Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.
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American Heart Association↗
Biomedical subjects
Michael Ho
Publications and source records attributed to Michael Ho.
Astrocytic-inducible nitric oxide synthase in the ischemic developing human brain.
Variability in the expression of apoptotic and inflammatory mediators with time after an ischemic insult and their role in the expansion of cerebral infarcts are still controversial. This study examines DNA degradation and the expression of activated caspase-3 and iNOS, inducible nitric oxide (iNOS) in the human developing brain. Autopsy specimens from children with a neuropathologic diagnosis of focal ischemic infarct were included in the study. The specimens were classified based on the clinical history as acute (< 24 h, n = 5), subacute (24-72 h, n = 8), or old (> 72 h, n = 6) infarcts. Immunohistochemical staining for caspase-3, iNOS and TUNEL were then performed on all infarcts alongside age-matched controls. TUNEL staining was detected in regions of all infarcts. Expression of iNOS was significantly higher than that of caspase-3 in the penumbra of subacute infarcts (p = 0.02). Glial fibrillary acidic protein and iNOS staining co-localized in the penumbra of acute and subacute infarcts. These results suggest that cell death continues to occur for more than 3 d post ischemic insult. Cell death in the penumbra of subacute infarcts is partially caspase-3 independent and may be attributed to nitric oxide. Astrocytes are a source of iNOS and may play a role in the evolution of pediatric brain injury days after the initial insult.
Adolescent↗
Pediatric undifferentiated sarcoma of the soft tissues: a clinicopathologic study.
Pediatric undifferentiated soft tissue sarcomas represent a major challenge for pathologists and clinicians. The goal of this study was to identify cases that warranted this diagnosis by current standards of analysis and then determine if there are clinicopathological commonalities that may be useful for diagnosis, management, and prognosis. Eighteen potential patients were identified using the institutional pathology database. Three cases were reclassified as specific sarcomas, and 2 cases had insufficient material for molecular analysis, leaving 13 cases for pathological review and 12 patients for radiological and clinical review. There were 7 males and 6 females. The median age at diagnosis was 11 years (1 month to 16 years). Tumors commonly involved the trunk (7 of 13; 54%) and ranged in size from 1.7 to 14.5 cm (mean, 6.7 cm). Eleven patients received ifosfamide/etoposide chemotherapy and 4 received irradiation. Five-year event-free and overall survival (EFS and OS) rates were 54% and 74%, respectively. The predominant histological pattern was round to plump spindled cells forming sheets (9 of 13; 69%) and severe atypia was associated with decreased survival (P = 0.048). Immunohistochemistry showed positivity for vimentin (92%), CD117 (92%), and vascular endothelial growth factor (69%), and 8% to 23% showed focal positivity for epithelial, neural, or myogenic markers. Tumors were uniformly negative for translocations associated with pediatric sarcomas. The presence of certain common morphological and immunohistochemical features in the absence of specific molecular genetic abnormalities allows for a diagnosis of pediatric undifferentiated soft tissue sarcoma; however, whether this group of neoplasms forms a unique category of tumors or a common precursor pathway for a number of different sarcomas awaits further study.
Adolescent↗
Safety climate and self-reported injury: assessing the mediating role of employee safety control.
To further reduce injuries in the workplace, companies have begun focusing on organizational factors which may contribute to workplace safety. Safety climate is an organizational factor commonly cited as a predictor of injury occurrence. Characterized by the shared perceptions of employees, safety climate can be viewed as a snapshot of the prevailing state of safety in the organization at a discrete point in time. However, few studies have elaborated plausible mechanisms through which safety climate likely influences injury occurrence. A mediating model is proposed to link safety climate (i.e., management commitment to safety, return-to-work policies, post-injury administration, and safety training) with self-reported injury through employees' perceived control on safety. Factorial evidence substantiated that management commitment to safety, return-to-work policies, post-injury administration, and safety training are important dimensions of safety climate. In addition, the data support that safety climate is a critical factor predicting the history of a self-reported occupational injury, and that employee safety control mediates the relationship between safety climate and occupational injury. These findings highlight the importance of incorporating organizational factors and workers' characteristics in efforts to improve organizational safety performance.
Accidents, Occupational↗
The relationship between safety climate and injury rates across industries: the need to adjust for injury hazards.
Previous studies have suggested that strong safety climates (shared perceptions of safe conducts at work) are associated with lower workplace-injury rates, but they rarely control for differences in industry hazards. Based on 33 companies, we assessed its association with injury rates using three rate based injury measures (claims per 100 employees, claims per 100,000 h worked, and claims per 1 million US dollars payroll), which were derived from workers' compensation injury claims. Linear regression models were used to test the predictability of safety climate on injury rates, followed by controlling for differences in hazard across industries gauged by national industry-specific injury rates. In the unadjusted model, company level safety climate were negatively and significantly associated with injury rates. However, all of the above associations were no longer apparent when controlling for the hazardousness of the specific industry. These findings may be due to over adjustment of hazard risk, or the overwhelming effects of industry specific hazards relative to safety climate effects that could not be differentiated with the statistical power in our study. Industry differences in hazard, conceptualized as one type of injury risk, however need to be considered when testing the association between safety climate and injury across different industries.
Accidents, Occupational↗
Leptin-mediated inhibition of the insulin-stimulated increase in fatty acid uptake in differentiated 3T3-L1 adipocytes.
The effects of insulin and leptin on fatty acid uptake in differentiated (adipocytes) and undifferentiated 3T3-L1 cells were investigated. It was demonstrated that in undifferentiated 3T3-L1 cells, insulin and leptin have no effect on fatty acid uptake. In differentiated 3T3-L1 adipocytes, insulin had a concentration-dependent stimulatory effect on fatty acid uptake, whereas leptin on its own had no effect. Leptin, when coincubated with 10 nmol/L insulin, resulted in a concentration-dependent inhibition of the insulin-stimulated fatty acid uptake in differentiated 3T3-L1 cells. These results indicate that leptin has a direct inhibitory effect on the stimulation of fatty acid uptake by insulin in differentiated murine adipocytes.
3T3 Cells↗
Use of chromogenic in situ hybridization to identify MYCN gene copy number in neuroblastoma using routine tissue sections.
Amplification of MYCN in neuroblastoma is associated with a poor prognosis. However, methods for estimating the number of MYCN genes based on pooled cells do not address copy number heterogeneity at the cell level and can underestimate or even miss amplification. MYCN copy number can be directly assessed by fluorescence in situ hybridization, but evaluation of tissue histology is next to impossible. We have used a chromogenic method for in situ hybridization (CISH) that enables determination of MYCN copy number using routine light microscopy on routinely processed paraffin sections. Of 41 cases studied, CISH identified 100% of the 18 cases that were determined to be amplified by other techniques and was more sensitive than Southern blotting or quantitative DNA polymerase chain reaction. Because the technique evaluates individual tumor cells, heterogeneity of MYCN copy number was apparent from cell to cell. When defined as 50% or greater variation in copy number between cells in amplified tumors, almost 30% of cases were scored as heterogeneous. Heterogeneity reflects different tumor clones and its role has likely been under-recognized and underestimated in neuroblastoma biology. CISH will provide a valuable tool to assess this phenomenon in conjunction with other morphologic parameters in neuroblastoma specimens, to further our understanding of the biology of this childhood tumor.
Blotting, Southern↗
Vascularity and angiogenesis as predictors of growth in optic pathway/hypothalamic gliomas.
OBJECT: The authors' aim in conducting this study was to investigate retrospectively the prognostic significance of angiogenic features in optic pathway/hypothalamic gliomas (OPHGs) in children. METHODS: Patients were identified in whom a diagnosis of OPHG was made using pathological analysis at the Toronto Hospital for Sick Children between 1985 and 2002. Tumor specimens were reviewed for diagnostic accuracy and adequacy of the specimen. Sections were immunostained with factor VIII to assess microvessel density (MVD). A ratio of alpha-smooth muscle actin to factor VIII immunostaining was calculated to arrive at a vascular maturity index (VMI). Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) immunostaining were performed to evaluate angiogenic factors. In addition, the MIB-1 labeling index (LI) was used to assess proliferation. These factors were evaluated with respect to progression-free survival (PFS). Forty-one of 60 patients originally identified had adequate samples and follow up for inclusion in the study. Of these, eight patients had coexisting neurofibromatosis Type 1. Twenty-eight patients experienced tumor progression after the initial treatment (surgery with or without adjuvant treatment). Thirty-eight patients are still alive. A high MVD (> 21 vessels/1.2 mm2) was associated with a significantly higher rate of progression compared with a low MVD (< 21 vessels/1.2 mm2; p = 0.017). Microvessel density was also predictive of reduced PFS on multivariate analysis stratified for extent of resection (p = 0.04), and VMI as well as intensity and distribution of VEGF and VEGFR staining and the MIB-1 LI were not significantly associated with PFS. CONCLUSIONS: These findings suggest that MVD is the best current predictor of PFS in incompletely resected OPHGs. This information highlights the importance of angiogenesis in regard to low-grade gliomas.
Adolescent↗
HER2 amplification and overexpression is not present in pediatric osteosarcoma: a tissue microarray study.
The HER2 gene, located on 17q, encodes a 185-kD transmembrane tyrosine kinase receptor. Amplification of this gene with overexpression of the gene product occurs in about 30% of cases of breast cancer and is considered to be a poor prognostic indicator for this tumor. Results for HER2 expression in osteosarcoma are controversial, with some studies reporting up to 61% of positive cases and others reporting only negative results. Further, expression of HER2 is reported to be a favorable prognostic indicator by some groups and unfavorable by others. The present study used tissue microarrays containing 34 samples of osteosarcoma from 18 patients to analyze HER2 expression by immunohistochemistry and gene copy number by chromogenic in situ hybridization. The microarray included 13 pretreatment biopsies, 11 posttreatment resection specimens, and 10 resected metastases and comprised 18 osteoblastic, 6 chondroblastic, 5 fibroblastic, and 5 mixed subtypes. HER2 protein expression was seen in 4 of 34 (12%) tumor samples that originated from 2 of 18 patients (11%). The staining pattern was consistently weak and focal, and immunohistochemical overexpression of the HER2 protein, defined as complete membrane positivity, was never observed. Further, the presence of HER2 gene amplification was not detected in any osteosarcoma by chromogenic in situ hybridization. Therefore, therapies based on antibodies directed against the HER2 protein are unlikely to have much value in the treatment of pediatric osteosarcomas. From a technical standpoint, this study also demonstrates the value of tissue microarrays in screening tumors at the protein and gene levels using conventional light microscopy.
Adolescent↗
Expression of DHX32 in lymphoid tissues.
DHX32 is a novel putative RNA helicase identified based on its downregulation in acute lymphoblastic leukemia. DHX32 gene has 12 exons, alternative usage of exons 1 and 2 results in the expression of two transcripts that differ in their 5' untranslated region (UTR), consistent with the involvement of two different promoters. In addition, exon 5 skipping results in the production of a full-length and alternatively spliced transcripts. We used transcript-specific primers in reverse transcriptase (RT)-PCR to show that the thymus and spleen express all of DHX32 transcripts. We also used immunohistochemistry to study the expression of DHX32 protein. The expression pattern of DHX32 protein in normal lymphoid tissues is variable but suggests association with state of lymphocyte activation and/or differentiation. Dysregulated expression of DHX32 is noted in some types of lymphoma compared to their normal counterpart.
Alternative Splicing↗
Synovial pathology in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.
At least 25 families with camptodactyly-arthropathy-coxa vara-pericarditis (CACP syndrome) have been reported, with descriptions of a distinctive synovial pathology based largely on light microscopy. Although described as "proliferative," with numerous multinucleated giant cells, the natures of proliferating cells and giant cells have not been determined. To clarify the pathogenesis of this disorder, we studied 3 patients who had CACP syndrome and underwent synovial biopsy. Cells in the biopsies were studied by immunohistochemistry and electron microscopy. Giant cells were identified as macrophage in origin based on CD68 expression and electron microscopic features of macrophages. Most cells in the synovium were CD68 positive, in keeping with macrophages. The degree of proliferation in synovial biopsies was estimated by MIB1 immunostaining, which showed that up to 30% of cells were cycling compared with fewer than 10% in control synovial biopsies. None of the giant cells was cycling. By double immunostaining, proliferating cells were determined to be fibroblastic synoviocytes rather than macrophages. Thus the proliferative synovitis in this CACP syndrome can be more accurately thought of as hypercellularity by infiltrating macrophages with a contribution by proliferating fibroblastic synoviocytes. The synoviocyte proliferation is likely a response to the underlying genetic mutations involving the proteoglycan-4 (or CACP) gene. The encoded protein normally acts as a lubricant and possibly controls cell proliferation. Loss of one or another of these functions may be a possible mechanism that leads to synoviocyte proliferation in this disease, but the exact pathophysiology leading to this change requires further study.
Antigens, CD↗
A clinicobiological model predicting survival in medulloblastoma.
PURPOSE: The purpose of this study was to determine the relative contributions of biological and clinical predictors of survival in patients with medulloblastoma (MB). EXPERIMENTAL DESIGN: Clinical presentation and survival information were obtained for 119 patients who had undergone surgery for MB at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1985 and 2001. A tissue microarray was constructed from the tumor samples. The arrays were assayed for immunohistochemical expression of MYC, p53, platelet-derived growth factor receptor-alpha, ErbB2, MIB-1, and TrkC and for apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling). Both univariable and multivariable analyses were conducted to characterize the association between survival and both clinical and biological markers. For the strongest predictors of survival, a weighted predictive score was calculated based on their hazard ratios (HRs). The sum of these scores was then used to give an overall prediction of survival using a nomogram. RESULTS: The four strongest predictors of survival in the final multivariable model were the presence of metastatic disease at presentation (HR, 2.02; P=0.01) and p53 (HR, 2.29; P=0.02), TrkC (HR, 0.65; P=0.14), and ErbB2 (HR, 1.51; P=0.21) immunopositivity. A linear prognostic index was derived, with coefficients equal to the logarithm of these HRs. The 5-year survival rate for patients at the 10th, 50th, and 90th percentiles of the score distribution was 80.0%, 71.0%, and 35.7%, respectively, with radiation therapy and 70.5%, 58.5%, and 20.0%, respectively, without radiation therapy. CONCLUSIONS: In this study, we demonstrate an approach to combining both clinical and biological markers to quantify risk in MB patients. This provides further prognostic information than can be obtained when either clinical factors or biological markers are studied separately and establishes a framework for comparing prognostic markers in future clinical studies.
Adolescent↗
C-kit expression and mutational analysis in medulloblastoma.
The proto-oncogene c-kit is a receptor tyrosine kinase recognized to initiate essential signal transduction pathways that transmit biological signals for cellular proliferation, differentiation, and metastasis. Aberrant expression or mutation of c-kit has been shown to be involved in the pathogenesis of many cancers. Studies using imatinib mesylate (STI 571, Gleevec, Novartis, East Hannover, NJ, USA), an inhibitor of the tyrosine kinases brc-abl, c-kit, and PDGFR, have shown significant response in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and, secondarily, may be responsive to imatinib mesylate treatment, we looked at the expression of c-kit in medulloblastoma. Medulloblastoma, a highly invasive primitive neuroectodermal tumor of the cerebellum, is the most common, malignant central nervous system tumor of childhood. Histologic features of medulloblastoma have failed to provide an accurate prediction of the clinical-biological behavior of these tumors. Characterizing the genetic events that play a role in the biology of these tumors may allow for molecular sub-typing and could lead to the development of novel therapeutic strategies. This study evaluated c-kit expression and mutational status in 10 medulloblastoma tumor samples. All 10 medulloblastoma tumors expressed c-kit by reverse transcriptase-polymerase chain reaction and 9 by immunohistochemical analysis. All tumor samples were screened for mutations in exons 9, 11, and 13 of the c-kit gene by direct sequencing. No sequence abnormalities were detected in these exons. These experiments lead us to the conclusion that c-kit activation in medulloblastoma is independent of mutation.
Adolescent↗
Effectiveness of statin therapy in adults with coronary heart disease.
BACKGROUND: We conducted a meta-analysis of patients with coronary heart disease (CHD) to determine the effectiveness of statin therapy; whether effectiveness varied according to patient characteristics, outcomes, or pretreatment low-density lipoprotein cholesterol (LDL-C) levels; and the optimal LDL-C goal and the level at which to initiate statin therapy. METHODS: Randomized trials or systematic reviews for secondary prevention of CHD with statin therapy published between January 1966 and December 2002 were identified through MEDLINE and the Cochrane Library. Studies were included if they randomly assigned adults with CHD to statin therapy or control, enrolled at least 100 individuals per arm, reported clinical outcomes and LDL-C levels, and were published as full studies in English. Two reviewers abstracted data using a prospectively designed protocol. RESULTS: Twenty-five studies enrolling 69 511 individuals were included. Participants in 19 placebo-controlled trials had a mean age of 63 years and a mean pretreatment LDL-C level of 149 mg/dL (3.85 mmol/L); 23% were women. Statin therapy reduced CHD mortality or nonfatal myocardial infarction 25% (relative risk [RR], 0.75; 95% confidence interval [CI], 0.71-0.79), all-cause mortality 16% (RR, 0.84; 95% CI, 0.79-0.89), and CHD mortality 23% (RR, 0.77; 95% CI, 0.71-0.83). Beneficial effects were seen in women and the elderly. There were no data to determine whether lowering the LDL-C level to less than 100 mg/dL (<2.59 mmol/L) was superior to lowering it to 100 to 130 mg/dL (2.59-3.36 mmol/L). Meta-regression analyses revealed risk reductions for CHD mortality or nonfatal myocardial infarction and major vascular events across available pretreatment LDL-C levels. CONCLUSION: Statin therapy reduces mortality and morbidity in adults with CHD, even at pretreatment LDL-C levels as low as 100 mg/dL (2.59 mmol/L).
Adult↗
Inositol 1,4,5-trisphosphate receptor (type 1) phosphorylation and modulation by Cdc2.
Calcium (Ca2+) release from the endoplasmic reticulum (ER) controls numerous cellular functions including proliferation, and is regulated in part by inositol 1,4,5-trisphosphate receptors (IP3Rs). IP3Rs are ubiquitously expressed intracellular Ca2+-release channels found in many cell types. Although IP3R-mediated Ca2+ release has been implicated in cellular proliferation, the biochemical pathways that modulate intracellular Ca2+ release during cell cycle progression are not known. Sequence analysis of IP3R1 reveals the presence of two putative phosphorylation sites for cyclin-dependent kinases (cdks). In the present study, we show that cdc2/CyB, a critical regulator of eukaryotic cell cycle progression, phosphorylates IP3R1 in vitro and in vivo at both Ser(421) and Thr(799) and that this phosphorylation increases IP3 binding. Taken together, these results indicate that IP3R1 may be a specific target for cdc2/CyB during cell cycle progression.
Amino Acid Sequence↗
Identification of endothelial cell genes by combined database mining and microarray analysis.
Vascular endothelial cells maintain the interface between the systemic circulation and soft tissues and mediate critical processes such as inflammation in a vascular bed-selective fashion. To expand our understanding of the genetic pathways that underlie these specific functions, we have focused on the identification of novel genes that are differentially expressed in all endothelial cells, as well as restricted groups of this cell type. Virtual subtraction was conducted employing gene expression data deposited in public databases and 384 genes identified. These genes were spotted on custom microarrays, along with 288 genes identified through subtraction cloning from TGF-beta-stimulated endothelial cells. Arrays were evaluated with RNA samples representing endothelial cells cultured from four vascular sources and five non-endothelial cell types. These studies identified 64 pan-endothelial markers that were differentially expressed with at least a threefold difference (range 3- to 55-fold). In addition, differences in gene expression profiles among endothelial cells from different vascular beds were identified. Validation of these findings was performed by RNA blot expression studies, and a number of the novel genes were shown to be expressed under angiogenic conditions in the developing mouse embryo. The combined tools of database mining and transcriptional profiling thus provide expanded knowledge of endothelial cell gene expression and endothelial cell biology.
Adult↗
Transcriptional profiling of medulloblastoma in children.
OBJECT: Although medulloblastoma is the most common malignant brain tumor found in children, little is known about its molecular pathogenesis. The authors have attempted to compare patterns of gene expression in medulloblastoma samples with those in the healthy cerebellum. METHODS: The authors used complementary (c)DNA microarray analysis to compare the expression of genes in samples of medulloblastoma and normal cerebellum. The expression levels of a subset of genes were then verified by immunohistochemical analysis. Six genes were identified that were expressed at a much higher level in at least five of six medulloblastomas: ezrin, cyclin D2, high mobility group protein 2, MAPRE1, histone deacetylase 2, and ornithine decarboxylase 1. A number of potentially important genes whose expression was much lower in medulloblastomas than in control cerebellum were also identified: tenascin R, TRK-B, FGF receptor, and death receptor 3. The expression levels of a subset of the identified genes were confirmed by immunohistochemical analysis, which was performed on fetal cerebellum and medulloblastoma samples. CONCLUSIONS: The authors demonstrate that cDNA microarray analysis is an effective method of increasing understanding of the molecular biology of medulloblastomas found in children. A comparison between gene expression patterns in medulloblastoma and those observed in healthy cerebellum may provide clues as to the origin of these tumors and may lead to the identification of new genes or pathways to be targeted for future therapies.
Brain Neoplasms↗
Comparison of sleep disturbance in mild versus severe Parkinson's disease.
STUDY OBJECTIVES: To determine the effect of mild vs severe Parkinson's disease on objective sleep parameters, in a subgroup of patients with subjective excessive daytime somnolence. DESIGN: Patients with either mild (Hoehn and Yahr stage 1 or 2) or severe (Hoehn and Yahr stage 4 or 5) idiopathic Parkinson's disease and subjective evidence of sleepiness (Epworth sleepiness scale > 8) were recruited. All patients underwent overnight polysomnography autonomic function testing and completed questionnaires assessing quality of life, mood, and drug dosages. Mild and severe groups were then compared using the paired t-test for normally distributed data and the Mann-Whitney U test for nonparametric data. SETTING: Accredited sleep centre and neurosciences unit at tertiary referral centre. PATIENTS OR PARTICIPANTS: Parkinson's disease outpatients referred by their treating neurologist. INTERVENTIONS: N/A. RESULTS: 11 patients with mild disease and 7 with severe disease were studied. Both groups slept poorly when compared to historic normal controls. Their sleep efficiency was decreased, and the architecture fragmented. However, there was no significant difference in objective sleep parameters between the two groups. There was a significant increase in the number of voids overnight in the severe disease group (p< 0.05). CONCLUSIONS: In this subgroup of patients with subjective excessive day-time somnolence, the severity of Parkinson's disease was not associated with a change in the measured sleep parameters. Other factors, such as drug effects, may have played a greater role. Alternatively, motor/functional measures of disease severity may poorly reflect the level of sleep disturbance. Nocturia is an important factor which disturbs sleep, particularly in the severe disease group.
Aged↗