Showing papers by "University of Texas Health Science Center at Houston published in 2004"
Thomas Jefferson University1, Cincinnati Children's Hospital Medical Center2, Yeshiva University3, Alfred I. duPont Hospital for Children4, University of Michigan5, Harvard University6, University of Iowa7, Mayo Clinic8, University of Texas Health Science Center at Houston9, Wake Forest University10, University of Minnesota11, University of Pennsylvania12, National Institutes of Health13, American Institutes for Research14
5,707 citations
National Institutes of Health1, Baylor University Medical Center2, University of California, San Francisco3, Ohio State University4, Thomas Jefferson University5, Mayo Clinic6, French Institute of Health and Medical Research7, University of Texas Health Science Center at Houston8, McGill University9, Karolinska Institutet10, Creighton University11, University of Helsinki12, Fred Hutchinson Cancer Research Center13, Harvard University14
TL;DR: This commentary summarizes the Workshop presentations on HNPCC and MSI testing; presents the issues relating to the performance, specificity, and specificity of the Bethesda Guidelines; outlines the revised Bethesda Guidelines for identifying individuals at risk for H NPCC; and recommend criteria for MSI testing.
Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.
2,899 citations
TL;DR: Evidence is presented in support of the idea that many poor readers are impaired because of inadequate instruction or other experiential factors, and Hypothesized deficits in general learning abilities and low-level sensory deficits have weak validity as causal factors in specific reading disability.
Abstract: We summarize some of the most important findings from research evaluating the hypothesized causes of specific reading disability (dyslexia) over the past four decades. After outlining components of reading ability, we discuss manifest causes of reading difficulties, in terms of deficiencies in component reading skills that might lead to such difficulties. The evidence suggests that inadequate facility in word identification due, in most cases, to more basic deficits in alphabetic coding is the basic cause of difficulties in learning to read. We next discuss hypothesized deficiencies in readingrelated cognitive abilities as underlying causes of deficiencies in component reading skills. The evidence in these areas suggests that, in most cases, phonological skills deficiencies associated with phonological coding deficits are the probable causes of the disorder rather than visual, semantic, or syntactic deficits, although reading difficulties in some children may be associated with general language deficits. Hypothesized deficits in general learning abilities (e.g., attention, association learning, cross-modal transfer etc.) and low-level sensory deficits have weak validity as causal factors in specific reading disability. These inferences are, by and large, supported by research evaluating the biological foundations of dyslexia. Finally, evidence is presented in support of the idea that many poor readers are impaired because of inadequate instruction or other experiential factors. This does not mean that biological factors are not relevant, because the brain and environment interact to produce the neural networks that support reading acquisition. We conclude with a discussion of the clinical implications of the research findings, focusing on the need for enhanced instruction.
2,275 citations
TL;DR: Recent progress on the characterization of plasmacytoid dendritic cell origin, development, migration and function in immunity and tolerance, as well as their effect on human diseases are reviewed.
Abstract: Human and mouse plasmacytoid dendritic cells have been shown to correspond to a specialized cell population that produces large amounts of type I interferons in response to viruses, the so-called natural interferon-producing cells. As a result, intensive investigation is now focused on the potential functions of plasmacytoid dendritic cells in both innate and adaptive immunity. Here we review recent progress on the characterization of plasmacytoid dendritic cell origin, development, migration and function in immunity and tolerance, as well as their effect on human diseases.
1,661 citations
TL;DR: These results confirm an evolving epidemic of cardiovascular risk in youth, as evidenced by an increase in the prevalence of overweight and hypertension, notably among ethnic minority children.
Abstract: Objectives. To describe the current prevalence of pediatric hypertension and the relationships between gender, ethnicity, overweight, and blood pressure. Methods. School-based screening was performed in 5102 children (13.5 ± 1.7 years) from May through November 2002. Age, gender, ethnicity, weight, and height were ascertained, and body mass index (BMI) was calculated as weight (kg)/height (m2). Overweight was defined as BMI ≥95th percentile. Students with blood pressure >95th percentile on the first screening underwent a second screening 1 to 2 weeks later, and then a third screening if blood pressure was >95th percentile at the second screening. Results. Ethnicity distribution was 44% white, 25% Hispanic, 22% African American, and 7% Asian. Overall, overweight prevalence was 20%, which varied significantly by ethnicity (31% Hispanic, 20% African American, 15% white, and 11% Asian). The prevalence of elevated blood pressure after first, second, and third screenings was 19.4%, 9.5%, and 4.5%, respectively. Elevated blood pressure on first screening was highest among Hispanics (25%) and lowest among Asians (14%). Ethnic differences in the prevalence of hypertension (elevated blood pressure on 3 screenings) were not significant after controlling for overweight. The prevalence of hypertension increased progressively as the BMI percentile increased from ≤5th percentile (2%) to ≥95th percentile (11%). After adjustment for gender, ethnicity, overweight, and age, the relative risk of hypertension was significant for gender (relative risk: 1.50; confidence interval: 1.15, 1.95) and overweight (relative risk: 3.26; confidence interval: 2.50, 4.24). Conclusions. These results confirm an evolving epidemic of cardiovascular risk in youth, as evidenced by an increase in the prevalence of overweight and hypertension, notably among ethnic minority children.
1,059 citations
TL;DR: In patients with acute ischemic stroke, continuous transcranial Doppler augments t-PA-induced arterial recanalization, with a nonsignificant trend toward an increased rate of recovery from stroke, as compared with placebo.
Abstract: BACKGROUND Transcranial Doppler ultrasonography that is aimed at residual obstructive intracranial blood flow may help expose thrombi to tissue plasminogen activator (t-PA). Our objective was to determine whether ultrasonography can safely enhance the thrombolytic activity of t-PA. METHODS We treated all patients who had acute ischemic stroke due to occlusion of the middle cerebral artery with intravenous t-PA within three hours after the onset of symptoms. The patients were randomly assigned to receive continuous 2-MHz transcranial Doppler ultrasonography (the target group) or placebo (the control group). The primary combined end point was complete recanalization as assessed by transcranial Doppler ultrasonography or dramatic clinical recovery. Secondary end points included recovery at 24 hours, a favorable outcome at three months, and death at three months. RESULTS A total of 126 patients were randomly assigned to receive continuous ultrasonography (63 patients) or placebo (63 patients). Symptomatic intracerebral hemorrhage occurred in three patients in the target group and in three in the control group. Complete recanalization or dramatic clinical recovery within two hours after the administration of a t-PA bolus occurred in 31 patients in the target group (49 percent), as compared with 19 patients in the control group (30 percent; P=0.03). Twenty-four hours after treatment of the patients eligible for follow-up, 24 in the target group (44 percent) and 21 in the control group (40 percent) had dramatic clinical recovery (P=0.7). At three months, 22 of 53 patients in the target group who were eligible for follow-up analysis (42 percent) and 14 of 49 in the control group (29 percent) had favorable outcomes (as indicated by a score of 0 to 1 on the modified Rankin scale) (P=0.20). CONCLUSIONS In patients with acute ischemic stroke, continuous transcranial Doppler augments t-PA-induced arterial recanalization, with a nonsignificant trend toward an increased rate of recovery from stroke, as compared with placebo.
1,020 citations
TL;DR: Evidence is provided for the negative regulation of FOXO factors by IKK as a key mechanism for promoting cell growth and tumorigenesis by showing that IkappaB kinase physically interacts with, phosphorylates, and inhibits FOXO3a independent of Akt and causes proteolysis of FOXo3a via the Ub-dependent proteasome pathway.
818 citations
TL;DR: The uptake of pristine single-walled carbon nanotube into macrophage-like cells has been studied using the nanotubes' intrinsic near-infrared fluorescence to occur through phagocytosis.
Abstract: The uptake of pristine single-walled carbon nanotubes into macrophage-like cells has been studied using the nanotubes' intrinsic near-infrared fluorescence. Macrophage samples that have been incubated in growth media containing suspended single-walled nanotubes show characteristic nanotube fluorescence spectra. The fluorescence intensities increase smoothly with incubation time and external nanotube concentration. Near-infrared fluorescence microscopy at wavelengths above 1100 nm provides high contrast images indicating localization of nanotubes in numerous intracellular vesicles. Nanotube uptake appears to occur through phagocytosis. Population growth of macrophage cultures is unaffected by exposure to single-walled nanotube concentrations of ca. 4 μg/mL for up to 96 h.
800 citations
TL;DR: This article assessed the relative importance of multiple measures obtained in a kindergarten sample for the prediction of reading outcomes at the end of 1st and 2nd grades and found that phonological awareness, letter sound knowledge, and naming speed consistently accounted for the unique variance across reading outcomes whereas measures of perceptual skills and oral language and vocabulary did not.
Abstract: There is considerable focus in public policy on screening children for reading difficulties. Sixty years of research have not resolved questions of what constructs assessed in kindergarten best predict subsequent reading outcomes. This study assessed the relative importance of multiple measures obtained in a kindergarten sample for the prediction of reading outcomes at the end of 1st and 2nd grades. Analyses revealed that measures of phonological awareness, letter sound knowledge, and naming speed consistently accounted for the unique variance across reading outcomes whereas measures of perceptual skills and oral language and vocabulary did not. These results show that measures of letter name and letter sound knowledge, naming speed, and phonological awareness are good predictors of multiple reading outcomes in Grades 1 and 2.
794 citations
TL;DR: A subgroup of patients with heart failure and severe metabolic dysregulation is identified characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.
Abstract: In animal models of lipotoxicity, accumulation of triglycerides within cardiomyocytes is associated with contractile dysfunction. However, whether intramyocardial lipid deposition is a feature of human heart failure remains to be established. We hypothesized that intramyocardial lipid accumulation is a common feature of non-ischemic heart failure and is associated with changes in gene expression similar to those found in an animal model of lipotoxicity. Intramyocardial lipid staining with oil red O and gene expression analysis was performed on heart tissue from 27 patients (9 female) with non-ischemic heart failure. We determined intramyocardial lipid, gene expression, and contractile function in hearts from 6 Zucker diabetic fatty (ZDF) and 6 Zucker lean (ZL) rats. Intramyocardial lipid overload was present in 30% of non-ischemic failing hearts. The highest levels of lipid staining were observed in patients with diabetes and obesity (BMI>30). Intramyocardial lipid deposition was associated with an up-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) -regulated genes, myosin heavy chain beta (MHC-beta), and tumor necrosis factor alpha (TNF-alpha). Intramyocardial lipid overload in the hearts of ZDF rats was associated with contractile dysfunction and changes in gene expression similar to changes found in failing human hearts with lipid overload. Our findings identify a subgroup of patients with heart failure and severe metabolic dysregulation characterized by intramyocardial triglyceride overload and changes in gene expression that are associated with contractile dysfunction.
725 citations
Columbia University1, University of Oxford2, Indiana University – Purdue University Indianapolis3, Harvard University4, Massachusetts Institute of Technology5, University of Zulia6, University of California, Los Angeles7, University of Texas Health Science Center at Houston8, University of South Florida9, University of Rochester10, Boston Children's Hospital11, North Shore-LIJ Health System12, University of Southern California13, Mount Sinai Hospital14, University of California, Berkeley15, New York University16, National Institutes of Health17, University of California, Irvine18, University of Alabama at Birmingham19, Thomas Jefferson University20, University of Iowa21, City University of New York22, Oregon Health & Science University23, Albany Medical College24, University of Ulm25
TL;DR: A model estimated the components of additive genetic, shared environment, and nonshared environment variances confirming that approximately 40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a triplet (CAG) expansion mutation. The length of the triplet repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. The Venezuelan HD kindreds encompass 18,149 individuals spanning 10 generations, 15,409 of whom are living. Of the 4,384 immortalized lymphocyte lines collected, 3,989 DNAs were genotyped for their HD alleles, representing a subset of the population at greatest genetic risk. There are 938 heterozygotes, 80 people with variably penetrant alleles, and 18 homozygotes. Analysis of the 83 kindreds that comprise the Venezuelan HD kindreds demonstrates that residual variability in age of onset has both genetic and environmental components. We created a residual age of onset phenotype from a regression analysis of the log of age of onset on repeat length. Familial correlations (correlation ± SE) were estimated for sibling (0.40 ± 0.09), parent-offspring (0.10 ± 0.11), avuncular (0.07 ± 0.11), and cousin (0.15 ± 0.10) pairs, suggesting a familial origin for the residual variance in onset. By using a variance-components approach with all available familial relationships, the additive genetic heritability of this residual age of onset trait is 38%. A model, including shared sibling environmental effects, estimated the components of additive genetic (0.37), shared environment (0.22), and nonshared environment (0.41) variances, confirming that ≈40% of the variance remaining in onset age is attributable to genes other than the HD gene and 60% is environmental.
TL;DR: Leukocytosis has been consistently shown to be an independent risk factor and prognostic indicator of future cardiovascular outcomes, regardless of disease status, and the leukocyte count is inexpensive, reliable, easy to interpret, and ordered routinely in inpatient and outpatient settings.
TL;DR: Data indicate that the nature of the remedial educational intervention is critical to successful outcomes in children with reading disabilities and that the use of an evidence-based phonologic reading intervention facilitates the development of those fast-paced neural systems that underlie skilled reading.
TL;DR: The Glucatell serum BG detection assay is highly sensitive and specific as a diagnostic adjunct for IFI.
Abstract: The Glucatell (1-->3)- beta-D-glucan (BG) detection assay (Associates of Cape Cod) was studied as a diagnostic adjunct for invasive fungal infections (IFIs). On the basis of findings from a preliminary study of 30 candidemic subjects and 30 healthy adults, a serum BG level of >or=60 pg/mL was chosen as the cutoff. Testing was performed with serial serum samples obtained from 283 subjects with acute myeloid leukemia or myelodysplastic syndrome who were receiving antifungal prophylaxis. At least 1 serum sample was positive for BG at a median of 10 days before the clinical diagnosis in 100% of subjects with a proven or probable IFI. IFIs included candidiasis, fusariosis, trichosporonosis, and aspergillosis. Absence of a positive BG finding had a 100% negative predictive value, and the specificity of the test was 90% for a single positive test result and >or=96% for >or=2 sequential positive results. The Glucatell serum BG detection assay is highly sensitive and specific as a diagnostic adjunct for IFI.
American Academy of Neurology1, Rush University Medical Center2, University of Texas Health Science Center at Houston3, Wake Forest University4, Harvard University5, Brown University6, University of Pittsburgh7, University of Washington8, Boston University9, Tufts University10, University of California, San Francisco11
TL;DR: TCD is of established value in the screening of children aged 2 to 16 years with sickle cell disease for stroke risk and the detection and monitoring of angiographic vasospasm after spontaneous subarachnoid hemorrhage, and contrast-enhanced TCD/TCCS can also provide useful information in right-to-left cardiac/extracardiac shunts and hemorrhagic cerebrovascular disease.
Abstract: Objective: To review the use of transcranial Doppler ultrasonography (TCD) and transcranial color-coded sonography (TCCS) for diagnosis. Methods: The authors searched the literature for evidence of 1) if TCD provides useful information in specific clinical settings; 2) if using this information improves clinical decision making, as reflected by improved patient outcomes; and 3) if TCD is preferable to other diagnostic tests in these clinical situations. Results: TCD is of established value in the screening of children aged 2 to 16 years with sickle cell disease for stroke risk (Type A, Class I) and the detection and monitoring of angiographic vasospasm after spontaneous subarachnoid hemorrhage (Type A, Class I to II). TCD and TCCS provide important information and may have value for detection of intracranial steno-occlusive disease (Type B, Class II to III), vasomotor reactivity testing (Type B, Class II to III), detection of cerebral circulatory arrest/brain death (Type A, Class II), monitoring carotid endarterectomy (Type B, Class II to III), monitoring cerebral thrombolysis (Type B, Class II to III), and monitoring coronary artery bypass graft operations (Type B to C, Class II to III). Contrast-enhanced TCD/TCCS can also provide useful information in right-to-left cardiac/extracardiac shunts (Type A, Class II), intracranial occlusive disease (Type B, Class II to IV), and hemorrhagic cerebrovascular disease (Type B, Class II to IV), although other techniques may be preferable in these settings.
TL;DR: Rates of colorectal cancer test use continue to be low and screening is effective in reducing the incidence and mortality of coloresceptic cancer.
Abstract: BACKGROUND
Screening is effective in reducing the incidence and mortality of colorectal cancer. Rates of colorectal cancer test use continue to be low.
METHODS
The authors analyzed data from the National Health Interview Survey concerning the use of the home-administered fecal occult blood test (FOBT) and sigmoidoscopy/colonoscopy/proctoscopy to estimate current rates of colorectal cancer test use and to identify factors associated with the use or nonuse of tests.
RESULTS
In 2000, 17.1% of respondents reported undergoing a home FOBT within the past year, 33.9% reported undergoing an endoscopy within the previous 10 years, and 42.5% reported undergoing either test within the recommended time intervals. The use of colorectal cancer tests varied by gender, race, ethnicity, age, education, income, health care coverage, and having a usual source of care. Having seen a physician within the past year had the strongest association with test use. Lack of awareness and lack of physician recommendation were the most commonly reported barriers to undergoing such tests.
CONCLUSIONS
Less than half of the U.S. population age ≥ 50 years underwent colorectal cancer tests within the recommended time intervals. Educational initiatives for patients and providers regarding the importance of colorectal cancer screening, efforts to reduce disparities in test use, and ensuring that all persons have access to routine primary care may help increase screening rates. Cancer 2004. © 2004 American Cancer Society.
TL;DR: It is shown that HER2 enhances the expression of CXCR4, which is required for HER2-mediated invasion in vitro and lung metastasis in vivo, and this work establishes a functional link between HER2 and CX CR4 signaling pathways.
TL;DR: Treatment of invasive mycoses continues to be challenging and complicated by the net state of immunosuppression among infected hosts combined with relative lack of efficacy, significant toxicity, drug–drug interactions, and drug resistance associated with available antifungal agents.
Abstract: Invasive fungal infections continue to cause significant morbidity and mortality among hospitalized patients. In particular, recent studies indicate an increase in the incidence of mould infections among transplant recipients, and Candida species have risen to be the third most common pathogen isolated among intensive care unit patients [1, 2]. Advances in modern medical treatment have led to growth in the at-risk population for fungal infections [3]. For example, Cryptococcus neoformans has re-emerged as a growing cause of invasive fungal disease due in large part to the development of novel immune therapy for malignancies, rheumatologic disorders, and management of rejection in transplant populations [4]. Unfortunately, these infections are associated with failures and high rates of relapse even when patients receive recommended therapy [5, 6]. Treatment of invasive mycoses continues to be challenging and complicated by the net state of immunosuppression among infected hosts combined with relative lack of efficacy, significant toxicity, drug–drug interactions, and drug resistance associated with available antifungal agents.
TL;DR: It is envisioned that the proteolytic processing of DMP1 and DSPP may be an activation process that plays a significant, crucial role in osteogenesis and dentinogenesis, and that a failure in this processing would cause defective mineralization in bone and dentIn, as observed in X-linked hypophosphatemic rickets.
Abstract: The extracellular matrix (ECM) of bone and dentin contains several non-collagenous proteins. One category of non-collagenous protein is termed the SIBLING (Small Integrin-Binding LIgand, N-linked Glycoprotein) family, that includes osteopontin (OPN), bone sialoprotein (BSP), dentin matrix protein 1 (DMP1), dentin sialophosphoprotein (DSPP), and matrix extracellular phosphoglycoprotein (MEPE). These polyanionic SIBLING proteins are believed to play key biological roles in the mineralization of bone and dentin. Although the specific mechanisms involved in controlling bone and dentin formation are still unknown, it is clear that some functions of the SIBLING family members are dependent on the nature and extent of post- translational modifications (PTMs), such as phosphorylation, glycosylation, and proteolytic processing, since these PTMs would have significant effects on their structure. OPN and BSP are present in the ECM of bone and dentin as full-length forms, whereas amino acid sequencing indicates that DMP1 and DSPP exist as proteolytically processed fragments that result from scission of X-Asp bonds. We hypothesized that the processing of DMP1 and DSPP is catalyzed by the PHEX enzyme, since this protein, an endopeptidase that is predominantly expressed in bone and tooth, has a strong preference for cleavage at the NH 2 - terminus of aspartyl residue. We envision that the proteolytic processing of DMP1 and DSPP may be an activation process that plays a significant, crucial role in osteogenesis and dentinogenesis, and that a failure in this processing would cause defective mineralization in bone and dentin, as observed in X-linked hypophosphatemic rickets.
TL;DR: An 11.7‐Å‐resolution cryo‐EM map of the yeast 80S·eEF2 complex in the presence of the antibiotic sordarin was interpreted in molecular terms, revealing large conformational changes within eEF2 and the 80S ribosome, including a rearrangement of the functionally important ribosomal intersubunit bridges.
Abstract: An 11.7-A-resolution cryo-EM map of the yeast 80S·eEF2 complex in the presence of the antibiotic sordarin was interpreted in molecular terms, revealing large conformational changes within eEF2 and the 80S ribosome, including a rearrangement of the functionally important ribosomal intersubunit bridges. Sordarin positions domain III of eEF2 so that it can interact with the sarcin–ricin loop of 25S rRNA and protein rpS23 (S12p). This particular conformation explains the inhibitory action of sordarin and suggests that eEF2 is stalled on the 80S ribosome in a conformation that has similarities with the GTPase activation state. A ratchet-like subunit rearrangement (RSR) occurs in the 80S·eEF2·sordarin complex that, in contrast to Escherichia coli 70S ribosomes, is also present in vacant 80S ribosomes. A model is suggested, according to which the RSR is part of a mechanism for moving the tRNAs during the translocation reaction.
TL;DR: HIV-1-induced maturation of both DC subsets may explain their disappearance from the blood of patients with high viral loads and may have important consequences on HIV-1 cellular transmission and HIV- 1-specific T-cell responses.
Abstract: In this study, we analyzed the phenotypic and physiological consequences of the interaction of plasmacytoid dendritic cells (pDCs) with human immunodeficiency virus type 1 (HIV-1). pDCs are one cellular target of HIV-1 and respond to the virus by producing alpha/beta interferon (IFN-alpha/beta) and chemokines. The outcome of this interaction, notably on the function of bystander myeloid DC (CD11c+ DCs), remains unclear. We therefore evaluated the effects of HIV-1 exposure on these two DC subsets under various conditions. Blood-purified pDCs and CD11c+ DCs were exposed in vitro to HIV-1, after which maturation markers, cytokine production, migratory capacity, and CD4 T-cell stimulatory capacity were analyzed. pDCs exposed to different strains of infectious or even chemically inactivated, nonreplicating HIV-1 strongly upregulated the expression of maturation markers, such as CD83 and functional CCR7, analogous to exposure to R-848, a synthetic agonist of toll-like receptor-7 and -8. In addition, HIV-1-activated pDCs produced cytokines (IFN-alpha and tumor necrosis factor alpha), migrated in response to CCL19 and, in coculture, matured CD11c+ DCs, which are not directly activated by HIV. pDCs also acquired the ability to stimulate naive CD4+ T cells, albeit less efficiently than CD11c+ DCs. This HIV-1-induced maturation of both DC subsets may explain their disappearance from the blood of patients with high viral loads and may have important consequences on HIV-1 cellular transmission and HIV-1-specific T-cell responses.
TL;DR: LVH occurs commonly in children with hypertension and is associated with an increased BMI, and may be more prevalent in Hispanic children than in other ethnic groups.
Abstract: Objective. To determine the prevalence of left ventricular hypertrophy (LVH) in a multiethnic group of children and adolescents with hypertension. Design/Methods. Pooled data from 1998 to 2001 from 3 sites belonging to the International Pediatric Hypertension Association were reviewed. Patients undergoing echocardiography to detect LVH as part of the evaluation for hypertension were included for analysis. Left ventricular mass was calculated from 2-dimensional guided M-mode echocardiographic measurements of the left ventricle. Left ventricular mass index (LVMI) was calculated as left ventricular mass/height2.7. LVH by adult criteria was defined as LVMI > 51 g/m2.7 and by pediatric criteria as LVMI > 38.6 g/m2.7. Left ventricle geometry was classified as concentric, concentric remodeling, eccentric, or normal. Results. Data on 129 patients with a mean age of 13.6 ± 3.6 years were analyzed. The population was 67% male, 46.5% white, 38.0% African American, and 15.5% Hispanic. The prevalence of LVH was 15.5% using adult criteria and 41.1% using pediatric criteria. Increasing body mass index (BMI) was associated with a higher LVMI. Using either pediatric or adult criteria LVH was associated with BMI ≥95th percentile for age and gender. LVH and concentric hypertrophy were identified most frequently in Hispanic children. Conclusions. LVH occurs commonly in children with hypertension and is associated with an increased BMI. LVH may be more prevalent in Hispanic children than in other ethnic groups. Prevention and treatment of obesity is important in reducing the cardiovascular risk for children with hypertension. Further evaluation of the frequency of LVH in multiethnic populations is needed.
TL;DR: The basic expectations for the methods of human and animal biological rhythm research are outlined, both from the perspective of the fundamental criteria necessary for quality chronobiology investigation and from the perspectives of humane and ethical research on human beings and animals.
Abstract: Most research papers published in Chronobiology International report the findings of investigations conducted on laboratory animals and human beings. The Journal, its editors and the publication committee endorse the compliance of investigators to the principles of the Declaration of Helsinki of the World Medical Association relating to the conduct of ethical research on human beings and the Guide for the Care and Use of Laboratory Animals of the Institute for Laboratory Animal Research of the National Research Council relating to the conduct of ethical research on laboratory and other animals. Chronobiology International requires that submitted manuscripts reporting the findings of human and animal research conform to the respective policy and mandates of the Declaration of Helsinki and the Guide for the Care and Use of Laboratory Animals. The peer review of manuscripts will thus include judgment of whether or not the involved research methods conform to the standards of good research practice. This article outlines the basic expectations for the methods of human and animal biological rhythm research, both from the perspective of the fundamental criteria necessary for quality chronobiology investigation and from the perspective of humane and ethical research on human beings and animals.
TL;DR: The data show that the circadian clock and haem biosynthesis are reciprocally regulated and suggest that porphyrin-containing molecules are potential targets for therapy of circadian disorders.
Abstract: The circadian clock is the central timing system that controls numerous physiological processes. In mammals, one such process is haem biosynthesis, which the clock controls through regulation of the rate-limiting enzyme aminolevulinate synthase 1 (Alas1)1,2. Several members of the core clock mechanism are PAS domain proteins, one of which, neuronal PAS 2 (NPAS2), has a haem-binding motif3,4. Indeed, haem controls activity of the BMAL1–NPAS2 transcription complex in vitro by inhibiting DNA binding in response to carbon monoxide3. Here we show that haem differentially modulates expression of the mammalian Period genes mPer1 and mPer2 in vivo by a mechanism involving NPAS2 and mPER2. Further experiments show that mPER2 positively stimulates activity of the BMAL1–NPAS2 transcription complex and, in turn, NPAS2 transcriptionally regulates Alas1. Vitamin B12 and haem compete for binding to NPAS2 and mPER2, but they have opposite effects on mPer2 and mPer1 expression in vivo. Our data show that the circadian clock and haem biosynthesis are reciprocally regulated and suggest that porphyrin-containing molecules are potential targets for therapy of circadian disorders.
TL;DR: The current findings, in combination with the known 53BP1 functions and how it is activated, implicate the DNA damage response to DSBs in the joining phase of class-switch recombination.
Abstract: The mammalian protein 53BP1 is activated in many cell types in response to genotoxic stress, including DNA double-strand breaks (DSBs). We now examine potential functions for 53BP1 in the specific genomic alterations that occur in B lymphocytes. Although 53BP1 was dispensable for V(D)J recombination and somatic hypermutation (SHM), the processes by which immunoglobulin (Ig) variable region exons are assembled and mutated, it was required for Igh class-switch recombination (CSR), the recombination and deletion process by which Igh constant region genes are exchanged. When stimulated to undergo CSR, 53BP1-deficient cells exhibited no defect in C(H) germline transcription or AID expression, however these cells had a profound decrease in switch junctions. The current findings, in combination with the known 53BP1 functions and how it is activated, implicate the DNA damage response to DSBs in the joining phase of class-switch recombination.
TL;DR: Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT, which has never been reported before, and is strongly correlated with imatinib resistance.
Abstract: KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T→C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT .
TL;DR: The role of AMPK activation in regulating protein synthesis during both phenylephrine- and Akt-induced cardiac hypertrophy is investigated and data suggest that the inhibition of protein synthesis by pharmacological activation of AM PK may be a key regulatory mechanism by which hypertrophic growth can be controlled.
TL;DR: The process of strong artificial selection during a domestication event is modeled, and its effect on the pattern of DNA polymorphism is investigated, and this model can be generalized to describe selective sweeps from standing genetic variation.
Abstract: The process of strong artificial selection during a domestication event is modeled, and its effect on the pattern of DNA polymorphism is investigated. The model also considers population bottleneck during domestication. Artificial selection during domestication is different from a regular selective sweep because artificial selection acts on alleles that may have been neutral variants before domestication. Therefore, the fixation of such a beneficial allele does not always wipe out DNA variation in the surrounding region. The amount by which variation is reduced largely depends on the initial frequency of the beneficial allele, p. As a consequence, p has a strong effect on the likelihood of detecting the signature of selection during domestication from patterns of polymorphism. These theoretical results are discussed in light of data collected from maize. Although the main focus of this article is on domestication, this model can also be generalized to describe selective sweeps from standing genetic variation.
01 Jan 2004
TL;DR: The concept of an integrated programmable general-purpose sample analysis processor (GSAP) architecture where raw samples are routed to separation and analysis functional blocks contained within a single device is presented.
Abstract: As the molecular origins of disease are better understood, the need for affordable, rapid, and automated technologies that enable microscale molecular diagnostics has become apparent. Widespread use of microsystems that perform sample preparation and molecular analysis could ensure that the benefits of new biomedical discoveries are realized by a maximum number of people, even those in environments lacking any infrastructure. While progress has been made in developing miniaturized diagnostic systems, samples are generally processed off-device using labor-intensive and time-consuming traditional sample preparation methods. We present the concept of an integrated programmable general-purpose sample analysis processor (GSAP) architecture where raw samples are routed to separation and analysis functional blocks contained within a single device. Several dielectrophoresis-based methods that could serve as the foundation for building GSAP functional blocks are reviewed including methods for cell and particle sorting, cell focusing, cell ac impedance analysis, cell lysis, and the manipulation of molecules and reagent droplets.