PubMed Health⌕ Search

Biomedical subjects

Michael L Cunningham

Publications and source records attributed to Michael L Cunningham.

At least 19 recordsLinked to original sources
PubMed2006

Neurodevelopment of children with single suture craniosynostosis: a review.

INTRODUCTION: Rates of neurocognitive risk range from 35-50% of school-aged children with isolated single suture craniosynostosis (SSC). It has been hypothesized that early surgical intervention to release suture fusion reduces risk for increased intracranial pressure (ICP) and the corresponding risk to neurodevelopment. However, studies assessing children with SSC have been inconsistent in finding an association between neurocognitive development, age of surgery, and ICP. REVIEW: SSC produces notable distortion of the cranial vault and underlying brain mass. Although a linear relationship between skull distortion, ICP, and neurocognitive deficits has generally been assumed, recent studies have postulated an interactive process between the skull and developing brain that results in neuroanatomical changes that are not limited to areas directly beneath the fused suture. The specific neuropsychological deficits identified in children with SSC including problems with attention and planning, processing speed, visual spatial skills, language, reading, and spelling may be related to the anatomic differences that persist after correction of suture fusion. CONCLUSIONS: Available literature on neurocognitive development of children with SSC is suggestive of mild but persistent neuropsychological deficits, which become more significant as cognitive demands increase at school age. Anatomical studies of children without SSC are beginning to identify particular groups of brain structures that if disrupted or malformed, may be associated with specific cognitive deficits. Controlled research investigating the relationship between persistent anatomical changes and neurocognitive functioning of school-aged children with SSC is needed.

Adolescent↗
PubMed2006

Hepatocellular proliferation in response to agonists of peroxisome proliferator-activated receptor alpha: a role for Kupffer cells?

BACKGROUND: It has been proposed that PPARalpha agonists stimulate Kupffer cells in rodents which in turn, release mitogenic factors leading to hepatic hyperplasia, and eventually cancer. However, Kupffer cells do not express PPARalpha receptors, and PPARalpha agonists stimulate hepatocellular proliferation in both TNFalpha- and TNFalpha receptor-null mice, casting doubt on the involvement of Kupffer cells in the mitogenic response to PPARalpha agonists. This study was therefore designed to investigate whether the PPARalpha agonist PFOA and the Kupffer cell inhibitor methylpalmitate produce opposing effects on hepatocellular proliferation and Kupffer cell activity in vivo, in a manner that would implicate these cells in the mitogenic effects of PPARalpha agonists. METHODS: Male Sprague-Dawley rats were treated intravenously via the tail vein with methylpalmitate 24 hrs prior to perfluorooctanoic acid (PFOA), and were sacrificed 24 hrs later, one hr after an intraperitoneal injection of bromodeoxyuridine (BrdU). Sera were analyzed for TNFalpha and IL-1beta. Liver sections were stained immunohistochemically and quantified for BrdU incorporated into DNA. RESULTS: Data show that PFOA remarkably stimulated hepatocellular proliferation in the absence of significant changes in the serum levels of either TNFalpha or IL-1beta. In addition, methylpalmitate did not alter the levels of these mitogens in PFOA-treated animals, despite the fact that it significantly blocked the hepatocellular proliferative effect of PFOA. Correlation between hepatocellular proliferation and serum levels of TNFalpha or IL-1beta was extremely poor. CONCLUSION: It is unlikely that mechanisms involving Kupffer cells play an eminent role in the hepatic hyperplasia, and consequently hepatocarcinogenicity attributed to PPARalpha agonists. This conclusion is based on the above mentioned published data and the current findings showing animals treated with PFOA alone or in combination with methylpalmitate to have similar levels of serum TNFalpha and IL-1beta, which are reliable indicators of Kupffer cell activity, despite a remarkable difference in hepatocellular proliferation.

Journal Article↗
PubMed2006

Sustained formation of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone radical adducts in mouse liver by peroxisome proliferators is dependent upon peroxisome proliferator-activated receptor-alpha, but not NADPH oxidase.

Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)alpha. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47phox-null) and PPARalpha-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPARalpha-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47phox-nulls was similar to that of wild-type mice. These results show that PPARalpha, not NADPH oxidase, is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver.

Animals↗
PubMed2006

Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are known to play a critical role in a variety of fundamental processes, including wound healing, angiogenesis, and development of multiple organ systems. Mutations in the FGFR gene family have been linked to a series of syndromes (the craniosynostosis syndromes) whose primary phenotype involves aberrant development of the craniofacial skeleton. Craniosynostosis syndrome-linked FGFR mutations have been shown to be gain of function in terms of receptor activation and have been presumed to result in increased levels of FGF/FGFR signaling. Unfortunately, studies attempting to link expression of mutant FGFRs with changes in cellular phenotype have yielded conflicting results. In an effort to better understand the biochemical consequences of these mutations on receptor function, here we have investigated the effect of the FGFR2C278F mutation of Crouzon craniosynostosis syndrome on receptor trafficking, ubiquitination, degradation, and signaling. We find that FGFR2C278F exhibits diminished glycosylation, increased degradation, and limited cellular sublocalization in the osteoblastic cell line, MC3T3E1(C4). Additionally, we show that trafficking and autoactivation of wild type FGFR2 is glycosylation-dependent. Both FGFR2C278F and unglycosylated wild type FGFR2 signal through phospholipase Cgamma in a ligand-independent manner as well as exhibit dramatically increased binding to the adaptor protein, Frs2. These findings suggest that autoactive FGFR2 can signal from intracellular compartments. Based upon our results, we propose that the functional signaling of craniosynostosis mutant, autoactive receptors is limited in some cell types by protective cellular responses, such as increased trafficking to lysosomes and proteasomes for degradation.

Animals↗
PubMed2006

Phenotypic anchoring of acetaminophen-induced oxidative stress with gene expression profiles in rat liver.

Toxicogenomics provides the ability to examine in greater detail the underlying molecular events that precede and accompany toxicity, thus allowing prediction of adverse events at much earlier times compared to classical toxicological end points. Acetaminophen (APAP) is a pharmaceutical that has similar metabolic and toxic responses in rodents and humans. Recent gene expression profiling studies with APAP found an oxidative stress signature at a subtoxic dose that we hypothesized can be phenotypically anchored to conventional biomarkers of oxidative stress. Liver tissue was obtained from experimental animals used to generate microarray data, where male rats were given APAP at subtoxic (150 mg/kg) or overtly toxic (1500 and 2000 mg/kg) doses and sacrificed at 6, 24, or 48 h. Oxidative stress in liver was evaluated by a diverse panel of markers that included assessing expression of base excision repair (BER) genes, quantifying oxidative lesions in genomic DNA, and evaluating protein and lipid oxidation. A subtoxic dose of APAP produced significant accumulation of nitrotyrosine protein adducts. Both subtoxic and toxic doses caused a significant increase in 8-hydroxy-deoxyguanosine (8-OH-dG) as well as a significant decrease in glutathione (GSH) content. Only toxic doses of APAP significantly induced expression levels of BER genes. None of the doses examined resulted in a significant increase in the number of abasic sites or in the amount of lipid peroxidation. The accumulation of nitrotyrosine and 8-OH-dG adducts along with reduced GSH content in the liver phenotypically anchors the oxidative stress gene expression signature observed with a subtoxic dose of APAP, lending support to the validity of gene expression studies as a sensitive and biologically meaningful end point in toxicology.

Acetaminophen↗
PubMed2006

Lymphocytopenia in children with lymphatic malformation.

OBJECTIVE: To determine whether an immunologic abnormality exists in patients with lymphatic malformation (LM). DESIGN: Retrospective case series. SETTING: Tertiary care pediatric hospital. PATIENTS: Twenty-one consecutive patients (11 male and 10 female) undergoing LM treatment. INTERVENTIONS: Clinical data (ie, age, clinical LM stage, radiographic appearance, and histologic findings) were correlated with complete blood cell count and detailed lymphocyte differential. Complete blood cell counts and lymphocyte subsets were measured in 21 and 18 patients, respectively. RESULTS: The average age at the time of testing was 67 months (range, 1-231 months). The patients were categorized according to LM stage, including 4 (19%) with stage 1, 4 (19%) with stage 2, 4 (19%) with stage 3, 7 (33%) with stage 4, and 2 (10%) with stage 5 disease. Radiographic LM appearance was macrocystic in 6 patients (29%), mixed macrocystic and microcystic in 8 (38%), and microcystic in 7 (33%). Complete blood cell count data demonstrated lymphocytopenia in 6 patients (29%). The results of the lymphocyte subset tests showed concomitant T-, B-, and natural killer (NK)-cell deficiency in 6 (33%) of 18 patients. All 6 patients with T-cell lymphocytopenia had normal neutrophil and platelet counts. Spearman rank and chi(2) analyses showed that LM stage 4 or 5 and microcystic LM were significantly associated with lymphocytopenia (P = .002 and P = .008, respectively). Histologic analysis did not demonstrate increased lymphocytes in any LM specimens. CONCLUSION: We found T, B, and NK lymphocytopenia in patients with large bilateral or microcystic LM. Although the relationship between lymphocytopenia and infection was not addressed in this study, the recognition of lymphocytopenia in patients with LM may have important clinical and prognostic implications.

Adolescent↗
PubMed2006

Cleidocranial dysplasia with severe parietal bone dysplasia: C-terminal RUNX2 mutations.

BACKGROUND: Cleidocranial dysplasia (CCD) is an autosomal-dominant skeletal dysplasia syndrome that is characterized by widely patent calvarial sutures, clavicular hypoplasia, supernumerary teeth, and short stature. CCD is caused by mutations in the transcription factor RUNX2, which is known to function as a major regulator of bone differentiation. Despite the characterization of 67 unique mutations in 97 individual cases, and the availability of animal models, no obvious genotype-phenotype correlation has emerged. METHODS: We describe 3 new cases that were ascertained on the basis of a severe calvarial phenotype, that were associated with 3 novel mutations in the C-terminal region of RUNX2 distal to the DNA-binding runt domain. In addition, a review of all previously described cases was undertaken in an effort to standardize mutation nomenclature, characterize the position of known mutations relative to the runt domain, and explore the hypothesis that C-terminal mutations that preserve the runt domain may lead to more-severe craniofacial phenotypes. RESULTS: Upon mutational analysis of RUNX2, we identified either frameshift or splice-site mutations that affect the C-terminal region of the resultant protein distal to the runt domain. CONCLUSIONS: In the context of previously described mutations, these cases suggest that C-terminal mutations that preserve the DNA-binding runt domain while disrupting the SMAD 1,2,3,5 binding domain and the nuclear matrix targeting signal may be responsible for the severe phenotype observed.

Amino Acid Sequence↗
PubMed2006

Modes of action and species-specific effects of di-(2-ethylhexyl)phthalate in the liver.

The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. DEHP belongs to a class of chemicals known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds that share many (but perhaps not all) biological effects and are characterized as non-genotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called 'peroxisome proliferation' that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)alpha, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARalpha and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARalpha in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolism-related genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained hepatomegaly; (vii) chronic low-level oxidative stress and accumulation of DNA damage; (viii) selective clonal expansion of the initiated cells; (ix) appearance of the pre-neoplastic nodules; (x) development of adenomas and carcinomas.

Animals↗
PubMed2006

Symbolic signatures for deformable shapes.

Recognizing classes of objects from their shape is an unsolved problem in machine vision that entails the ability of a computer system to represent and generalize complex geometrical information on the basis of a finite amount of prior data. A practical approach to this problem is particularly difficult to implement, not only because the shape variability of relevant object classes is generally large, but also because standard sensing devices used to capture the real world only provide a partial view of a scene, so there is partial information pertaining to the objects of interest. In this work, we develop an algorithmic framework for recognizing classes of deformable shapes from range data. The basic idea of our component-based approach is to generalize existing surface representations that have proven effective in recognizing specific 3D objects to the problem of object classes using our newly introduced symbolic-signature representation that is robust to deformations, as opposed to a numeric representation that is often tied to a specific shape. Based on this approach, we present a system that is capable of recognizing and classifying a variety of object shape classes from range data. We demonstrate our system in a series of large-scale experiments that were motivated by specific applications in scene analysis and medical diagnosis.

Algorithms↗
PubMed2006

New scaphocephaly severity indices of sagittal craniosynostosis: a comparative study with cranial index quantifications.

OBJECTIVE: To describe a novel set of scaphocephaly severity indices (SSIs) for predicting and quantifying head- and skull-shape deformity in children diagnosed with isolated sagittal synostosis (ISS) and compare their sensitivity and specificity with those of the traditional cranial index (CI). METHODS: Computed tomography head scans were obtained from 60 patients diagnosed with ISS and 41 age-matched control patients. Volumetric reformations of the skull and overlying skin were used to trace two-dimensional planes defined in terms of skull-base plane and internal or surface landmarks. For each patient, novel SSIs were computed as the ratio of head width and length as measured on each of these planes. A traditional CI was also calculated and a receiver operating characteristic curve analysis was applied to compare the sensitivity and specificity of the proposed indices with those of CI. RESULTS: Although the CI is a sensitive measure of scaphocephaly, it is not specific and therefore not a suitable predictor of ISS in many practical applications. The SSI-A provides a specificity of 95% at a sensitivity level of 98%, in contrast with the 68% of CI. On average, the sensitivity and specificity of all proposed indices are superior to those of CI. CONCLUSIONS: Measurements of cranial width and length derived from planes that are defined in terms of internal or surface landmarks and skull-base plane produce SSIs that outperform traditional CI measurements.

Case-Control Studies↗
PubMed2005

Skeletal changes in epidermal nevus syndrome: does focal bone disease harbor clues concerning pathogenesis?

Epidermal nevus syndrome (ENS) is a rare, sporadic, congenital disorder of unknown etiology featuring a complex and highly variable phenotype that can include focal or generalized skeletal disease. We describe a young man with ENS manifesting right-sided linear skin lesions, generalized weakness, diffuse osteopenia associated with hypophosphatemic rickets, and distinctive focal bone lesions ipsilateral to the skin findings. Review of the literature concerning ENS-associated skeletal disease suggested such focal bone defects are fibrous dysplasia, but our patient did not have the typical radiographic or histopathologic findings of fibrous dysplasia. Nevertheless, his circulating fibroblast growth factor 23 (FGF-23) level was elevated, likely functioning as a "phosphatonin," yet no activating mutations in GNAS previously reported in fibrous dysplasia or McCune-Albright syndrome were detected in his leukocytes or affected skin. We postulate that the focal skeletal disease, although different than fibrous dysplasia, may be a source of FGF-23 in ENS.

Adolescent↗
PubMed2005

Chemical effects in biological systems--data dictionary (CEBS-DD): a compendium of terms for the capture and integration of biological study design description, conventional phenotypes, and 'omics data.

A critical component in the design of the Chemical Effects in Biological Systems (CEBS) Knowledgebase is a strategy to capture toxicogenomics study protocols and the toxicity endpoint data (clinical pathology and histopathology). A Study is generally an experiment carried out during a period of time for the purpose of obtaining data, and the Study Design Description captures the methods, timing, and organization of the Study. The CEBS Data Dictionary (CEBS-DD) has been designed to define and organize terms in an attempt to standardize nomenclature needed to describe a toxicogenomics Study in a structured yet intuitive format and provide a flexible means to describe a Study as conceptualized by the investigator. The CEBS-DD will organize and annotate information from a variety of sources, thereby facilitating the capture and display of toxicogenomics data in biological context in CEBS, i.e., associating molecular events detected in highly-parallel data with the toxicology/pathology phenotype as observed in the individual Study Subjects and linked to the experimental treatments. The CEBS-DD has been developed with a focus on acute toxicity studies, but with a design that will permit it to be extended to other areas of toxicology and biology with the addition of domain-specific terms. To illustrate the utility of the CEBS-DD, we present an example of integrating data from two proteomics and transcriptomics studies of the response to acute acetaminophen toxicity (A. N. Heinloth et al., 2004, Toxicol. Sci. 80, 193-202).

Acetaminophen↗
PubMed2005

Standardizing global gene expression analysis between laboratories and across platforms.

To facilitate collaborative research efforts between multi-investigator teams using DNA microarrays, we identified sources of error and data variability between laboratories and across microarray platforms, and methods to accommodate this variability. RNA expression data were generated in seven laboratories, which compared two standard RNA samples using 12 microarray platforms. At least two standard microarray types (one spotted, one commercial) were used by all laboratories. Reproducibility for most platforms within any laboratory was typically good, but reproducibility between platforms and across laboratories was generally poor. Reproducibility between laboratories increased markedly when standardized protocols were implemented for RNA labeling, hybridization, microarray processing, data acquisition and data normalization. Reproducibility was highest when analysis was based on biological themes defined by enriched Gene Ontology (GO) categories. These findings indicate that microarray results can be comparable across multiple laboratories, especially when a common platform and set of procedures are used.

Gene Expression Profiling↗
PubMed2005

Pregnancy outcomes after maternal exposure to simvastatin and lovastatin.

BACKGROUND: Our objective was to determine the frequency of adverse outcomes after maternal exposure to simvastatin and/or lovastatin during pregnancy in postmarketing experience. METHODS: We reviewed the Merck & Co., Inc. (West Point, PA) pharmacovigilance database for reports of exposure to simvastatin or lovastatin during pregnancy. The reports were classified as prospective (reported prior to pregnancy outcome) or retrospective (reported after pregnancy outcome) and were evaluated for timing of exposure, outcome, congenital anomalies, and other events. Outcome rates were calculated for prospective pregnancies. RESULTS: We identified 477 reports (386 prospective and 91 retrospective) with 225 prospective outcomes reported: 154 live born infants, 49 elective abortions, 18 spontaneous abortions, and 4 fetal deaths. Six congenital anomalies were reported: chromosomal translocation, trisomy 18, hypospadias, duodenal atresia, cleft lip, and skin tag. The rate of congenital anomalies (congenital anomalies/live births plus fetal deaths) was 3.8%, which is similar to the background population rate (3.2%; relative ratio, 1.21; 95% 1-sided upper confidence interval [CI], 2.02). There were 13 retrospective reports describing a range of congenital anomalies. No specific pattern of anomalies was identified in either the prospective or retrospective reports. Rates for other outcomes were similar to background rates. CONCLUSIONS: Although the number of reports was relatively small, there was no evidence of a notable increase in congenital anomalies in women exposed to simvastatin or lovastatin versus the general population. Greater reporting of congenital abnormalities in the retrospective cohort is not unexpected and may reflect a reporting bias. Drugs should be used during pregnancy only if the benefits outweigh the risks. Simvastatin and lovastatin remain contraindicated during pregnancy.

Abnormalities, Drug-Induced↗
PubMed2005

In vitro differentiation profile of osteoblasts derived from patients with Saethre-Chotzen syndrome.

Seathre-Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome, associated with loss-of-function mutations in the basic helix-loop-helix transcription factor, TWIST1. The biologic activity of TWIST1 has been implicated in the inhibition of differentiation of multiple cell lineages. Therefore, premature fusion of cranial sutures (craniosynostosis) in SCS may be mediated by altered differentiation of calvarial osteoblasts. In this study, we evaluated osteoblasts derived from calvarial bone of three patients with SCS and three unaffected individuals as controls to investigate the principle stages of osteoblast differentiation: (1) proliferation, (2) matrix maturation, and (3) mineralization. Using a BrdU-Hoechst flow cytometry assay, we found that the percent of proliferating cells was significantly reduced in cells derived from patients with SCS compared with those derived from controls (P < or = 0.05). In the matrix maturation stage, alkaline phosphatase (ALP) enzyme activity and the expression of extracellular matrix genes, collagen I alpha 2 (COL1A2), osteopontin (OPN), osteocalcin (OC), and the runt-related transcription factor RUNX2 were examined by enzymatic assay and real-time quantitative RT-PCR, respectively. We identified no significant differences in the expression of matrix related transcripts. However, we found significant reductions in ALP activity on days 3 and 7 and in RUNX2 expression on days 14 and 21 (P < or = 0.05). Quantitative alizarin red S mineralization assays showed a trend toward increased mineralization in osteoblasts derived from patients with SCS at days 21 and 28, although not statistically significant. Our results demonstrated that loss-of-function mutations of TWIST1 led to reduced proliferation regardless of the functional domain affected. We did not find any conclusive differences in matrix maturation or mineralization in these primary osteoblasts. It is plausible that mutations in different functional domains of TWIST1 have divergent effects on these later stages of differentiation.

Acrocephalosyndactylia↗