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Philip J Boyer

Publications and source records attributed to Philip J Boyer.

13 recordsLinked to original sources
PubMed2006

Is ferroportin-hepcidin signaling altered in restless legs syndrome?

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.

Age of Onset↗
PubMed2006

Abeta42 gene vaccination reduces brain amyloid plaque burden in transgenic mice.

OBJECTIVE: To demonstrate that in APPswe/PS1DeltaE9 transgenic mice, gene gun mediated Abeta42 gene vaccination elicits a high titer of anti-Abeta42 antibodies causal of a significant reduction of Abeta42 deposition in brain. METHODS: Gene gun immunization is conducted with transgenic mice using the Abeta42 gene in a bacterial plasmid with the pSP72-E3L-Abeta42 construct. Enzyme-linked immunoabsorbent assays (ELISA) and Western blots are used to monitor anti-Abeta42 antibody levels in serum and Abeta42 levels in brain tissues. Enzyme-linked immunospot (ELISPOT) assays are used for detection of peripheral blood T cells to release gamma-interferon. Immunofluorescence detection of Abeta42 plaques and quantification of amyloid burden of brain tissue were measured and sections were analyzed with Image J (NIH) software. RESULTS: Gene gun vaccination with the Abeta42 gene resulted in high titers of anti-Abeta42 antibody production of the Th2-type. Levels of Abeta42 in treated transgenic mouse brain were reduced by 60-77.5%. The Mann-Whitney U-test P=0.0286. INTERPRETATION: We have developed a gene gun mediated Abeta42 gene vaccination method that is efficient to break host Abeta42 tolerance without using adjuvant and induces a Th2 immune response. Abeta42 gene vaccination significantly reduces the Abeta42 burden of the brain in treated APPswe/PS1DeltaE9 transgenic mice with no overlap between treated and control mice.

Alzheimer Disease↗
PubMed2006

Nephrogenic systemic fibrosis: an update.

Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an emerging systemic fibrosing disorder that develops in the setting of renal insufficiency. Since its recognition in 1997, several case reports of NSF have been published in the rheumatology literature, reflecting the increasing incidence and recognition of this disorder in the United States and abroad. As rheumatology professionals are commonly the first to encounter newly developing cases, it is imperative that they recognize the symptoms and comorbidities of NSF and initiate work-up and treatment. To date, the precise causes of NSF have not been established; however, several promising lines of inquiry have led to a new model of the disorder. This model speculates that circulating fibrocytes of bone marrow origin are aberrantly recruited to the skin and other systemic sites by a process likely triggered or exacerbated by endothelial damage.

Diagnosis, Differential↗
PubMed2006

Differential expression of genes in amyotrophic lateral sclerosis revealed by profiling the post mortem cortex.

The possible causes of ALS are unknown and multiple biological systems have been implicated. The goal of this study was to use gene expression profiling to evaluate a broad spectrum of systems in ALS. For this study, the medial lip of the human motor cortex and adjacent sensory cortex were collected at autopsy from five ALS patients and three normal individuals. Quantitative filter analysis revealed differential expression of mRNAs normalized to internal standards. A significant difference in expression of 275 genes was found in the ALS motor cortex; of the genes whose expression was changed, 10 were up-regulated and 265 were down-regulated. Six of the up-regulated genes were associated with cell surface activity and two were glutamate receptors; the latter is potentially consistent with the idea of excitotoxicity contributing to neurodegeneration in ALS. Of the down-regulated genes, the largest number were associated with transcription followed by those involved in antioxidant systems, inflammation, regulation of motor neuron function, lipid metabolism, protease inhibition, and protection against apoptosis including vascular endothelial growth factor. There were no significant differences in gene expression patterns between the sensory and motor cortex in the ALS brains. A total of 10% of the genes identified by microarray were chosen from each of the gene groups for validation by quantitative real time PCR (QRT-PCR). In order to increase the reliability of our gene array data, newly acquired motor and sensory cortex of ALS and control cases (n = 4 each) were used for validation. Of these, 86.4% changed in the same direction as determined in the microarrays. The gene profile data reported here are consistent with evidence that the ALS brain is characterized by an environment that is permissive for apoptosis, excitotoxicity and abnormal ubiquitination. This gene array study also suggested that a metal imbalance particularly for zinc could exist in ALS. Finally, given the amount of cellular stress that is thought to be part of the pathogenesis in ALS, there was a notable lack of increase in genes required to mount a protective response. This latter observation provides a conceptual framework in which to consider the possibility that ALS could result from a failure to mount adequate protective responses to physiological insults that, left unchecked, could progress to neurodegeneration.

Aged↗
PubMed2006

Novel ubiquitin neuropathology in frontotemporal dementia with valosin-containing protein gene mutations.

Frontotemporal dementia (FTD) with inclusion body myopathy and Paget disease of bone (IBMPFD) is a rare, autosomal-dominant disorder caused by mutations in the valosin-containing protein (VCP) gene, a member of the AAA-ATPase gene superfamily. The neuropathology associated with sporadic FTD is heterogeneous and includes tauopathies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U). However, there is limited information on the neuropathology in IBMPFD. We performed a detailed, systematic analysis of the neuropathologic changes in 8 patients with VCP mutations. A novel pattern of ubiquitin pathology was identified in IBMPFD that was distinct from sporadic and familial FTLD-U without VCP gene mutations. This was characterized by ubiquitin-positive neuronal intranuclear inclusions and dystrophic neurites. In contrast to FTLD-U, only rare intracytoplasmic inclusions were identified. The ubiquitin pathology was abundant in the neocortex, less robust in limbic and subcortical nuclei, and absent in the dentate gyrus. Only rare inclusions were detected with antibodies to VCP and there was no biochemical alteration in the VCP protein. VCP is associated with a variety of cellular activities, including regulation of the ubiquitin-proteasome system. Our findings are consistent with the hypothesis that the pathology associated with VCP gene mutations is the result of impairment of ubiquitin-based degradation pathways.

Adenosine Triphosphatases↗
PubMed2004

Gene vaccination to bias the immune response to amyloid-beta peptide as therapy for Alzheimer disease.

BACKGROUND: The amyloid-beta (Abeta) peptide has a central role in the neurodegeneration of Alzheimer disease (AD). Immunization of AD transgenic mice with Abeta(1-42) (Abeta(42)) peptide reduces both the spatial memory impairments and AD-like neuropathologic changes in these mice. Therapeutic immunization with Abeta in patients with AD was shown to be effective in reducing Abeta deposition, but studies were discontinued owing to the development of an autoimmune, cell-mediated meningoencephalitis. We hypothesized that gene vaccination could be used to generate an immune response to Abeta(42) that produced antibody response but avoided an adverse cell-mediated immune effect. OBJECTIVE: To develop an effective genetic immunization approach for treatment and prevention of AD without causing an autoimmune, cell-mediated meningoencephalitis. METHODS: Mice were vaccinated with a plasmid that encodes Abeta(42), administered by gene gun. The immune response of the mice to Abeta(42) was monitored by measurement of (1) antibody levels by enzyme-linked immunosorbent assay (ELISA) and Western blot and (2) Abeta(42)-specific T-cell response as measured by interferon-gamma enzyme-linked immunospot (ELISPOT) assay. RESULTS: Gene-gun delivery of the mouse Abeta(42) dimer gene induced significant humoral immune responses in BALB/c wild-type mice after 3 vaccinations in 10-day intervals. All 3 mice in the treated group showed significant humoral immune responses. The ELISPOT assay for interferon-gamma release with mouse Abeta(42) peptide and Abeta(9-18) showed no evident cytotoxic T-lymphocyte response. We further tested the responses of wild-type BALB/c mice to the monomer Abeta(42) gene vaccine. Western blot evaluation showed both human and mouse Abeta monomer gene vaccine elicited detectable humoral immune responses. We also introduced the human Abeta(42) monomer gene vaccine into AD double transgenic mice APPswe/PSEN1(A246E). Mice were vaccinated with plasmids that encode Abeta(1-42) and Abeta(1-16), or with plasmid without the Abeta gene. Treated mice showed significant humoral immune responses as demonstrated by ELISA and by Western blot. These mice also showed no significant cellular immune response as tested by ELISPOT. One of the treated mice was killed at 7 months of age for histological observations, and scattered amyloid plaques were noted in all layers of the cerebral cortex and in the hippocampus in both Abeta(42)- and control-vaccinated mice. No definite difference was discerned between the experimental and control animals. CONCLUSIONS: Gene-gun-administered genetic immunization with the Abeta(42) gene in wild-type BALB/c and AD transgenic mice can effectively elicit humoral immune responses without a significant T-cell-mediated immune response to the Abeta peptide. This immunotherapeutic approach could provide an alternative active immunization method for therapy and prevention of AD.

Alzheimer Disease↗
PubMed2004

Granular cell tumor: immunohistochemical assessment of inhibin-alpha, protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation.

CONTEXT: Granular cell tumor (GCT) is a rare tumor of nerve sheath origin with a predilection for upper aerodigestive tract, skin, and soft tissue. The neoplastic cells typically express S100 and CD68 (KP-1), the latter due to cytoplasmic lysosome content. However, the histogenesis of this tumor is unknown. Additionally, distinction between benign and malignant GCT is difficult because of histologic similarity and lack of reliable criteria that can predict clinical behavior. OBJECTIVE: To perform a comparative, side-by-side immunohistochemical assessment of the traditional immunohistochemical markers for GCTs (S100, CD68), along with the newer markers (inhibin-alpha, protein gene product 9.5) for these tumors. DESIGN: To address diagnostic and prognostic issues, we studied 30 specimens of GCT (27 primary and 3 recurrent tumors, 2 of which occurred consecutively in the same patient) for (1) nuclear pleomorphism, prominent nucleoli, necrosis, spindling, high nuclear-cytoplasmic ratio, and mitoses; (2) immunohistochemical expression of inhibin-alpha, protein gene product 9.5, S100, CD68 (KP-1), and Ki-67 using the avidin-biotin complex method on formalin-fixed, paraffin-embedded sections; and (3) correlation between tumor grade, proliferative fraction, and clinical data. RESULTS: Twenty-seven of 27 primary GCTs and 1 of 3 recurrent GCTs had typical histologic features, while the 2 consecutive recurrent GCT specimens from the same patient were atypical (moderate nuclear atypia and prominent nucleoli alone). The mean age for primary GCT was 37.3 years (range, 5-67 years), and mean size was 1.89 cm. None of the cases metastasized. All 30 specimens showed diffuse (2+ to 3+) staining for S100, CD68, and inhibin-alpha, and 3+ staining for protein gene product 9.5; pseudoepitheliomatous hyperplasia was nonreactive. The Ki-67 proliferative index was less than 1% to 20% in typical nonrecurrent cases, 1% in the typical recurrent case, and 1% and 10% in 2 sequential recurrences of the atypical case. CONCLUSION: Our study expands the immunophenotype of GCT (S100, CD68, protein gene product 9.5, and inhibin-alpha) regardless of location and supports a neural origin. Intensity of immunohistochemical staining had no prognostic significance. Although 1 of the 2 recurrent GCTs had atypical features, the Ki-67 proliferative index did not distinguish reliably between typical (nonrecurrent) and atypical or recurrent GCTs. The significance of inhibin expression with regard to cell differentiation and pathogenesis is unclear and warrants further investigation.

Adolescent↗
PubMed2003

Muscle biopsy in the evaluation of patients with modestly elevated creatine kinase levels.

The utility of muscle biopsy in patients with modest elevations of serum creatine kinase (CK) level but normal neurological examinations and nondiagnostic electrodiagnostic studies is uncertain. We performed systematic, extensive studies on muscle biopsies of 20 such patients. A definitive diagnosis was arrived at in only 1 by histochemical studies, although 4 others demonstrated minor myopathic changes. Biochemical evaluation led to a diagnosis in an additional 5. Muscle biopsy is useful for evaluating such patients, but extensive studies of the muscle are necessary.

AMP Deaminase↗
PubMed2003

Informatics training in pathology residency programs: proposed learning objectives and skill sets for the new millennium.

CONTEXT: To be successful in tomorrow's health care environment, to make the most appropriate decisions for their laboratories, to optimize training and continuing medical education opportunities, and to advance pathology as a professional specialty, pathologists must possess basic informatics knowledge and proficiency. Traditional areas of anatomic and clinical pathology residency training employ learning objectives, knowledge expectations, and skill sets, but such items have not been as well developed or widely implemented for pathology informatics training. OBJECTIVE: We present a proposal that defines a standard and specific set of learning (knowledge) objectives and skill set (proficiency) expectations for resident training in pathology informatics. DESIGN: The proposal includes a comprehensive and detailed set of knowledge applications and proficiencies that will assist residency programs in developing basic pathology informatics training for residents. The content of the proposal is based on and compiled from existing successful pathology informatics training programs. Learning objectives include those related to general and enterprise computing as well as objectives related specifically to pathology informatics. Skill set expectations include the ability to use software that facilitates and adds value to the work of pathologists, including the use of a laboratory information system and of productivity software and other tools. Other topics include guidelines for evaluating residents' informatics competency, suggestions regarding curriculum structure and implementation, and recommendations for residents' computing infrastructure. CONCLUSION: This proposal provides a foundation for building effective and standard curricula for residency training in pathology informatics. These curricula will be able to meet increasing expectations and needs for pathologists to contribute to clinical information management.

Clinical Competence↗
PubMed2002

Hypothyroid myopathy with a strikingly elevated serum creatine kinase level.

Although serum creatine kinase (CK) levels are frequently modestly elevated in patients with hypothyroid myopathy, elevations in serum CK to the levels usually seen in inflammatory myopathies or dystrophies are rare. We report a patient with progressive proximal weakness and a serum CK level of over 29,000 IU/L, in whom subsequent laboratory evaluation identified profound hypothyroidism. Thyroid hormone replacement therapy resulted in resolution of clinical symptoms and a marked reduction in the serum CK level. Such a high serum CK level in a patient with hypothyroidism underscores the importance of assessing thyroid function in patients with weakness, regardless of serum CK levels, even when systemic symptoms and signs of hypothyroidism are minimal or absent.

Adult↗
PubMed2002

Dural lesions mimicking meningiomas.

Recently, a number of neoplastic and nonneoplastic entities have been reported that radiographically and clinically mimic meningiomas. Because these lesions occur infrequently and may resemble a meningioma during intraoperative analysis, they may not be considered in the differential diagnosis. This review (and case illustrations) considers some of the newly recognized and notable lesions that can mimic meningiomas, including solitary fibrous tumors, gliosarcomas, leiomyosarcomas, hemangiopericytomas, melanocytomas, Hodgkin's disease, plasmacytomas, inflammatory pseudotumors, neurosarcoidosis, plasma cell granulomas, Rosai-Dorfman disease, Castleman's disease, xanthomas, rheumatoid nodules, and tuberculomas. Awareness that these lesions involve the dura may facilitate intraoperative recognition and, in some cases, preclude unnecessary additional surgery.

Adolescent↗
PubMedDate not supplied

Capsaicin-mediated denervation of sensory neurons promotes mammary tumor metastasis to lung and heart.

Capsaicin specifically activates or destroys small diameter nociceptive sensory neurons that contain the capsaicin receptor, also called vanilloid receptor 1. Neurons sensitive to capsaicin mediate inflammatory pain and are important targets for management of chronic pain. These neurons also regulate local tissue homeostasis, inflammation, healing and development, especially under conditions of psychological stress. Stress contributes to increased cancer recurrence and metastasis through as yet undefined mechanisms. Likewise, activity of capsaicin-sensitive neurons is altered by pathological conditions that may lead to metastatic growth (e.g. stress). Therefore, we examined effects of a treatment that induces sensory nerve denervation on breast cancer metastases. Systemic denervation of sensory neurons caused by treatment with 125 mg/kg capsaicin resulted in significantly more lung and cardiac metastases in adult mice injected orthotopically with syngeneic 4T1 mammary carcinoma cells than was observed in vehicle-treated controls. Heart metastases, normally very rare, occurred as pericardial nodules, intra-myocardial nodules, or combined pericardial-myocardial lesions. Since the rate of primary tumor growth was unaffected, effects on metastases appear to be host tissue-specific. Although preliminary, these observations provide one possible explanation for resistance of cardiac tissue to tumor involvement and highlight contributions of host tissue, including sensory neurons, in the efficiency of cancer metastasis.

Animals↗