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Biomedical subjects

D Yin

Publications and source records attributed to D Yin.

At least 19 recordsLinked to original sources
PubMed2006

DLK1: increased expression in gliomas and associated with oncogenic activities.

DLK1 (delta-like) is a transmembrane and secreted protein in the epidermal growth factor-like homeotic family. Although expressed widely during embryonic development, only a few tissues retain the expression in adults. Neuroendocrine tumors often highly express this protein; therefore, we hypothesized that brain tumors might also express it. This study found that the expression of DLK1 in gliomas was higher than that in normal brain (P < 0.05). After stable transfection of a DLK1 cDNA expression vector into GBM cell lines, their proliferation was increased. Furthermore, they lost contact inhibition, had enhanced anchorage-independent growth in soft agar, and had significantly greater capacity to migrate. Western blot studies showed that expression of cyclin D1, CDK2, and E2F4 were increased, and Rb levels were decreased in these cells. DLK1 was found on the cell surface and secreted in the medium from the transfected GBM cells. DLK1-enriched condition medium stimulated the growth of glioblastoma multiforme cell lines and explants. DLK1 antibody blocked cell growth stimulated by DLK1. In summary, these results suggest that DLK1 may play a role in the formation or progression of gliomas.

Blotting, Western↗
PubMed2006

Liver ischemia contributes to early islet failure following intraportal transplantation: benefits of liver ischemic-preconditioning.

Early graft failure following intraportal islet transplantation (IPIT) represents a major obstacle for successful islet transplantation. Here, we examined the role of islet emboli in the induction of early graft failure and utilized a strategy of ischemic-preconditioning (IP) to prevent early islet destruction in a model of syngeneic IPIT in STZ-induced diabetic mice. Numerous focal areas of liver necrosis associated with the islet emboli were observed within 24 h post-IPIT. Pro-inflammatory cytokines, IL-1beta and IL-6, were significantly increased 3 h after IPIT, while TNF-alpha was elevated for up to 5 days post-IPIT. Caspase-3 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells were observed in the transplanted islets trapped in areas of necrotic liver at 3 h and 1 day post-IPIT. Hyperglycemia was corrected immediately following IPIT of 200 islets, but recurrence of hyperglycemia was observed within 14 days associated with a poor response to glucose challenge. IP, a procedure of pre-exposure of the liver to transient ischemia and reperfusion, protected the liver from embolism-induced ischemic injury and prevented early islet graft failure. These data suggest that islet embolism in the portal vein is a major cause of functional loss following IPIT that can be prevented by liver IP.

Animals↗
PubMed2006

TLR engagement prevents transplantation tolerance.

In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.

Animals↗
PubMed2005

Long-term achievement of the therapeutic objectives of lipid-lowering agents in primary prevention patients and cardiovascular outcomes: an observational study.

AIMS: Lowering elevated cholesterol levels reduces cardiovascular (CV) morbidity and mortality. Nonetheless, most patients treated with lipid-lowering agents (LLA) do not reach recommended therapeutic objectives. In a setting of primary care in France, we investigated the association between LDL-cholesterol goal attainment and the occurrence of CV events in primary prevention patients with multiple CV risk factors (> or = 3). According to national guidelines, the therapeutic objective (TO) for such patients is an LDL-cholesterol value below 130 mg/dL. METHODS: 579 patients treated with LLA and with LDL-cholesterol values documented at least once a year over a period of at least 3 years (2000-2002) were allocated to three groups based on the number of years the TO was attained during the follow-up period: in all 3 years (TO+++: n=145), only part of the time (TO intermediate: n=256), and never (TO---: n=178). CV events (angina pectoris, myocardial infarction, heart failure, stroke, peripheral artery disease) occurring during the last year of observation (2002) were retrospectively collected. The occurrence risk (OR) of CV events was assessed based on TO status, with a logistic regression model to adjust for baseline differences in CV risk factors. RESULTS: Only a quarter of patients attained TO during all 3 study years. CV events during the third year of observation occurred in 5.5%, 10.5% and 12.9% of patients in the TO+++, TO intermediate and TO--- groups, respectively. Compared with TO+++ patients, the risk of CV events increased significantly in TO intermediate (OR=2.34, 95% CI=[1.01-5.39]) and TO--- patients (OR=2.99, 95% CI=[1.26-7.08]). CONCLUSION: In real practice, a prolonged attainment of TO is rarely observed in high CV risk patients treated with LLA as primary prevention. Therapeutic failure is related to an increased incidence of cardiovascular morbidity. Our data strongly support the need to improve adherence to treatment guidelines to achieve effective cardiovascular prevention.

Aged↗
PubMed2005

Reaction of pyridoxamine with malondialdehyde: mechanism of inhibition of formation of advanced lipoxidation end-products.

Advanced glycation end products (AGEs) and advanced lipoxidation end products (ALEs) are implicated in many age-related chronic diseases and in protein aging. Recent studies suggest that pyridoxamine (PM) is an efficient AGEs/ALEs inhibitor in various biological systems. Because malondialdehyde (MDA) is an important intermediate in the formation of ALEs during lipid peroxidation, the purpose of this study is to determine whether PM can trap MDA directly and thereby prevent ALEs formation. PM reacted readily with MDA under physiological conditions. Within 6 h, a 1-pyridoxamino-propenal adduct derived from reaction of equimolar PM + MDA was detected. A 1-amino-3-iminopropene complex and a dihydropyridine-pyridinium complex were also identified after 7 d incubation. PM also greatly inhibited the lipofuscin-like fluorescence formation induced by MDA reaction with bovine serum albumin (BSA). Our results showed clearly that PM inhibited the formation of ALEs by trapping MDA directly under physiological condition, and provide insight into the mechanism of action of PM in protecting proteins against carbonyl stress.

Animals↗
PubMed2005

Dlk1 in normal and abnormal hematopoiesis.

Dlk1 (Pref-1) is a transmembrane and secreted protein, which is a member of the epidermal growth factor-like family, homologous to Notch/Delta/Serrate. We have found by real-time RT-PCR that Dlk1 mRNA levels were high in CD34(+) cells in 10 of 12 MDS samples compared with CD34(+) cells from 11 normals. Also, Dlk1 mRNA was elevated in mononuclear, low density bone marrow cells from 11/38 MDS patients, 5/11 AML M6 and 2/4 AML M7 samples. Furthermore, 5/6 erythroleukemia and 2/2 megakaryocytic leukemia cell lines highly expressed Dlk1 mRNA. Levels of Dlk1 mRNA markedly increased during megakaryocytic differentiation of both CMK megakaryoblasts as well as normal CD34(+) hematopoietic stem cells. High serum levels of Dlk1 occurred in RA (4/10) and essential thrombocythemia (2/10) patients. Functional studies showed that forced expression of Dlk1 enhanced proliferation of K562 cells growing in 1% fetal bovine serum. Analysis of hematopoiesis of Dlk1 knockout mice suggested that Dlk1 contributed to granulocyte, megakaryocyte and B-cell clonogenic growth and was needed for generation of splenic B-cells. In summary, Dlk1 is overexpressed in selected samples of MDS (especially RA and RAEB) and AML (particularly M6, M7), and it appears to be associated with normal development of megakaryocytes and B cells.

Animals↗
PubMed2005

Ineffectiveness of lipid-lowering therapy in primary care.

BACKGROUND: Evidence confirms the positive effects of lipid-lowering agents on the risk of cardiovascular disease. Local guidelines in France (AFSSAPS) have defined therapeutic objectives for LDL-cholesterol. These objectives vary with the number of cardiovascular risk factors in addition to dyslipidaemia. We determined the proportions of patients at therapeutic objective in different classes of cardiovascular risk to test the hypothesis that compliance with guidelines varies across the levels of risk. Comparison with international guidelines (ANDEM) was also performed. METHODS: A group of 3173 dyslipidaemic patients treated with lipid-lowering agents and managed by general practitioners was randomly selected from BKL-Thales panel, a French computerized database. For each patient, history of coronary heart disease and the number of cardiovascular risk factors were documented. Compliance with guidelines was assessed from achievement of therapeutic objective. RESULTS: The study population included 79% primary prevention patients (1.6, 25.5, 31.7 and 20.1%, with 1, 2, 3, and >3 risk factors, respectively) and 21.0% secondary prevention patients. Applying AFSSAPS guidelines, the proportions of primary prevention patients not at LDL-cholesterol objectives varied across risk categories (P < 0.0001), from 3.9% for patients with one risk factor to 46.5% for patients with >3 risk factors, and therapeutic failure reached 39.9% in secondary prevention. Only 26% of patients who were at high cardiovascular risk (>3 risk factors or prior coronary heart disease) and not at therapeutic objective received high doses (>standard recommended doses) of lipid-lowering agents in monotherapy. Applying ANDEM guidelines, 74% of secondary prevention patients were not at treatment goal. CONCLUSION: Compliance with guidelines varied inversely with the level of cardiovascular risk. Besides, most patients not at therapeutic objective were not up-titrated. The use of lipid-lowering agents is inadequate, depriving many patients of an effective protection against cardiovascular diseases.

Adult↗
PubMed2004

Effect of inappropriate initial empiric antibiotic therapy on outcome of patients with community-acquired intra-abdominal infections requiring surgery.

To assess the significance of initial empiric parenteral antibiotic therapy in patients requiring surgery for community-acquired secondary peritonitis, 425 patients hospitalized between January 1999 and September 2001 in 20 clinics across Germany were followed for a total of 6,521 patient days. Perforated appendix (38%), colon (27%), or gastroduodenum (22%) were the most common sites of infection. Escherichia coli was the most common pathogen. A total of 54 (13%) patients received inappropriate initial parenteral therapy not covering all bacteria isolated, or not covering both aerobes and anaerobes in the absence of culture results. Clinical success, predefined as the infection resolving with initial or step-down therapy after primary surgery, was achieved in 322 patients (75.7%; 95% confidence interval (CI), 70.6-81.2). Patients were more likely to have clinical success if initial antibiotic therapy was appropriate (78.6%; 95% CI, 73.6-83.9) rather than inappropriate (53.4%; 95% CI, 41.1-69.3). Patients having clinical success were estimated to stay 13.9 days in hospital (95% CI, 13.1-14.7), while those who had clinical failure stayed 19.8 days (95% CI, 17.3-22.3). In conclusion, appropriateness of initial parenteral antibiotic therapy was a predictor of clinical success, which in turn was associated with length of stay.

Abdomen, Acute↗
PubMed2004

Current lipid management and low cholesterol goal attainment in common daily practice in Spain. The REALITY Study.

OBJECTIVE: To evaluate prescribing patterns of lipid-lowering drugs used in management of patients at risk of coronary heart disease (CHD) in usual clinical practice in Spain and to assess low-density lipoprotein cholesterol (LDL-C) goal attainment among CHD and CHD equivalent patients (< 100 mg/dL) and non-CHD patients with two or more risk factors (< 130 mg/dL) who were prescribed lipid-lowering drugs. METHODS: Cohort study with retrospective chart review at 23 primary care centres and 16 lipid treatment centres across Spain (59% primary care; 41% outpatient lipid centres). Physicians consecutively identified eligible patients. Adults (aged > or = 18 years) with CHD/CHD equivalent or two or more major risk factors prior to first prescription of lipid-lowering drugs were eligible. Medical records were reviewed by physicians to collect patient characteristics, baseline and follow-up laboratory values and lipid-lowering drug treatment data. RESULTS: 619 patients (45.5% CHD and CHD equivalent patients and 54.5% non-CHD with two or more major risk factors) were included in the study with an average study follow-up of 3.6 years. Mean age was 60.1 years (SD 10.2), and 47.8% were female. Mean baseline LDL-C was 178 mg/dL (SD 45.0) for the CHD/CHD equivalent patients and 191 mg/dL (SD 56.95) for patients with two or more risk factors. Statins were the initial lipid-lowering drugs in 90.2% of patients; 52.5% of patients were initiated on low-dose (simvastatin 10mg or lower potency) statins. Overall 20.2% of CHD/CHD equivalent and 31.4% of patients with two or more risk factors attained LDL-C goal during the study period; of patients not attaining goal, 28.7% required an additional LDL-C reduction of > 30% to attain goal. In a logistic regression model for goal attainment, CHD/CHD equivalent patients (odds ratio [OR] 0.47; 95% confidence interval [CI] 0.31, 0.72) and patients with baseline LDL-C > 190 mg/dL (OR 0.53; 95% CI 0.35, 0.80) were least likely to reach cholesterol goal when compared with patients having baseline LDL-C > 100 mg/dL and < 130 mg/dL. CONCLUSION: Only 12.9% of patients attained LDL-C goal on their initial lipid-lowering drugs, and an additional 13.4% achieved goal after a change in their lipid-lowering therapy, resulting in 73.7% of patients not attaining goal after at least 3 years of follow-up, after initiation of lipid-lowering therapy. Patients who would gain the most from aggressive lipid lowering (CHD patients and patients with high baseline LDL-C) were least likely to achieve goal. More effective lipid management is needed to help these patients lower their cholesterol to goal levels or even lower.

Cholesterol, HDL↗
PubMed2003

Risk factors for antibiotic-resistant infection and treatment outcomes among hospitalized patients transferred from long-term care facilities: does antimicrobial choice make a difference?

A prospective observational study of 153 patients transferred from long-term care facilities and admitted to acute-care hospitals who had microbiologically confirmed infections was undertaken to determine the risk factors, outcomes, and resource use associated with isolation of antibiotic-resistant bacteria (ARB). Eighty patients (52%) were infected with ARB. In multivariable logistic analysis, the presence of a feeding tube (odds ratio, 3.0) or polymicrobial infection (odds ratio, 4.6) was associated with isolation of ARB. Forty-nine percent of patients infected with ARB received an initial antibiotic regimen to which their isolate was not susceptible. Fifty-one percent of all patients had a change in their antibiotic regimen during their hospital course. For these patients, length of stay, number of days of antibiotic therapy, and cost of hospitalization were significantly higher. However, neither infection with ARB nor appropriateness of initial treatment regimen was significantly related to outcome or resource use.

Aged↗
PubMed2003

Pharmacokinetics, metabolism and excretion of an inhibitor of inducible nitric oxide synthase, L-NIL-TA, in dog.

1. The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog. 2. The dose of [14C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5 mg kg-1), with Cmax of radioactivity of 6.45-7.07 microg equivalents g-1 occurring at 0.33-0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively. 3. Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [14C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%. 4. Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.

Administration, Oral↗
PubMed2001

Mutation of Tyr138 disrupts the structural coupling between the opposing domains in vertebrate calmodulin.

We have used circular dichroism and frequency-domain fluorescence spectroscopy to determine how the site-specific substitution of Tyr138 with either Phe138 or Gln138 affects the structural coupling between the opposing domains of calmodulin (CaM). A double mutant was constructed involving conservative substitution of Tyr99 --> Trp99 and Leu69 --> Cys69 to assess the structural coupling between the opposing domains, as previously described [Sun, H., Yin, D., and Squier, T. C. (1999) Biochemistry 38, 12266-12279]. Trp99 acts as a fluorescence resonance energy transfer (FRET) donor in distance measurements to probe the conformation of the central helix. Cys69 provides a reactive group for the covalent attachment of 5-((((2-iodoacetyl)amino)ethyl)amino)naphthalene-1-sulfonic acid (IAEDANS), which functions as a FRET acceptor and permits the measurement of the rotational dynamics of the amino-terminal domain. These CaM mutants demonstrate normal calcium-dependent gel-mobility shifts and changes in their near-UV CD spectra, have similar secondary structures to wild-type CaM following calcium activation, and retain the ability to fully activate the plasma membrane Ca-ATPase. The global folds, therefore, of both the carboxyl- and amino-terminal domains in these CaM mutants are similar to that of wild-type CaM. However, in comparison to wild-type CaM, the substitution of Tyr138 with either Phe138 or Gln138 results in (i) alterations in the average spatial separation and increases in the conformational heterogeneity between the opposing globular domains and (ii) the independent rotational dynamics of the amino-terminal domain. These results indicate that alterations in either the hydrogen bond between Tyr138 and Glu82 or contact interactions between aromatic amino acid side chains have the potential to initiate the structural collapse of CaM normally associated with target protein binding and activation.

Animals↗
PubMed2001

Gene therapy for streptozotocin-induced diabetic mice by electroporational transfer of naked human insulin precursor DNA into skeletal muscle in vivo.

Transfer of naked plasmid with insulin precursor DNA into skeletal muscle of streptozotocin (STZ)-induced diabetic mice through electroporation and detection of gene expression is described. Four different human insulin precursor DNA fragments were inserted into pcDNA3.1(-), downstream of a CMV promoter. Three of them, with a secretion signal sequence, succeeded in lowering blood glucose at a range of 30-50% in STZ diabetic mice. The other, with a synthetic DNA fragment encoding human proinsulin, failed. The mortality rate of very seriously STZ diabetic mice was reduced significantly by the treatment. The circulating insulin-like protein (mouse insulin, human proinsulin, or intermediates during conversion of proinsulin to insulin) level in the blood of less seriously STZ diabetic mice treated with the human preproinsulin gene with an intron was about 15-23 microU/ml, while that of STZ diabetic mice treated with empty vector was only about 6 microU/ml and that of normal mice was about 18 microU/ml. Transcription of the three human insulin precursor DNAs in mouse skeletal muscle was also detected by RT-PCR. The human preproinsulin gene with the intron showed a slightly higher potency in reducing blood glucose of mildly diabetic mice. These studies indicate that the skeletal muscle transferred with appropriate preproinsulin DNA by electroporation in vivo can secrete insulin-like protein resulting in reduction of blood glucose, and a basal blood insulin level can be achieved for at least 1 month.

Animals↗