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Biomedical subjects

Nancy Johnson

Publications and source records attributed to Nancy Johnson.

At least 19 recordsLinked to original sources
PubMed2011

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2007

Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.

BACKGROUND: Primary progressive aphasia (PPA) is a language-based dementia characterized by fluent or nonfluent language disorder as its principal feature. OBJECTIVE: To describe progranulin gene mutations in 2 families with PPA. DESIGN: Report of affected families. SETTING: Academic research. PATIENTS: Two families, PPA1 and PPA3, were studied. Genomic DNA was isolated from 3 of 4 siblings in PPA1, from all 3 siblings in PPA3, and from more than 200 control subjects. MAIN OUTCOME MEASURES: All 12 coding exons of the progranulin gene and the 5" and 3" untranslated regions were amplified by polymerase chain reaction and were sequenced in both directions using relevant primers. RESULTS: Both affected members of PPA1 for whom DNA was available and both affected sisters of PPA3 had a progranulin gene mutation not found in the unaffected siblings or in the controls. The mutations likely cause a null allele and a reduction in the level of functional progranulin protein. Both affected members of PPA1 with autopsies had frontotemporal lobar degeneration with tau-negative ubiquinated inclusions. CONCLUSIONS: To our knowledge, these are the only known families in which affected members display phenotypical homogeneity for PPA in the initial stages of the disease. In both families, the disease segregated with progranulin gene mutations. Whether progranulin dysfunction also extends to sporadic PPA and how it affects the initial anatomical specificity of neurodegeneration remain to be determined.

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PubMed2006

Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.

Null mutations in the progranulin gene (PGRN) were recently reported to cause tau-negative frontotemporal dementia linked to chromosome 17. We assessed the genetic contribution of PGRN mutations in an extended population of patients with frontotemporal lobar degeneration (FTLD) (N=378). Mutations were identified in 10% of the total FTLD population and 23% of patients with a positive family history. This mutation frequency dropped to 5% when analysis was restricted to an unbiased FTLD subpopulation (N=167) derived from patients referred to Alzheimer's Disease Research Centers (ADRC). Among the ADRC patients, PGRN mutations were equally frequent as mutations in the tau gene (MAPT). We identified 23 different pathogenic PGRN mutations, including a total of 21 nonsense, frameshift and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay. We also observed an unusual splice-site mutation in the exon 1 5' splice site, which leads to loss of the Kozac sequence, and a missense mutation in the hydrophobic core of the PGRN signal peptide. Both mutations revealed novel mechanisms that result in loss of functional PGRN. One mutation, c.1477C>T (p.Arg493X), was detected in eight independently ascertained familial FTLD patients who were shown to share a common extended haplotype over the PGRN genomic region. Clinical examination of patients with PGRN mutations revealed highly variable onset ages with language dysfunction as a common presenting symptom. Neuropathological examination showed FTLD with ubiquitin-positive cytoplasmic and intranuclear inclusions in all PGRN mutation carriers.

Adult↗
PubMed2006

Who let the dogs out? Infection control did: utility of dogs in health care settings and infection control aspects.

Research has substantiated that animals improve human health, both psychologically and physiologically. Therefore, healthcare facilities have begun to implement programs, such as the "Furry Friends Foundation," that bring animals into the facility to improve the quality of life of patients. When implementing these programs, consideration must be given to potential adverse events such as phobias, allergies, and particularly the possibility of zoonotic disease transmission. Santa Clara Valley Medical Centre (SCVMC), a 600-bed county teaching hospital with specialized units (e.g., for burns, rehabilitation, and pediatric care), has implemented programs that incorporate animals into the healthcare setting. This facility allows three categories of dogs to interact with their patients: service dogs, therapy dogs, and pet visitation dogs by the "Furry Friends Foundation." A blurring of the roles of the three categories of dogs occurred when these programs were put into place at SCVMC. The American with Disabilities Act (ADA) states that service animals cannot be prohibited from any area. For example, a "no pet allowed" policy could not apply to these animals. Proof of a person's disability or proof of the service animal's health or training cannot be required. The purpose of this project was to maintain these programs by clarifying the policies regarding animals, specifically dogs, in the healthcare setting. This had to take place to provide a safe and enjoyable environment for the patients and the staff. A comprehensive table was developed to delineate the three categories of dogs and the corresponding policies. Therapy dogs and the visitation animals are more restricted than service dogs. Both therapy dogs and visitation dogs require identification and certification of health and are excluded from certain areas of the facility, including intensive care units and isolation rooms. By complying with the current policies and regulations, the risks from these programs can be minimized. Staff should be educated on the proper terminology and procedures to prevent a blurring of the categories and roles of these animals.

Animals↗
PubMed2006

Vasectomy in men with primary progressive aphasia.

OBJECTIVE: To study the frequency of vasectomy in men with primary progressive aphasia (PPA). BACKGROUND: PPA is a dementia syndrome in which aphasia emerges in relative isolation during the initial stages of illness. On the basis of a clinical observation in a patient who dated the onset of symptoms to the period after a vasectomy, and because of the curious sharing of the tau protein exclusively by brain and sperm, vasectomy rates were examined in men with PPA. METHOD: This study used a case control design. Forty-seven men with PPA and 57 men with no cognitive impairment (NC) between 55 and 80 years of age were surveyed about a history of vasectomy. RESULTS: The age-adjusted rate of vasectomy in PPA patients (40%) was higher than in NC (16%, P=0.02). There was a younger age at onset for the patients with vasectomy (58.8 vs. 62.9 y, P=0.03). CONCLUSIONS: Vasectomy may constitute one risk factor for PPA in men. Potential mechanisms mediating risk include vasectomy-induced immune responses to sperm, which shares antigenic epitopes with brain. Antisperm antibodies can also develop in women and become risk factors for PPA.

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PubMed2006

Mechanical esophageal deflection during ablation of atrial fibrillation.

To prevent esophageal damage during ablation of atrial fibrillation, we developed a technique to move the esophagus away from a desired ablation site too close to the esophagus. Under fluoroscopy, a transesophageal echocardiography probe was used to deflect the barium-opacified esophagus from the ablation site. This technique was successfully employed in three patients where critical sites of the posterior left atrial wall were very close to the esophagus.

Atrial Fibrillation↗
PubMed2005

Paradoxical features of word finding difficulty in primary progressive aphasia.

Impaired word retrieval is a main symptom of primary progressive aphasia (PPA). The cognitive features of this impairment in PPA are poorly understood. We studied 12 patients with PPA (6 English-speaking and 6 Dutch-speaking), 7 patients with early-stage clinically probable Alzheimer's disease (PRAD), 5 patients with mild cognitive impairment (MCI), and 15 age-matched, cognitively intact, control subjects. Subjects had to name a picture (the probe), which was preceded by a written word (the prime) that could be the correct name of the picture, a noun belonging to the same semantic subcategory (related prime), a semantically unrelated noun (unrelated prime), or a pseudoword (neutral control). Naming latencies were longer in PPA and PRAD patients than in control subjects. Critically, the interaction between group and prime type was highly significant. PPA patients named the probe more slowly after a related compared with an unrelated prime. In contrast, PRAD patients, mild cognitive impairment patients, and healthy control subjects tended to name the probe faster when it was preceded by a related prime. The semantic interference effect in PPA generalized across languages and PPA subtypes. Selection among competing word forms sharing a same semantic field is abnormal in PPA. The semantic interference effect constitutes a positive distinguishing feature between PPA and PRAD.

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PubMed2005

Prion protein codon 129 genotype prevalence is altered in primary progressive aphasia.

The prion protein (PrP) is central to the prion diseases, although a role in other neurodegenerative diseases has been postulated. A common polymorphism (Met or Val) at codon 129 of the PrP gene (PRNP) features prominently in the risk and phenotype, of prion disease, and an abnormality in its distribution frequency may signal a role for PrP in other diseases. We conducted a case-control study to compare the PRNP codon 129 genotype distribution in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and primary progressive aphasia (PPA), including 281 AD, 256 ALS, 39 PPA, and 415 healthy control subjects. Statistical analysis was applied to determine the presence or absence of disease-specific genotype associations. The distribution of codon 129 genotypes was similar among healthy control, AD, and ALS subjects, although the heterozygous state was significantly overrepresented (age-adjusted odds ratio, 8.47) in PPA, a rare condition of unknown cause. Although these findings do not entirely exclude a role for PrP in AD or ALS, they do not support the codon 129 genotype as a risk factor for either disease. However, the strong association between heterozygosity and PPA raises new questions about its cause and the role of PrP in other neurodegenerative diseases.

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PubMed2004

Many P-element insertions affect wing shape in Drosophila melanogaster.

A screen of random, autosomal, homozygous-viable P-element insertions in D. melanogaster found small effects on wing shape in 11 of 50 lines. The effects were due to single insertions and remained stable and significant for over 5 years, in repeated, high-resolution measurements. All 11 insertions were within or near protein-coding transcription units, none of which were previously known to affect wing shape. Many sites in the genome can affect wing shape.

Animals↗
PubMed2004

Dementia-like presentation of striatal hypermetabolic state with antistriatal antibodies responsive to steroids.

BACKGROUND: Hypermetabolic lesions of the striatum are rare. They usually involve autoimmunity and are associated with choreatic disorders such as Sydenham chorea, lupus, and the antiphospholipid antibody syndrome. PATIENT: A 48-year-old woman was initially seen with a 1-year history of progressive changes in personality and attention. There were minor associated involuntary movements. Negative routine investigation results, including regular autoimmune serologies and magnetic resonance imaging, led to the diagnosis of a frontal dementia. Positron emission tomographic results demonstrated hypermetabolism in the left striatum. Western blot technique results demonstrated plasma antistriatal antibodies. Treatment with corticosteroids induced a resolution of her attentional deficits and a return of her personality to its premorbid state. The repeated positron emission tomographic scan results were near normal, and the titer of antistriatal antibodies was significantly reduced. CONCLUSION: Autoimmune striatal dysfunction can initially appear with a clinical picture suggestive of a degenerative dementia. Recognition of the underlying etiology and treatment was possible because of abnormalities uncovered on positron emission tomographic images.

Adrenal Cortex Hormones↗
PubMed2004

Streptococcus bovis septic shock due to contaminated transfused platelets.

Although most physicians and the public are primarily concerned about the risk of transmitting human immunodeficiency virus (HIV) or hepatitis virus during a platelet transfusion, bacterial contamination is actually the most common infectious complication. Unlike red blood cells, platelets are stored at room temperature (20-24 degrees C), which raises the risk of bacterial proliferation. The risk of bacterial sepsis is 2.5-fold higher for each unit of transfused platelets compared to each unit of red blood cells. We report an unusual case of Streptococcus bovis septic shock associated with a contaminated platelet transfusion.

Adult↗
PubMed2004

Preservation of reasoning in primary progressive aphasia: further differentiation from Alzheimer's disease and the behavioral presentation of frontotemporal dementia.

Primary Progressive Aphasia (PPA) is a clinical dementia syndrome characterized by the gradual dissolution of language without impairment of other cognitive domains for at least the first 2 years of illness (M.-M. Mesulam, 1982, 2001). It is difficult to demonstrate the integrity of nonlanguage domains in PPA because most neuropsychological tests of memory, reasoning, and attention require language competence for their performance. In the present study, reasoning and cognitive flexibility were tested nonverbally in patients with PPA using a modified ten-item version of the Visual Verbal Test (Feldman & Drasgow, 1959). This test measures the ability to detect similarities among objects and to sort a single set of objects according to two different principles. The performance of PPA patients (n = 20) was compared with that of patients with dementia of the Alzheimer type (AD) (n = 20), patients with the comportmental/executive dysfunction variant of frontotemporal dementia (FTD) (n = 16), and cognitively intact controls (n = 20). Patients with PPA and controls performed similarly, detecting commonalities among objects and shifting from one sorting principle to another. In contrast, both AD and FTD subjects were significantly impaired on both measures. These results provide evidence of preserved reasoning in PPA, further differentiating this syndrome from other behaviorally focal dementia syndromes.

Aged↗
PubMed2003

The use of daclizumab, tacrolimus and mycophenolate mofetil in african-american and Hispanic first renal transplant recipients.

Limited data are available on the use of tacrolimus and mycophenolate mofetil in conjunction with anti-IL-2 receptor antibody, in groups of kidney transplant recipients considered to be at higher risk. This study compared the incidence of acute rejection between African-American (AA), Hispanic (H), and non-African-American, non-Hispanics (non-AA, non-H) first renal transplant recipients. We studied 233 sequential first renal transplants. Of the 233, 37 recipients (16%) were AA, 85 (36.5%) were H and 111 (47.5%) were non-AA, non-H. All received daclizumab induction therapy (1 mg/kg) on the day of surgery, and every other week for a total of 5 doses, as well as mycophenolate mofetil, tacrolimus, and steroids. At 1 year, patient and graft survival were 97% and 95% in AA, 98% and 98% in H, and 96% and 95% in non-AA, non-H, respectively (not statistically different). Biopsy-proven acute rejection episodes were 8.1% in AA, 4.7% in H, and 4.5% in non-AA, non-H (also not statistically different). This immunosuppressive protocol appears to be safe and effective in helping to minimize biopsy-proven acute rejection and optimize renal allograft survival in African-American and Hispanic renal transplant recipients in the first year post transplantation.

Adult↗
PubMed2002

A holistic look at minimizing adverse environmental impact under Section 316(b) of the Clean Water Act.

Section 316(b) of the Clean Water Act (CWA) requires that "the location, design, construction, and capacity of cooling water intake structures reflect the best technology available for minimizing adverse environmental impact." As the U.S. Environmental Protection Agency (EPA) develops new regulations to implement Section 316(b), much of the debate has centered on adverse impingement and entrainment impacts of cooling-water intake structures. Depending on the specific location and intake layout, once-through cooling systems withdrawing many millions of gallons of water per day can, to a varying degree, harm fish and other aquatic organisms in the water bodies from which the cooling water is withdrawn. Therefore, opponents of once-through cooling systems have encouraged the EPA to require wet or dry cooling tower systems as the best technology available (BTA), without considering site-specific conditions. However, within the context of the broader scope of the CWA mandate, this focus seems too narrow. Therefore, this article examines the phrase "minimizing adverse environmental impact" in a holistic light. Emphasis is placed on the analysis of the terms "environmental" and "minimizing." Congress chose "environmental" in lieu of other more narrowly focused terms like "impingement and entrainment," "water quality," or "aquatic life." In this light, BTA for cooling-water intake structures must minimize the entire suite of environmental impacts, as opposed to just those associated with impingement and entrainment. Wet and dry cooling tower systems work well to minimize entrainment and impingement, but they introduce other equally important impacts because they impose an energy penalty on the power output of the generating unit. The energy penalty results from a reduction in plant operating efficiency and an increase in internal power consumption. As a consequence of the energy penalty, power companies must generate additional electricity to achieve the same net output. This added production leads to additional environmental impacts associated with extraction and processing of the fuel, air emissions from burning the fuel, and additional evaporation of freshwater supplies during the cooling process. Wet towers also require the use of toxic biocides that are subsequently discharged or disposed. The other term under consideration, "minimizing," does not equal "eliminating." Technologies may be available to minimize but not totally eliminate adverse environmental impacts.

Air Pollution↗
PubMed2002

Formation in vitro of hybrid dimers of H463F and Y74F mutant Escherichia coli tryptophan indole-lyase rescues activity with L-tryptophan.

Y74F and H463F mutant forms of Escherichia coli tryptophan indole-lyase (Trpase) have been prepared. These mutant proteins have very low activity with L-Trp as substrate (kcat and kcat/Km values less than 0.1% of wild-type Trpase). In contrast, these mutant enzymes exhibit much higher activity with S-(o-nitrophenyl)-L-cysteine and S-ethyl-L-cysteine (kcat/Km values about 1-50% of wild-type Trpase). Thus, Tyr-74 and His-463 are important for the substrate specificity of Trpase for L-Trp. H463F Trpase is not inhibited by a potent inhibitor of wild-type Trpase, oxindolyl-L-alanine, and does not exhibit the pK(a) of 6.0 seen in previous pH dependence studies [Kiick, D. M., and Phillips, R. S. (1988) Biochemistry 27, 7333]. These results suggest that His-463 may be the catalytic base with a pK(a) of 6.0 and Tyr-74 may be a general acid catalyst for the elimination step, as we found previously with tyrosine phenol-lyase [Chen, H., Demidkina, T. V., and Phillips, R. S. (1995) Biochemistry 34, 12776]. H463F Trpase reacts with L-Trp and S-ethyl-L-cysteine in rapid-scanning stopped-flow experiments to form equilibrating mixtures of external aldimine and quinonoid intermediates, similar to those observed with wild-type Trpase. In contrast to the results with wild-type Trpase, the addition of benzimidazole to reactions of H463F Trpase with L-Trp does not result in the formation of an aminoacrylate intermediate. However, addition of benzimidazole with S-ethyl-L-cysteine results in the formation of an aminoacrylate intermediate, with lambda(max) at 345 nm, as was seen previously with wild-type Trpase [Phillips, R. S. (1991) Biochemistry 30, 5927]. This suggests that His-463 plays a specific role in the elimination step of the reaction of L-Trp. Refolding of equimolar mixtures of H463F and Y74F Trpase after unfolding in 4 M guanidine hydrochloride results in a dramatic increase in activity with L-Trp, indicating the formation of a hybrid H463F/Y74F dimer with one normal active site.

Dimerization↗
PubMed2002

Warfarin dose adjustments based on CYP2C9 genetic polymorphisms.

BACKGROUND: The dose response relationship of warfarin is unpredictable. Polymorphism of the Cytochrome P4502C9 enzyme leads to warfarin hypersensitivity presumably due to decreased metabolism of the S-enantiomer. The purpose of this study was to further characterize the relationship between CYP2C9 genotype and phenotype and to develop a basis for guidelines to interpret CYP2C9 genotype for warfarin dosing. METHODS AND RESULTS: Patients stabilized on warfarin therapy were recruited from an anticoagulation clinic. Patients were genotyped for CYP2C9*2, CYP2C9*3 and CYP2C9*5 alleles by standard methods of polymerase chain reaction amplification and restriction endonuclease digestion. Phenotype was determined by; dose (mg/kg/d) required to maintain anticoagulation, (INR 2.0-3.0), oral plasma S-warfarin clearance, and the plasma S:R-warfarin ratio. In this cohort, no subjects were found to have the CYP2C9*5 allele. The plasma S-warfarin concentration did not differ with age, dose or CYP2C9 genotype. Both CYP2C9*2 and *3 alleles were associated with lower maintenance dosages, lower total and R-warfarin plasma concentrations, decreased oral clearance of S-warfarin, increased plasma S:R-warfarin ratio and extended S-warfarin elimination half-life. Advancing age was found to decrease Warfarin maintenance dose in subjects with the common active CYP2C9*1/*1 genotype but did not influence dose requirement of subjects with one or more variant CYP2C9 alleles. CONCLUSIONS: Subjects who have been titrated to a consistent target INR demonstrate comparable plasma S-warfarin concentrations independent of CYP2C9 genotype. The warfarin dose required to maintain a consistent target INR between subjects differs as a function of S-warfarin clearance which is decreased by both CYP2C9*2 and or CYP2C9*3 variant alleles. The variables of CYP2C9 genotype and age can be applied to restrict the dosage range considered for individual patients.

Adult↗
PubMedDate not supplied

Word list versus story memory in Alzheimer disease and frontotemporal dementia.

Memory impairment, characterized by a pattern of rapid forgetting, is the hallmark deficit in Alzheimer's disease (AD). Memory deficits have also been reported in frontotemporal dementia (FTD), and are thought to reflect diminished organizational and attentional abilities leading to a pattern of decreased acquisition of new information. The present study compared patients with AD, the behavioral variant of FTD, and cognitively intact elderly control subjects on two types of memory tests: story memory and word list recall. The percent of information recalled immediately (encoded), after a delay, and the percent retention between these conditions was calculated for both tests. The results showed that FTD patients encoded and recalled more information from the story than AD patients. No difference was found between FTD and AD patients for encoding of the word list. However, FTD patients recalled more words after a delay than AD patients. Percent retention on both tasks was also greater for the FTD group. The results suggest that patterns of performance on different tests of memory, and, in particular, measures of retention, can be useful in differentiating memory impairment in AD from that of FTD on cognitive testing.

Aged↗