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1.
J Dent Res ; 98(11): 1253-1261, 2019 10.
Article in English | MEDLINE | ID: mdl-31393749

ABSTRACT

Tooth germs undergo a series of dynamic morphologic changes through bud, cap, and bell stages, in which odontogenic epithelium continuously extends into the underlying mesenchyme. During the transition from the bud stage to the cap stage, the base of the bud flattens and then bends into a cap shape whose edges are referred to as "cervical loops." Although genetic mechanisms for cap formation have been well described, little is understood about the morphogenetic mechanisms. Computer modeling and cell trajectory tracking have suggested that the epithelial bending is driven purely by differential cell proliferation and adhesion in different parts of the tooth germ. Here, we show that, unexpectedly, inhibition of cell proliferation did not prevent bud-to-cap morphogenesis. We quantified cell shapes and actin and myosin distributions in different parts of the tooth epithelium at the critical stages and found that these are consistent with basal relaxation in the forming cervical loops and basal constriction around enamel knot at the center of the cap. Inhibition of focal adhesion kinase, which is required for basal constriction in other systems, arrested the molar explant morphogenesis at the bud stage. Together, these results show that the bud-to-cap transition is largely proliferation independent, and we propose that it is driven by classic actomyosin-driven cell shape-dependent mechanisms. We discuss how these results can be reconciled with the previous models and data.


Subject(s)
Cell Proliferation , Molar/growth & development , Odontogenesis , Tooth Germ/growth & development , Animals , Female , Gene Expression Regulation, Developmental , Mesoderm , Mice , Morphogenesis , Pregnancy
2.
Diabet Med ; 36(4): 491-498, 2019 04.
Article in English | MEDLINE | ID: mdl-30306620

ABSTRACT

AIMS: In people with metformin-treated diabetes, to evaluate the risk of acute pancreatitis, pancreatic cancer and other diseases of the pancreas post second-line anti-hyperglycaemic agent initiation. METHODS: People with Type 2 diabetes diagnosed after 2004 who received metformin plus a dipeptidyl peptidase-4 inhibitor (DPP-4i, n = 50 095), glucagon-like peptide-1 receptor agonist (GLP-1RA, n = 12 654), sulfonylurea (n = 110 747), thiazolidinedione (n = 17 597) or insulin (n = 34 805) for at least 3 months were identified in the US Centricity Electronic Medical Records. Time to developing acute pancreatitis, other diseases of the pancreas and pancreatic cancer was estimated, balancing and adjusting anti-hyperglycaemic drug groups for appropriate confounders. RESULTS: In the DPP-4i group, the adjusted mean time to acute pancreatitis was 2.63 [95% confidence intervals (CI) 2.38, 2.88] years; time to pancreatic cancer was 2.70 (2.19, 3.21) years; and time to other diseases of the pancreas was 2.73 (2.33, 3.12) years. Compared with DPP-4i, the insulin group developed acute pancreatitis 0.48 years (P < 0.01) earlier and the GLP-1RA group developed pancreatic cancer 3 years later (P < 0.01). However, with the constraint of no event within 6 months of insulin initiation, the risk of acute pancreatitis in the insulin group was insignificant. No other significant differences were observed between groups. CONCLUSIONS: No significant differences in the risk of developing pancreatic diseases in those treated with various anti-hyperglycaemic drug classes were found.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Incretins/administration & dosage , Incretins/adverse effects , Metformin/administration & dosage , Pancreatic Diseases/epidemiology , Acute Disease , Aged , Diabetes Mellitus, Type 2/epidemiology , Dipeptidyl-Peptidase IV Inhibitors/administration & dosage , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Drug Therapy, Combination/adverse effects , Female , Glucagon-Like Peptide-1 Receptor/agonists , Humans , Insulin/administration & dosage , Insulin/adverse effects , Male , Metformin/adverse effects , Middle Aged , Pancreatic Diseases/chemically induced , Pancreatic Neoplasms/chemically induced , Pancreatic Neoplasms/epidemiology , Pancreatitis/chemically induced , Pancreatitis/epidemiology
3.
Nutr Metab Cardiovasc Dis ; 26(9): 767-72, 2016 09.
Article in English | MEDLINE | ID: mdl-27378397

ABSTRACT

AIMS: The increased risk of cardiovascular disease in patients with type 2 diabetes has been known for many years. However, until recently the cardiovascular (CV) impact of glucose lowering strategies has been inadequately understood. Major clinical trials have now investigated the impact of intensification of glycemic control upon CV outcomes, as well as the CV effects of glucose management with newer antihyperglycemic agents. DATA SYNTHESIS: Key findings from recently completed CV outcomes trials of dipeptidyl peptidase-4 (DPP4) inhibitors, GLP-1 receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors completed thus far are reviewed and summarized. CONCLUSIONS: Multiple trials designed to meet regulatory requirements for CV safety of antihyperglycemic medications have been initiated. The results of several completed CV outcomes trials clarify the risks and benefits associated with newer medications used to manage hyperglycemia in patients with type 2 diabetes, particularly in individuals at high CV risk. Important differences have been noted with respect to heart failure outcomes within the DPP4 inhibitor class, and thus far one agent in the SGLT2 inhibitor class has been found to significantly reduce rates of important CV outcomes. Robust safety related information from trials designed to assess the CV effects of diabetes therapies will permit the incorporation of outcomes-based evidence into the formulation of diabetes care guidelines.


Subject(s)
Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/therapeutic use , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/etiology , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/mortality , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Humans , Hypoglycemic Agents/adverse effects , Incretins/therapeutic use , Patient Safety , Patient Selection , Risk Assessment , Risk Factors , Treatment Outcome
4.
Diabetes Obes Metab ; 17(4): 395-402, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25600421

ABSTRACT

AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.


Subject(s)
Cardiovascular Diseases/prevention & control , Diabetes Mellitus, Type 2/drug therapy , Diabetic Angiopathies/prevention & control , Diabetic Cardiomyopathies/prevention & control , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Sitagliptin Phosphate/therapeutic use , Age Factors , Aged , Asia/epidemiology , Cardiovascular Diseases/complications , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/therapy , Cohort Studies , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/complications , Diabetic Angiopathies/epidemiology , Diabetic Angiopathies/therapy , Diabetic Cardiomyopathies/complications , Diabetic Cardiomyopathies/epidemiology , Diabetic Cardiomyopathies/therapy , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Double-Blind Method , Drug Therapy, Combination/adverse effects , Europe/epidemiology , Female , Hospitalization , Humans , Hypoglycemic Agents/adverse effects , Hypoglycemic Agents/therapeutic use , Latin America/epidemiology , Male , Middle Aged , Mortality , North America/epidemiology , Risk Factors , Sex Characteristics , Sitagliptin Phosphate/adverse effects
5.
Diabetologia ; 56(6): 1226-35, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23564296

ABSTRACT

AIMS/HYPOTHESIS: Clinical trials assessing interventions for treating and preventing diabetes mellitus and its complications are needed to inform evidence-based practice. To examine whether current studies adequately address these needs, we conducted a descriptive analysis of diabetes-related trials registered with ClinicalTrials.gov from 2007 to 2010. METHODS: From a dataset including 96,346 studies registered in ClinicalTrials.gov downloaded on 27 September, 2010, a subset of 2,484 interventional trials was created by selecting trials with disease condition terms relevant to diabetes. RESULTS: Of the diabetes-related trials, 74.8% had a primarily therapeutic purpose while 10% were preventive. Listed interventions included drugs (63.1%) and behavioural (11.7%). Most trials were designed to enrol ≤ 500 (91.1%) or ≤ 100 (58.6%) participants, with mean/median times to completion of 1.8/1.4 years. Small percentages of trials targeted persons aged ≤ 18 years (3.7%) or ≥ 65 years (0.6%), while 30.8% excluded patients >65 years and the majority excluded those >75 years. Funding sources included industry (50.9%), NIH (7.5%) or other, with most being single-centre trials of other sponsorship (37.7%) or industry-funded multicentre studies (27.4%). A small number of trials (1.4%) listed primary outcomes including mortality or clinically significant cardiovascular complications. The distribution of trials by global region and US state does not correlate with prevalence of diabetes. CONCLUSIONS/INTERPRETATION: The majority of diabetes-related trials include small numbers of participants, exclude those at the extremes of age, are of short duration, involve drug therapy rather than preventive or non-drug interventions and do not focus upon significant cardiovascular outcomes. Recently registered diabetes trials may not sufficiently address important diabetes care issues or involve affected populations.


Subject(s)
Clinical Trials as Topic , Diabetes Mellitus/therapy , Cardiovascular Diseases/complications , Cardiovascular Diseases/prevention & control , Diabetes Complications/therapy , Evidence-Based Medicine , Humans , Research Design , Treatment Outcome , United States
6.
Skin Therapy Lett ; 16(10): 1-3, 2011.
Article in English | MEDLINE | ID: mdl-22337077

ABSTRACT

Since the elucidation of the concept of selective photothermolysis, quality-switched lasers have been the gold standard for tattoo removal. Proper patient education prior to commencing treatment is crucial to ensure realistic expectations and compliance. This article reviews appropriate device selection and technique. Clinical pearls and pitfalls are presented, as well as cutting-edge techniques and technologies are discussed in order to enable the laser practitioner to optimize outcomes.


Subject(s)
Laser Therapy/methods , Lasers, Solid-State/therapeutic use , Tattooing , Equipment Design , Humans , Laser Therapy/adverse effects , Laser Therapy/instrumentation , Patient Compliance , Patient Education as Topic
7.
G Ital Dermatol Venereol ; 143(4): 229-33, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18833079

ABSTRACT

AIM: Toxic epidermal necrolysis (TEN) is a severe drug reaction characterized by massive epidermal cell death. The authors of the current study and others have noted improved outcomes in TEN patients treated with human intravenous immunoglobulin (IVIG), purportedly due to its ability to inhibit the fas/fas-ligand (Fas-L) apoptotic pathway, but published case series evaluating TEN through the use of immunohistochemical antibody stains for Fas and Fas-L before and after IVIG treatment are lacking. The authors hypothesized that due to IVIG's ability to arrest the evolution of TEN, expression of Fas/Fas-L on keratinocytes would be decreased or absent following IVIG treatment. METHODS: Ten patients diagnosed with TEN underwent biopsies of their lesions prior to and five days after treatment with IVIG. Seven post-treatment biopsies were of sufficient quality to undergo evaluation. RESULTS: All ten pretreatment biopsies had Fas and Fas-L expression by immunohistochemistry, while six out of seven (85.7%) post-treatment biopsies failed to demonstrate Fas or Fas-L expression. One of seven post-treatment biopsies stained positive for Fas and Fas-L. CONCLUSION: This reduced immunohistochemical expression of apoptotic markers may represent IVIG inhibition of the pathogenic mechanism of TEN. Alternatively reduced Fas and Fas-L may be a feature of reepithelialization in TEN, or characteristic of rapidly proliferating epidermis.


Subject(s)
Fas Ligand Protein/drug effects , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Stevens-Johnson Syndrome/pathology , Stevens-Johnson Syndrome/therapy , fas Receptor/drug effects , Adult , Apoptosis/drug effects , Biopsy , Female , Humans , Immunohistochemistry , Male , Middle Aged , Signal Transduction/drug effects , Stevens-Johnson Syndrome/immunology , Treatment Outcome
8.
Public Health ; 122(8): 809-20, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18294665

ABSTRACT

OBJECTIVE: To investigate cardiorespiratory health effects associated with chronic exposure to volcanogenic sulphur dioxide (SO2) and fine sulphate particle (< or = 0.3 microm) air pollution emitted from Kilauea Volcano, Hawaii. STUDY DESIGN: Environmental-epidemiological cross-sectional study. METHODS: An air study was conducted to measure exposure levels in the downwind area, and to confirm non-exposure in a reference area. Cross-sectional health data were collected from 335 adults, > or = 20 years of age, who had resided for > or = 7 years in the study areas. Prevalence was estimated for cardiorespiratory signs, and self-reported symptoms and diseases. Logistic regression analysis estimated effect measures between exposed and unexposed groups considering potential confounding including age, gender, race, smoking, dust and body mass index (BMI). Student's t-tests compared mean differences in blood pressure (BP), pulse and respiratory rates. RESULTS: There were statistically significant positive associations between chronic exposure and increased prevalence of cough, phlegm, rhinorrhoea, sore/dry throat, sinus congestion, wheezing, eye irritation and bronchitis. The magnitude of the associations differed according to SO2 and fine sulphate particulate exposure. Group analyses found no differences in pulse rate or BP; however, significantly faster mean pulse rates were detected in exposed non-medicated, non-smoking participants with BMI <25, and in participants aged > or = 65 years. Higher mean systolic BP was found in exposed participants with BMI <25. CONCLUSIONS: Long-term residency in active degassing volcanic areas may have an adverse effect on cardiorespiratory health in adults. Further study at Kilauea is recommended, and the authors encourage investigations in communities near active volcanoes worldwide. Public health interventions of community education, and smoking prevention and cessation are suggested.


Subject(s)
Air Pollutants/adverse effects , Cardiovascular Diseases/chemically induced , Environmental Exposure/adverse effects , Respiratory Tract Diseases/chemically induced , Sulfur Dioxide/adverse effects , Volcanic Eruptions/adverse effects , Air Pollutants/analysis , Cross-Sectional Studies , Environmental Monitoring , Female , Humans , Logistic Models , Male , Middle Aged , Particulate Matter/adverse effects , Particulate Matter/analysis , Sulfates/adverse effects
9.
J Paediatr Child Health ; 39(9): 700-3, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14629504

ABSTRACT

Health professionals frequently write at the same level for lay readers as they write for peers. In relation to health research and ethical requirements to provide written explanation of studies, this can complicate the notion of informed consent. Plain language information statements need to be clearly understood by research subjects if the ethics process for research approval is to fulfil its objective. Many delays in gaining ethics approval for child-related research are caused by substandard plain language statements (PLS). We describe specific issues for information statements for research with children, young people and their parents/guardians, particularly in consideration of the literacy capabilities of the general population. We highlight the usefulness of everyday language when explaining research and science in writing to families, and present some guidelines for writing PLS that have emerged from the introduction of a plain language service by an Ethics in Human Research Committee.


Subject(s)
Communication , Ethics, Research , Informed Consent , Therapeutic Human Experimentation/ethics , Child , Child, Preschool , Female , Humans , Language , Male , Parental Consent , Pediatrics/ethics , Terminology as Topic , Victoria
10.
Proc Natl Acad Sci U S A ; 98(21): 12078-83, 2001 Oct 09.
Article in English | MEDLINE | ID: mdl-11593018

ABSTRACT

The breast and ovarian susceptibility protein 1 (BRCA1) heterodimerizes with its structural relative, the BRCA1-associated RING domain protein (BARD1), which may have tumor suppressing function in its own right. Both proteins have evolved from a common evolutionary ancestor, and both exist in Xenopus laevis where, similar to their mammalian homologs, they form functional heterodimers. Depleting frog embryos of either BARD1 or BRCA1 led to similar and widely defective developmental phenotypes as well as depletion of the other polypeptide due to its decreased stability. Thus, each protein, in part, controls the abundance, stability, and function of the other, and these effects are heterodimerization-dependent. The interdependent nature of BRCA1 and BARD1 function supports the view that BARD1/BRCA1 heterodimers play a major role in breast and ovarian cancer suppression.


Subject(s)
BRCA1 Protein/physiology , Carrier Proteins/physiology , Tumor Suppressor Proteins , Ubiquitin-Protein Ligases , Zinc Fingers/physiology , Animals , BRCA1 Protein/genetics , Base Sequence , Carrier Proteins/genetics , Conserved Sequence , DNA, Complementary , Dimerization , Gene Expression , Humans , Molecular Sequence Data , Oligonucleotides, Antisense , Oocytes/metabolism , Xenopus laevis/embryology , Zinc Fingers/genetics
12.
J Nutr ; 131(5): 1544-7, 2001 May.
Article in English | MEDLINE | ID: mdl-11340113

ABSTRACT

Although increases in dietary vitamin A increase milk vitamin A, little is known about effects of vitamin A intake on mammary tissue vitamin A levels during and after the reproductive cycle. First, we measured vitamin A concentrations in milk, mammary tissue and liver of lactating rats fed 0, 4, or 50 micromol of vitamin A/kg diet during pregnancy and through d 12 of lactation. Liver vitamin A concentration was significantly affected by diet in lactating females and pups 12 d after parturition. Milk vitamin A concentrations were significantly higher (7.1 +/- 2.2 micromol/L, n = 8) in dams fed 50 micromol/kg than in those fed 0 or 4 micromol/kg (1.9 +/- 0.3, n = 5 and 2.9 +/- 0.7 micromol/L, n = 7; P < 0.001), as were mammary tissue vitamin A concentrations (5.1 +/- 1.1 versus 2.2 +/- 0.4 and 2.4 +/- 0.6 nmol/g; P < 0.001). Next, we maintained female rats on 50 or 10 micromol vitamin A/kg diet during pregnancy and lactation and then on 4 micromol/kg diet after pups were weaned on d 21. On d 21, mammary tissue vitamin A concentrations were 3.14 +/- 0.75 versus 1.52 +/- 0.21 nmol/g in dams fed 50 versus 10 micromol/kg (n = 4/group; P < 0.001). Mammary tissue vitamin A concentrations were not significantly affected by time from 7 to 49 d after lactation and averaged 8.5 +/- 0.4 and 4.9 +/- 0.8 nmol/g on d 49 in dams fed 50 versus 10 micromol/kg (n = 4; P < 0.001). We conclude that diet-induced differences in rat mammary tissue vitamin A developed during pregnancy and lactation are maintained for > or =7 wk after lactation.


Subject(s)
Breast/chemistry , Lactation/metabolism , Liver/metabolism , Vitamin A/metabolism , Animals , Female , Milk/chemistry , Organ Size , Pregnancy , Rats , Rats, Sprague-Dawley , Vitamin A/administration & dosage
13.
J Nutr ; 131(4): 1279-82, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11285338

ABSTRACT

To investigate the influence of vitamin A intake on the contribution of chylomicrons vs. holo retinol-binding protein to milk vitamin A, female rats were fed diets containing either 10 (n = 6) or 50 micromol vitamin A/kg body (n = 4) during pregnancy and through d 13 of lactation. [3H]Vitamin A was incorporated into each diet beginning on d 6 of lactation. Vitamin A concentrations on d 13 were significantly higher in dam liver (x 3), pup liver (x 2.6), milk (x 2.5) and mammary tissue (x 1.3) in rats consuming the higher level of vitamin A. In both groups, vitamin A specific activities in plasma and milk reached apparent plateaus by 2.33 d after addition of [3H]vitamin A to the diets. Vitamin A specific activity in milk was higher than in plasma at all times in both groups. The estimated minimum contribution of chylomicrons to milk vitamin A was 32 +/- 3% in rats fed the lower level of vitamin A vs. 52 +/- 10% at the higher level (P = 0.014). We concluded that dietary vitamin A, like triglycerides, may be directed to mammary tissue during lactation for preferential secretion into milk; thus, increasing vitamin A intakes will increase the contribution of dietary vitamin A to milk. In contrast to milk, mammary tissue vitamin A turns over very slowly.


Subject(s)
Chylomicrons/metabolism , Lactation/metabolism , Milk/metabolism , Retinol-Binding Proteins/metabolism , Vitamin A/metabolism , Vitamin A/pharmacokinetics , Animals , Animals, Newborn/metabolism , Diet , Female , Liver/metabolism , Male , Mammary Glands, Animal/metabolism , Pregnancy , Rats , Rats, Sprague-Dawley , Retinol-Binding Proteins, Plasma , Vitamin A/blood
15.
Dev Dyn ; 219(1): 77-83, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10974673

ABSTRACT

In Xenopus embryos, the maternally encoded transcription factor VegT (also known as Xombi, Antipodean, Brat, and Xtbx6) is essential for normal endoderm and mesoderm formation. This finding and the localization of VegT mRNA in the vegetal hemisphere of the oocyte are consistent with several models of germ layer patterning. Specific models have been proposed in which (1) combinations of cytoplasmic determinants, (2) inductive signals, or (3) intracellular concentration (morphogen effects) predominate. We test predictions of these models. We show that contrary to previous proposals, FGF does not suppress endoderm formation and so cannot be an anti-endoderm mesodermal determinant. We further show that, at the right dose, VegT can induce mesodermal marker expression cell autonomously and that it induces mesoderm at concentrations below those that induce endoderm. These results are consistent with a dual mechanism of mesoderm establishment in which both VegT-initiated inductive signals and an intracellular VegT morphogen gradient play a part.


Subject(s)
Embryo, Nonmammalian/metabolism , Endoderm/metabolism , Mesoderm/metabolism , Nuclear Proteins/genetics , T-Box Domain Proteins/genetics , Xenopus Proteins , Animals , Embryonic Induction , Fibroblast Growth Factors/genetics , Gene Expression Regulation, Developmental , Microinjections , Nuclear Proteins/metabolism , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , T-Box Domain Proteins/metabolism , Xenopus
16.
Toxicol Sci ; 55(2): 478-84, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10828281

ABSTRACT

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant that prevents the normal accumulation of vitamin A in liver and causes increased excretion of vitamin A. To determine what alterations in vitamin A metabolism occur first in response to TCDD treatment, we administered TCDD (7.0 microg/kg b.w. ) orally to rats that had received a nonperturbing (tracer) iv dose of [(3)H]vitamin A-labeled plasma (n = 3) or lymph (n = 3) 21 days earlier. Within a few days after TCDD administration, fraction of the injected radiolabel in plasma, which had been in a terminal slope when plotted on a semilog scale, increased and remained elevated until the experiment was terminated (day 42). At that time, liver vitamin A levels were 65% lower in TCDD-perturbed rats than in controls. Using model-based compartmental analysis and compartmental models developed previously for control rats (S. K. Kelley et al., 1998, Toxicol. Sci, 44:1-13), we determined the minimal changes needed to account for the perturbation in plasma [(3)H] tracer responses after TCDD administration. We determined that the effects of TCDD could be explained by adjusting the value of one fractional transfer coefficient corresponding to the mobilization of vitamin A from large, slowly turning-over pools. We speculate that this change corresponds to an increased fractional rate of retinyl ester hydrolysis, and that it precedes the TCDD-associated increased irreversible utilization and excretion of vitamin A.


Subject(s)
Environmental Pollutants/toxicity , Liver/metabolism , Polychlorinated Dibenzodioxins/toxicity , Vitamin A/pharmacokinetics , Administration, Oral , Animals , Animals, Newborn , Body Weight/drug effects , Liver/drug effects , Liver/pathology , Male , Models, Biological , Organ Size/drug effects , Rats , Rats, Sprague-Dawley , Thymus Gland/drug effects , Thymus Gland/pathology
17.
J Nutr ; 130(5): 1291-6, 2000 May.
Article in English | MEDLINE | ID: mdl-10801932

ABSTRACT

In view of evidence that nutritional status of iron and vitamin A may affect the other nutrient's metabolism, we used model-based compartmental analysis to examine effects of iron deficiency on whole-body vitamin A dynamics in rats. Weanling male Sprague-Dawley rats were fed the AIN93G diet with 2.5 nmol retinyl palmitate/g and either 45 [control (CN)] or 4 microg/g Fe [iron-deficient (ID)] for 8 wk. ID rats consumed food ad libitum; CN rats were food-restricted so that their body weights were the same as ID rats. Two rats/group were killed; liver vitamin A was determined and used for vitamin A balance calculations. [(3)H]Retinol-labeled plasma was administered intravenously to remaining rats, and 27 serial blood samples were collected for 7 wk. At killing, plasma vitamin A was 0.52+/-0.12 (ID, n = 5) vs. 1.34+/-0.12 micromol/L (CN, n = 6; P<0.001), and liver vitamin A was 809+/-94 (ID) vs. 112+/-24 nmol (CN, P<0.001). Plasma tracer data were fit to a three- or four-compartment model using the Simulation, Analysis and Modeling computer program and kinetic parameters were calculated. Vitamin A transfer rate between the retinyl ester storage pool [14+/-3 (ID) vs. 24+/-4 nmol/d (CN), P<0.05] and plasma was lower in ID rats. Vitamin A remained longer in the body [44+/-11 (ID) vs. 22+/-3 d (CN), P<0.05]. Adjusted mean disposal rate was lower in ID (10.0) than CN rats (19.9 nmol/d), as was estimated vitamin A absorption efficiency [58% (ID) vs. 76% (CN)]. Our results suggest that iron deficiency inhibits mobilization of vitamin A stores and may decrease the absorption and irreversible utilization of vitamin A.


Subject(s)
Iron Deficiencies , Liver/metabolism , Vitamin A/metabolism , Animals , Male , Models, Biological , Rats , Rats, Sprague-Dawley , Vitamin A/blood , Vitamin A/pharmacokinetics
18.
Development ; 127(4): 861-8, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10648244

ABSTRACT

Cortical rotation and concomitant dorsal translocation of cytoplasmic determinants are the earliest events known to be necessary for dorsoventral patterning in Xenopus embryos. The earliest known molecular target is beta-catenin, which is essential for dorsal development and becomes dorsally enriched shortly after cortical rotation. In mammalian cells cytoplasmic accumulation of beta-catenin follows reduction of the specific activity of glycogen synthase kinase 3-beta (GSK3beta). In Xenopus embryos, exogenous GSK3beta) suppresses dorsal development as predicted and GSK3beta dominant negative (kinase dead) mutants cause ectopic axis formation. However, endogenous GSK3beta regulation is poorly characterized. Here we demonstrate two modes of GSK3beta regulation in Xenopus. Endogenous mechanisms cause depletion of GSK3beta protein on the dorsal side of the embryo. The timing, location and magnitude of the depletion correspond to those of endogenous beta-catenin accumulation. UV and D(2)O treatments that abolish and enhance dorsal character of the embryo, respectively, correspondingly abolish and enhance GSK3beta depletion. A candidate regulator of GSK3beta, GSK3-binding protein (GBP), known to be essential for axis formation, also induces depletion of GSK3beta. Depletion of GSK3beta is a previously undescribed mode of regulation of this signal transducer. The other mode of regulation is observed in response to Wnt and dishevelled expression. Neither Wnt nor dishevelled causes depletion but instead they reduce GSK3beta-specific activity. Thus, Wnt/Dsh and GBP appear to effect two biochemically distinct modes of GSK3beta regulation.


Subject(s)
Body Patterning/physiology , Calcium-Calmodulin-Dependent Protein Kinases/metabolism , Trans-Activators , Xenopus Proteins , Xenopus/embryology , Xenopus/metabolism , Amino Acid Sequence , Animals , Body Patterning/genetics , Calcium-Calmodulin-Dependent Protein Kinases/genetics , Carrier Proteins/metabolism , Cytoskeletal Proteins/metabolism , Down-Regulation , Glycogen Synthase Kinase 3 , Glycogen Synthase Kinases , Intracellular Signaling Peptides and Proteins , Molecular Sequence Data , Mutation , Peptides/chemistry , Substrate Specificity , Xenopus/genetics , beta Catenin
19.
Stroke ; 30(12): 2659-65, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10582993

ABSTRACT

BACKGROUND AND PURPOSE: Multimodal neuroimaging with positron emission tomography (PET) scanning or functional MRI can detect and display functional reorganization of the brain's motor control in poststroke hemiplegia. We undertook a study to determine whether the new modality of 128-electrode high-resolution EEG, coregistered with MRI, could detect changes in cortical motor control in patients after hemiplegic stroke. METHODS: We recorded movement-related cortical potentials with left and right finger movements in 10 patients with varying degrees of recovery after hemiplegic stroke. All patients were male, and time since stroke varied from 6 to 144 months. All patients were right-handed. There was also a comparison group of 20 normal control subjects. RESULTS: Five of 8 patients with left hemiparesis had evidence of ipsilateral motor control of finger movements. There were only 2 cases of right hemiparesis; in addition, 1 patient had a posteriorly displaced motor potential originating behind a large left frontal infarct (rim). CONCLUSIONS: Reorganization of motor control takes place after stroke and may involve the ipsilateral or contralateral cortex, depending on the site and size of the brain lesion and theoretically, the somatotopic organization of the residual pyramidal tracts. Our results are in good agreement with PET and functional MRI studies in the current literature. High-resolution EEG coregistered with MRI is a noninvasive imaging technique capable of displaying cortical motor reorganization.


Subject(s)
Brain Infarction/physiopathology , Brain Mapping/methods , Electroencephalography/methods , Motor Cortex/physiology , Movement/physiology , Paresis/physiopathology , Aged , Case-Control Studies , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Motor Cortex/blood supply , Somatosensory Cortex/physiology
20.
Neurology ; 53(4): 736-43, 1999 Sep 11.
Article in English | MEDLINE | ID: mdl-10489034

ABSTRACT

OBJECTIVE: To determine whether a previously identified posterior reorganization of the cortical motor network after spinal cord injury (SCI) is correlated with prognosis and outcome. METHODS: We applied the techniques of high-resolution EEG and dipole source analysis to record and map the motor potentials (MPs) of the movement-related cortical potentials in 44 patients after SCI. Twenty normal controls were also tested. Results were analyzed using a distance metric to compare MP locations. EEG was coregistered with individual specific MR images and a boundary element model created for dipole source analysis. RESULTS: MPs with finger movements were mapped to a posterior location in 20 of 24 tetraplegics compared with normal controls. Two patients, one studied 4 and one 6 weeks after injury, initially had posterior MPs that, on serial testing, moved to an anterior position with recovery. Dipole source localization of the MP generators confirmed these results. Nine of 20 paraplegics had a posterior MP location with actual or attempted toe movements. All 5 patients who could move their toes had posterior MPs. The MP was posterior in 4 of the 15 paralyzed patients. This is a significant difference in proportions. The only patient with paraparesis whose testing was repeated had an MP that moved to an anterior position with recovery. CONCLUSIONS: Posterior reorganization has a significant relationship to prognosis in paraplegia and is reversed in some SCI patients who recover function. Posterior reorganization may result from a preferential survival of axons that originate in somatosensory cortex and contribute to the corticospinal tract. These preliminary results should be verified by a larger prospective study.


Subject(s)
Motor Cortex/physiopathology , Paraplegia/physiopathology , Spinal Cord Injuries/physiopathology , Adult , Brain Mapping , Electroencephalography , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Motor Cortex/pathology , Paraplegia/etiology , Paraplegia/pathology , Spinal Cord Injuries/complications
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