase II study was undertaken to determine the neoadjuvant clinical and pathologic response rate and the acute and chronic cardiac toxicity of trastuzumab given with weekly paclitaxel after AC (doxorubicin/cyclophosphamide). PATIENTS AND METHODS: Fifty-two women with newly diagnosed, stage II-IV, HER2-overexpressing breast cancer received AC for 4 cycles, followed by weekly TP (paclitaxel/trastuzumab) for 12 weeks, neoadjuvantly or adjuvantly, followed by 40 weeks of adjuvant trastuzumab. RESULTS: Congestive heart failure occurred in 4% of patients (95% confidence interval [CI], 0.5%-13.2%). Asymptomatic left ventricular ejection fraction (LVEF) decreases to < 50% occurred in 21% of patients (95% CI, 11.1%-34.7%); all but 1 recovered by 1.5 years. Median LVEF decreased progressively during therapy from 65% before therapy (95% CI, 63%-66%) to 62% after AC (95% CI, 59%-64%) and 58% after AC-TP (95% CI, 56%-64%; P < 0.01 for each decrease). The decrease in LVEF persisted 1.5 years after study entry at 57% (95% CI, 54%-60%), although all but 1 of the most severe decreases to < 50% recovered to normal. Clinical response rate among 37 patients treated neoadjuvantly was 86%, and the pathologic complete response rate was 19% (95% CI, 8%-35.2%). Because of withdrawals for toxicity, refractory disease, and patient preference, only 35% of patients completed the entire regimen. CONCLUSION: In this study, the AC-TP regimen resulted in a high clinical but moderate pathologic response rate, and although asymptomatic cardiac systolic dysfunction was common, most of the severe decreases recovered over time.

Adult↗